CA2762921A1 - Improved formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents - Google Patents
Improved formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents Download PDFInfo
- Publication number
- CA2762921A1 CA2762921A1 CA2762921A CA2762921A CA2762921A1 CA 2762921 A1 CA2762921 A1 CA 2762921A1 CA 2762921 A CA2762921 A CA 2762921A CA 2762921 A CA2762921 A CA 2762921A CA 2762921 A1 CA2762921 A1 CA 2762921A1
- Authority
- CA
- Canada
- Prior art keywords
- release
- implant
- drug
- dexamethasone
- concentration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
- A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
Abstract
Combinations of hydrophilic and hydrophobic entities in a biodegradable sustained release implant are shown to modulate each other's rate of release. Formulations of a therapeutically active agent and modulator provide substantially constant rate of release for an extended period of time.
Description
IMPROVED FORMULATION FOR CONTROLLED RELEASE OF DRUGS BY
COMBINING HYDROPHILIC AND HYDROPHOBIC AGENTS
This application is a divisional of Canadian patent application No. 2 222 889 filed May 31, 1996.
INTRODUCTION
Technical Field Biodegradable implants formulated for controlled, sustained drug release.
Background of the Invention Solid pharmaceutically active implants that provide sustained release of an active ingredient are able to provide a relatively uniform concentration of active ingredients in the body. Implants are particularly useful for providing a high local concentration at a particular target site for extended periods of time. These sustained release forms reduce the number of doses of the drug to be administered, and avoid the peaks and troughs of drug concentration found with traditional drug therapies.
Use of a biodegradable drug delivery system has the further benefit that the spent implant need not be removed from the target site.
Many of the anticipated benefits of delayed release implants are dependent upon sustained release at a relatively constant level. However, formulations of hydrophobic drugs with biodegradable matrices may have a release profile which shows little or no release until erosion of the matrix occurs, at which point there is a dumping of drug.
The eye is of particular interest when formulating implantable drugs, because one can reduce the amount of surgical manipulation required, and provide effective levels of the drug specifically to the eye. When a solution is injected directly into the eye, the drug quickly washes out or is depleted from within the eye into the general circulation. From the therapeutic standpoint, this may be as useless as giving no drug at all. Because of this inherent difficulty of delivering drugs into the eye, successful medical treatment of ocular disease is inadequate.
Improved sustained release formulations which allow for a constant drug release rate are of considerable interest for medical and veterinary uses.
Relevant Literature U.S. Patents 4,997,652 and 5,164,188 disclose biocompatible implants for -1a-'76-2 introducing into an anterior chamber or posterior segment of an eye for the treatment of an ocular condition.
Heller, Biodegradable Polymers in Controlled Drug Delivery, in: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press, Boca Raton, FL, 1987, pp 39-90, describes encapsulation for controlled drug delivery. Heller in: Hydrogels in Medicine and Pharmacy, N.A. Peppes ed., Vol. III, CRC Press, Boca Raton, FL, 1987, pp 137-149, further describes bioerodible polymers.
Anderson et al., Contraception (1976) 13:375 and Miller et al., J. Biomed. Materials Res. (1977) 11:711, describe various properties of poly(dL-lactic acid).
U.S. Patent 5,075,115 discloses sustained release formulations with lactic acid polymers and co-polymers.
Di Colo (1992) Biomaterials 13:850-856 describes controlled drug release from hydrophobic polymers.
Stricker et al. (Canadian Patent No. 1,333,770) describe a biodegradable implant for releasing an active substance, wherein the implant comprises a poly-D,L-lactide based carrier material containing the active substance and the carrier contains at least one additive material selected from solvents, plasticizers, pore-forming agents and low-molecular weight polymers. The additive material is used to control the rate of decomposition of the Stricker implant.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides an implant for controlled, sustained drug release comprising:
COMBINING HYDROPHILIC AND HYDROPHOBIC AGENTS
This application is a divisional of Canadian patent application No. 2 222 889 filed May 31, 1996.
INTRODUCTION
Technical Field Biodegradable implants formulated for controlled, sustained drug release.
Background of the Invention Solid pharmaceutically active implants that provide sustained release of an active ingredient are able to provide a relatively uniform concentration of active ingredients in the body. Implants are particularly useful for providing a high local concentration at a particular target site for extended periods of time. These sustained release forms reduce the number of doses of the drug to be administered, and avoid the peaks and troughs of drug concentration found with traditional drug therapies.
Use of a biodegradable drug delivery system has the further benefit that the spent implant need not be removed from the target site.
Many of the anticipated benefits of delayed release implants are dependent upon sustained release at a relatively constant level. However, formulations of hydrophobic drugs with biodegradable matrices may have a release profile which shows little or no release until erosion of the matrix occurs, at which point there is a dumping of drug.
The eye is of particular interest when formulating implantable drugs, because one can reduce the amount of surgical manipulation required, and provide effective levels of the drug specifically to the eye. When a solution is injected directly into the eye, the drug quickly washes out or is depleted from within the eye into the general circulation. From the therapeutic standpoint, this may be as useless as giving no drug at all. Because of this inherent difficulty of delivering drugs into the eye, successful medical treatment of ocular disease is inadequate.
Improved sustained release formulations which allow for a constant drug release rate are of considerable interest for medical and veterinary uses.
Relevant Literature U.S. Patents 4,997,652 and 5,164,188 disclose biocompatible implants for -1a-'76-2 introducing into an anterior chamber or posterior segment of an eye for the treatment of an ocular condition.
Heller, Biodegradable Polymers in Controlled Drug Delivery, in: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press, Boca Raton, FL, 1987, pp 39-90, describes encapsulation for controlled drug delivery. Heller in: Hydrogels in Medicine and Pharmacy, N.A. Peppes ed., Vol. III, CRC Press, Boca Raton, FL, 1987, pp 137-149, further describes bioerodible polymers.
Anderson et al., Contraception (1976) 13:375 and Miller et al., J. Biomed. Materials Res. (1977) 11:711, describe various properties of poly(dL-lactic acid).
U.S. Patent 5,075,115 discloses sustained release formulations with lactic acid polymers and co-polymers.
Di Colo (1992) Biomaterials 13:850-856 describes controlled drug release from hydrophobic polymers.
Stricker et al. (Canadian Patent No. 1,333,770) describe a biodegradable implant for releasing an active substance, wherein the implant comprises a poly-D,L-lactide based carrier material containing the active substance and the carrier contains at least one additive material selected from solvents, plasticizers, pore-forming agents and low-molecular weight polymers. The additive material is used to control the rate of decomposition of the Stricker implant.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides an implant for controlled, sustained drug release comprising:
/ U
- G
a pharmacologically acceptable biodegradable polymer at a concentration of at least about 20 weight percent of the implant; a first therapeutically active agent at a concentration from 10 to 50 weight percent of the implant; a release modulator at a concentration from 10 to 50 weight percent of the implant; wherein: (a) said release modulator comprises a second therapeutically active agent; (b) said implant is degraded at the site of implantation, and releases said first therapeutically active agent within a therapeutic dosage which does not vary by more than about 100% for a period of at least about 3 days after implantation; and (c) one of said first therapeutically active agent and said release modulator is a hydrophobic entity and the other is a hydrophilic entity.
In another aspect, the present invention provides an implant for controlled, sustained drug release comprising: poly-lactate glycolic acid copolymer at a concentration of at least about 20 weight percent of the implant; a therapeutically active anti-inflammatory drug at a concentration from 10 to 50 weight percent of the implant;
and a release modulator at a concentration from 10 to 50 weight percent of the implant; wherein: (a) said release modulator is a therapeutically active agent.; (b) said implant is degraded at the site of implantation, and releases said therapeutically active anti-inflammatory drug within a therapeutic dosage which does not vary by more than about 100% for a period of at least about 3 days after implantation; and (c) one of said therapeutically active anti-inflammatory drug and said release modulator (i) is a hydrophobic entity and the other is a hydrophilic entity, and (ii) is other than a chemical form of the same compound of the other.
-2a-J V / / O - G
In another aspect, the present invention provides a bioerodible implant comprising a polylactic acid/polyglycolic acid (PLGA) polymer matrix and dexamethasone dispersed within the PLGA polymer matrix, wherein: said dexamethasone in the implant (i) is between about 40 percent and about 60 percent by weight of the implant, and (ii) is present in a single chemical form; the implant has a cumulative release profile providing for each time in a plurality of times a cumulative amount of dexamethasone released in vitro prior to the time expressed as a percentage of the dose of dexamethasone in the implant;
and the cumulative release profile comprises a linear portion in which the cumulative amount of dexamethasone released in vitro is an approximately linear function of time.
In another aspect, the present invention provides a bioerodible implant comprising: (a) a polylactic acid/polyglycolic acid (PLGA) polymer matrix at a concentration from 10 to 50 weight percent of the implant;
(b) dexamethasone; and (c) a release modifier at a concentration from 10 to 50 weight percent of the implant;
wherein: the dexamethasone is in a single chemical form and the release modifier is hydroxypropylmethylcellulose (HPMC) or ciprofloxacin; the implant has a cumulative release profile providing for each time in a plurality of times a cumulative amount of dexamethasone released in vitro prior to the time expressed as a percentage of the dose of dexamethasone in the implant; and the cumulative release profile comprises a linear portion in which the cumulative amount of dexamethasone released in vitro is an approximately linear function of time.
-2b-3V J i76-2 In another aspect, the present invention provides a batch of bioerodible implants comprising a plurality of bioerodible implants, wherein: (a) each bioerodible implant is sized for implantation within an ocular region; (b) each bioerodible implant comprises a PLGA polymer matrix and dexamethasone dispersed within the PLGA polymer matrix, and said dexamethasone in the implant (i) is between about 40 percent and about 60 percent by weight of the implant, and (ii) is present in a single chemical form; (c) each implant has a cumulative release profile providing for each time in a plurality of times a cumulative amount of dexamethasone released in vitro prior to the time, and (d) for each time in a time period, for each implant in the batch the cumulative amount of dexamethasone released in vitro is within about 30% of an average cumulative amount of dexamethasone released in vitro for all implants in the batch.
In another aspect, the present invention provides a batch of bioerodible implants comprising a plurality of bioerodible implants, wherein: (a) each bioerodible implant is sized for implantation within an ocular region; (b) each bioerodible implant comprises: (i) a PLGA polymer matrix at a concentration from 10 to 50 weight percent of the implant;
(ii) dexamethasone; and (iii) a release modifier at a concentration from 10 to 50 weight percent of the implant;
(c) the dexamethasone is in a single chemical form and the release modifier is hydroxypropylmethylcellulose (HPMC) or ciprofloxacin; (d) each implant has a cumulative release profile providing for each time in a plurality of times a cumulative amount of dexamethasone released in vitro prior to the time, and (e) for each time in a time period, for each implant in the batch the cumulative amount of dexamethasone released in vitro is within about 30% of an -2c-~. 7C ) J V % / V G
average cumulative amount of dexamethasone released in vitro for all implants in the batch.
In another aspect, the present invention provides use of an implant described above, for drug delivery in a subject. Further uses of the implant include the treatment of an ocular condition in a subject, wherein said condition is a viral infection, a bacterial infection, inflammation, a tumour, a post-surgical eye complication, or any combination thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1A shows the release profile of a hydrophobic drug from an extended release drug delivery system. Figure 1B shows the release profile of the same drug when formulated in a drug delivery system with a release modulator.
Figure 2A shows the release profile of dexamethasone in the absence or presence of the release modifier, ciproflaxacin HC1. Figure 2B shows the release of ciprofloxacin in the presence of dexamethasone. Figure 2C
shows the release of ciprofloxacin in the absence of a release modifier. Figure 2D shows the release profile from a drug delivery system having combined hydrophilic and hydrophobic drugs, and further having a pharmaceutically inactive release modifier.
Figure 3 shows a cross-sectional view of an eye.
-2d-3i,'. 6-2 DESCRIPTION OF THE SPECIFIC EMBODIMENTS
A controlled drug release is achieved by an improved formulation of slow release biodegradable implants. The release rate of a drug from an implant can be modulated by addition of a release modulator to the implant. Release of a hydrophobic agent is increased by inclusion of an accelerator in the implant, while retardants are included to decrease the release rate of hydrophilic agents. The release modulator may be physiologically inert, or a therapeutically active agent. Formulations of interest includes anti inflammatory drugs,, e.g. glucocorticoids, NSAIDS, etc., combined with an ophthalmically active agent.
The rate of release of the therapeutically active agent is controlled by the rate of transport through the polymeric matrix of the implant, and the action of the modulator.
By modulating the release rate, the agent is released at a substantially constant rate within a 'therapeutic dosage range, over the desired period of time. The rate of release will usually not vary by more than about 100% over the desired period of time, more usually by not. more than about 50% The agent is made available at the specific site(s) where the agent is needed, and it is maintained at an effective dosage.
The transport of drug through the polymer barrier is also affected by drug solubility, polymer hydrophilicity, extent of polymer cross-linking, expansion of the polymer upon water absorption so as to make the polymer barrier more permeable to the drug, geometry of the implant, and the like. At high drug loadings, i.e. at a loading concentration above the theoretical percolation threshold, percolation theory predicts the potential for drug leaching from the drug delivery system matrix. In such cases release modulators are useful to slow down the leaching process.
The release modulator is an agent that alters the release of a drug from a biodegradable implant in a defined manner. It may be an accelerator or a retardant.
Accelerators will be hydrophilic compounds, which are used in combination with hydrophobic agents to increase the rate of release. Hydrophilic agents are those compounds which have at least about 100 gg/ml solubility in water at ambient temperature. Hydrophobic agents are those compounds which have less than about 100 g/ml solubility in water at ambient temperature.
Therapeutically active agents that benefit from formulation with a release modulator may come from, but are not limited to, the following therapeutic classes:
Ace-inhibitor; endogenous cytokines that influence basement membrane; agents that influence growth of endothelial cells; adrenergic agonist or blocker; aldose reductose inhibitor; analgesic; anesthetic; antiallergic; antibacterial; antifibrotic;
antifungal, e.g.
amphoteracin B; antiglaucoma; antihyper- or hypotensive; anti-inflammatory;
antineoplastic; antiprotozoal; antitumor; antiviral; carbonic anhydrase inhibitor; chelating agents; cholinergic; cholinesterase inhibitor; CNS stimulant; contraceptive;
dopamine receptor agonist or antagonist; estrogen; glucocorticoid; glucosidase inhibitor; releasing factor; growth hormone inhibitor; growth stimulant; hemolytic; heparin antagonist;
immunomodulator; immunosuppressant; LH-RH agonist; antimitotics; NSAID;
progesterone; thrombolytic; vasodilator; vasopressor; and vitamin. Among hydrophobic drugs, which typically have a slow release profile and therefore benefit from formulation with a release accelerator, are cyclosporines, e.g. cyclosporin A, cyclosporin G, etc.; vinca alkaloids, e.g. vincristine and vinblastine; methotrexate; retinoic acid;
certain antibiotics, e.g. ansamycins such as rifampin; nitrofurans such as nifuroxazide; non-steroidal anti-inflammatory drugs, e.g diclofenac, keterolac, flurbiprofen, naproxen, suprofen, ibuprofen, aspirin; steroids, etc.
Steroids are of specific interest, in particular steroidal compounds with anti-inflammatory activity, i.e. glucocorticoids. Glucocorticoids include the following:
21-acctoxy re nenolone flumethasone me rednisone alclometasone flunisolide mcthvl rednisolonc alaestone fluocinolone acetonide mometasonc furoate amcinonide fluocinonidc prednisolone sodium2l -m-sulfobenzoatc beclomethasonc fluocortinbutyl prednisolone2l-stea 1 ivcolatc betamethasone fluocortolone prednisolonc tcbutatc budesonidc fluorometholone prednisolonc 21-trimethvlacetate chloroprednisone flu roloneacetate prcdnisone clobetasol fluprednidenc acetate prednival clobetasone flu rednisolone ramethasone clo redno) flurandrenolide rednvlidene clocortolone formocortal prednicarbate corticosterone halcinonide prednylidene 21-diethvlaminoacetate cortisone halometasone prednisolone cortivazol halopredone acetate prednisolone 21-diethvlaminoaeetate deffazacort hvdrocortamate tixocortol desonide diflorasonc triamcinolone desoximetasonc hydrocortisone rcdnisolone sodium phosphate dexamethasonc hvdrocortisone acetate triamcinolone acetonide diflucortolone hvdrocortisone phosphate rcdnisolone sodium succinatc diruprednate hydrocortisone 21-sodium triamcinolone benctonide succinate enoxolonc hvdrocortisonetebutate triamcinolone hexacctonide.
fluazacort mazi redone flucloronide medrvsonc These hydrocortisone derivatives have been recognized of having significant therapeutic effects that are beneficial in the treatment of ocular inflammatory diseases, varying in their potency and biotolerability as function of their chemical substitutions.
The following are examples of glucocorticoids that have been used in the treatment of ocular inflammation, and are of interest for use in the subject invention.
dexamethasone sodium phosphate; prednisolone sodium phosphate; prednisolone acetate;
fluorometholone acetate; dexamethasone; fluoromethalone; and medrysone. Of these, dexamethasone is thought to be the most potent, and is therefore a good candidate for the use in an intraocular drug delivery system, because a small drug release rate is sufficient to establish therapeutic concentration levels inside the eye. Triamcinolone is another drug of interest for sustained release intraocular administration.
Accelerators may be physiologically inert, water soluble polymers, e.g. low molecular weight methyl cellulose or hydroxypropyl methyl cellulose (HPMC);
sugars, e.g.
monosaccharides such as fructose and glucose, disaccharides such as lactose, sucrose, or polysaccharides, usually neutral or uncharged, such as cellulose, amylose, dextran, etc.
Alternatively, the accelerator may be a physiologically active agent, allowing for a combined therapeutic formulation. The choice of accelerator in such a case will be determined by the desired combination of therapeutic activities.
Release retardants are hydrophobic compounds that slow the rate of release of hydrophilic drugs, allowing for a more extended release profile. Hydrophilic drugs of interest which may benefit from release modulation include water soluble antibiotics, as described above, nucleotide analogs, e.g. acyclovir, gancyclovir, vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine; epinephrine; isoflurphate;
adriamycin;
bleomycin; mitomycin; ara-C; actinomycin D; scopolamine; and the like.
Agents of interest as release retardants include non-water soluble polymers, e.g.
high molecular weight methylcellulose and ethylcellulose, etc., low water soluble organic compounds, and pharmaceutically active hydrophobic agents, as previously described.
A category of drugs that is of interest as active ingredient and/or as active release modulator in a combination are drugs with antimicrobial activity.
Antibacterial drug classes that have found successful use in care of the infected eye are:
aminoglycosides, amphenicols, ansamycins, lactams, lincosamides, macrolides, polypeptides, tetracyclines, diaminopyrimidines, nitrofurans, quinolones and analogs, sulfonamides, sulfones, etc.
Where one compound does not cover the range of the bacterial infection, products may combine several antibacterial drugs in one combination product. Examples of antibiotics useful in treating ocular infections include: chloramphenicol; polymyxin b, neomycin, gramicidin; neomycin; bacitracin; sulfacetamide sodium; gentamicin;
ciprofloxacin;
tobramycin; trimethprim sulfate; ofloxacin; erythromycin; norfloxacin;
vancomycin;
tetracycline; and chlortetracycline.
