CA2472373C - Combination of paclitaxel and a polymer - Google Patents
Combination of paclitaxel and a polymer Download PDFInfo
- Publication number
- CA2472373C CA2472373C CA002472373A CA2472373A CA2472373C CA 2472373 C CA2472373 C CA 2472373C CA 002472373 A CA002472373 A CA 002472373A CA 2472373 A CA2472373 A CA 2472373A CA 2472373 C CA2472373 C CA 2472373C
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- Prior art keywords
- paclitaxel
- polymer
- combination
- microspheres
- stent
- Prior art date
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Abstract
A combination preferably for use as or with a solid support comprising a paclitaxel constituent and a polymer which may be a carrier for the paclitaxel. The polymer is selected for elution of the paclitaxel within a range of preferred rates. Th e polymer may be a coating on the solid support. The solid support may be, for example, a tube, suture, surgical mesh or film. The paclitaxel and polymer may be in admixture with o ne another or the paclitaxel constituent may be adsorbed into the polymer.
Description
Y:V\g004\2860 CA\spec & claims\as filed\Sub spec 080205.wpd COMBINATION OF PACLITAXEL AND A POLYMER
[0001] Related Application
[0001] Related Application
[0002] This application is a division of Canadian Patent Application Serial No.
2,167,268 filed on 19 July 1994.
2,167,268 filed on 19 July 1994.
[0003] Technical Field
[0004] The present invention, in conjunction with the inventions protected by the aforementioned parent application Serial No. 2,167,268 and other divisions thereof, relates generally to the technical field of compositions and methods for treating cancer and other angiogenic-dependent diseases, and more specifically, to compositions comprising anti-angiogenic factors and polymeric carriers, stents that have been coated with such compositions, as well as methods for utilizing these stents and compositions.
[0005] Backaround Of The Invention
[0006] A variety of methods are at present used to treat cancer, including for example, various surgical procedures. If treated with surgery alone, however, many patients (particularly those with certain types of cancer, such as breast, brain, colon and hepatic cancer) will experience recurrence of the cancer. In addition to surgery, many cancers are also treated with a combination of therapies involving cytotoxic chemotherapeutic drugs (e.g., vincristine, vinblastine, cisplatin, methotrexate, 5-FU, etc.) and/or radiation therapy. A difficulty with this latter approach, however, is that radiotherapeutic and chemotherapeutic agents are toxic to normal tissues, and sometimes create life-threatening side effects. In addition, these therapiess often have high failure/remission rates.
[0007] In addition to surgical, chemo- and radiation therapies, others have attempted to utilize an individual's own immune system in order to eliminate cancerous cells. For example, some have suggested the use of bacterial or viral components as adjuvants, in order to stimulate the immune system to destroy tumor cells.
(See generally "Principles of Cancer Biotherapy," Oldham (ed.), Raven Press, New York, 1987.) Such agents have generally been useful as adjuvants and as nonspecific stimulants in animal tumor models, but have not as of yet proved to be generally effective in humans.
(See generally "Principles of Cancer Biotherapy," Oldham (ed.), Raven Press, New York, 1987.) Such agents have generally been useful as adjuvants and as nonspecific stimulants in animal tumor models, but have not as of yet proved to be generally effective in humans.
[0008] Lymphokines have also been utilized in the treatment of cancer.
Briefly, lymphokines are secreted by a variety of cells, and generally have an effect on specific cells in the generation of an immune response. Examples of lymphokines include Interleukins (IL)-1, -2, -3, and -4, as well as colony-stimulating factors such as G-CSF, GM-CSF, and M-CSF. One group has utilized IL-2 to stimulate peripheral blood cells in order to expand and produce large quantities of cells which are cytotoxic to tumor cells (Rosenberg et al., N. Engl. J. Med. 313:1485-1492, 1985).
Briefly, lymphokines are secreted by a variety of cells, and generally have an effect on specific cells in the generation of an immune response. Examples of lymphokines include Interleukins (IL)-1, -2, -3, and -4, as well as colony-stimulating factors such as G-CSF, GM-CSF, and M-CSF. One group has utilized IL-2 to stimulate peripheral blood cells in order to expand and produce large quantities of cells which are cytotoxic to tumor cells (Rosenberg et al., N. Engl. J. Med. 313:1485-1492, 1985).
[0009] Others have suggested the use of antibodies in the treatment of cancer.
Briefly, antibodies may be developed that recognize certain cell surface antigens that are either unique, or more prevalent on cancer cells compared to normal cells.
These antibodies, or "magic bullets," may be utilized either alone or conjugated with a toxin in order to specifically target and kill tumor cells (Dillman, "Antibody Therapy," Principles of Cancer Biotherapy, Oldham (ed.), Raven Press, Ltd., New York, 1987). However, one difficulty is that most monoclonal antibodies are of murine origin, and thus hypersensitivity against the murine antibody may limit its efficacy, particularly after repeated therapies.
Common side effects include fever, sweats and chills, skin rashes, arthritis, and nerve palsies.
Briefly, antibodies may be developed that recognize certain cell surface antigens that are either unique, or more prevalent on cancer cells compared to normal cells.
These antibodies, or "magic bullets," may be utilized either alone or conjugated with a toxin in order to specifically target and kill tumor cells (Dillman, "Antibody Therapy," Principles of Cancer Biotherapy, Oldham (ed.), Raven Press, Ltd., New York, 1987). However, one difficulty is that most monoclonal antibodies are of murine origin, and thus hypersensitivity against the murine antibody may limit its efficacy, particularly after repeated therapies.
Common side effects include fever, sweats and chills, skin rashes, arthritis, and nerve palsies.
[0010] One additional difficulty of present methods of treating cancer is that local recurrence and local disease control remain major challenges in the treatment of malignancy. In particular, taking available U.S. figures by way of example, a total of 630,000 patients annually have localized disease (no evidence of distant metastatic spread) at the time of presentation; this represents 64% of all those patients diagnosed with malignancy (this does not include nonmelanoma skin cancer or carcinoma in situ). For the vast majority of these patients, surgical resection of the disease represents the greatest chance for a cure, and indeed 428,000 of the 630,000 can be expected to be cured after the initial treatment. Unfortunately, it can be expected that 202,000 (or 32%
of all patients with localized disease) will relapse after the initial treatment. Of those who relapse, the number who will relapse due to local recurrence of the disease (and continuing to use the same U.S. figures) amounts to an expected 133,000 patients annually (or 21 %
of all those with localized disease). The number who will relapse due to distant metastases of the disease is 68,000 patients annually (11% of all those with localized disease).
Another 102,139 patients annually will die as a direct result of an inability to control the local growth of the disease.
of all patients with localized disease) will relapse after the initial treatment. Of those who relapse, the number who will relapse due to local recurrence of the disease (and continuing to use the same U.S. figures) amounts to an expected 133,000 patients annually (or 21 %
of all those with localized disease). The number who will relapse due to distant metastases of the disease is 68,000 patients annually (11% of all those with localized disease).
Another 102,139 patients annually will die as a direct result of an inability to control the local growth of the disease.
[0011] Nowhere is this problem more evident than in breast cancer, which affects 186,000 women annually in the U.S. (again taking available statistics) and whose mortality rate has remained unchanged for 50 years. Surgical resection of the disease through radical mastectomy, modified radical mastectomy, or lumpectomy remains the mainstay of treatment for this condition. Unfortunately, 39% of those treated with lumpectomy alone will develop a local recurrence of the disease, and surprisingly, so will 25%
of those in which the resection margin is found to be clear of tumor histologically. As many as 90%
of these local recurrences will occur with 2 cm of the previous excision site.
of those in which the resection margin is found to be clear of tumor histologically. As many as 90%
of these local recurrences will occur with 2 cm of the previous excision site.
[0012] Similarly, in 1991, over 113,00 deaths and 238,600 new cases of liver metastasis were reported in North America alone. The mean survival time for patients with liver metastases is only 6.6 months once liver lesions have developed. Non-surgical treatment for hepatic metastases include systemic chemotherapy, radiation, chemoembolization, hepatic arterial chemotherapy, and intraarterial radiation.
However, despite evidence that such treatments can transiently decrease the size of the hepatic lesions (e.g., systemic chemotherapy and hepatic arterial chemotherapy initially reduces lesions in 15-20% and 80% of patients, respectively), the lesions invariably recur. Surgical resection of liver metastases represents the only possibility for a cure, but such a procedure is possible in only 5% of patients with metastases, and in only 15-20% of patients with primary hepatic cancer.
However, despite evidence that such treatments can transiently decrease the size of the hepatic lesions (e.g., systemic chemotherapy and hepatic arterial chemotherapy initially reduces lesions in 15-20% and 80% of patients, respectively), the lesions invariably recur. Surgical resection of liver metastases represents the only possibility for a cure, but such a procedure is possible in only 5% of patients with metastases, and in only 15-20% of patients with primary hepatic cancer.
[0013] One method that has been attempted for the treatment of tumors with limited success is therapeutic embolization. Briefly, blood vessels that nourish a tumor are deliberately blocked by injection of an embolic material into the vessels. A
variety of materials have been attempted for this purpose, including autologous substances such as fat, blood clot, and chopped muscle fragments, as well as artificial materials such as wool, cotton, steel balls, plastic or glass beads, tantalum powder, silicone compounds, radioactive particles, sterile absorbable gelatin sponge (SterisponTM', GelfoamT""), oxidized cellulose (OxycelTM), steel coils, alcohol, lyophilized human dura mater (LyoduraTM), microfibrillar collagen (AviteneT""), collagen fibrils (TachotopT""), polyvinyl alcohol sponge (PVA; IvalonTM), Barium-impregnated silicon spheres (Biss), detachable balloons and liquids such as alcohol. The size of liver metastases may be temporarily decreased utilizing such methods, but tumors typically respond by causing the growth of new blood vessels into the tumor.
variety of materials have been attempted for this purpose, including autologous substances such as fat, blood clot, and chopped muscle fragments, as well as artificial materials such as wool, cotton, steel balls, plastic or glass beads, tantalum powder, silicone compounds, radioactive particles, sterile absorbable gelatin sponge (SterisponTM', GelfoamT""), oxidized cellulose (OxycelTM), steel coils, alcohol, lyophilized human dura mater (LyoduraTM), microfibrillar collagen (AviteneT""), collagen fibrils (TachotopT""), polyvinyl alcohol sponge (PVA; IvalonTM), Barium-impregnated silicon spheres (Biss), detachable balloons and liquids such as alcohol. The size of liver metastases may be temporarily decreased utilizing such methods, but tumors typically respond by causing the growth of new blood vessels into the tumor.
[0014] A related problem to tumor formation is the development of cancerous blockages that inhibit the flow of material through body passageways, such as the bile ducts, trachea, esophagus, vasculature and urethra. One device, the stent, has been developed in order to hold open passageways that have been blocked by tumors or other materials found in the body. Representative examples of common stents include the Wallstent, Strecker stent, Gianturco stent and the Palmaz stent. The major problem with stents, however, is that they do not prevent the ingrowth of tumor or inflammatory material through the interstices of the stent. If this material reaches the inside of a stent and thus reduces the size of the stent lumen, it may result in blockage of the body passageway into which it has been inserted. In addition, presence of a stent in the body may induce reactive or inflammatory tissue (e.g., blood vessels, fibroblasts, white blood cells) to enter the stent lumen, resulting in partial or comlete closure of the stent.
[0015] Summary of the Collectivity of Inventions
[0016] In this description, "the present invention" or "the invention" may refer to the collectivity of inventions described in the present divisional application, its parent, and other divisions of the parent application, or to certain ones of such inventions, depending upon the context.
[0017] The present invention includes compositions and methods suitable for treating cancers and other angiogenesis-dependent diseases that address the problems associated with the previously known procedures discussed above, and further provides other related advantages.
[0018] In a number of aspects, the present invention includes anti-angiogenic compositions, as well as methods and devices that utilize such compositions, for the treatment of cancer and other angiogenesis-dependent diseases. Within one aspect of the present invention, combinations or compositions are provided (hereinafter referred to as "anti-angiogenic compositions") comprising (a) an anti-angiogenic factor and (b) a polymer, typically present as a carrier for the anti-angiogenic factor. Other factors may be present in the composition to serve purposes complementary, ancillary or peripheral to anti-angiogenesis.
[0019] A wide variety of molecules may be utilized within the scope of the present invention as anti-angiogenic factors, including for example Anti-Invasive Factor, retinoic acids and their derivatives, paclitaxel, paclitaxel analogues and paclitaxel derivatives, and members of the group consisting of Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Plasminogen Activator Inhibitor-1 and Plasminogen Activator Inhibitor-2.
[0020] Similarly, a wide variety of polymeric carriers may be utilized, representative examples of which include poly(ethylene-vinyl acetate) crosslinked with 40%
vinyl acetate, poly (lactic-co-glycolic acid), polycaprolactone polylactic acid, copolymers of poly(ethylene-vinyl acetate) crosslinked with 40% vinyl acetate and polylactic acid, and copolymers of polylactic acid and polycaprolactone. Within one embodiment of the invention, the composition has an average size of 15 to 200 pm.
vinyl acetate, poly (lactic-co-glycolic acid), polycaprolactone polylactic acid, copolymers of poly(ethylene-vinyl acetate) crosslinked with 40% vinyl acetate and polylactic acid, and copolymers of polylactic acid and polycaprolactone. Within one embodiment of the invention, the composition has an average size of 15 to 200 pm.
[0021] Within yet another aspect of the present invention, stents are provided comprising, when placed in situ in the body, a generally tubular structure, the surface being coated or otherwise suitably provided with one or more anti-angiogenic compositions.
Within other aspects of the present invention, methods are provided for expanding (including maintaining open a previous expansion of) the lumen of a body passageway, comprising inserting a stent into the passageway, the surface of the stent being coated or otherwise suitably provided with an anti-angiogenic composition as described above, such that the passageway becomes or remains expanded. Within various embodiments of the invention, methods are provided for eliminating biliary obstructions, comprising inserting a biliary stent into a biliary passageway; for eliminating urethral obstructions, comprising inserting a urethral stent into a urethra; for eliminating esophageal obstructions, comprising inserting an esophageal stent into an esophagus; and for eliminating tracheal/bronchial obstructions, comprising inserting a tracheai/bronchial stent into the trachea or bronchi.
In each of these embodiments, the stent has a generally tubular structure, at least portions of the surface of which are coated or otherwise suitably provided with an anti-angiogenic composition as described above.
Within other aspects of the present invention, methods are provided for expanding (including maintaining open a previous expansion of) the lumen of a body passageway, comprising inserting a stent into the passageway, the surface of the stent being coated or otherwise suitably provided with an anti-angiogenic composition as described above, such that the passageway becomes or remains expanded. Within various embodiments of the invention, methods are provided for eliminating biliary obstructions, comprising inserting a biliary stent into a biliary passageway; for eliminating urethral obstructions, comprising inserting a urethral stent into a urethra; for eliminating esophageal obstructions, comprising inserting an esophageal stent into an esophagus; and for eliminating tracheal/bronchial obstructions, comprising inserting a tracheai/bronchial stent into the trachea or bronchi.
In each of these embodiments, the stent has a generally tubular structure, at least portions of the surface of which are coated or otherwise suitably provided with an anti-angiogenic composition as described above.
[0022] Within another aspect of the present invention, methods are provided for treating tumor excision sites, comprising administering an anti-angiogenic composition as described above to the resection margins of a tumor subsequent to excision, such that the local recurrence of cancer and the formation of new blood vessels at the site is inhibited.
Within yet another aspect of the invention, methods for treating corneal neovascularization are provided, comprising the step of administering a therapeutically effective amount of an anti-angiogenic composition as described above to the cornea, such that the formation of blood vessels is inhibited. Within one embodiment, the anti-angiogenic composition further comprises or is supplemented by a topical corticosteroid.
Within yet another aspect of the invention, methods for treating corneal neovascularization are provided, comprising the step of administering a therapeutically effective amount of an anti-angiogenic composition as described above to the cornea, such that the formation of blood vessels is inhibited. Within one embodiment, the anti-angiogenic composition further comprises or is supplemented by a topical corticosteroid.
[0023] Within another aspect of the present invention, methods are provided for inhibiting angiogenesis in patients with non-tumorigenic, angiogenesis-dependent diseases, comprising administering a therapeutically effective amount of a composition comprising Taxol T"" to a patient with a non-tumorigenic angiogenesis-dependent disease, such that the formation of new blood vessels is inhibited. Within other aspects, methods are provided for embolizing blood vessels in non-tumorigenic, angiogenesis-dependent diseases, comprising delivering to the vessel a therapeutically effective amount of a composition comprising TaxolT"', such that the blood vessel is effectively occluded.
[0024] Within yet other aspects of the present invention, methods are provided for expanding the lumen of a body passageway, comprising inserting a stent such as described above into the passageway, such that the passageway is expanded (or its expansion is maintained). Within various embodiments of the invention, methods are provided for eliminating biliary obstructions, comprising inserting a biliary stent into a biliary passageway; for eliminating urethral obstructions, comprising inserting a urethral stent into a urethra; for eliminating esophageal obstructions, comprising inserting an esophageal stent into an esophagus; and for eliminating tracheal/bronchial obstructions, comprising inserting a tracheal/bronchial stent into the trachea or bronchi.
[0025] Within another aspect of the present invention, methods are provided for treating a tumor excision site, comprising administering a composition comprising a suitable selected anti-angiogenic factor to the resection margin of a tumor subsequent to excision, such that the local recurrence of cancer and the formation of new blood vessels at the site is inhibited. Within other aspects, methods are provided for treating corneal neovascularization, comprising administering a therapeutically effective amount of a composition comprising a suitable selected anti-angiogenic factor to the cornea, such that the formation of new vessels is inhibited.
[0026] A preferred anti-angiogenic factor for use in the foregoing aspects of the invention is paclitaxel (sometimes referred to as "TaxolT"""), its analogues and derivatives.
[0027] Within yet another aspect of the invention, pharmaceutical products are provided, comprising (a) paclitaxel or another suitable selected anti-angiogenic factor in a container, and (b) a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency, for human or veterinary administration to treat non-tumorigenic angiogenesis-dependent diseases. Regulations vary from country to country.
[0028] Summary of the Invention of this Divisional Apclication
[0029] This divisional application is particularly directed to aspects of the invention involving a combination of (i) paclitaxel, a paclitaxel derivative or a paclitaxel analogue; and (ii) a suitable selected polymer, preferably acting as a carrier for the paclitaxel, and preferably for use as or with a solid support. The polymer will be selected to meet the usual biocompatibility criteria as well as any others specific to the particular application.
Since a principal objective in most such applications is the elution over time of an effective amount of paclitaxel from the polymeric carrier, the carrier should in such cases be chosen to be effective and efficient to achieve this purpose.
Since a principal objective in most such applications is the elution over time of an effective amount of paclitaxel from the polymeric carrier, the carrier should in such cases be chosen to be effective and efficient to achieve this purpose.
[0030] The foregoing combination may, for example, be used for the manufacture of a paclitaxel-eluting stent for the inhibition of restenosis. Other exemplary uses are for the treatment of a resection margin of a tumour, and for the manufacture of a medicament for the treatment of a resection margin of a tumour. If used as or in association with a solid support, the structure may be formed as a film, surgical mesh, tube, or other suitable form.
[0031] Various substances are suitable for selection as suitable polymers for the foregoing purposes. The polymer may be, for example, a selected protein such as albumin, gelatin or fibrinogen. Or the polymer may be a selected polysaccharide such as dextran, starch or cellulose. Other suitable selections include poly(D,L lactide), poly(caprolactone), a suitable ethylene vinyl acetate polymer or copolymer, silicone, or poiy(methylmethacrylate).
[0032] These and other aspects of the present invention will become evident from the following detailed description and attached diagrams.
[0033] Brief Description of the Drawings
[0034] Figure 1, presented as five views (Figures 1A, 16, 1C, 1D and 1E), constitutes a set of bit-map images that show the typical vascular and capillary networks observed in a chick chorioallantoic ("CAM") after 5-6 days of incubation. The smaller capillaries are approximately 15 microns in diameter.
[0035] Figure 2, presented as four views (Figures 2A, 2B, 2C, and 2E), constitutes a set of bit-map images that show a CAM after exposure to Anti-Invasive Factor.
[0036] Figure 3, presented as three views (Figures 3A, 3B, and 3C), constitutes a set of bit-map images that show a CAM after exposure to suramin/cortisone acetate.
[0037] Figure 4, presented as three views (Figures 4A, 4B, and 4C), constitutes a set of bit-map images that show a CAM after exposure to paclitaxel.
[0038] Figure 5 is a bar graph which depicts the size distribution of microspheres by number (5% ELVAXTM with 10 mg sodium suramin into 5% PVA).
[0039] Figure 6 is a bar graph which depicts the size distribution of microspheres by weight (5% ELVAX with 10 mg sodium suramin into 5% PVA).
[0040] Figure 7 is a line graph which depicts the weight of encapsulation of Sodium Suramin in 1 mi of 5% ELVAX.
[0041] Figure 8 is a line graph which depicts the percent of encapsulation of Sodium Suramin in ELVAX.
[0042] Figure 9 is a bar graph which depicts the size distribution of 5% ELVAX
microspheres containing 10 mg sodium suramin made in 5% PVA containing 10%
NaCi.
microspheres containing 10 mg sodium suramin made in 5% PVA containing 10%
NaCi.
[0043] Figure 10 is a bar graph which depicts the size distribution by weight of 5%
PLL microspheres containing 10 mg sodium suramin made in 5% PVA containing 10%
NaCI.
PLL microspheres containing 10 mg sodium suramin made in 5% PVA containing 10%
NaCI.
[0044] Figure 11 is a bar graph which depicts the size distribution by number of 5%
PLL microspheres containing 10 mg sodium suramin made in 5% PVA containing 10%
NaCi.
PLL microspheres containing 10 mg sodium suramin made in 5% PVA containing 10%
NaCi.
[0045] Figure 12 is a line graph which depicts the time course of sodium suramin release.
[0046] Figure 13, presented as two views 13A and 13B, illustrates schematically a representative embodiment of hepatic tumor embolization.
[0047] Figure 14, presented as two views 14A and 14B, illustrates schematically a representative stent coated with an anti-angiogenic composition of the present invention.
[0048] Figure 15A is a graph that shows the effect of the EVA:PLA polymer blend ratio upon aggregation of microspheres. Figure 15B is a scanning electron micrograph that shows the size of "small" microsperes. Figure 15C is a scanning electron micrograph that shows the size of "large" microspheres. Figure 15D is a graph that depicts the time course of in vitro paclitaxel release from 0.6% w/v paclitaxel-loaded 50:50 EVA:PLA
polymer blend microspheres into phosphate buffered saline (pH 7.4) at 37 C. Open circles are "small"
sized microspheres, and closed circles are "large" sized microspheres. Figure 15E is a photograph of a CAM which shows the results of paclitaxel release by microspheres ("MS").
Figure 15F is a photograph similar to that of 15E at increased maginification.
polymer blend microspheres into phosphate buffered saline (pH 7.4) at 37 C. Open circles are "small"
sized microspheres, and closed circles are "large" sized microspheres. Figure 15E is a photograph of a CAM which shows the results of paclitaxel release by microspheres ("MS").
Figure 15F is a photograph similar to that of 15E at increased maginification.
[0049] Figure 16A is a graph showing release rate probiles from polycaprolactone microspheres containing 1%, 2%, 5% or 10% paclitaxel into phosphate buffered saline at 37 . Figure 16B is a photograph showing a CAM treated with control microspheres.
Figure 16C is a photograph showing a CAM treated with 5% paclitaxel loaded microspheres.
Figure 16C is a photograph showing a CAM treated with 5% paclitaxel loaded microspheres.
[0050] Figures 17A and 17B, respectively, are two graphs which show the release of paclitaxel from EVA films, and the percent paclitaxel remaining in those same films over time. Figure 17C is a graph which shows the swelling of EVA/F127 films with no paclitaxel over time. Figure 17D is a graph which shows the swelling of EVA/SpanTm 80 films with no paclitaxel over time. Figure 17E is a graph which depicts a stress vs. strain curve for various EVA/F127 blends.
[0051] Figures 18A and 18B are two graphs which show the melting point of PCL/MePEG poiymer blends as a function of % MePEG in the formulation (18A), and the percent increase in time needed for PCL paste at 60 C to begin to solidify as a function of the amount of MePEG in the formulation (18B). Figure 18C is a graph which depicts the brittleness of varying PCL/MePEG polymer blends. Figure 18D is a graph which shows the percent weight change over time for polymer blends of various MePEG
concentrations.
Figure 18E is a graph which depicts the rate of paclitaxel release over time from various polymer blends loaded with 1% paclitaxel. Figures 18F and 18G are graphs which depict the effect of varying quantities of paclitaxel on the total amount of tazol released from a 20%MePEG/PCL blend. Figure 18H is a graph which depicts the effect of MePEG on the tensile strength of a MePEG/PCL polymer.
concentrations.
Figure 18E is a graph which depicts the rate of paclitaxel release over time from various polymer blends loaded with 1% paclitaxel. Figures 18F and 18G are graphs which depict the effect of varying quantities of paclitaxel on the total amount of tazol released from a 20%MePEG/PCL blend. Figure 18H is a graph which depicts the effect of MePEG on the tensile strength of a MePEG/PCL polymer.
[0052] Figure 19A is a photograph which shows control (unloaded) thermopaste on a CAM. Figure 19B is a photograph of 20% paclitaxel-loaded thermopoaste on a CAM.
[0053] Figures 20A and 20B are two photographs of a CAM having a tumor treated with control (unloaded) thermopaste. Figures 20C and 20D are two photographs of a CAM
having a tumor treated with paclitaxel-loaded thermopaste.
having a tumor treated with paclitaxel-loaded thermopaste.
[0054] Figure 21A is a graph which shows the effect of paclitaxel/PCL on tumor growth. Figures 21 B and 21 C are two photographs which show the effect of control, 10%, and 20% paclitaxel-loaded thermopaste on tumor growth.
[0055] Figure 22A is a photograph of synovium from a PBS injected joint.
Figure 22B is a photograph of synovium from a microsphere injected joint. Figure 22C
is a photograph of cartilage from joints injected with PBS, and Figure 22D is a photograph of cartilage from joints injected with microspheres.
Figure 22B is a photograph of synovium from a microsphere injected joint. Figure 22C
is a photograph of cartilage from joints injected with PBS, and Figure 22D is a photograph of cartilage from joints injected with microspheres.
[0056] Detailed Description of the Invention
[0057] As noted above, the present invention provides methods and compositions that utilize anti-angiogenic factors. Briefly, within the context of the present invention, anti-angiogenic factors should be understood to include any protein, peptide, chemical, or other molecule, which acts to inhibit vascular growth. A variety of methods may be readily utilized to determine the anti-angiogenic activity of a given factor, including for example, chick chorioallantoic membrane ("CAM") assays. Briefly, as described in more detail below in Example 2A and 2C, a portion of the shell from a freshly fertilized chicken egg is removed, and a methyl cellulose disk containing a sample of the anti-angiogenic factor to be tested is placed on the membrane. After several days (e.g., 48 hours), inhibition of vascular growth by the sample to be tested may be readily determined by visualization of the chick chorioallantoic membrane in the region surrounding the methyl cellulose disk.
Inhibition of vascular growth may also be determined quantitatively, for example, by determining the number and size of blood vessels surrounding the methyl cellulose disk, as compared to a control methyl cellulose disk. Particularly preferred anti-angiogenic factors suitable for use within the present invention completely inhibit the formation of new blood vessels in the assay described above.
Inhibition of vascular growth may also be determined quantitatively, for example, by determining the number and size of blood vessels surrounding the methyl cellulose disk, as compared to a control methyl cellulose disk. Particularly preferred anti-angiogenic factors suitable for use within the present invention completely inhibit the formation of new blood vessels in the assay described above.
[0058] A variety of assays may also be utilized to determine the efficacy of anti-angiogenic factors in vivo, including for example, mouse models which have been developed for this purpose (see Roberston et al., Cancer. Res. 51:1339-1344, 1991). In addition, a variety of representative in vivo assays relating to various aspects of the inventions described herein have been described in more detail below in Examples 5 to 7, and 17 to 19.
[0059] As noted above, the present invention provides compositions comprising an anti-angiogenic factor and a polymeric carrier. Briefly, a wide variety of anti-angiogenic factors may be readily utilized within the context of the present invention.
Representative examples include Anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel, paclitaxel analogues and paclitaxel derivatives and members of the group consisting of Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Plasminogen Activator Inhibitor-1 and Plasminogen Activator Inhibitor-2. These and other anti-angiogenic factors will be discussed in more detail below.
Representative examples include Anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel, paclitaxel analogues and paclitaxel derivatives and members of the group consisting of Suramin, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Plasminogen Activator Inhibitor-1 and Plasminogen Activator Inhibitor-2. These and other anti-angiogenic factors will be discussed in more detail below.
[0060] Briefly, Anti-Invasive Factor, or "AIF" which is prepared from extracts of cartilage, is known to contain constituents which are responsible for inhibiting the growth of new blood vessels. These constituents comprise a family of 7 low molecular weight proteins (<50,000 daltons) (Kuettner and Pauli, "Inhibition of neovascularization by a cartilage factor" in Development of the Vascular System, Pitman Books (Ciba Foundation Symposium 100), pp. 163-173, 1983), including a variety of proteins which have inhibitory effects against a variety of proteases (Eisentein et al, Am. J. Pathol. 81:337-346, 1975;
Langer et al., Science 193:70-72, 1976; and Horton et ai., Science 199:1342-1345, 1978).
AIF suitable for use within the present invention may be readily prepared utilizing techniques known in the art (e.g., Eisentein et al, supra; Kuettner and Pauli, supra; and Langer et al., supra). Purified constituents of AIF such as Cartilage-Derived Inhibitor ("CDI") (see Moses et al., Science 248:1408-1410, 1990) may also be readily prepared and utilized within the context of the present invention.
Langer et al., Science 193:70-72, 1976; and Horton et ai., Science 199:1342-1345, 1978).
AIF suitable for use within the present invention may be readily prepared utilizing techniques known in the art (e.g., Eisentein et al, supra; Kuettner and Pauli, supra; and Langer et al., supra). Purified constituents of AIF such as Cartilage-Derived Inhibitor ("CDI") (see Moses et al., Science 248:1408-1410, 1990) may also be readily prepared and utilized within the context of the present invention.
[0061] Retinoic acids alter the metabolism of extracellular matrix components, resulting in the inhibition of angiogenesis. Addition of proline analogs, angiostatic steroids, or heparin may be utilized in order to synergistically increase the anti-angiogenic effect of transretinoic acid. Retinoic acid, as well as derivatives thereof which may also be utilized in the context of the present invention, may be readily obtained from commercial sources, including for example, Sigma Chemical Co. (# R2625).
[0062] Paclitaxel, sometimes known as TaxolTM', is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc. 93:2325, 1971) which has been obtained from the harvested and dried bark of Taxus brevifoiia (Pacific Yew.) and Taxomyces Andreanae and Endophytic Fungus of the Pacific Yew. (Stierle et al., Science 60:214-216, 1993).
Generally, paclitaxel acts to stabilize microtubular structures by binding tubulin to form abnormal mitotic spindles. "Paclitaxel" (which should be understood herein to include analogues and derivatives of paclitaxel such as, for example, baccatin and taxotere) may be readily prepared utilizing techniques known to those skilled in the art (see also WO
94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076, U.S.
Patent Nos. 5,294,637, 5,283,253, 5,279,949, 5,274,137, 5,202,448, 5,200,534, 5,229,526, and EP 590267) or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Missouri (T7402 - from Taxus brevifolia).
Generally, paclitaxel acts to stabilize microtubular structures by binding tubulin to form abnormal mitotic spindles. "Paclitaxel" (which should be understood herein to include analogues and derivatives of paclitaxel such as, for example, baccatin and taxotere) may be readily prepared utilizing techniques known to those skilled in the art (see also WO
94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076, U.S.
Patent Nos. 5,294,637, 5,283,253, 5,279,949, 5,274,137, 5,202,448, 5,200,534, 5,229,526, and EP 590267) or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Missouri (T7402 - from Taxus brevifolia).
[0063] Suramin is a polysulfonated naphthylurea compound that is typically used as a trypanocidal agent. Briefly, Suramin blocks the specific cell surface binding of various growth factors such as platelet derived growth factor ("PDGF"), epidermal growth factor ("EGF"), transforming growth factor ("TGF-R"), insulin-like growth factor ("IGF-1"), and fibroblast growth factor ("(3FGF"). Suramin may be prepared in accordance with known techniques, or readily obtained from a variety of commercial sources, including for example Mobay Chemical Co., New York. ( see Gagliardi et al., Cancer Res. 52:5073-5075, 1992;
and Coffey, Jr., et al., J. of Cell. Phys. 132:143-148, 1987).
and Coffey, Jr., et al., J. of Cell. Phys. 132:143-148, 1987).
[0064] Tissue Inhibitor of Metalloproteinases-1 ("TIMP") is secreted by endothelial cells which also secrete MTPases. TIMP is glycosylated and has a molecular weight of 28.5 kDa. TIMP-1 regulates angiogenesis by binding to activated metalloproteinases, thereby suppressing the invasion of blood vessels into the extracellular matrix. Tissue Inhibitor of Metalloproteinases-2 ("TIMP- 2") may also be utilized to inhibit angiogenesis.
Briefly, TIMP-2 is a 21 kDa nonglycosylated protein which binds to metalloproteinases in both the active and latent, proenzyme forms. Both TIMP-1 and TIMP-2 may be obtained from commercial sources such as Synergen, Boulder, Colorado.
Briefly, TIMP-2 is a 21 kDa nonglycosylated protein which binds to metalloproteinases in both the active and latent, proenzyme forms. Both TIMP-1 and TIMP-2 may be obtained from commercial sources such as Synergen, Boulder, Colorado.
[0065] Plasminogen Activator Inhibitor - 1 (PA) is a 50 kDa glycoprotein which is present in blood platelets, and can also be synthesized by endothelial cells and muscle cells. PAI-1 inhibits t-PA and urokinase plasminogen activator at the basolateral site of the endothelium, and additionally regulates the fibrinolysis process. Plasminogen Activator lnhibitor-2 (PAI-2) is generally found only in the blood under certain circumstances such as in pregnancy, and in the presence of tumors. Briefly, PAI-2 is a 56 kDa protein which is secreted by monocytes and macrophages. It is believed to regulate fibrinolytic activity, and in particular inhibits urokinase plasminogen activator and tissue plasminogen activator, thereby preventing fibrinolysis.
[0066] A wide variety of other anti-angiogenic factors may also be utilized within the context of the present invention. Representative examples include Platelet Factor 4(Sigma Chemical Co., #F1385); Protamine Sulphate (Clupeine) (Sigma Chemical Co., #P4505);
Sulphated Chitin Derivatives (prepared from queen crab shells), (Sigma Chemical Co., #C3641; Murata et al., Cancer Res. 51:22-26, 1991); Sulphated Polysaccharide Peptidoglycan Complex (SP-PG) (the function of this compound may be enhanced by the presence of steroids such as estrogen, and tamoxifen citrate); Staurosporine (Sigma Chemical Co., #S4400); Modulators of Matrix Metabolism, including for example, proline analogs {[(L-azetidine-2-carboxylic acid (LACA) (Sigma Chemical Co., #A0760)), cishydroxyproline, d,L-3,4-dehydroproline (Sigma Chemical Co., #D0265), Thiaproline (Sigma Chemical Co., #T0631)], a,a-dipyridyl (Sigma Chemical Co., #D7505), (3-aminopropionitrile fumarate (Sigma Chemical Co., #A3134)]}; MDL 27032 (4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Merion Merrel Dow Research Institute);
Methotrexate (Sigma Chemical Co., #A6770; Hirata et al., Arthritis and Rheumatism 32:1065-1073, 1989);
Mitoxantrone (Polverini and Novak, Biochem. Biophys. Res. Comm. 140:901-907);
Heparin (Folkman, Bio. Phar. 34:905-909, 1985; Sigma Chemical Co., #P8754);
Interferons (e.g., Sigma Chemical Co., #13265); 2 Macroglobulin-serum (Sigma Chemical Co., #M7151);
ChIMP-3 (Pavloff et al., J. Bio. Chem. 267:17321-17326, 1992); Chymostatin (Sigma Chemical Co., #C7268; Tomkinson et al., Biochem J. 286:475-480, 1992); (3-Cyclodextrin Tetradecasulfate (Sigma Chemical Co., #C4767); Eponemycin; Estramustine (available from Sigma; Wang and Stearns Cancer Res. 48:6262-6271, 1988); Fumagillin (Sigma Chemical Co., #F6771; Canadian Patent No. 2,024,306; Ingberetal., Nature 348:555-557, 1990); Gold Sodium Thiomalate ("GST"; Sigma:G4022; Matsubara and Ziff, J.
Clin. Invest.
79:1440-1446, 1987); (D-Penicillamine ("CDPT"; Sigma Chemical Co., #P4875 or P5000(HCI)); 0-1-anticollagenase-serum; a2-antiplasmin (Sigma Chem. Co.:A0914;
Holmes et al., J. Biol. Chem. 262(4):1659-1664, 1987); Bisantrene (National Cancer Institute); Lobenzarit disodium (N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or "CCA"; Takeuchi et al., Agents Actions 36:312-316, 1992); Thalidomide, Angiostatic steroid, AGM-1470, carboxyaminolmidazole, metalloproteinase inhibitors such as BB94 and the peptide CDPGYIGSR-NH2 (SEQUENCE ID NO. 1) (Iwaki Glass, Tokyo, Japan).
Sulphated Chitin Derivatives (prepared from queen crab shells), (Sigma Chemical Co., #C3641; Murata et al., Cancer Res. 51:22-26, 1991); Sulphated Polysaccharide Peptidoglycan Complex (SP-PG) (the function of this compound may be enhanced by the presence of steroids such as estrogen, and tamoxifen citrate); Staurosporine (Sigma Chemical Co., #S4400); Modulators of Matrix Metabolism, including for example, proline analogs {[(L-azetidine-2-carboxylic acid (LACA) (Sigma Chemical Co., #A0760)), cishydroxyproline, d,L-3,4-dehydroproline (Sigma Chemical Co., #D0265), Thiaproline (Sigma Chemical Co., #T0631)], a,a-dipyridyl (Sigma Chemical Co., #D7505), (3-aminopropionitrile fumarate (Sigma Chemical Co., #A3134)]}; MDL 27032 (4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; Merion Merrel Dow Research Institute);
Methotrexate (Sigma Chemical Co., #A6770; Hirata et al., Arthritis and Rheumatism 32:1065-1073, 1989);
Mitoxantrone (Polverini and Novak, Biochem. Biophys. Res. Comm. 140:901-907);
Heparin (Folkman, Bio. Phar. 34:905-909, 1985; Sigma Chemical Co., #P8754);
Interferons (e.g., Sigma Chemical Co., #13265); 2 Macroglobulin-serum (Sigma Chemical Co., #M7151);
ChIMP-3 (Pavloff et al., J. Bio. Chem. 267:17321-17326, 1992); Chymostatin (Sigma Chemical Co., #C7268; Tomkinson et al., Biochem J. 286:475-480, 1992); (3-Cyclodextrin Tetradecasulfate (Sigma Chemical Co., #C4767); Eponemycin; Estramustine (available from Sigma; Wang and Stearns Cancer Res. 48:6262-6271, 1988); Fumagillin (Sigma Chemical Co., #F6771; Canadian Patent No. 2,024,306; Ingberetal., Nature 348:555-557, 1990); Gold Sodium Thiomalate ("GST"; Sigma:G4022; Matsubara and Ziff, J.
Clin. Invest.
79:1440-1446, 1987); (D-Penicillamine ("CDPT"; Sigma Chemical Co., #P4875 or P5000(HCI)); 0-1-anticollagenase-serum; a2-antiplasmin (Sigma Chem. Co.:A0914;
Holmes et al., J. Biol. Chem. 262(4):1659-1664, 1987); Bisantrene (National Cancer Institute); Lobenzarit disodium (N-(2)-carboxyphenyl-4-chloroanthronilic acid disodium or "CCA"; Takeuchi et al., Agents Actions 36:312-316, 1992); Thalidomide, Angiostatic steroid, AGM-1470, carboxyaminolmidazole, metalloproteinase inhibitors such as BB94 and the peptide CDPGYIGSR-NH2 (SEQUENCE ID NO. 1) (Iwaki Glass, Tokyo, Japan).
[0067] Anti-angiogenic compositions of the present invention may additionally comprise a wide variety of compounds in addition to the anti-angiogenic factor and a polymeric carrier. For example, anti-angiogenic compositions of the present invention may also, within certain embodiments of the invention, also comprise one or more antibiotics, anit-inflamatories, anti- viral agents, anti-fungal agents and/or anti-protozoal agent.
Representative examples of antibiotics included within the compositions described herein include: penicillins; cephalosporins such as cefadroxil, cefazolin, cefaclor;
aminoglycosides such as gentamycin and tobramycin; sulfonamides such as sulfamethoxazole; and metronidazole. Representative examples of anti-inflammatories include:
steroids such as prednisone, prednisolone, hydrocortisone, adrenocorticotropic hormone, and sulfasalazine;
and non- steroidal anti-inflammatory drugs ("NSAIDS") such as AspirinTM, ibuprofen, naproxen, fenoporfen, indomethacin, and phenylbutazone. Representative examples of antiviral agents include acyclovir, ganciclovir, zidovudine. Representative examples of antifungal agents include: nystatin, ketoconazole, griseofulvin, flucytosine, miconazole, clotrimazole. Representative examples of antiprotozoal agents include:
pentamidine isethionate, quinine, chloroquine, and mefloquine.
Representative examples of antibiotics included within the compositions described herein include: penicillins; cephalosporins such as cefadroxil, cefazolin, cefaclor;
aminoglycosides such as gentamycin and tobramycin; sulfonamides such as sulfamethoxazole; and metronidazole. Representative examples of anti-inflammatories include:
steroids such as prednisone, prednisolone, hydrocortisone, adrenocorticotropic hormone, and sulfasalazine;
and non- steroidal anti-inflammatory drugs ("NSAIDS") such as AspirinTM, ibuprofen, naproxen, fenoporfen, indomethacin, and phenylbutazone. Representative examples of antiviral agents include acyclovir, ganciclovir, zidovudine. Representative examples of antifungal agents include: nystatin, ketoconazole, griseofulvin, flucytosine, miconazole, clotrimazole. Representative examples of antiprotozoal agents include:
pentamidine isethionate, quinine, chloroquine, and mefloquine.
[0068] Anti-angiogenic compositions of the present invention may also contain one or more hormones such as thyroid hormone, estrogen, progesterone, cortisone and/or growth hormone, other biologically active molecules such as insulin, as well as TH1 (e.g., Interleukins -2, -12, and -15, gamma interferon or TH2 (e.g., Interleukins -4 and -10) cytokines.
[0069] Anti-angiogenic compositions of the present invention may also comprise additional ingredients such as surfactants (either hydrophilic or hydrophobic;
see Example 13), anti-neoplastic or chemotherpeutic agents (e.g., 5-fluorouracil, vanblastine, doxyrubicin, adriamycin, or tamocifen), radioactive agents (e.g., Cu-64, Ga-67, Ga-68, Zr-89, Ru-97, Tc-99m, Rh-105, Pd-109, In-111, 1-123, 1-125, 1-131, Re-186, Re-188, Au-198, Au-199,Pb-203,At-211,Pb-212 and Bi-212) or toxins (e.g., ricin, abrin, diptheria toxin, cholera toxin, gelonin, pokeweed antiviral protein, tritin, Shigella toxin, and Pseudomonas exotoxin A).
see Example 13), anti-neoplastic or chemotherpeutic agents (e.g., 5-fluorouracil, vanblastine, doxyrubicin, adriamycin, or tamocifen), radioactive agents (e.g., Cu-64, Ga-67, Ga-68, Zr-89, Ru-97, Tc-99m, Rh-105, Pd-109, In-111, 1-123, 1-125, 1-131, Re-186, Re-188, Au-198, Au-199,Pb-203,At-211,Pb-212 and Bi-212) or toxins (e.g., ricin, abrin, diptheria toxin, cholera toxin, gelonin, pokeweed antiviral protein, tritin, Shigella toxin, and Pseudomonas exotoxin A).