Antiviral drugs are also of interest. These include a number of water soluble nucleotide analogs, e.g. acyclovir, gancyclovir, vidarabine, azidothymidine, dideoxyinosine and dideoxycytosine.
Of particular interest as an antibacterial compound are the quinolones, which are very potent, broad spectrum antibiotics. The high activity of these drugs allows a therapeutic concentration to be reached at low levels of the drug. Examples include ciprofloxacin; norfloxacin; ofloxacin; enoxacin, lomefloxacin; fleroxacin;
temafloxacin, tosufloxacin and perfloxacin.
In a preferred embodiment of the invention, the implant comprises an anti-inflammatory drug, e.g. non-steroidal anti-inflammatory drug or glucocorticoids, as described above, and a release modulator, where the release modulator is an ophthalmically active agent. Certain diseases require the combined administration of drugs from different therapeutic categories. The combination is determined by the specific condition to be treated, e.g. viral infection, tumor, bacterial infection, etc. A suitable anti-inflammatory drug is then chosen to optimize the release profile of the combined therapeutically active agents. Combinations of interest include anti-inflammatory and anti-tumor, e.g. glucocorticoid and methotrexate, glucocorticoid and 5-fluorouracil, NSAID and methotrexate; anti-inflammatory and antiviral; e.g. glucocorticoid or NSAID
in combination with vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine, acyclovir, foscarnet, or gancyclovir; anti-inflammatory and antibacterial, e.g.
glucocorticoid and quinolone, MAID and quinolone.
An example for the medical requirement of co-delivery of therapeutic agents from two different therapeutic classes is eye surgery. Eye surgery is often complicated with infection and inflammation, therefore drug products have been made available to administer an anti-inflammatory and antibacterial drug simultaneously. Of particular interest for the treatment of post-surgical eye complication is a drug delivery system delivering the combination of an anti-inflammatory drug and an antibacterial drug, e.g.
dexamethasone and ciprofloxacin. These two drugs are good candidates for intraocular drug delivery because of their high activity.
A combined anti-inflammatory drug, and antibiotic or antiviral, may be further combined with an additional therapeutic agent. The additional agent may be an analgesic, e.g. codeine, morphine, keterolac, naproxen, etc., an anesthetic, e.g.
lidocaine; b-adrenergic blocker or b-adrenergic agonist, e.g. ephidrine, epinephrine, etc.;
aldose reductase inhibitor, e.g. epalrestat, ponalrestat, sorbinil, tolrestat;
antiallergic, e.g cromolyn, beclomethasone, dexamethasone, and flunisolide; colchicine_ Anihelminthic agents, e.g ivermectin And suramin sodium; antiamebic agents, e.g. chloroquine and chlortetracycline; and antifungal agent, e.g. amphotericin, etc. may be co-formulated with an antibiotic and an anti-inflammatory drug. For intra-ocular use, anti-giaucomas agents, e.g. acetozolamide (dimox), befunolol, n-blockers, Ca-blockers, etc. in combinations with anti-inflammatory and antimicrobial agents are of interest. For the treatment of neoplasia, combinations with anti-neoplastics, particularly vinblastine, vincristine, interferons a, b and g, antimetabolites, e.g. folic acid analogs, purine analogs, pyrimidine analogs may be used. Immunosuppressants such as azathioprine, cyclosporine and mizoribine are of interest in combinations. Also useful combinations include miotic agents, e.g.
carbachol, mydriatic agents such as atropine, etc., protease inhibitors such as aprotinin, camostat, gabexate, vasodilators such as bradykinin, etc., and various growth factors, such epidermal growth factor, basic fibroblast growth factor, nerve growth factors, and the like.
The amount of active agent employed in the implant, individually or in combination, will vary widely depending on the effective dosage required and rate of release from the implant. Usually the agent will be at least about 1, more usually at least about 10 weight percent of the implant, and usually not more than about 80, more usually not more than about 40 weight percent of the implant. The amount of release modulator employed will be dependent on the desired release profile, the activity of the modulator, and on the release profile of the active agent in the absence of modulator. An agent that is released very slowly or very quickly will require relatively high amounts of modulator.
Generally the modulator will be at least 10, more usually at least about 20 weight percent of the implant, and usually not more than about 50, more usually not more than about 40 weight percent of the implant.
Where a combination of active agents is to be employed, the desired release profile of each active agent is determined. If necessary, a physiologically inert modulator is added to precisely control the release profile. The drug release will provide a therapeutic level of each active agent-The exact proportion of modulator and active agent will be empirically determined by formulating several implants having varying amounts of modulator. A USP
approved method for dissolution or release test will be used to measure the rate of release (USP 23;
NF 18 (1995) pp. 1790-1798). For example, using the infinite sink method, a weighed sample of the drug delivery device is added to a measured volume of a solution containing four parts by weight of ethanol and six parts by weight of deionized water, where the solution volume will be such that the drug concentration after release is less than 5% of saturation. The mixture is maintained at 37 C and stirred slowly to maintain the implants in suspension. The appearance of the dissolved drug as a function of time may be followed by various methods known in the art, such as spectrophotometrically, HPLC, mass spectroscopy, etc. The drug concentration after 1 h in the medium is indicative of the amount of free unencapsulated drug in the dose, while the time required for 90% drug to be released is related to the expected duration of action of the dose in vivo.
Normally the release will be free of larger fluctuations from some average value which allows for a relatively uniform release.
Normally the implant will be formulated to release the active agent(s) over a period of at least about 3 days, more usually at least about one week, and usually not more than about one year, more usually not more than about three months. For the most part, the matrix of the implant will have a physiological lifetime at the site of implantation at least equal to the desired period of administration, usually at least twice the desired period of administration, and may have lifetimes of 5 to 10 times the desired period of administration. The desired period of release will vary with the condition that is being treated. For example, implants designed for post-cataract surgery will have a release period of from about 3 days to 1 week; treatment of uveitis may require release over a period of about 4 to 6 weeks; while treatment for cytomegalovirus infection may require release over 3 to 6 months, or longer.
The implants are of dimensions commensurate with the size and shape of the region selected as the site of implantation and will not migrate from the insertion site following implantation. The implants may be rigid, or somewhat flexible so as to facilitate both insertion of the implant at the target site and accommodation of the implant.
The implants may be particles, sheets, patches, plaques, fibers, microcapsules and the like and may be of any size or shape compatible with the selected site of insertion.
The implants may be monolithic, i.e. having the active agent homogenously distributed through the polymeric matrix, or encapsulated, where a reservoir of active agent is encapsulated by the polymeric matrix. Due to ease of manufacture, monolithic implants are usually preferred over encapsulated forms. However, the greater control afforded by the encapsulated, reservoir-type may be of benefit in some circumstances, where the therapeutic level of the drug falls within a narrow window. The selection of the polymeric composition to be employed will vary with the site of administration, the desired period of treatment, patient tolerance, the nature of the disease to be treated and the like.
Characteristics of the polymers will include biodegradability at the site of implantation, compatibility with the agent of interest, ease of encapsulation, a half-life in the physiological environment of at least 7 days, preferably greater than two weeks, water solubility, and the like. The polymer will usually comprise at least about 10, more usually at least about 20 weight percent of the implant, and may comprise as much as about 70 weight percent or more.
Biodegradable polymeric compositions that may be employed may be organic esters or ethers, which when degraded result in physiologically acceptable degradation products, including the monomers. Anhydrides, amides, orthoesters or the like, by themselves or in combination with other monomers, may find use. The polymers will be 30,16-2 condensation polymers. The polymers may be cross-linked or non-cross-linked, usually not more than lightly cross-linked, generally less than 5%, usually less than 1%. For the most part, besides carbon and hydrogen, the polymers will include oxygen and nitrogen, particularly oxygen. The oxygen may be present as oxy, e.g., hydroxy or ether, carbonyl, e.g., non-oxo-carbonyl, such as carboxylic acid ester, and the like. The nitrogen may be present as amide, cyano and amino. The polymers set forth in Heller, supra, may find use.
Of particular interest are polymers of hydroxyaliphatic carboxylic acids, either homo- or copolymers, and polysaccharides. Included among the polyesters of interest are polymers of D-lactic acid, L-lactic acid, racemic lactic. acid, glycolic acid, polycaprolactone, and combinations thereof. By employing the L-lactate or D-lactate, a slowly biodegrading polymer is achieved, while degradation is substantially enhanced with the racemate. Copolymers of glycolic and lactic acid are of particular interest, where the rate of biodegradation is controlled by the ratio of glycolic to lactic acid.
The most rapidly degraded copolymer has roughly equal amounts of glycolic and lactic acid.
Homopolymers, or copolymers having ratios other than equal, are more resistant to degradation.
Among the polysaccharides will be calcium alginate, and functionalized celluloses, particularly carboxymethylcellulose esters characterized by being water insoluble, a molecular weight of about 5 kD to 500 kD, etc. Biodegradable hydrogels may also be employed in the implants of the subject invention. Hydrogels are typically a copolymer material, characterized by the ability to imbibe a liquid. Exemplary biodegradable hydrogels which may be employed are described in Heller in: Hydrogels in Medicine and Pharmacy, N.A. Peppes ed., Vol. III, CRC Press, Boca Raton, FL, 1987, pp 137-149.
Particles can be prepared where the center may be of one material and the surface have one or more layers of the same or different composition, where the layers may be cross-linked, of different molecular weight, different density or porosity, or the like. For example, the center would comprise a polylactate coated with a polylactate-polyglycolate copolymer, so as to enhance the rate of initial degradation. Most ratios of lactate to glycolate employed will be in the range of about 1:0.1 to 1:1. Alternatively, the center could be polyvinyl alcohol coated with polylactate, so that on degradation of the polylactate the center would dissolve and be rapidly washed out of the implantation site.
The implants find use in the treatment of a variety of conditions in which it is convenient to employ a depot for the active agent, where the implant serves as such as a depot. Therefore, depending on the particular condition to be treated, the implant may be introduced into a variety of different locations of the host where it is convenient to have an active agent depot, including in the eye, central nervous system, vascular system, in the bones, in the skin, in the muscels, in the ears, etc...
The formulation of implants for use in the treatment of ocular conditions, diseases, tumors and disorders are of particular interest. The biodegradable implants may be implanted at various sites, depending on the shape and formulation of the implant, the condition being treated, etc. Suitable sites include the anterior chamber, posterior chamber, posterior segment, including vitreous cavity, suprachoroidal space, subconjunctiva, episcleral, intracorneal, epicorneal and sclera. Suitable sites extrinsic to the vitreous comprise the suprachoroidal space, the pars plana and the like.
The suprachoroid is a potential space lying between the inner scleral wall and the apposing choroid. Implants that are introduced into the suprachoroid may deliver drugs to the choroid and to the anatomically apposed retina, depending upon the diffusion of the drug from the implant, the concentration of drug comprised in the implant and the like.
Implants may be introduced over or into an avascular region. The avascular region may be naturally occurring, such as the pars plana, or a region made to be avascular by surgical and chemical methods. Surgically-induced avascular regions may be produced in an eye by methods known in the art such as laser ablation, photocoagulation, cryotherapy, heat coagulation, cauterization and the like. It may be particularly desirable to produce such an avascular region over or near the desired site of treatment, particularly where the desired site of treatment is distant from the pars plana or placement of the implant at the pars plana is not possible. Introduction of implants over an avascular region will allow for diffusion of the drug from the implant and into the inner eye and avoids diffusion of the drug into the bloodstream.
Turning now to Figure 3, a cross-sectional view of the eye is shown, illustrating the sites for implantation in accordance with the subject invention. The eye comprises a lens 16 and encompasses the vitreous chamber 3. Adjacent to the vitreous chamber 3 is the optic part of the retina 11. Implantation may be intraretinal 11 or subretinal 12. The retina is surrounded by the choroid 18. Implantation may be intrachoroidal or supr achoroidal 4. Between the optic part of the retina and the lens, adjacent to the vitreous, is the pars plana 19. Surrounding the choroid 18 is the sclera 8.
Implantation may be intrascleral 8 or episcleral 7. The external surface of the eye is the cornea 9.
Implantation maybe epicorneal 9 or intra-corneal 10. The internal surface of the eye is the conjunctiva 6. Behind the cornea is the anterior chamber 1, behind which is the lens 16.
The posterior chamber 2 surrounds the lens, as shown in the figure. Opposite from the external surface is the optic nerves, and the arteries and vein of the retina.
Implantation into the meningeal spaces 13, the optic nerve 15 and the intraoptic nerve 14 allows for drug delivery into the central nervous system, and provides a mechanism whereby the blood-brain barrier may be crossed.
Other sites of implantation include the delivery of anti-tumor drugs to neoplastic lesions, e.g. tumor, or lesion area, e.g. surrounding tissues, or in those situations where the tumor mass has been removed, tissue adjacent to the previously removed tumor and/or into the cavity remaining after removal of the tumor. The implants may be administered in a variety of ways, including surgical means, injection, trocar, etc.
Other agents may be employed in the formulation for a variety of purposes. For example, buffering agents and preservatives may be employed. Water soluble preservatives which may be employed include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol. These agents may be present in individual amounts of from about 0.001 to about 5% by weight and preferably about 0.01 to about 2%. Suitable water soluble buffering agents that may be employed are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc., as approved by the FDA for the desired route of administration.
These agents may be present in amounts sufficient to maintain a pH of the system of between 2 to 9 and preferably 4 to 8. As such the buffering agent may be as much as 5%
on a weight to weight basis of the total composition. Where the buffering agent or enhancer is hydrophilic, it may also act as a release accelerator, and will have an cumulative effect with other modulator(s). Similarly, a hydrophobic buffering agent may act as a release retardant.
The implants may be of any geometry including fibers, sheets, films, microspheres, spheres, circular discs, plaques and the like. The upper limit for the implant size will be 3(.,6-2 determined by factors such as toleration for the implant, size limitations on insertion, ease of handling, etc. Where sheets or films are employed, the sheets or films will be in the range of at least about 0.5 mm x 0.5 mm, usually about 3-10 mm x 5-10 mm with a thickness of about 025-1.0 mm for ease of handling. Where fibers are employed, the diameter of the fiber will generally be in the range of 0.05 to 3 mm. The length of the fiber will generally be in the range of 0.5-10 mm. Spheres will be in the range of 2 gm to 4 mm in diameter, with comparable volumes for other shaped particles.
The size and form of the implant can be used to control the rate of release, period of treatment, and drug concentration at the site of implantation. Larger implants will deliver a proportionately larger dose, but depending on the surface to mass ratio, may have a slower release rate. The particular size and geometry of an implant will be chosen to best suit the site of implantation. The chambers, e.g. anterior chamber, posterior chamber and vitreous chamber, are able to accomodate relatively large implants of varying geometries, having diameters of 1 to 3 mm.. A sheet, or circular disk is preferable for implantation in the suprachoroidal space. The restricted space for intraretinal implantation requires relatively small implants, having diameters from 0.05 to 1 mm.
In some situations mixtures of implants may be utilized employing the same or different pharmacological agents. In this way, a cocktail of release profiles, giving a biphasic or triphasic release with a single administration is achieved, where the pattern of release may be greatly varied.
Various techniques may be employed to produce the implants. Useful techniques include solvent evaporation methods, phase separation methods, interfacial methods, extrusion methods, molding methods, injection molding methods, heat press methods and the like. Specific methods are discussed in U.S. Patent 4,997,652.
In a preferred embodiment, extrusion methods are used to avoid the need for solvents in manufacturing. When using extrusion methods, the polymer and drug are chosen so as to be stable at the temperatures required for manufacturing, usually at least about 85 C.
The following examples are offered by way of illustration and not by way of limitation.
EXPERIMENTAL
- G
a pharmacologically acceptable biodegradable polymer at a concentration of at least about 20 weight percent of the implant; a first therapeutically active agent at a concentration from 10 to 50 weight percent of the implant; a release modulator at a concentration from 10 to 50 weight percent of the implant; wherein: (a) said release modulator comprises a second therapeutically active agent; (b) said implant is degraded at the site of implantation, and releases said first therapeutically active agent within a therapeutic dosage which does not vary by more than about 100% for a period of at least about 3 days after implantation; and (c) one of said first therapeutically active agent and said release modulator is a hydrophobic entity and the other is a hydrophilic entity.
In another aspect, the present invention provides an implant for controlled, sustained drug release comprising: poly-lactate glycolic acid copolymer at a concentration of at least about 20 weight percent of the implant; a therapeutically active anti-inflammatory drug at a concentration from 10 to 50 weight percent of the implant;
and a release modulator at a concentration from 10 to 50 weight percent of the implant; wherein: (a) said release modulator is a therapeutically active agent.; (b) said implant is degraded at the site of implantation, and releases said therapeutically active anti-inflammatory drug within a therapeutic dosage which does not vary by more than about 100% for a period of at least about 3 days after implantation; and (c) one of said therapeutically active anti-inflammatory drug and said release modulator (i) is a hydrophobic entity and the other is a hydrophilic entity, and (ii) is other than a chemical form of the same compound of the other.
-2a-J V / / O - G
In another aspect, the present invention provides a bioerodible implant comprising a polylactic acid/polyglycolic acid (PLGA) polymer matrix and dexamethasone dispersed within the PLGA polymer matrix, wherein: said dexamethasone in the implant (i) is between about 40 percent and about 60 percent by weight of the implant, and (ii) is present in a single chemical form; the implant has a cumulative release profile providing for each time in a plurality of times a cumulative amount of dexamethasone released in vitro prior to the time expressed as a percentage of the dose of dexamethasone in the implant;
and the cumulative release profile comprises a linear portion in which the cumulative amount of dexamethasone released in vitro is an approximately linear function of time.
In another aspect, the present invention provides a bioerodible implant comprising: (a) a polylactic acid/polyglycolic acid (PLGA) polymer matrix at a concentration from 10 to 50 weight percent of the implant;
(b) dexamethasone; and (c) a release modifier at a concentration from 10 to 50 weight percent of the implant;
wherein: the dexamethasone is in a single chemical form and the release modifier is hydroxypropylmethylcellulose (HPMC) or ciprofloxacin; the implant has a cumulative release profile providing for each time in a plurality of times a cumulative amount of dexamethasone released in vitro prior to the time expressed as a percentage of the dose of dexamethasone in the implant; and the cumulative release profile comprises a linear portion in which the cumulative amount of dexamethasone released in vitro is an approximately linear function of time.
-2b-3V J i76-2 In another aspect, the present invention provides a batch of bioerodible implants comprising a plurality of bioerodible implants, wherein: (a) each bioerodible implant is sized for implantation within an ocular region; (b) each bioerodible implant comprises a PLGA polymer matrix and dexamethasone dispersed within the PLGA polymer matrix, and said dexamethasone in the implant (i) is between about 40 percent and about 60 percent by weight of the implant, and (ii) is present in a single chemical form; (c) each implant has a cumulative release profile providing for each time in a plurality of times a cumulative amount of dexamethasone released in vitro prior to the time, and (d) for each time in a time period, for each implant in the batch the cumulative amount of dexamethasone released in vitro is within about 30% of an average cumulative amount of dexamethasone released in vitro for all implants in the batch.