[0070] As noted above, anti-agiogenic compositions of the present invention comprise an anti-angiogenic factor and polymeric carrier. In addition to the wide array of anti-agiogenic factors and other compounds discussed above, anti-angiogenic compositions of the present invention may include a wide variety of polymeric carriers, including for example both biodegradable and non-biodegradable compositions.
Representative examples of biodegradable compositions include albumin, gelatin, starch, cellulose, destrans, polysaccharides, fibrinogen, poly (d,l lactide), poly (d, I-lactide-co-glycolide), poly (glycolide), poly (hydroxybutyrate), poly (alkylcarbonate) and poly (orthoesters) (see generally, Ilium, L., Davids, S.S. (eds.) "Polymers in controlled Drug Delivery" Wright, Bristol, 1987; Archady, J. Controlled Release 17:1-22, 1991;
Pitt, Int. J.
Phar. 59:173-196, 1990; Holland et al., J. Controlled Release 4:155-0180, 1986).
Representative examples of nondegradable polymers include EVA copolymers, silicone rubber and poly (mehtyimethacrylate). Particularly preferred polymeric carriers include EVA
copolymer(e.g., ELVAX 40, poly(ethylene-vinyl acetate) crosslinked with 40%
vinyl acetate;
DuPont), poly(lactic-co-glycolic acid), polycaprolactone, polylactic acid, copolymers of poly(ethylene-vinyl acetate) crosslinked with 40% vinyl acetate and polylactic acid, and copolymers of polylactic acid and polycaprolactone.
Representative examples of biodegradable compositions include albumin, gelatin, starch, cellulose, destrans, polysaccharides, fibrinogen, poly (d,l lactide), poly (d, I-lactide-co-glycolide), poly (glycolide), poly (hydroxybutyrate), poly (alkylcarbonate) and poly (orthoesters) (see generally, Ilium, L., Davids, S.S. (eds.) "Polymers in controlled Drug Delivery" Wright, Bristol, 1987; Archady, J. Controlled Release 17:1-22, 1991;
Pitt, Int. J.
Phar. 59:173-196, 1990; Holland et al., J. Controlled Release 4:155-0180, 1986).
Representative examples of nondegradable polymers include EVA copolymers, silicone rubber and poly (mehtyimethacrylate). Particularly preferred polymeric carriers include EVA
copolymer(e.g., ELVAX 40, poly(ethylene-vinyl acetate) crosslinked with 40%
vinyl acetate;
DuPont), poly(lactic-co-glycolic acid), polycaprolactone, polylactic acid, copolymers of poly(ethylene-vinyl acetate) crosslinked with 40% vinyl acetate and polylactic acid, and copolymers of polylactic acid and polycaprolactone.
[0071] Polymeric carriers may be fashioned in a variety of forms, including for example, as nanospheres or microspheres, rod-shaped devices, pellets, slabs, or capsules (see, e.g., Goodell et al., Am. J. Hosp. Pharm. 43:1454-1461, 1986; Langer et al., "Controlled release of macromolecules from polymers", in Biomedical polymers, Polymeric materials and pharmaceuticals for biomedical use, Goldberg, E.P., Nakagim, A.
(eds.) Academic Press, pp. 113-137, 1980; Rhine et al., J. Pharm. Sci. 69:265-270, 1980; Brown et al., J. Pharm. Sci. 72:1181-1185, 1983; and Bawa et al., J. Controlled Release 1:259-267, 1985).
(eds.) Academic Press, pp. 113-137, 1980; Rhine et al., J. Pharm. Sci. 69:265-270, 1980; Brown et al., J. Pharm. Sci. 72:1181-1185, 1983; and Bawa et al., J. Controlled Release 1:259-267, 1985).
[0072] Preferably, anti-angiogenic compositions of the present invention (which comprise one or more anti-angiogenic factors, and a polymeric carrier) are fashioned in a manner appropriate to the intended use. Within preferred aspects of the present invention, the anti-angiogenic composition should be biocompatible, and release one or more anti-angiogenic factors over a period of several weeks to months. In addition, anti-angiogenic compositions of the present invention should preferably be stable for several months and capable of being produced and maintained under sterile conditions.
[0073] Within certain aspects of the present invention, anti-angiogenic compositions may be fashioned in any size ranging from nanospheres to microspheres (e.g., from 0.1 pm to 500 pm), depending upon the particular use. For example, when used for the purpose of tumor embolization (as discussed below), it is generally preferable to fashion the anti-angiogenic compostion in microspheres of between 15 and 500 pm, preferably between 15 and 200 pm, and most preferably, between 25 and 150 pm. Such nanoparticies may also be readily applied as a "spray", which solidifies into a film or coating.
Nanoparticles (also termed "nanospheres") may be prepared in a wide array of sizes, including for example, from 0.1 pm to 3 pm, from 10 pm to 30 pm, and from 30 pm to 100 pm (see Example 8).
Nanoparticles (also termed "nanospheres") may be prepared in a wide array of sizes, including for example, from 0.1 pm to 3 pm, from 10 pm to 30 pm, and from 30 pm to 100 pm (see Example 8).
[0074] Anti-angiogenic compositions may also be prepared, given the disclosure provided herein, for a variety of other applications. For example, for the administration of anti-angiogenic compositions to the cornea, the compositions of the present invention may be incorporated into polymers as nanoparticles (see generally, Kreuter J.
Controlled Release 16:169-176, 1991; Couvreur and Vauthier, J. Controlled Re/ease 17:187-198, 1991). Such nanoparticies may also be readily applied as a "spray", which solidifies into a film or coating. Nanoparticles (also termed "nanospheres") may be prepared in a wide array of sizes, including for examp(e, from 0.1 pm to 3 um, from 10 Nm to 30 pm, and from 30 pm to 100 pm (see Example 8).
Controlled Release 16:169-176, 1991; Couvreur and Vauthier, J. Controlled Re/ease 17:187-198, 1991). Such nanoparticies may also be readily applied as a "spray", which solidifies into a film or coating. Nanoparticles (also termed "nanospheres") may be prepared in a wide array of sizes, including for examp(e, from 0.1 pm to 3 um, from 10 Nm to 30 pm, and from 30 pm to 100 pm (see Example 8).
[0075] Anti-angiogenic compositions of the present invention may also be prepared in a variety of "paste" or gel forms. For example, within one embodiment of the invention, anti-angiogenic compostions are provided which are liquid at one temperature (e.g., temperature greater than 37 C, such as 40 C, 45 C, 50 C, 55 C or 60 C), and solid or semi-solid at another temperature (e.g., ambient body temperature, or any temperature lower than 37 C). Such "thermopastes" may be readily made given the disclosure provided herein (see, e.g., Examples 10 and 14).
[0076] Within yet other aspects of the invention, the anti-angiogenic compostions of the present invention may be formed as a film. Preferably, such films are generally less than 5, 4, 3, 2, or 1, mm thick, more preferably less than 0.75mm or 0.5mm thick, and most preferably less than 500 pm to 100 pm thick. Such films are preferably flexible with good tensile strength (e.g., greater than 50, preferably greater than 100, and more preferably greater than 150 or 200 N/cm2), good adhesive properties (i.e., readily adheres to moist or wet surfaces), and has controlled permeability. Representative examples of such films are set forth below in the Examples (see e.g., Example 13).
[0077] Representative examples of incorporation of anti-angiogenic factors such as into a polymeric carriers are described in more detail below in Examples 3, 4 and 8-15.
[0078] Arterial Embolization
[0079] In addition to the compositions described above, the present invention also provides a variety of methods which utilize the above-described anti-angiogenic compositions. In particular, within one aspect of the present invention methods are provided for embolizing a blood vessel, comprising the step of delivering into the vessel a therapeutically effective amount of an anti-angiogenic composition (as described above), such that the blood vessel is effectively occluded. Therapeutically effective amounts suitable for occluding blood vessels may be readily determined given the disclosure provided below, and as described in Example 6. Within a particularly preferred embodiment, the anti-angiogenic composition is delivered to a blood vessel which nourishes a tumor (see Figure 13).
[0080] Briefly, there are a number of clinical situations (e.g., bleeding, tumor development) where it is desirable to reduce or abolish the blood supply to an organ or region. As described in greater detail below, this may be accomplished by injecting anti-angiogenic compositions of the present invention into a desired blood vessel through a selectiveiy positioned catheter (see Figure 13). The composition travels via the blood stream until it becomes wedged in the vasculature, thereby physically (or chemically) occluding the blood vessel. The reduced or abolished blood flow to the selected area results in infarction (cell death due to an inadequate supply of oxygen and nutrients) or reduced blood loss from a damaged vessel.
[0081] For use in embolization therapy, anti-angiogenic compositions of the present invention are preferably non-toxic, thrombogenic, easy to inject down vascular catheters, radio-opaque, rapid and permanent in effect, sterile, and readily available in different shapes or sizes at the time of the procedure. In addition, the compositions preferably result in the slow (ideally, over a period of several weeks to months) release of an anti-angiogenic factor. Particularly preferred anti-angiogenic compositions should have a predictable size of 15-200 Im after being injected into the vascular system. Preferably, they should not clump into larger particles either in solution or once injected. In addition, preferable compositions should not change shape or physical properties during storage prior to use.
[0082] Embolization therapy may be utilized in at least three principal ways to assist in the management of neoplasms: (1) definitive treatment of tumors (usually benign); (2) for preoperative embolization; and (3) for palliative embolization. Briefly, benign tumors may sometimes be successfully treated by embolization therapy alone. Examples of such tumors include simple tumors of vascular origin (e.g., haemangiomas), endocrine tumors such as parathyroid adenomas, and benign bone tumors.
[0083] For other tumors, (e.g., renal adenocarcinoma), preoperative embolization may be employed hours or days before surgical resection in order to reduce operative blood loss, shorten the duration of the operation, and reduce the risk of dissemination of viable malignant cells by surgical manipulation of the tumor. Many tumors may be successfully embolized preoperatively, including for example nasopharyngeal tumors, glomus jugular tumors, meningiomas, chemodectomas, and vagal neuromas.
[0084] Embolization may also be utilized as a primary mode of treatment in inoperable malignancy, in order to extend the survival time of patients with advanced disease. Embolization may produce a marked improvement in the quality of life of patients with malignant tumors by alleviating unpleasant symptoms such as bleeding, venous obstruction and tracheal compression. The greatest benefit from palliative tumor embolization, however, may be seen in patients suffering from the humoral effects of malignant endocrine tumors, wherein metastases from carcinoid tumors and other endocrine neoplasms such as insulinomas and glucagonomas may be slow growing, and yet cause great distress by virtue of the endocrine syndromes which they produce.
[0085] In general, embolization therapy utilizing anti-angiogenic compositions of the present invention is typically performed in a similar manner, regardless of the site. Briefly, angiography (a road map of the blood vessels) of the area to be embolized is first performed by injecting radiopaque contrast through a catheter inserted into an artery or vein (depending on the site to be embolized) as an X-ray is taken. The catheter may be inserted either percutaneously or by surgery. The blood vessel is then embolized by refluxing anti-angiogenic compositions of the present invention through the catheter, until flow is observed to cease. Occlusion may be confirmed by repeating the angiogram.
[0086] Embolization therapy generally results in the distribution of compositions containing anti-angiogenic factors throughout the interstices of the tumor or vascular mass to be treated. The physical bulk of the embolic particles clogging the arterial lumen results in the occlusion of the blood supply. In addition to this effect, the presence of an anti-angiogenic factor(s) prevents the formation of new blood vessels to supply the tumor or vascular mass, enhancing the devitalizing effect of cutting off the blood supply.
[0087] Therefore, it should be evident that a wide variety of tumors may be embolized utilizing the compositions of the present invention. Briefly, tumors are typically divided into two classes: benign and malignant. In a benign tumor the cells retain their differentiated features and do not divide in a completely uncontrolled manner.
In addition, the tumor is localized and nonmetastatic. In a malignant tumor, the cells become undifferentiated, do not respond to the body's growth and hormonal signals, and multiply in an uncontrolled manner; the tumor is invasive and capable of spreading to distant sites (metastasizing).
In addition, the tumor is localized and nonmetastatic. In a malignant tumor, the cells become undifferentiated, do not respond to the body's growth and hormonal signals, and multiply in an uncontrolled manner; the tumor is invasive and capable of spreading to distant sites (metastasizing).
[0088] Within one aspect of the present invention, metastases (secondary tumors) of the liver may be treated utilizing embolization therapy. Briefly, a catheter is inserted via the femoral or brachial artery and advanced into the hepatic artery by steering it through the arterial system under fluoroscopic guidance. The catheter is advanced into the hepatic arterial tree as far as necessary to allow complete blockage of the blood vessels supplying the tumor(s), while sparing as many of the arterial branches supplying normal structures as possible. Ideally this will be a segmental branch of the hepatic artery, but it could be that the entire hepatic artery distal to the origin of the gastroduodenal artery, or even multiple separate arteries, will need to be blocked depending on the extent of tumor and its individual blood supply. Once the desired catheter position is achieved, the artery is embolized by injecting anti-angiogenic compositions (as described above) through the arterial catheter until flow in the artery to be blocked ceases, preferably even after observation for 5 minutes. Occlusion of the artery may be confirmed by injecting radiopaque contrast through the catheter and demonstrating by fluoroscopy or X-ray film that the vessel which previously filled with contrast no longer does so. The same procedure may be repeated with each feeding artery to be occluded.
[0089] As noted above, both benign and malignant tumors may be embolized utilizing compositions of the present invention. Representative examples of benign hepatic tumors include Hepatocellular Adenoma, Cavernous Haemangioma, and Focal Nodular Hyperplasia. Other benign tumors which are more rare, and often do not have clinical manifestations, may also be treated. These include Bile Duct Adenomas, Bile Duct Cystadenomas, Fibromas, Lipomas, Leiomyomas, Mesotheliomas, Teratomas, Myxomas, and Nodular Regenerative Hyperplasia.
[0090] Malignant Hepatic Tumors are generally subdivided into two categories:
primary and secondary. Primary tumors arise directly from the tissue in which they are found. Thus, a primary liver tumor is derived originally from the cells which make up the liver tissue (such as hepatocytes and biliary cells). Representative examples of primary hepatic malignancies which may be treated by arterial embolization include Hepatocellularcarcinoma, Cholangiocarcinoma, Angiosarcoma, Cystadenocar-cinoma, Squamous Cell Carcinoma, and Hepatoblastoma.
primary and secondary. Primary tumors arise directly from the tissue in which they are found. Thus, a primary liver tumor is derived originally from the cells which make up the liver tissue (such as hepatocytes and biliary cells). Representative examples of primary hepatic malignancies which may be treated by arterial embolization include Hepatocellularcarcinoma, Cholangiocarcinoma, Angiosarcoma, Cystadenocar-cinoma, Squamous Cell Carcinoma, and Hepatoblastoma.
[0091] A secondary tumor, or metastasis, is a tumor which originated elsewhere in the body but has now spread to a distant organ. The common routes for metastasis are direct growth into adjacent structures, spread through the vascular or lymphatic systems, and tracking along tissue planes and body spaces (peritoneal fluid, cerebrospinal fluid, etc.). Secondary hepatic tumors are one of the most common causes of death in the cancer patient. and are by far and away the most common form of liver tumor.
Although virtually any malignancy can metastasize to the liver, tumors which are most likely to spread to the liver include: cancer of the stomach, colon, and pancreas;
melanoma; tumors of the lung, oropharynx, and bladder; Hodgkin's and non-Hodgkin's lymphoma;
tumors of the breast, ovary, and prostate. Each one of the above-named primary tumors has numerous different tumor types which may be treated by arterial embolization (for example, there are over 32 different types of ovarian cancer).
Although virtually any malignancy can metastasize to the liver, tumors which are most likely to spread to the liver include: cancer of the stomach, colon, and pancreas;
melanoma; tumors of the lung, oropharynx, and bladder; Hodgkin's and non-Hodgkin's lymphoma;
tumors of the breast, ovary, and prostate. Each one of the above-named primary tumors has numerous different tumor types which may be treated by arterial embolization (for example, there are over 32 different types of ovarian cancer).
[0092] As noted above, embolization therapy utilizing anti-angiogenic compositions of the present invention may also be applied to a variety of other clinical situations where it is desired to occlude blood vessels. Within one aspect of the present invention, arteriovenous malformation may be treated by administration of one of the above-described compositions. Briefly, arteriovenous malformations (vascular malformations) refers to a group of diseases wherein at least one (and most typically, many) abnormal communications between arteries and veins occur, resulting in a local tumor-like mass composed predominantly of blood vessels. Such disease may be either congenital or acquired.
[0093] Within one embodiment of the invention, an arteriovenous malformation may be treated by inserting a catheter via the femoral or brachial artery, and advancing it into the feeding artery under fluoroscopic guidance. The catheter is preferably advanced as far as necessary to allow complete blockage of the blood vessels supplying the vascular malformation, while sparing as many of the arterial branches supplying normal structures as possible (ideally this will be a single artery, but most often multiple separate arteries may need to be occluded, depending on the extent of the vascular malformation and its individual blood supply). Once the desired catheter position is achieved, each artery may be embolized utilizing anti-angiogenic compositions of the present invention.
[0094] Within another aspect of the invention, embolization may be accomplished in order to treat conditions of excessive bleeding. For example, menorrhagia (excessive bleeding with menstruation) may be readily treated by embolization of uterine arteries.
Briefly, the uterine arteries are branches of the internal iliac arteries bilaterally. Within one embodiment of the invention, a catheter may be inserted via the femoral or brachial artery, and advanced into each uterine artery by steering it through the arterial system under fluoroscopic guidance. The catheter should be advanced as far as necessary to allow complete blockage of the blood vessels to the uterus, while sparing as many arterial branches that arise from the uterine artery and supply normal structures as possible.
Ideally a single uterine artery on each side may be embolized, but occasionally multiple separate arteries may need to be blocked depending on the individual blood supply. Once the desired catheter position is achieved, each artery may be embolized by administration of the anti-angiogenic compositions as described above.
Briefly, the uterine arteries are branches of the internal iliac arteries bilaterally. Within one embodiment of the invention, a catheter may be inserted via the femoral or brachial artery, and advanced into each uterine artery by steering it through the arterial system under fluoroscopic guidance. The catheter should be advanced as far as necessary to allow complete blockage of the blood vessels to the uterus, while sparing as many arterial branches that arise from the uterine artery and supply normal structures as possible.
Ideally a single uterine artery on each side may be embolized, but occasionally multiple separate arteries may need to be blocked depending on the individual blood supply. Once the desired catheter position is achieved, each artery may be embolized by administration of the anti-angiogenic compositions as described above.
[0095] In a like manner, arterial embolization may be accomplished in a variety of other conditions, including for example, for acute bleeding, vascular abnormalities, central nervous system disorders, and hyperspienism.
[0096] Use of Anti-Angiogenic Compositions as Coatings for Stents
[0097] As noted above, the present invention also provides stents, comprising a generally tubular structure (which includes for example, spiral shapes), the surface of which is coated with a composition as described above. Briefly, a stent is a scaffolding, usually cylindrical in shape, that may be inserted into a body passageway (e.g., bile ducts), which has been narrowed by a disease process (e.g., ingrowth by a tumor) in order to prevent closure or reclosure of the passageway. Stents act by physically holding open the walls of the body passage into which they are inserted.
[0098] A variety of stents may be utilized within the context of the present invention, including for example, esophageal stents, vascular stents, biliary stents, pancreatic stents, urethral stents, lacrimal stents, eustachian tube stents, fallopian tube stents and tracheal/bronchial stents. Other potential sites where stents may also be inserted include:
the pancreatic duct, the ureter, the lacrimal ducts, the Eustachian tubes, and the fallopian tubes.
the pancreatic duct, the ureter, the lacrimal ducts, the Eustachian tubes, and the fallopian tubes.
[0099] Stents may be readily obtained from commercial sources, or constructed in accordance with well known techniques. Representative examples of stents include those described in U.S. Patent No. 4,776,337, entitled "Expandable Intraluminal Graft, and Method and Apparatus for Implanting and Expandable Intraluminal Graft", U.S.
Patent No.
5,176,626, entitled "Indwelling Stent", U.S. Patent No. 5,147,370 entitled "Nitinol Stent for Hollow Body Conduits", U.S. Patent No. 5,064,435 entitled "Self-Expanding Prosthesis Having Stable Axial Length", U.S. Patent No. 5,052,998 entitled "Indwelling Stent and Method of Use", and U.S. Patent No. 5,041,126 entitled "Endovascular Stent and Delivery System.
Patent No.
5,176,626, entitled "Indwelling Stent", U.S. Patent No. 5,147,370 entitled "Nitinol Stent for Hollow Body Conduits", U.S. Patent No. 5,064,435 entitled "Self-Expanding Prosthesis Having Stable Axial Length", U.S. Patent No. 5,052,998 entitled "Indwelling Stent and Method of Use", and U.S. Patent No. 5,041,126 entitled "Endovascular Stent and Delivery System.
[0100] Stents and other solid supports including tubes, film, vasculargrafts, threads, sutures or surgical mesh may be coated with anti-angiogenic compositions or anti-angiogenic factors of the present invention in at least two ways: (a) by directly affixing to the stent an anti-angiogenic composition, or (b) by coating the stent with a substance such as a hydrogel, or other polymers, which will in turn absorb the anti-angiogenic composition (or anti-angiogenic factor above). Within preferred embodiments of the invention, the composition should firmly adhere to the stent during storage and at the time of insertion, and should not be dislodged from the stent when the diameter is expanded from its collapsed size to its full expansion size. The anti-agiogenic composition should also preferably not degrade during storage, prior to insertion, or when warmed to body temperature after expansion inside the body. In addition, it should preferably coat the stent smoothly and evenly, with a uniform distribution of angiogenesis inhibitor, while not changing the stent contour. Within preferred embodiments of the invention, the anti-angiogenic composition should provide a uniform, predictable, prolonged release of the anti-angiogenic factor into the tissue surrounding the stent once it has been deployed. For vascular stents, in addition to the above properties, the composition should not render the stent thrombogenic (causing blood clots to form), or cause significant turbulence in blood flow (more than the stent itself would be expected to cause if it was uncoated).
(0101] Within another aspect of the present invention, methods are provided for expanding the lumen of a body passageway, comprising inserting a stent into the passageway, the stent having a generally tubular structure, the surface of the structure being coated with an anti-angiogenic composition (or, an anti-angiogenic factor alone), such that the passageway is expanded. A variety of embodiments are described below wherein the lumen of a body passageway is expanded in order to eliminate a biliary, esophogeal, tracheal/bronchial, urethral or vascular obstruction. In addition, a representative example is described in more detail below in Example 7.
[0102] Generally, stents are inserted in a similar fashion regardless of the site or the disease being treated. Briefly, a preinsertion examination, usually a diagnostic imaging procedure, endoscopy, or direct visualization at the time of surgery, is generally first performed in order to determine the appropriate positioning for stent insertion. A guidewire is then advanced through the lesion or proposed site of insertion, and over this is passed a delivery catheter which allows a stent in its collapsed form to be inserted.
Typically, stents are capable of being compressed, so that they can be inserted through tiny cavities via small catheters, and then expanded to a larger diameter once they are at the desired location. Once expanded, the stent physically forces the walls of the passageway apart and holds it open. As such, they are capable of insertion via a small opening, and yet are still able to hold open a large diameter cavity or passageway. The stent may be self-expanding (e.g., the Walistent and Gianturco stents), balloon expandable (e.g., the Palmaz stent and Strecker stent), or implanted by a change in temperature (e.g., the Nitinol stent).
Typically, stents are capable of being compressed, so that they can be inserted through tiny cavities via small catheters, and then expanded to a larger diameter once they are at the desired location. Once expanded, the stent physically forces the walls of the passageway apart and holds it open. As such, they are capable of insertion via a small opening, and yet are still able to hold open a large diameter cavity or passageway. The stent may be self-expanding (e.g., the Walistent and Gianturco stents), balloon expandable (e.g., the Palmaz stent and Strecker stent), or implanted by a change in temperature (e.g., the Nitinol stent).
[0103] Stents are typically maneuvered into place under radiologic or direct visual control, taking particular care to place the stent precisely across the narrowing in the organ being treated. The delivery catheter is then removed, leaving the stent standing on its own as a scaffold. A post insertion examination, usually an x-ray, is often utilized to confirm appropriate positioning.
[0104] Within a preferred embodiment of the invention, methods are provided for eliminating biliary obstructions, comprising inserting a biliary stent into a biliary passageway, the stent having a generally tubular structure, the surface of the structure being coated with a composition as described above, such that the biliary obstruction is eliminated. Briefly, tumor overgrowth of the common bile duct results in progressive cholestatic jaundice which is incompatible with life. Generally, the biliary system which drains bile from the liver into the duodenum is most often obstructed by (1) a tumor composed of bile duct cells (cholangiocarcinoma), (2) a tumor which invades the bile duct (e.g., pancreatic carcinoma), or (3) a tumor which exerts extrinsic pressure and compresses the bile duct (e.g., enlarged lymph nodes).
[0105] Both primary biliary tumors, as well as other tumors which cause compression of the biliary tree may be treated utilizing the stents described herein. One example of primary biliary tumors are adenocarcinomas (which are also called Klatskin tumors when found at the bifurcation of the common hepatic duct). These tumors are also referred to as biliary carcinomas, choledocholangiocarcinomas, or adenocarcinomas of the biliary system. Benign tumors which affect the bile duct (e.g., adenoma of the biliary system), and, in rare cases, squamous cell carcinomas of the bile duct and adenocarcinomas of the gallbladder, may also cause compression of the biliary tree and therefore, result in biliary obstruction.
[0106] Compression of the biliary tree is most commonly due to tumors of the liver and pancreas which compress and therefore obstruct the ducts. Most of the tumors from the pancreas arise from cells of the pancreatic ducts. This is a highly fatal form of cancer (5% of all cancer deaths; 26,000 new cases per year in the U.S.) with an average of 6 months survival and a 1 year survival rate of only 10%. When these tumors are located in the head of the pancreas they frequently cause biliary obstruction, and this detracts significantly from the quality of life of the patient. While all types of pancreatic tumors are generally referred to as "carcinoma of the pancreas" there are histologic subtypes including: adenocarcinoma, adenosquamous carcinoma, cystadeno-carcinoma, and acinar cell carcinoma. Hepatic tumors, as discussed above, may also cause compression of the biliary tree, and therefore cause obstruction of the biliary ducts.
[0107] Within one embodiment of the invention, a biliary stent is first inserted into a biliary passageway in one of several ways: from the top end by inserting a needle through the abdominal wall and through the liver (a percutaneous transhepatic cholangiogram or "PTC"); from the bottom end by cannulating the bile duct through an endoscope inserted through the mouth, stomach, and duodenum (an endoscopic retrograde cholangiogram or "ERCP"); or by direct incision during a surgical procedure. A
preinsertion examination, PTC, ERCP, or direct visualization at the time of surgery should generally be performed to determine the appropriate position for stent insertion. A
guidewire is then advanced through the lesion, and over this a delivery catheter is passed to allow the stent to be inserted in its collapsed form. If the diagnostic exam was a PTC, the guidewire and delivery catheter will be inserted via the abdominal wall, while if the original exam was an ERCP the stent will be placed via the mouth. The stent is then positioned under radiologic, endoscopic, or direct visual control taking particular care to place it precisely across the narrowing in the bile duct. The delivery catheter will be removed leaving the stent standing as a scaffolding which holds the bile duct open. A further cholangiogram will be performed to document that the stent is appropriately positioned.
preinsertion examination, PTC, ERCP, or direct visualization at the time of surgery should generally be performed to determine the appropriate position for stent insertion. A
guidewire is then advanced through the lesion, and over this a delivery catheter is passed to allow the stent to be inserted in its collapsed form. If the diagnostic exam was a PTC, the guidewire and delivery catheter will be inserted via the abdominal wall, while if the original exam was an ERCP the stent will be placed via the mouth. The stent is then positioned under radiologic, endoscopic, or direct visual control taking particular care to place it precisely across the narrowing in the bile duct. The delivery catheter will be removed leaving the stent standing as a scaffolding which holds the bile duct open. A further cholangiogram will be performed to document that the stent is appropriately positioned.
[0108] Within yet another embodiment of the invention, methods are provided for eliminating esophageal obstructions, comprising inserting an esophageal stent into an esophagus, the stent having a generally tubular structure, the surface of the structure being coated with an anti-angiogenic composition as described above, such that the esophageal obstruction is eliminated. Briefly, the esophagus is the hollow tube which transports food and liquids from the mouth to the stomach. Cancer of the esophagus or invasion by cancer arising in adjacent organs (e.g., cancer of the stomach or lung) results in the inability to swallow food or saliva. Within this embodiment, a preinsertion examination, usually a barium swallow or endoscopy should generally be performed in order to determine the appropriate position for stent insertion. A catheter or endoscope may then be positioned through the mouth, and a guidewire is advanced through the blockage. A stent delivery catheter is passed over the guidewire under radiologic or endoscopic control, and a stent is placed precisely across the narrowing in the esophagus. A post insertion examination, usually a barium swallow x-ray, may be utilized to confirm appropriate positioning.
[0109] Within other embodiments of the invention, methods are provided for eliminating tracheal/bronchial obstructions, comprising inserting a tracheal/bronchial stent into the trachea or bronchi, the stent having a generally tubular structure, the surface of which is coated with an anti-angiogenic composition as described above, such that the tracheal/bronchial obstruction is eliminated. Briefly, the trachea and bronchi are tubes which carry air from the mouth and nose to the lungs. Blockage of the trachea by cancer, invasion by cancer arising in adjacent organs (e.g., cancer of the lung), or collapse of the trachea or bronchi due to chondromalacia (weakening of the cartilage rings) results in -inability to breathe. Within this embodiment of the invention, preinsertion examination, usually an endoscopy, should generally be performed in order to determine the appropriate position for stent insertion. A catheter or endoscope is then positioned through the mouth, and a guidewire advanced through the blockage. A delivery catheter is then passed over the guidewire in order to allow a collapsed stent to be inserted. The stent is placed under radiologic or endoscopic control in order to place it precisely across the narrowing. The delivery catheter may then be removed leaving the stent standing as a scaffold on its own.
A post insertion examination, usually a bronchoscopy may be utilized to confirm appropriate positioning.
A post insertion examination, usually a bronchoscopy may be utilized to confirm appropriate positioning.
[0110] Within another embodiment of the invention, methods are provided for eliminating urethral obstructions, comprising inserting a urethral stent into a urethra, the stent having a generally tubular structure, the surface of the structure being coated with an anti-angiogenic composition as described above, such that the urethral obstruction is eliminated. Briefly, the urethra is the tube which drains the bladder through the penis.
Extrinsic narrowing of the urethra as it passes through the prostate, due to hypertrophy of the prostate, occurs in virtually every man over the age of 60 and causes progressive difficulty with urination. Within this embodiment, a preinsertion examination, usually an endoscopy or urethrogram should generally first be performed in order to determine the appropriate position for stent insertion, which is above the external urinary sphincter at the lower end, and close to flush with the bladder neck at the upper end. An endoscope or catheter is then positioned through the penile opening and a guidewire advanced into the bladder. A delivery catheter is then passed over the guidewire in order to allow stent insertion. The delivery catheter is then removed, and the stent expanded into place. A
post insertion examination, usually endoscopy or retrograde urethrogram, may be utilized to confirm appropriate position.
Extrinsic narrowing of the urethra as it passes through the prostate, due to hypertrophy of the prostate, occurs in virtually every man over the age of 60 and causes progressive difficulty with urination. Within this embodiment, a preinsertion examination, usually an endoscopy or urethrogram should generally first be performed in order to determine the appropriate position for stent insertion, which is above the external urinary sphincter at the lower end, and close to flush with the bladder neck at the upper end. An endoscope or catheter is then positioned through the penile opening and a guidewire advanced into the bladder. A delivery catheter is then passed over the guidewire in order to allow stent insertion. The delivery catheter is then removed, and the stent expanded into place. A
post insertion examination, usually endoscopy or retrograde urethrogram, may be utilized to confirm appropriate position.
[0111] Within another embodiment of the invention, methods are provided for eliminating vascular obstructions, comprising inserting a vascular stent into a blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with an anti-angiogenic composition as described above, such that the vascular obstruction is eliminated. Briefly, stents may be placed in a wide array of blood vessels, both arteries and veins, to prevent recurrent stenosis at the site of failed angioplasties, to treat narrowings that would likely fail if treated with angioplasty, and to treat post surgical narrowings (e.g., dialysis graft stenosis). Representative examples of suitable sites include the iliac, renal, and coronary arteries, the superior vena cava, and in dialysis grafts. Within one embodiment, angiography is first performed in order to localize the site for placement of the stent. This is typically accomplished by injecting radiopaque contrast through a catheter inserted into an artery or vein as an x-ray is taken. A catheter may then be inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering it through the vascular system under fluoroscopic guidance. A stent may then be positioned across the vascular stenosis. A post insertion angiogram may also be utilized in order to confirm appropriate positioning.
[0112] Use Of Anti-Angiogenic Compositions In Surqical Procedures
[0113] As noted above, anti-angiogenic compositions may be utilized in a wide variety of surgical procedures. For example, within one aspect of the present invention an anti-agiogenic compositions (in the form of, for example, a spray or film) may be utilized to coat or spray an area prior to removal of a tumor, in order to isolate normal surrounding tissues from malignant tissue, and/or to prevent the spread of disease to surrounding tissues. Within other aspects of the present invention, anti-angiogenic compositions (e.g., in the form of a spray) may be delivered via endoscopic procedures in order to coat tumors, or inhibit angiogenesis in a desired locale. Within yet other aspects of the present invention, surgical meshes which have been coated with anti-angiogenic compositions of the present invention may be utilized in any procedure wherein a surgical mesh might be utilized. For example, within one embodiment of the invention a surgical mesh ladened with an anti-angiogenic compositions may be utilized during abdominal cancer resection surgery (e.g., subsequent to colon resection) in order to provide support to the structure, and to release an amount of the anti-angiogenic factor.
[0114] Within further aspects of the present invention, methods are provided for treating tumor exision sites, comprising administering an anti-angiogenic composition as described above to the resection margins of a tumor subsequent to excision, such that the local recurrence of cancer and the formation of new blood vessels at the site is inhibited.
Within one embodiment of the invention, the anti-angiogenic composition(s) (or anti-angiogenic factor(s) alone) are administered directly to the tumor excision site (e.g., applied by swabbing, brushing or otherwise coating the resection margins of the tumor with the anti-angiogenic composition(s) or factor(s)). Alternatively, the anti-antiogenic composition(s) or factor(s) may be incorporated into known surgical pastes prior to administration. Within particularly preferred embodiments of the invention, the anti-angiogenic compositions are applied after hepatic resections for malignancy, and after neurosurgical operations.
Within one embodiment of the invention, the anti-angiogenic composition(s) (or anti-angiogenic factor(s) alone) are administered directly to the tumor excision site (e.g., applied by swabbing, brushing or otherwise coating the resection margins of the tumor with the anti-angiogenic composition(s) or factor(s)). Alternatively, the anti-antiogenic composition(s) or factor(s) may be incorporated into known surgical pastes prior to administration. Within particularly preferred embodiments of the invention, the anti-angiogenic compositions are applied after hepatic resections for malignancy, and after neurosurgical operations.
[0115] Within one aspect of the present invention, anti-agiogenic compositions (as described above) may be administered to the resection margin of a wide variety of tumors, including for example, breast, colon, brain and hepatic tumors. For example, within one embodiment of the invention anti-angiogenic compositions may be administered to the site of a neurological tumor subsequent to excision, such that the formation of new blood vessels at the site are inhibited. Briefly, the brain is highly functionally localized; i.e., each specific anatomical region is specialized to carry out a specific function.
Therefore it is the location of brain pathology that is often more important than the type. A
relatively small lesion in a key area can be far more devastating than a much larger lesion in a less important area. Similarly, a lesion on the surface of the brain may be easy to resect surgically, while the same tumor located deep in the brain may not (one would have to cut through too many vital structures to reach it). Also, even benign tumors can be dangerous for several reasons: they may grow in a key area and cause significant damage;
even though they would be cured by surgical resection this may not be possible; and finally, if left unchecked they can cause increased intracranial pressure. The skull is an enclosed space incapable of expansion. Therefore, if something is growing in one location, something else must be being compressed in another location - the result is increased pressure in the skull or increased intracranial pressure. If such a condition is left untreated, vital structures can be compressed, resulting in death. The incidence of CNS
(central nervous system) malignancies is 8-16 per 100,000. The prognosis of primary malignancy of the brain is dismal, with a median survival of less than one year, even following surgical resection. These tumors, especially gliomas, are predominantly a local disease which recur within 2 centimeters of the original focus of disease after surgical removal.
Therefore it is the location of brain pathology that is often more important than the type. A
relatively small lesion in a key area can be far more devastating than a much larger lesion in a less important area. Similarly, a lesion on the surface of the brain may be easy to resect surgically, while the same tumor located deep in the brain may not (one would have to cut through too many vital structures to reach it). Also, even benign tumors can be dangerous for several reasons: they may grow in a key area and cause significant damage;
even though they would be cured by surgical resection this may not be possible; and finally, if left unchecked they can cause increased intracranial pressure. The skull is an enclosed space incapable of expansion. Therefore, if something is growing in one location, something else must be being compressed in another location - the result is increased pressure in the skull or increased intracranial pressure. If such a condition is left untreated, vital structures can be compressed, resulting in death. The incidence of CNS
(central nervous system) malignancies is 8-16 per 100,000. The prognosis of primary malignancy of the brain is dismal, with a median survival of less than one year, even following surgical resection. These tumors, especially gliomas, are predominantly a local disease which recur within 2 centimeters of the original focus of disease after surgical removal.
[0116] Representative examples of brain tumors which may be treated utilizing the compositions and methods described herein include Glial Tumors (such as Anaplastic Astrocytoma, Glioblastoma Multiform, Pilocytic Astrocytoma, Oligodendroglioma, Ependymoma, Myxopapillary Ependymoma, Subependymoma, Choroid Plexus Papilloma);
Neuron Tumors (e.g., Neuroblastoma, Ganglioneuroblastoma, Ganglioneuroma, and Medulloblastoma); Pineal Gland Tumors (e.g., Pineoblastoma and Pineocytoma);
Menigeal Tumors (e.g., Meningioma, Meningeal Hemangiopericytoma, Meningeal Sarcoma);
Tumors of Nerve Sheath Cells (e.g., Schwannoma (Neurolemmoma) and Neurofibroma);
Lymphomas (e.g., Hodgkin's and Non-Hodgkin's Lymphoma (including numerous subtypes, both primary and secondary); Malformative Tumors (e.g., Craniopharyngioma, Epidermoid Cysts, Dermoid Cysts and Colloid Cysts); and Metastatic Tumors (which can be derived from virtually any tumor, the most common being from lung, breast, melanoma, kidney, and gastrointestinal tract tumors).
Neuron Tumors (e.g., Neuroblastoma, Ganglioneuroblastoma, Ganglioneuroma, and Medulloblastoma); Pineal Gland Tumors (e.g., Pineoblastoma and Pineocytoma);
Menigeal Tumors (e.g., Meningioma, Meningeal Hemangiopericytoma, Meningeal Sarcoma);
Tumors of Nerve Sheath Cells (e.g., Schwannoma (Neurolemmoma) and Neurofibroma);
Lymphomas (e.g., Hodgkin's and Non-Hodgkin's Lymphoma (including numerous subtypes, both primary and secondary); Malformative Tumors (e.g., Craniopharyngioma, Epidermoid Cysts, Dermoid Cysts and Colloid Cysts); and Metastatic Tumors (which can be derived from virtually any tumor, the most common being from lung, breast, melanoma, kidney, and gastrointestinal tract tumors).
[0117] Other Therapeutic Uses of Anti-Angiogenic Compositions
[0118] In addition to tumors, numerous other non-tumorigenic angiogenesis-dependent diseases which are characterized by the abnormal growth of blood vessels may also be treated with the anti-angiogenic compositions, or anti-angiogenic factors of the present invention. Representative examples of such non-tumorigenic angiogenesis-dependent diseases include corneal neovascularization, hypertrophic scars and keloids, proliferative diabetic retinopathy, rheumatoid arthritis, arteriovenous malformations (discussed above), atherosclerotic plaques, delayed wound healing, hemophilic joints, nonunion fractures, Osler-Weber syndrome, psoriasis, pyogenic granuloma, scieroderma, tracoma, menorrhagia (discussed above) and vascular adhesions.
[0119] In particular, within one aspect of the present invention methods are provided for treating corneal neovascularization (including corneal graft neovascularization), comprising the step of administering a therapeutically effective amount of an anti-angiogenic composition (as described above) to the cornea, such that the formation of blood vessels is inhibited. Briefly, the cornea is a tissue which normally lacks blood vessels. In certain pathological conditions however, capillaries may extend into the cornea from the pericorneal vascular plexus of the limbus. When the cornea becomes vascularized, it also becomes clouded, resulting in a decline in the patient's visual acuity.
Visual loss may become complete if the cornea completely opacitates.
Visual loss may become complete if the cornea completely opacitates.
[0120] Blood vessels can enter the cornea in a variety of patterns and depths, depending upon the process which incites the neovascularization. These patterns have been traditionally defined by ophthalmologists in the following types: pannus trachomatosus, pannus leprosus, pannus phylctenulosus, pannus degenerativus, and glaucomatous pannus. The corneal stroma may also be invaded by branches of the anterior ciliary artery (called interstitial vascularization) which causes several distinct clinical lesions: terminal loops, a "brush-like" pattern, an umbel form, a lattice form, interstitial arcades (from episcleral vessels), and aberrant irregular vessels.
[0121] A wide variety of disorders can result in corneal neovascularization, inciuding for example, corneal infections (e.g., trachoma, herpes simplex keratitis, leishmaniasis and onchocerciasis), immunological processes (e.g., graft rejection and Stevens-Johnson's syndrome), akali burns, trauma, inflammation (of any cause), toxic and nutritional deficiency states, and as a complication of wearing contact lenses.
[0122] While the cause of corneal neovascularization may vary, the response of the cornea to the insult and the subsequent vascular ingrowth is similar regardless of the cause. Briefly, the location of the injury appears to be of importance as only those lesions situated within a critical distance of the limbus will incite an angiogenic response. This is likely due to the fact that the angiogenic factors responsible for eliciting the vascular invasion are created at the site of the lesion, and must diffuse to the site of the nearest blood vessels (the limbus) in order to exert their effect. Past a certain distance from the limbus, this would no longer be possible and the limbic endothelium would not be induced to grow into the cornea. Several angiogenic factors are likely involved in this process, many of which are products of the inflammatory response. Indeed, neovascularization of the cornea appears to only occur in association with an inflammatory cell infiltrate, and the degree of angiogenesis is proportional to the extent of the inflammatory reaction. Corneal edema further facilitates blood vessel ingrowth by loosening the corneal stromal framework and providing a pathway of'9east resistance" through which the capillaries can grow.
[0123] Following the initial inflammatory reaction, capillary growth into the cornea proceeds in the same manner as it occurs in other tissues. The normally quiescent endothelial cells of the limbic capillaries and venules are stimulated to divide and migrate.
The endothelial cells project away from their vessels of origin, digest their surrounding basement membrane and the tissue through which they will travel, and migrate towards the source of the angiogenic stimulus. The blind ended sprouts acquire a lumen and then anastomose together to form capillary loops. The end result is the establishment of a vascular plexus within the corneal stroma.
The endothelial cells project away from their vessels of origin, digest their surrounding basement membrane and the tissue through which they will travel, and migrate towards the source of the angiogenic stimulus. The blind ended sprouts acquire a lumen and then anastomose together to form capillary loops. The end result is the establishment of a vascular plexus within the corneal stroma.
[0124] Anti-angiogenic compositions of the present invention are useful by blocking the stimulatory effects of angiogenesis promoters, reducing endothelial cell division, decreasing endothelial cell migration, and impairing the activity of the proteolytic enzymes secreted by the endothelium.
[0125] Within particularly preferred embodiments of the invention, an anti-angiogenic factor may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eyedrop form. The anti-angiogenic factor solution may be prepared in its pure form and administered several times daily. Alternatively, anti-angiogenic compositions, prepared as described above, may also be administered directly to the cornea. Within preferred embodiments, the anti-angiogenic composition is prepared with a muco-adhesive polymer which binds to cornea. Within further embodiments, the anti-angiogenic factors or anti-angiogenic compositions may be utilized as an adjunct to conventional steroid therapy.
[0126] Topical therapy may also be useful prophylactically in corneal lesions which are known to have a high probability of inducing an angiogenic response (such as chemical burns). In these instances the treatment, likely in combination with steroids, may be instituted immediately to help prevent subsequent complications.
[0127] Within other embodiments, the anti-angiogenic compositions described above may be injected directly into the corneal stroma by an ophthalmologist under microscopic guidance. The preferred site of injection may vary with the morphology of the individual lesion, but the goal of the administration would be to place the composition at the advancing front of the vasculature (i.e., interspersed between the blood vessels and the normal cornea). In most cases this would involve perilimbic corneal injection to "protect"
the cornea from the advancing blood vessels. This method may also be utilized shortly after a corneal insult in order to prophylactically prevent corneal neovascularization. In this situation the material could be injected in the perilimbic cornea interspersed between the corneal lesion and its undesired potential limbic blood supply. Such methods may also be utilized in a similar fashion to prevent capillary invasion of transplanted corneas. In a sustained-release form injections might only be required 2-3 times per year. A
steroid could also be added to the injection solution to reduce inflammation resulting from the injection itself.
the cornea from the advancing blood vessels. This method may also be utilized shortly after a corneal insult in order to prophylactically prevent corneal neovascularization. In this situation the material could be injected in the perilimbic cornea interspersed between the corneal lesion and its undesired potential limbic blood supply. Such methods may also be utilized in a similar fashion to prevent capillary invasion of transplanted corneas. In a sustained-release form injections might only be required 2-3 times per year. A
steroid could also be added to the injection solution to reduce inflammation resulting from the injection itself.
[0128] Within another aspect of the present invention, methods are provided for treating hypertrophic scars and keloids, comprising the step of administering one of the above-described anti-angiogenic compositions to a hypertrophic scar or keloid.
[0129] Briefly, healing of wounds and scar formation occurs in three phases:
inflammation, proliferation, and maturation. The first phase, inflammation, occurs in response to an injury which is severe enough to break the skin. During this phase, which lasts 3 to 4 days, blood and tissue fluid form an adhesive coaguium and fibrinous network which serves to bind the wound surfaces together. This is then followed by a proliferative phase in which there is ingrowth of capillaries and connective tissue from the wound edges, and closure of the skin defect. Finally, once capillary and fibroblastic proliferation has ceased, the maturation process begins wherein the scar contracts and becomes less cellular, less vascular, and appears flat and white. This final phase may take between 6 and 12 months.
inflammation, proliferation, and maturation. The first phase, inflammation, occurs in response to an injury which is severe enough to break the skin. During this phase, which lasts 3 to 4 days, blood and tissue fluid form an adhesive coaguium and fibrinous network which serves to bind the wound surfaces together. This is then followed by a proliferative phase in which there is ingrowth of capillaries and connective tissue from the wound edges, and closure of the skin defect. Finally, once capillary and fibroblastic proliferation has ceased, the maturation process begins wherein the scar contracts and becomes less cellular, less vascular, and appears flat and white. This final phase may take between 6 and 12 months.
[0130] If too much connective tissue is produced and the wound remains persistently cellular, the scar may become red and raised. If the scar remains within the boundaries of the original wound it is referred to as a hypertrophic scar, but if it extends beyond the original scar and into the surrounding tissue, the lesion is referred to as a keloid. Hypertrophic scars and keloids are produced during the second and third phases of scar formation. Several wounds are particularly prone to excessive endothelial and fibroblastic proliferation, including burns, open wounds, and infected wounds.
With hypertrophic scars, some degree of maturation occurs and gradual improvement occurs.
In the case of keloids however, an actual tumor is produced which can become quite large.
Spontaneous improvement in such cases rarely occurs.
With hypertrophic scars, some degree of maturation occurs and gradual improvement occurs.
In the case of keloids however, an actual tumor is produced which can become quite large.
Spontaneous improvement in such cases rarely occurs.
[0131] Therefore, within one embodiment of the present invention either anti-angiogenic factors alone, or, anti-angiogenic compositions as described above, are directly injected into a hypertrophic scar or keloid, in order to prevent the progression of these lesions. The frequency of injections will depend upon the release kinetics of the polymer used (if present), and the clinical response. This therapy is of particular value in the prophylactic treatment of conditions which are known to result in the development of hypertrophic scars and keloids (e.g., burns), and is preferably initiated after the proliferative phase has had time to progress (approximately 14 days after the initial injury), but before hypertrophic scar or keloid development.
[0132] Within another aspect of the present invention methods are provided for treating neovascular glaucoma, comprising the step of administering a therapeutically effective amount of an anti-angiogenic composition to the eye, such that the formation of blood vessels is inhibited.
[0133] Briefly, neovascular glaucoma is a pathological condition wherein new capillaries develop in the iris of the eye. The angiogenesis usually originates from vessels located at the pupillary margin, and progresses across the root of the iris and into the trabecular meshwork. Fibroblasts and other connective tissue elements are associated with the capillary growth and a fibrovascular membrane develops which spreads across the anterior surface of the iris. Eventually this tissue reaches the anterior chamber angle where it forms synechiae. These synechiae in turn coalesce, scar, and contract to ultimately close off the anterior chamber angle. The scar formation prevents adequate drainage of aqueous humor through the angle and into the trabecular meshwork, resulting in an increase in intraocular pressure that may result in blindness.
[0134] Neovascular glaucoma generally occurs as a complication of diseases in which retinal ischemia is predominant. In particular, about one third of the patients with this disorder have diabetic retinopathy and 28% have central retinal vein occlusion. Other causes include chronic retinal detachment, end-stage glaucoma, carotid artery obstructive disease, retrolental fibroplasia, sickle-cell anemia, intraocular tumors, and carotid cavernous fistulas. In its early stages, neovascular glaucoma may be diagnosed by high magnification slitiamp biomicroscopy, where it reveals small, dilated, disorganized capillaries (which leak fluorescein) on the surface of the iris. Later gonioscopy demonstrates progressive obliteration of the anterior chamber angle by fibrovascular bands. While the anterior chamber angle is still open, conservative therapies may be of assistance. However, once the angle closes surgical intervention is required in order to alleviate the pressure.
[0135] Therefore, within one embodiment of the invention anti- angiogenic factors (either alone or in an anti-angiogenic composition, as described above) may be administered topically to the eye in order to treat early forms of neovascular glaucoma.
[0136] Within other embodiments of the invention, anti-angiogenic compositions may be implanted by injection of the composition into the region of the anterior chamber angle.
This provides a sustained localized increase of anti-angiogenic factor, and prevents blood vessel growth into the area. Implanted or injected anti-angiogenic compositions which are placed between the advancing capillaries of the iris and the anterior chamber angle can "defend" the open angle from neovascularization. As capillaries will not grow within a significant radius of the anti-angiogenic composition, patency of the angle could be maintained. Within other embodiments, the anti-angiogenic composition may also be placed in any location such that the anti-angiogenic factor is continuously released into the aqueous humor. This would increase the anti-angiogenic factor concentration within the humor, which in turn bathes the surface of the iris and its abnormal capillaries, thereby providing another mechanism by which to deliver the medication. These therapeutic modalities may also be useful prophylactically and in combination with existing treatments.
This provides a sustained localized increase of anti-angiogenic factor, and prevents blood vessel growth into the area. Implanted or injected anti-angiogenic compositions which are placed between the advancing capillaries of the iris and the anterior chamber angle can "defend" the open angle from neovascularization. As capillaries will not grow within a significant radius of the anti-angiogenic composition, patency of the angle could be maintained. Within other embodiments, the anti-angiogenic composition may also be placed in any location such that the anti-angiogenic factor is continuously released into the aqueous humor. This would increase the anti-angiogenic factor concentration within the humor, which in turn bathes the surface of the iris and its abnormal capillaries, thereby providing another mechanism by which to deliver the medication. These therapeutic modalities may also be useful prophylactically and in combination with existing treatments.
[0137] Within another aspect of the present invention, methods are provided for treating proliferative diabetic retinopathy, comprising the step of administering a therapeutically effective amount of an anti-angiogenic composition to the eyes, such that the formation of blood vessels is inhibited.
[0138] Briefly, the pathology of diabetic retinopathy is thought to be similar to that described above for neovascular glaucoma. In particular, background diabetic retinopathy is believed to convert to proliferative diabetic retinopathy under the influence of retinal hypoxia. Generally, neovascular tissue sprouts from the optic nerve (usually within 10 mm of the edge), and from the surface of the retina in regions where tissue perfusion is poor.
Initially the capillaries grow between the inner limiting membrane of the retina and the posterior surface of the vitreous. Eventually, the vessels grow into the vitreous and through the inner limiting membrane. As the vitreous contracts, traction is applied to the vessels, often resulting in shearing of the vessels and blinding of the vitreous due to hemorrhage.
Fibrous traction from scarring in the retina may also produce retinal detachment.
Initially the capillaries grow between the inner limiting membrane of the retina and the posterior surface of the vitreous. Eventually, the vessels grow into the vitreous and through the inner limiting membrane. As the vitreous contracts, traction is applied to the vessels, often resulting in shearing of the vessels and blinding of the vitreous due to hemorrhage.
Fibrous traction from scarring in the retina may also produce retinal detachment.
[0139] The conventional therapy of choice is panretinal photocoagulation to decrease retinal tissue, and thereby decrease retinal oxygen demands. Although initially effective, there is a high relapse rate with new lesions forming in other parts of the retina.
Complications of this therapy include a decrease in peripheral vision of up to 50% of patients, mechanical abrasions of the cornea, laser-induced cataract formation, acute glaucoma, and stimulation of subretinal neovascular growth (which can result in loss of vision). As a result, this procedure is performed only when several risk factors are present, and the risk-benefit ratio is clearly in favor of intervention.
Complications of this therapy include a decrease in peripheral vision of up to 50% of patients, mechanical abrasions of the cornea, laser-induced cataract formation, acute glaucoma, and stimulation of subretinal neovascular growth (which can result in loss of vision). As a result, this procedure is performed only when several risk factors are present, and the risk-benefit ratio is clearly in favor of intervention.
[0140] Therefore, within particularly preferred embodiments of the invention, proliferative diabetic retinopathy may be treated by injection of an anti-angiogenic factor(s) (or anti-angiogenic composition) into the aqueous humor or the vitreous, in order to increase the local concentration of anti-angiogenic factor in the retina.
Preferably, this treatment should be initiated prior to the acquisition of severe disease requiring photocoagulation. Within other embodiments of the invention, arteries which feed the neovascular lesions may be embolized (utilizing anti-angiogenic compositions, as described above)
Preferably, this treatment should be initiated prior to the acquisition of severe disease requiring photocoagulation. Within other embodiments of the invention, arteries which feed the neovascular lesions may be embolized (utilizing anti-angiogenic compositions, as described above)
[0141] Within another aspect of the present invention, methods are provided for treating retrolental fibroblasia, comprising the step of administering a therapeutically effective amount of an anti-angiogenic factor (or anti-angiogenic composition) to the eye, such that the formation of blood vessels is inhibited.
[0142] Briefly, retrolental fibroblasia is a condition occurring in premature infants who receive oxygen therapy. The peripheral retinal vasculature, particularly on the temporal side, does not become fully formed until the end of fetal life.
Excessive oxygen (even levels which would be physiologic at term) and the formation of oxygen free radicals are thought to be important by causing damage to the blood vessels of the immature retina.
These vessels constrict, and then become structurally obliterated on exposure to oxygen.
As a result, the peripheral retina fails to vascularize and retinal ischemia ensues. In response to the ischemia, neovascularization is induced at the junction of the normal and the ischemic retina.
Excessive oxygen (even levels which would be physiologic at term) and the formation of oxygen free radicals are thought to be important by causing damage to the blood vessels of the immature retina.
These vessels constrict, and then become structurally obliterated on exposure to oxygen.
As a result, the peripheral retina fails to vascularize and retinal ischemia ensues. In response to the ischemia, neovascularization is induced at the junction of the normal and the ischemic retina.
[0143] In 75% of the cases these vessels regress spontaneously. However, in the remaining 25% there is continued capillary growth, contraction of the fibrovascular component, and traction on both the vessels and the retina. This results in vitreous hemorrhage and/or retinal detachment which can lead to blindness. Neovascular angle-closure glaucoma is also a complication of this condition.
[0144] As it is often impossible to determine which cases will spontaneously resolve and which will progress in severity, conventional treatment (i.e., surgery) is generally initiated only in patients with established disease and a well developed pathoiogy. This "wait and see" approach precludes early intervention, and allows the progression of disease in the 25% who follow a complicated course. Therefore, within one embodiment of the invention, topical administration of anti-angiogenic factors (or anti-angiogenic compositions, as described above) may be accomplished in infants which are at high risk for developing this condition in an attempt to cut down on the incidence of progression of retrolental fibroplasia. Within other embodiments, intravitreous injections and/or intraocular implants of an anti-angiogenic composition may be utilized. Such methods are particularly preferred in cases of established disease, in order to reduce the need for surgery.
[0145] Within another aspect of the present invention, methods are provided for treating rheumatoid arthritis, comprising the step of administering a therapeutically effective amount of an anti-angiogenic composition to a joint, such that the formation of blood vessels is inhibited.
[0146] Briefly, in rheumatoid arthritis articular cartilage is destroyed when it is invaded by pannus tissue (which is composed of inflammatory cells, blood vessels, and connective tissue). Generally, chronic inflammation in itself is insufficient to result in damage to the joint surface, but a permanent deficit is created once fibrovascular tissue digests the cartilage tissue.
[0147] Within a preferred embodiment of the invention, anti-angiogenic factors (including anti-angiogenic compositions, as described above) may be administered by intra-articular injection, as a surgical paste, or as an oral agent, in order to inhibit the formation of blood vessels within the joint.
[0148] As noted above, within yet another aspect of the present invention, vascular grafts are provided comprising a synthetic tube, the surface of which is coated with an anti-angiogenic composition as described above. Briefly, vascular grafts are synthetic tubes, usually made of Dacron or Gore-TexT6A, inserted surgically to bypass arterial blockages, most frequently from the aorta to the femoral, or the femoral to the popliteal artery. A major problem which particularly complicates femoral-popliteal bypass grafts is the formation of a subendothelial scar-like reaction in the blood vessel wall called neointimal hyperplasia, which narrows the lumen within and adjacent to either end of the graft, and which can be progressive. A graft coated with or containing anti-angiogenic factors (or anti-angiogenic compositions, as described above) may be utilized to limit the formation of neointimal hyperplasia at either end of the graft. The graft may then be surgically placed by conventional bypass techniques.
[0149] Anti-angiogenic compositions of the present invention may also be utilized in a variety of other manners. For example, they may be incorporated into threads such as surgical sutures in order to prevent stitch granulomas, implanted in the uterus (in the same manner as an IUD) for the treatment of menorrhagia or as a form of female birth control, administered as either a peritoneal lavage fluid or for peritoneal implantation in the treatment of endometriosis, attached to a monoclonal antibody directed against activated endothelial cells as a form of systemic chemotherapy, or utilized in diagnostic imaging when attached to a radioactively labelled monoclonal antibody which recognizes activated endothelial cells.
[0150] The following examples are offered by way of illustration, and not by way of limitation.
EXAMPLES
EXAMPLES
[0151] EXAMPLE 1
[0152] PREPARATION OF ANTI-INVASIVE FACTOR
[0153] The shoulder girdle and skull from a dogfish is excised, then scraped with a scalpel in order to remove all muscle and associated connective tissue from the cartilage.
The cartilage is then homogenized with a tissue grinder, and extracted by continuous stirring at room temperature for 2 to 5 days in a solution containing 2.0 M
guanidium hydrochloride and 0.02 M MES at pH 6Ø
The cartilage is then homogenized with a tissue grinder, and extracted by continuous stirring at room temperature for 2 to 5 days in a solution containing 2.0 M
guanidium hydrochloride and 0.02 M MES at pH 6Ø
[0154] ]After 2 to 5 days, the cartilage extract is passed through gauze netting in order to remove the larger constituents. The filtrate is then passed through an AmiconT""
ultrafiltration unit which utilizes spiral-wound cartridges, with a molecular weight cutoff of 100,000. The filtrate (containing proteins with a molecular weight of less than 100,000 daltons) is then dialyzed against 0.02 M MES buffer (pH 6) with an Amicon ultrafiltration unit which retains proteins with a molecular weight of greater than 3,000 daltons. Utilizing this method, low molecular weight proteins and constituents are removed, as well as excessive amounts of guanidium HCI. The dialysate is concentrated to a final concentration 9 mg/ml.
ultrafiltration unit which utilizes spiral-wound cartridges, with a molecular weight cutoff of 100,000. The filtrate (containing proteins with a molecular weight of less than 100,000 daltons) is then dialyzed against 0.02 M MES buffer (pH 6) with an Amicon ultrafiltration unit which retains proteins with a molecular weight of greater than 3,000 daltons. Utilizing this method, low molecular weight proteins and constituents are removed, as well as excessive amounts of guanidium HCI. The dialysate is concentrated to a final concentration 9 mg/ml.
[0155] EXAMPLE 2
[0156] ANALYSIS OF VARIOUS AGENTS FOR ANTI-ANGIOGENIC ACTIVITY
[0157] A. Chick Chorioallantoic Membrane ("Cam") Assays
[0158] Fertilized, domestic chick embryos were incubated for 3 days prior to shell-less culturing. In this procedure, the egg contents were emptied by removing the shell located around the air space, the interior shell membrane was then severed and the opposite end of the shell was perforated to allow the contents of the egg to gently slide out from the blunted end. The egg contents were emptied into round-bottom sterilized glass bowls and covered with petri dish covers. These were then placed into an incubator at 90%
relative humidity and 3% CO2 and incubated for 3 days.
relative humidity and 3% CO2 and incubated for 3 days.
[0159] Paclitaxel (Sigma, St. Louis, MI) was mixed at concentrations of 1, 5, 10, 30mg per 10mI aliquot of 0.5% aqueous methylcellulose. Since paclitaxel is insoluble in water, glass beads were used to produce fine particles. Ten microliter aliquots of this solution were dried on ParafilmT"" for 1 hour forming disks 2mm in diameter.
The dried disks containing paclitaxel were then carefully placed at the growing edge of each CAM at day 6 of incubation. Controls were obtained by placing paclitaxel-free methylcellufose disks on the CAMs over the same time course. After a 2 day exposure (day 8 of incubation) the vasculature was examined with the aid of a stereomicroscope. Liposyn IIT"", a white opaque solution, was injected into the CAM to increase the visibility of the vascular details. The vasculature of unstained, living embryos were imaged using a Zeiss stereomicroscope which was interfaced with a video camera (Dage-MTI Inc., Michigan City, IN).
These video signals were then displayed at 160 times magnification and captured using an image analysis system (Vidas, Kontron; Etching, Germany). Image negatives were then made on a graphics recorder (Model 3000; Matrix Instruments, Orangeburg, NY).
The dried disks containing paclitaxel were then carefully placed at the growing edge of each CAM at day 6 of incubation. Controls were obtained by placing paclitaxel-free methylcellufose disks on the CAMs over the same time course. After a 2 day exposure (day 8 of incubation) the vasculature was examined with the aid of a stereomicroscope. Liposyn IIT"", a white opaque solution, was injected into the CAM to increase the visibility of the vascular details. The vasculature of unstained, living embryos were imaged using a Zeiss stereomicroscope which was interfaced with a video camera (Dage-MTI Inc., Michigan City, IN).
These video signals were then displayed at 160 times magnification and captured using an image analysis system (Vidas, Kontron; Etching, Germany). Image negatives were then made on a graphics recorder (Model 3000; Matrix Instruments, Orangeburg, NY).
[0160] The membranes of the 8 day-old shell-less embryo were flooded with 2%
glutaraldehyde in 0.1 M Na cacodylate buffer; additional fixative was injected under the CAM. After 10 minutes in situ, the CAM was removed and placed into fresh fixative for 2 hours at room temperature. The tissue was then washed overnight in cacodylate buffer containing 6% sucrose. The areas of interest were postfixed in 1% osmium tetroxide for 1.5 hours at 4 C. The tissues were then dehydrated in a graded series of ethanols, solvent exchanged with propylene oxide, and embedded in Spurr resin. Thin sections were cut with a diamond knife, place on copper grids, stained, and examined in a Joel 1200EX
electron microscope. Similarly, 0.5mm sections were cut and stained with toluene blue for light microscopy.
glutaraldehyde in 0.1 M Na cacodylate buffer; additional fixative was injected under the CAM. After 10 minutes in situ, the CAM was removed and placed into fresh fixative for 2 hours at room temperature. The tissue was then washed overnight in cacodylate buffer containing 6% sucrose. The areas of interest were postfixed in 1% osmium tetroxide for 1.5 hours at 4 C. The tissues were then dehydrated in a graded series of ethanols, solvent exchanged with propylene oxide, and embedded in Spurr resin. Thin sections were cut with a diamond knife, place on copper grids, stained, and examined in a Joel 1200EX
electron microscope. Similarly, 0.5mm sections were cut and stained with toluene blue for light microscopy.
[0161] At day 11 of development, chick embryos were used for the corrosion casting technique. MercoxTM resin (Ted Pella, Inc., Redding CA) was injected into the CAM
vasculature using a 30-gauge hypodermic needle. The casting material consisted of 2.5 grams of MercoxTM CL-2B polymer and 0.05 grams of catalyst (55% benzoyl peroxide) having a 5 minute polymerization time. After injection, the plastic was allowed to sit in situ for an hour at room temperature and then overnight in an oven at 65 C. The CAM
was then placed in 50% aqueous solution of sodium hydroxide to digest all organic components. The plastic casts were washed extensively in distilled water, air-dried, coated with gold/palladium, and viewed with the Philips 501 B scanning electron microscope.
vasculature using a 30-gauge hypodermic needle. The casting material consisted of 2.5 grams of MercoxTM CL-2B polymer and 0.05 grams of catalyst (55% benzoyl peroxide) having a 5 minute polymerization time. After injection, the plastic was allowed to sit in situ for an hour at room temperature and then overnight in an oven at 65 C. The CAM
was then placed in 50% aqueous solution of sodium hydroxide to digest all organic components. The plastic casts were washed extensively in distilled water, air-dried, coated with gold/palladium, and viewed with the Philips 501 B scanning electron microscope.
[0162] Results of the above experiments are shown in Figures 1-4. Briefly, the general features of the normal chick shell-less egg culture are shown in Figure IA. At day 6 of incubation, the embryo is centrally positioned to a radially expanding network of blood vessels; the CAM developes adjacent to the embryo. These growing vessels lie close to the surface and are readily visible making this system an idealized model for the study of angiogenesis. Living, unstained capillary networks of the CAM can be imaged noninvasively with a stereomicroscope. Figure 1 B illustrates such a vascular area in which the cellular blood elements within capillaries were recorded with the use of a video/computer interface. The 3-dimensional architecture of such CAM capillary networks is shown by the corrosion casting method and viewed in the scanning electron microscope (Figure 1 C). These casting revealed underlying vessels which project toward the CAM
surface where they form a single layer of anastomic capillaries.
surface where they form a single layer of anastomic capillaries.
[0163] Transverse sections through the CAM show an outer ectoderm consisting of a double cell layer, a broader mesodermal layer containing capillaries which lie subjacent to the ectoderm, adventitial cells, and an inner, single endodermal cell layer (Figure 1 D).
At the electron microscope level, the typical structural details of the CAM
capillaries are demonstrated. Typically, these vessels lie in close association with the inner cell layer of ectoderm (Figure 1 E).
At the electron microscope level, the typical structural details of the CAM
capillaries are demonstrated. Typically, these vessels lie in close association with the inner cell layer of ectoderm (Figure 1 E).
[0164] After 48 hours exposure to paclitaxel at concentrations of 1, 5, 10, or 30 mg, each CAM was examined under living conditions with a stereomicroscope equipped with a video/computer interface in order to evaluate the effects on angiogenesis.
This imaging setup was used at a maginification of 160 times which permitted the direct visualization of blood cells within the capillaries; thereby blood flow in areas of interest could be easily assessed and recorded. For this study, the inhibition of angiogenesis was defined as an area of the CAM devoid of a capillary network ranging from 2-6 mm in diameter.
Areas of inhibition lacked vascular blood flow and thus were only observed under experimental conditions of methylcellulose containing paclitaxel; under control conditions of disks lacking paclitaxel there was no effect on the developing capillary system. The dose-dependent, experimental data of the effects of paclitaxel at different concentrations are shown in Table li.
TABLE II
Angioaenic Inhibition by Paclitaxel Paclitaxel Concentration pg Embryos Evaluated % Inhibifion (Positive/Total) Control 0/30 0
This imaging setup was used at a maginification of 160 times which permitted the direct visualization of blood cells within the capillaries; thereby blood flow in areas of interest could be easily assessed and recorded. For this study, the inhibition of angiogenesis was defined as an area of the CAM devoid of a capillary network ranging from 2-6 mm in diameter.
Areas of inhibition lacked vascular blood flow and thus were only observed under experimental conditions of methylcellulose containing paclitaxel; under control conditions of disks lacking paclitaxel there was no effect on the developing capillary system. The dose-dependent, experimental data of the effects of paclitaxel at different concentrations are shown in Table li.
TABLE II
Angioaenic Inhibition by Paclitaxel Paclitaxel Concentration pg Embryos Evaluated % Inhibifion (Positive/Total) Control 0/30 0
[0165] Typical paclitaxel-created CAMs (Figures 2A and 2B) are shown with the transparent methylcellulose disk centrally positioned over the avascular zone measuring 6 mm in diameter. At a slightly higher magnification, the periphery of such avascular zones is clearly evident (Figure 2C); the surrounding functional vessels were often redirected away from the source of paclitaxel (Figures 2C and 2D). Such angular redirecting of blood flow was never observed under normal conditions. Another feature of the effects of paclitaxel was the formation of blood islands within the avascular zone representing the aggregation of blood cells.
[0166] The associated morphological alterations of the paclitaxel-treated CAM
are readily apparent at both the light and electron microscopic levels. For the convenience of presentation, three distinct phases of general transition from the normal to the avascular state are shown. Near the periphery of the avascular zone the CAM is hallmarked by an abundance of mitotic cells within all three germ layers (Figures 3A and 4A).
This enhanced mitotic division was also a consistent oberservation for capillary endothelial cells.
However, the endothelial cells remained junctionally intact with no extravasation of blood cells. With further degradation, the CAM is characterized by the breakdown and dissolution of capillaries (Figures 3B and 4B). The presumptive endothelial cells, typically arrested in mitosis, still maintain a close spatial relationship with blood cells and lie subjacent to the ectoderm; however, these cells are not junctionally linked. The most central portion of the avascular zone was characterized by a thickened ectodermal and endodermal layer (Figures 3C and 4C). Although these layers were thickened, the cellular junctions remained intact and the layers maintained their structural characteristics.
Within the mesoderm, scattered mitotically arrested cells were abundant; these cells did not exhibit the endothelial cell polarization observed in the former phase. Also, throughout this avascular region, degenerating cells were common as noted by the electron dense vacuoles and cellular debris (Figure 4C).
are readily apparent at both the light and electron microscopic levels. For the convenience of presentation, three distinct phases of general transition from the normal to the avascular state are shown. Near the periphery of the avascular zone the CAM is hallmarked by an abundance of mitotic cells within all three germ layers (Figures 3A and 4A).
This enhanced mitotic division was also a consistent oberservation for capillary endothelial cells.
However, the endothelial cells remained junctionally intact with no extravasation of blood cells. With further degradation, the CAM is characterized by the breakdown and dissolution of capillaries (Figures 3B and 4B). The presumptive endothelial cells, typically arrested in mitosis, still maintain a close spatial relationship with blood cells and lie subjacent to the ectoderm; however, these cells are not junctionally linked. The most central portion of the avascular zone was characterized by a thickened ectodermal and endodermal layer (Figures 3C and 4C). Although these layers were thickened, the cellular junctions remained intact and the layers maintained their structural characteristics.
Within the mesoderm, scattered mitotically arrested cells were abundant; these cells did not exhibit the endothelial cell polarization observed in the former phase. Also, throughout this avascular region, degenerating cells were common as noted by the electron dense vacuoles and cellular debris (Figure 4C).
[0167] In summary, this study demonstrated that 48 hours after paclitaxel application to the CAM, angiogensis was inhibited. The blood vessel inhibition formed an avascular zone, which was represented by three transitional phases of paclitaxel's effect.
The central, most affected area of the avascular zone contained disrupted capillaries with extravasated red blood cells; this indicated that intercellular junctions between endothelial cells were absent. The cells of the endotherm and ectoderm maintained their intercellular juctions and therefore these germ layers remained intact; however, they were slightly thickened. As the normal vascular area was approached, the blood vessels retained their junctional complexes and therefore also remained intact. At the periphery of the paclitaxel-treated zone, further blood vessel growth was inhibited which was evident by the typical redirecting or "elbowing" effect of the blood vessels (Figure 24D).
The central, most affected area of the avascular zone contained disrupted capillaries with extravasated red blood cells; this indicated that intercellular junctions between endothelial cells were absent. The cells of the endotherm and ectoderm maintained their intercellular juctions and therefore these germ layers remained intact; however, they were slightly thickened. As the normal vascular area was approached, the blood vessels retained their junctional complexes and therefore also remained intact. At the periphery of the paclitaxel-treated zone, further blood vessel growth was inhibited which was evident by the typical redirecting or "elbowing" effect of the blood vessels (Figure 24D).
[0168] Paclitaxel-treated avascular zones also revealed an abundance of cells arrested in mitosis in all three germ layers of the CAM; this was unique to paclitaxel since no previous study has illustrated such an even. By being arrested in mitosis, endothelial cells could not undergo their normal metabolic functions involved in agiogenesis. In comparison, the avascular zone formed by suramin and cortisone acetate do not produce mitotically arrested cells in the CAM; they only prevented further blood vessel growth into the treated area. Therefore, even though agents are anti-angiogenic, there are many points in which the angiogenesis process may be targeted.
[0169] We also observed the effects of paclitaxel over the 48 hour duration and noticed that inhibition of angiogenesis occurs as early as 9 hours after application.
Histological sections revealed a similar morphology as seen in the first transition phase of the avascular zone at 48 hours illustrated in figure 3a and 4a. Also, we observed the revascularization process into the avascular zone previously observed. It has been found that the avascular zone formed by heparin and angiostatic steroids became revascularized 60 hours after application. In our study, paclitaxel-treated avascular zones did not revascularize for at least 7 days after application implying a more potent long-term effect.
Histological sections revealed a similar morphology as seen in the first transition phase of the avascular zone at 48 hours illustrated in figure 3a and 4a. Also, we observed the revascularization process into the avascular zone previously observed. It has been found that the avascular zone formed by heparin and angiostatic steroids became revascularized 60 hours after application. In our study, paclitaxel-treated avascular zones did not revascularize for at least 7 days after application implying a more potent long-term effect.
[0170] EXAMPLE 3
[0171] ENCAPSULATION OF SURAMIN
[0172] One milliliterof 5% ELVAX (poly(ethylene-vinyl acetate) cross-linked with 5%
vinyl acetate) in dicloromethane ("DCM") is mixed with a fixed weight of sub-micron ground sodium suramin. This mixture is injected into 5 ml of 5% Polyvinyl Alcohol ("PVA") in water in a 30 ml flat bottomed test tube. Tubes containing different weights of the drug are then suspended in a multi-sample water bath at 40 for 90 minutes with automated stirring. The mixes are removed, and microsphere samples taken for size analysis. Tubes are centrifuged at 1000g for 5 min. The PVA supernatant is removed and saved for analysis (nonencapsulated drug). The microspheres are then washed (vortexed) in 5 ml of water and recentrifuged. The 5 ml wash is saved for analysis (surface bound drug).
Microspheres are then wetted in 50 ul of methanol, and vortexed in 1 ml of DCM
to dissolve the ELVAX. The microspheres are then warmed to 40 C, and 5 ml of 50 C water is slowly added with stirring. This procedure results in the immediate evaporation of DCM, thereby causing the release of sodium suramin into the 5 ml of water. All three 5 ml samples were then assayed for drug content.
vinyl acetate) in dicloromethane ("DCM") is mixed with a fixed weight of sub-micron ground sodium suramin. This mixture is injected into 5 ml of 5% Polyvinyl Alcohol ("PVA") in water in a 30 ml flat bottomed test tube. Tubes containing different weights of the drug are then suspended in a multi-sample water bath at 40 for 90 minutes with automated stirring. The mixes are removed, and microsphere samples taken for size analysis. Tubes are centrifuged at 1000g for 5 min. The PVA supernatant is removed and saved for analysis (nonencapsulated drug). The microspheres are then washed (vortexed) in 5 ml of water and recentrifuged. The 5 ml wash is saved for analysis (surface bound drug).
Microspheres are then wetted in 50 ul of methanol, and vortexed in 1 ml of DCM
to dissolve the ELVAX. The microspheres are then warmed to 40 C, and 5 ml of 50 C water is slowly added with stirring. This procedure results in the immediate evaporation of DCM, thereby causing the release of sodium suramin into the 5 ml of water. All three 5 ml samples were then assayed for drug content.
[0173] Sodium suramin absorbs uv/vis with a lambda max of 312nm. The absorption is linear in the 0 to 100 ug/mi range in both water and 5% PVA. The drug fluoresces strongly with an excitation maximum at 312nm, and emission maximum at 400nm. This fluorescence is quantifiable in the 0 to 25 ug/ml range.
[0174] Results are shown in Figures 5-10. Briefly, the size distribution of microspheres appears to be unaffected by inclusion of the drug in the DCM (see Figures 5 and 6). Good yields of microspheres in the 20 to 60 pm range may be obtained.
[0175] The encapsulation of suramin is very low (<1 %) (see Figure 8). However as the weight of drug is increased in the DCM the total amount of drug encapsulated increased although the % encapsulation decreased. As is shown in Figure 7, 50ug of drug may be encapsulated in 50 mg of ELVAX. Encapsulation of sodium suramin in 5% PVA
containing 10% NaCI is shown in Figures 9-10.
containing 10% NaCI is shown in Figures 9-10.
[0176] EXAMPLE 4
[0177] ENCAPSULATION OF PACLITAXEL
[0178] Five hundred micrograms of either paclitaxel or baccatin (a paclitaxel analog, available from Inflazyme Pharmaceuticals Inc., Vancouver, British Columbia, Canada) are dissolved in 1 ml of a 50:50 ELVAX:poly-l-lactic acid mixture in dcm.
Microspheres are then prepared in a dissolution machine (Six-spindle dissolution tester, VanderKanp, Van Kell Industries Inc., U.S.A.) in triplicate at 200 rpm, 42 C, for 3 hours.
Microspheres so prepared are washed twice in water and sized on the microscope.
Microspheres are then prepared in a dissolution machine (Six-spindle dissolution tester, VanderKanp, Van Kell Industries Inc., U.S.A.) in triplicate at 200 rpm, 42 C, for 3 hours.
Microspheres so prepared are washed twice in water and sized on the microscope.
[0179] Determination of paclitaxel encapsulation is undertaken in a uv/vis assay (uv/vis lamda max. at 237 nm, fluorescence assay at excitation 237, emission at 325 nm;
Fluorescence results are presented in square brackets []). Utilizing the procedures described above, 58 pg (+/-12 pg) [75 pg (+/-25 pg)] of paclitaxel may be encapsulated from a total 500 pg of starting material. This represents 12% (+/-2.4%) [15%
(+/-5%)] of the original weight, or 1.2% (+/-0.25%) [1.5% (+/-0.5%)] by weight of the polymer. After 18 hours of tumbling in an oven at 37 C, 10.3% (+/-10%) [6% (+/-5.6%)] of the total paclitaxel had been released from the microspheres.
Fluorescence results are presented in square brackets []). Utilizing the procedures described above, 58 pg (+/-12 pg) [75 pg (+/-25 pg)] of paclitaxel may be encapsulated from a total 500 pg of starting material. This represents 12% (+/-2.4%) [15%
(+/-5%)] of the original weight, or 1.2% (+/-0.25%) [1.5% (+/-0.5%)] by weight of the polymer. After 18 hours of tumbling in an oven at 37 C, 10.3% (+/-10%) [6% (+/-5.6%)] of the total paclitaxel had been released from the microspheres.
[0180] For baccatin, 100 +/-15 pg [83 +/-23pg] of baccatin can be encapsulated from a total of 500 pg starting material. This represents a 20% (+/-3%) [17% (+/-5%) of the original weight of baccatin, and 2% (+/-0.3%) [1.7% (+/-0.5%)] by weight of the polymer.
After 18 hours of tumbling in an oven at 37 C, 55% (+/-13%) [60% (+/- 23%)] of the baccatin is released from the microspheres.
After 18 hours of tumbling in an oven at 37 C, 55% (+/-13%) [60% (+/- 23%)] of the baccatin is released from the microspheres.
[0181] EXAMPLE 5
[0182] ANALYSIS OF SURGICAL PASTE CONTAINING ANTI-ANGIOGENIC
COMPOSITIONS
COMPOSITIONS
[0183] Fisher rats weighing approximately 300 grams are anesthetized, and a 1 cm transverse upper abdominal incision is made. Two-tenths of a milliliter of saline containing 1 x 106 live 9L gliosarcoma cells (eluted immediately prior to use from tissue culture) are injected into 2 of the 5 hepatic lobes by piercing a 27 gauge needle 1 cm through the liver capsule. The abdominal wound is closed with 6.0 resorptible suture and skin clips and the GA terminated.
[0184] After 2 weeks, the tumor deposits will measure approximately 1 cm. At this time, both hepatic tumors are resected and the bare margin of the liver is packed with a hemostatic agent. The rats are divided into two groups: half is administered polymeric carrier alone, and the other half receives an anti-angiogenic composition.
[0185] Rats are sacrificed 2, 7, 14, 21 and 84 days post hepatic resection. In particular, the rats are euthanized by injecting EuthanylT"' into the dorsal vein of the tail.
The liver, spleen, and both lungs are removed, and histologic analysis is performed in order to study the tumors for evidence of anti-angiogenic activity.
The liver, spleen, and both lungs are removed, and histologic analysis is performed in order to study the tumors for evidence of anti-angiogenic activity.
[0186] EXAMPLE 6
[0187] EMBOLIZATION OF RAT ARTERIES
[0188] Fisher rats weighing approximately 300 grams are anesthetized.
Utilizing aseptic procedures, a 1 cm transverse upper abdominal incision is made, and the liver identified. Two-tenths of a milliliter of saline containing 1 million live 9L
gliosarcoma cells (eluted immediately prior from tissue culture) is injected into each of the 5 hepatic lobes by piercing a 27 gauge needle 1 cm through the liver capsule. One-tenth of a milliliter of normal saline is injected into the needle as it is withdrawn to ensure that there is no spillage of cells into the peritoneal cavity. A pledget of gelfoam is placed on each of the puncture sites to ensure hemostasis. The abdominal wound is closed with 6.0 resorptible suture with skin clips, and the anesthetic terminated. The rat is returned to the animal care facility to have a standard diet for 14 days, at which time each tumor deposit will measure 1 cm in diameter. The same procedure is repeated using Westar rats and a Colon Cancer cell line (Radiologic Oncology Lab, M.D. Anderson, Houston, Texas). In this instance, 3 weeks are required post-injection for the tumor deposits to measure 1 cm in diameter each.
Utilizing aseptic procedures, a 1 cm transverse upper abdominal incision is made, and the liver identified. Two-tenths of a milliliter of saline containing 1 million live 9L
gliosarcoma cells (eluted immediately prior from tissue culture) is injected into each of the 5 hepatic lobes by piercing a 27 gauge needle 1 cm through the liver capsule. One-tenth of a milliliter of normal saline is injected into the needle as it is withdrawn to ensure that there is no spillage of cells into the peritoneal cavity. A pledget of gelfoam is placed on each of the puncture sites to ensure hemostasis. The abdominal wound is closed with 6.0 resorptible suture with skin clips, and the anesthetic terminated. The rat is returned to the animal care facility to have a standard diet for 14 days, at which time each tumor deposit will measure 1 cm in diameter. The same procedure is repeated using Westar rats and a Colon Cancer cell line (Radiologic Oncology Lab, M.D. Anderson, Houston, Texas). In this instance, 3 weeks are required post-injection for the tumor deposits to measure 1 cm in diameter each.
[0189] After 2 or 3 weeks, depending on the rat species, the same general anesthetic procedure is followed and a midline abdominal incision is performed. The duodenum is fiipped and the gastroduodenal artery is identified and mobilized.
Ties are placed above and below a cutdown site on the midportion of the gastroduodenal artery (GDA), and 0.038 inch polyethylene tubing is introduced in a retrograde fashion into the artery using an operating microscope. The tie below the insertion point will ligate the artery, while the one above will fix the catheter in place. Angiography is performed by injecting 0.5 ml of 60% radiopaque contrast material through the catheter as an x-ray is taken. The hepatic artery is then embolized by refluxing particles measuring 15-200 pm through the gastroduodenal artery catheter until flow, observed via the operating microscope, is seen to cease for at least 30 seconds. Occlusion of the hepatic artery is confirmed by repeating an angiogram through the GDA catheter. Utilizing this procedure, one-half of the rats receive 15-200 pm particles of polymer alone, and the other half receive 15-200 pm particles of the polymer-anti-angiogenic factor composition.
The upper GDA ligature is tightened to occlude the GDA as the catheter is withdrawn to ensure hemostasis, and the hepatic artery (although embolized) is left intact. The abdomen is closed with 6.0 absorbable suture and surgical clips.
Ties are placed above and below a cutdown site on the midportion of the gastroduodenal artery (GDA), and 0.038 inch polyethylene tubing is introduced in a retrograde fashion into the artery using an operating microscope. The tie below the insertion point will ligate the artery, while the one above will fix the catheter in place. Angiography is performed by injecting 0.5 ml of 60% radiopaque contrast material through the catheter as an x-ray is taken. The hepatic artery is then embolized by refluxing particles measuring 15-200 pm through the gastroduodenal artery catheter until flow, observed via the operating microscope, is seen to cease for at least 30 seconds. Occlusion of the hepatic artery is confirmed by repeating an angiogram through the GDA catheter. Utilizing this procedure, one-half of the rats receive 15-200 pm particles of polymer alone, and the other half receive 15-200 pm particles of the polymer-anti-angiogenic factor composition.
The upper GDA ligature is tightened to occlude the GDA as the catheter is withdrawn to ensure hemostasis, and the hepatic artery (although embolized) is left intact. The abdomen is closed with 6.0 absorbable suture and surgical clips.
[0190] The rats are subsequently sacrificed at 2, 7, 14, 21 and 84 days post-embolization in order to determine efficacy of the anti-angiogenic factor.
Briefly, general anesthetic is given, and utilizing aseptic precautions, a midline incision performed. The GDA is mobilized again, and after placing a ligature near the junction of the GDA and the hepatic artery (i.e., well above the site of the previous cutdown), a 0.038-inch polyethylene tubing is inserted via cutdown of the vessel and angiography is performed. The rat is then euthanized by injecting Euthanyl into the dorsal vein of the tail. Once euthanasia is confirmed, the liver is removed en bloc along with the stomach, spleen and both lungs.
Briefly, general anesthetic is given, and utilizing aseptic precautions, a midline incision performed. The GDA is mobilized again, and after placing a ligature near the junction of the GDA and the hepatic artery (i.e., well above the site of the previous cutdown), a 0.038-inch polyethylene tubing is inserted via cutdown of the vessel and angiography is performed. The rat is then euthanized by injecting Euthanyl into the dorsal vein of the tail. Once euthanasia is confirmed, the liver is removed en bloc along with the stomach, spleen and both lungs.
[0191] Histologic analysis is performed on a prepared slide stained with hematoxylin and eosin ("H and E") stain. Briefly, the lungs are sectioned at 1 cm intervals to assess passage of embolic material through the hepatic veins and into the right side of circulation.
The stomach and spleen are also sectioned in order to assess inadvertent immobilization from reflux of particles into the celiac access of the collateral circulation.