In another aspect, the present invention provides a batch of bioerodible implants comprising a plurality of bioerodible implants, wherein: (a) each bioerodible implant is sized for implantation within an ocular region; (b) each bioerodible implant comprises: (i) a PLGA polymer matrix at a concentration from 10 to 50 weight percent of the implant;
(ii) dexamethasone; and (iii) a release modifier at a concentration from 10 to 50 weight percent of the implant;
(c) the dexamethasone is in a single chemical form and the release modifier is hydroxypropylmethylcellulose (HPMC) or ciprofloxacin; (d) each implant has a cumulative release profile providing for each time in a plurality of times a cumulative amount of dexamethasone released in vitro prior to the time, and (e) for each time in a time period, for each implant in the batch the cumulative amount of dexamethasone released in vitro is within about 30% of an -2c-~. 7C ) J V % / V G
average cumulative amount of dexamethasone released in vitro for all implants in the batch.
In another aspect, the present invention provides use of an implant described above, for drug delivery in a subject. Further uses of the implant include the treatment of an ocular condition in a subject, wherein said condition is a viral infection, a bacterial infection, inflammation, a tumour, a post-surgical eye complication, or any combination thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1A shows the release profile of a hydrophobic drug from an extended release drug delivery system. Figure 1B shows the release profile of the same drug when formulated in a drug delivery system with a release modulator.
Figure 2A shows the release profile of dexamethasone in the absence or presence of the release modifier, ciproflaxacin HC1. Figure 2B shows the release of ciprofloxacin in the presence of dexamethasone. Figure 2C
shows the release of ciprofloxacin in the absence of a release modifier. Figure 2D shows the release profile from a drug delivery system having combined hydrophilic and hydrophobic drugs, and further having a pharmaceutically inactive release modifier.
Figure 3 shows a cross-sectional view of an eye.
-2d-3i,'. 6-2 DESCRIPTION OF THE SPECIFIC EMBODIMENTS
A controlled drug release is achieved by an improved formulation of slow release biodegradable implants. The release rate of a drug from an implant can be modulated by addition of a release modulator to the implant. Release of a hydrophobic agent is increased by inclusion of an accelerator in the implant, while retardants are included to decrease the release rate of hydrophilic agents. The release modulator may be physiologically inert, or a therapeutically active agent. Formulations of interest includes anti inflammatory drugs,, e.g. glucocorticoids, NSAIDS, etc., combined with an ophthalmically active agent.
The rate of release of the therapeutically active agent is controlled by the rate of transport through the polymeric matrix of the implant, and the action of the modulator.
By modulating the release rate, the agent is released at a substantially constant rate within a 'therapeutic dosage range, over the desired period of time. The rate of release will usually not vary by more than about 100% over the desired period of time, more usually by not. more than about 50% The agent is made available at the specific site(s) where the agent is needed, and it is maintained at an effective dosage.
The transport of drug through the polymer barrier is also affected by drug solubility, polymer hydrophilicity, extent of polymer cross-linking, expansion of the polymer upon water absorption so as to make the polymer barrier more permeable to the drug, geometry of the implant, and the like. At high drug loadings, i.e. at a loading concentration above the theoretical percolation threshold, percolation theory predicts the potential for drug leaching from the drug delivery system matrix. In such cases release modulators are useful to slow down the leaching process.
The release modulator is an agent that alters the release of a drug from a biodegradable implant in a defined manner. It may be an accelerator or a retardant.
Accelerators will be hydrophilic compounds, which are used in combination with hydrophobic agents to increase the rate of release. Hydrophilic agents are those compounds which have at least about 100 gg/ml solubility in water at ambient temperature. Hydrophobic agents are those compounds which have less than about 100 g/ml solubility in water at ambient temperature.
Therapeutically active agents that benefit from formulation with a release modulator may come from, but are not limited to, the following therapeutic classes:
Ace-inhibitor; endogenous cytokines that influence basement membrane; agents that influence growth of endothelial cells; adrenergic agonist or blocker; aldose reductose inhibitor; analgesic; anesthetic; antiallergic; antibacterial; antifibrotic;
antifungal, e.g.
amphoteracin B; antiglaucoma; antihyper- or hypotensive; anti-inflammatory;
antineoplastic; antiprotozoal; antitumor; antiviral; carbonic anhydrase inhibitor; chelating agents; cholinergic; cholinesterase inhibitor; CNS stimulant; contraceptive;
dopamine receptor agonist or antagonist; estrogen; glucocorticoid; glucosidase inhibitor; releasing factor; growth hormone inhibitor; growth stimulant; hemolytic; heparin antagonist;
immunomodulator; immunosuppressant; LH-RH agonist; antimitotics; NSAID;
progesterone; thrombolytic; vasodilator; vasopressor; and vitamin. Among hydrophobic drugs, which typically have a slow release profile and therefore benefit from formulation with a release accelerator, are cyclosporines, e.g. cyclosporin A, cyclosporin G, etc.; vinca alkaloids, e.g. vincristine and vinblastine; methotrexate; retinoic acid;
certain antibiotics, e.g. ansamycins such as rifampin; nitrofurans such as nifuroxazide; non-steroidal anti-inflammatory drugs, e.g diclofenac, keterolac, flurbiprofen, naproxen, suprofen, ibuprofen, aspirin; steroids, etc.
Steroids are of specific interest, in particular steroidal compounds with anti-inflammatory activity, i.e. glucocorticoids. Glucocorticoids include the following:
21-acctoxy re nenolone flumethasone me rednisone alclometasone flunisolide mcthvl rednisolonc alaestone fluocinolone acetonide mometasonc furoate amcinonide fluocinonidc prednisolone sodium2l -m-sulfobenzoatc beclomethasonc fluocortinbutyl prednisolone2l-stea 1 ivcolatc betamethasone fluocortolone prednisolonc tcbutatc budesonidc fluorometholone prednisolonc 21-trimethvlacetate chloroprednisone flu roloneacetate prcdnisone clobetasol fluprednidenc acetate prednival clobetasone flu rednisolone ramethasone clo redno) flurandrenolide rednvlidene clocortolone formocortal prednicarbate corticosterone halcinonide prednylidene 21-diethvlaminoacetate cortisone halometasone prednisolone cortivazol halopredone acetate prednisolone 21-diethvlaminoaeetate deffazacort hvdrocortamate tixocortol desonide diflorasonc triamcinolone desoximetasonc hydrocortisone rcdnisolone sodium phosphate dexamethasonc hvdrocortisone acetate triamcinolone acetonide diflucortolone hvdrocortisone phosphate rcdnisolone sodium succinatc diruprednate hydrocortisone 21-sodium triamcinolone benctonide succinate enoxolonc hvdrocortisonetebutate triamcinolone hexacctonide.
fluazacort mazi redone flucloronide medrvsonc These hydrocortisone derivatives have been recognized of having significant therapeutic effects that are beneficial in the treatment of ocular inflammatory diseases, varying in their potency and biotolerability as function of their chemical substitutions.
The following are examples of glucocorticoids that have been used in the treatment of ocular inflammation, and are of interest for use in the subject invention.
dexamethasone sodium phosphate; prednisolone sodium phosphate; prednisolone acetate;
fluorometholone acetate; dexamethasone; fluoromethalone; and medrysone. Of these, dexamethasone is thought to be the most potent, and is therefore a good candidate for the use in an intraocular drug delivery system, because a small drug release rate is sufficient to establish therapeutic concentration levels inside the eye. Triamcinolone is another drug of interest for sustained release intraocular administration.
Accelerators may be physiologically inert, water soluble polymers, e.g. low molecular weight methyl cellulose or hydroxypropyl methyl cellulose (HPMC);
sugars, e.g.
monosaccharides such as fructose and glucose, disaccharides such as lactose, sucrose, or polysaccharides, usually neutral or uncharged, such as cellulose, amylose, dextran, etc.
Alternatively, the accelerator may be a physiologically active agent, allowing for a combined therapeutic formulation. The choice of accelerator in such a case will be determined by the desired combination of therapeutic activities.
Release retardants are hydrophobic compounds that slow the rate of release of hydrophilic drugs, allowing for a more extended release profile. Hydrophilic drugs of interest which may benefit from release modulation include water soluble antibiotics, as described above, nucleotide analogs, e.g. acyclovir, gancyclovir, vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine; epinephrine; isoflurphate;
adriamycin;
bleomycin; mitomycin; ara-C; actinomycin D; scopolamine; and the like.
Agents of interest as release retardants include non-water soluble polymers, e.g.
high molecular weight methylcellulose and ethylcellulose, etc., low water soluble organic compounds, and pharmaceutically active hydrophobic agents, as previously described.
A category of drugs that is of interest as active ingredient and/or as active release modulator in a combination are drugs with antimicrobial activity.
Antibacterial drug classes that have found successful use in care of the infected eye are:
aminoglycosides, amphenicols, ansamycins, lactams, lincosamides, macrolides, polypeptides, tetracyclines, diaminopyrimidines, nitrofurans, quinolones and analogs, sulfonamides, sulfones, etc.
Where one compound does not cover the range of the bacterial infection, products may combine several antibacterial drugs in one combination product. Examples of antibiotics useful in treating ocular infections include: chloramphenicol; polymyxin b, neomycin, gramicidin; neomycin; bacitracin; sulfacetamide sodium; gentamicin;
ciprofloxacin;
tobramycin; trimethprim sulfate; ofloxacin; erythromycin; norfloxacin;
vancomycin;
tetracycline; and chlortetracycline.
Antiviral drugs are also of interest. These include a number of water soluble nucleotide analogs, e.g. acyclovir, gancyclovir, vidarabine, azidothymidine, dideoxyinosine and dideoxycytosine.
Of particular interest as an antibacterial compound are the quinolones, which are very potent, broad spectrum antibiotics. The high activity of these drugs allows a therapeutic concentration to be reached at low levels of the drug. Examples include ciprofloxacin; norfloxacin; ofloxacin; enoxacin, lomefloxacin; fleroxacin;
temafloxacin, tosufloxacin and perfloxacin.
In a preferred embodiment of the invention, the implant comprises an anti-inflammatory drug, e.g. non-steroidal anti-inflammatory drug or glucocorticoids, as described above, and a release modulator, where the release modulator is an ophthalmically active agent. Certain diseases require the combined administration of drugs from different therapeutic categories. The combination is determined by the specific condition to be treated, e.g. viral infection, tumor, bacterial infection, etc. A suitable anti-inflammatory drug is then chosen to optimize the release profile of the combined therapeutically active agents. Combinations of interest include anti-inflammatory and anti-tumor, e.g. glucocorticoid and methotrexate, glucocorticoid and 5-fluorouracil, NSAID and methotrexate; anti-inflammatory and antiviral; e.g. glucocorticoid or NSAID
in combination with vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine, acyclovir, foscarnet, or gancyclovir; anti-inflammatory and antibacterial, e.g.
glucocorticoid and quinolone, MAID and quinolone.
An example for the medical requirement of co-delivery of therapeutic agents from two different therapeutic classes is eye surgery. Eye surgery is often complicated with infection and inflammation, therefore drug products have been made available to administer an anti-inflammatory and antibacterial drug simultaneously. Of particular interest for the treatment of post-surgical eye complication is a drug delivery system delivering the combination of an anti-inflammatory drug and an antibacterial drug, e.g.
dexamethasone and ciprofloxacin. These two drugs are good candidates for intraocular drug delivery because of their high activity.
A combined anti-inflammatory drug, and antibiotic or antiviral, may be further combined with an additional therapeutic agent. The additional agent may be an analgesic, e.g. codeine, morphine, keterolac, naproxen, etc., an anesthetic, e.g.
lidocaine; b-adrenergic blocker or b-adrenergic agonist, e.g. ephidrine, epinephrine, etc.;
aldose reductase inhibitor, e.g. epalrestat, ponalrestat, sorbinil, tolrestat;
antiallergic, e.g cromolyn, beclomethasone, dexamethasone, and flunisolide; colchicine_ Anihelminthic agents, e.g ivermectin And suramin sodium; antiamebic agents, e.g. chloroquine and chlortetracycline; and antifungal agent, e.g. amphotericin, etc. may be co-formulated with an antibiotic and an anti-inflammatory drug. For intra-ocular use, anti-giaucomas agents, e.g. acetozolamide (dimox), befunolol, n-blockers, Ca-blockers, etc. in combinations with anti-inflammatory and antimicrobial agents are of interest. For the treatment of neoplasia, combinations with anti-neoplastics, particularly vinblastine, vincristine, interferons a, b and g, antimetabolites, e.g. folic acid analogs, purine analogs, pyrimidine analogs may be used. Immunosuppressants such as azathioprine, cyclosporine and mizoribine are of interest in combinations. Also useful combinations include miotic agents, e.g.
carbachol, mydriatic agents such as atropine, etc., protease inhibitors such as aprotinin, camostat, gabexate, vasodilators such as bradykinin, etc., and various growth factors, such epidermal growth factor, basic fibroblast growth factor, nerve growth factors, and the like.
The amount of active agent employed in the implant, individually or in combination, will vary widely depending on the effective dosage required and rate of release from the implant. Usually the agent will be at least about 1, more usually at least about 10 weight percent of the implant, and usually not more than about 80, more usually not more than about 40 weight percent of the implant. The amount of release modulator employed will be dependent on the desired release profile, the activity of the modulator, and on the release profile of the active agent in the absence of modulator. An agent that is released very slowly or very quickly will require relatively high amounts of modulator.
Generally the modulator will be at least 10, more usually at least about 20 weight percent of the implant, and usually not more than about 50, more usually not more than about 40 weight percent of the implant.
Where a combination of active agents is to be employed, the desired release profile of each active agent is determined. If necessary, a physiologically inert modulator is added to precisely control the release profile. The drug release will provide a therapeutic level of each active agent-The exact proportion of modulator and active agent will be empirically determined by formulating several implants having varying amounts of modulator. A USP
approved method for dissolution or release test will be used to measure the rate of release (USP 23;
NF 18 (1995) pp. 1790-1798). For example, using the infinite sink method, a weighed sample of the drug delivery device is added to a measured volume of a solution containing four parts by weight of ethanol and six parts by weight of deionized water, where the solution volume will be such that the drug concentration after release is less than 5% of saturation. The mixture is maintained at 37 C and stirred slowly to maintain the implants in suspension. The appearance of the dissolved drug as a function of time may be followed by various methods known in the art, such as spectrophotometrically, HPLC, mass spectroscopy, etc. The drug concentration after 1 h in the medium is indicative of the amount of free unencapsulated drug in the dose, while the time required for 90% drug to be released is related to the expected duration of action of the dose in vivo.
Normally the release will be free of larger fluctuations from some average value which allows for a relatively uniform release.
Normally the implant will be formulated to release the active agent(s) over a period of at least about 3 days, more usually at least about one week, and usually not more than about one year, more usually not more than about three months. For the most part, the matrix of the implant will have a physiological lifetime at the site of implantation at least equal to the desired period of administration, usually at least twice the desired period of administration, and may have lifetimes of 5 to 10 times the desired period of administration. The desired period of release will vary with the condition that is being treated. For example, implants designed for post-cataract surgery will have a release period of from about 3 days to 1 week; treatment of uveitis may require release over a period of about 4 to 6 weeks; while treatment for cytomegalovirus infection may require release over 3 to 6 months, or longer.
The implants are of dimensions commensurate with the size and shape of the region selected as the site of implantation and will not migrate from the insertion site following implantation. The implants may be rigid, or somewhat flexible so as to facilitate both insertion of the implant at the target site and accommodation of the implant.
The implants may be particles, sheets, patches, plaques, fibers, microcapsules and the like and may be of any size or shape compatible with the selected site of insertion.
The implants may be monolithic, i.e. having the active agent homogenously distributed through the polymeric matrix, or encapsulated, where a reservoir of active agent is encapsulated by the polymeric matrix. Due to ease of manufacture, monolithic implants are usually preferred over encapsulated forms. However, the greater control afforded by the encapsulated, reservoir-type may be of benefit in some circumstances, where the therapeutic level of the drug falls within a narrow window. The selection of the polymeric composition to be employed will vary with the site of administration, the desired period of treatment, patient tolerance, the nature of the disease to be treated and the like.
Characteristics of the polymers will include biodegradability at the site of implantation, compatibility with the agent of interest, ease of encapsulation, a half-life in the physiological environment of at least 7 days, preferably greater than two weeks, water solubility, and the like. The polymer will usually comprise at least about 10, more usually at least about 20 weight percent of the implant, and may comprise as much as about 70 weight percent or more.
Biodegradable polymeric compositions that may be employed may be organic esters or ethers, which when degraded result in physiologically acceptable degradation products, including the monomers. Anhydrides, amides, orthoesters or the like, by themselves or in combination with other monomers, may find use. The polymers will be 30,16-2 condensation polymers. The polymers may be cross-linked or non-cross-linked, usually not more than lightly cross-linked, generally less than 5%, usually less than 1%. For the most part, besides carbon and hydrogen, the polymers will include oxygen and nitrogen, particularly oxygen. The oxygen may be present as oxy, e.g., hydroxy or ether, carbonyl, e.g., non-oxo-carbonyl, such as carboxylic acid ester, and the like. The nitrogen may be present as amide, cyano and amino. The polymers set forth in Heller, supra, may find use.
Of particular interest are polymers of hydroxyaliphatic carboxylic acids, either homo- or copolymers, and polysaccharides. Included among the polyesters of interest are polymers of D-lactic acid, L-lactic acid, racemic lactic. acid, glycolic acid, polycaprolactone, and combinations thereof. By employing the L-lactate or D-lactate, a slowly biodegrading polymer is achieved, while degradation is substantially enhanced with the racemate. Copolymers of glycolic and lactic acid are of particular interest, where the rate of biodegradation is controlled by the ratio of glycolic to lactic acid.
The most rapidly degraded copolymer has roughly equal amounts of glycolic and lactic acid.
Homopolymers, or copolymers having ratios other than equal, are more resistant to degradation.
Among the polysaccharides will be calcium alginate, and functionalized celluloses, particularly carboxymethylcellulose esters characterized by being water insoluble, a molecular weight of about 5 kD to 500 kD, etc. Biodegradable hydrogels may also be employed in the implants of the subject invention. Hydrogels are typically a copolymer material, characterized by the ability to imbibe a liquid. Exemplary biodegradable hydrogels which may be employed are described in Heller in: Hydrogels in Medicine and Pharmacy, N.A. Peppes ed., Vol. III, CRC Press, Boca Raton, FL, 1987, pp 137-149.
Particles can be prepared where the center may be of one material and the surface have one or more layers of the same or different composition, where the layers may be cross-linked, of different molecular weight, different density or porosity, or the like. For example, the center would comprise a polylactate coated with a polylactate-polyglycolate copolymer, so as to enhance the rate of initial degradation. Most ratios of lactate to glycolate employed will be in the range of about 1:0.1 to 1:1. Alternatively, the center could be polyvinyl alcohol coated with polylactate, so that on degradation of the polylactate the center would dissolve and be rapidly washed out of the implantation site.