The stomach and spleen are also sectioned in order to assess inadvertent immobilization from reflux of particles into the celiac access of the collateral circulation.
[0192] EXAMPLE 7
[0193] TRANSPLANTATION OF BILIARY STENTS IN RATS
[0194] General anesthetic is administered to 300 gram Fisher rats. A 1 cm transverse incision is then made in the upper abdomen, and the liver identified. In the most superficial lobe, 0.2 ml of saline containing 1 million cells of 9L
gliosarcoma cells (eluted from tissue culture immediately prior to use) is injected via a 27 gauge needle to a depth of 1 cm into the liver capsule. Hemostasis is achieved after removal of the needle by placing a pledget of gelfoam at the puncture sites. Saline is injected as the needle is removed to ensure no spillage of cells into the peritoneal cavity or along the needle track.
The general anesthetic is terminated, and the animal returned to the animal care center and placed on a normal diet.
gliosarcoma cells (eluted from tissue culture immediately prior to use) is injected via a 27 gauge needle to a depth of 1 cm into the liver capsule. Hemostasis is achieved after removal of the needle by placing a pledget of gelfoam at the puncture sites. Saline is injected as the needle is removed to ensure no spillage of cells into the peritoneal cavity or along the needle track.
The general anesthetic is terminated, and the animal returned to the animal care center and placed on a normal diet.
[0195] Two weeks later, general anesthetic is administered, and utilizing aseptic precautions, the hepatic lobe containing the tumor is identified through a midline incision.
A 16 gauge angiographic needle is then inserted through the hepatic capsule into the tumor, a 0.038-inch guidewire passed through the needle, and the needle withdrawn over the guidewire. A number 5 French dilator is passed over the guide into the tumor and withdrawn. A number 5 French delivery catheter is then passed over the wire containing a self-expanding stainless steel Wallstent (5 mm in diameter and 1 cm long).
The stent is deployed into the tumor and the guidewire delivery catheter is removed. One-third of the rats have a conventional stainless steel stent inserted into the tumor, one-third a stainless steel stent coated with polymer, and one third a stent coated with the polymer-anti-angiogenic factor compound. The general anesthetic is terminated and the rat returned to the animal care facility.
A 16 gauge angiographic needle is then inserted through the hepatic capsule into the tumor, a 0.038-inch guidewire passed through the needle, and the needle withdrawn over the guidewire. A number 5 French dilator is passed over the guide into the tumor and withdrawn. A number 5 French delivery catheter is then passed over the wire containing a self-expanding stainless steel Wallstent (5 mm in diameter and 1 cm long).
The stent is deployed into the tumor and the guidewire delivery catheter is removed. One-third of the rats have a conventional stainless steel stent inserted into the tumor, one-third a stainless steel stent coated with polymer, and one third a stent coated with the polymer-anti-angiogenic factor compound. The general anesthetic is terminated and the rat returned to the animal care facility.
[0196] A plain abdominal X-ray is performed at 2 days in order to assess the degree of stent opening. Rats are sacrificed at 2, 7, 14, 28 and 56 days post-stent insertion by injecting Euthanyl, and their livers removed en bloc once euthanasia is confirmed. After fixation in formaldehyde for 48 hours, the liver is sectioned at 0.5 mm intervals; including severing the stent transversely using a fresh blade for each slice. Histologic sections stained with H and E are then analyzed to assess the degree of tumor ingrowth into the stent lumen.
[0197] EXAMPLE 8
[0198] MANUFACTURE OF MICROSPHERES
[0199] Equipment which is preferred for the manufacture of microspheres described below include: 200 ml water jacketed beaker (KimaxTM' or PyrexT""), Haake.
circulating water bath, overhead stirrer and controller with 2 inch diameter (4 blade, propeller type stainless steel stirrer - Fisher brand), 500 ml glass beaker, hot plate/stirrer (CorningT"" brand), 4 X 50 ml polypropylene centrifuge tubes (NalgeneTM), glass scintillation vials with plastic insert caps, table top centrifuge (GPR Beckman), high speed centrifuge-floor model (JS 21 Beckman), Mettler analytical balance (AJ 100, 0.1 mg), Mettler digital top loading balance (AE 163, 0.01 mg), automatic pipetter (Gilson). Reagents include Polycaprolactone ("PCL" - mol wt 10,000 to 20,000; Polysciences, Warrington Pennsylvania, USA), "washed" Ethylene Vinyl Acetate ("EVA" washed so as to remove the anti-oxidant BHT), Poly(DL)Iactic acid ("PLA" - mol wt 15,000 to 25,000;
Polysciences), Polyvinyl Alcohol ("PVA" - mol wt 124,000 to 186,000; 99% hydrolyzed; Aldrich Chemical Co., Milwaukee WI, USA), Dichloromethane ("DCM" or "methylene chloride"; HPLC
grade Fisher Scientific), and distilled water.
circulating water bath, overhead stirrer and controller with 2 inch diameter (4 blade, propeller type stainless steel stirrer - Fisher brand), 500 ml glass beaker, hot plate/stirrer (CorningT"" brand), 4 X 50 ml polypropylene centrifuge tubes (NalgeneTM), glass scintillation vials with plastic insert caps, table top centrifuge (GPR Beckman), high speed centrifuge-floor model (JS 21 Beckman), Mettler analytical balance (AJ 100, 0.1 mg), Mettler digital top loading balance (AE 163, 0.01 mg), automatic pipetter (Gilson). Reagents include Polycaprolactone ("PCL" - mol wt 10,000 to 20,000; Polysciences, Warrington Pennsylvania, USA), "washed" Ethylene Vinyl Acetate ("EVA" washed so as to remove the anti-oxidant BHT), Poly(DL)Iactic acid ("PLA" - mol wt 15,000 to 25,000;
Polysciences), Polyvinyl Alcohol ("PVA" - mol wt 124,000 to 186,000; 99% hydrolyzed; Aldrich Chemical Co., Milwaukee WI, USA), Dichloromethane ("DCM" or "methylene chloride"; HPLC
grade Fisher Scientific), and distilled water.
[0200] A. Preparation of 5% (w/v) Polymer Solutions
[0201] Depending on the polymer solution being prepared, 1.00 g of PCL or PLA, or 0.50 g each of PLA and washed EVA is weighed directly into a 20 ml glass scintillation vial. Twenty milliliters of DCM is then added, and the vial tightly capped.
The vial is stored at room temperature (25 C) for one hour (occasional shaking may be used), or until all the polymer has dissolved (the solution should be clear). The solution may be stored at room temperature for at least two weeks.
The vial is stored at room temperature (25 C) for one hour (occasional shaking may be used), or until all the polymer has dissolved (the solution should be clear). The solution may be stored at room temperature for at least two weeks.
[0202] B. Preparation of 5% (w/v) Stock Solution of PVA
[0203] Twenty-five grams of PVA is weighed directly into a 600 ml glass beaker.
Five hundred milliliters of distilled water is added, along with a 3 inch TeflonTM coated stir bar. The beaker is covered with glass to decrease evaporation losses, and placed into a 2000 ml glass beaker containing 300 ml of water (which acts as a water bath).
The PVA is stirred at 300 rpm at 85 C (CorningT"" hot plate/stirrer) for 2 hours or until fully dissolved.
Dissolution of the PVA may be determined by a visual check; the solution should be clear.
The solution is then transferred to a glass screw top storage container and stored at 4 C
for a maximum of two months. The solution, however should be warmed to room temperature before use or dilution.
Five hundred milliliters of distilled water is added, along with a 3 inch TeflonTM coated stir bar. The beaker is covered with glass to decrease evaporation losses, and placed into a 2000 ml glass beaker containing 300 ml of water (which acts as a water bath).
The PVA is stirred at 300 rpm at 85 C (CorningT"" hot plate/stirrer) for 2 hours or until fully dissolved.
Dissolution of the PVA may be determined by a visual check; the solution should be clear.
The solution is then transferred to a glass screw top storage container and stored at 4 C
for a maximum of two months. The solution, however should be warmed to room temperature before use or dilution.
[0204] C. Procedure for Producing Microspheres
[0205] Based on the size of microspheres being made (see Table 1), 100 ml of the PVA solution (concentrations given in Table III) is placed into the 200 mi water jacketed beaker. Haake circulating water bath is connected to this beaker and the contents are allowed to equilibrate at 27 C (+/-10 C) for 10 minutes. Based on the size of microspheres being made (see Table III), the start speed of the overhead stirrer is set, and the blade of the overhead stirrer placed half way down in the PVA solution. The stirrer is then started, and 10 mi of polymer solution (polymer solution used based on type of microspheres being produced) is then dripped into the stirring PVA over a period of 2 minutes using a 5 ml automatic pipetter. After 3 minutes the stir speed is adjusted (see Table III), and the solution stirred for an additional 2.5 hours. The stirring blade is then removed from the microsphere preparation, and rinsed with 10 ml of distilled water so that the rinse solution drains into the microsphere preparation. The microsphere preparation is then poured into a 500 ml beaker, and the jacketed water bath washed with 70 ml of distilled water, which is also allowed to drain into the microsphere preparation. The 180 ml microsphere preparation is then stirred with a glass rod, and equal amounts are poured into four polypropylene 50 mi centrifuge tubes. The tubes are then capped, and centrifuged for 10 minutes (force given in Table 1). A 5 mi automatic pipetter or vacuum suction is then utilized to draw 45 ml of the PVA solution off of each microsphere pellet.
TABLE III
PVA concentrations, stir speeds, and centrifugal force requirements for each diameter range of microspheres.
PRODUCTION MICROSPHERE DIAMETER RANGES
STAGE 30 Nm to 100 Nm 10 Nm to 30 Nm 0.1 Nm to 3 Nm PVA 2.5% (w/v) (i.e., 5% (w/v) (i.e., 3.5% (w/v) (i.e., Concentration dilute 5% stock undiluted stock) dilute 5% stock with distilled water with distilled water Starting Stir 500 rpm 500 rpm 3000 rpm Speed +/- 50 rpm +/- 50 rpm +/- 200 rpm Adjusted Stir 500 rpm 500 rpm 2500 rpm Speed +/- 50 rpm +/- 50 rpm +/- 200 rpm Centrifuge Force 1000 g 1000 g 10 000 g +/-100g +/-100g +/-1000g (Table top model) (Table top model) (High speed model)
TABLE III
PVA concentrations, stir speeds, and centrifugal force requirements for each diameter range of microspheres.
PRODUCTION MICROSPHERE DIAMETER RANGES
STAGE 30 Nm to 100 Nm 10 Nm to 30 Nm 0.1 Nm to 3 Nm PVA 2.5% (w/v) (i.e., 5% (w/v) (i.e., 3.5% (w/v) (i.e., Concentration dilute 5% stock undiluted stock) dilute 5% stock with distilled water with distilled water Starting Stir 500 rpm 500 rpm 3000 rpm Speed +/- 50 rpm +/- 50 rpm +/- 200 rpm Adjusted Stir 500 rpm 500 rpm 2500 rpm Speed +/- 50 rpm +/- 50 rpm +/- 200 rpm Centrifuge Force 1000 g 1000 g 10 000 g +/-100g +/-100g +/-1000g (Table top model) (Table top model) (High speed model)
[0206] Five milliliters of distilled water is then added to each centrifuge tube, which is then vortexed to resuspend the microspheres. The four microsphere suspensions are then pooled into one centrifuge tube along with 20 ml of distilled water, and centrifuged for another 10 minutes (force given in Table 1). This process is repeated two additional times for a total of three washes. The microspheres are then centrifuged a final time, and resuspended in 10 ml of distilled water. After the final wash, the microsphere preparation is transferred into a preweighed glass scintillation vial. The vial is capped, and left overnight at room temperature (25 C) in order to allow the microspheres to sediment out under gravity. Microspheres which fall in the size range of 0.1 um to 3 um do not sediment out under gravity, so they are left in the 10 ml suspension.
[0207] D. Drying of 10 Nm to 30 Um or 30 um to 100 um Diameter Microspheres
[0208] After the microspheres have sat at room temperature overnight, a 5 ml automatic pipetter or vacuum suction is used to draw the supernatant off of the sedimented microspheres. The microspheres are allowed to dry in the uncapped vial in a drawer for a period of one week or until they are fully dry (vial at constant weight).
Faster drying may be accomplished by leaving the uncapped vial under a slow stream of nitrogen gas (flow approx. 10 m!/min.) in the fume hood. When fully dry (vial at constant weight), the vial is weighed and capped. The labelled, capped vial is stored at room temperature in a drawer.
Microspheres are normally stored no longer than 3 months.
Faster drying may be accomplished by leaving the uncapped vial under a slow stream of nitrogen gas (flow approx. 10 m!/min.) in the fume hood. When fully dry (vial at constant weight), the vial is weighed and capped. The labelled, capped vial is stored at room temperature in a drawer.
Microspheres are normally stored no longer than 3 months.
[0209] E. Drving of 0.1 um to 3 gm Diameter Microspheres This size range of microspheres will not sediment out, so they are left in suspension at 4 C
for a maximum of four weeks. To determine the concentration of microspheres in the 10 ml suspension, a 200 Ni sample of the suspension is pipetted into a 1.5 mi preweighed microfuge tube. The tube is then centrifuged at 10,000 g (Eppendorf table top microfuge), the supernatant removed, and the tube allowed to dry at 50 C overnight. The tube is then reweighed in order to determine the weight of dried microspheres within the tube.
for a maximum of four weeks. To determine the concentration of microspheres in the 10 ml suspension, a 200 Ni sample of the suspension is pipetted into a 1.5 mi preweighed microfuge tube. The tube is then centrifuged at 10,000 g (Eppendorf table top microfuge), the supernatant removed, and the tube allowed to dry at 50 C overnight. The tube is then reweighed in order to determine the weight of dried microspheres within the tube.
[0210] F. Manufacture of Paclitaxel Loaded Microsahere
[0211] In order to prepare paclitaxel containing microspheres, an appropriate amount of weighed paclitaxel (based upon the percentage of paclitaxel to be encapsulated) is placed directly into a 20 mi glass scintillation vial. Ten milliliters of an appropriate polymer solution is then added to the vial containing the paclitaxel, which is then vortexed until the paclitaxel has dissolved.
[0212] Microspheres containing paclitaxel may then be produced essentially as described above in steps (C) through (E).
[0213] EXAMPLE 9
[0214] MANUFACTURE OF STENT COATING
[0215] Reagents and equipment which are utilized within the following experiments include (medical grade stents obtained commercially from a variety of manufacturers; e.g., the "Strecker" stent) and holding apparatus, 20 mi glass scintillation vial with cap (plastic insert type), TLC atomizer, Nitrogen gas tank, glass test tubes (various sizes from 1 ml and up), glass beakers (various sizes), Pasteur pipette, tweezers, Polycaprolactone ("PCL" -mol wt 10,000 to 20,000; Polysciences), Paclitaxel (Sigma Chemical Co., St.
Louis, Mo., 95% purity), Ethylene vinyl acetate ("EVA" - washed - see previous), Poly(DL)Iactic acid ("PLA" - mol wt 15,000 to 25,000; Polysciences), dichloromethane ("DCM" - HPLC
grade, Fisher Scientific).
Louis, Mo., 95% purity), Ethylene vinyl acetate ("EVA" - washed - see previous), Poly(DL)Iactic acid ("PLA" - mol wt 15,000 to 25,000; Polysciences), dichloromethane ("DCM" - HPLC
grade, Fisher Scientific).
[0216] A. Procedure for Sprayed Stents
[0217] The following describes a typical method using a 3 mm crimped diameter interleaving metal wire stent of approximately 3 cm length. For larger diameter stents, larger volumes of polymer/drug solution are used.
[0218] Weigh sufficient polymer directly into a 20 ml glass scintillation vial and add sufficient DCM to achieve a 2% w/v solution. Cap the vial and mix the solution to dissolve the polymer (hand shaking). Assemble the stent in a vertical orientation. This can be accomplished using a piece of nylon and tying the stent to a retort stand.
Position this stent holding apparatus 6 to 12 inches above the fume hood floor on a suitable support (e.g., inverted 2000 ml glass beaker) to enable horizontal spraying. Using an automatic pipette, transfer a suitable volume (minimum 5 ml) of the 2% polymer solution to a separate 20 ml glass scintillation vial. Add an appropriate amount of paclitaxel to the solution and dissolve it by hand shaking the capped vial.
Position this stent holding apparatus 6 to 12 inches above the fume hood floor on a suitable support (e.g., inverted 2000 ml glass beaker) to enable horizontal spraying. Using an automatic pipette, transfer a suitable volume (minimum 5 ml) of the 2% polymer solution to a separate 20 ml glass scintillation vial. Add an appropriate amount of paclitaxel to the solution and dissolve it by hand shaking the capped vial.
[0219] To prepare for spraying, remove the cap of this vial and dip the barrel (only) of an TLC atomizer into the polymer solution. Note that the reservoir of the atomizer need not be used in this procedure: the 20 ml glass vial acts as a reservoir.
Connect the nitrogen tank to the gas inlet of the atomizer. Gradually increase the pressure until atomization and spraying begins. Note the pressure and use this pressure throughout the procedure. To spray the stent use 5 second oscillating sprays with a 15 second dry time between sprays. After 5 sprays, rotate the stent 90 and spray that portion of the stent.
Repeat until all sides of the stent have been sprayed. During the dry time, finger crimp the gas line to avoid wastage of the spray. Spraying is continued until a suitable amount of polymer is deposited on the stents. The amount may be based on the specific stent application in vivo. To determine the amount, weigh the stent after spraying has been completed and the stent has dried. Subtract the original weight of the stent from the finished weight and this produces the amount of polymer (plus paclitaxel) applied to the stent. Store the coated stent in a sealed container.
Connect the nitrogen tank to the gas inlet of the atomizer. Gradually increase the pressure until atomization and spraying begins. Note the pressure and use this pressure throughout the procedure. To spray the stent use 5 second oscillating sprays with a 15 second dry time between sprays. After 5 sprays, rotate the stent 90 and spray that portion of the stent.
Repeat until all sides of the stent have been sprayed. During the dry time, finger crimp the gas line to avoid wastage of the spray. Spraying is continued until a suitable amount of polymer is deposited on the stents. The amount may be based on the specific stent application in vivo. To determine the amount, weigh the stent after spraying has been completed and the stent has dried. Subtract the original weight of the stent from the finished weight and this produces the amount of polymer (plus paclitaxel) applied to the stent. Store the coated stent in a sealed container.
[0220] B. Procedure for Dipped Stents
[0221] The following describes a typical method using a 3 mm crimped diameter interleaving metal wire stent of approximately 3 cm length. For larger diameter stents, larger volumes of polymer/drug solution are used in larger sized test tubes.
[0222] Weigh 2 g of EVA into a 20 ml glass scintillation vial and add 20 ml of DCM.
Cap the vial and leave it for 2 hours to dissolve (hand shake the vial frequently to assist the dissolving process). Weigh a known weight of paclitaxel directly into a I ml glass test tube and add 0.5 ml of the polymer solution. Using a glass Pasteur pipette, dissolve the paclitaxel by gently pumping the polymer solution. Once the paclitaxel is dissolved, hold the test tube in a near horizontal position (the sticky polymer solution will not flow out).
Using tweezers, insert the stent into the tube all the way to the bottom.
Allow the polymer solution to flow almost to the mouth of the test tube by angling the mouth below horizontal and then restoring the test tube to an angle slightly above the horizontal.
While slowly rotating the stent in the tube, slowly remove the stent (approximately 30 seconds).
Cap the vial and leave it for 2 hours to dissolve (hand shake the vial frequently to assist the dissolving process). Weigh a known weight of paclitaxel directly into a I ml glass test tube and add 0.5 ml of the polymer solution. Using a glass Pasteur pipette, dissolve the paclitaxel by gently pumping the polymer solution. Once the paclitaxel is dissolved, hold the test tube in a near horizontal position (the sticky polymer solution will not flow out).
Using tweezers, insert the stent into the tube all the way to the bottom.
Allow the polymer solution to flow almost to the mouth of the test tube by angling the mouth below horizontal and then restoring the test tube to an angle slightly above the horizontal.
While slowly rotating the stent in the tube, slowly remove the stent (approximately 30 seconds).
[0223] Hold the stent in a vertical position to dry. Some of the sealed perforations may pop so that a hole exists in the continuous sheet of polymer. This may be remedied by repeating the previous dipping procedure, however repetition of the procedure can also lead to further popping and a general uneven build up of polymer. Generally, it is better to dip the stent just once and to cut out a section of stent that has no popped perforations.
Store the dipped stent in a sealed container.
Store the dipped stent in a sealed container.
[0224] EXAMPLE 10
[0225] MANUFACTURE OF SURGICAL "PASTES"
[0226] As noted above, the present invention provides a variety of polymeric-containing drug compositions that may be utilized within a variety of clinical situations. For example, compositions may be produced: (1) as a "thermopaste" that is applied to a desired site as a fluid, and hardens to a solid of the desired shape at a specified temperature (e.g., body temperature); (2) as a spray (i.e., "nanospray") which may delivered to a desired site either directly or through a specialized apparatus (e.g., endoscopy), and which subsequently hardens to a solid which adheres to the tissue to which it is applied; (3) as an adherent, pliable, resilient, angiogeneis inhibitor-polymer film applied to a desired site either directly or through a specialized apparatus, and which preferably adheres to the site to which it is applied; and (4) as a fluid composed of a suspension of microspheres in an appropriate carrier medium, which is applied to a desired site either directly or via a specialized apparatus, and which leaves a layer of microspheres at the application site. Representative examples of each of the above embodiments is set forth in more detail below.
[0227] A. Procedure for Producing Thermopaste
[0228] Reagents and equipment which are utilized within the following experiments include a sterile glass syringe (1 ml), CorningT"' hot plate/stirrer, 20 ml glass scintillation vial, moulds (e.g., 50 NI DSC pan or 50 ml centrifuge tube cap inner portion), scalpel and tweezers, Polycaprolactone ("PCL" - mol wt 10,000 to 20,000; Polysciences, Warrington, Pennsylvania USA), and Paclitaxel (Sigma grade 95% purity minimum).
[0229] Weigh 5.00 g of polycaprolactone directly into a 20 ml glass scintillation vial.
Place the vial in a 600 ml beaker containing 50 ml of water. Gently heat the beaker to 65 C
and hold it at that temperature for 20 minutes. This allows the polymer to melt. Thoroughly mix a known weight of paclitaxel, or other angiogenesis inhibitor into the melted polymer at 65 C. Pour the melted polymer into a prewarmed (60 C oven) mould. Use a spatula to assist with the pouring process. Allow the mould to cool so the polymer solidifies. Cut or break the polymer into small pieces (approximately 2 mm by 2 mm in size).
These pieces must fit into a 1 ml glass syringe. Remove the plunger from the 1 ml glass syringe (do not remove the cap from the tip) and place it on a balance. Zero the balance.
Place the vial in a 600 ml beaker containing 50 ml of water. Gently heat the beaker to 65 C
and hold it at that temperature for 20 minutes. This allows the polymer to melt. Thoroughly mix a known weight of paclitaxel, or other angiogenesis inhibitor into the melted polymer at 65 C. Pour the melted polymer into a prewarmed (60 C oven) mould. Use a spatula to assist with the pouring process. Allow the mould to cool so the polymer solidifies. Cut or break the polymer into small pieces (approximately 2 mm by 2 mm in size).
These pieces must fit into a 1 ml glass syringe. Remove the plunger from the 1 ml glass syringe (do not remove the cap from the tip) and place it on a balance. Zero the balance.
[0230] WeighØ5 g of the pieces directly into the open end of the syringe.
Place the glass syringe upright (capped tip downwards) into a 500 ml glass beaker containing distilled water at 65'C (CorningT"" hot plate) so that no water enters the barrel. The polymer melts completely within 10 minutes in this apparatus. When the polymer pieces have melted, remove the barrel from the water bath, hold it horizontally and remove the cap. Insert the plunger into the barrel and compress the melted polymer into a sticky mass at the tip end of the barrel. Cap the syringe and allow it to cool to room temperature.
Place the glass syringe upright (capped tip downwards) into a 500 ml glass beaker containing distilled water at 65'C (CorningT"" hot plate) so that no water enters the barrel. The polymer melts completely within 10 minutes in this apparatus. When the polymer pieces have melted, remove the barrel from the water bath, hold it horizontally and remove the cap. Insert the plunger into the barrel and compress the melted polymer into a sticky mass at the tip end of the barrel. Cap the syringe and allow it to cool to room temperature.
[0231] For application, the syringe may be reheated to 60 C and administered as a liquid which solidifies when cooled to body temperature.
[0232] B. Procedure for Producing Nanospray
[0233] Nanospray is a suspension of small microspheres in saline. If the microspheres are very small (i.e., under 1 pm in diameter) they form a colloid so that the suspension will not sediment under gravity. As is described in more detail below, a suspension of 0.1 Nm to 1 Nm microparticies may be created suitable for deposition onto tissue through a finger pumped aerosol. Equipment and materials which may be utilized to produce nanospray include 200 ml water jacketed beaker (KimaxT" or PyrexT""), Haake circulating water bath, overhead stirrer and controller with 2 inch diameter (4 blade, propeller type stainless steel stirrer; Fisher brand), 500 ml glass beaker, hot plate/stirrer (CorningTM brand), 4X50 ml polypropylene centrifuge tubes (NalgeneTM), glass scintillation vials with plastic insert caps, table top centrifuge (Beckman), high speed centrifuge - floor model (JS 21 Beckman), Mettler analytical balance (AJ 100, 0.1 mg), Mettler digital top loading balance (AE 163, 0.01 mg), automatic pipetter (Gilson), sterile pipette tips, pump action aerosol (Pfeiffer pharmaceuticals) 20 ml, laminar flow hood, Polycaprolactone ("PCL"
- mol wt 10,000 to 20,000; Polysciences, Warrington, Pennsylvania USA), "washed" (see previous) Ethylene Vinyl Acetate ("EVA"), Poly(DL)Iactic acid ("PLA" mol wt 15,000 to 25,000; Polysciences), Polyvinyl Alcohol ("PVA" - mol wt 124,000 to 186,000;
99%
hydrolyzed; Aldrich Chemical Co., Milwaukee, WI USA), Dichloromethane ("DCM"
or "methylene chloride;" HPLC grade Fisher scientific), Distilled water, sterile saline (Becton and Dickenson or equivalent)
- mol wt 10,000 to 20,000; Polysciences, Warrington, Pennsylvania USA), "washed" (see previous) Ethylene Vinyl Acetate ("EVA"), Poly(DL)Iactic acid ("PLA" mol wt 15,000 to 25,000; Polysciences), Polyvinyl Alcohol ("PVA" - mol wt 124,000 to 186,000;
99%
hydrolyzed; Aldrich Chemical Co., Milwaukee, WI USA), Dichloromethane ("DCM"
or "methylene chloride;" HPLC grade Fisher scientific), Distilled water, sterile saline (Becton and Dickenson or equivalent)
[0234] 1. Preparation of 5% (w/v) Polymer Solutions
[0235] Depending on the polymer solution being prepared, weigh 1.00 g of PCL
or PLA or 0.50 g each of PLA and washed EVA directly into a 20 ml glass scintillation vial.
Using a measuring cylinder, add 20 ml of DCM and tightly cap the vial. Leave the vial at room temperature (25 C) for one hour or until all the polymer has dissolved (occasional hand shaking may be used). Dissolving of the polymer can be determined by a visual check; the solution should be clear. Label the vial with the name of the solution and the date it was produced. Store the solutions at room temperature and use within two weeks.
or PLA or 0.50 g each of PLA and washed EVA directly into a 20 ml glass scintillation vial.
Using a measuring cylinder, add 20 ml of DCM and tightly cap the vial. Leave the vial at room temperature (25 C) for one hour or until all the polymer has dissolved (occasional hand shaking may be used). Dissolving of the polymer can be determined by a visual check; the solution should be clear. Label the vial with the name of the solution and the date it was produced. Store the solutions at room temperature and use within two weeks.
[0236] 2. Preparation of 3.5% (w/v) Stock Solution of PVA
[0237] The solution can be prepared by following the procedure given below, or by diluting the 5% (w/v) PVA stock solution prepared for production of microspheres (see Example 8). Briefly, 17.5 g of PVA is weighed directly into a 600 ml glass beaker, and 500 ml of distilled water is added. Place a 3 inch TeflonTM coated stir bar in the beaker. Cover the beaker with a cover glass to reduce evaporation losses. Place the beaker in a 2000 ml glass beaker containing 300 ml of water. This will act as a water bath.
Stir the PVA at 300 rpm at 85 C (CorningTM hot plate/stirrer) for 2 hours or until fully dissolved. Dissolving of the PVA can be determined by a visual check; the solution should be clear.
Use a pipette to transfer the solution to a glass screw top storage container and store at 4 C for a maximum of two months. This solution should be warmed to room temperature before use or dilution.
Stir the PVA at 300 rpm at 85 C (CorningTM hot plate/stirrer) for 2 hours or until fully dissolved. Dissolving of the PVA can be determined by a visual check; the solution should be clear.
Use a pipette to transfer the solution to a glass screw top storage container and store at 4 C for a maximum of two months. This solution should be warmed to room temperature before use or dilution.
[0238] 3. Procedure for Producing Nanospray
[0239] Place the stirring assembly in a fume hood. Place 100 ml of the 3.5%
PVA
solution in the 200 ml water jacketed beaker. Connect the Haake water bath to this beaker and allow the contents to equilibrate at 27 C (+/-1'C) for 10 minutes. Set the start speed of the overhead stirrer at 3000 rpm (+/- 200 rpm). Place the blade of the overhead stirrer half way down in the PVA solution and start the stirrer. Drip 10 ml of polymer solution (polymer solution used based on type of nanospray being produced) into the stirring PVA
over a period of 2 minutes using a 5 ml automatic pipetter. After 3 minutes, adjust the stir speed to 2500 rpm (+/- 200 rpm) and leave the assembly for 2.5 hours. After 2.5 hours, remove the stirring blade from the nanospray preparation and rinse with 10 ml of distilled water. Allow the rinse solution to go into the nanospray preparation.
PVA
solution in the 200 ml water jacketed beaker. Connect the Haake water bath to this beaker and allow the contents to equilibrate at 27 C (+/-1'C) for 10 minutes. Set the start speed of the overhead stirrer at 3000 rpm (+/- 200 rpm). Place the blade of the overhead stirrer half way down in the PVA solution and start the stirrer. Drip 10 ml of polymer solution (polymer solution used based on type of nanospray being produced) into the stirring PVA
over a period of 2 minutes using a 5 ml automatic pipetter. After 3 minutes, adjust the stir speed to 2500 rpm (+/- 200 rpm) and leave the assembly for 2.5 hours. After 2.5 hours, remove the stirring blade from the nanospray preparation and rinse with 10 ml of distilled water. Allow the rinse solution to go into the nanospray preparation.
[0240] Pour the microsphere preparation into a 500 ml beaker. Wash the jacketed water bath with 70 mi of distilled water. Allow the 70 ml rinse solution to go into the microsphere preparation. Stir the 180 ml microsphere preparation with a glass rod and pour equal amounts of it into four polypropylene 50 mi centrifuge tubes. Cap the tubes.
Centrifuge the capped tubes at 10 000 g(+/- 1000 g) for 10 minutes. Using a 5 ml automatic pipetter or vacuum suction, draw 45 ml of the PVA solution off of each microsphere pellet and discard it. Add 5 ml of distilled water to each centrifuge tube and use a vortex to resuspend the microspheres in each tube. Using 20 ml of distilled water, pool the four microsphere suspensions into one centrifuge tube. To wash the microspheres, centrifuge the nanospray preparation for 10 minutes at 10 000 g(+/- 1000 g). Draw the supernatant off of the microsphere pellet. Add 40 ml of distilled water and use a vortex to resuspend the microspheres. Repeat this process two more times for a total of three washes. Do a fourth wash but use only 10 ml (not 40 ml) of distilled water when resuspending the microspheres. After the fourth wash, transfer the microsphere preparation into a preweighed glass scintillation vial.
Centrifuge the capped tubes at 10 000 g(+/- 1000 g) for 10 minutes. Using a 5 ml automatic pipetter or vacuum suction, draw 45 ml of the PVA solution off of each microsphere pellet and discard it. Add 5 ml of distilled water to each centrifuge tube and use a vortex to resuspend the microspheres in each tube. Using 20 ml of distilled water, pool the four microsphere suspensions into one centrifuge tube. To wash the microspheres, centrifuge the nanospray preparation for 10 minutes at 10 000 g(+/- 1000 g). Draw the supernatant off of the microsphere pellet. Add 40 ml of distilled water and use a vortex to resuspend the microspheres. Repeat this process two more times for a total of three washes. Do a fourth wash but use only 10 ml (not 40 ml) of distilled water when resuspending the microspheres. After the fourth wash, transfer the microsphere preparation into a preweighed glass scintillation vial.
[0241] Cap the vial and let it to sit for 1 hour at room temperature (25 C) to allow the 2 pm and 3 pm diameter microspheres to sediment out under gravity. After 1 hour, draw off the top 9 mi of suspension using a 5 mi automatic pipetter. Place the 9 ml into a sterile capped 50 ml centrifuge tube. Centrifuge the suspension at 10 000 g(+/-1000 g) for 10 minutes. Discard the supernatant and resuspend the pellet in 20 ml of sterile saline.
Centrifuge the suspension at 10 000 g(+/-1000 g) for 10 minutes. Discard the supernatant and resuspend the pellet in sterile saline. The quantity of saline used is dependent on the final required suspension concentration (usually 10% w/v). Thoroughly rinse the aerosol apparatus in sterile saline and add the nanospray suspension to the aerosol.
Centrifuge the suspension at 10 000 g(+/-1000 g) for 10 minutes. Discard the supernatant and resuspend the pellet in sterile saline. The quantity of saline used is dependent on the final required suspension concentration (usually 10% w/v). Thoroughly rinse the aerosol apparatus in sterile saline and add the nanospray suspension to the aerosol.
[0242] C. Manufacture of Paclitaxel Loaded Nanospray
[0243] To manufacture nanospray containing paclitaxel, use Paclitaxel (Sigma grade 95% purity). To prepare the polymer drug stock solution, weigh the appropriate amount of paclitaxel directly into a 20 ml glass scintillation vial. The appropriate amount is determined based on the percentage of paclitaxel to be in the nanospray. For example, if nanospray containing 5% paclitaxel was required, then the amount of paclitaxel weighed would be 25 mg since the amount of polymer added is 10 ml of a 5% polymer in DCM
solution (see next step).
Add 10 ml of the appropriate 5% polymer solution to the vial containing the paclitaxel. Cap the vial and vortex or hand swirl it to dissolve the paclitaxel (visual check to ensure paclitaxel dissolved). Label the vial with the date it was produced. This is to be used the day it is produced.
solution (see next step).
Add 10 ml of the appropriate 5% polymer solution to the vial containing the paclitaxel. Cap the vial and vortex or hand swirl it to dissolve the paclitaxel (visual check to ensure paclitaxel dissolved). Label the vial with the date it was produced. This is to be used the day it is produced.
[0244] Follow the procedures as described above, except that polymer/drug (e.g., paclitaxel) stock solution is substituted for the polymer solution.
[0245] D. Procedure for Producing Film
[0246] The term film refers to a polymer formed into one of many geometric shapes.
The film may be a thin, elastic sheet of polymer or a 2 mm thick disc of polymer. This film is designed to be placed on exposed tissue so that any encapsulated drug is released from the polymer over a long period of time at the tissue site. Films may be made by several processes, including for example, by casting, and by spraying.
The film may be a thin, elastic sheet of polymer or a 2 mm thick disc of polymer. This film is designed to be placed on exposed tissue so that any encapsulated drug is released from the polymer over a long period of time at the tissue site. Films may be made by several processes, including for example, by casting, and by spraying.
[0247] In the casting technique, polymer is either melted and poured into a shape or dissolved in dichloromethane and poured into a shape. The polymer then either solidifies as it cools or solidifies as the solvent evaporates, respectively.
In the spraying technique, the polymer is dissolved in solvent and sprayed onto glass, as the solvent evaporates the polymer solidifies on the glass. Repeated spraying enables a build up of polymer into a film that can be peeled from the glass.
In the spraying technique, the polymer is dissolved in solvent and sprayed onto glass, as the solvent evaporates the polymer solidifies on the glass. Repeated spraying enables a build up of polymer into a film that can be peeled from the glass.
[0248] Reagents and equipment which were utilized within these experiments include a small beaker, CorningT"" hot plate stirrer, casting moulds (e.g., 50 ml centrifuge tube caps) and mould holding apparatus, 20 ml glass scintillation vial with cap (Plastic insert type), TLC atomizer, Nitrogen gas tank, Polycaprol8actone ("PCL" - mol wt 10,000 to 20,000; Polysciences), Paclitaxel (Sigma 95% purity), Ethanol, "washed"
(see previous) Ethylene vinyl acetate ("EVA"), Poly(DL)lactic acid ("PLA" - mol wt 15,000 to 25,000;
Polysciences), Dichloromethane (HPLC grade Fisher Scientific).
(see previous) Ethylene vinyl acetate ("EVA"), Poly(DL)lactic acid ("PLA" - mol wt 15,000 to 25,000;
Polysciences), Dichloromethane (HPLC grade Fisher Scientific).
[0249] 1. Procedure for Producing Films - Melt Casting
[0250] Weigh a known weight of PCL directly into a small glass beaker. Place the beaker in a larger beaker containing water (to act as a water bath) and put it on the hot plate at 70 C for 15 minutes or until the polymer has fully melted. Add a known weight of drug to the melted polymer and stir the mixture thoroughly. To aid dispersion of the drug in the melted PCL, the drug may be suspended/dissolved in a small volume (<10%
of the volume of the melted PCL) of 100% ethanol. This ethanol suspension is then mixed into the melted polymer. Pour the melted polymer into a mould and let it to cool.
After cooling, store the film in a container.
of the volume of the melted PCL) of 100% ethanol. This ethanol suspension is then mixed into the melted polymer. Pour the melted polymer into a mould and let it to cool.
After cooling, store the film in a container.
[0251] 2. Procedure for Producing Films - Solvent Casting
[0252] Weigh a known weight of PCL directly into a 20 mi glass scintillation vial and add sufficient DCM to achieve a 10% w/v solution. Cap the vial and mix the solution. Add sufficient paclitaxel to the solution to achieve the desired final paclitaxel concentration.
Use hand shaking or vortexing to dissolve the paclitaxel in the solution. Let the solution sit for one hour (to diminish the presence of air bubbles) and then pour it slowly into a mould. The mould used is based on the shape required. Place the mould in the fume hood overnight. This will allow the DCM to evaporate. Either leave the film in the mould to store it or peel it out and store it in a sealed container.
Use hand shaking or vortexing to dissolve the paclitaxel in the solution. Let the solution sit for one hour (to diminish the presence of air bubbles) and then pour it slowly into a mould. The mould used is based on the shape required. Place the mould in the fume hood overnight. This will allow the DCM to evaporate. Either leave the film in the mould to store it or peel it out and store it in a sealed container.
[0253] 3. Procedure for Producing Films - Sprayed
[0254] Weigh sufficient polymer directly into a 20 ml glass scintillation vial and add sufficient DCM to achieve a 2% w/v solution. Cap the vial and mix the solution to dissolve the polymer (hand shaking). Assemble the moulds in a vertical orientation in a suitable mould holding apparatus in the fume hood. Position this mould holding apparatus 6 to 12 inches above the fume hood floor on a suitable support (e.g., inverted 2000 ml glass beaker) to enable horizontal spraying. Using an automatic pipette, transfer a suitable volume (minimum 5 ml) of the 2% polymer solution to a separate 20 mi glass scintillation vial. Add sufficient paclitaxel to the solution and dissolve it by hand shaking the capped vial. To prepare for spraying, remove the cap of this vial and dip the barrel (only) of an TLC
atomizer into the polymer solution. Note: the reservoir of the atomizer is not used in this procedure - the 20 ml glass vial acts as a reservoir.
atomizer into the polymer solution. Note: the reservoir of the atomizer is not used in this procedure - the 20 ml glass vial acts as a reservoir.
[0255] Connect the nitrogen tank to the gas inlet of the atomizer. Gradually increase the pressure until atomization and spraying begins. Note the pressure and use this pressure throughout the procedure. To spray the moulds use 5 second oscillating sprays with a 15 second dry time between sprays. During the dry time, finger crimp the gas line to avoid wastage of the spray. Spraying is continued until a suitable thickness of polymer is deposited on the mould. The thickness is based on the request.
Leave the sprayed films attached to the moulds and store in sealed containers.
Leave the sprayed films attached to the moulds and store in sealed containers.
[0256] E. Procedure for Producing Nanopaste
[0257] Nanopaste is a suspension of microspheres suspended in a hydrophilic gel.
Within one aspect of the invention, the gel or paste can be smeared over tissue as a method of locating drug loaded microspheres close to the target tissue. Being water based, the paste will soon become diluted with bodily fluids causing a decrease in the stickiness of the paste and a tendency of the microspheres to be deposited on nearby tissue. A pool of microsphere encapsulated drug is thereby located close to the target tissue.
Within one aspect of the invention, the gel or paste can be smeared over tissue as a method of locating drug loaded microspheres close to the target tissue. Being water based, the paste will soon become diluted with bodily fluids causing a decrease in the stickiness of the paste and a tendency of the microspheres to be deposited on nearby tissue. A pool of microsphere encapsulated drug is thereby located close to the target tissue.
[0258] Reagents and equipment which were utilized within these experiments include glass beakers, CarbopolT"" 925 (pharmaceutical grade, Goodyear Chemical Co.), distilled water, sodium hydroxide (1 M) in water solution, sodium hydroxide solution (5 M) in water solution, microspheres in the 0.1 pm to 3 pm size range suspended in water at 20% w/v (See previous).
[0259] 1. Preparation of 5% w/v CarbopolT"" Gel
[0260] Add a sufficient amount of CarbopolT"" to 1 M sodium hydroxide to achieve a 5% wlv solution. To dissolve the CarbopolT"" in the 1 M sodium hydroxide, allow the mixture to sit for approximately one hour. During this time period, stir the mixture using a glass rod. After one hour, take the pH of the mixture. A low pH indicates that the CarbopolTM is not fully dissolved. The pH you want to achieve is 7.4. Use 5 M
sodium hydroxide to adjust the pH. This is accomplished by slowly adding drops of 5 M
sodium hydroxide to the mixture, stirring the mixture and taking the pH of the mixture. It usually takes approximately one hour to adjust the pH to 7.4. Once a pH of 7.4 is achieved, cover the gel and let it sit for 2 to 3 hours. After this time period, check the pH
to ensure it is still at 7.4. If it has changed, adjust back to pH 7.4 using 5 M sodium hydroxide.
Allow the gel to sit for a few hours to ensure the pH is stable at 7.4. Repeat the process until the desired pH is achieved and is stable. Label the container with the name of the gel and the date.
The gel is to be used to make nanopaste within the next week.
sodium hydroxide to adjust the pH. This is accomplished by slowly adding drops of 5 M
sodium hydroxide to the mixture, stirring the mixture and taking the pH of the mixture. It usually takes approximately one hour to adjust the pH to 7.4. Once a pH of 7.4 is achieved, cover the gel and let it sit for 2 to 3 hours. After this time period, check the pH
to ensure it is still at 7.4. If it has changed, adjust back to pH 7.4 using 5 M sodium hydroxide.
Allow the gel to sit for a few hours to ensure the pH is stable at 7.4. Repeat the process until the desired pH is achieved and is stable. Label the container with the name of the gel and the date.
The gel is to be used to make nanopaste within the next week.
[0261] 2. Procedure for Producing Nanopaste
[0262] Add sufficient 0.1 pm to 3/im microspheres to water to produce a 20%
suspension of the microspheres. Put 8 ml of the 5% w/v CarbopolT"" gel in a glass beaker.
Add 2 ml of the 20% microsphere suspension to the beaker. Using a glass rod or a mixing spatula, stir the mixture to thoroughly disperse the microspheres throughout the gel. This usually takes 30 minutes. Once the microspheres are dispersed in the gel, place the mixture in a storage jar. Store the jar at 4 C. It must be used within a one month period.
suspension of the microspheres. Put 8 ml of the 5% w/v CarbopolT"" gel in a glass beaker.