The implants find use in the treatment of a variety of conditions in which it is convenient to employ a depot for the active agent, where the implant serves as such as a depot. Therefore, depending on the particular condition to be treated, the implant may be introduced into a variety of different locations of the host where it is convenient to have an active agent depot, including in the eye, central nervous system, vascular system, in the bones, in the skin, in the muscels, in the ears, etc...
The formulation of implants for use in the treatment of ocular conditions, diseases, tumors and disorders are of particular interest. The biodegradable implants may be implanted at various sites, depending on the shape and formulation of the implant, the condition being treated, etc. Suitable sites include the anterior chamber, posterior chamber, posterior segment, including vitreous cavity, suprachoroidal space, subconjunctiva, episcleral, intracorneal, epicorneal and sclera. Suitable sites extrinsic to the vitreous comprise the suprachoroidal space, the pars plana and the like.
The suprachoroid is a potential space lying between the inner scleral wall and the apposing choroid. Implants that are introduced into the suprachoroid may deliver drugs to the choroid and to the anatomically apposed retina, depending upon the diffusion of the drug from the implant, the concentration of drug comprised in the implant and the like.
Implants may be introduced over or into an avascular region. The avascular region may be naturally occurring, such as the pars plana, or a region made to be avascular by surgical and chemical methods. Surgically-induced avascular regions may be produced in an eye by methods known in the art such as laser ablation, photocoagulation, cryotherapy, heat coagulation, cauterization and the like. It may be particularly desirable to produce such an avascular region over or near the desired site of treatment, particularly where the desired site of treatment is distant from the pars plana or placement of the implant at the pars plana is not possible. Introduction of implants over an avascular region will allow for diffusion of the drug from the implant and into the inner eye and avoids diffusion of the drug into the bloodstream.
Turning now to Figure 3, a cross-sectional view of the eye is shown, illustrating the sites for implantation in accordance with the subject invention. The eye comprises a lens 16 and encompasses the vitreous chamber 3. Adjacent to the vitreous chamber 3 is the optic part of the retina 11. Implantation may be intraretinal 11 or subretinal 12. The retina is surrounded by the choroid 18. Implantation may be intrachoroidal or supr achoroidal 4. Between the optic part of the retina and the lens, adjacent to the vitreous, is the pars plana 19. Surrounding the choroid 18 is the sclera 8.
Implantation may be intrascleral 8 or episcleral 7. The external surface of the eye is the cornea 9.
Implantation maybe epicorneal 9 or intra-corneal 10. The internal surface of the eye is the conjunctiva 6. Behind the cornea is the anterior chamber 1, behind which is the lens 16.
The posterior chamber 2 surrounds the lens, as shown in the figure. Opposite from the external surface is the optic nerves, and the arteries and vein of the retina.
Implantation into the meningeal spaces 13, the optic nerve 15 and the intraoptic nerve 14 allows for drug delivery into the central nervous system, and provides a mechanism whereby the blood-brain barrier may be crossed.
Other sites of implantation include the delivery of anti-tumor drugs to neoplastic lesions, e.g. tumor, or lesion area, e.g. surrounding tissues, or in those situations where the tumor mass has been removed, tissue adjacent to the previously removed tumor and/or into the cavity remaining after removal of the tumor. The implants may be administered in a variety of ways, including surgical means, injection, trocar, etc.
Other agents may be employed in the formulation for a variety of purposes. For example, buffering agents and preservatives may be employed. Water soluble preservatives which may be employed include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol. These agents may be present in individual amounts of from about 0.001 to about 5% by weight and preferably about 0.01 to about 2%. Suitable water soluble buffering agents that may be employed are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc., as approved by the FDA for the desired route of administration.
These agents may be present in amounts sufficient to maintain a pH of the system of between 2 to 9 and preferably 4 to 8. As such the buffering agent may be as much as 5%
on a weight to weight basis of the total composition. Where the buffering agent or enhancer is hydrophilic, it may also act as a release accelerator, and will have an cumulative effect with other modulator(s). Similarly, a hydrophobic buffering agent may act as a release retardant.
The implants may be of any geometry including fibers, sheets, films, microspheres, spheres, circular discs, plaques and the like. The upper limit for the implant size will be 3(.,6-2 determined by factors such as toleration for the implant, size limitations on insertion, ease of handling, etc. Where sheets or films are employed, the sheets or films will be in the range of at least about 0.5 mm x 0.5 mm, usually about 3-10 mm x 5-10 mm with a thickness of about 025-1.0 mm for ease of handling. Where fibers are employed, the diameter of the fiber will generally be in the range of 0.05 to 3 mm. The length of the fiber will generally be in the range of 0.5-10 mm. Spheres will be in the range of 2 gm to 4 mm in diameter, with comparable volumes for other shaped particles.
The size and form of the implant can be used to control the rate of release, period of treatment, and drug concentration at the site of implantation. Larger implants will deliver a proportionately larger dose, but depending on the surface to mass ratio, may have a slower release rate. The particular size and geometry of an implant will be chosen to best suit the site of implantation. The chambers, e.g. anterior chamber, posterior chamber and vitreous chamber, are able to accomodate relatively large implants of varying geometries, having diameters of 1 to 3 mm.. A sheet, or circular disk is preferable for implantation in the suprachoroidal space. The restricted space for intraretinal implantation requires relatively small implants, having diameters from 0.05 to 1 mm.
In some situations mixtures of implants may be utilized employing the same or different pharmacological agents. In this way, a cocktail of release profiles, giving a biphasic or triphasic release with a single administration is achieved, where the pattern of release may be greatly varied.
Various techniques may be employed to produce the implants. Useful techniques include solvent evaporation methods, phase separation methods, interfacial methods, extrusion methods, molding methods, injection molding methods, heat press methods and the like. Specific methods are discussed in U.S. Patent 4,997,652.
In a preferred embodiment, extrusion methods are used to avoid the need for solvents in manufacturing. When using extrusion methods, the polymer and drug are chosen so as to be stable at the temperatures required for manufacturing, usually at least about 85 C.
The following examples are offered by way of illustration and not by way of limitation.
EXPERIMENTAL
Example 1 1' Manufacture and Testing of a Drug DeliveSystem (DDS) without a Release vModullfir Release of the hydrophobic drug dexamethasone from an extended release drug delivery system was measured. The drug delivery system was made with dexamethasone and polylactic acid/polyglycolic acid copolymer. Dexamethasone powder and a powder of polylactic acid polyglycolic acid (PLGA) copolymer were mixed throughly at a ratio of 50/50. The well mixed powder was filled into an extruder, and heated for 1 hour at 95 C, then extruded through a 20 gauge orifice. Six DDS of approximately 100-120 g were cut from the extruded filaments for drug release assessment.
Each individual DDS was placed in a glass vial filled with receptor medium (9% NaCl in water). To allow for "infin ite sink" conditions, the receptor medium volume was chosen so that the concentration would never exceed 5% of saturation. To minimize secondary transport phenomena, e.g. concentration polarization in the stagnant boundary layer, each of the glass vials was placed into a shaking water bath at 37 C.
Samples were taken for HPLC analysis from each vial at defined time points. The HPLC method was as described in USP 23 (1995) pp. 1791-1798. The concentration values were used to calculate the cumulative relase profiles. The release profile is shown in Figure IA. It is seen that drug release is very slow with this DDS. Appreciable drug release begins in the fourth week after initiation, at approximately the time of polymer disintegration.
Manufacture and Testing of a DDS with HPMC Release Modifier A drug delivery system was manufactured as described above, except that various concentrations of hydrophilic hydroxypropylmethylcellulose (HPMC) were included as a release modifier. The combinations of drug, polymer and HPMC shown in Table 1 were used.
Table 1 Lot # PLGA HPMC Dexamethasone Total XT014 3.5 1.5 5 10 XT013 1.5 1.5 5 8 The release of drug was tested as described above. The data is shown in Figure lB. It is seen that with the addition of HPMC, there is a pronounced increase in the rate of release. Close to zero order release is observed for :xT014 and XTO15, where the ratio of release modulator to drug is 0.3 to 0.4. By selection of the appropriate polymer and release modifier, drug release and delivery interval can be custom-tailored to provide a release profile that is accelerated or retarded.
Example 2 Manufacture and Testing of A DDS with a Pharmaceutically Active Release Modifier A drug delivery system was manufactured as described in Example 1, except that ciprofloxacin, a pharmaceutically active, hydrophilic compound, was included as a release modifier. The combinations of drug and polymer shown in Table 2 were used.
Table 2 Lot # PLGA Release Modifier Drug XT029 5 - 5 dexamethasone XT032 4 2 ciprofloxacin 4 dexamethasone XT030 5 - 5 ciprofloxacin The release of dexamethasone is increased with the addition of ciprofloxacin, as shown by the data in Figure 2A. The actual drug release is almost doubled when compared to the DDS without a modifier. In addition to the benefits of increased drug delivery, there are therapeutic benefits introduced with the antibiotic activity of ciprofloxacin. The release of ciprofloxacin from from the same DDS is shown in Figure 2B. The release rate is higher than that of dexamethasone. However, the overall release of ciprofloxacin is slower when co-formulated with dexamethasone than it is without ^
3G, 16-2 dexamethasone, as shown in Figure 2C.
Example 3 Manufacture and Testing of A DDS with Multiple Release Modifiers A drug delivery system was formulated with hydroxypropylmethylcellulose, ciprofloxacin and dexamethasone, according to the Table 3.
Table 3 Lot 4 PLGA HPMC Ciprofloxacin Dexamethasone XT035 3.4 0.4 2.4 3.8 The data show that after an initial higher release of dexamethasone in the first day, an almost zero-order release thereafter can be observed, as shown in Figure 2D. The overall release characteristic would be therapeutically acceptable from a therapeutic efficiency aspect.
Example 4 Manufacture and Testing of a Drug Delivery System (DDS) with a Glucocorticoid and Ganciclovir for Treatment of CMV Infection A drug delivery system is manufactured as described in Example 1, except that ganciclovir, a pharmaceutically active, hydrophilic compound, is included as a release modifier. The combinations of drugs and polymer are as follows:
PLGA Anti-Viral Anti-Inflammatory 50% - 50% dexamethasone 20 % 40 % ganciclovir 40 % dexamethasone 40% 20% ganciclovir 40% dexamethasone % 30 % ganciclovir 30 % dexamethasone ^ CA 02762921 2011-12-21 J~ 76L
50% - 50% ganciclovir The release of dexamethasone is increased with the addition of ganciclovir. In addition to the benefits of increased drug delivery, there are therapeutic benefits introduced with the antiviral activity of ganciclovir.
Example 5 Manufacture and Testing of a Drug Delivery System DS) with a Glucocorticoid and 5-Fluorouracil for Antitumor Treatment A drug delivery system is manufactured as described in Example 1, except that 5- .
fluorouracil, a pharmaceutically active, hydrophilic compound, is included as a release modifier. The combinations of drugs and polymer are as follows:
PLGA Anti-tumor Anti-Inflammatory 50% - 50% dexamethasone % 40 % 5-fluorouracil 40 % dexamethasone 20 40 /a 20% 5-fluorouracil 40% dexamethasone 40 % 30 % 5-fluorouracil 30 % dexamethasone 50 /a - 50% 5-fluorouracil 25. The release of dexamethasone is increased with the addition of 5-fluorouracil. In addition to the benefits of increased drug delivery, there are therapeutic benefits introduced with the antitumor activity of 5-fluorouracil.
Example 6 Manufacture and Testing of a Drug Delivery System (DDS) with an NSAID and Quinolone A drug delivery system is manufactured as described in Example 1, except that ciprofl oxacin, a pharmaceutically active, hydrophilic compound, is included as a release modifier. - The combinations of drugs and polymer are as follows:
30, i6-2 PLGA Quinolone Anti-Inflammatory 50% - 50% naproxen 20% 40% ciprofloxacin 40% naproxen 40% 20% ciprofloxacin 40% naproxen 40% 30% ci rofloxacin 30% naproxen 50% 50% ciprofloxacin -The release of ciprofloxacin is decreased with the addition of naproxen. In addition to the benefits of increased drug delivery, there are therapeutic benefits introduced with the combined formulation.
It is evident from the above results that biodegradable implants formulated with an active agent and release modulator provide for release kinetics where the drug is released at a constant rate over long periods of time, avoiding the need of a patient to administer drugs in much less effective ways, such as topically. The implants provide an improved method of treating ocular and other conditions, by avoiding peaks and troughs of drug release.
All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.
Each individual DDS was placed in a glass vial filled with receptor medium (9% NaCl in water). To allow for "infin ite sink" conditions, the receptor medium volume was chosen so that the concentration would never exceed 5% of saturation. To minimize secondary transport phenomena, e.g. concentration polarization in the stagnant boundary layer, each of the glass vials was placed into a shaking water bath at 37 C.
Samples were taken for HPLC analysis from each vial at defined time points. The HPLC method was as described in USP 23 (1995) pp. 1791-1798. The concentration values were used to calculate the cumulative relase profiles. The release profile is shown in Figure IA. It is seen that drug release is very slow with this DDS. Appreciable drug release begins in the fourth week after initiation, at approximately the time of polymer disintegration.
Manufacture and Testing of a DDS with HPMC Release Modifier A drug delivery system was manufactured as described above, except that various concentrations of hydrophilic hydroxypropylmethylcellulose (HPMC) were included as a release modifier. The combinations of drug, polymer and HPMC shown in Table 1 were used.
Table 1 Lot # PLGA HPMC Dexamethasone Total XT014 3.5 1.5 5 10 XT013 1.5 1.5 5 8 The release of drug was tested as described above. The data is shown in Figure lB. It is seen that with the addition of HPMC, there is a pronounced increase in the rate of release. Close to zero order release is observed for :xT014 and XTO15, where the ratio of release modulator to drug is 0.3 to 0.4. By selection of the appropriate polymer and release modifier, drug release and delivery interval can be custom-tailored to provide a release profile that is accelerated or retarded.
Example 2 Manufacture and Testing of A DDS with a Pharmaceutically Active Release Modifier A drug delivery system was manufactured as described in Example 1, except that ciprofloxacin, a pharmaceutically active, hydrophilic compound, was included as a release modifier. The combinations of drug and polymer shown in Table 2 were used.
Table 2 Lot # PLGA Release Modifier Drug XT029 5 - 5 dexamethasone XT032 4 2 ciprofloxacin 4 dexamethasone XT030 5 - 5 ciprofloxacin The release of dexamethasone is increased with the addition of ciprofloxacin, as shown by the data in Figure 2A. The actual drug release is almost doubled when compared to the DDS without a modifier. In addition to the benefits of increased drug delivery, there are therapeutic benefits introduced with the antibiotic activity of ciprofloxacin. The release of ciprofloxacin from from the same DDS is shown in Figure 2B. The release rate is higher than that of dexamethasone. However, the overall release of ciprofloxacin is slower when co-formulated with dexamethasone than it is without ^
3G, 16-2 dexamethasone, as shown in Figure 2C.
Example 3 Manufacture and Testing of A DDS with Multiple Release Modifiers A drug delivery system was formulated with hydroxypropylmethylcellulose, ciprofloxacin and dexamethasone, according to the Table 3.
Table 3 Lot 4 PLGA HPMC Ciprofloxacin Dexamethasone XT035 3.4 0.4 2.4 3.8 The data show that after an initial higher release of dexamethasone in the first day, an almost zero-order release thereafter can be observed, as shown in Figure 2D. The overall release characteristic would be therapeutically acceptable from a therapeutic efficiency aspect.
Example 4 Manufacture and Testing of a Drug Delivery System (DDS) with a Glucocorticoid and Ganciclovir for Treatment of CMV Infection A drug delivery system is manufactured as described in Example 1, except that ganciclovir, a pharmaceutically active, hydrophilic compound, is included as a release modifier. The combinations of drugs and polymer are as follows:
PLGA Anti-Viral Anti-Inflammatory 50% - 50% dexamethasone 20 % 40 % ganciclovir 40 % dexamethasone 40% 20% ganciclovir 40% dexamethasone % 30 % ganciclovir 30 % dexamethasone ^ CA 02762921 2011-12-21 J~ 76L
50% - 50% ganciclovir The release of dexamethasone is increased with the addition of ganciclovir. In addition to the benefits of increased drug delivery, there are therapeutic benefits introduced with the antiviral activity of ganciclovir.
Example 5 Manufacture and Testing of a Drug Delivery System DS) with a Glucocorticoid and 5-Fluorouracil for Antitumor Treatment A drug delivery system is manufactured as described in Example 1, except that 5- .
fluorouracil, a pharmaceutically active, hydrophilic compound, is included as a release modifier. The combinations of drugs and polymer are as follows:
PLGA Anti-tumor Anti-Inflammatory 50% - 50% dexamethasone % 40 % 5-fluorouracil 40 % dexamethasone 20 40 /a 20% 5-fluorouracil 40% dexamethasone 40 % 30 % 5-fluorouracil 30 % dexamethasone 50 /a - 50% 5-fluorouracil 25. The release of dexamethasone is increased with the addition of 5-fluorouracil. In addition to the benefits of increased drug delivery, there are therapeutic benefits introduced with the antitumor activity of 5-fluorouracil.
Example 6 Manufacture and Testing of a Drug Delivery System (DDS) with an NSAID and Quinolone A drug delivery system is manufactured as described in Example 1, except that ciprofl oxacin, a pharmaceutically active, hydrophilic compound, is included as a release modifier. - The combinations of drugs and polymer are as follows:
30, i6-2 PLGA Quinolone Anti-Inflammatory 50% - 50% naproxen 20% 40% ciprofloxacin 40% naproxen 40% 20% ciprofloxacin 40% naproxen 40% 30% ci rofloxacin 30% naproxen 50% 50% ciprofloxacin -The release of ciprofloxacin is decreased with the addition of naproxen. In addition to the benefits of increased drug delivery, there are therapeutic benefits introduced with the combined formulation.
It is evident from the above results that biodegradable implants formulated with an active agent and release modulator provide for release kinetics where the drug is released at a constant rate over long periods of time, avoiding the need of a patient to administer drugs in much less effective ways, such as topically. The implants provide an improved method of treating ocular and other conditions, by avoiding peaks and troughs of drug release.
All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.
Claims (4)
1. An implant for sustained drug release comprising:
a pharmacologically acceptable biodegradable polymer which is degraded at the site of implantation, wherein said biodegradable polymer comprises at least about 20 weight percent of the implant;
a therapeutically active agent at a concentration from 10 to 50 weight percent of the implant;
a release modulator at a concentration from 10 to 50 weight percent of the implant.
a pharmacologically acceptable biodegradable polymer which is degraded at the site of implantation, wherein said biodegradable polymer comprises at least about 20 weight percent of the implant;
a therapeutically active agent at a concentration from 10 to 50 weight percent of the implant;
a release modulator at a concentration from 10 to 50 weight percent of the implant.
2. An implant according to Claim 1, wherein said release modulator is a hydrophilic entity and said therapeutically active agent is a hydrophobic entity.
3. An implant according to Claim 2, wherein said release modulator is hydroxypropylmethylcellulose.
4. An implant for controlled, sustained drug release comprising:
poly-lactate glycolic acid copolymer at a concentration of at least about 20 weight percent of the implant;
a therapeutically active anti-inflammatory drug at a concentration from to 50 weight percent of the implant; and a release modulator at a concentration from 10 to 50 weight percent of the implant;
wherein:
(a) said release modulator is a therapeutically active agent;
(b) said implant is degraded at the site of implantation, and releases said therapeutically active anti-inflammatory drug within a therapeutic dosage which does not vary by more than about 100% for a period of at least about 3 days after implantation; and (c) one of said therapeutically active anti-inflammatory drug and said release modulator (i) is a hydrophobic entity and the other is a hydrophilic entity, and (ii) is other than a chemical form of the same compound of the other.
poly-lactate glycolic acid copolymer at a concentration of at least about 20 weight percent of the implant;
a therapeutically active anti-inflammatory drug at a concentration from to 50 weight percent of the implant; and a release modulator at a concentration from 10 to 50 weight percent of the implant;
wherein:
(a) said release modulator is a therapeutically active agent;
(b) said implant is degraded at the site of implantation, and releases said therapeutically active anti-inflammatory drug within a therapeutic dosage which does not vary by more than about 100% for a period of at least about 3 days after implantation; and (c) one of said therapeutically active anti-inflammatory drug and said release modulator (i) is a hydrophobic entity and the other is a hydrophilic entity, and (ii) is other than a chemical form of the same compound of the other.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/459,134 US5869079A (en) | 1995-06-02 | 1995-06-02 | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US08/459,134 | 1995-06-02 | ||
CA2222889A CA2222889C (en) | 1995-06-02 | 1996-05-31 | Improved formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2222889A Division CA2222889C (en) | 1995-06-02 | 1996-05-31 | Improved formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2762921A1 true CA2762921A1 (en) | 1996-12-05 |
Family
ID=23823541
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2762921A Abandoned CA2762921A1 (en) | 1995-06-02 | 1996-05-31 | Improved formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
CA2222889A Expired - Fee Related CA2222889C (en) | 1995-06-02 | 1996-05-31 | Improved formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2222889A Expired - Fee Related CA2222889C (en) | 1995-06-02 | 1996-05-31 | Improved formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
Country Status (18)
Country | Link |
---|---|
US (9) | US5869079A (en) |
EP (4) | EP1477187B9 (en) |
JP (3) | JPH11506450A (en) |
KR (1) | KR19990022212A (en) |
CN (1) | CN1191492A (en) |
AT (2) | ATE516049T1 (en) |
AU (1) | AU721421B2 (en) |
BR (1) | BR9608642A (en) |
CA (2) | CA2762921A1 (en) |
DE (1) | DE69635734T3 (en) |
DK (1) | DK1477187T3 (en) |
ES (2) | ES2256859T5 (en) |
MY (1) | MY132179A (en) |
PL (1) | PL323747A1 (en) |
PT (1) | PT1477187E (en) |
RU (1) | RU2175561C2 (en) |
TW (1) | TW487580B (en) |
WO (1) | WO1996038174A1 (en) |
Families Citing this family (337)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5869079A (en) * | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US6369116B1 (en) * | 1995-06-02 | 2002-04-09 | Oculex Pharmaceuticals, Inc. | Composition and method for treating glaucoma |
KR100441821B1 (en) * | 1996-03-05 | 2004-10-15 | 구르뉘 로베르 | Pharmaceutical compositions containing buffered orthoester polymers |
FR2748205A1 (en) * | 1996-05-06 | 1997-11-07 | Debio Rech Pharma Sa | PHARMACEUTICAL COMPOSITIONS FOR THE CONTROLLED RELEASE OF INSOLUBLE ACTIVE SUBSTANCES |
US5942508A (en) * | 1997-02-04 | 1999-08-24 | Senju Pharmaceutical Co., Ltd. | Method for solubilizing pyridonecarboxylic acid solubilizer thereof and aqueous solution containing solubilized pyridonecarboxylic acid |
CA2300154C (en) * | 1997-08-11 | 2008-07-08 | Allergan Sales, Inc. | Sterile bioerodible implant device with improved biocompatability and method |
US7399480B2 (en) * | 1997-09-26 | 2008-07-15 | Abbott Laboratories | Methods of administering tetrazole-containing rapamycin analogs with other therapeutic substances using medical devices |
US6890546B2 (en) * | 1998-09-24 | 2005-05-10 | Abbott Laboratories | Medical devices containing rapamycin analogs |
US20030129215A1 (en) * | 1998-09-24 | 2003-07-10 | T-Ram, Inc. | Medical devices containing rapamycin analogs |
US7445792B2 (en) * | 2003-03-10 | 2008-11-04 | Abbott Laboratories | Medical device having a hydration inhibitor |
DE19756314C2 (en) * | 1997-12-12 | 2000-06-29 | Roland Bodmeier | Preparation with extended residence time at the application site |
EP0985413A1 (en) * | 1998-08-06 | 2000-03-15 | Jörg Michael Dr. Dr. Schierholz | Medical articles with sustained pharmacological activity and process for their preparation |
US6641831B1 (en) | 1998-08-06 | 2003-11-04 | Schierholz Joerg | Medical products with sustained pharmacological activity and process for producing them |
US7455853B2 (en) * | 1998-09-24 | 2008-11-25 | Abbott Cardiovascular Systems Inc. | Medical devices containing rapamycin analogs |
FR2770134B1 (en) * | 1998-10-28 | 2002-06-07 | Delab | SOLID OR SEMI-SOLID FORMULATIONS FOR LOCAL ADMINISTRATION |
CA2358296A1 (en) * | 1999-01-05 | 2000-07-13 | Anthony P. Adamis | Targeted transscleral controlled release drug delivery to the retina and choroid |
US6113638A (en) * | 1999-02-26 | 2000-09-05 | Williams; Lytton A. | Method and apparatus for intervertebral implant anchorage |
US6331313B1 (en) * | 1999-10-22 | 2001-12-18 | Oculex Pharmaceticals, Inc. | Controlled-release biocompatible ocular drug delivery implant devices and methods |
US20010049422A1 (en) * | 2000-04-14 | 2001-12-06 | Phaneuf Matthew D. | Methods of applying antibiotic compounds to polyurethane biomaterials using textile dyeing technology |
US7708711B2 (en) * | 2000-04-14 | 2010-05-04 | Glaukos Corporation | Ocular implant with therapeutic agents and methods thereof |
US20040033241A1 (en) * | 2000-06-02 | 2004-02-19 | Allergan, Inc. | Controlled release botulinum toxin system |
US6692759B1 (en) * | 2000-06-28 | 2004-02-17 | The Regents Of The University Of California | Methods for preparing and using implantable substance delivery devices |
EP3167872B1 (en) | 2000-07-05 | 2020-10-14 | Allergan, Inc. | Methods for treating inflammation-mediated conditions of the eye |
US6726918B1 (en) * | 2000-07-05 | 2004-04-27 | Oculex Pharmaceuticals, Inc. | Methods for treating inflammation-mediated conditions of the eye |
PE20020146A1 (en) * | 2000-07-13 | 2002-03-31 | Upjohn Co | OPHTHALMIC FORMULATION INCLUDING A CYCLOOXYGENASE-2 (COX-2) INHIBITOR |
AR031135A1 (en) | 2000-10-10 | 2003-09-10 | Upjohn Co | TOPIC ANTIBIOTIC COMPOSITIONS FOR THE TREATMENT OF OCULAR INFECTIONS |
US20030082183A1 (en) * | 2000-11-01 | 2003-05-01 | Wheeler Larry A. | Methods and compositions for treatment of ocular neovascularization and neural injury |
WO2002058730A2 (en) * | 2000-11-01 | 2002-08-01 | Allergan, Inc. | Compositions for treatment of ocular neovascularization |
EP1621219A3 (en) * | 2000-11-29 | 2006-03-22 | Allergan, Inc. | Intraocular implants for preventing transplant rejection in the eye |
DE60114229T2 (en) * | 2000-11-29 | 2006-07-06 | Allergan, Inc., Irvine | PREVENTING TRANSPLANT DISCHARGE IN THE EYE |
KR100446101B1 (en) * | 2000-12-07 | 2004-08-30 | 주식회사 삼양사 | Sustained delivery composition for poorly water soluble drugs |
US20020082678A1 (en) * | 2000-12-22 | 2002-06-27 | Motasim Sirhan | Intravascular delivery of mizoribine |
ATE359762T1 (en) * | 2001-01-09 | 2007-05-15 | Microchips Inc | FLEXIBLE MICROCHIP DEVICES FOR OPHTHALMOLOGICAL AND OTHER APPLICATIONS |
US7431710B2 (en) | 2002-04-08 | 2008-10-07 | Glaukos Corporation | Ocular implants with anchors and methods thereof |
EP1387671A1 (en) | 2001-05-03 | 2004-02-11 | MASSACHUSETTS EYE & EAR INFIRMARY | Implantable drug delivery device and use thereof |
US7592016B2 (en) * | 2001-06-28 | 2009-09-22 | Regents Of The University Of California | Methods for preparing and using implantable substance delivery devices |
GB0116920D0 (en) * | 2001-07-11 | 2001-09-05 | Sulzer Vascutek Ltd | Delivery system |
US20080145402A1 (en) * | 2001-09-10 | 2008-06-19 | Abbott Cardiovascular Systems Inc. | Medical Devices Containing Rapamycin Analogs |
KR20100102749A (en) * | 2002-02-22 | 2010-09-24 | 산텐 세이야꾸 가부시키가이샤 | Drug delivery system for the subconjunctival administration of fine grains |
US20030180294A1 (en) * | 2002-02-22 | 2003-09-25 | Devries Gerald W. | Methods of extending corneal graft survival |
KR101127502B1 (en) * | 2002-03-11 | 2012-03-23 | 알콘, 인코퍼레이티드 | Implantable drug delivery system |
US7074426B2 (en) * | 2002-03-27 | 2006-07-11 | Frank Kochinke | Methods and drug delivery systems for the treatment of orofacial diseases |
AU2003217531A1 (en) * | 2002-05-02 | 2003-11-17 | Massachusetts Eye And Ear Infirmary | Ocular drug delivery systems and use thereof |
WO2003096991A2 (en) | 2002-05-17 | 2003-11-27 | Othera Pharmaceuticals, Inc. | Amelioration of the development of cataracts and other opthalmic diseases |
JP4773721B2 (en) * | 2002-06-13 | 2011-09-14 | ノバルティス アーゲー | Quaternized ammonium cyclodextrin compound |
EP1521573B1 (en) * | 2002-07-15 | 2008-01-02 | Alcon, Inc. | Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use |
US20070184089A1 (en) * | 2002-07-15 | 2007-08-09 | Alcon, Inc. | Non-Polymeric Lipophilic Pharmaceutical Implant Compositions for Intraocular Use |
DE10238310A1 (en) * | 2002-08-21 | 2004-03-04 | Erich Jaeger Gmbh | electrode assembly |
CZ294328B6 (en) * | 2002-08-22 | 2004-11-10 | Pliva-Lachema A. S. | Biologically degradable composition with protracted release of a biologically active substance and process for preparing thereof |
WO2004022124A1 (en) * | 2002-09-06 | 2004-03-18 | Abbott Laboratories | Medical device having hydration inhibitor |
CA2689424A1 (en) * | 2002-09-29 | 2004-04-08 | Surmodics, Inc. | Methods for treatment and/or prevention of retinal disease |
AU2003301347A1 (en) * | 2002-10-17 | 2004-05-04 | Control Delivery Systems, Inc. | Methods for monitoring treatment of disease |
AU2003284028B2 (en) * | 2002-10-17 | 2007-05-10 | Alkermes, Inc. | Sustained release profile modification |
JP2004196787A (en) * | 2002-12-04 | 2004-07-15 | Santen Pharmaceut Co Ltd | Drug delivery system with subconjunctival depot |
CN100453066C (en) * | 2002-12-04 | 2009-01-21 | 参天制药株式会社 | Drug delivery system using subconjunctival depot |
US20050048099A1 (en) | 2003-01-09 | 2005-03-03 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US20040137059A1 (en) * | 2003-01-09 | 2004-07-15 | Thierry Nivaggioli | Biodegradable ocular implant |
EP1594484A2 (en) * | 2003-02-17 | 2005-11-16 | Cipla Ltd. | Pharmaceutical patch |
WO2004073551A2 (en) * | 2003-02-18 | 2004-09-02 | Massachusetts Eye And Ear Infirmary | Transscleral drug delivery device and related methods |
US8012115B2 (en) * | 2003-02-18 | 2011-09-06 | S.K. Pharmaceuticals, Inc. | Optic nerve implants |
CN1750828A (en) * | 2003-02-20 | 2006-03-22 | 爱尔康公司 | Use of steroids to treat persons suffering from ocular disorders |
US20040167109A1 (en) * | 2003-02-20 | 2004-08-26 | Bingaman David P | Formulations of glucocorticoids to treat pathologic ocular angiogenesis |
US7825134B2 (en) * | 2003-05-19 | 2010-11-02 | Othera Holding, Inc. | Amelioration of cataracts, macular degeneration and other ophthalmic diseases |
US7589107B2 (en) | 2003-05-19 | 2009-09-15 | Othera Holding, Inc. | Amelioration of vitrectomy-induced cataracts |
RU2006101150A (en) * | 2003-06-13 | 2006-06-10 | Алькон, Инк. (Ch) | COMPOSITIONS OF NESTEROID ANTI-INFLAMMATORY AGENTS FOR TREATMENT OF PATHOLOGICAL ANGIOGENESIS OF EYES |
US20040253293A1 (en) * | 2003-06-16 | 2004-12-16 | Afshin Shafiee | Rate controlled release of a pharmaceutical agent in a biodegradable device |
EP1641914B1 (en) * | 2003-06-27 | 2016-07-20 | DePuy Synthes Products, Inc. | Postpartum cells derived from placental tissue, and methods of making and using the same |
US9592258B2 (en) | 2003-06-27 | 2017-03-14 | DePuy Synthes Products, Inc. | Treatment of neurological injury by administration of human umbilical cord tissue-derived cells |
US8790637B2 (en) * | 2003-06-27 | 2014-07-29 | DePuy Synthes Products, LLC | Repair and regeneration of ocular tissue using postpartum-derived cells |
US8518390B2 (en) | 2003-06-27 | 2013-08-27 | Advanced Technologies And Regenerative Medicine, Llc | Treatment of stroke and other acute neural degenerative disorders via intranasal administration of umbilical cord-derived cells |
US8491883B2 (en) * | 2003-06-27 | 2013-07-23 | Advanced Technologies And Regenerative Medicine, Llc | Treatment of amyotrophic lateral sclerosis using umbilical derived cells |
US20060223177A1 (en) | 2003-06-27 | 2006-10-05 | Ethicon Inc. | Postpartum cells derived from umbilical cord tissue, and methods of making and using the same |
US7875272B2 (en) | 2003-06-27 | 2011-01-25 | Ethicon, Incorporated | Treatment of stroke and other acute neuraldegenerative disorders using postpartum derived cells |
US20100158880A1 (en) * | 2008-12-19 | 2010-06-24 | Ethicon, Incorporated | Regeneration and repair of neural tissue following injury |
US9572840B2 (en) | 2003-06-27 | 2017-02-21 | DePuy Synthes Products, Inc. | Regeneration and repair of neural tissue using postpartum-derived cells |
CN1835735B (en) * | 2003-08-20 | 2010-05-12 | 参天制药株式会社 | Drug delivery system for administering fine particle under tenon's capsule |
WO2005037317A2 (en) * | 2003-10-17 | 2005-04-28 | Cornell Research Foundation, Inc. | Mast cell-derived renin |
US20070224278A1 (en) * | 2003-11-12 | 2007-09-27 | Lyons Robert T | Low immunogenicity corticosteroid compositions |
US20060141049A1 (en) * | 2003-11-12 | 2006-06-29 | Allergan, Inc. | Triamcinolone compositions for intravitreal administration to treat ocular conditions |
US20050101582A1 (en) | 2003-11-12 | 2005-05-12 | Allergan, Inc. | Compositions and methods for treating a posterior segment of an eye |
US20090148527A1 (en) * | 2007-12-07 | 2009-06-11 | Robinson Michael R | Intraocular formulation |
EP2052720A3 (en) | 2003-11-20 | 2009-05-06 | Othera Holding, Inc. | Use of at least one hydroxylamine compound for the treatment of eye disease |
US20080220049A1 (en) * | 2003-12-05 | 2008-09-11 | Adnexus, A Bristol-Myers Squibb R&D Company | Compositions and methods for intraocular delivery of fibronectin scaffold domain proteins |
RU2402567C2 (en) | 2003-12-05 | 2010-10-27 | Бристоль-Майерз Сквибб Компани | Inhibitors of receptors of type 2 vessel endothelium growth factor |
WO2005061003A1 (en) * | 2003-12-12 | 2005-07-07 | Medtronic, Inc. | Anti-infective medical device |
US8691258B2 (en) * | 2003-12-12 | 2014-04-08 | Medtronic, Inc. | Anti-infective medical device |
WO2005072701A1 (en) | 2004-01-20 | 2005-08-11 | Allergan, Inc. | Compositions for localized therapy of the eye, comprising preferably triamcinolone acetonide and hyaluronic acid |
US8119154B2 (en) | 2004-04-30 | 2012-02-21 | Allergan, Inc. | Sustained release intraocular implants and related methods |
US20050244463A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Sustained release intraocular implants and methods for treating ocular vasculopathies |
US8591885B2 (en) * | 2004-04-30 | 2013-11-26 | Allergan, Inc. | Carbonic anhydrase inhibitor sustained release intraocular drug delivery systems |
US7589057B2 (en) | 2004-04-30 | 2009-09-15 | Allergan, Inc. | Oil-in-water method for making alpha-2 agonist polymeric drug delivery systems |
US20070059336A1 (en) * | 2004-04-30 | 2007-03-15 | Allergan, Inc. | Anti-angiogenic sustained release intraocular implants and related methods |
US20050244478A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Anti-excititoxic sustained release intraocular implants and related methods |
US20060182781A1 (en) * | 2004-04-30 | 2006-08-17 | Allergan, Inc. | Methods for treating ocular conditions with cyclic lipid contraining microparticles |
US20050244500A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Intravitreal implants in conjuction with photodynamic therapy to improve vision |
US8722097B2 (en) | 2004-04-30 | 2014-05-13 | Allergan, Inc. | Oil-in-water method for making polymeric implants containing a hypotensive lipid |
US7771742B2 (en) * | 2004-04-30 | 2010-08-10 | Allergan, Inc. | Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods |
US8673341B2 (en) | 2004-04-30 | 2014-03-18 | Allergan, Inc. | Intraocular pressure reduction with intracameral bimatoprost implants |
US20050244462A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Devices and methods for treating a mammalian eye |
WO2005110374A1 (en) | 2004-04-30 | 2005-11-24 | Allergan, Inc. | Intraocular drug delivery systems containing a therapeutic component, a cyclodextrin, and a polymeric component |