Add 2 ml of the 20% microsphere suspension to the beaker. Using a glass rod or a mixing spatula, stir the mixture to thoroughly disperse the microspheres throughout the gel. This usually takes 30 minutes. Once the microspheres are dispersed in the gel, place the mixture in a storage jar. Store the jar at 4 C. It must be used within a one month period.
[0263] EXAMPLE 11
[0264] CONTROLLED DELIVERY OF PACLITAXEL FROM MICROSPHERES
COMPOSED OF A BLEND OF ETHYLENE-VINYL-ACETATE COPOLYMER AND POLY
(D,L LACTIC ACID). IN VIVO TESTING OF THE MICROSPHERES ON THE CAM ASSA
COMPOSED OF A BLEND OF ETHYLENE-VINYL-ACETATE COPOLYMER AND POLY
(D,L LACTIC ACID). IN VIVO TESTING OF THE MICROSPHERES ON THE CAM ASSA
[0265] This example describes the preparation of paclitaxel-loaded microspheres composed of a blend of biodegradable poly (d,l-lactic acid) (PLA) polymer and nondegradable ethylene-vinyl acetate (EVA) copolymer. In addition, the in vitro release rate and anti-angiogenic activity of paclitaxel released from microspheres placed on a CAM
are demonstrated.
are demonstrated.
[0266] Reagents which were utilized in these experiments include paclitaxel, which is purchased from Sigma Chemical Co. (St. Louis, MO); PLA (molecular weight 15,000-25,000) and EVA (60% vinyl acetate) (purchased from Polysciences (Warrington, PA);
polyvinyl alcohol (PVA) (molecular weight 124,000-186,000, 99% hydrolysed, purchased from Aldrich Chemical Co. (Milwaukee, WI)) and Dichloromethane (DCM) (HPLC
grade, obtained from Fisher Scientific Co). Distilled water is used throughout.
polyvinyl alcohol (PVA) (molecular weight 124,000-186,000, 99% hydrolysed, purchased from Aldrich Chemical Co. (Milwaukee, WI)) and Dichloromethane (DCM) (HPLC
grade, obtained from Fisher Scientific Co). Distilled water is used throughout.
[0267] A. Preparation of microspheres
[0268] Microspheres are prepared essentially as described in Example 8 utilizing the solvent evaporation method. Briefly, 5% w/v polymer solutions in 20 mL DCM
are prepared using blends of EVA:PLA between 35:65 to 90:10. To 5 mL of 2.5% w/v PVA in water in a 20 mL glass vial is added 1 mL of the polymer solution dropwise with stirring.
Six similar vials are assembled in a six position overhead stirrer, dissolution testing apparatus (Vanderkamp) and stirred at 200 rpm. The temperature of the vials is increased from room temperature to 40 C over 15 min and held at 40 C for 2 hours. Vials are centrifuged at 500xg and the microspheres washed three times in water. At some EVA:PLA
polymer blends, the microsphere samples aggregated during the washing stage due to the removal of the dispersing or emulsifying agent, PVA. This aggregation effect could be analyzed semi-quantitatively since aggregated microspheres fused and the fused polymer mass floated on the surface of the wash water. This surface polymer layer is discarded during the wash treatments and the remaining, pelleted microspheres are weighed.
are prepared using blends of EVA:PLA between 35:65 to 90:10. To 5 mL of 2.5% w/v PVA in water in a 20 mL glass vial is added 1 mL of the polymer solution dropwise with stirring.
Six similar vials are assembled in a six position overhead stirrer, dissolution testing apparatus (Vanderkamp) and stirred at 200 rpm. The temperature of the vials is increased from room temperature to 40 C over 15 min and held at 40 C for 2 hours. Vials are centrifuged at 500xg and the microspheres washed three times in water. At some EVA:PLA
polymer blends, the microsphere samples aggregated during the washing stage due to the removal of the dispersing or emulsifying agent, PVA. This aggregation effect could be analyzed semi-quantitatively since aggregated microspheres fused and the fused polymer mass floated on the surface of the wash water. This surface polymer layer is discarded during the wash treatments and the remaining, pelleted microspheres are weighed.
[0269] The % aggregation is determined from % aggregation = 1- (weight of gelleted microspheres) x 100 initial polymer weight
[0270] Paclitaxel loaded microspheres (0.6% w/w paclitaxel) are prepared by dissolving the paclitaxel in the 5% w/v polymer solution in DCM. The polymer blend used is 50:50 EVA:PLA. A "large" size fraction and "small" size fraction of microspheres are produced by adding the paclitaxel/polymer solution dropwise into 2.5% w/v PVA
and 5%
w/v PVA, respectively. The dispersions are stirred at 40 C at 200 rpm for 2 hours, centrifuged and washed 3 times in water as described previously. Microspheres are air dried and samples are sized using an optical microscope with a stage micrometer. Over 300 microspheres are counted per sample. Control microspheres (paclitaxel absent) are prepared and sized as described previously.
and 5%
w/v PVA, respectively. The dispersions are stirred at 40 C at 200 rpm for 2 hours, centrifuged and washed 3 times in water as described previously. Microspheres are air dried and samples are sized using an optical microscope with a stage micrometer. Over 300 microspheres are counted per sample. Control microspheres (paclitaxel absent) are prepared and sized as described previously.
[0271] B. Encapsulation efficiency
[0272] Known weights of paclitaxel-loaded microspheres are dissolved in I mL
DCM, 20 mL of 40% acetonitrile in water at 50 C are added and vortexed until the DCM had been evaporated. The concentration of paclitaxel in the 40% acetonitrile is determined by HPLC using a mobile phase of water:methanol:acetonitrile (37:5:58) at a flow rate of 1 mL/min (Beckman isocratic pump), a C8 reverse phase column (Beckman) and UV
detection at 232 nm. To determine the recovery efficiency of this extraction procedure, known weights of paclitaxel from 100-1000 pg are dissolved in 1 mL of DCM and subjected to the same extraction procedure in triplicate as described previously.
Recoveries are always greater than 85% and the values of encapsulation efficiency are corrected appropriately.
DCM, 20 mL of 40% acetonitrile in water at 50 C are added and vortexed until the DCM had been evaporated. The concentration of paclitaxel in the 40% acetonitrile is determined by HPLC using a mobile phase of water:methanol:acetonitrile (37:5:58) at a flow rate of 1 mL/min (Beckman isocratic pump), a C8 reverse phase column (Beckman) and UV
detection at 232 nm. To determine the recovery efficiency of this extraction procedure, known weights of paclitaxel from 100-1000 pg are dissolved in 1 mL of DCM and subjected to the same extraction procedure in triplicate as described previously.
Recoveries are always greater than 85% and the values of encapsulation efficiency are corrected appropriately.
[0273] C. Drug release studies In 15 mL glass, screw capped tubes are placed 10 mL of 10 mM phosphate buffered saline (PBS), pH 7.4 and 35 mg paclitaxel-loaded microspheres. The tubes are tumbled at 37 C
and at given time intervals, centrifuged at 1500xg for 5 min and the supernatant saved for analysis. Microsphere pellets are resuspended in fresh PBS (10mL) at 37 C and reincubated. Paclitaxel concentrations are determined by extraction into 1 mL
DCM
followed by evaporation to dryness under a stream of nitrogen, reconstitution in 1 mL of 40% acetonitrile in water and analysis using HPLC as previously described.
and at given time intervals, centrifuged at 1500xg for 5 min and the supernatant saved for analysis. Microsphere pellets are resuspended in fresh PBS (10mL) at 37 C and reincubated. Paclitaxel concentrations are determined by extraction into 1 mL
DCM
followed by evaporation to dryness under a stream of nitrogen, reconstitution in 1 mL of 40% acetonitrile in water and analysis using HPLC as previously described.
[0274] D. Scanning Electron Microscopy1SEML
Microspheres are placed on sample holders, sputter coated with gold and micrographs obtained using a Philips 501 B SEM operating at 15 W.
Microspheres are placed on sample holders, sputter coated with gold and micrographs obtained using a Philips 501 B SEM operating at 15 W.
[0275] E. CAM Studies
[0276] Fertilized, domestic chick embryos are incubated for 4 days prior to shell-less culturing. The egg contents are incubated at 90% relative humidity and 3% CO2 for 2 days.
On day 6 of incubation, 1 mg aliquots of 0.6% paclitaxel loaded or control (paclitaxel free) microspheres are placed directly on the CAM surface. After a 2 day exposure the vasculature is examined using a stereomicroscope interfaced with a video camera; the video signals are then displayed on a computer and video printed.
On day 6 of incubation, 1 mg aliquots of 0.6% paclitaxel loaded or control (paclitaxel free) microspheres are placed directly on the CAM surface. After a 2 day exposure the vasculature is examined using a stereomicroscope interfaced with a video camera; the video signals are then displayed on a computer and video printed.
[0277] F. Results
[0278] Microspheres prepared from 100% EVA are freely suspended in solutions of PVA but aggregated and coalesced or fused extensively on subsequent washing in water to remove the PVA. Blending EVA with an increasing proportion of PLA produced microspheres showing a decreased tendency to aggregate and coalesce when washed in water, as described in Figure 15A. A 50:50 blend of EVA:PLA formed microspheres with good physical stability, that is the microspheres remained discrete and well suspended with negligible aggregation and coalescence.
[0279] The size range for the "small" size fraction microspheres is determined to be >95% of the microsphere sample (by weight) between 10-30 mm and for the "large" size fraction, >95% of the sample (by weight) between 30-100 mm. Representative scanning electron micrographs of paclitaxel loaded 50:50 EVA:PLA microspheres in the "small" and "large" size ranges are shown in Figures 15B and 15C, respectively. The microspheres are spherical with a smooth surface and with no evidence of solid drug on the surface of the microspheres. The efficiency of loading 50:50 EVA:PLA microspheres with paclitaxel is between 95-100% at initial paclitaxel concentrations of between 100-1000 mg paclitaxel per 50 mg polymer. There is no significant difference (Student t-test, p <0.05) between the encapsulation efficiencies for either "small" or "large" microspheres.
[0280] The time course of paclitaxel release from 0.6% w/v loaded 50:50 EVA:PLA
microspheres is shown in Figure 15D for "small" size (open circles) and "large" size (closed circles) microspheres. The release rate studies are carried out in triplicate tubes in 3 separate experiments. The release profiles are biphasic with an initial rapid release of paclitaxel or "burst" phase occurring over the first 4 days from both size range microspheres. This is followed by a phase of much slower release. There is no significant difference between the release rates from "small" or "large" microspheres.
Between 10-13% of the total paclitaxel content of the microspheres is released in 50 days.
microspheres is shown in Figure 15D for "small" size (open circles) and "large" size (closed circles) microspheres. The release rate studies are carried out in triplicate tubes in 3 separate experiments. The release profiles are biphasic with an initial rapid release of paclitaxel or "burst" phase occurring over the first 4 days from both size range microspheres. This is followed by a phase of much slower release. There is no significant difference between the release rates from "small" or "large" microspheres.
Between 10-13% of the total paclitaxel content of the microspheres is released in 50 days.
[0281] The paclitaxel loaded microspheres (0.6% w/v loading) are tested using the CAM assay and the results are shown in Figure 15E. The paclitaxel microspheres released sufficient drug to produce a zone of avascularity in the surrounding tissue (Figure 15F).
Note that immediately adjacent to the microspheres ("MS" in Figures 15E and 15F) is an area in which blood vessels are completely absent (Zone 1); further from the microspheres is an area of disrupted, non-functioning capillaries (Zone 2); it is only at a distance of approximately 6 mm from the microspheres that the capillaries return to normal. In CAMs treated with control microspheres (paclitaxel absent) there is a normal capillary network architecture.
Note that immediately adjacent to the microspheres ("MS" in Figures 15E and 15F) is an area in which blood vessels are completely absent (Zone 1); further from the microspheres is an area of disrupted, non-functioning capillaries (Zone 2); it is only at a distance of approximately 6 mm from the microspheres that the capillaries return to normal. In CAMs treated with control microspheres (paclitaxel absent) there is a normal capillary network architecture.
[0282] Discussion
[0283] Arterial chemoembolization is an invasive surgical technique.
Therefore, ideally, a chemoembolic formulation of an anti-angiogenic and anticancer drug such as paclitaxel would release the drug at the tumor site at concentrations sufficient for activity for a prolonged period of time, of the order of several months. EVA is a tissue compatible nondegradable polymer which has been used extensively for the controlled delivery of macromolecules over long time periods (> 100 days).
Therefore, ideally, a chemoembolic formulation of an anti-angiogenic and anticancer drug such as paclitaxel would release the drug at the tumor site at concentrations sufficient for activity for a prolonged period of time, of the order of several months. EVA is a tissue compatible nondegradable polymer which has been used extensively for the controlled delivery of macromolecules over long time periods (> 100 days).
[0284] EVA is initially selected as a polymeric biomaterial for preparing microspheres with paclitaxel dispersed in the polymer matrix. However, microspheres prepared with 100% EVA aggregated and coalesced almost completely during the washing procedure.
[0285] Polymers and copolymers based on lactic acid and glycolic acid are physiologically inert and biocompatible and degrade by hydrolysis to toxicologically acceptable products. Copolymers of lactic acid and glycolic acids have faster degradation rates than PLA and drug loaded microspheres prepared using these copolymers are unsuitable for prolonged, controlled release over several months. Dollinger and Sawan blended PLA with EVA and showed that the degradation lifetime of PLA is increased as the proportion of EVA in the blend is increased. They suggested that blends of EVA
and PLA
should provide a polymer matrix with better mechanical stability and control of drug release rates than PLA.
and PLA
should provide a polymer matrix with better mechanical stability and control of drug release rates than PLA.
[0286] Figure 15A shows that increasing the proportion of PLA in a EVA:PLA
blend decreased the extent of aggregation of the microsphere suspensions. Blends of 50% or less EVA in the EVA:PLA matrix produced physically stable microsphere suspensions in water or PBS. A blend of 50:50 EVA:PLA is selected for all subsequent studies.
blend decreased the extent of aggregation of the microsphere suspensions. Blends of 50% or less EVA in the EVA:PLA matrix produced physically stable microsphere suspensions in water or PBS. A blend of 50:50 EVA:PLA is selected for all subsequent studies.
[0287] Different size range fractions of microspheres could be prepared by changing the concentration of the emulsifier, PVA, in the aqueous phase. "Small"
microspheres are produced at the higher PVA concentration of 5% w/v whereas "large"
microspheres are produced at 2.5% w/v PVA. All other production variables are the same for both microsphere size fractions. The higher concentration of emulsifier gave a more viscous aqueous dispersion medium and produced smaller droplets of polymer/paclitaxel/DCM
emulsified in the aqueous phase and thus smaller microspheres. The paclitaxel loaded microspheres contained between 95-100% of the initial paclitaxel added to the organic phase encapsulated within the solid microspheres. The low water solubility of paclitaxel favoured partitioning into the organic phase containing the polymer.
microspheres are produced at the higher PVA concentration of 5% w/v whereas "large"
microspheres are produced at 2.5% w/v PVA. All other production variables are the same for both microsphere size fractions. The higher concentration of emulsifier gave a more viscous aqueous dispersion medium and produced smaller droplets of polymer/paclitaxel/DCM
emulsified in the aqueous phase and thus smaller microspheres. The paclitaxel loaded microspheres contained between 95-100% of the initial paclitaxel added to the organic phase encapsulated within the solid microspheres. The low water solubility of paclitaxel favoured partitioning into the organic phase containing the polymer.
[0288] Release rates of paclitaxel from the 50:50 EVA:PLA microspheres are very slow with less than 15% of the loaded paclitaxel being released in 50 days.
The initial burst phase of drug release may be due to diffusion of drug from the superficial region of the microspheres (close to the microsphere surface).
The initial burst phase of drug release may be due to diffusion of drug from the superficial region of the microspheres (close to the microsphere surface).
[0289] The mechanism of drug release from nondegradable polymeric matrices such as EVA is thought to involve the diffusion of water through the dispersed drug phase within the polymer, dissolution of the drug and diffusion of solute through a series of interconnecting, fluid filled pores. Blends of EVA and PLA have been shown to be immiscible or bicontinuous over a range of 30 to 70% EVA in PLA. In degradation studies in PBS buffer at 37 C, following an induction or lag period, PLA
hydrolytically degraded and eroded from the EVA:PLA polymer blend matrix leaving an inactive sponge-like skeleton.
Although the induction period and rate of PLA degradation and erosion from the blended matrices depended on the proportion of PLA in the matrix and on process history, there is consistently little or no loss of PLA until after 40-50 days.
hydrolytically degraded and eroded from the EVA:PLA polymer blend matrix leaving an inactive sponge-like skeleton.
Although the induction period and rate of PLA degradation and erosion from the blended matrices depended on the proportion of PLA in the matrix and on process history, there is consistently little or no loss of PLA until after 40-50 days.
[0290] Although some erosion of PLA from the 50:50 EVA:PLA microspheres may have occurred within the 50 days of the in vitro release rate study (Figure 15C), it is likely that the primary mechanism of drug release from the polymer blend is diffusion of solute through a pore network in the polymer matrix.
[0291] At the conclusion of the release rate study, the microspheres are analyzed from the amount of drug remaining. The values for the percent of paclitaxel remaining in the 50 day incubation microsphere samples are 94% +/- 9% and 89% +/- 12% for "large"
and "small" size fraction microspheres, respectively.
and "small" size fraction microspheres, respectively.
[0292] Microspheres loaded with 6mg per mg of polymer (0.6%) provided extensive inhibition of angiogenesis when placed on the CAM of the embryonic chick (Figures 15E
and 15F).
and 15F).
[0293] EXAMPLE 12
[0294] PACLITAXEL ENCAPSULATION IN POLY(E-CAPROLACTONE) MICROSPHERES. INHIBITION OF ANGIOGENESIS ON THE CAM ASSAY BY
PACLITAXEL-LOADED MICROSPHERES
PACLITAXEL-LOADED MICROSPHERES
[0295] This example evaluates the in vitro release rate profile of paclitaxel from biodegradable microspheres of poly(e-caprolactone) and demonstrates the anti-angiogenic activity of paclitaxel released from these microspheres when placed on the CAM.
[0296] Reagents which were utilized in these experiments include: poly(e-caprolactone) ("PCL") (molecular weight 35,000 - 45,000; purchased from Polysciences (Warrington, PA)); dichloromethane ("DCM") from Fisher Scientific Co., Canada;
polyvinyl alcohol (PVP) (molecular weight 12,00 - 18,000, 99% hydrolysed) from Aldrich Chemical Co. (Milwaukee, Wis.), and paclitaxel from Sigma Chemical Co. (St. Louis, MO).
Unless otherwise stated all chemicals and reagents are used as supplied. Distilled water is used throughout.
polyvinyl alcohol (PVP) (molecular weight 12,00 - 18,000, 99% hydrolysed) from Aldrich Chemical Co. (Milwaukee, Wis.), and paclitaxel from Sigma Chemical Co. (St. Louis, MO).
Unless otherwise stated all chemicals and reagents are used as supplied. Distilled water is used throughout.
[0297] A. Preparation of microspheres
[0298] Microspheres are prepared essentially as described in Example 8 utilizing the solvent evaporation method. Briefly, 5%w/w paclitaxel loaded microspheres are prepared by dissolving 10 mg of paclitaxel and 190 mg of PCL in 2 mi of DCM, adding to 100 ml of 1% PVP aqueous solution and stirring at 1000 r.p.m. at 25 C for 2 hours. The suspension of microspheres is centrifuged at 1000 x g for 10 minutes (Beckman GPR), the supernatant removed and the microspheres washed three times with water. The washed microspheres are air-dried overnight and stored at room temperature. Control microspheres (paclitaxel absent) are prepared as described above. Microspheres containing 1% and 2% paclitaxel are also prepared. Microspheres are sized using an optical microscope with a stage micrometer.
[0299] B. Encapsulation efficiency
[0300] A known weight of drug-loaded microspheres (about 5 mg) is dissolved in ml of acetonitrile and 2 ml distilled water is added to precipitate the polymer. The mixture is centrifuged at 1000 g for 10 minutes and the amount of paclitaxel encapsulated is calculated from the absorbance of the supernatant measured in a UV
spectrophotometer (Hewlett-Packard 8452A Diode Array Spectrophotometer) at 232 nm.
spectrophotometer (Hewlett-Packard 8452A Diode Array Spectrophotometer) at 232 nm.
[0301] C. Drug release studies
[0302] About 10 mg of paclitaxel-loaded microspheres are suspended in 20 mi of mM phosphate buffered saline, pH 7.4 (PBS) in screw-capped tubes. The tubes are tumbled end-over-end at 37 C and at given time intervals 19.5 ml of supernatant is removed (after allowing the microspheres to settle at the bottom), filtered through a 0.45 mm membrane filter and retained for paclitaxel analysis. An equal volume of PBS is replaced in each tube to maintain sink conditions throughout the study. The filtrates are extracted with 3 x 1 ml DCM, the DCM extracts evaporated to dryness under a stream of nitrogen, redissolved in 1 ml acetonitrile and analyzed by HPLC using a mobile phase of water:methanol:acetonitrile (37:5:58) at a flow rate of 1 ml min' (Beckman Isocratic Pump), a C8 reverse phase column (Beckman), and UV detection (Shimadzu SPD A) at 232 nm.
[0303] D. CAM studies
[0304] Fertilized, domestic chick embryos are incubated for 4 days prior to shell-less culturing. On day 6 of incubation, 1 mg aliquots of 5% paclitaxel-loaded or control (paclitaxel-free) microspheres are placed directly on the CAM surface. After a 2-day exposure the vasculature is examined using a stereomicroscope interfaced with a video camera; the video signals are then displayed on a computer and video printed.
[0305] E. Scanning electron microscopy
[0306] Microspheres are placed on sample holders, sputter-coated with gold and then placed in a Philips 501 B Scanning Electron Microscope operating at 15 W.
[0307] F. Results
[0308] The size range for the microsphere samples is between 30 - 100 mm, although there is evidence in all paclitaxel-loaded or control microsphere batches of some microspheres falling outside this range. The efficiency of loading PCL
microspheres with paclitaxel is always greater than 95% for all drug loadings studied. Scanning electron microscopy demonstrated that the microspheres are all spherical and many showed a rough or pitted surface morphology. There appeared to be no evidence of solid drug on the surface of the microspheres.
microspheres with paclitaxel is always greater than 95% for all drug loadings studied. Scanning electron microscopy demonstrated that the microspheres are all spherical and many showed a rough or pitted surface morphology. There appeared to be no evidence of solid drug on the surface of the microspheres.
[0309] The time courses of paclitaxel release from 1%, 2% and 5% loaded PCL
microspheres are shown in Figure 16A. The release rate profiles are bi-phasic.
There is an initial rapid release of paclitaxel or "burst phase" at all drug loadings.
The burst phase occurred over 1-2 days at 1% and 2% paclitaxel loading and over 3-4 days for 5% loaded microspheres. The initial phase of rapid release is followed by a phase of significantly slower drug release. For microspheres containing 1 % or 2% paclitaxel there is no further drug release after 21 days. At 5% paclitaxel loading, the microspheres had released about 20% of the total drug content after 21 days.
microspheres are shown in Figure 16A. The release rate profiles are bi-phasic.
There is an initial rapid release of paclitaxel or "burst phase" at all drug loadings.
The burst phase occurred over 1-2 days at 1% and 2% paclitaxel loading and over 3-4 days for 5% loaded microspheres. The initial phase of rapid release is followed by a phase of significantly slower drug release. For microspheres containing 1 % or 2% paclitaxel there is no further drug release after 21 days. At 5% paclitaxel loading, the microspheres had released about 20% of the total drug content after 21 days.
[0310] Figure 16B shows CAMs treated with control PCL microspheres, and Figure 16C shows treatment with 5% paclitaxel loaded microspheres. The CAM with the control microspheres shows a normal capillary network architecture. The CAM treated with paclitaxel-PCL microspheres shows marked vascular regression and zones which are devoid of a capillary network.
[0311] G. Discussion
[0312] The solvent evaporation method of manufacturing paclitaxel-loaded microspheres produced very high paclitaxel encapsulation efficiencies of between 95-100%. This is due to the poor water solubility of paclitaxel and its hydrophobic nature favouring partitioning in the organic solvent phase containing the polymer.
[0313] The biphasic release profile for paclitaxel is typical of the release pattern for many drugs from biodegradable polymer matrices. Poly(e-caprolactone) is an aliphatic polyester which can be degraded by hydrolysis under physiological conditions and it is non-toxic and tissue compatible. The degradation of PCL is significantly slower than that of the extensively investigated polymers and copolymers of lactic and glycolic acids and is therefore suitable for the design of long-term drug delivery systems. The initial rapid or burst phase of paclitaxel release is thought to be due to diffusional release of the drug from the superficial region of the microspheres (close to the microsphere surface).
Release of paclitaxel in the second (slower) phase of the release profiles is not likely due to degradation or erosion of PCL because studies have shown that under in vitro conditions in water there is no significant weight loss or surface erosion of PCL over a 7.5-week period. The slower phase of paclitaxel release is probably due to dissolution of the drug within fluid-filled pores in the polymer matrix and diffusion through the pores. The greater release rate at higher paclitaxel loading is probably a result of a more extensive pore network within the polymer matrix.
Release of paclitaxel in the second (slower) phase of the release profiles is not likely due to degradation or erosion of PCL because studies have shown that under in vitro conditions in water there is no significant weight loss or surface erosion of PCL over a 7.5-week period. The slower phase of paclitaxel release is probably due to dissolution of the drug within fluid-filled pores in the polymer matrix and diffusion through the pores. The greater release rate at higher paclitaxel loading is probably a result of a more extensive pore network within the polymer matrix.
[0314] Paclitaxel microspheres with 5% loading have been shown to release sufficient drug to produce extensive inhibition of angiogenesis when placed on the CAM.
The inhibition of blood vessel growth resulted in an avascular zone as shown in Figure 16C.
The inhibition of blood vessel growth resulted in an avascular zone as shown in Figure 16C.
[0315] EXAMPLE 13
[0316] PACLITAXEL-LOADED POLYMERIC FILMS COMPOSED OF ETHYLENE
VINYL ACETATE AND A SURFACTANT
VINYL ACETATE AND A SURFACTANT
[0317] Two types of films are prepared essentially as described in Example 10:
pure EVA films loaded with paclitaxel and EVA/surfactant blend films (i.e., PluronicTM F127, SpanTM 80 and PluronicTM L101) loaded with paclitaxel.
pure EVA films loaded with paclitaxel and EVA/surfactant blend films (i.e., PluronicTM F127, SpanTM 80 and PluronicTM L101) loaded with paclitaxel.
[0318] The surfactants being examined are two hydrophobic surfactants (SpanTM
80 and PluronicTM L101) and one hydrophilic surfactant (PluronicTM F127). The PluronicTM
surfactants are themselves polymers, which is an attractive property since they can be blended with EVA to optimize various drug delivery properties. SpanT"" 80 is a smaller molecule which is in some manner dispersed in the polymer matrix, and does not form a blend.
80 and PluronicTM L101) and one hydrophilic surfactant (PluronicTM F127). The PluronicTM
surfactants are themselves polymers, which is an attractive property since they can be blended with EVA to optimize various drug delivery properties. SpanT"" 80 is a smaller molecule which is in some manner dispersed in the polymer matrix, and does not form a blend.
[0319] Surfactants will be useful in modulating the release rates of paclitaxel from films and optimizing certain physical parameters of the films. One aspect of the surfactant blend films which indicates that drug release rates can be controlled is the ability to vary the rate and extent to which the compound will swell in water. Diffusion of water into a polymer-drug matrix is critical to the release of drug from the carrier.
Figures 17C and 17D
show the degree of swelling of the films as the level of surfactant in the blend is altered.
Pure EVA films do not swell to any significant extent in over 2 months.
However, by increasing the level of surfactant added to the EVA it is possible to increase the degree of swelling of the compound, and by increasing hydrophilicity swelling can also be increased.
Figures 17C and 17D
show the degree of swelling of the films as the level of surfactant in the blend is altered.
Pure EVA films do not swell to any significant extent in over 2 months.
However, by increasing the level of surfactant added to the EVA it is possible to increase the degree of swelling of the compound, and by increasing hydrophilicity swelling can also be increased.
[0320] Results of experiments with these films are shown below in Figures 17A-E.
Briefly, Figure 17A shows paclitaxel release (in mg) over time from pure EVA
films. Figure 17B shows the percentage of drug remaining for the same films. As can be seen from these two figures, as paclitaxel loading increases (i.e., percentage of paclitaxel by weight is increased), drug release rates increase, showing the expected concentration dependence. As paclitaxel loading is increased, the percent paclitaxel remaining in the film also increases, indicating that higher loading may be more attractive for long-term release formulations.
Briefly, Figure 17A shows paclitaxel release (in mg) over time from pure EVA
films. Figure 17B shows the percentage of drug remaining for the same films. As can be seen from these two figures, as paclitaxel loading increases (i.e., percentage of paclitaxel by weight is increased), drug release rates increase, showing the expected concentration dependence. As paclitaxel loading is increased, the percent paclitaxel remaining in the film also increases, indicating that higher loading may be more attractive for long-term release formulations.
[0321] Physical strength and elasticity of the films is assessed in Figure 17E.
Briefly, Figure 17E shows stress/strain curves for pure EVA and EVA-Surfactant blend films. This crude measurement of stress demonstrates that the elasticity of films is increased with the addition of PluronicTM F127, and that the tensile strength (stress on breaking) is increased in a concentration dependant manner with the addition of PluronicTM
F127. Elasticity and strength are important considerations in designing a film which can be manipulated for particular clinical applications without causing permanent deformation of the compound.
Briefly, Figure 17E shows stress/strain curves for pure EVA and EVA-Surfactant blend films. This crude measurement of stress demonstrates that the elasticity of films is increased with the addition of PluronicTM F127, and that the tensile strength (stress on breaking) is increased in a concentration dependant manner with the addition of PluronicTM
F127. Elasticity and strength are important considerations in designing a film which can be manipulated for particular clinical applications without causing permanent deformation of the compound.
[0322] The above data demonstrates the ability of certain surfactant additives to control drug release rates and to alter the physical characteristics of the vehicle.
[0323] EXAMPLE 14
[0324] INCORPORATING METHOXYPOLYETHYLENE GLYCOL 350 (MEPEG) INTO POLY(E-CAPROLACTONE) TO DEVELOP A FORMULATION FOR THE
CONTROLLED DELIVERY OF PACLITAXEL FROM A PASTE
CONTROLLED DELIVERY OF PACLITAXEL FROM A PASTE
[0325] Reagents and equipment which were utilized within these experiments include methoxypolyethylene glycol 350 ("MePEG" - Union Carbide, Danbury, CT).
MePEG
is liquid at room temperature, and has a freezing point of 10 to -5 C.
MePEG
is liquid at room temperature, and has a freezing point of 10 to -5 C.
[0326] A. Preparation of a MePEG/PCL paclitaxel-containinqpaste
[0327] MePEG/PCL paste is prepared by first dissolving a quantity of paclitaxel into MePEG, and then incorporating this into melted PCL. One advantage with this method is that no DCM is required.
[0328] B. Analysis of melting point
[0329] The melting point of PCL/MePEG polymer blends may be determined by differential scanning calorimetry from 30 C to 70 C at a heating rate of 2.5 C
per minute.
Results of this experiment are shown in Figures 18A and 18B. Briefly, as shown in Figure 18A the melting point of the polymer blend (as determined by thermal analysis) is decreased by MePEG in a concentration dependent manner. The melting point of the polymer blends as a function of MePEG concentration is shown in Figure 18A.
This lower melting point also translates into an increased time for the polymer blends to solidify from melt as shown in Figure 18B. A 30:70 blend of MePEG:PCL takes more than twice as long to solidify from the fluid melt than does PCL alone.
per minute.
Results of this experiment are shown in Figures 18A and 18B. Briefly, as shown in Figure 18A the melting point of the polymer blend (as determined by thermal analysis) is decreased by MePEG in a concentration dependent manner. The melting point of the polymer blends as a function of MePEG concentration is shown in Figure 18A.
This lower melting point also translates into an increased time for the polymer blends to solidify from melt as shown in Figure 18B. A 30:70 blend of MePEG:PCL takes more than twice as long to solidify from the fluid melt than does PCL alone.
[0330] C. Measurement of brittleness
[0331] Incorporation of MePEG into PCL appears to produce a less brittle solid, as compared to PCL alone. As a "rough" way of quantitating this, a weighted needle is dropped from an equal height into polymer blends containing from 0% to 30%
MePEG in PCL, and the distance that the needle penetrates into the solid is then measured. The resulting graph is shown as Figure 18C. Points are given as the average of four measurements +/- 1 S.D.
MePEG in PCL, and the distance that the needle penetrates into the solid is then measured. The resulting graph is shown as Figure 18C. Points are given as the average of four measurements +/- 1 S.D.
[0332] For purposes of comparison, a sample of paraffin wax is also tested and the needle penetrated into this a distance of 7.25 mm +/- 0.3 mm.
[0333] D. Measurement of paclitaxel release
[0334] Pellets of polymer (PCL containing 0%, 5%, 10% or 20% MePEG) are incubated in phosphate buffered saline (PBS, pH 7.4) at 37 C, and % change in polymer weight is measured over time. As can be seen in Figure 18D, the amount of weight lost increases with the concentration of MePEG originally present in the blend. It is likely that this weight loss is due to the release of MePEG from the polymer matrix into the incubating fluid. This would indicate that paclitaxel will readily be released from a MePEG/PCL blend since paclitaxel is first dissolved in MePEG before incorporation into PCL.
[0335] E. Effect of varxing quantities of MePEG on paclitaxel release
[0336] Thermopastes are made up containing between 0.8% and 20% MePEG in PCL. These are loaded with 1% paclitaxel. The release of paclitaxel over time from 10 mg pellets in PBS buffer at 37 C is monitored using HPLC. As is shown in Figure 18E, the amount of MePEG in the formulation does not affect the amount of paclitaxel that is released.
[0337] F. Effect of varying auantities of paclitaxel on the total amount of paclitaxel released from a 20% MePEG/PCL blend
[0338] Thermopastes are made up containing 20% MePEG in PCL and loaded with between 0.2% and 10% paclitaxel. The release of paclitaxel over time is measured as described above. As shown in Figure 18F, the amount of paclitaxel released over time increases with increased paclitaxel loading. When piotted as the percent total paclitaxel released, however, the order is reversed (Figure 18G). This gives information about the residual paclitaxel remaining in the paste and, if assumptions are made about the validity of extrapolating this data, allows for a projection of the period of time over which paclitaxel will be released from the 20% MePEG Thermopaste.
[0339] G. Strength anaiysis of various MePEG/PCL blends
[0340] A CT-40 mechanical strength tester is used to measure the strength of solid polymer "tablets" of diameter 0.88 cm and an average thickness of 0.560 cm.
The polymer tablets are blends of MePEG at concentrations of 0%, 5%, 10% or 20% in PCL.
The polymer tablets are blends of MePEG at concentrations of 0%, 5%, 10% or 20% in PCL.
[0341] Results of this test are shown in Figure 18H, where both the tensile strength and the time to failure are plotted as a function of %MePEG in the blend.
Single variable ANOVA indicated that the tablet thicknesses within each group are not different. As can be seen from Figure 18H, the addition of MePEG into PCL decreased the hardness of the resulting solid.
Single variable ANOVA indicated that the tablet thicknesses within each group are not different. As can be seen from Figure 18H, the addition of MePEG into PCL decreased the hardness of the resulting solid.
[0342] EXAMPLE 15
[0343] EFFECT OF PACLITAXEL-LOADED THERMOPASTE ON ANGIOGENESIS
IN VIVO
IN VIVO
[0344] Fertilized, domestic chick embryos were incubated for 4 days prior to shell-less culturing as described in Example 2. The egg contents are removed from the shell and emptied into round-bottom sterilized glass bowls and covered with petri dish covers.
[0345] Paclitaxel is incorporated into thermopaste at concentrations of 5%, 10%, and 20% (w/v) essentially as described above (see Example 10), and used in the following experiments. Dried cut thermopaste is then heated to 60 C and pressed between two sheets of parafilm, flattening it, and allowing it to cool. Six embryos received 20%
paclitaxel-loaded thermopaste and 6 embryos received unloaded thermopaste prepared in this manner. One embryo died in each group leaving 5 embryos in each of the control and treated groups.
paclitaxel-loaded thermopaste and 6 embryos received unloaded thermopaste prepared in this manner. One embryo died in each group leaving 5 embryos in each of the control and treated groups.
[0346] Unloaded thermopaste and thermopaste containing 20% paclitaxel was also heated to 60 C and placed directly on the growing edge of each CAM at day 6 of incubation; two embryos each were treated in this manner.
[0347] There was no observable difference in the results obtained using the different methods of administration, indicating that the temperature of the paste at the time of application was not a factor in the outcome.
[0348] Thermopaste with 10% paclitaxel was applied to 11 CAMs and unloaded thermopaste was applied to an additional 11 CAMs, while 5% paclitaxel-loaded thermopaste was applied to 10 CAMs and unloaded thermopaste was applied to 10 other control CAMs. After a 2 day exposure (day 8 of incubation) the vasculature was examined with the aid of a stereomicroscope. Liposyn II, a white opaque solution, was injected into the CAM to increase the visibility of the vascular details.
[0349] In the embryos treated with 5% paclitaxel-loaded paste, only 2 animals demonstrated maximum inhibition of angiogenesis, while the remaining 8 were only marginally affected. Of the animals treated with 10% paclitaxel-loaded thermopaste only 2 showed maximal inhibition while the other 9 were only marginally affected.
[0350] The 20% paclitaxel-loaded thermopaste showed extensive areas of avascularity (see Figure 19B) in all 5 of the CAMs receiving this treatment.
The highest degree of inhibition was defined as a region of avascularity covering 6 mm by 6 mm in size.
All of the CAMs treated with 20% paclitaxel-loaded thermopaste displayed this degree of angiogenesis inhibition.
The highest degree of inhibition was defined as a region of avascularity covering 6 mm by 6 mm in size.
All of the CAMs treated with 20% paclitaxel-loaded thermopaste displayed this degree of angiogenesis inhibition.
[0351] By comparison, the control (unloaded) thermopaste did not inhibit angiogenesis on the CAM (see Figure 19A); this higher magnification view (note that the edge of the paste is seen at the top of the image) demonstrates that the vessels adjacent to the paste are unaffected by the thermopaste. This suggests that the effect observed is due to the sustained release of paclitaxel and is not due to the polymer itself or due to a secondary pressure effect of the paste on the developing vasculature.
[0352] This study demonstrates that thermopaste releases sufficient quantities of angiogenesis inhibitor(in this case paclitaxel) to inhibit the normal development of the CAM
vasculature.
vasculature.
[0353] EXAMPLE 16
[0354] EFFECT OF PACLITAXEL-LOADED THERMOPASTE ON TUMOR
GROWTH AND TUMOR ANGIOGENESIS IN VIVO
GROWTH AND TUMOR ANGIOGENESIS IN VIVO
[0355] Fertilized domestic chick embryos are incubated for 3 days prior to having their shells removed. The egg contents are emptied by removing the shell located around the airspace, severing the interior shell membrane, perforating the opposite end of the shell and allowing the egg contents to gently slide out from the blunted end. The contents are emptied into round-bottom sterilized glass bowls, covered with petri dish covers and incubated at 90% relative humidity and 3% carbon dioxide (see Example 2).
[0356] MDAY-D2 cells (a murine lymphoid tumor) is injected into mice and allowed to grow into tumors weighing 0.5-1.0 g. The mice are sacrificed, the tumor sites wiped with alcohol, excised, placed in sterile tissue culture media, and diced into 1 mm pieces under a laminar flow hood. Prior to placing the dissected tumors onto the 9-day old chick embryos, CAM surfaces are gently scraped with a 30 gauge needle to insure tumor implantation. The tumors are then placed on the CAMs after 8 days of incubation (4 days after deshelling), and allowed to grow on the CAM for four days to establish a vascular supply. Four embryos are prepared utilizing this method, each embryo receiving 3 tumors.
For these embryos, one tumor receives 20% paclitaxel-loaded thermopaste, the second tumor unloaded thermopaste, and the third tumor no treatment. The treatments are continued for two days before the results were recorded.
For these embryos, one tumor receives 20% paclitaxel-loaded thermopaste, the second tumor unloaded thermopaste, and the third tumor no treatment. The treatments are continued for two days before the results were recorded.
[0357] The explanted MDAY-D2 tumors secrete angiogenic factors which induce the ingrowth of capillaries (derived from the CAM) into the tumor mass and allow it to continue to grow in size. Since all the vessels of the tumor are derived from the CAM, while all the tumor cells are derived from the explant, it is possible to assess the effect of therapeutic interventions on these two processes independently. This assay has been used to determine the effectiveness of paclitaxel-loaded thermopaste on: (a) inhibiting the vascularization of the tumor and (b) inhibiting the growth of the tumor cells themselves.
[0358] Direct in vivo stereomicroscopic evaluation and histological examination of fixed tissues from this study demonstrated the following. In the tumors treated with 20%
paclitaxel-loaded thermopaste, there was a reduction in the number of the blood vessels which supplied the tumor (see Figures 20C and 20D), a reduction in the number of blood vessels within the tumor, and a reduction in the number of blood vessels in the periphery of the tumor (the area which is typically the most highly vascularized in a solid tumor) when compared to control tumors. The tumors began to decrease in size and mass during the two days the study was conducted. Additionally, numerous endothelial cells were seen to be arrested in cell division indicating that endothelial cell proliferation had been affected.
Tumor cells were also frequently seen arrested in mitosis. All 4 embryos showed a consistent pattern with the 20% paclitaxel-loaded thermopaste suppressing tumor vascularity while the unioaded thermopaste had no effect.
paclitaxel-loaded thermopaste, there was a reduction in the number of the blood vessels which supplied the tumor (see Figures 20C and 20D), a reduction in the number of blood vessels within the tumor, and a reduction in the number of blood vessels in the periphery of the tumor (the area which is typically the most highly vascularized in a solid tumor) when compared to control tumors. The tumors began to decrease in size and mass during the two days the study was conducted. Additionally, numerous endothelial cells were seen to be arrested in cell division indicating that endothelial cell proliferation had been affected.
Tumor cells were also frequently seen arrested in mitosis. All 4 embryos showed a consistent pattern with the 20% paclitaxel-loaded thermopaste suppressing tumor vascularity while the unioaded thermopaste had no effect.
[0359] By comparison, in CAMs treated with unloaded thermopaste, the tumors were well vascularized with an increase in the number and density of vessels when compared to that of the normal surrounding tissue, and dramatically more vessels than were observed in the tumors treated with paclitaxel-loaded paste. The newly formed vessels entered the tumor from all angles appearing like spokes attached to the center of a wheel (see Figures 20A and 20B). The control tumors continued to increase in size and mass during the course of the study. Histologically, numerous dilated thin-walled capillaries were seen in the periphery of the tumor and few endothelial were seen to be in cell division. The tumor tissue was well vascularized and viable throughout.
[0360] As an example, in two similarly-sized (initially, at the time of explantation) tumors placed on the same CAM the following data was obtained. For the tumor treated with 20% paclitaxel-loaded thermopaste the tumor measured 330 mm x 597 mm; the immediate periphery of the tumor has 14 blood vessels, while the tumor mass has only 3-4 small capillaries. For the tumor treated with unloaded thermopaste the tumor size was 623 mm x 678 mm; the immediate periphery of the tumor has 54 blood vessels, while the tumor mass has 12-14 small blood vessels. In addition, the surrounding CAM itself contained many more blood vessels as compared to the area surrounding the paclitaxel-treated tumor.
[0361] This study demonstrates that thermopaste releases sufficient quantities of angiogenesis inhibitor (in this case paclitaxel) to inhibit the pathological angiogenesis which accompanies tumor growth and development. Under these conditions angiogenesis is maximally stimulated by the tumor cells which produce angiogenic factors capable of inducing the ingrowth of capillaries from the surrounding tissue into the tumor mass. The 20% paclitaxel-loaded thermopaste is capable of blocking this process and limiting the ability of the tumor tissue to maintain an adequate blood supply. This results in a decrease in the tumor mass both through a cytotoxic effect of the drug on the tumor cells themselves and by depriving the tissue of the nutrients required for growth and expansion.