US8529927B2 (en) * | 2004-04-30 | 2013-09-10 | Allergan, Inc. | Alpha-2 agonist polymeric drug delivery systems |
WO2005107708A1 (en) | 2004-04-30 | 2005-11-17 | Allergan, Inc. | Biodegradable intravitreal tyrosine kinase inhibitors implants |
US20050244458A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Sustained release intraocular implants and methods for treating ocular neuropathies |
US7993634B2 (en) | 2004-04-30 | 2011-08-09 | Allergan, Inc. | Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods |
US8685435B2 (en) * | 2004-04-30 | 2014-04-01 | Allergan, Inc. | Extended release biodegradable ocular implants |
US20050244471A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Estradiol derivative and estratopone containing sustained release intraocular implants and related methods |
US20050244465A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Drug delivery systems and methods for treatment of an eye |
US20070212395A1 (en) * | 2006-03-08 | 2007-09-13 | Allergan, Inc. | Ocular therapy using sirtuin-activating agents |
US8425929B2 (en) * | 2004-04-30 | 2013-04-23 | Allergan, Inc. | Sustained release intraocular implants and methods for preventing retinal dysfunction |
US20050244461A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Controlled release drug delivery systems and methods for treatment of an eye |
US20050244466A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Photodynamic therapy in conjunction with intraocular implants |
US20060182783A1 (en) * | 2004-04-30 | 2006-08-17 | Allergan, Inc. | Sustained release intraocular drug delivery systems |
US8147865B2 (en) * | 2004-04-30 | 2012-04-03 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
US9498457B2 (en) | 2004-04-30 | 2016-11-22 | Allergan, Inc. | Hypotensive prostamide-containing biodegradable intraocular implants and related implants |
AU2011213904B2 (en) * | 2004-04-30 | 2014-06-05 | Allergan, Inc. | Sustained release intraocular implants comprising a beta adrenergic receptor antagonist and methods for treating ocular neuropathies |
US7799336B2 (en) | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
US20050244469A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
CN1964711A (en) * | 2004-05-25 | 2007-05-16 | 奥特拉药物公司 | Oculoselective drugs and prodrugs |
WO2006014484A2 (en) | 2004-07-02 | 2006-02-09 | Surmodics, Inc. | Methods and devices for the treatment of ocular conditions |
AU2013221985B2 (en) * | 2004-07-12 | 2016-09-01 | Allergan, Inc. | Ophthalmic compositions and methods for treating ophthalmic conditions |
JP2008505978A (en) * | 2004-07-12 | 2008-02-28 | アラーガン、インコーポレイテッド | Ophthalmic composition and eye disease treatment method |
WO2006078320A2 (en) | 2004-08-04 | 2006-07-27 | Brookwood Pharmaceuticals, Inc. | Methods for manufacturing delivery devices and devices thereof |
US20160106717A1 (en) | 2004-09-24 | 2016-04-21 | Gen Pharma Holdings LLC | Cai-based systems and methods for the localized treatment of uveitis |
US20060116404A1 (en) | 2004-09-24 | 2006-06-01 | Gary Robinson | CAI-based systems and methods for the localized treatment of ocular and other diseases |
US20060067978A1 (en) * | 2004-09-29 | 2006-03-30 | Bausch & Lomb Incorporated | Process for preparing poly(vinyl alcohol) drug delivery devices |
US20060068012A1 (en) * | 2004-09-29 | 2006-03-30 | Bausch & Lomb Incorporated | Process for preparing poly (vinyl alcohol) drug delivery devices with humidity control |
JP5682991B2 (en) | 2004-10-01 | 2015-03-11 | ラムズコア, インコーポレイテッド | Convenient implantable sustained release drug formulation |
US8541413B2 (en) * | 2004-10-01 | 2013-09-24 | Ramscor, Inc. | Sustained release eye drop formulations |
US20080038316A1 (en) * | 2004-10-01 | 2008-02-14 | Wong Vernon G | Conveniently implantable sustained release drug compositions |
US9993558B2 (en) | 2004-10-01 | 2018-06-12 | Ramscor, Inc. | Sustained release eye drop formulations |
WO2006043965A1 (en) * | 2004-10-14 | 2006-04-27 | Allergan, Inc. | Therapeutic ophthalmic compositions containing retinal friendly excipients and related methods |
KR20070095921A (en) | 2004-12-10 | 2007-10-01 | 탈리마 테라퓨틱스 인코포레이티드 | Compositions and methods for treating conditions of the nail unit |
US20060275230A1 (en) | 2004-12-10 | 2006-12-07 | Frank Kochinke | Compositions and methods for treating conditions of the nail unit |
US20060166361A1 (en) * | 2004-12-21 | 2006-07-27 | Agnieszka Seyda | Postpartum cells derived from placental tissue, and methods of making, culturing, and using the same |
US20060153815A1 (en) * | 2004-12-21 | 2006-07-13 | Agnieszka Seyda | Tissue engineering devices for the repair and regeneration of tissue |
US20060171930A1 (en) * | 2004-12-21 | 2006-08-03 | Agnieszka Seyda | Postpartum cells derived from umbilical cord tissue, and methods of making, culturing, and using the same |
US20060134174A1 (en) * | 2004-12-22 | 2006-06-22 | Bausch & Lomb Incorporated | Pharmaceutical delivery system and method of use |
US20060134175A1 (en) * | 2004-12-22 | 2006-06-22 | Stephen Bartels | Drug eluting pharmaceutical delivery system for treatment of ocular disease and method of use |
WO2006071802A2 (en) | 2004-12-23 | 2006-07-06 | Ethicon Incorporated | Treatment of stroke and other acute neural degenerative disorders using postpartum derived cells |
US20060165810A1 (en) * | 2004-12-28 | 2006-07-27 | The Trustees Of The University Of Pennsylvania | Controlled release from block co-polymer worm micelles |
US20060204548A1 (en) * | 2005-03-01 | 2006-09-14 | Allergan, Inc. | Microimplants for ocular administration |
US20060233858A1 (en) * | 2005-03-08 | 2006-10-19 | Allergan, Inc. | Systems and methods providing targeted intraocular drug delivery |
US8003124B2 (en) * | 2005-04-08 | 2011-08-23 | Surmodics, Inc. | Sustained release implants and methods for subretinal delivery of bioactive agents to treat or prevent retinal disease |
US7931909B2 (en) * | 2005-05-10 | 2011-04-26 | Allergan, Inc. | Ocular therapy using alpha-2 adrenergic receptor compounds having enhanced anterior clearance rates |
WO2006127592A2 (en) * | 2005-05-26 | 2006-11-30 | Othera Pharmaceuticals, Inc. | Use of hydroxylamine derivates for inhibiting vitrectomy-induced cataracts |
AU2006272497B2 (en) | 2005-07-27 | 2012-07-19 | University Of Florida Research Foundation, Inc. | Small compounds that correct protein misfolding and uses thereof |
WO2007037849A2 (en) * | 2005-09-16 | 2007-04-05 | Allergan, Inc. | Compositions and methods for the intraocular transport of therapeutic agents |
JP2009510114A (en) | 2005-09-30 | 2009-03-12 | ビテ ファーマシューティカルズ, インコーポレイテッド | Cancer treatment with specific RXR agonists |
US8168584B2 (en) | 2005-10-08 | 2012-05-01 | Potentia Pharmaceuticals, Inc. | Methods of treating age-related macular degeneration by compstatin and analogs thereof |
WO2007047626A1 (en) * | 2005-10-14 | 2007-04-26 | Alcon, Inc. | Combination treatment with anecortave acetate and bevacizumab or ranibizumab for pathologic ocular angiogenesis |
JP5745208B2 (en) * | 2005-10-18 | 2015-07-08 | アラーガン インコーポレイテッドAllergan,Incorporated | Ocular treatment with glucocorticoid derivatives that selectively penetrate the posterior tissue. |
SI1968594T1 (en) | 2005-11-29 | 2011-01-31 | Glaxosmithkline Llc | Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema |
PL1971681T3 (en) * | 2005-12-16 | 2018-01-31 | Depuy Synthes Products Inc | Compositions and methods for inhibiting adverse immune response in histocompatibility-mismatched transplantation |
JP5179376B2 (en) * | 2005-12-19 | 2013-04-10 | エシコン・インコーポレイテッド | In vitro growth of postpartum-extracted cells in roller bottles |
US20070160588A1 (en) * | 2005-12-28 | 2007-07-12 | Ethicon, Incorporated | Treatment Of Peripheral Vascular Disease Using Postpartum-Derived Cells |
US9125906B2 (en) | 2005-12-28 | 2015-09-08 | DePuy Synthes Products, Inc. | Treatment of peripheral vascular disease using umbilical cord tissue-derived cells |
US7756524B1 (en) | 2006-01-31 | 2010-07-13 | Nextel Communications Inc. | System and method for partially count-based allocation of vocoder resources |
US20070178138A1 (en) * | 2006-02-01 | 2007-08-02 | Allergan, Inc. | Biodegradable non-opthalmic implants and related methods |
EP1993584B1 (en) | 2006-02-02 | 2012-05-30 | Allergan, Inc. | Inhibitors of CXCR4 activity for use in the treatment of ocular disorders |
US20070203190A1 (en) * | 2006-02-22 | 2007-08-30 | Ghanshyam Patil | Hydroxylamines and derivatives for the inhibition of complement activation |
US20070232660A1 (en) * | 2006-04-04 | 2007-10-04 | Allergan, Inc. | Therapeutic and delivery methods of prostaglandin ep4 agonists |
US20070260203A1 (en) * | 2006-05-04 | 2007-11-08 | Allergan, Inc. | Vasoactive agent intraocular implant |
US8668676B2 (en) * | 2006-06-19 | 2014-03-11 | Allergan, Inc. | Apparatus and methods for implanting particulate ocular implants |
US8802128B2 (en) * | 2006-06-23 | 2014-08-12 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
US20070298073A1 (en) * | 2006-06-23 | 2007-12-27 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
US20080097335A1 (en) * | 2006-08-04 | 2008-04-24 | Allergan, Inc. | Ocular implant delivery assemblies |
JP5694664B2 (en) * | 2006-09-29 | 2015-04-01 | サーモディクス,インコーポレイティド | Biodegradable ocular implant and method for treating ocular diseases |
CA2667890C (en) | 2006-10-31 | 2015-01-27 | Surmodics Pharmaceuticals, Inc. | Spheronized polymer particles |
US8039010B2 (en) | 2006-11-03 | 2011-10-18 | Allergan, Inc. | Sustained release intraocular drug delivery systems comprising a water soluble therapeutic agent and a release modifier |
US8586556B2 (en) * | 2006-11-03 | 2013-11-19 | Allergan, Inc. | Methods, compositions and drug delivery systems for intraocular delivery of siRNA molecules |
EP3156415A1 (en) | 2006-11-22 | 2017-04-19 | Bristol-Myers Squibb Company | Targeted therapeutics based on engineered proteins for tyrosine kinases receptors, including igf-ir |
US8969415B2 (en) * | 2006-12-01 | 2015-03-03 | Allergan, Inc. | Intraocular drug delivery systems |
WO2008070479A2 (en) | 2006-12-01 | 2008-06-12 | Allergan, Inc. | Method for determining optimum intraocular locations for drug delivery systems |
US8846073B2 (en) | 2006-12-19 | 2014-09-30 | Allergan, Inc. | Low temperature processes for making cyclic lipid implants for intraocular use |
US20090092574A1 (en) | 2006-12-29 | 2009-04-09 | Scott Richard W | Ophthalmic And Otic Compositions Of Facially Amphiphilic Polymers And Oligomers And Uses Thereof |
CA2679066A1 (en) | 2007-02-22 | 2008-08-28 | Othera Holding, Inc. | Hydroxylamine compounds and methods of their use |
US7911053B2 (en) * | 2007-04-19 | 2011-03-22 | Marvell World Trade Ltd. | Semiconductor packaging with internal wiring bus |
AU2008254989B2 (en) * | 2007-05-14 | 2013-06-06 | Sustained Nano Systems Llc | Hypercompressed particles for controlled release of ophthalmic medications |
US8231892B2 (en) * | 2007-05-24 | 2012-07-31 | Allergan, Inc. | Biodegradable drug delivery system |
US20080317805A1 (en) * | 2007-06-19 | 2008-12-25 | Mckay William F | Locally administrated low doses of corticosteroids |
WO2009029543A1 (en) | 2007-08-24 | 2009-03-05 | Aegis Therapeutics, Llc | Controlled release formulations |
WO2009046299A2 (en) * | 2007-10-04 | 2009-04-09 | Boston Scientific Scimed, Inc | Implantable drug depot for intrathecal drug delivery system for pain management |
AU2008308531B2 (en) * | 2007-10-05 | 2014-04-24 | Ethicon, Incorporated | Repair and regeneration of renal tissue using human umbilical cord tissue-derived cells |
CN101918019B (en) | 2007-10-08 | 2014-11-26 | 奥里尼亚制药有限公司 | Ophthalmic compositions comprising calcineurin inhibitors or mTOR inhibitors |
US8124601B2 (en) * | 2007-11-21 | 2012-02-28 | Bristol-Myers Squibb Company | Compounds for the treatment of Hepatitis C |
US8236538B2 (en) | 2007-12-20 | 2012-08-07 | Advanced Technologies And Regenerative Medicine, Llc | Methods for sterilizing materials containing biologically active agents |
WO2009085952A1 (en) | 2007-12-20 | 2009-07-09 | Brookwood Pharmaceuticals, Inc. | Process for preparing microparticles having a low residual solvent volume |
KR20100128291A (en) | 2008-02-14 | 2010-12-07 | 브리스톨-마이어스 스큅 컴퍼니 | Targeted therapeutics based on engineered proteins that bind egfr |
US9192571B2 (en) | 2008-03-03 | 2015-11-24 | Allergan, Inc. | Ketorolac tromethamine compositions for treating or preventing ocular pain |
US8524267B2 (en) * | 2008-04-18 | 2013-09-03 | Warsaw Orthopedic, Inc. | Dexamethasone formulations in a biodegradable material |
US9095404B2 (en) | 2008-05-12 | 2015-08-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US9877973B2 (en) | 2008-05-12 | 2018-01-30 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
WO2009140246A2 (en) | 2008-05-12 | 2009-11-19 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US10064819B2 (en) | 2008-05-12 | 2018-09-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US10588855B2 (en) | 2008-05-12 | 2020-03-17 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
JP2011520961A (en) | 2008-05-22 | 2011-07-21 | ブリストル−マイヤーズ スクイブ カンパニー | Scaffold domain protein based on multivalent fibronectin |
US10517839B2 (en) * | 2008-06-09 | 2019-12-31 | Cornell University | Mast cell inhibition in diseases of the retina and vitreous |
US8821870B2 (en) * | 2008-07-18 | 2014-09-02 | Allergan, Inc. | Method for treating atrophic age related macular degeneration |
PT2320911E (en) | 2008-08-01 | 2014-11-11 | Eye Therapies Llc | Vasoconstriction compositions and methods of use |
WO2010036961A1 (en) * | 2008-09-25 | 2010-04-01 | Invivo Therapeutics Corporation | Spinal cord injury, inflammation, and immune-disease: local controlled release of therapeutic agents |
US20100104654A1 (en) | 2008-10-27 | 2010-04-29 | Allergan, Inc. | Prostaglandin and prostamide drug delivery systems and intraocular therapeutic uses thereof |
US9095506B2 (en) | 2008-11-17 | 2015-08-04 | Allergan, Inc. | Biodegradable alpha-2 agonist polymeric implants and therapeutic uses thereof |
US8034813B2 (en) | 2008-11-18 | 2011-10-11 | Bausch & Lomb Incorporated | Polymorphs of brimonidine pamoate |
TWI496582B (en) | 2008-11-24 | 2015-08-21 | 必治妥美雅史谷比公司 | Bispecific egfr/igfir binding molecules |
ES2520393T3 (en) * | 2008-12-19 | 2014-11-11 | DePuy Synthes Products, LLC | Cells derived from umbilical cord tissue to treat neuropathic pain and spasticity |
US10179900B2 (en) * | 2008-12-19 | 2019-01-15 | DePuy Synthes Products, Inc. | Conditioned media and methods of making a conditioned media |
AU2009327384B2 (en) | 2008-12-19 | 2014-07-10 | DePuy Synthes Products, LLC | Treatment of lung and pulmonary diseases and disorders |
US8545554B2 (en) * | 2009-01-16 | 2013-10-01 | Allergan, Inc. | Intraocular injector |
US20100291182A1 (en) * | 2009-01-21 | 2010-11-18 | Arsenal Medical, Inc. | Drug-Loaded Fibers |
US20100204325A1 (en) * | 2009-02-11 | 2010-08-12 | Allergan, Inc. | Valproic acid drug delivery systems and intraocular therapeutic uses thereof |
US9636255B2 (en) | 2009-02-13 | 2017-05-02 | Dose Medical Corporation | Uveoscleral drug delivery implant and methods for implanting the same |
US20100239632A1 (en) * | 2009-03-23 | 2010-09-23 | Warsaw Orthopedic, Inc. | Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue |
CN102498204B (en) | 2009-03-26 | 2015-02-04 | 德普伊新特斯产品有限责任公司 | Human umbilical cord tissue cells as therapy for Alzheimer's disease |
US10206813B2 (en) | 2009-05-18 | 2019-02-19 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
AU2010259184B2 (en) * | 2009-06-09 | 2015-08-13 | Aurinia Pharmaceuticals Inc. | Topical drug delivery systems for ophthalmic use |
IN2012DN00352A (en) | 2009-06-16 | 2015-08-21 | Bikam Pharmaceuticals Inc | |
GB201111485D0 (en) | 2011-07-05 | 2011-08-17 | Biocopea Ltd | Drug composition and its use in therapy |
WO2010148352A1 (en) | 2009-06-19 | 2010-12-23 | Altos Vision Limited | Time-release and micro-dose formulations for topical application of estrogen and estrogen analogs or other estrogen receptor modulators in the treatment of dry eye syndrome, and methods of preparation and application |
JP2013501033A (en) * | 2009-08-05 | 2013-01-10 | ピエリス アーゲー | Controlled release formulation of lipocalin mutein |
US20110202016A1 (en) * | 2009-08-24 | 2011-08-18 | Arsenal Medical, Inc. | Systems and methods relating to polymer foams |
US9173817B2 (en) | 2009-08-24 | 2015-11-03 | Arsenal Medical, Inc. | In situ forming hemostatic foam implants |
US10420862B2 (en) | 2009-08-24 | 2019-09-24 | Aresenal AAA, LLC. | In-situ forming foams for treatment of aneurysms |
US9044580B2 (en) | 2009-08-24 | 2015-06-02 | Arsenal Medical, Inc. | In-situ forming foams with outer layer |
WO2011039648A1 (en) | 2009-09-30 | 2011-04-07 | Glaxo Wellcome Manufacturing Pte Ltd. | Methods of administration and treatment |
WO2011048070A1 (en) | 2009-10-20 | 2011-04-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of disorders of glucose homeostasis |
CN102724951A (en) | 2009-11-09 | 2012-10-10 | 阿勒根公司 | Compositions and methods for stimulating hair growth |
EP2512389B1 (en) | 2009-12-16 | 2015-09-02 | Allergan, Inc. | Intracameral devices for sustained delivery |