[0362] EXAMPLE 17
[0363] EFFECT OF ANGIOGENESIS INHIBITOR-LOADED THERMOPASTE ON
TUMOR GROWTH IN VIVO IN A MURINE TUMOR
TUMOR GROWTH IN VIVO IN A MURINE TUMOR
[0364] The murine MDAY-D2 tumor model may be used to examine the effect of local slow release of the chemotherapeutic and anti-angiogenic compounds such as paclitaxel on tumor growth, tumor metastasis, and animal survival. The MDAY-D2 tumor cell line is grown in a cell suspension consisting of 5% Fetal Calf Serum in alpha mem media. The cells are incubated at 37 C in a humidified atmosphere supplemented with 5%
carbon dioxide, and are diluted by a factor of 15 every 3 days until a sufficient number of cells are obtained. Following the incubation period the cells are examined by light microscopy for viability and then are centrifuged at 1500 rpm for 5 minutes.
PBS is added to the cells to achieve a dilution of 1,000,000 cells per ml.
carbon dioxide, and are diluted by a factor of 15 every 3 days until a sufficient number of cells are obtained. Following the incubation period the cells are examined by light microscopy for viability and then are centrifuged at 1500 rpm for 5 minutes.
PBS is added to the cells to achieve a dilution of 1,000,000 cells per ml.
[0365] Ten week old DBA/2j female mice are acclimatized for 3-4 days after arrival.
Each mouse is then injected subcutaneously in the posteriolateral flank with 100,000 MDAY-D2 cells in 100 ml of PBS. Previous studies have shown that this procedure produces a visible tumor at the injection site in 3-4 days, reach a size of 1.0-1.7g by 14 days, and produces visible metastases in the liver 19-25 days post-injection.
Depending upon the objective of the study a therapeutic intervention can be instituted at any point in the progression of the disease.
Each mouse is then injected subcutaneously in the posteriolateral flank with 100,000 MDAY-D2 cells in 100 ml of PBS. Previous studies have shown that this procedure produces a visible tumor at the injection site in 3-4 days, reach a size of 1.0-1.7g by 14 days, and produces visible metastases in the liver 19-25 days post-injection.
Depending upon the objective of the study a therapeutic intervention can be instituted at any point in the progression of the disease.
[0366] Using the above animal model, 20 mice are injected with 140,000 MDAY-D2 cells s.c. and the tumors allowed to grow. On day 5 the mice are divided into groups of 5.
The tumor site was surgically opened under anesthesia, the local region treated with the drug-loaded thermopaste or control thermopaste without disturbing the existing tumor tissue, and the wound was closed. The groups of 5 received either no treatment (wound merely closed), polymer (PCL) alone, 10% paclitaxei-loaded thermopaste, or 20%
paclitaxel-loaded thermopaste (only 4 animals injected) implanted adjacent to the tumor site. On day 16, the mice were sacrificed, the tumors were dissected and examined (grossly and histologically) for tumor growth, tumor metastasis, local and systemic toxicity resulting from the treatment, effect on wound healing, effect on tumor vascularity, and condition of the paste remaining at the incision site.
The tumor site was surgically opened under anesthesia, the local region treated with the drug-loaded thermopaste or control thermopaste without disturbing the existing tumor tissue, and the wound was closed. The groups of 5 received either no treatment (wound merely closed), polymer (PCL) alone, 10% paclitaxei-loaded thermopaste, or 20%
paclitaxel-loaded thermopaste (only 4 animals injected) implanted adjacent to the tumor site. On day 16, the mice were sacrificed, the tumors were dissected and examined (grossly and histologically) for tumor growth, tumor metastasis, local and systemic toxicity resulting from the treatment, effect on wound healing, effect on tumor vascularity, and condition of the paste remaining at the incision site.
[0367] The weights of the tumors for each animal is shown in the table below:
Table IV
Tumor Weights (gm) Animal No. Control Control 10% Paclitaxel 20% Paclitaxel (empty) (PCL) Thermopaste Thermopaste 1 1.387 1.137 0.487 0.114 2 0.589 0.763 0.589 0.192 3 0.461 0.525 0.447 0.071 4 0.606 0.282 0.274 0.042 0.353 0.277 0.362 Mean 0.6808 0.6040 0.4318 0.1048 Std. Deviation 0.4078 0.3761 0.1202 0.0653 P Value 0.7647 0.358 0.036
Table IV
Tumor Weights (gm) Animal No. Control Control 10% Paclitaxel 20% Paclitaxel (empty) (PCL) Thermopaste Thermopaste 1 1.387 1.137 0.487 0.114 2 0.589 0.763 0.589 0.192 3 0.461 0.525 0.447 0.071 4 0.606 0.282 0.274 0.042 0.353 0.277 0.362 Mean 0.6808 0.6040 0.4318 0.1048 Std. Deviation 0.4078 0.3761 0.1202 0.0653 P Value 0.7647 0.358 0.036
[0368] Thermopaste loaded with 20% paclitaxel reduced tumor growth by over 85%
(average weight 0.105) as compared to control animals (average weight 0.681).
Animals treated with thermopaste alone or thermopaste containing 10% paclitaxel had only modest effects on tumor growth; tumor weights were reduced by only 10% and 35%
respectively (Figure 21A). Therefore, thermopaste containing 20% paclitaxei was more effective in reducing tumor growth than thermopaste containing 10% paclitaxel (see Figure 21 C; see also Figure 21 B).
(average weight 0.105) as compared to control animals (average weight 0.681).
Animals treated with thermopaste alone or thermopaste containing 10% paclitaxel had only modest effects on tumor growth; tumor weights were reduced by only 10% and 35%
respectively (Figure 21A). Therefore, thermopaste containing 20% paclitaxei was more effective in reducing tumor growth than thermopaste containing 10% paclitaxel (see Figure 21 C; see also Figure 21 B).
[0369] Thermopaste was detected in some of the animals at the site of administration. Polymer varying in weight between 0.026 g to 0.078 g was detected in 8 of 15 mice. Every animal in the group containing 20% paclitaxel-loaded thermopaste contained some residual polymer suggesting that it was less susceptible to dissolution.
Histologically, the tumors treated with paclitaxel-loaded thermopaste contained lower cellularity and more tissue necrosis than control tumors. The vasculature was reduced and endothelial cells were frequently seen to be arrested in cell division. The paclitaxel-loaded thermopaste did not appear to affect the integrity or cellularity of the skin or tissues surrounding the tumor. Grossly, wound healing was unaffected.
Histologically, the tumors treated with paclitaxel-loaded thermopaste contained lower cellularity and more tissue necrosis than control tumors. The vasculature was reduced and endothelial cells were frequently seen to be arrested in cell division. The paclitaxel-loaded thermopaste did not appear to affect the integrity or cellularity of the skin or tissues surrounding the tumor. Grossly, wound healing was unaffected.
[0370] EXAMPLE 18
[0371] THE USE OF ANGIOGENESIS-INHIBITOR LOADED SURGICAL FILMS IN
THE PREVENTION OF IATROGENIC METASTATIC SEEDING OF TUMOR CELLS
DURING CANCER RESECTION SURGERY
THE PREVENTION OF IATROGENIC METASTATIC SEEDING OF TUMOR CELLS
DURING CANCER RESECTION SURGERY
[0372] As a sterile, pliable, stretchable drug-polymer compound would be useful during cancer resection procedures. Often it is desirable to isolate the normal surrounding tissues from malignant tissue during resection operations to prevent iatrogenic spread of the disease to adjacent organs through inadvertent contamination by cancer cells. A drug-loaded parafilm could be stretched across normai tissues prior to manipulation of the tumor.
This would be most useful if placed around the liver and other abdominal contents during bowel cancer resection surgery to prevent intraperitoneal spread of the disease to the liver.
A biodegradable film could be left in situ to provide continued protection.
This would be most useful if placed around the liver and other abdominal contents during bowel cancer resection surgery to prevent intraperitoneal spread of the disease to the liver.
A biodegradable film could be left in situ to provide continued protection.
[0373] Incision sites are also a common location of post-operative recurrence of malignancy. This is thought to be due to contamination of the wound site with tumor cells during the surgical procedure. To address these issues, experiments are being conducted to determine the ability of angiogenesis inhibitor-loaded films to prevent this phenomenon.
[0374] A. Materials and Methods
[0375] Preparation of Surgical Film. Surgical films are prepared as described in Example 10. Thin films measuring approximately 1 cm x 1 cm are prepared containing either polymer alone (PCL) or PCL loaded with 5% paclitaxel.
[0376] Rat Hepatic Tumor Model. In an initial study Wistar rats weighing approximately 300 g underwent general anesthesia and a 3-5 cm abdominal incision is made along the midline. In the largest hepatic lobe, a 1 cm incision is made in the hepatic parenchyma and part of the liver edge is resected. A concentration of 1 million live 9L
Glioma tumor cells (eluted from tissue culture immediately prior to the procedure) suspended in 100 mi of phosphate buffered saline are deposited onto the cut liver edge with a 30 gauge needle. The surgical is then placed over the cut liver edge containing the tumor cells and affixed in place with Gelfoam. Two animals received PCL films containing 5% paclitaxel and two animals received films containing PCL alone. The abdominal wall is closed with 3.0 Dexon and skin clips. The general anesthetic is terminated and the animal is allowed to recover. Ten days later the animals are sacrificed and the livers examined histologically.
Glioma tumor cells (eluted from tissue culture immediately prior to the procedure) suspended in 100 mi of phosphate buffered saline are deposited onto the cut liver edge with a 30 gauge needle. The surgical is then placed over the cut liver edge containing the tumor cells and affixed in place with Gelfoam. Two animals received PCL films containing 5% paclitaxel and two animals received films containing PCL alone. The abdominal wall is closed with 3.0 Dexon and skin clips. The general anesthetic is terminated and the animal is allowed to recover. Ten days later the animals are sacrificed and the livers examined histologically.
[0377] B. Results Local tumour growth is seen in the 2 livers treated with polymer alone. Both livers treated with polymer plus paclitaxel are completely free of tumour when examined histologically.
Also of importance, the liver capsule had regenerated and grown completely over the polymeric film and the cut surface of the liver indicating that there is no significant effect on wound healing. There is no evidence of local hepatic toxicity surrounding any (drug-loaded or drug-free) of the surgical films.
Also of importance, the liver capsule had regenerated and grown completely over the polymeric film and the cut surface of the liver indicating that there is no significant effect on wound healing. There is no evidence of local hepatic toxicity surrounding any (drug-loaded or drug-free) of the surgical films.
[0378] C. Discussion
[0379] This study indicates that surgical films placed around normal tissues and incision sites during surgery may be capable of decreasing the incidence of accidental implantation of tumor cells into normal surrounding tissue during resection of malignant tumors. This may help reduce the incidence of the significant problem of post-operative local recurrence of the disease.
[0380] EXAMPLE 19
[0381] INTRA-ARTICULAR INJECTION OF ANGIOGENESIS-INHIBITOR-LOADED
BIODEGRADABLE MICROSPHERES IN THE TREATMENT OF ARTHRITIS
BIODEGRADABLE MICROSPHERES IN THE TREATMENT OF ARTHRITIS
[0382] Articular damage in arthritis is due to a combination of inflammation (including WBCs and WBC products) and pannus tissue development (a tissue composed on neovascular tissue, connective tissue, and inflammatory cells). Paclitaxel has been chosen for the initial studies because it is a potent inhibitor of neovascularization. In this manner, paclitaxel in high local concentrations will prove to be a disease modifying agent in arthritis.
In order to determine whether microspheres have a deleterious effect on joints, the following experiments are conducted. Briefly, plain PCL and paclitaxel-loaded microspheres are prepared as described previously in Example 8.
In order to determine whether microspheres have a deleterious effect on joints, the following experiments are conducted. Briefly, plain PCL and paclitaxel-loaded microspheres are prepared as described previously in Example 8.
[0383] Three rabbits are injected intra-articularly with 0.5-5.0 pm, 10-30 pm, or 30-80 pm microspheres in a total volume of 0.2 mis (containing 0.5 mg of microspheres). The joints are assessed visually (clinically) on a daily basis. After two weeks the animals are sacrificed and the joints examined histologically for evidence of inflammation and depletion of proteoglycans.
[0384] The rabbit inflammatory arthritis and osteoarthritis models are being used to evaluate the use of microspheres in reducing synovitis and cartilage degradation.
Degenerative arthritis is induced by a partial tear of the cruciate ligament and meniscus of the knee. After 4 to 6 weeks, the rabbits develop erosions in the cartilage similar to that observed in human osteoarthritis. Inflammatory arthritis is induced by immunizing rabbits with bovine serum albumen (BSA) in Complete Freund's Adjuvent (CFA). After 3 weeks, rabbits containing a high titer of anti-BSA antibody receive an intra-articular injection of BSA (5 mg). Joint swelling and pronounced synovitis is apparent by seven days, a proteoglycan depletion is observed by 7 to 14 days, and cartilage erosions are observed by 4 to 6 weeks.
Degenerative arthritis is induced by a partial tear of the cruciate ligament and meniscus of the knee. After 4 to 6 weeks, the rabbits develop erosions in the cartilage similar to that observed in human osteoarthritis. Inflammatory arthritis is induced by immunizing rabbits with bovine serum albumen (BSA) in Complete Freund's Adjuvent (CFA). After 3 weeks, rabbits containing a high titer of anti-BSA antibody receive an intra-articular injection of BSA (5 mg). Joint swelling and pronounced synovitis is apparent by seven days, a proteoglycan depletion is observed by 7 to 14 days, and cartilage erosions are observed by 4 to 6 weeks.
[0385] Inflammatory arthritis is induced as described above. After 4 days, the joints are injected with microspheres containing 5% paclitaxel or vehicle. One group of animals will be sacrificed on day 14 and another on day 28. The joints are examined histologically for inflammation and cartilage degradation. The experiment is designed to determine if paclitaxel microspheres can affect joint inflammation and cartilage matrix degradation.
[0386] Angiogenesis-inhibitor microspheres may be further examined in an osteoarthritis model. Briefly, degenerative arthritis is induced in rabbits as described above, and the joints receive an intra-articular injection of microspheres (5%
paclitaxel or vehicle only) on day 4. The animals are sacrificed on day 21 and day 42 and the joints examined histologically for evidence of cartilage degradation.
paclitaxel or vehicle only) on day 4. The animals are sacrificed on day 21 and day 42 and the joints examined histologically for evidence of cartilage degradation.
[0387] Studies are conducted to assess angiogenesis inhibitors delivered via intra-articular microspheres as chondroprotective agents.
[0388] Results
[0389] Unloaded PCL microspheres of differing sizes (0.5-5.0 pm, 10-30 Nm, or 80 pm) were injected intra-articularly into the rabbit knee joint. Results of these experiments are shown in Figures 22A to D. Briefly, Figure 22A is a photograph of synovium from PBS injected joints. Figure 22B is a photograph of joints injected with microspheres. Figure 22C is a photograph of cartilage from joints injected with PBS, and Figure 22D is a photograph of cartilage from joints injected with microspheres.
[0390] As can be seen from these photographs, histologically, there is no difference between joints receiving a microsphere injection and those which did not.
Clinically, there was no evidence of joint inflammation during the 14 days the experiment was conducted.
Grossly, there is no evidence of joint inflammation or cartilage damage in joints where microspheres are injected, as compared to untreated normal joints.
Clinically, there was no evidence of joint inflammation during the 14 days the experiment was conducted.
Grossly, there is no evidence of joint inflammation or cartilage damage in joints where microspheres are injected, as compared to untreated normal joints.
[0391] Conclusions
[0392] Microspheres can be injected intra-articularlywithout causing anydiscernible changes to the joint surface. This indicates that this method may be an effective means of delivering a targeted, sustained-release of disease-modifying agents to diseased joints, while minimizing the toxicity which could be associated with the systemic administration of such biologically active compounds.
[0393] As discussed above, microspheres can be formulated into specific sizes with defined drug release kinetics. It has also been demonstrated that paclitaxel is a potent inhibitor of angiogenesis and that it is released from microspheres in quantities sufficient to block neovascularization on the CAM assay. Therefore, intra-articular administration of angiogenesis-inhibitor-loaded (e.g., paclitaxel-loaded) microspheres should be capable of blocking the neovascularization that occurs in diseases such as rheumatoid arthritis and leads to cartilage destruction in the joint. In this manner the drug-loaded microspheres can act as a "chondroprotective" agent which protects the cartilage from irreversible destruction from invading neovascular pannus tissue.
[0394] From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended claims.
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) (A) APPLICANT: Angiotech Pharmaceuticals Inc.
(B) INVENTORS: Hunter, William L.
Machan, Lindsay S.
Arsenault, A. Larry (ii) TITLE OF INVENTION: COMBINATION OF PACLITAXEL AND A POLYMER
(iii) NUMBER OF SEQUENCES: 1 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Barrigar Intellectual Property Law (B) STREET: Suite 1500, 601 W. Hastings St.
(C) CITY: Vancouver (D) PROVINCE: BC
(E) COUNTRY: CANADA
(F) POSTAL CODE: V6B 5A6 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentln Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(C) CLASSIFICATION:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Barrigar, Robert H.
(C) REFERENCE/DOCKET NUMBER: AG004 2860 CA
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: (604) 689-9255 (B) TELEFAX: (604) 689-9265 (2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
Cys Asp Pro Gly Tyr IIe GIy Ser Arg SEQUENCE LISTING:
(1) GENERAL INFORMATION:
(i) (A) APPLICANTS: Angiotech Pharmaceuticals Inc.; and University of British Columbia (B) INVENTORS: Hunter, William L.
Machan, Lindsay S.
Arsenault, A. Larry Burt, Helen M.
Jackson, John K.
(ii) TITLE OF INVENTION: Anti-Angiogenic Compositions and Methods of Use (iii) NUMBER OF SEQUENCES: 1 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Barrigar Intellectual Property Law (B) STREET: Suite 1500, 601 W. Hastings St.
(C) CITY: Vancouver (D) PROVINCE: BC
(E) COUNTRY: CANADA
(F) POSTAL CODE: V6B 5A6 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentln Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(C) CLASSIFICATION:
(viii) PATENT AGENT INFORMATION:
(A) NAME: Barrigar, Robert H., Barrigar Intellectual Property Law (C) REFERENCE/DOCKET NUMBER: AG004 2819 CA
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: (604) 689-9255 (B) TELEFAX: (604) 689-9265 (2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
Cys Asp Pro Gly Tyr Ile Gly Ser Arg
Accordingly, the invention is not limited except as by the appended claims.
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) (A) APPLICANT: Angiotech Pharmaceuticals Inc.
(B) INVENTORS: Hunter, William L.
Machan, Lindsay S.
Arsenault, A. Larry (ii) TITLE OF INVENTION: COMBINATION OF PACLITAXEL AND A POLYMER
(iii) NUMBER OF SEQUENCES: 1 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Barrigar Intellectual Property Law (B) STREET: Suite 1500, 601 W. Hastings St.
(C) CITY: Vancouver (D) PROVINCE: BC
(E) COUNTRY: CANADA
(F) POSTAL CODE: V6B 5A6 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentln Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(C) CLASSIFICATION:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Barrigar, Robert H.
(C) REFERENCE/DOCKET NUMBER: AG004 2860 CA
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: (604) 689-9255 (B) TELEFAX: (604) 689-9265 (2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
Cys Asp Pro Gly Tyr IIe GIy Ser Arg SEQUENCE LISTING:
(1) GENERAL INFORMATION:
(i) (A) APPLICANTS: Angiotech Pharmaceuticals Inc.; and University of British Columbia (B) INVENTORS: Hunter, William L.
Machan, Lindsay S.
Arsenault, A. Larry Burt, Helen M.
Jackson, John K.
(ii) TITLE OF INVENTION: Anti-Angiogenic Compositions and Methods of Use (iii) NUMBER OF SEQUENCES: 1 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Barrigar Intellectual Property Law (B) STREET: Suite 1500, 601 W. Hastings St.
(C) CITY: Vancouver (D) PROVINCE: BC
(E) COUNTRY: CANADA
(F) POSTAL CODE: V6B 5A6 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentln Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(C) CLASSIFICATION:
(viii) PATENT AGENT INFORMATION:
(A) NAME: Barrigar, Robert H., Barrigar Intellectual Property Law (C) REFERENCE/DOCKET NUMBER: AG004 2819 CA
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: (604) 689-9255 (B) TELEFAX: (604) 689-9265 (2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: N-terminal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
Cys Asp Pro Gly Tyr Ile Gly Ser Arg
Claims (41)
1. A combination for use as a non-biodegradable solid support, other than a stent, the combination comprising a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative; and a non-biodegradable polymer, wherein the non-biodegradable polymer is for delivery of the paclitaxel compound.
2. The combination of claim 1 wherein the polymer is a carrier for the paclitaxel compound.
3. The combination of claim 1 or 2 further comprising a polymeric substance for absorbing the paclitaxel compound and the polymer.
4. The combination of any one of claims 1 to 3 wherein at least a portion of the outer surface of the solid support is provided with the paclitaxel compound.
5. The combination of any one of claims 1 to 4, wherein the paclitaxel compound and the polymer are mixed with one another.
6. The combination of any one of claims 1 to 5, wherein the paclitaxel compound is absorbed into the polymer.
7. The combination of any one of claims 1 to 6, in the form of a film.
8. The combination of any one of claims 1 to 6, in the form of a surgical mesh.
9. The combination of any one of claims 1 to 6, in the form of a tube.
10. The combination of claim 9, wherein the tube is a vascular graft.
11. The combination of any one of claims 1 to 6, in the form of a thread.
12. The combination of any one of claims 1 to 6, in the form of a suture.
13. The combination of any one of claims 1 to 12 wherein the paclitaxel compound is paclitaxel.
14. The combination of any one of claims 1 to 13, wherein the polymer is an ethylene vinyl acetate polymer.
15. The combination of any one of claims 1 to 13, wherein the polymer is an ethylene vinyl acetate copolymer.
16. The combination of any one of claims 1 to 13, wherein the polymer is silicone(methylmethacrylate).
17. The combination of any one of claims 1 to 13, wherein the polymer is poly (methylmethacrylate).
18. A combination for use with a solid support other than a stent, the combination comprising a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative; and a non-biodegradable polymer, wherein the non-biodegradable polymer is for delivery of the paclitaxel compound.
19. The combination of claim 18 wherein the polymer is a carrier for the paclitaxel compound.
20. The combination of claim 18 or 19 further comprising a polymeric substance for absorbing the paclitaxel compound and the polymer.
21. The combination of any one of claims 18 to 20, wherein the paclitaxel compound and the polymer are mixed with one another.
22. The combination of any one of claims 18 to 20, wherein the paclitaxel compound is absorbed into the polymer.
23. The combination of any one of claims 18 to 22 wherein the paclitaxel compound is paclitaxel.
24. The combination of any one of claims 18 to 23, wherein the polymer is an ethylene vinyl acetate polymer.
25. The combination of any one of claims 18 to 23, wherein the polymer is an ethylene vinyl acetate copolymer.
26. The combination of any one of claims 18 to 23, wherein the polymer is silicone(methylmethacrylate).
27. The combination of any one of claims 18 to 23, wherein the polymer is poly (methylmethacrylate).
28. A combination comprising:
(i) a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative;
(ii) a non-biodegradable polymer; and (iii) a suture.
(i) a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative;
(ii) a non-biodegradable polymer; and (iii) a suture.
29. A combination comprising:
(i) a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative;
(ii) a non-biodegradable polymer; and (iii) a thread.
(i) a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative;
(ii) a non-biodegradable polymer; and (iii) a thread.
30. A combination comprising:
(i) a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative;
(ii) a non-biodegradable polymer; and (iii) a device selected from a vascular graft or a tube other than a stent.
(i) a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative;
(ii) a non-biodegradable polymer; and (iii) a device selected from a vascular graft or a tube other than a stent.
31. The combination of claim 30 wherein the device is a vascular graft.
32. The combination of any one of claims 28 to 31, wherein the paclitaxel compound is paclitaxel.
33. The combination of any one of claims 28 to 32, wherein the polymer is an ethylene vinyl acetate copolymer.
34. The combination of any one of claims 28 to 32, wherein the polymer is silicone(methylmethacrylate).
35. The combination of any one of claims 28 to 32, wherein the polymer is poly (methylmethacrylate).
36. A combination comprising:
(i) a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative;
(ii) a non-biodegradable polymer; and (iii) a surgical mesh.
(i) a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative;
(ii) a non-biodegradable polymer; and (iii) a surgical mesh.
37. The combination claim 36, wherein the paclitaxel compound is paclitaxel.
38. The combination of claim 36 or 37, wherein the polymer is an ethylene vinyl acetate copolymer.
39. The combination of claim 36 or 37, wherein the polymer is silicone(methylmethacrylate).
40. The combination of claim 36 or 37, wherein the polymer is poly (methylmethacrylate).
41. For use as a polymeric matrix for coating a solid support other than a stent, a combination comprising: a non-biodegradable polymer; and a paclitaxel compound selected from the group consisting of paclitaxel, a paclitaxel analogue and a paclitaxel derivative.
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CA002167268A Expired - Lifetime CA2167268C (en) | 1993-07-19 | 1994-07-19 | Anti-angiogenic compositions and methods of use |
CA002472404A Abandoned CA2472404A1 (en) | 1993-07-19 | 1994-07-19 | Combination of stent and anti-angiogenic factor |
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CA002472404A Abandoned CA2472404A1 (en) | 1993-07-19 | 1994-07-19 | Combination of stent and anti-angiogenic factor |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5853746A (en) * | 1991-01-31 | 1998-12-29 | Robert Francis Shaw | Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone using functional barrier |
US6515009B1 (en) * | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5981568A (en) | 1993-01-28 | 1999-11-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US20030203976A1 (en) * | 1993-07-19 | 2003-10-30 | William L. Hunter | Anti-angiogenic compositions and methods of use |
DK0797988T3 (en) * | 1993-07-19 | 2009-05-11 | Univ British Columbia | Anti-angiogenic compositions and methods for their use |
US5994341A (en) * | 1993-07-19 | 1999-11-30 | Angiogenesis Technologies, Inc. | Anti-angiogenic Compositions and methods for the treatment of arthritis |
PT1118325E (en) † | 1993-07-29 | 2006-05-31 | Us Health | USES OF PACLITAXEL AND ITS DERIVATIVES IN THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF RESTENOSE |
US5618925A (en) * | 1994-04-28 | 1997-04-08 | Les Laboratories Aeterna Inc. | Extracts of shark cartilage having an anti-angiogenic activity and an effect on tumor regression; process of making thereof |
US6380366B1 (en) | 1994-04-28 | 2002-04-30 | Les Laboratoires Aeterna Inc. | Shark cartilage extract:process of making, methods of using and compositions thereof |
US6025334A (en) * | 1994-04-28 | 2000-02-15 | Les Laboratoires Aeterna Inc. | Extracts of shark cartilage having anti-collagenolytic, anti-inflammatory, anti-angiogenic and anti-tumoral activities; process of making, methods of using and compositions thereof |
US6028118A (en) * | 1996-08-08 | 2000-02-22 | Les Laboratoires Aeterna Inc. | Methods of using extracts of shark cartilage |
US6558798B2 (en) | 1995-02-22 | 2003-05-06 | Scimed Life Systems, Inc. | Hydrophilic coating and substrates coated therewith having enhanced durability and lubricity |
US5605696A (en) * | 1995-03-30 | 1997-02-25 | Advanced Cardiovascular Systems, Inc. | Drug loaded polymeric material and method of manufacture |
US7846202B2 (en) * | 1995-06-07 | 2010-12-07 | Cook Incorporated | Coated implantable medical device |
US7550005B2 (en) * | 1995-06-07 | 2009-06-23 | Cook Incorporated | Coated implantable medical device |
US6774278B1 (en) * | 1995-06-07 | 2004-08-10 | Cook Incorporated | Coated implantable medical device |
US20070203520A1 (en) * | 1995-06-07 | 2007-08-30 | Dennis Griffin | Endovascular filter |
US7611533B2 (en) * | 1995-06-07 | 2009-11-03 | Cook Incorporated | Coated implantable medical device |
US7896914B2 (en) * | 1995-06-07 | 2011-03-01 | Cook Incorporated | Coated implantable medical device |
US7867275B2 (en) * | 1995-06-07 | 2011-01-11 | Cook Incorporated | Coated implantable medical device method |
CN1156961A (en) | 1995-06-09 | 1997-08-13 | 欧罗赛铁克股份有限公司 | Formulations and method for providing prolonged local anesthesia |
US6441025B2 (en) | 1996-03-12 | 2002-08-27 | Pg-Txl Company, L.P. | Water soluble paclitaxel derivatives |
NZ332234A (en) * | 1996-03-12 | 2000-06-23 | Pg Txl Company Lp | Water soluble paclitaxel prodrugs formed by conjugating paclitaxel or docetaxel with a polyglutamic acid polymer and use for treating cancer |
ATE302599T1 (en) * | 1996-05-24 | 2005-09-15 | Angiotech Pharm Inc | PREPARATIONS AND METHODS FOR THE TREATMENT OR PREVENTION OF DISEASES OF THE BODY PASSAGES |
AU775787B2 (en) * | 1996-05-24 | 2004-08-12 | Angiotech Pharmaceuticals, Inc. | Compositions and methods for treating or preventing diseases of body passageways |
US6143037A (en) * | 1996-06-12 | 2000-11-07 | The Regents Of The University Of Michigan | Compositions and methods for coating medical devices |
CA2260750C (en) | 1996-06-24 | 2004-11-09 | Euro-Celtique, S.A. | Methods for providing safe local anesthesia |
US7351421B2 (en) * | 1996-11-05 | 2008-04-01 | Hsing-Wen Sung | Drug-eluting stent having collagen drug carrier chemically treated with genipin |
US6515016B2 (en) | 1996-12-02 | 2003-02-04 | Angiotech Pharmaceuticals, Inc. | Composition and methods of paclitaxel for treating psoriasis |
US6495579B1 (en) | 1996-12-02 | 2002-12-17 | Angiotech Pharmaceuticals, Inc. | Method for treating multiple sclerosis |
US6867305B2 (en) * | 1996-12-03 | 2005-03-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
AU756699B2 (en) | 1996-12-03 | 2003-01-23 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US6204388B1 (en) * | 1996-12-03 | 2001-03-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US20050043376A1 (en) * | 1996-12-03 | 2005-02-24 | Danishefsky Samuel J. | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
EP0967987B1 (en) | 1997-03-11 | 2003-06-04 | Les Laboratoires Aeterna Inc. | Compositions for treating tumors containing shark cartilage extracts and anti-neoplastic agents |
US6511477B2 (en) * | 1997-03-13 | 2003-01-28 | Biocardia, Inc. | Method of drug delivery to interstitial regions of the myocardium |
US6273913B1 (en) * | 1997-04-18 | 2001-08-14 | Cordis Corporation | Modified stent useful for delivery of drugs along stent strut |
US20030199425A1 (en) * | 1997-06-27 | 2003-10-23 | Desai Neil P. | Compositions and methods for treatment of hyperplasia |
US8853260B2 (en) | 1997-06-27 | 2014-10-07 | Abraxis Bioscience, Llc | Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
CA2298543A1 (en) * | 1997-08-13 | 1999-02-25 | James Barry | Loading and release of water-insoluble drugs |
US6306166B1 (en) * | 1997-08-13 | 2001-10-23 | Scimed Life Systems, Inc. | Loading and release of water-insoluble drugs |
DE69841984D1 (en) * | 1997-09-05 | 2010-12-16 | Maruho K K | COMPOSITION OF NANOCAPSULES FOR THE TREATMENT OF INTRAARTICULAR DISEASES |
DE19744135C1 (en) * | 1997-09-29 | 1999-03-25 | Schering Ag | Medical implants coated with epothilone |
US6485514B1 (en) | 1997-12-12 | 2002-11-26 | Supergen, Inc. | Local delivery of therapeutic agents |
HUP0101439A3 (en) | 1998-03-04 | 2002-09-30 | Takeda Chemical Industries Ltd | Sustained-release preparation for a ii antagonist, production and use thereof |
US7208010B2 (en) | 2000-10-16 | 2007-04-24 | Conor Medsystems, Inc. | Expandable medical device for delivery of beneficial agent |
US20040254635A1 (en) | 1998-03-30 | 2004-12-16 | Shanley John F. | Expandable medical device for delivery of beneficial agent |
US6241762B1 (en) | 1998-03-30 | 2001-06-05 | Conor Medsystems, Inc. | Expandable medical device with ductile hinges |
US7208011B2 (en) * | 2001-08-20 | 2007-04-24 | Conor Medsystems, Inc. | Implantable medical device with drug filled holes |
ATE219693T1 (en) | 1998-04-27 | 2002-07-15 | Surmodics Inc | BIOACTIVE ACTIVE COATINGS |
US6168807B1 (en) | 1998-07-23 | 2001-01-02 | Les Laboratoires Aeterna Inc. | Low molecular weight components of shark cartilage, processes for their preparation and therapeutic uses thereof |
US6299604B1 (en) * | 1998-08-20 | 2001-10-09 | Cook Incorporated | Coated implantable medical device |
WO2000010552A2 (en) * | 1998-08-24 | 2000-03-02 | Global Vascular Concepts, Inc. | Use of anti-angiogenic agents for inhibiting vessel wall injury |
US6293967B1 (en) | 1998-10-29 | 2001-09-25 | Conor Medsystems, Inc. | Expandable medical device with ductile hinges |
CA2353606A1 (en) * | 1998-12-03 | 2000-06-08 | Boston Scientific Limited | Stent having drug crystals thereon |
US6120847A (en) * | 1999-01-08 | 2000-09-19 | Scimed Life Systems, Inc. | Surface treatment method for stent coating |
US6419692B1 (en) | 1999-02-03 | 2002-07-16 | Scimed Life Systems, Inc. | Surface protection method for stents and balloon catheters for drug delivery |
AU768527B2 (en) * | 1999-02-23 | 2003-12-18 | Angiotech International Ag | Compositions and methods for improving integrity of compromised body passageways and cavities |
US20020058286A1 (en) * | 1999-02-24 | 2002-05-16 | Danishefsky Samuel J. | Synthesis of epothilones, intermediates thereto and analogues thereof |
WO2000056283A1 (en) * | 1999-03-24 | 2000-09-28 | The B.F.Goodrich Company | Inhibition of matrix metalloproteinases with polymers and pharmaceutical applications thereof |
US6156373A (en) | 1999-05-03 | 2000-12-05 | Scimed Life Systems, Inc. | Medical device coating methods and devices |
US6290673B1 (en) * | 1999-05-20 | 2001-09-18 | Conor Medsystems, Inc. | Expandable medical device delivery system and method |
US20040110722A1 (en) * | 1999-05-27 | 2004-06-10 | Ornberg Richard L. | Modified hyaluronic acid polymers |
JP2003500174A (en) * | 1999-05-27 | 2003-01-07 | フアルマシア・コーポレーシヨン | Biomaterials modified with superoxide dismutase mimics |
US6258121B1 (en) | 1999-07-02 | 2001-07-10 | Scimed Life Systems, Inc. | Stent coating |
DE29911689U1 (en) * | 1999-07-06 | 2000-04-06 | Sterk Peter | Agents for occluding organic tissue |
US7687462B2 (en) | 1999-10-05 | 2010-03-30 | The Regents Of The University Of California | Composition for promoting cartilage formation or repair comprising a nell gene product and method of treating cartilage-related conditions using such composition |
CA2388844A1 (en) * | 1999-11-12 | 2001-05-25 | Angiotech Pharmaceuticals, Inc. | Compositions and methods for treating disease utilizing a combination of radioactive therapy and cell-cycle inhibitors |
WO2001047451A1 (en) * | 1999-12-29 | 2001-07-05 | Gishel New | Apparatus and method for delivering compounds to a living organism |
WO2001064214A2 (en) * | 2000-02-28 | 2001-09-07 | The University Of British Columbia | Compositions and methods for the treatment of inflammatory diseases using topoisomerase inhibitors |
DE60139112D1 (en) * | 2000-03-06 | 2009-08-13 | Boston Scient Ltd | ULTRALSCHALL VISIBLE EMBOLIZING SUBSTANCES |
US20020077290A1 (en) | 2000-03-17 | 2002-06-20 | Rama Bhatt | Polyglutamic acid-camptothecin conjugates and methods of preparation |
ES2246431T3 (en) * | 2000-03-18 | 2006-02-16 | Polyzenix Gmbh | DENTAL IMPLANTS THAT HAVE BACTERIAL RESISTANCE. |
US20030212022A1 (en) * | 2001-03-23 | 2003-11-13 | Jean-Marie Vogel | Compositions and methods for gene therapy |
CN101708165A (en) * | 2000-03-24 | 2010-05-19 | 生物领域医疗公司 | Microspheres for active embolization |
WO2001072280A2 (en) * | 2000-03-24 | 2001-10-04 | Biosphere Medical Inc. | Microspheres for gene therapy |
JP2004500918A (en) | 2000-04-11 | 2004-01-15 | ポリゼニックス ゲーエムベーハー | Poly-tri-fluoro-ethoxy polyphosphazene covering and film |
US20090004240A1 (en) * | 2000-08-11 | 2009-01-01 | Celonova Biosciences, Inc. | Implants with a phosphazene-containing coating |
EP1179353A1 (en) * | 2000-08-11 | 2002-02-13 | B. Braun Melsungen Ag | Antithrombogenic implants with coating of polyphosphazenes and a pharmacologically active agent |
ATE547080T1 (en) | 2000-08-30 | 2012-03-15 | Univ Johns Hopkins | DEVICES FOR INTRAOCULAR DRUG DELIVERY |
US7101391B2 (en) * | 2000-09-18 | 2006-09-05 | Inflow Dynamics Inc. | Primarily niobium stent |
US7402173B2 (en) * | 2000-09-18 | 2008-07-22 | Boston Scientific Scimed, Inc. | Metal stent with surface layer of noble metal oxide and method of fabrication |
CA2424029C (en) † | 2000-09-29 | 2008-01-29 | Cordis Corporation | Coated medical devices |
PT1328213E (en) | 2000-10-16 | 2005-10-31 | Conor Medsystems Inc | EXPANSIVE MEDICAL DEVICE FOR THE ADMINISTRATION OF A BENEFICIAL AGENT |
US6764507B2 (en) | 2000-10-16 | 2004-07-20 | Conor Medsystems, Inc. | Expandable medical device with improved spatial distribution |
US7425217B2 (en) | 2000-11-16 | 2008-09-16 | Maier Nathan C | System and method for inhibiting cellular proliferation with tachykinins |
US7776310B2 (en) | 2000-11-16 | 2010-08-17 | Microspherix Llc | Flexible and/or elastic brachytherapy seed or strand |
US6746661B2 (en) | 2000-11-16 | 2004-06-08 | Microspherix Llc | Brachytherapy seed |
WO2002068000A2 (en) * | 2000-11-16 | 2002-09-06 | Microspherix Llc | Polymeric imagable brachytherapy seed |
EP1335760B1 (en) | 2000-11-21 | 2006-08-30 | Schering Aktiengesellschaft | Tubular vascular implants (stents) and methods for producing the same |
GB0100761D0 (en) | 2001-01-11 | 2001-02-21 | Biocompatibles Ltd | Drug delivery from stents |
US9080146B2 (en) | 2001-01-11 | 2015-07-14 | Celonova Biosciences, Inc. | Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with a micro-structured surface |
GB0100760D0 (en) | 2001-01-11 | 2001-02-21 | Biocompatibles Ltd | Drug delivery from stents |
DE10100961B4 (en) * | 2001-01-11 | 2005-08-04 | Polyzenix Gmbh | Body-compatible material and substrate coated with this material for the cultivation of cells and artificial organic implants constructed or grown from cells |
US20020176893A1 (en) * | 2001-02-02 | 2002-11-28 | Wironen John F. | Compositions, implants, methods, and kits for closure of lumen openings, repair of ruptured tissue, and for bulking of tissue |