KR20180117211A (en) | 2010-01-22 | 2018-10-26 | 알러간, 인코포레이티드 | Intracameral sustained release therapeutic agent implants |
WO2011106697A1 (en) | 2010-02-25 | 2011-09-01 | Schepens Eye Research Institute | Therapeutic compositions for the treatment of dry eye disease |
KR20130055562A (en) | 2010-03-08 | 2013-05-28 | 스펙트럼 파마슈티컬즈 인크 | Thioxanthone-based autophagy inhibitor therapies to treat cancer |
JP6327852B2 (en) | 2010-05-04 | 2018-05-23 | コリウム インターナショナル, インコーポレイテッド | Methods and devices for transdermal delivery of parathyroid hormone using microprojection arrays |
EP2977084B1 (en) | 2010-05-10 | 2017-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for the treatment of fluid accumulation in and/ or under the retina |
EP2576615B1 (en) | 2010-05-26 | 2016-03-30 | Bristol-Myers Squibb Company | Fibronectin based scaffold proteins having improved stability |
WO2011159824A1 (en) | 2010-06-16 | 2011-12-22 | Allergan, Inc. | Composition and method for treating overactive bladder |
CA2803923A1 (en) | 2010-06-25 | 2011-12-29 | Ignacio R. Rodriguez | Methods of treatment using sterculic acid |
EP2595602B1 (en) | 2010-07-21 | 2018-05-23 | Allergan, Inc. | SUSTAINED RELEASE siRNA FOR OCULAR DRUG DELIVERY |
EP2605762A1 (en) | 2010-08-19 | 2013-06-26 | Allergan, Inc. | Compositions comprising adipose tissue and a pge2 analogue and their use in the treatment of a soft tissue condition |
US8697057B2 (en) | 2010-08-19 | 2014-04-15 | Allergan, Inc. | Compositions and soft tissue replacement methods |
US9668915B2 (en) | 2010-11-24 | 2017-06-06 | Dose Medical Corporation | Drug eluting ocular implant |
US8349005B2 (en) | 2011-01-03 | 2013-01-08 | Masatoshi Murata | Method for burying implant to choroid |
US20140024627A1 (en) | 2011-01-03 | 2014-01-23 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Methods and pharmaceutical compositions for the treatment of ocular inflammatory diseases |
US8968626B2 (en) | 2011-01-31 | 2015-03-03 | Arsenal Medical, Inc. | Electrospinning process for manufacture of multi-layered structures |
US9194058B2 (en) | 2011-01-31 | 2015-11-24 | Arsenal Medical, Inc. | Electrospinning process for manufacture of multi-layered structures |
US9034240B2 (en) | 2011-01-31 | 2015-05-19 | Arsenal Medical, Inc. | Electrospinning process for fiber manufacture |
WO2012112757A2 (en) | 2011-02-17 | 2012-08-23 | Allergan, Inc. | Compositions and improved soft tissue replacement methods |
EP2678022A2 (en) | 2011-02-23 | 2014-01-01 | Allergan, Inc. | Compositions and improved soft tissue replacement methods |
CN103732218A (en) | 2011-06-03 | 2014-04-16 | 阿勒根公司 | Targeted delivery of retinoid compounds to the sebaceous glands |
US10245178B1 (en) | 2011-06-07 | 2019-04-02 | Glaukos Corporation | Anterior chamber drug-eluting ocular implant |
EP2720539B1 (en) | 2011-06-14 | 2018-10-24 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
EP2723357A4 (en) | 2011-06-21 | 2015-04-01 | Bvw Holding Ag | Medical device comprising boswellic acid |
ES2666857T3 (en) | 2011-07-18 | 2018-05-08 | Mor-Research Applications Ltd. | A device to adjust intraocular pressure |
AU2012325341B2 (en) | 2011-10-19 | 2017-01-05 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
US8993831B2 (en) | 2011-11-01 | 2015-03-31 | Arsenal Medical, Inc. | Foam and delivery system for treatment of postpartum hemorrhage |
EP2944628B1 (en) | 2011-11-30 | 2017-01-04 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
EP2785178B1 (en) | 2011-12-01 | 2019-05-01 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
KR20190090048A (en) | 2011-12-05 | 2019-07-31 | 인셉트, 엘엘씨 | Medical organogel processes and compositions |
CN110151745A (en) | 2011-12-13 | 2019-08-23 | Io治疗公司 | Use the treatment of the autoimmune disorder of rxr agonist |
US10653650B2 (en) | 2011-12-13 | 2020-05-19 | Io Therapeutics, Inc. | Treatment of diseases by concurrently eliciting remyelination effects and immunomodulatory effects using selective RXR agonists |
AU2012358810B2 (en) | 2011-12-23 | 2018-03-15 | DePuy Synthes Products, Inc. | Detection of human umbilical cord tissue-derived cells |
EP2802622A4 (en) * | 2012-01-13 | 2015-08-26 | Univ Missouri | Low temperature plasma coating for anti-biofilm formation |
EP2814510A1 (en) | 2012-02-16 | 2014-12-24 | Allergan, Inc. | Compositions and improved soft tissue replacement methods |
EP2814526B1 (en) | 2012-02-16 | 2016-11-02 | Allergan, Inc. | Compositions and improved soft tissue replacement methods |
WO2013123275A1 (en) | 2012-02-16 | 2013-08-22 | Allergan, Inc. | Compositions and improved soft tissue replacement methods |
WO2013123270A1 (en) | 2012-02-16 | 2013-08-22 | Allergan, Inc. | Compositions and improved soft tissue replacement methods |
MX367782B (en) | 2012-09-26 | 2019-09-04 | Tangent Reprofiling Ltd | Modulators of androgen synthesis. |
CA2886081A1 (en) * | 2012-09-27 | 2014-04-03 | Allergan, Inc. | Biodegradable drug delivery systems for the sustained release of proteins |
WO2014058742A1 (en) | 2012-10-09 | 2014-04-17 | Sears Douglas | Therapeutic treatment |
WO2014064191A2 (en) | 2012-10-24 | 2014-05-01 | Biocopea Limited | Drug combinations and uses |
PT3660033T (en) | 2012-11-15 | 2021-07-06 | Apellis Pharmaceuticals Inc | Long-acting compstatin analogs and related compositions and methods |
JP6865524B2 (en) | 2012-12-21 | 2021-04-28 | コリウム, インコーポレイテッド | Microarrays and usages for delivering therapeutic agents |
JP6513576B2 (en) | 2013-01-14 | 2019-05-15 | ヘルス クリニックス リミテッド | Anticancer agents and uses |
NZ710444A (en) | 2013-02-11 | 2020-08-28 | Univ California | Compositions and methods for treating neurodegenerative diseases and cardiomyopathy |
KR20150119254A (en) | 2013-02-15 | 2015-10-23 | 알러간, 인코포레이티드 | Sustained drug delivery implant |
RS60026B1 (en) | 2013-02-18 | 2020-04-30 | Vegenics Pty Ltd | Ligand binding molecules and uses thereof |
CA2940513C (en) | 2013-03-11 | 2023-08-15 | University Of Florida Research Foundation, Inc. | Delivery of card protein as therapy for ocular inflammation |
US9890127B2 (en) | 2013-03-11 | 2018-02-13 | The Broad Institute, Inc. | Compounds and compositions for the treatment of cancer |
EP2967824B1 (en) | 2013-03-12 | 2020-11-04 | Carnegie Mellon University | Coated vaso-occlusive device for treatment of aneurysms |
US10245422B2 (en) | 2013-03-12 | 2019-04-02 | Corium International, Inc. | Microprojection applicators and methods of use |
WO2014159060A1 (en) | 2013-03-14 | 2014-10-02 | Hallux, Inc. | Method of treating infections, diseases or disorders of nail unit |
CN105246458B (en) | 2013-03-15 | 2020-09-15 | 考里安公司 | Microarrays for therapeutic agent delivery and methods of use thereof |
US10308687B2 (en) | 2013-03-15 | 2019-06-04 | Apellis Pharmaceuticals, Inc. | Cell-penetrating compstatin analogs and uses thereof |
WO2014151769A1 (en) | 2013-03-15 | 2014-09-25 | Allergan, Inc. | Compositions including encapsulated isotretinoin and methods for use thereof |
US10517759B2 (en) | 2013-03-15 | 2019-12-31 | Glaukos Corporation | Glaucoma stent and methods thereof for glaucoma treatment |
EP2994758B1 (en) | 2013-05-08 | 2017-12-20 | Opthea Limited | Biomarkers for age-related macular degeneration (amd) |
KR102373982B1 (en) | 2013-08-21 | 2022-03-14 | 센세오닉스, 인코포레이티드 | Drug elution for in vivo protection of bio-sensing analytes |
JP6543431B2 (en) * | 2013-10-10 | 2019-07-10 | ユニバーシティー オブ ユタ リサーチ ファウンデーションUniversity of Utah Research Foundation | Intraocular drug delivery device and associated method |
WO2015116709A1 (en) | 2014-01-28 | 2015-08-06 | Allergan, Inc. | Topical retinoid formulations and methods of use |
EP3104706B1 (en) | 2014-02-11 | 2022-03-23 | Mitokinin, Inc. | Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease |
EP3132804B1 (en) | 2014-04-17 | 2021-05-05 | Seed Co., Ltd. | Medical device including anionic drug |
WO2015184173A1 (en) | 2014-05-29 | 2015-12-03 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
WO2016005599A1 (en) | 2014-07-10 | 2016-01-14 | Biocopea Limited | Compositions, methods and uses for treating gender-biased immune disorders |
WO2016036866A1 (en) | 2014-09-04 | 2016-03-10 | Corium International, Inc. | Microstructure array, methods of making, and methods of use |
WO2016144832A1 (en) | 2015-03-06 | 2016-09-15 | Envisia Therapeutics, Inc. | Implant applicators and methods of administering implants |
WO2017004067A1 (en) | 2015-06-29 | 2017-01-05 | Corium International, Inc. | Microarray for delivery of therapeutic agent, methods of use, and methods of making |
EP3324944A4 (en) | 2015-07-23 | 2019-04-03 | Aerie Pharmaceuticals, Inc. | Intravitreal drug delivery systems for the treatment of ocular conditions |
ES2828694T3 (en) | 2015-07-29 | 2021-05-27 | Allergan Inc | Heavy chain-only antibodies to ANG-2 |
US10308711B2 (en) | 2015-08-14 | 2019-06-04 | Allergan, Inc. | Heavy chain only antibodies to PDGF |
US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
MA43313B1 (en) | 2015-09-02 | 2022-06-30 | Trevena Inc | 6-membered heterocyclic aza containing delta opioid receptor modulating compounds, and methods of making and using the same |
US11564833B2 (en) | 2015-09-25 | 2023-01-31 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
CN117503905A (en) | 2015-10-07 | 2024-02-06 | 阿佩利斯制药有限公司 | dosing regimen |
EP3362095B1 (en) | 2015-10-13 | 2020-11-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of choroidal neovascularisation |
EP4088719A1 (en) | 2015-10-13 | 2022-11-16 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods and pharmaceutical compositions for the treatment of retinal capillary non-perfusion |
WO2017064119A1 (en) | 2015-10-13 | 2017-04-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of retinal capillary non-perfusion |
AU2016344018B2 (en) | 2015-10-31 | 2019-02-28 | Io Therapeutics, Inc. | Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones |
PT109154B (en) * | 2016-02-12 | 2019-11-05 | Univ De Coimbra | NON-INVASIVE EYE INSERT TECHNOLOGY FOR CONTROLLED DRUG RELEASE |
IL261669B2 (en) | 2016-03-10 | 2023-12-01 | Io Therapeutics Inc | Treatment of autoimmune diseases with combinations of rxr agonists and thyroid hormones |
WO2017155578A1 (en) | 2016-03-10 | 2017-09-14 | Io Therapeutics, Inc. | Treatment of muscular disorders with combinations of rxr agonists and thyroid hormones |
WO2017173327A1 (en) | 2016-03-31 | 2017-10-05 | The Schepens Eye Research Institute, Inc. | Endomucin inhibitor as an anti-angiogenic agent |
US20190125669A1 (en) * | 2016-04-17 | 2019-05-02 | Children's Medical Center Corporation | Systems and methods for steroidal gels |
EP3442479A1 (en) | 2016-04-20 | 2019-02-20 | Harold Alexander Heitzmann | Bioresorbable ocular drug delivery device |
MX2019000050A (en) | 2016-07-05 | 2019-05-02 | Janssen Biotech Inc | Treatment of retinal vascular disease using progenitor cells. |
EP3484463B1 (en) | 2016-08-19 | 2020-02-12 | The United States of America, as Represented by The Secretary, Department of Health and Human Services Office of Technology Transfer | Selective estrogen-receptor modulators (serms) confer protection against photoreceptor degeneration |
WO2018093797A1 (en) | 2016-11-15 | 2018-05-24 | The Schepens Eye Research Institute, Inc. | Compositions and methods for the treatment of aberrant angiogenesis |
BR112019016775A2 (en) | 2017-02-17 | 2020-03-31 | Trevena, Inc. | DELTA-OPIOIDE MODULATING RECEIVER COMPOUNDS CONTAINING 7-MEMBER AZA-HETEROCYCLIC, METHODS OF USE AND PRODUCTION OF THE SAME |
KR20190129867A (en) | 2017-02-17 | 2019-11-20 | 트레베나, 인코포레이티드. | 5-membered aza-heterocycle-containing delta-opioid receptor modulating compounds, and methods of using and preparing the same |
CA3059304A1 (en) | 2017-04-07 | 2018-10-11 | Apellis Pharmaceuticals, Inc. | Dosing regimens and related compositions and methods |
EP3618841B1 (en) | 2017-05-05 | 2023-03-22 | University of Pittsburgh - of The Commonwealth System of Higher Education | Ocular applications of matrix bound vesicles (mbvs) |
US20190224275A1 (en) | 2017-05-12 | 2019-07-25 | Aurinia Pharmaceuticals Inc. | Protocol for treatment of lupus nephritis |
WO2018237145A1 (en) | 2017-06-21 | 2018-12-27 | Mitokinin, Inc. | Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease |
CA3072673A1 (en) | 2017-08-11 | 2019-02-14 | Unity Biotechnology, Inc. | Treatment of ophthalmic conditions such as macular degeneration, glaucoma, and diabetic retinopathy using pharmaceutical agents that eliminate senescent cells |
CA3076373A1 (en) | 2017-09-20 | 2019-03-28 | Io Therapeutics, Inc. | Treatment of disease with esters of selective rxr agonists |
WO2019070917A1 (en) | 2017-10-03 | 2019-04-11 | The Schepens Eye Research Institute, Inc. | Compounds and compositions for inhibiting retinal pigment epithelium degeneration and methods using the same |
US20220104839A1 (en) | 2017-10-16 | 2022-04-07 | Retriever Medical, Inc. | Clot Removal Methods and Devices with Multiple Independently Controllable Elements |
AU2021362245A1 (en) | 2017-10-16 | 2023-05-25 | Retriever Medical, Inc. | Clot removal methods and devices with multiple independently controllable elements |
US10258357B1 (en) | 2017-10-16 | 2019-04-16 | Michael Bruce Horowitz | Catheter based retrieval device with proximal body having axial freedom of movement |
AU2018369784B2 (en) | 2017-11-14 | 2023-06-01 | Massachusetts Eye And Ear Infirmary | RUNX1 inhibition for treatment of proliferative vitreoretinopathy and conditions associated with epithelial to mesenchymal transition |
US20210009651A1 (en) | 2018-03-02 | 2021-01-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Se | Use of il-34 to treat retinal inflammation and neurodegeneration |
BR112020022083A2 (en) * | 2018-05-01 | 2021-02-02 | Chibi, Inc. | liquid depot, case and method to treat the retina. |
US11672860B2 (en) | 2018-11-02 | 2023-06-13 | Senseonics, Incorporated | Drug eluting matrix on analyte indicator |
US10966950B2 (en) | 2019-06-11 | 2021-04-06 | Io Therapeutics, Inc. | Use of an RXR agonist in treating HER2+ cancers |
US11471426B2 (en) | 2019-10-16 | 2022-10-18 | American River Nutrition, Llc | Compositions comprising quinone and/or quinol and methods of preparations and use thereof |
CA3165922A1 (en) | 2020-01-17 | 2021-07-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Gene therapy for treatment of crx-autosomal dominant retinopathies |
WO2021244964A1 (en) | 2020-06-01 | 2021-12-09 | Black Cat Bio Limited | Compositions and methods for treating infections and netopathy |
WO2023105417A1 (en) | 2021-12-06 | 2023-06-15 | Breye Therapeutics Aps | Danegaptide formulation for applicatoin in the eye |
WO2023108012A1 (en) | 2021-12-07 | 2023-06-15 | Io Therapeutics, Inc. | Use of an rxr agonist and taxanes in treating her2+ cancers |
US11779553B1 (en) * | 2022-11-28 | 2023-10-10 | Atif B. D. Collins | Methods and devices for treatment of eyelid ptosis |
Family Cites Families (142)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE636865A (en) * | 1962-08-31 | |||
US3416530A (en) * | 1966-03-02 | 1968-12-17 | Richard A. Ness | Eyeball medication dispensing tablet |
US3986510A (en) * | 1971-09-09 | 1976-10-19 | Alza Corporation | Bioerodible ocular device |
US3960150A (en) * | 1971-09-09 | 1976-06-01 | Alza Corporation | Bioerodible ocular device |
US3845770A (en) * | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3916899A (en) * | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US3914402A (en) * | 1973-06-14 | 1975-10-21 | Alza Corp | Ophthalmic dosage form, for releasing medication over time |
SE390255B (en) * | 1974-02-18 | 1976-12-13 | N G Y Torphammar | RELEASE DEVICE PREFERRED FOR A SAFETY BELT IN A VEHICLE |
US3961628A (en) * | 1974-04-10 | 1976-06-08 | Alza Corporation | Ocular drug dispensing system |
US3921632A (en) * | 1974-08-16 | 1975-11-25 | Frank M Bardani | Implant device |
GB1478759A (en) * | 1974-11-18 | 1977-07-06 | Alza Corp | Process for forming outlet passageways in pills using a laser |
US4180646A (en) * | 1975-01-28 | 1979-12-25 | Alza Corporation | Novel orthoester polymers and orthocarbonate polymers |
US4144317A (en) * | 1975-05-30 | 1979-03-13 | Alza Corporation | Device consisting of copolymer having acetoxy groups for delivering drugs |
US4014334A (en) * | 1976-02-02 | 1977-03-29 | Alza Corporation | Laminated osmotic system for dispensing beneficial agent |
US4063064A (en) * | 1976-02-23 | 1977-12-13 | Coherent Radiation | Apparatus for tracking moving workpiece by a laser beam |
US4201210A (en) * | 1976-06-22 | 1980-05-06 | The United States Of America As Represented By The Secretary Of Agriculture | Veterinary ocular ring device for sustained drug release |
US4186184A (en) * | 1977-12-27 | 1980-01-29 | Alza Corporation | Selective administration of drug with ocular therapeutic system |
US4285987A (en) * | 1978-10-23 | 1981-08-25 | Alza Corporation | Process for manufacturing device with dispersion zone |
US4200098A (en) * | 1978-10-23 | 1980-04-29 | Alza Corporation | Osmotic system with distribution zone for dispensing beneficial agent |
US4300557A (en) * | 1980-01-07 | 1981-11-17 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Method for treating intraocular malignancies |