US6685626B2 (en) | 2001-02-02 | 2004-02-03 | Regeneration Technologies, Inc. | Compositions, devices, methods, and kits for induction of adhesions |
US20040073294A1 (en) * | 2002-09-20 | 2004-04-15 | Conor Medsystems, Inc. | Method and apparatus for loading a beneficial agent into an expandable medical device |
US20040204756A1 (en) * | 2004-02-11 | 2004-10-14 | Diaz Stephen Hunter | Absorbent article with improved liquid acquisition capacity |
US6964680B2 (en) * | 2001-02-05 | 2005-11-15 | Conor Medsystems, Inc. | Expandable medical device with tapered hinge |
GB0104383D0 (en) | 2001-02-22 | 2001-04-11 | Psimedica Ltd | Cancer Treatment |
WO2002072150A2 (en) * | 2001-03-13 | 2002-09-19 | Angiotech Pharmaceuticals Inc. | Micellar drug delivery vehicles and uses thereof |
US7771468B2 (en) | 2001-03-16 | 2010-08-10 | Angiotech Biocoatings Corp. | Medicated stent having multi-layer polymer coating |
DE10115740A1 (en) * | 2001-03-26 | 2002-10-02 | Ulrich Speck | Preparation for restenosis prophylaxis |
US20040185101A1 (en) * | 2001-03-27 | 2004-09-23 | Macromed, Incorporated. | Biodegradable triblock copolymers as solubilizing agents for drugs and method of use thereof |
DE60220519T2 (en) * | 2001-04-20 | 2007-09-27 | The University Of British Columbia, Vancouver | MICELLAR DRUG DISPERSION SYSTEM FOR HYDROPHOBIC DRUGS |
US20030157161A1 (en) * | 2001-05-01 | 2003-08-21 | Angiotech Pharmaceuticals, Inc. | Compositions and methods for treating inflammatory conditions utilizing protein or polysaccharide containing anti-microtubule agents |
US7651695B2 (en) * | 2001-05-18 | 2010-01-26 | Advanced Cardiovascular Systems, Inc. | Medicated stents for the treatment of vascular disease |
US20030032935A1 (en) * | 2001-08-10 | 2003-02-13 | Scimed Life Systems, Inc. | Packages facilitating convenient mixing and delivery of liquids |
EP1432380B1 (en) * | 2001-08-17 | 2006-09-27 | Polyzenix GmbH | Device based on nitinol with a polyphosphazene coating |
US7056338B2 (en) * | 2003-03-28 | 2006-06-06 | Conor Medsystems, Inc. | Therapeutic agent delivery device with controlled therapeutic agent release rates |
US20040249443A1 (en) * | 2001-08-20 | 2004-12-09 | Shanley John F. | Expandable medical device for treating cardiac arrhythmias |
US7842083B2 (en) | 2001-08-20 | 2010-11-30 | Innovational Holdings, Llc. | Expandable medical device with improved spatial distribution |
US20040121981A1 (en) * | 2001-11-21 | 2004-06-24 | Glycogenesys, Inc. | Method for controlling angiogenesis in animals |
US7927368B2 (en) | 2002-03-25 | 2011-04-19 | Kieran Murphy Llc | Device viewable under an imaging beam |
US9375203B2 (en) | 2002-03-25 | 2016-06-28 | Kieran Murphy Llc | Biopsy needle |
US20030181810A1 (en) | 2002-03-25 | 2003-09-25 | Murphy Kieran P. | Kit for image guided surgical procedures |
US7094369B2 (en) * | 2002-03-29 | 2006-08-22 | Scimed Life Systems, Inc. | Processes for manufacturing polymeric microspheres |
US7131997B2 (en) * | 2002-03-29 | 2006-11-07 | Scimed Life Systems, Inc. | Tissue treatment |
US7462366B2 (en) * | 2002-03-29 | 2008-12-09 | Boston Scientific Scimed, Inc. | Drug delivery particle |
US7053134B2 (en) * | 2002-04-04 | 2006-05-30 | Scimed Life Systems, Inc. | Forming a chemically cross-linked particle of a desired shape and diameter |
US20040038303A1 (en) * | 2002-04-08 | 2004-02-26 | Unger Gretchen M. | Biologic modulations with nanoparticles |
CA2482147A1 (en) * | 2002-04-22 | 2003-10-30 | Research Foundation Itsuu Laboratory | Medicament for therapeutic treatment of vascular disease |
US8313760B2 (en) | 2002-05-24 | 2012-11-20 | Angiotech International Ag | Compositions and methods for coating medical implants |
PT1509256E (en) * | 2002-05-24 | 2009-10-15 | Angiotech Int Ag | Compositions and methods for coating medical implants |
CZ294371B6 (en) * | 2002-06-10 | 2004-12-15 | Pliva - Lachema, A. S. | Stabilized pharmaceutical composition based on polyoxyethylated castor oil and process for preparing thereof |
US7649023B2 (en) | 2002-06-11 | 2010-01-19 | Novartis Ag | Biodegradable block copolymeric compositions for drug delivery |
CA2492339A1 (en) | 2002-06-12 | 2003-12-24 | Boston Scientific Limited | Bulking agents |
US7097850B2 (en) | 2002-06-18 | 2006-08-29 | Surmodics, Inc. | Bioactive agent release coating and controlled humidity method |
US20030232087A1 (en) * | 2002-06-18 | 2003-12-18 | Lawin Laurie R. | Bioactive agent release coating with aromatic poly(meth)acrylates |
CN100346850C (en) * | 2003-05-28 | 2007-11-07 | 微创医疗器械(上海)有限公司 | Medicine coating rack |
US20080138377A1 (en) * | 2002-07-05 | 2008-06-12 | Celonova Biosciences, Inc. | Vasodilator Eluting Luminal Stent Devices With A Specific Polyphosphazene Coating and Methods for Their Manufacture and Use |
US20080138433A1 (en) * | 2002-07-05 | 2008-06-12 | Celonova Biosciences, Inc. | Vasodilator eluting blood storage and administration devices with a specific polyphosphazene coating and methods for their manufacture and use |
DK1521603T3 (en) | 2002-07-12 | 2011-04-18 | Cook Inc | Coated medical device |
US20050163821A1 (en) * | 2002-08-02 | 2005-07-28 | Hsing-Wen Sung | Drug-eluting Biodegradable Stent and Delivery Means |
US20040076582A1 (en) * | 2002-08-30 | 2004-04-22 | Dimatteo Kristian | Agent delivery particle |
US7842377B2 (en) * | 2003-08-08 | 2010-11-30 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
US7449236B2 (en) * | 2002-08-09 | 2008-11-11 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
US7649006B2 (en) * | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
WO2004018478A2 (en) | 2002-08-23 | 2004-03-04 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US6921769B2 (en) | 2002-08-23 | 2005-07-26 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
JP3887588B2 (en) * | 2002-08-30 | 2007-02-28 | 株式会社リガク | Stress measurement method by X-ray diffraction |
US8012454B2 (en) | 2002-08-30 | 2011-09-06 | Boston Scientific Scimed, Inc. | Embolization |
EP1539157B1 (en) | 2002-09-18 | 2013-08-21 | Trustees Of The University Of Pennsylvania | Rapamycin for use in inhibiting or preventing choroidal neovascularization |
US20040127976A1 (en) * | 2002-09-20 | 2004-07-01 | Conor Medsystems, Inc. | Method and apparatus for loading a beneficial agent into an expandable medical device |
WO2004026174A2 (en) * | 2002-09-20 | 2004-04-01 | Conor Medsystems, Inc. | Expandable medical device with openings for delivery of multiple beneficial agents |
DE10244847A1 (en) | 2002-09-20 | 2004-04-01 | Ulrich Prof. Dr. Speck | Medical device for drug delivery |
DE60325240D1 (en) * | 2002-09-26 | 2009-01-22 | Angiotech Int Ag | PERIVASCULAR COVERS |
AU2003267751A1 (en) * | 2002-10-15 | 2004-05-04 | Board Of Supervisors Of Louisiana State Universityand Agricultural And Mechanical College | Use of epothilone derivatives for the treatment of hyperparathyroidism |
US7544932B2 (en) * | 2002-10-21 | 2009-06-09 | The United States Of America, As Represented By The Secretary, Of The Department Of Health And Human Services | Contiguous capillary electrospray sources and analytical devices |
US7588825B2 (en) * | 2002-10-23 | 2009-09-15 | Boston Scientific Scimed, Inc. | Embolic compositions |
US7883490B2 (en) | 2002-10-23 | 2011-02-08 | Boston Scientific Scimed, Inc. | Mixing and delivery of therapeutic compositions |
US20040142014A1 (en) * | 2002-11-08 | 2004-07-22 | Conor Medsystems, Inc. | Method and apparatus for reducing tissue damage after ischemic injury |
CA2513721C (en) * | 2002-11-08 | 2013-04-16 | Conor Medsystems, Inc. | Method and apparatus for reducing tissue damage after ischemic injury |
AU2003291470A1 (en) * | 2002-11-08 | 2004-06-03 | Innovational Holdings, Llc | Expandable medical device and method for treating chronic total occlusions with local delivery of an angiogenic factor |
ATE402675T1 (en) | 2002-11-13 | 2008-08-15 | Setagon Inc | MEDICAL DEVICES WITH POROUS LAYERS AND PRODUCTION PROCESSES THEREOF |
US20060121080A1 (en) | 2002-11-13 | 2006-06-08 | Lye Whye K | Medical devices having nanoporous layers and methods for making the same |
US9770349B2 (en) | 2002-11-13 | 2017-09-26 | University Of Virginia Patent Foundation | Nanoporous stents with enhanced cellular adhesion and reduced neointimal formation |
DK1585548T3 (en) | 2002-12-09 | 2018-09-03 | Abraxis Bioscience Llc | COMPOSITIONS AND PROCEDURES FOR THE DELIVERY OF PHARMACOLOGICAL AGENTS |
US7338557B1 (en) * | 2002-12-17 | 2008-03-04 | Advanced Cardiovascular Systems, Inc. | Nozzle for use in coating a stent |
US7842791B2 (en) | 2002-12-19 | 2010-11-30 | Nancy Jean Britten | Dispersible pharmaceutical compositions |
BRPI0408775A (en) * | 2003-03-26 | 2006-03-28 | Polyzenix Gmbh | coated dental implants |
US20040202692A1 (en) * | 2003-03-28 | 2004-10-14 | Conor Medsystems, Inc. | Implantable medical device and method for in situ selective modulation of agent delivery |
JP2006523235A (en) * | 2003-03-28 | 2006-10-12 | コーザン バイオサイエンシス インコーポレイテッド | Apparatus, method and composition for preventing restenosis |
EP2272544A1 (en) | 2003-03-28 | 2011-01-12 | Conor Medsystems, Inc. | Implantable medical device with beneficial agent concentration gradient |
US20050010170A1 (en) * | 2004-02-11 | 2005-01-13 | Shanley John F | Implantable medical device with beneficial agent concentration gradient |
US7306580B2 (en) | 2003-04-16 | 2007-12-11 | Cook Incorporated | Medical device with therapeutic agents |
US20040220534A1 (en) * | 2003-04-29 | 2004-11-04 | Martens Paul W. | Medical device with antimicrobial layer |
CA2524271C (en) * | 2003-05-02 | 2012-09-04 | Surmodics, Inc. | Controlled release bioactive agent delivery device |
US8246974B2 (en) * | 2003-05-02 | 2012-08-21 | Surmodics, Inc. | Medical devices and methods for producing the same |
US7169179B2 (en) * | 2003-06-05 | 2007-01-30 | Conor Medsystems, Inc. | Drug delivery device and method for bi-directional drug delivery |
US20050064005A1 (en) * | 2003-08-13 | 2005-03-24 | Dinh Thomas Q. | Active agent delivery systems including a miscible polymer blend, medical devices, and methods |
WO2005018600A2 (en) * | 2003-08-22 | 2005-03-03 | Cube Medical A/S | Method of treating a patient suffering from a solid tumour |
US7976823B2 (en) | 2003-08-29 | 2011-07-12 | Boston Scientific Scimed, Inc. | Ferromagnetic particles and methods |
AU2004274026A1 (en) * | 2003-09-18 | 2005-03-31 | Macusight, Inc. | Transscleral delivery |
US7785653B2 (en) | 2003-09-22 | 2010-08-31 | Innovational Holdings Llc | Method and apparatus for loading a beneficial agent into an expandable medical device |
US7056337B2 (en) * | 2003-10-21 | 2006-06-06 | Cook Incorporated | Natural tissue stent |
US7901770B2 (en) | 2003-11-04 | 2011-03-08 | Boston Scientific Scimed, Inc. | Embolic compositions |
FR2861993B1 (en) * | 2003-11-06 | 2006-01-21 | Jean Claude Rigaud | ANTI RESTENOSE MOLECULAR COMPLEX FOR INTRACORONARY ENDOPROTHESIS |
US20050100529A1 (en) * | 2003-11-06 | 2005-05-12 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders |
EP1682196A2 (en) * | 2003-11-10 | 2006-07-26 | Angiotech International Ag | Medical implants and anti-scarring agents |
US20050100577A1 (en) * | 2003-11-10 | 2005-05-12 | Parker Theodore L. | Expandable medical device with beneficial agent matrix formed by a multi solvent system |
CA2536188A1 (en) * | 2003-11-20 | 2005-06-09 | Angiotech International Ag | Electrical devices and anti-scarring agents |
US20050209664A1 (en) * | 2003-11-20 | 2005-09-22 | Angiotech International Ag | Electrical devices and anti-scarring agents |
US20050208095A1 (en) * | 2003-11-20 | 2005-09-22 | Angiotech International Ag | Polymer compositions and methods for their use |
WO2005074913A2 (en) * | 2004-01-30 | 2005-08-18 | Angiotech International Ag | Compositions and methods for treating contracture |
US7349971B2 (en) * | 2004-02-05 | 2008-03-25 | Scenera Technologies, Llc | System for transmitting data utilizing multiple communication applications simultaneously in response to user request without specifying recipient's communication information |
US7294145B2 (en) * | 2004-02-26 | 2007-11-13 | Boston Scientific Scimed, Inc. | Stent with differently coated inside and outside surfaces |
US7736671B2 (en) | 2004-03-02 | 2010-06-15 | Boston Scientific Scimed, Inc. | Embolization |
US8173176B2 (en) | 2004-03-30 | 2012-05-08 | Boston Scientific Scimed, Inc. | Embolization |
US8003122B2 (en) * | 2004-03-31 | 2011-08-23 | Cordis Corporation | Device for local and/or regional delivery employing liquid formulations of therapeutic agents |
WO2005099787A1 (en) * | 2004-04-06 | 2005-10-27 | Surmodics, Inc. | Coating compositions for bioactive agents |
US20060083772A1 (en) * | 2004-04-06 | 2006-04-20 | Dewitt David M | Coating compositions for bioactive agents |
US20050238870A1 (en) * | 2004-04-22 | 2005-10-27 | Marcia Buiser | Embolization |
ATE367132T1 (en) * | 2004-05-25 | 2007-08-15 | Cook William Europ | STENT AND STENT REMOVING DEVICE |
US7311861B2 (en) | 2004-06-01 | 2007-12-25 | Boston Scientific Scimed, Inc. | Embolization |
US20050287287A1 (en) * | 2004-06-24 | 2005-12-29 | Parker Theodore L | Methods and systems for loading an implantable medical device with beneficial agent |
WO2006004774A2 (en) * | 2004-06-28 | 2006-01-12 | Stanford University | Laulimalide analogues as therapeutic agents |
US8236338B2 (en) | 2004-07-13 | 2012-08-07 | The University Of Tennessee Research Foundation | Adhesive composition for carrying therapeutic agents as delivery vehicle on coatings applied to vascular grafts |
US8119153B2 (en) * | 2004-08-26 | 2012-02-21 | Boston Scientific Scimed, Inc. | Stents with drug eluting coatings |
US20060079956A1 (en) * | 2004-09-15 | 2006-04-13 | Conor Medsystems, Inc. | Bifurcation stent with crushable end and method for delivery of a stent to a bifurcation |
EP1807018A4 (en) * | 2004-10-21 | 2012-07-04 | Univ Iowa Res Found | In situ controlled release drug delivery system |
US20210299056A9 (en) | 2004-10-25 | 2021-09-30 | Varian Medical Systems, Inc. | Color-Coded Polymeric Particles of Predetermined Size for Therapeutic and/or Diagnostic Applications and Related Methods |
US9107850B2 (en) | 2004-10-25 | 2015-08-18 | Celonova Biosciences, Inc. | Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same |
US9114162B2 (en) | 2004-10-25 | 2015-08-25 | Celonova Biosciences, Inc. | Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same |
US20060093647A1 (en) * | 2004-10-29 | 2006-05-04 | Villafana Manuel A | Multiple layer coating composition |
JP2008519036A (en) * | 2004-11-08 | 2008-06-05 | バクスター・インターナショナル・インコーポレイテッド | Nanoparticle composition of tubulin inhibitory compounds |
US8425550B2 (en) | 2004-12-01 | 2013-04-23 | Boston Scientific Scimed, Inc. | Embolic coils |
JP2008528204A (en) * | 2005-01-28 | 2008-07-31 | テファ, インコーポレイテッド | Embolization using poly-4-hydroxybutyrate particles |
WO2006082221A1 (en) * | 2005-02-03 | 2006-08-10 | Cinvention Ag | Drug delivery materials made by sol/gel technology |
US9050393B2 (en) | 2005-02-08 | 2015-06-09 | Bruce N. Saffran | Medical devices and methods for modulation of physiology using device-based surface chemistry |
KR101387456B1 (en) | 2005-02-09 | 2014-04-21 | 산텐 세이야꾸 가부시키가이샤 | Liquid formulations for treatment of diseases or conditions |
US8663639B2 (en) | 2005-02-09 | 2014-03-04 | Santen Pharmaceutical Co., Ltd. | Formulations for treating ocular diseases and conditions |
US8735394B2 (en) | 2005-02-18 | 2014-05-27 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
EP2301531B1 (en) | 2005-02-18 | 2018-06-06 | Abraxis BioScience, LLC | Combinations and modes of administration of therapeutic agents and combination therapy |
AU2005100176A4 (en) * | 2005-03-01 | 2005-04-07 | Gym Tv Pty Ltd | Garbage bin clip |
US7858183B2 (en) | 2005-03-02 | 2010-12-28 | Boston Scientific Scimed, Inc. | Particles |
US7727555B2 (en) | 2005-03-02 | 2010-06-01 | Boston Scientific Scimed, Inc. | Particles |
US20060224170A1 (en) * | 2005-03-30 | 2006-10-05 | Michael Duff | Surgical marker clip and method for cholangiography |
EP1868664A2 (en) | 2005-04-15 | 2007-12-26 | Interface Biologics Inc. | Methods and compositions for the delivery of biologically active agents |
US7963287B2 (en) | 2005-04-28 | 2011-06-21 | Boston Scientific Scimed, Inc. | Tissue-treatment methods |
JO3058B1 (en) | 2005-04-29 | 2017-03-15 | Applied Molecular Evolution Inc | Anti-IL-6 Antibodies,Compositions,Methods and uses |
US8226926B2 (en) | 2005-05-09 | 2012-07-24 | Biosphere Medical, S.A. | Compositions and methods using microspheres and non-ionic contrast agents |
US20060280787A1 (en) * | 2005-06-14 | 2006-12-14 | Baxter International Inc. | Pharmaceutical formulation of the tubulin inhibitor indibulin for oral administration with improved pharmacokinetic properties, and process for the manufacture thereof |
US20070004973A1 (en) * | 2005-06-15 | 2007-01-04 | Tan Sharon M L | Tissue treatment methods |
US20060286071A1 (en) * | 2005-06-21 | 2006-12-21 | Epstein Samuel J | Therapeutic pastes for medical device coating |
US9463426B2 (en) | 2005-06-24 | 2016-10-11 | Boston Scientific Scimed, Inc. | Methods and systems for coating particles |
US7736293B2 (en) | 2005-07-22 | 2010-06-15 | Biocompatibles Uk Limited | Implants for use in brachytherapy and other radiation therapy that resist migration and rotation |
US8187159B2 (en) | 2005-07-22 | 2012-05-29 | Biocompatibles, UK | Therapeutic member including a rail used in brachytherapy and other radiation therapy |
AU2006278328A1 (en) * | 2005-08-04 | 2007-02-15 | Angiotech International Ag | Block copolymer compositions and uses thereof |
KR101420445B1 (en) | 2005-08-31 | 2014-07-16 | 아브락시스 바이오사이언스, 엘엘씨 | Compositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents |
US8034765B2 (en) * | 2005-08-31 | 2011-10-11 | Abraxis Bioscience, Llc | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
WO2007040249A1 (en) | 2005-10-06 | 2007-04-12 | Kaneka Corporation | Stent to be placed in the living body |
US8007509B2 (en) | 2005-10-12 | 2011-08-30 | Boston Scientific Scimed, Inc. | Coil assemblies, components and methods |
US8101197B2 (en) | 2005-12-19 | 2012-01-24 | Stryker Corporation | Forming coils |
US8152839B2 (en) | 2005-12-19 | 2012-04-10 | Boston Scientific Scimed, Inc. | Embolic coils |
US7501179B2 (en) * | 2005-12-21 | 2009-03-10 | Boston Scientific Scimed, Inc. | Block copolymer particles |
US7947368B2 (en) | 2005-12-21 | 2011-05-24 | Boston Scientific Scimed, Inc. | Block copolymer particles |
EP2001438A2 (en) | 2006-02-09 | 2008-12-17 | Macusight, Inc. | Stable formulations, and methods of their preparation and use |
CN100464736C (en) * | 2006-03-17 | 2009-03-04 | 山东蓝金生物工程有限公司 | Slow released anticancer injection with both antimetabolite and its synergist |
DK2001466T3 (en) | 2006-03-23 | 2016-02-29 | Santen Pharmaceutical Co Ltd | LOW-DOSAGE RAPAMYCINE FOR TREATMENT OF VASCULAR PERMEABILITY-RELATED DISEASES |
US7993675B2 (en) | 2006-05-10 | 2011-08-09 | Medtronic Xomed, Inc. | Solvating system and sealant for medical use in the sinuses and nasal passages |
EP2338488A1 (en) * | 2006-05-26 | 2011-06-29 | Bayer HealthCare, LLC | Drug combinations with substituted diaryl ureas for the treatment of cancer |
US20070298069A1 (en) * | 2006-06-26 | 2007-12-27 | Boston Scientific Scimed, Inc. | Medical devices for release of low solubility therapeutic agents |
US8328752B2 (en) * | 2006-06-30 | 2012-12-11 | Cvdevices, Llc | Devices, systems, and methods for promotion of infarct healing and reinforcement of border zone |
NZ573919A (en) | 2006-06-30 | 2012-08-31 | Cvdevices Llc | A system for engaging heart tisue utilising a vacuum for percutaneous intravascular access to cardiac tissue |
US9023075B2 (en) * | 2006-06-30 | 2015-05-05 | Cvdevices, Llc | Devices, systems, and methods for lead delivery |
US20080051702A1 (en) * | 2006-08-24 | 2008-02-28 | Herrmann Robert A | Therapeutic agent delivery for the treatment of asthma via implantable and insertable medical devices |
JP2010505597A (en) | 2006-10-10 | 2010-02-25 | セロノバ バイオサイエンシーズ, インコーポレイテッド | Bioprosthetic heart valve using polyphosphazene |
CN101646468A (en) * | 2006-10-10 | 2010-02-10 | 西洛诺瓦生物科学公司 | Compositions and devices comrising silicone and specific polyphosphazenes |
US20080167592A1 (en) * | 2006-10-26 | 2008-07-10 | Greer Steven E | Preventing or treating wounds with a collodion barrier incorporating active agents |
US8414927B2 (en) | 2006-11-03 | 2013-04-09 | Boston Scientific Scimed, Inc. | Cross-linked polymer particles |
BRPI0718696A2 (en) | 2006-11-09 | 2013-12-31 | Alcon Res Ltd | WATER INSOLUBLE POLYMER MATRIX FOR PHARMACEUTICAL RELEASE. |
WO2008060929A1 (en) * | 2006-11-09 | 2008-05-22 | Alcon Research, Ltd. | Punctal plug comprising a water-insoluble polymeric matrix |
US8414910B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US20080276935A1 (en) | 2006-11-20 | 2008-11-13 | Lixiao Wang | Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs |
US8414526B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids |
US20080175887A1 (en) | 2006-11-20 | 2008-07-24 | Lixiao Wang | Treatment of Asthma and Chronic Obstructive Pulmonary Disease With Anti-proliferate and Anti-inflammatory Drugs |
US8425459B2 (en) | 2006-11-20 | 2013-04-23 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent |
US8998846B2 (en) | 2006-11-20 | 2015-04-07 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
US8414525B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US9737640B2 (en) | 2006-11-20 | 2017-08-22 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US9700704B2 (en) | 2006-11-20 | 2017-07-11 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
US20080171068A1 (en) * | 2007-01-17 | 2008-07-17 | Etcetera Llc | Antimicrobial, infection-control and odor-control film and film composite |
DE102007003184A1 (en) | 2007-01-22 | 2008-07-24 | Orlowski, Michael, Dr. | Method for loading structured surfaces |
WO2008097511A2 (en) | 2007-02-07 | 2008-08-14 | Cook Incorporated | Medical device coatings for releasing a therapeutic agent at multiple rates |
US8088095B2 (en) | 2007-02-08 | 2012-01-03 | Medtronic Xomed, Inc. | Polymeric sealant for medical use |
US20100076489A1 (en) * | 2007-03-06 | 2010-03-25 | Joshua Stopek | Wound closure material |
US9888924B2 (en) * | 2007-03-06 | 2018-02-13 | Covidien Lp | Wound closure material |
US8529819B2 (en) * | 2007-03-06 | 2013-09-10 | Covidien Lp | Wound closure material |
US9375164B2 (en) | 2007-03-08 | 2016-06-28 | Sync-Rx, Ltd. | Co-use of endoluminal data and extraluminal imaging |
US11064964B2 (en) | 2007-03-08 | 2021-07-20 | Sync-Rx, Ltd | Determining a characteristic of a lumen by measuring velocity of a contrast agent |
EP2358269B1 (en) | 2007-03-08 | 2019-04-10 | Sync-RX, Ltd. | Image processing and tool actuation for medical procedures |
US10716528B2 (en) | 2007-03-08 | 2020-07-21 | Sync-Rx, Ltd. | Automatic display of previously-acquired endoluminal images |
US9968256B2 (en) | 2007-03-08 | 2018-05-15 | Sync-Rx Ltd. | Automatic identification of a tool |
US11197651B2 (en) | 2007-03-08 | 2021-12-14 | Sync-Rx, Ltd. | Identification and presentation of device-to-vessel relative motion |
US9629571B2 (en) | 2007-03-08 | 2017-04-25 | Sync-Rx, Ltd. | Co-use of endoluminal data and extraluminal imaging |
JP5639764B2 (en) | 2007-03-08 | 2014-12-10 | シンク−アールエックス,リミティド | Imaging and tools for use with moving organs |
US20080265343A1 (en) * | 2007-04-26 | 2008-10-30 | International Business Machines Corporation | Field effect transistor with inverted t shaped gate electrode and methods for fabrication thereof |
JP5174891B2 (en) | 2007-04-27 | 2013-04-03 | シーヴィ デヴァイシズ,エルエルシー | Devices, systems, and methods for accessing the epicardial surface of the heart |
US9050064B2 (en) * | 2007-04-27 | 2015-06-09 | Cvdevices, Llc | Systems for engaging a bodily tissue and methods of using the same |
EP2144569A4 (en) * | 2007-04-27 | 2014-03-26 | Cvdevices Llc | Devices, systems, and methods for accessing the epicardial surface of the heart |
US8540674B2 (en) | 2007-04-27 | 2013-09-24 | Cvdevices, Llc | Devices, systems, and methods for transeptal atrial puncture using an engagement catheter platform |
WO2009099464A1 (en) * | 2008-02-05 | 2009-08-13 | Cvdevices, Llc | Steering engagement catheter devices, systems and methods |
DE112008001301T5 (en) | 2007-05-14 | 2010-04-29 | Reserach Foundation Of State University Of New York | Induction of a physiological dispersion response in bacterial cells in a biofilm |
US8147769B1 (en) | 2007-05-16 | 2012-04-03 | Abbott Cardiovascular Systems Inc. | Stent and delivery system with reduced chemical degradation |
JP2008305262A (en) * | 2007-06-08 | 2008-12-18 | Konica Minolta Business Technologies Inc | Printer introduction method in server and thin client environment |
US9192697B2 (en) | 2007-07-03 | 2015-11-24 | Hemoteq Ag | Balloon catheter for treating stenosis of body passages and for preventing threatening restenosis |
WO2009036368A2 (en) * | 2007-09-14 | 2009-03-19 | Nitto Denko Corporation | Drug carriers |
FR2922452B1 (en) * | 2007-10-19 | 2010-01-22 | Coatex Sas | FORMULATIONS OF ORGANOPLATINIC COMPOUNDS IN THE PRESENCE OF ASSOCIATIVE POLYMERS, PRODUCTS OBTAINED AND USES THEREOF |
EP2050441A1 (en) * | 2007-10-19 | 2009-04-22 | Université Victor Segalen Bordeaux 2 | Use of beta blocker for the manufacture of a medicament for the treatment of hemangiomas |
US20090110730A1 (en) * | 2007-10-30 | 2009-04-30 | Celonova Biosciences, Inc. | Loadable Polymeric Particles for Marking or Masking Individuals and Methods of Preparing and Using the Same |
DE102008008263A1 (en) | 2008-02-08 | 2009-08-13 | Thomas Kuczera | Percutaneous transluminal coronary angioplasty catheter with a coating, useful e.g. to treat restenosis, comprises amino-/carboxyl-functional group, oligonucleotides, microbodies, C-type natriuretic peptide, proteins and/or oligopeptide |
CN101970964B (en) * | 2008-03-19 | 2012-05-23 | 株式会社盛本医药 | Freeze-drying method and freeze-drying apparatus |
JP5731372B2 (en) * | 2008-04-10 | 2015-06-10 | ヴァージニア コモンウェルス ユニバーシティ | Induction of tumor hypoxia for cancer treatment |
DE202008006190U1 (en) | 2008-05-06 | 2008-07-17 | Sellin, Lothar | restenosis prophylaxis |
DE202008007347U1 (en) | 2008-05-31 | 2008-10-16 | Orlowski, Benjamin Daniel | Copper stent |
CA2727432C (en) | 2008-06-12 | 2016-10-11 | Medtronic Xomed, Inc. | Method for treating chronic wounds with an extracellular polymeric substance solvating system |
US8188235B2 (en) | 2008-06-18 | 2012-05-29 | Pfizer Inc. | Antibodies to IL-6 and their uses |
US20090319031A1 (en) * | 2008-06-19 | 2009-12-24 | Yunbing Wang | Bioabsorbable Polymeric Stent With Improved Structural And Molecular Weight Integrity |
ES2770273T3 (en) | 2008-06-27 | 2020-07-01 | Tepha Inc | Injectable administration of microparticles and compositions therefor |
WO2010003076A2 (en) * | 2008-07-03 | 2010-01-07 | Vesseltek Biomedical, Llc | Controlled and localized release of retinoids to improve neointimal hyperplasia |
WO2010024898A2 (en) | 2008-08-29 | 2010-03-04 | Lutonix, Inc. | Methods and apparatuses for coating balloon catheters |
US8257722B2 (en) | 2008-09-15 | 2012-09-04 | Cv Ingenuity Corp. | Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens |
US9198968B2 (en) | 2008-09-15 | 2015-12-01 | The Spectranetics Corporation | Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens |
US8114429B2 (en) | 2008-09-15 | 2012-02-14 | Cv Ingenuity Corp. | Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens |
US8128951B2 (en) | 2008-09-15 | 2012-03-06 | Cv Ingenuity Corp. | Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens |
US20100070013A1 (en) * | 2008-09-18 | 2010-03-18 | Medtronic Vascular, Inc. | Medical Device With Microsphere Drug Delivery System |
US8049061B2 (en) | 2008-09-25 | 2011-11-01 | Abbott Cardiovascular Systems, Inc. | Expandable member formed of a fibrous matrix having hydrogel polymer for intraluminal drug delivery |
US8076529B2 (en) | 2008-09-26 | 2011-12-13 | Abbott Cardiovascular Systems, Inc. | Expandable member formed of a fibrous matrix for intraluminal drug delivery |
US8226603B2 (en) | 2008-09-25 | 2012-07-24 | Abbott Cardiovascular Systems Inc. | Expandable member having a covering formed of a fibrous matrix for intraluminal drug delivery |
US8500687B2 (en) | 2008-09-25 | 2013-08-06 | Abbott Cardiovascular Systems Inc. | Stent delivery system having a fibrous matrix covering with improved stent retention |
US9782565B2 (en) | 2008-10-01 | 2017-10-10 | Covidien Lp | Endoscopic ultrasound-guided biliary access system |
US9186128B2 (en) | 2008-10-01 | 2015-11-17 | Covidien Lp | Needle biopsy device |
US11298113B2 (en) | 2008-10-01 | 2022-04-12 | Covidien Lp | Device for needle biopsy with integrated needle protection |
US9332973B2 (en) | 2008-10-01 | 2016-05-10 | Covidien Lp | Needle biopsy device with exchangeable needle and integrated needle protection |
US8968210B2 (en) | 2008-10-01 | 2015-03-03 | Covidien LLP | Device for needle biopsy with integrated needle protection |
US9095313B2 (en) | 2008-11-18 | 2015-08-04 | Sync-Rx, Ltd. | Accounting for non-uniform longitudinal motion during movement of an endoluminal imaging probe |
US11064903B2 (en) | 2008-11-18 | 2021-07-20 | Sync-Rx, Ltd | Apparatus and methods for mapping a sequence of images to a roadmap image |
US9101286B2 (en) | 2008-11-18 | 2015-08-11 | Sync-Rx, Ltd. | Apparatus and methods for determining a dimension of a portion of a stack of endoluminal data points |
US10362962B2 (en) | 2008-11-18 | 2019-07-30 | Synx-Rx, Ltd. | Accounting for skipped imaging locations during movement of an endoluminal imaging probe |
US9144394B2 (en) | 2008-11-18 | 2015-09-29 | Sync-Rx, Ltd. | Apparatus and methods for determining a plurality of local calibration factors for an image |
US8855744B2 (en) | 2008-11-18 | 2014-10-07 | Sync-Rx, Ltd. | Displaying a device within an endoluminal image stack |
US9974509B2 (en) | 2008-11-18 | 2018-05-22 | Sync-Rx Ltd. | Image super enhancement |
DE102009059070A1 (en) | 2008-12-19 | 2010-07-01 | Lothar Sellin | Medical device e.g. percutaneous transluminal coronary angioplasty catheter, for direct application of C-type natriuretic peptide on blood vessel wall, has base body with coating, where device consists of C-type natriuretic peptide |
EP2210584A1 (en) * | 2009-01-27 | 2010-07-28 | Bayer Schering Pharma Aktiengesellschaft | Stable polymeric composition comprising an epothilone and an amphiphilic block copolymer |
WO2010093945A2 (en) | 2009-02-13 | 2010-08-19 | Glaukos Corporation | Uveoscleral drug delivery implant and methods for implanting the same |
JP4782850B2 (en) * | 2009-02-24 | 2011-09-28 | シャープ株式会社 | Image data processing device |
US7828996B1 (en) * | 2009-03-27 | 2010-11-09 | Abbott Cardiovascular Systems Inc. | Method for the manufacture of stable, nano-sized particles |
WO2010114770A1 (en) * | 2009-03-30 | 2010-10-07 | Cerulean Pharma Inc. | Polymer-agent conjugates, particles, compositions, and related methods of use |
JP2012522055A (en) * | 2009-03-30 | 2012-09-20 | セルリアン・ファーマ・インコーポレイテッド | Polymer-drug conjugates, particles, compositions, and related methods of use |
WO2010114768A1 (en) * | 2009-03-30 | 2010-10-07 | Cerulean Pharma Inc. | Polymer-epothilone conjugates, particles, compositions, and related methods of use |
EP2243501A1 (en) | 2009-04-24 | 2010-10-27 | Eurocor Gmbh | Shellac and paclitaxel coated catheter balloons |
EP2424581B1 (en) | 2009-04-28 | 2017-03-01 | SurModics, Inc. | Devices and methods for delivery of bioactive agents |
DE202009006632U1 (en) | 2009-05-07 | 2009-07-16 | Sellin, Lothar | Coating of medical surfaces |
US20100285085A1 (en) * | 2009-05-07 | 2010-11-11 | Abbott Cardiovascular Systems Inc. | Balloon coating with drug transfer control via coating thickness |
US10206813B2 (en) | 2009-05-18 | 2019-02-19 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
US9309347B2 (en) | 2009-05-20 | 2016-04-12 | Biomedical, Inc. | Bioresorbable thermoset polyester/urethane elastomers |
US8888840B2 (en) * | 2009-05-20 | 2014-11-18 | Boston Scientific Scimed, Inc. | Drug eluting medical implant |
US9265633B2 (en) | 2009-05-20 | 2016-02-23 | 480 Biomedical, Inc. | Drug-eluting medical implants |
US20110319987A1 (en) | 2009-05-20 | 2011-12-29 | Arsenal Medical | Medical implant |
US8992601B2 (en) | 2009-05-20 | 2015-03-31 | 480 Biomedical, Inc. | Medical implants |
AU2010249558A1 (en) * | 2009-05-20 | 2011-12-08 | Arsenal Medical, Inc. | Medical implant |
EP2944332B1 (en) | 2009-07-10 | 2016-08-17 | Boston Scientific Scimed, Inc. | Use of nanocrystals for a drug delivery balloon |
US10080821B2 (en) | 2009-07-17 | 2018-09-25 | Boston Scientific Scimed, Inc. | Nucleation of drug delivery balloons to provide improved crystal size and density |
US8372133B2 (en) * | 2009-10-05 | 2013-02-12 | 480 Biomedical, Inc. | Polymeric implant delivery system |
CA2777682C (en) | 2009-10-13 | 2015-02-24 | The Regents Of The University Of Michigan | Dendrimer compositions and methods of synthesis |
DE202009014776U1 (en) | 2009-11-02 | 2010-03-11 | Sellin, Lothar | coating |
CN102695500A (en) | 2009-11-09 | 2012-09-26 | 聚光灯技术合伙有限责任公司 | Polysaccharide based hydrogels |
JP2013509963A (en) | 2009-11-09 | 2013-03-21 | スポットライト テクノロジー パートナーズ エルエルシー | Fragmented hydrogel |
US8900603B2 (en) | 2009-12-18 | 2014-12-02 | Interface Biologics, Inc. | Local delivery of drugs from self assembled coatings |
DE202009017490U1 (en) | 2009-12-22 | 2010-04-08 | Sellin, Lothar | Frankincense and / or boswellic acid coating |
US20110218606A1 (en) * | 2010-03-02 | 2011-09-08 | Medtronic Vascular, Inc. | Methods for Stabilizing Femoral Vessels |
US20110224720A1 (en) * | 2010-03-11 | 2011-09-15 | Cvdevices, Llc | Devices, systems, and methods for closing a hole in cardiac tissue |
KR20130028727A (en) | 2010-03-29 | 2013-03-19 | 아브락시스 바이오사이언스, 엘엘씨 | Methods of enhancing drug delivery and effectiveness of therapeutic agents |
WO2011123395A1 (en) | 2010-03-29 | 2011-10-06 | Abraxis Bioscience, Llc | Methods of treating cancer |
US10413506B2 (en) | 2010-04-03 | 2019-09-17 | Praful Doshi | Medical devices including medicaments and methods of making and using same including enhancing comfort, enhancing drug penetration, and treatment of myopia |
US9554888B2 (en) * | 2010-04-20 | 2017-01-31 | University Of Utah Research Foundation | Phase separation sprayed scaffold |
WO2011146483A1 (en) | 2010-05-17 | 2011-11-24 | Aerie Pharmaceuticals, Inc. | Drug delivery devices for delivery of ocular therapeutic agents |
US8945156B2 (en) | 2010-05-19 | 2015-02-03 | University Of Utah Research Foundation | Tissue fixation |
US8858577B2 (en) | 2010-05-19 | 2014-10-14 | University Of Utah Research Foundation | Tissue stabilization system |
JP2013527232A (en) * | 2010-06-02 | 2013-06-27 | アブラクシス バイオサイエンス, エルエルシー | How to treat bladder cancer |
NZ604031A (en) | 2010-06-04 | 2015-05-29 | Abraxis Bioscience Llc | Methods of treatment of pancreatic cancer |
EP2611476B1 (en) | 2010-09-02 | 2016-08-10 | Boston Scientific Scimed, Inc. | Coating process for drug delivery balloons using heat-induced rewrap memory |
US8884027B2 (en) | 2010-10-22 | 2014-11-11 | University Of Rochester | Melampomagnolide B derivatives as antileukemic and cytotoxic agents |
US9668915B2 (en) | 2010-11-24 | 2017-06-06 | Dose Medical Corporation | Drug eluting ocular implant |
EP2857032A3 (en) | 2010-12-02 | 2015-07-15 | Maruzen Pharmaceuticals Co., Ltd. | Tie2 activator, vascular endothelial growth factor (vegf) inhibitor, anti-angiogenic agent, agent for maturing blood vessels, agent for normalizing blood vessels, agent for stabilizing blood vessels, and pharmaceutical composition |
SG192181A1 (en) * | 2011-01-28 | 2013-08-30 | Univ Dalhousie | Radiopaque embolic particles |
US8852214B2 (en) | 2011-02-04 | 2014-10-07 | University Of Utah Research Foundation | System for tissue fixation to bone |
DE202011002713U1 (en) | 2011-02-14 | 2011-04-14 | Sellin, Lothar | Biodegradable medical coating and its use |
US9757497B2 (en) | 2011-05-20 | 2017-09-12 | Surmodics, Inc. | Delivery of coated hydrophobic active agent particles |
US10213529B2 (en) | 2011-05-20 | 2019-02-26 | Surmodics, Inc. | Delivery of coated hydrophobic active agent particles |
US9861727B2 (en) | 2011-05-20 | 2018-01-09 | Surmodics, Inc. | Delivery of hydrophobic active agent particles |
US10245178B1 (en) | 2011-06-07 | 2019-04-02 | Glaukos Corporation | Anterior chamber drug-eluting ocular implant |
JP6099640B2 (en) | 2011-06-23 | 2017-03-22 | シンク−アールエックス,リミティド | Lumen background sharpening |
RU2467705C1 (en) * | 2011-06-30 | 2012-11-27 | ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ И СОЦИАЛЬНОГО РАЗВИТИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ (ФГУ "РНЦРХТ" Минздравсоцразвития России) | Method of treating obliterating arterial sclerosis of lower extremities |
WO2013028208A1 (en) | 2011-08-25 | 2013-02-28 | Boston Scientific Scimed, Inc. | Medical device with crystalline drug coating |
EP2574918B1 (en) | 2011-09-28 | 2014-12-10 | Mems Ag | Microthermal method and sensor for determining physical gas properties |
DE202011106744U1 (en) | 2011-10-15 | 2011-11-11 | Lothar Sellin | Better bioavailability of shellac / paclitaxel coatings |
US20130197657A1 (en) * | 2011-12-08 | 2013-08-01 | Diana Anca | Central airway stent |
US20130245759A1 (en) * | 2012-03-09 | 2013-09-19 | The Florida International University Board Of Trustees | Medical devices incorporating silicone nanoparticles, and uses thereof |
EP2852319B1 (en) * | 2012-05-21 | 2017-05-17 | Sync-RX, Ltd. | Co-use of endoluminal data and extraluminal imaging |
US20130317622A1 (en) * | 2012-05-25 | 2013-11-28 | Antonio Sambusseti | Surgical method for grafting an artificial implant in a bladder and/or in a urethral or ureteral segment |
MX351261B (en) | 2012-06-01 | 2017-10-06 | Surmodics Inc | Apparatus and method for coating balloon catheters. |
US9827401B2 (en) | 2012-06-01 | 2017-11-28 | Surmodics, Inc. | Apparatus and methods for coating medical devices |
JP6134789B2 (en) | 2012-06-26 | 2017-05-24 | シンク−アールエックス,リミティド | Image processing related to flow in luminal organs |
US9956385B2 (en) | 2012-06-28 | 2018-05-01 | The Spectranetics Corporation | Post-processing of a medical device to control morphology and mechanical properties |
WO2014008875A1 (en) | 2012-07-12 | 2014-01-16 | Cardionovum Gmbh | Catheter balloon, method for producing a coated catheter balloon and use of the pharmacological active ingredient |
US10390935B2 (en) | 2012-07-30 | 2019-08-27 | Conextions, Inc. | Soft tissue to bone repair devices, systems, and methods |
US11253252B2 (en) | 2012-07-30 | 2022-02-22 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US11944531B2 (en) | 2012-07-30 | 2024-04-02 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US10219804B2 (en) | 2012-07-30 | 2019-03-05 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US9427309B2 (en) | 2012-07-30 | 2016-08-30 | Conextions, Inc. | Soft tissue repair devices, systems, and methods |
US9629632B2 (en) | 2012-07-30 | 2017-04-25 | Conextions, Inc. | Soft tissue repair devices, systems, and methods |
US10835241B2 (en) | 2012-07-30 | 2020-11-17 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US11957334B2 (en) | 2012-07-30 | 2024-04-16 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
CA2889981A1 (en) | 2012-10-29 | 2014-05-08 | Ariste Medical, Inc. | Polymer coating compositions and coated products |
JP6438406B2 (en) | 2012-11-05 | 2018-12-12 | サーモディクス,インコーポレイテッド | Compositions and methods for delivering hydrophobic bioactive agents |
US11246963B2 (en) | 2012-11-05 | 2022-02-15 | Surmodics, Inc. | Compositions and methods for delivery of hydrophobic active agents |
RU2528249C2 (en) * | 2012-11-23 | 2014-09-10 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Method for angiogenesis inhibition with recombinant forms of urokinase |
US20140212355A1 (en) * | 2013-01-28 | 2014-07-31 | Abbott Cardiovascular Systems Inc. | Trans-arterial drug delivery |
WO2014140684A1 (en) * | 2013-03-15 | 2014-09-18 | Microtech Medical Technologies Ltd. | Implantable anchor |
DE202013002567U1 (en) | 2013-03-18 | 2013-05-07 | Lothar Sellin | NABP coating |
CN105188666A (en) | 2013-04-01 | 2015-12-23 | 阿勒根公司 | Microsphere drug delivery system for sustained intraocular release |
KR20160093609A (en) * | 2013-10-25 | 2016-08-08 | 머케이터 메드시스템즈, 인크. | Maintenance of bronchial patency by local delivery of cytotoxic, cytostatic, or anti-neoplastic agent |
US10842969B2 (en) | 2013-10-25 | 2020-11-24 | Mercator Medsystems, Inc. | Systems and methods of treating malacia by local delivery of hydrogel to augment tissue |
US10525171B2 (en) | 2014-01-24 | 2020-01-07 | The Spectranetics Corporation | Coatings for medical devices |
US11583384B2 (en) | 2014-03-12 | 2023-02-21 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
JP6681872B2 (en) | 2014-03-21 | 2020-04-15 | ユニバーシティ オブ ピッツバーグ −オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション | Method for preparing final sterile hydrogel derived from extracellular matrix |
WO2015164524A1 (en) | 2014-04-22 | 2015-10-29 | Ariste Medical, Inc. | Methods and processes for application of drug delivery polymeric coatings |
AU2015266850B2 (en) | 2014-05-29 | 2019-12-05 | Glaukos Corporation | Implants with controlled drug delivery features and methods of using same |
RU2555378C1 (en) * | 2014-07-10 | 2015-07-10 | Вадим Викторович Евдокимов | Method of endoscopic arrest and prevention of ulcerous bleedings from duodenum defects |
SG10201902499VA (en) | 2014-09-03 | 2019-04-29 | Genesegues Inc | Therapeutic nanoparticles and related compositions, methods and systems |
JP6826992B2 (en) | 2014-11-26 | 2021-02-10 | エービーケー バイオメディカル インコーポレイテッドAbk Biomedical Inc. | Radiation embolic particles |
WO2016093412A1 (en) * | 2014-12-10 | 2016-06-16 | 주식회사 에이치제이메디칼 | Gelatin sponge containing phosphate buffer solution (pbs) or phosphate buffer and applied to transcatheter arterial chemoembolization, and method for preparing same |
DE202015002048U1 (en) | 2015-03-16 | 2015-09-24 | Han Bock-Sun | implant |
KR101620090B1 (en) * | 2015-04-20 | 2016-05-12 | 주식회사 티젤바이오 | Kit for drug delivery, Apparatus for preparing drug delivery system, and A preparation method of drug delivery system |
JP6869902B2 (en) * | 2015-06-18 | 2021-05-12 | アキュイティバイオ コーポレーション | Implantable drug delivery composition and its usage |
KR101748120B1 (en) * | 2015-07-13 | 2017-06-16 | 서울대학교산학협력단 | Compositions comprising nanoparticle-protein complex based on vitreous as an active ingredient for inhibiting angiogenesis, and uses thereof |
US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
BR112018005200A2 (en) | 2015-09-16 | 2018-10-09 | Dfb Soria Llc | release of drug nanoparticles and methods of using them |
WO2017053885A1 (en) | 2015-09-25 | 2017-03-30 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
US11185361B2 (en) | 2015-10-12 | 2021-11-30 | Landy Toth | Controlled and precise treatment of cardiac tissues |
WO2017123883A1 (en) | 2016-01-13 | 2017-07-20 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Vascular extracellular matrix hydrogel |
AU2017252294B2 (en) | 2016-04-20 | 2021-12-02 | Dose Medical Corporation | Bioresorbable ocular drug delivery device |
US11696822B2 (en) | 2016-09-28 | 2023-07-11 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US10898446B2 (en) | 2016-12-20 | 2021-01-26 | Surmodics, Inc. | Delivery of hydrophobic active agents from hydrophilic polyether block amide copolymer surfaces |
CN110636833A (en) | 2017-03-15 | 2019-12-31 | Dfb索里亚有限责任公司 | Topical therapy using taxane nanoparticles for the treatment of skin malignancies |
US11634400B2 (en) | 2017-08-19 | 2023-04-25 | University Of Rochester | Micheliolide derivatives, methods for their preparation and their use as anticancer and antiinflammatory agents |
US11547397B2 (en) | 2017-12-20 | 2023-01-10 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
WO2019164853A1 (en) | 2018-02-20 | 2019-08-29 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
WO2019178024A1 (en) | 2018-03-16 | 2019-09-19 | Dfb Soria, Llc | Topical therapy for the treatment of cervical intraepithelial neoplasia (cin) and cervical cancer using nanoparticles of taxanes |
EP3796948A4 (en) | 2018-05-22 | 2022-03-02 | Interface Biologics Inc. | Compositions and methods for delivering drugs to a vessel wall |
CN109224119B (en) * | 2018-10-30 | 2021-02-23 | 北京大学深圳医院 | Pi conjugated nano self-assembled particle intratumoral injection embolization tumor blood vessel anticancer agent |
WO2020112816A1 (en) | 2018-11-29 | 2020-06-04 | Surmodics, Inc. | Apparatus and methods for coating medical devices |
US11819590B2 (en) | 2019-05-13 | 2023-11-21 | Surmodics, Inc. | Apparatus and methods for coating medical devices |
CN111388757B (en) * | 2020-03-21 | 2022-07-15 | 哈尔滨工程大学 | Degradable magnesium-based composite material prepared from spiral magnesium wires |
WO2022133251A1 (en) * | 2020-12-17 | 2022-06-23 | Mobius Therapeutics, Llc | Injection apparatus and method of use |
Family Cites Families (248)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3016308A (en) * | 1957-08-06 | 1962-01-09 | Moore Business Forms Inc | Recording paper coated with microscopic capsules of coloring material, capsules and method of making |
US3029188A (en) | 1958-02-20 | 1962-04-10 | Olin Mathieson | Gelatin adhesive pharmaceutical preparations |
US3991527A (en) | 1975-07-10 | 1976-11-16 | Bates Abrasive Products, Inc. | Coated abrasive disc |
USRE30239E (en) | 1975-11-10 | 1980-03-25 | Cell proliferation and tissue invasion inhibitor | |
US4042457A (en) | 1975-11-10 | 1977-08-16 | Rush-Presbyterian-St. Luke's Medical Center | Preparation of tissue invasion inhibitor and method of treatment utilizing the inhibitor |
US4391797A (en) | 1977-01-05 | 1983-07-05 | The Children's Hospital Medical Center | Systems for the controlled release of macromolecules |
US4176177A (en) | 1978-11-16 | 1979-11-27 | Rush-Presbyterian-St. Luke's Medical Center | Inhibition of bone resorption |
US4416877A (en) | 1979-02-13 | 1983-11-22 | Symphar S.A. | Anti-atherosclerotic pharmaceutical compositions containing diphosphonate compounds |
US4300244A (en) | 1979-09-19 | 1981-11-17 | Carbomedics, Inc. | Cardiovascular grafts |
US4356261A (en) | 1980-04-22 | 1982-10-26 | Rush-Presbyterian-St. Luke's Medical Center | Anti-invasion factor containing cultures |
US4531936A (en) * | 1981-01-29 | 1985-07-30 | Gordon Robert T | Device and method for the selective delivery of drugs to the myocardium |
US4768523A (en) | 1981-04-29 | 1988-09-06 | Lifecore Biomedical, Inc. | Hydrogel adhesive |
US4357312A (en) | 1981-07-16 | 1982-11-02 | The Children's Hospital Medical Center | Method of making prolonged release body |
US4534899A (en) * | 1981-07-20 | 1985-08-13 | Lipid Specialties, Inc. | Synthetic phospholipid compounds |
US5441745A (en) | 1982-03-30 | 1995-08-15 | Vestar, Inc. | Method of delivering micellular particles encapsulating chemotherapeutic agents to tumors in a body |
US4542025A (en) | 1982-07-29 | 1985-09-17 | The Stolle Research And Development Corporation | Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents |
US5001116A (en) | 1982-12-20 | 1991-03-19 | The Children's Medical Center Corporation | Inhibition of angiogenesis |
US4994443A (en) | 1982-12-20 | 1991-02-19 | The Children's Medical Center Corporation | Inhibition of angiogenesis |
US5286763A (en) | 1983-03-22 | 1994-02-15 | Massachusetts Institute Of Technology | Bioerodible polymers for drug delivery in bone |
US4906474A (en) | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
US4834755A (en) * | 1983-04-04 | 1989-05-30 | Pfizer Hospital Products Group, Inc. | Triaxially-braided fabric prosthesis |
US4959358A (en) | 1983-06-06 | 1990-09-25 | Beth Israel Hospital Assn. | Drug administration |
US4500676A (en) | 1983-12-15 | 1985-02-19 | Biomatrix, Inc. | Hyaluronate modified polymeric articles |
GB8334484D0 (en) | 1983-12-24 | 1984-02-01 | Smith & Nephew Ass | Surgical dressing |
US4591496A (en) | 1984-01-16 | 1986-05-27 | Massachusetts Institute Of Technology | Process for making systems for the controlled release of macromolecules |
CA1295796C (en) | 1984-03-27 | 1992-02-18 | Conrad Whyne | Biodegradable matrix and methods for producing same |
US4779806A (en) | 1984-07-23 | 1988-10-25 | Massachusetts Institute Of Technology | Ultrasonically modulated polymeric devices for delivering compositions |
US4580568A (en) * | 1984-10-01 | 1986-04-08 | Cook, Incorporated | Percutaneous endovascular stent and method for insertion thereof |
US4789501A (en) | 1984-11-19 | 1988-12-06 | The Curators Of The University Of Missouri | Glass microspheres |
US5128326A (en) | 1984-12-06 | 1992-07-07 | Biomatrix, Inc. | Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same |
US4916219A (en) | 1985-03-28 | 1990-04-10 | University Of Iowa Research Foundation | Oligosaccharide heparin fragments as inhibitors of complement cascade |
US4824436A (en) * | 1985-04-09 | 1989-04-25 | Harvey Wolinsky | Method for the prevention of restenosis |
US4733665C2 (en) | 1985-11-07 | 2002-01-29 | Expandable Grafts Partnership | Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft |
US5102417A (en) | 1985-11-07 | 1992-04-07 | Expandable Grafts Partnership | Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft |
US4771042A (en) | 1985-11-25 | 1988-09-13 | The Upjohn Company | Inhibition of angiogenesis involving the coadministration of steroids with heparin or heparin fragments |
GB8601100D0 (en) | 1986-01-17 | 1986-02-19 | Cosmas Damian Ltd | Drug delivery system |
US4806621A (en) | 1986-01-21 | 1989-02-21 | Massachusetts Institute Of Technology | Biocompatible, bioerodible, hydrophobic, implantable polyimino carbonate article |
DE3786721D1 (en) * | 1986-02-24 | 1993-09-02 | Fischell Robert | DEVICE FOR DETECTING BLOOD VESSELS AND SYSTEM FOR ITS INTRODUCTION. |
US4955878A (en) * | 1986-04-04 | 1990-09-11 | Biotechnology, Inc. | Kit for preventing or treating arterial dysfunction resulting from angioplasty procedures |
US4966890A (en) | 1986-04-04 | 1990-10-30 | Angiogenics, Ltd. | Method and composition for arresting angiogenesis and capillary, cell or membrane leakage |
US4746729A (en) | 1986-07-30 | 1988-05-24 | Kuettner Klaus E | Cartilage-derived leukocyte elastase-inhibitor |
US4882168A (en) | 1986-09-05 | 1989-11-21 | American Cyanamid Company | Polyesters containing alkylene oxide blocks as drug delivery systems |
GB2194885A (en) | 1986-09-10 | 1988-03-23 | Ephraim Kaplan | Pharmaceutical compositions containing vanadium |
US4893623A (en) | 1986-12-09 | 1990-01-16 | Advanced Surgical Intervention, Inc. | Method and apparatus for treating hypertrophy of the prostate gland |
CH673117A5 (en) | 1986-12-10 | 1990-02-15 | Ajinomoto Kk | |
US5092885A (en) * | 1987-02-12 | 1992-03-03 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Peptides with laminin activity |
US5084441A (en) | 1987-03-04 | 1992-01-28 | Shaw Jack M | Acetylated low density lipoproteins: a delivery system to phagocytic cells for stimulating immunologic response and host resistance |
US4800882A (en) * | 1987-03-13 | 1989-01-31 | Cook Incorporated | Endovascular stent and delivery system |
US5041126A (en) | 1987-03-13 | 1991-08-20 | Cook Incorporated | Endovascular stent and delivery system |
US4861627A (en) | 1987-05-01 | 1989-08-29 | Massachusetts Institute Of Technology | Preparation of multiwall polymeric microcapsules |
US4808402A (en) | 1987-05-29 | 1989-02-28 | Northwestern University | Method and compositions for modulating neovascularization |
NL8701337A (en) | 1987-06-09 | 1989-01-02 | Sentron V O F | SUBSTRATE PROVIDED WITH A BLOOD COMPATIBLE SURFACE OBTAINED BY COUPLING WITH THE SURFACE OF A PHYSIOLOGICALLY ACTIVE SUBSTANCE WITH AN INHIBITORY INFLUENCE ON THE FORMATION OF BLOOD CLOTS AND / OR CONTAINED FROM HARMFOLIC CIRCULARS. |
US5059211A (en) * | 1987-06-25 | 1991-10-22 | Duke University | Absorbable vascular stent |
US4829099A (en) | 1987-07-17 | 1989-05-09 | Bioresearch, Inc. | Metabolically acceptable polyisocyanate adhesives |
US5019379A (en) | 1987-07-31 | 1991-05-28 | Massachusetts Institute Of Technology | Unsaturated polyanhydrides |
GB8720440D0 (en) | 1987-08-28 | 1987-10-07 | Smith & Nephew Ass | Curable compositions |
US5001009A (en) | 1987-09-02 | 1991-03-19 | Sterilization Technical Services, Inc. | Lubricious hydrophilic composite coated on substrates |
US5059189A (en) | 1987-09-08 | 1991-10-22 | E. R. Squibb & Sons, Inc. | Method of preparing adhesive dressings containing a pharmaceutically active ingredient |
US4983395A (en) | 1987-11-12 | 1991-01-08 | Theratech Inc. | Device for administering an active agent to the skin or mucosa |
US5135919A (en) * | 1988-01-19 | 1992-08-04 | Children's Medical Center Corporation | Method and a pharmaceutical composition for the inhibition of angiogenesis |
ES2017808A6 (en) * | 1988-01-19 | 1991-03-01 | Moses Judah Folkman | Growth inhibiting agent and the use thereof. |
US5460817A (en) | 1988-01-19 | 1995-10-24 | Allied Colloids Ltd. | Particulate composition comprising a core of matrix polymer with active ingredient distributed therein |
US5446070A (en) | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US5157049A (en) * | 1988-03-07 | 1992-10-20 | The United States Of America As Represented By The Department Of Health & Human Services | Method of treating cancers sensitive to treatment with water soluble derivatives of taxol |
US4942184A (en) | 1988-03-07 | 1990-07-17 | The United States Of America As Represented By The Department Of Health And Human Services | Water soluble, antineoplastic derivatives of taxol |
JPH0722576B2 (en) | 1988-04-11 | 1995-03-15 | 三菱電機株式会社 | Magnetic resonance device |
US4989601A (en) * | 1988-05-02 | 1991-02-05 | Medical Engineering & Development Institute, Inc. | Method, apparatus, and substance for treating tissue having neoplastic cells |
JP3038339B2 (en) | 1988-05-02 | 2000-05-08 | ザイナクシス・テクノロジーズ・インコーポレーテッド | Compounds that bind bioaffecting substances to the surface membrane of bioparticles |
US5096892A (en) | 1988-05-27 | 1992-03-17 | The Children's Medical Center Corporation | Arylsulfatase inhibition and potentiation of angiostatic steroids and heparin |
US5100668A (en) | 1988-06-14 | 1992-03-31 | Massachusetts Institute Of Technology | Controlled release systems containing heparin and growth factors |
JPH0643336B2 (en) | 1988-06-30 | 1994-06-08 | 呉羽化学工業株式会社 | Vascular growth inhibitor |
DE3825374A1 (en) * | 1988-07-26 | 1990-02-01 | Schwendener Reto Dipl Apotheke | Complex of at least one lipophilic acid and mitoxantrone and/or bisantrene |
US4966605A (en) | 1988-07-28 | 1990-10-30 | Thieler William R | Method for opening and closing surgical wounds |
JPH0255064A (en) * | 1988-08-03 | 1990-02-23 | Toa O | Skin removal for throm bus in blood vessel using catheter and throm bus removing system in blood vessel using catheter |
US5213580A (en) * | 1988-08-24 | 1993-05-25 | Endoluminal Therapeutics, Inc. | Biodegradable polymeric endoluminal sealing process |
US5019090A (en) * | 1988-09-01 | 1991-05-28 | Corvita Corporation | Radially expandable endoprosthesis and the like |
US5053048A (en) * | 1988-09-22 | 1991-10-01 | Cordis Corporation | Thromboresistant coating |
US5252713A (en) * | 1988-09-23 | 1993-10-12 | Neorx Corporation | Polymeric carriers for non-covalent drug conjugation |
US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
US5091176A (en) | 1988-11-02 | 1992-02-25 | W. R. Grace & Co.-Conn. | Polymer-modified peptide drugs having enhanced biological and pharmacological activities |
US5211657A (en) * | 1988-11-07 | 1993-05-18 | The United States Government As Represented By The Secretary Of The Department Of Health And Human Services | Laminin a chain deduced amino acid sequence, expression vectors and active synthetic peptides |
LU87410A1 (en) * | 1988-12-20 | 1990-07-10 | Cird | COSMETIC OR PHARMACEUTICAL COMPOSITION CONTAINING POLYMERIC OR FATTY BODY MICROSPHERES CHARGED WITH AT LEAST ONE ACTIVE PRODUCT |
US5086164A (en) | 1989-01-10 | 1992-02-04 | Repligen Corporation | Novel methods and compositions for treatment of angiogenic diseases |
US5356630A (en) | 1989-02-22 | 1994-10-18 | Massachusetts Institute Of Technology | Delivery system for controlled release of bioactive factors |
US4960790A (en) | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
US4905694A (en) | 1989-04-04 | 1990-03-06 | Ethicon, Inc. | Intracorporeal temporary wound closure |
WO1990013332A1 (en) * | 1989-05-11 | 1990-11-15 | Cedars-Sinai Medical Center | Stent with sustained drug delivery |
AU648505B2 (en) * | 1989-05-19 | 1994-04-28 | Amgen, Inc. | Metalloproteinase inhibitor |
US5132315A (en) | 1989-05-19 | 1992-07-21 | The United States Of America As Represented By The Department Of Health And Human Services | Therapeutic application of an anti-invasive compound |
US4990155A (en) * | 1989-05-19 | 1991-02-05 | Wilkoff Howard M | Surgical stent method and apparatus |
US5171262A (en) | 1989-06-15 | 1992-12-15 | Cordis Corporation | Non-woven endoprosthesis |
CA2015946A1 (en) * | 1989-06-27 | 1990-12-27 | Lawrence P. Klemann | Diol lipid analogues as edible fat replacements |
US5290807A (en) | 1989-08-10 | 1994-03-01 | Children's Medical Center Corporation | Method for regressing angiogenesis using o-substituted fumagillol derivatives |
EP0415294A3 (en) * | 1989-08-31 | 1991-06-12 | Takeda Chemical Industries, Ltd. | Cyclohexanol derivatives, production and use thereof |
CA1340994C (en) * | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
JPH03109324A (en) | 1989-09-22 | 1991-05-09 | Microbial Chem Res Found | Vascularization inhibitor |
US5461081A (en) | 1989-09-28 | 1995-10-24 | Alcon Laboratories, Inc. | Topical ophthalmic pharmaceutical vehicles |
US5525348A (en) | 1989-11-02 | 1996-06-11 | Sts Biopolymers, Inc. | Coating compositions comprising pharmaceutical agents |
US5120548A (en) | 1989-11-07 | 1992-06-09 | Merck & Co., Inc. | Swelling modulated polymeric drug delivery device |
AU6747790A (en) | 1989-11-13 | 1991-06-13 | President And Fellows Of Harvard College | Extraluminal regulation of the growth and repair of tubular structures in vivo |
US5527532A (en) | 1989-11-13 | 1996-06-18 | President And Fellows Of Harvard College | Extraluminal regulation of the growth and repair of tubular structures in vivo |
US5059166A (en) * | 1989-12-11 | 1991-10-22 | Medical Innovative Technologies R & D Limited Partnership | Intra-arterial stent with the capability to inhibit intimal hyperplasia |
US5176617A (en) * | 1989-12-11 | 1993-01-05 | Medical Innovative Technologies R & D Limited Partnership | Use of a stent with the capability to inhibit malignant growth in a vessel such as a biliary duct |
US5304121A (en) * | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
US5439446A (en) * | 1994-06-30 | 1995-08-08 | Boston Scientific Corporation | Stent and therapeutic delivery system |
US5049132A (en) * | 1990-01-08 | 1991-09-17 | Cordis Corporation | Balloon catheter for delivering therapeutic agents |
US5192744A (en) * | 1990-01-12 | 1993-03-09 | Northwestern University | Method of inhibiting angiogenesis of tumors |
WO1991011193A1 (en) * | 1990-01-25 | 1991-08-08 | Children's Hospital | Method and compositions for inhibiting angiogenesis |
DE69108423T2 (en) * | 1990-02-08 | 1995-07-27 | Howmedica | Inflatable dilator. |
US5075112A (en) | 1990-02-12 | 1991-12-24 | Cartilage Technologies Inc. | Method of and dosage unit for inhibiting angiogenesis or vascularization in an animal using shark cartilage |
US5200397A (en) | 1990-02-22 | 1993-04-06 | W. R. Grace & Co.-Conn. | Use of peptide analogs of thrombospondin for the inhibition of angiogenic activity |
US5545208A (en) * | 1990-02-28 | 1996-08-13 | Medtronic, Inc. | Intralumenal drug eluting prosthesis |
DE69110787T2 (en) † | 1990-02-28 | 1996-04-04 | Medtronic Inc | INTRALUMINAL PROSTHESIS WITH ACTIVE ELEMENTATION. |
DE4006609A1 (en) | 1990-03-02 | 1991-09-26 | Max Planck Gesellschaft | INHIBITOR OF PROLIFERATION OF ENDOTHEL CELLS |
US5052998A (en) | 1990-04-04 | 1991-10-01 | Zimmon David S | Indwelling stent and method of use |
US5290271A (en) * | 1990-05-14 | 1994-03-01 | Jernberg Gary R | Surgical implant and method for controlled release of chemotherapeutic agents |
CA2082398C (en) | 1990-05-14 | 2004-06-29 | Gary R. Jernberg | Surgical implant and method incorporating chemotherapeutic agents |
US5219564A (en) | 1990-07-06 | 1993-06-15 | Enzon, Inc. | Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon |
WO1991017724A1 (en) * | 1990-05-17 | 1991-11-28 | Harbor Medical Devices, Inc. | Medical device polymer |
US5092841A (en) * | 1990-05-17 | 1992-03-03 | Wayne State University | Method for treating an arterial wall injured during angioplasty |
US5407683A (en) | 1990-06-01 | 1995-04-18 | Research Corporation Technologies, Inc. | Pharmaceutical solutions and emulsions containing taxol |
CA2081896A1 (en) * | 1990-06-15 | 1991-12-16 | James E. Shapland | Drug delivery apparatus and method |
US5462751A (en) | 1990-06-22 | 1995-10-31 | The Regeants Of The University Of California | Biological and pharmaceutical agents having a nanomeric biodegradable core |
US5064435A (en) | 1990-06-28 | 1991-11-12 | Schneider (Usa) Inc. | Self-expanding prosthesis having stable axial length |
JP3120187B2 (en) * | 1990-08-08 | 2000-12-25 | 武田薬品工業株式会社 | Endovascular embolic agent containing angiogenesis inhibitor |
EP0470569B1 (en) * | 1990-08-08 | 1995-11-22 | Takeda Chemical Industries, Ltd. | Intravascular embolizing agent containing angiogenesis inhibiting substance |
US5210155A (en) * | 1990-08-24 | 1993-05-11 | Exxon Chemical Patents Inc. | Phenol terminated diester compositions derived from dicarboxylic acids, polyester polymers or alkyd polymers, and curable compositions containing same |
US5278324A (en) | 1990-08-28 | 1994-01-11 | Virginia Tech Intellectual Properties, Inc. | Water soluble derivatives of taxol |
NO302481B1 (en) | 1990-10-16 | 1998-03-09 | Takeda Chemical Industries Ltd | Polymer for an extended release preparation, as well as an extended release preparation |
AU8850391A (en) * | 1990-10-18 | 1992-05-20 | Ho Young Song | Self-expanding endovascular stent |
WO1992006701A1 (en) | 1990-10-18 | 1992-04-30 | Huffstutler, M., Conrad, Jr. | Preparation of concentrated fluid symphytum extracts, therapeutic forms and methods of use |
CA2096520C (en) | 1990-11-20 | 2000-12-19 | Hiroshi Nakao | Therapeutic agent for skin or corneal disease |
US5268384A (en) | 1990-11-21 | 1993-12-07 | Galardy Richard E | Inhibition of angiogenesis by synthetic matrix metalloprotease inhibitors |
JP2928892B2 (en) | 1990-11-27 | 1999-08-03 | 三洋化成工業株式会社 | Surgical adhesive |
US5149368A (en) | 1991-01-10 | 1992-09-22 | Liu Sung Tsuen | Resorbable bioactive calcium phosphate cement |
AU1579092A (en) * | 1991-02-27 | 1992-10-06 | Nova Pharmaceutical Corporation | Anti-infective and anti-inflammatory releasing systems for medical devices |
US5540928A (en) | 1991-02-27 | 1996-07-30 | President And Fellows Of Harvard College | Extraluminal regulation of the growth and repair of tubular structures in vivo |
US5171217A (en) | 1991-02-28 | 1992-12-15 | Indiana University Foundation | Method for delivery of smooth muscle cell inhibitors |
KR0177492B1 (en) * | 1991-03-08 | 1999-05-01 | 케이지 이가키 | Stent for vessel, structure of holding said stent, and device for mounting said stent |
IT1250421B (en) | 1991-05-30 | 1995-04-07 | Recordati Chem Pharm | CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION WITH BIO-ADHESIVE PROPERTIES. |
US5147370A (en) | 1991-06-12 | 1992-09-15 | Mcnamara Thomas O | Nitinol stent for hollow body conduits |
US5330768A (en) | 1991-07-05 | 1994-07-19 | Massachusetts Institute Of Technology | Controlled drug delivery using polymer/pluronic blends |
FR2678833B1 (en) | 1991-07-08 | 1995-04-07 | Rhone Poulenc Rorer Sa | NEW PHARMACEUTICAL COMPOSITIONS BASED ON DERIVATIVES OF THE TAXANE CLASS. |
US5344644A (en) | 1991-08-01 | 1994-09-06 | Takeda Chemical Industries, Ltd. | Water-soluble composition for sustained-release |
JPH0558882A (en) * | 1991-09-04 | 1993-03-09 | Yoshiaki Kawashima | Production of nanocapsule |
US5283253A (en) | 1991-09-23 | 1994-02-01 | Florida State University | Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them |
US5229526A (en) | 1991-09-23 | 1993-07-20 | Florida State University | Metal alkoxides |
US6515009B1 (en) * | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
WO1993006792A1 (en) * | 1991-10-04 | 1993-04-15 | Scimed Life Systems, Inc. | Biodegradable drug delivery vascular stent |
US5464450A (en) | 1991-10-04 | 1995-11-07 | Scimed Lifesystems Inc. | Biodegradable drug delivery vascular stent |
CA2380683C (en) * | 1991-10-28 | 2006-08-08 | Advanced Cardiovascular Systems, Inc. | Expandable stents and method for making same |
US5318780A (en) | 1991-10-30 | 1994-06-07 | Mediventures Inc. | Medical uses of in situ formed gels |
JPH05131753A (en) * | 1991-11-15 | 1993-05-28 | Fujicopian Co Ltd | Many-time usable thermal transfer ink sheet |
US5302397A (en) | 1991-11-19 | 1994-04-12 | Amsden Brian G | Polymer-based drug delivery system |
US5270047A (en) * | 1991-11-21 | 1993-12-14 | Kauffman Raymond F | Local delivery of dipyridamole for the treatment of proliferative diseases |
AU3140093A (en) | 1991-11-22 | 1993-06-15 | University Of Mississippi, The | Synthesis and optical resolution of the taxol side chain and related compounds |
AU3221993A (en) * | 1991-11-27 | 1993-06-28 | Phanos Technologies, Inc. | Compounds, compositions and methods for binding bio-affecting substances to surface membranes of bio-particles |
US5260002A (en) | 1991-12-23 | 1993-11-09 | Vanderbilt University | Method and apparatus for producing uniform polymeric spheres |
US5516781A (en) | 1992-01-09 | 1996-05-14 | American Home Products Corporation | Method of treating restenosis with rapamycin |
CA2086642C (en) | 1992-01-09 | 2004-06-15 | Randall E. Morris | Method of treating hyperproliferative vascular disease |
US5176626A (en) | 1992-01-15 | 1993-01-05 | Wilson-Cook Medical, Inc. | Indwelling stent |
US5260066A (en) | 1992-01-16 | 1993-11-09 | Srchem Incorporated | Cryogel bandage containing therapeutic agent |
US6080777A (en) | 1992-01-31 | 2000-06-27 | The Trustees Of Columbia University In The City Of New York | Taxol as a radiation sensitizer |
US5301664A (en) | 1992-03-06 | 1994-04-12 | Sievers Robert E | Methods and apparatus for drug delivery using supercritical solutions |
US5200534A (en) | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
DE69326631T2 (en) | 1992-03-19 | 2000-06-08 | Medtronic Inc | Intraluminal expansion device |
US5474765A (en) * | 1992-03-23 | 1995-12-12 | Ut Sw Medical Ctr At Dallas | Preparation and use of steroid-polyanionic polymer-based conjugates targeted to vascular endothelial cells |
PT706373E (en) | 1992-03-23 | 2000-11-30 | Univ Georgetown | TAXOL ENCAPSULATED IN A LIPOSOM AND A METHOD |
AU670937B2 (en) | 1992-04-28 | 1996-08-08 | Wyeth | Method of treating hyperproliferative vascular disease |
DE4214215A1 (en) * | 1992-04-30 | 1993-11-04 | Behringwerke Ag | USE OF INHIBITORS OF PLASMINOGEN ACTIVATORS FOR TREATING INFLAMMATION |
US5461140A (en) | 1992-04-30 | 1995-10-24 | Pharmaceutical Delivery Systems | Bioerodible polymers for solid controlled release pharmaceutical compositions |
WO1993023075A1 (en) * | 1992-05-14 | 1993-11-25 | Oncologix, Inc. | Treatment of vascular leakage syndrome and collagenase induced disease by administration of matrix metalloproteinase inhibitors |
AU4242993A (en) | 1992-05-21 | 1993-12-13 | Penn State Research Foundation, The | Cultured (taxus) tissues as a source of taxol, related taxanes and other novel anti-tumor/anti-viral compounds |
WO1993024476A1 (en) | 1992-06-04 | 1993-12-09 | Clover Consolidated, Limited | Water-soluble polymeric carriers for drug delivery |
US5383928A (en) * | 1992-06-10 | 1995-01-24 | Emory University | Stent sheath for local drug delivery |
GB9213077D0 (en) | 1992-06-19 | 1992-08-05 | Erba Carlo Spa | Polymerbound taxol derivatives |
US5274137A (en) | 1992-06-23 | 1993-12-28 | Nicolaou K C | Intermediates for preparation of taxols |
US5294637A (en) | 1992-07-01 | 1994-03-15 | Bristol-Myers Squibb Company | Fluoro taxols |
US5273965A (en) | 1992-07-02 | 1993-12-28 | Cambridge Biotech Corporation | Methods for enhancing drug delivery with modified saponins |
FR2693193B1 (en) * | 1992-07-03 | 1994-09-02 | Rhone Poulenc Rorer Sa | New derivatives of 10-deacetyl baccatin III, their preparation and the pharmaceutical compositions containing them. |
US5472954A (en) | 1992-07-14 | 1995-12-05 | Cyclops H.F. | Cyclodextrin complexation |
KR940003548U (en) | 1992-08-14 | 1994-02-21 | 김형술 | Laundry dryer |
US5202448A (en) | 1992-08-14 | 1993-04-13 | Napro Biotherapeutics, Inc. | Processes of converting taxanes into baccatin III |
WO1994005282A1 (en) | 1992-09-04 | 1994-03-17 | The Scripps Research Institute | Water soluble taxol derivatives |
US5342621A (en) * | 1992-09-15 | 1994-08-30 | Advanced Cardiovascular Systems, Inc. | Antithrombogenic surface |
EP0752885B1 (en) | 1992-09-25 | 2003-07-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5770609A (en) | 1993-01-28 | 1998-06-23 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US6306421B1 (en) * | 1992-09-25 | 2001-10-23 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
CA2100808A1 (en) | 1992-10-01 | 1994-04-02 | Vittorio Farina | Deoxy paclitaxels |
FR2696462B1 (en) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for obtaining 10-deacetyl baccatin III. |
FR2696461B1 (en) | 1992-10-05 | 1994-11-10 | Rhone Poulenc Rorer Sa | New derivatives of taxol analogs, their preparation and compositions containing them. |
FR2696464B1 (en) | 1992-10-05 | 1994-11-10 | Rhone Poulenc Rorer Sa | New esterification process for baccatin III and 10-deacetyl baccatin III. |
FR2696463B1 (en) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for obtaining 10-deacetyl baccatin III. |
FR2698543B1 (en) | 1992-12-02 | 1994-12-30 | Rhone Poulenc Rorer Sa | New taxoid-based compositions. |
US5380751A (en) | 1992-12-04 | 1995-01-10 | Bristol-Myers Squibb Company | 6,7-modified paclitaxels |
US5342348A (en) * | 1992-12-04 | 1994-08-30 | Kaplan Aaron V | Method and device for treating and enlarging body lumens |
US5279949A (en) | 1992-12-07 | 1994-01-18 | Board Of Trustees Operating Michigan State University | Process for the isolation and purification of taxol and taxanes from Taxus spp |
EP0604022A1 (en) | 1992-12-22 | 1994-06-29 | Advanced Cardiovascular Systems, Inc. | Multilayered biodegradable stent and method for its manufacture |
US5419760A (en) * | 1993-01-08 | 1995-05-30 | Pdt Systems, Inc. | Medicament dispensing stent for prevention of restenosis of a blood vessel |
US6663881B2 (en) | 1993-01-28 | 2003-12-16 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5981568A (en) * | 1993-01-28 | 1999-11-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5439686A (en) | 1993-02-22 | 1995-08-08 | Vivorx Pharmaceuticals, Inc. | Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor |
US5378456A (en) * | 1993-03-25 | 1995-01-03 | American Cyanamid Company | Antitumor mitoxantrone polymeric compositions |
WO1994024961A1 (en) | 1993-04-23 | 1994-11-10 | Schneider (Usa) Inc. | Covered stent and stent delivery device |
US5464650A (en) | 1993-04-26 | 1995-11-07 | Medtronic, Inc. | Intravascular stent and method |
CA2162587C (en) * | 1993-05-13 | 2008-07-08 | Kunz, Lawrence Leroy | Therapeutic inhibitor of vascular smooth muscle cells |
IT1276342B1 (en) | 1993-06-04 | 1997-10-30 | Ist Naz Stud Cura Dei Tumori | METAL STENT COVERED WITH BIOCOMPATIBLE POLYMERIC MATERIAL |
US5468769A (en) | 1993-07-15 | 1995-11-21 | Abbott Laboratories | Paclitaxel derivatives |
US5994341A (en) | 1993-07-19 | 1999-11-30 | Angiogenesis Technologies, Inc. | Anti-angiogenic Compositions and methods for the treatment of arthritis |
AU728873B2 (en) | 1993-07-19 | 2001-01-18 | Angiotech Pharmaceuticals, Inc. | Anti-angiogenic compositions and methods of use |
US20030203976A1 (en) * | 1993-07-19 | 2003-10-30 | William L. Hunter | Anti-angiogenic compositions and methods of use |
AU771815B2 (en) | 1993-07-19 | 2004-04-01 | Angiotech Pharmaceuticals, Inc. | Anti-angiogenic compositions and methods of use |
DK0797988T3 (en) | 1993-07-19 | 2009-05-11 | Univ British Columbia | Anti-angiogenic compositions and methods for their use |
PT1118325E (en) | 1993-07-29 | 2006-05-31 | Us Health | USES OF PACLITAXEL AND ITS DERIVATIVES IN THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF RESTENOSE |
US5380299A (en) * | 1993-08-30 | 1995-01-10 | Med Institute, Inc. | Thrombolytic treated intravascular medical device |
US5455046A (en) | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
US5457113A (en) * | 1993-10-15 | 1995-10-10 | Eli Lilly And Company | Methods for inhibiting vascular smooth muscle cell proliferation and restinosis |
US5643575A (en) | 1993-10-27 | 1997-07-01 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5415869A (en) | 1993-11-12 | 1995-05-16 | The Research Foundation Of State University Of New York | Taxol formulation |
US5443505A (en) | 1993-11-15 | 1995-08-22 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
CA2176934A1 (en) * | 1993-11-17 | 1995-05-26 | Ramnath Sasisekharan | Method for inhibiting angiogenesis using heparinase |
US5462726A (en) | 1993-12-17 | 1995-10-31 | Bristol-Myers Squibb Company | Method of inhibiting side effects of solvents containing ricinoleic acid or castor oil or derivatives thereof employing a thromboxane A2 receptor antagonist and pharmaceutical compositions containing such solvents |
CA2147813A1 (en) | 1994-04-28 | 1995-10-29 | Richard Dixon | Intravascular prosthesis with anti-thrombogenic coating |
US5626862A (en) * | 1994-08-02 | 1997-05-06 | Massachusetts Institute Of Technology | Controlled local delivery of chemotherapeutic agents for treating solid tumors |
US5489589A (en) | 1994-12-07 | 1996-02-06 | Bristol-Myers Squibb Company | Amino acid derivatives of paclitaxel |
US6231600B1 (en) | 1995-02-22 | 2001-05-15 | Scimed Life Systems, Inc. | Stents with hybrid coating for medical devices |
JP3224121B2 (en) | 1995-04-24 | 2001-10-29 | ヤマハ発動機株式会社 | Steering head members for motorcycles |
US5801191A (en) | 1995-06-01 | 1998-09-01 | Biophysica Foundation | Taxoids |
US5766584A (en) | 1995-06-02 | 1998-06-16 | Massachusetts Institute Of Technology | Inhibition of vascular smooth muscle cell proliferation with implanted matrix containing vascular endothelial cells |
US6783543B2 (en) * | 2000-06-05 | 2004-08-31 | Scimed Life Systems, Inc. | Intravascular stent with increasing coating retaining capacity |
ATE302599T1 (en) * | 1996-05-24 | 2005-09-15 | Angiotech Pharm Inc | PREPARATIONS AND METHODS FOR THE TREATMENT OR PREVENTION OF DISEASES OF THE BODY PASSAGES |
EP0969853A4 (en) | 1997-03-25 | 2004-07-14 | Massachusetts Inst Technology | Modulation of vascular healing by inhibition of leukocyte adhesion and function |
ES2388248T3 (en) | 1997-03-31 | 2012-10-11 | Boston Scientific Scimed Limited | Dosage form comprising taxol in crystalline form |
US6273908B1 (en) * | 1997-10-24 | 2001-08-14 | Robert Ndondo-Lay | Stents |
WO1999048536A2 (en) | 1998-03-23 | 1999-09-30 | Conjuchem, Inc. | Delivery of long lasting therapeutic agents by forming covalent attachments in vivo |
US7208010B2 (en) | 2000-10-16 | 2007-04-24 | Conor Medsystems, Inc. | Expandable medical device for delivery of beneficial agent |
US6241762B1 (en) * | 1998-03-30 | 2001-06-05 | Conor Medsystems, Inc. | Expandable medical device with ductile hinges |
EP1132058A1 (en) | 2000-03-06 | 2001-09-12 | Advanced Laser Applications Holding S.A. | Intravascular prothesis |
US6395326B1 (en) * | 2000-05-31 | 2002-05-28 | Advanced Cardiovascular Systems, Inc. | Apparatus and method for depositing a coating onto a surface of a prosthesis |
WO2002045717A1 (en) | 2000-12-06 | 2002-06-13 | Tularik Inc. | Lometrexol combination therapy |
JP3502053B2 (en) | 2001-03-15 | 2004-03-02 | パナソニック コミュニケーションズ株式会社 | MFP |
AU2003245607A1 (en) * | 2002-06-20 | 2004-01-06 | Federal-Mogul Powertrain, Inc. | Multiple layer insulating sleeve |
JP3990961B2 (en) * | 2002-09-09 | 2007-10-17 | 株式会社コナミデジタルエンタテインメント | Game machines and bingo game machines |
US20040127976A1 (en) * | 2002-09-20 | 2004-07-01 | Conor Medsystems, Inc. | Method and apparatus for loading a beneficial agent into an expandable medical device |
US20070003636A1 (en) * | 2003-01-22 | 2007-01-04 | Francois Mach | Statins (HMG-COA reductase inhibitors) as a novel type of immunomodulator, immunosuppressor and anti-inflammatory agent |
US20050100577A1 (en) | 2003-11-10 | 2005-05-12 | Parker Theodore L. | Expandable medical device with beneficial agent matrix formed by a multi solvent system |
-
1994
- 1994-07-19 DK DK96119361T patent/DK0797988T3/en active
- 1994-07-19 DK DK01117863T patent/DK1155689T3/en active
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- 1994-07-19 EP EP01117882A patent/EP1159975B1/en not_active Revoked
- 1994-07-19 WO PCT/CA1994/000373 patent/WO1995003036A1/en active Application Filing
- 1994-07-19 JP JP50482395A patent/JP3423317B2/en not_active Expired - Fee Related
- 1994-07-19 EP EP05020783A patent/EP1695697A3/en not_active Withdrawn
- 1994-07-19 AT AT01117873T patent/ATE367173T1/en not_active IP Right Cessation
- 1994-07-19 DE DE69435185T patent/DE69435185D1/en not_active Expired - Lifetime
- 1994-07-19 ES ES96119361T patent/ES2321241T3/en not_active Expired - Lifetime
- 1994-07-19 CN CNA2006100998901A patent/CN101007173A/en active Pending
- 1994-07-19 NZ NZ511762A patent/NZ511762A/en not_active IP Right Cessation
- 1994-07-19 EP EP08006468A patent/EP1946749A1/en not_active Withdrawn
- 1994-07-19 DE DE69434856T patent/DE69434856T4/en not_active Expired - Lifetime
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1996
- 1996-01-18 NO NO19960226A patent/NO324275B1/en not_active IP Right Cessation
-
1997
- 1997-09-24 GR GR970402471T patent/GR3024833T3/en unknown
- 1997-11-17 NZ NZ329193A patent/NZ329193A/en not_active IP Right Cessation
-
1999
- 1999-04-19 US US09/294,458 patent/US6506411B2/en not_active Expired - Fee Related
-
2001
- 2001-08-08 US US09/925,220 patent/US6544544B2/en not_active Expired - Fee Related
- 2001-08-09 US US09/927,882 patent/US20020119202A1/en not_active Abandoned
- 2001-11-28 RU RU2001132111/15A patent/RU2304433C2/en not_active Application Discontinuation
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2002
- 2002-03-11 JP JP2002066179A patent/JP4476536B2/en not_active Expired - Lifetime
- 2002-05-29 HK HK02103990.2A patent/HK1042054B/en not_active IP Right Cessation
- 2002-11-29 KR KR1020027016338A patent/KR100934111B1/en not_active IP Right Cessation
-
2003
- 2003-03-13 US US10/389,262 patent/US20040076672A1/en not_active Abandoned
- 2003-03-14 US US10/390,534 patent/US20040062810A1/en not_active Abandoned
-
2004
- 2004-10-07 US US10/959,349 patent/US7820193B2/en not_active Expired - Fee Related
- 2004-10-07 US US10/959,398 patent/US20050208137A1/en not_active Abandoned
-
2005
- 2005-06-14 US US11/151,399 patent/US20060127445A1/en not_active Abandoned
-
2006
- 2006-01-17 US US11/332,170 patent/US20060121117A1/en not_active Abandoned
- 2006-02-28 HK HK06102632.4A patent/HK1079715A1/en not_active IP Right Cessation
- 2006-05-18 US US11/435,742 patent/US20060240113A1/en not_active Abandoned
- 2006-05-18 US US11/435,780 patent/US20070003629A1/en not_active Abandoned
- 2006-05-18 US US11/435,854 patent/US20070003630A1/en not_active Abandoned
- 2006-09-04 JP JP2006239650A patent/JP4920353B2/en not_active Expired - Lifetime
- 2006-12-07 JP JP2006331088A patent/JP4597115B2/en not_active Expired - Lifetime
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2007
- 2007-03-29 RU RU2007111679/15A patent/RU2007111679A/en unknown
- 2007-06-15 NO NO20073066A patent/NO20073066L/en not_active Application Discontinuation
- 2007-07-30 US US11/830,080 patent/US20070298123A1/en not_active Abandoned
- 2007-07-30 US US11/830,186 patent/US20080020063A1/en not_active Abandoned
- 2007-07-30 US US11/830,208 patent/US20090074830A1/en not_active Abandoned
- 2007-07-30 US US11/830,240 patent/US20080166387A1/en not_active Abandoned
-
2008
- 2008-04-04 US US12/098,173 patent/US20090036517A1/en not_active Abandoned
-
2010
- 2010-03-03 US US12/716,854 patent/US8221794B2/en not_active Expired - Fee Related
- 2010-06-17 US US12/817,682 patent/US20110071612A1/en not_active Abandoned
- 2010-06-22 US US12/820,614 patent/US20110118825A1/en not_active Abandoned
- 2010-06-22 US US12/820,572 patent/US20100292314A1/en not_active Abandoned
- 2010-06-22 US US12/820,523 patent/US20110066251A1/en not_active Abandoned
-
2012
- 2012-07-13 US US13/549,282 patent/US20130102657A1/en not_active Abandoned
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2014
- 2014-04-03 LU LU92422C patent/LU92422I2/en unknown
- 2014-04-03 LU LU92423C patent/LU92423I2/en unknown
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