US4402979A (en) * | 1980-03-21 | 1983-09-06 | Merck & Co., Inc. & Laboratories | Ophthalmic formulations of 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid |
US4304765A (en) * | 1980-10-14 | 1981-12-08 | Alza Corporation | Ocular insert housing steroid in two different therapeutic forms |
US4327725A (en) * | 1980-11-25 | 1982-05-04 | Alza Corporation | Osmotic device with hydrogel driving member |
JPS58126435U (en) * | 1982-02-19 | 1983-08-27 | オリンパス光学工業株式会社 | Aperture control circuit for TTL auto strobe |
US4451254A (en) * | 1982-03-15 | 1984-05-29 | Eli Lilly And Company | Implant system |
US4599353A (en) * | 1982-05-03 | 1986-07-08 | The Trustees Of Columbia University In The City Of New York | Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma |
DE3220156C2 (en) * | 1982-05-28 | 1990-01-25 | Heida Houston Tex. Thurlow | Cooking and roasting utensils with lids provided with metal handles, in particular stainless steel handles |
US4530840A (en) † | 1982-07-29 | 1985-07-23 | The Stolle Research And Development Corporation | Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents |
US4478818A (en) * | 1982-12-27 | 1984-10-23 | Alza Corporation | Ocular preparation housing steroid in two different therapeutic forms |
US4521210A (en) * | 1982-12-27 | 1985-06-04 | Wong Vernon G | Eye implant for relieving glaucoma, and device and method for use therewith |
US6217911B1 (en) * | 1995-05-22 | 2001-04-17 | The United States Of America As Represented By The Secretary Of The Army | sustained release non-steroidal, anti-inflammatory and lidocaine PLGA microspheres |
US6309669B1 (en) * | 1984-03-16 | 2001-10-30 | The United States Of America As Represented By The Secretary Of The Army | Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix |
US4629621A (en) * | 1984-07-23 | 1986-12-16 | Zetachron, Inc. | Erodible matrix for sustained release bioactive composition |
US5082655A (en) * | 1984-07-23 | 1992-01-21 | Zetachron, Inc. | Pharmaceutical composition for drugs subject to supercooling |
US4668506A (en) * | 1985-08-16 | 1987-05-26 | Bausch & Lomb Incorporated | Sustained-release formulation containing and amino acid polymer |
US4966849A (en) * | 1985-09-20 | 1990-10-30 | President And Fellows Of Harvard College | CDNA and genes for human angiogenin (angiogenesis factor) and methods of expression |
US4640941A (en) * | 1985-11-25 | 1987-02-03 | Alcon Laboratories | Hydrogels containing siloxane comonomers |
DE3612212A1 (en) * | 1986-04-11 | 1987-10-15 | Basf Ag | METHOD FOR PRODUCING SOLID PHARMACEUTICAL FORMS |
US4756911A (en) * | 1986-04-16 | 1988-07-12 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
US4959217A (en) * | 1986-05-22 | 1990-09-25 | Syntex (U.S.A.) Inc. | Delayed/sustained release of macromolecules |
US4962091A (en) * | 1986-05-23 | 1990-10-09 | Syntex (U.S.A.) Inc. | Controlled release of macromolecular polypeptides |
US5322691A (en) * | 1986-10-02 | 1994-06-21 | Sohrab Darougar | Ocular insert with anchoring protrusions |
US4863457A (en) * | 1986-11-24 | 1989-09-05 | Lee David A | Drug delivery device |
US5006342A (en) * | 1986-12-22 | 1991-04-09 | Cygnus Corporation | Resilient transdermal drug delivery device |
US4821210A (en) * | 1987-04-02 | 1989-04-11 | General Electric Co. | Fast display of three-dimensional images |
DE3851152T2 (en) * | 1987-09-03 | 1995-01-26 | Univ Georgia Res Found | CYCLOSPORINE EYE PRODUCTS. |
DE3734223A1 (en) * | 1987-10-09 | 1989-04-20 | Boehringer Ingelheim Kg | IMPLANTABLE, BIODEGRADABLE ACTIVE SUBSTANCE RELEASE SYSTEM |
US4997652A (en) * | 1987-12-22 | 1991-03-05 | Visionex | Biodegradable ocular implants |
US4853224A (en) | 1987-12-22 | 1989-08-01 | Visionex | Biodegradable ocular implants |
US4945089A (en) * | 1987-12-29 | 1990-07-31 | Alcon Laboratories, Inc. | Use of tetrahydrocortexolone to prevent elevations in intraocular pressure caused by corticosteroids |
US4865846A (en) * | 1988-06-03 | 1989-09-12 | Kaufman Herbert E | Drug delivery system |
GB8820353D0 (en) * | 1988-08-26 | 1988-09-28 | Staniforth J N | Controlled release tablet |
US5004601A (en) * | 1988-10-14 | 1991-04-02 | Zetachron, Inc. | Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith |
US5019400A (en) * | 1989-05-01 | 1991-05-28 | Enzytech, Inc. | Very low temperature casting of controlled release microspheres |
US5028624A (en) * | 1989-07-27 | 1991-07-02 | Allergan, Inc. | Intraocular pressure reducing 9,15-diacyl prostaglandins |
US5034413A (en) * | 1989-07-27 | 1991-07-23 | Allergan, Inc. | Intraocular pressure reducing 9,11-diacyl prostaglandins |
SG49267A1 (en) * | 1989-08-14 | 1998-05-18 | Photogenesis Inc | Surgical instrument and cell isolation and transplantation |
US5112614A (en) * | 1989-09-14 | 1992-05-12 | Alza Corporation | Implantable delivery dispenser |
US5268178A (en) * | 1989-09-25 | 1993-12-07 | The Board Of Regents, The University Of Texas System | Biodegradable antibiotic implants and methods of their use in treating and preventing infections |
US5164188A (en) * | 1989-11-22 | 1992-11-17 | Visionex, Inc. | Biodegradable ocular implants |
US5660851A (en) * | 1989-12-26 | 1997-08-26 | Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem | Ocular inserts |
US5075115A (en) * | 1990-04-02 | 1991-12-24 | Fmc Corporation | Process for polymerizing poly(lactic acid) |
DE69101291T2 (en) † | 1990-08-30 | 1994-07-07 | Senju Pharma Co | Composition for the controlled delivery of medicines. |
KR0185215B1 (en) * | 1990-11-30 | 1999-05-01 | 요시다 쇼오지 | A controlled-release pharmaceutical preparation for intra-ocular implant |
US5378475A (en) | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
DK0591392T3 (en) * | 1991-06-21 | 1996-09-30 | Genetics Inst | Pharmaceutical formulations of osteogenic proteins |
US5356629A (en) * | 1991-07-12 | 1994-10-18 | United States Surgical Corporation | Composition for effecting bone repair |
US5169638A (en) * | 1991-10-23 | 1992-12-08 | E. R. Squibb & Sons, Inc. | Buoyant controlled release powder formulation |
US5543154A (en) * | 1991-12-27 | 1996-08-06 | Merck & Co., Inc. | Controlled release nifedipine delivery device |
US6045791A (en) * | 1992-03-06 | 2000-04-04 | Photogenesis, Inc. | Retinal pigment epithelium transplantation |
US5656297A (en) * | 1992-03-12 | 1997-08-12 | Alkermes Controlled Therapeutics, Incorporated | Modulated release from biocompatible polymers |
US5384333A (en) * | 1992-03-17 | 1995-01-24 | University Of Miami | Biodegradable injectable drug delivery polymer |
US5178635A (en) * | 1992-05-04 | 1993-01-12 | Allergan, Inc. | Method for determining amount of medication in an implantable device |
US5700485A (en) * | 1992-09-10 | 1997-12-23 | Children's Medical Center Corporation | Prolonged nerve blockade by the combination of local anesthetic and glucocorticoid |
DK0659073T3 (en) * | 1992-09-10 | 2002-03-11 | Childrens Medical Center | Biodegradable polymer matrices with sustained release of local anesthetics |
US5972991A (en) * | 1992-09-21 | 1999-10-26 | Allergan | Cyclopentane heptan(ene) oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US5688819A (en) * | 1992-09-21 | 1997-11-18 | Allergan | Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
ES2079994B1 (en) * | 1992-10-07 | 1996-08-01 | Cusi Lab | PHARMACEUTICAL FORMULATION BASED ON POLYMIXINE-TRIMETOPRIM AND AN ANTI-INFLAMMATORY AGENT FOR ITS TOPICAL OPHTHALMIC AND ETHICAL USE. |
US5330992A (en) * | 1992-10-23 | 1994-07-19 | Sterling Winthrop Inc. | 1-cyclopropyl-4-pyridyl-quinolinones |
US5314419A (en) * | 1992-10-30 | 1994-05-24 | Pelling George E | Method for dispensing ophthalmic drugs to the eye |
DE69326015T2 (en) * | 1992-11-18 | 2000-02-03 | Fujisawa Pharmaceutical Co | PHARMACEUTICAL PREPARATION WITH EXTENDED EFFECT |
TW333456B (en) * | 1992-12-07 | 1998-06-11 | Takeda Pharm Ind Co Ltd | A pharmaceutical composition of sustained-release preparation the invention relates to a pharmaceutical composition of sustained-release preparation which comprises a physiologically active peptide. |
US5707643A (en) * | 1993-02-26 | 1998-01-13 | Santen Pharmaceutical Co., Ltd. | Biodegradable scleral plug |
US5456917A (en) * | 1993-04-12 | 1995-10-10 | Cambridge Scientific, Inc. | Method for making a bioerodible material for the sustained release of a medicament and the material made from the method |
US5385887A (en) * | 1993-09-10 | 1995-01-31 | Genetics Institute, Inc. | Formulations for delivery of osteogenic proteins |
US5443505A (en) * | 1993-11-15 | 1995-08-22 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
US5393765A (en) † | 1993-12-13 | 1995-02-28 | Hoffmann-La Roche Inc. | Pharmaceutical compositions with constant erosion volume for zero order controlled release |
US6051576A (en) * | 1994-01-28 | 2000-04-18 | University Of Kentucky Research Foundation | Means to achieve sustained release of synergistic drugs by conjugation |
DE4403326C1 (en) * | 1994-02-03 | 1995-06-22 | Hans Reinhard Prof Dr Koch | Intraocular lens arrangement for astigmatism correction |
US5773021A (en) * | 1994-03-14 | 1998-06-30 | Vetoquinol S.A. | Bioadhesive ophthalmic insert |
US5466233A (en) * | 1994-04-25 | 1995-11-14 | Escalon Ophthalmics, Inc. | Tack for intraocular drug delivery and method for inserting and removing same |
US5755785A (en) * | 1994-08-12 | 1998-05-26 | The University Of South Florida | Sutureless corneal transplantation method |
US6063116A (en) * | 1994-10-26 | 2000-05-16 | Medarex, Inc. | Modulation of cell proliferation and wound healing |
CA2149164C (en) * | 1995-05-11 | 2009-03-03 | Zlatko Korunic | Diatomaceous earth insecticidal composition |
US5869079A (en) * | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US6369116B1 (en) * | 1995-06-02 | 2002-04-09 | Oculex Pharmaceuticals, Inc. | Composition and method for treating glaucoma |
US5693335A (en) * | 1995-06-07 | 1997-12-02 | Cygnus, Inc. | Skin permeation enhancer composition for use with sex steroids |
US5773019A (en) * | 1995-09-27 | 1998-06-30 | The University Of Kentucky Research Foundation | Implantable controlled release device to deliver drugs directly to an internal portion of the body |
US6046187A (en) * | 1996-09-16 | 2000-04-04 | Children's Medical Center Corporation | Formulations and methods for providing prolonged local anesthesia |
US5941250A (en) * | 1996-11-21 | 1999-08-24 | University Of Louisville Research Foundation Inc. | Retinal tissue implantation method |
PT973499E (en) * | 1997-03-31 | 2003-12-31 | Alza Corp | IMPLANTABLE DIFFUSER ADMINISTRATION SYSTEM |
CA2300154C (en) * | 1997-08-11 | 2008-07-08 | Allergan Sales, Inc. | Sterile bioerodible implant device with improved biocompatability and method |
US6306426B1 (en) * | 1997-08-11 | 2001-10-23 | Allergan Sales, Inc. | Implant device with a retinoid for improved biocompatibility |
US5902598A (en) * | 1997-08-28 | 1999-05-11 | Control Delivery Systems, Inc. | Sustained release drug delivery devices |
JP3937533B2 (en) * | 1997-11-07 | 2007-06-27 | セイコーエプソン株式会社 | Remote coordinate input device and remote coordinate input method |
US6841684B2 (en) * | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
US6329369B1 (en) * | 1997-12-04 | 2001-12-11 | Allergan Sales, Inc. | Methods of treating pain and other conditions |
EP1131114B1 (en) * | 1998-11-20 | 2004-06-16 | The University of Connecticut | Apparatus and method for control of tissue/implant interactions |
US6217895B1 (en) * | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US6331313B1 (en) * | 1999-10-22 | 2001-12-18 | Oculex Pharmaceticals, Inc. | Controlled-release biocompatible ocular drug delivery implant devices and methods |
US6545182B2 (en) * | 2000-04-13 | 2003-04-08 | Allergan Sales, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
US7335803B2 (en) * | 2001-10-19 | 2008-02-26 | Allergan, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
US20040170665A1 (en) * | 2000-06-02 | 2004-09-02 | Allergan, Inc. | Intravitreal botulinum toxin implant |
US6726918B1 (en) * | 2000-07-05 | 2004-04-27 | Oculex Pharmaceuticals, Inc. | Methods for treating inflammation-mediated conditions of the eye |
DE60114229T2 (en) * | 2000-11-29 | 2006-07-06 | Allergan, Inc., Irvine | PREVENTING TRANSPLANT DISCHARGE IN THE EYE |
US6534542B2 (en) * | 2001-02-27 | 2003-03-18 | Allergen Sales, Inc. | (2-hydroxy)ethyl-thioureas useful as modulators of α2B adrenergic receptors |
US6713081B2 (en) * | 2001-03-15 | 2004-03-30 | The United States Of America As Represented By The Department Of Health And Human Services | Ocular therapeutic agent delivery devices and methods for making and using such devices |
US7386835B1 (en) * | 2002-03-22 | 2008-06-10 | Emc Corporation | Technique for graphical user interface modification |
US6541504B1 (en) * | 2002-04-03 | 2003-04-01 | Allergan Sales, Llc | (3Z)-3-(2,3-dihydro-1H-inden-1-ylidene)-1,3-dihydro-2H-indol-2-ones as kinase inhibitors |
US7091232B2 (en) * | 2002-05-21 | 2006-08-15 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
US7345065B2 (en) * | 2002-05-21 | 2008-03-18 | Allergan, Inc. | Methods and compositions for alleviating pain |
US20040266776A1 (en) * | 2003-06-25 | 2004-12-30 | Gil Daniel W. | Methods of preventing and reducing the severity of stress-associated conditions |
US7276522B2 (en) * | 2002-05-21 | 2007-10-02 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones, 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
US20040048099A1 (en) * | 2002-08-29 | 2004-03-11 | Chen Jian Ping | Organic light-emitting device using iptycene derivatives |
KR20050088288A (en) * | 2002-11-06 | 2005-09-05 | 알자 코포레이션 | Controlled release depot formulations |
US20050048099A1 (en) * | 2003-01-09 | 2005-03-03 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US20040137059A1 (en) * | 2003-01-09 | 2004-07-15 | Thierry Nivaggioli | Biodegradable ocular implant |
US20050059664A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Novel methods for identifying improved, non-sedating alpha-2 agonists |
US7141597B2 (en) * | 2003-09-12 | 2006-11-28 | Allergan, Inc. | Nonsedating α-2 agonists |
US20050059744A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions |
US20050058696A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions |
US20050101582A1 (en) * | 2003-11-12 | 2005-05-12 | Allergan, Inc. | Compositions and methods for treating a posterior segment of an eye |
WO2005072701A1 (en) * | 2004-01-20 | 2005-08-11 | Allergan, Inc. | Compositions for localized therapy of the eye, comprising preferably triamcinolone acetonide and hyaluronic acid |
US7691381B2 (en) * | 2004-04-15 | 2010-04-06 | Allergan, Inc. | Stabilized biodegradable neurotoxin implants |
US20050244469A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US7993634B2 (en) * | 2004-04-30 | 2011-08-09 | Allergan, Inc. | Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods |
US8119154B2 (en) * | 2004-04-30 | 2012-02-21 | Allergan, Inc. | Sustained release intraocular implants and related methods |
US7799336B2 (en) * | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
JP2008505978A (en) * | 2004-07-12 | 2008-02-28 | アラーガン、インコーポレイテッド | Ophthalmic composition and eye disease treatment method |
US7357394B2 (en) * | 2004-10-01 | 2008-04-15 | Sri Acquisition Corp. | Modular shooting range |
US20060233857A1 (en) * | 2005-04-14 | 2006-10-19 | Amsden Brian G | Degradable elastomeric network |
US20070298073A1 (en) * | 2006-06-23 | 2007-12-27 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
-
1995
- 1995-06-02 US US08/459,134 patent/US5869079A/en not_active Expired - Lifetime
-
1996
- 1996-05-31 EP EP04019466A patent/EP1477187B9/en not_active Expired - Lifetime
- 1996-05-31 JP JP8536741A patent/JPH11506450A/en active Pending
- 1996-05-31 EP EP10012665A patent/EP2298353A1/en not_active Withdrawn
- 1996-05-31 AU AU59624/96A patent/AU721421B2/en not_active Ceased
- 1996-05-31 EP EP05027625A patent/EP1637164A3/en not_active Ceased
- 1996-05-31 CA CA2762921A patent/CA2762921A1/en not_active Abandoned
- 1996-05-31 KR KR1019970708691A patent/KR19990022212A/en not_active Application Discontinuation
- 1996-05-31 PL PL96323747A patent/PL323747A1/en unknown
- 1996-05-31 ES ES96916903T patent/ES2256859T5/en not_active Expired - Lifetime
- 1996-05-31 PT PT04019466T patent/PT1477187E/en unknown
- 1996-05-31 EP EP96916903A patent/EP0831912B2/en not_active Expired - Lifetime
- 1996-05-31 BR BR9608642A patent/BR9608642A/en not_active Application Discontinuation
- 1996-05-31 CA CA2222889A patent/CA2222889C/en not_active Expired - Fee Related
- 1996-05-31 AT AT04019466T patent/ATE516049T1/en active
- 1996-05-31 DE DE69635734T patent/DE69635734T3/en not_active Expired - Lifetime
- 1996-05-31 AT AT96916903T patent/ATE315409T1/en not_active IP Right Cessation
- 1996-05-31 WO PCT/US1996/008250 patent/WO1996038174A1/en active IP Right Grant
- 1996-05-31 CN CN96195703A patent/CN1191492A/en active Pending
- 1996-05-31 DK DK04019466.4T patent/DK1477187T3/en active
- 1996-05-31 ES ES04019466T patent/ES2368951T3/en not_active Expired - Lifetime
- 1996-05-31 RU RU98100252/14A patent/RU2175561C2/en active
- 1996-06-03 MY MYPI96002133A patent/MY132179A/en unknown
- 1996-06-07 TW TW085106878A patent/TW487580B/en active
-
1998
- 1998-09-24 US US09/160,635 patent/US7048946B1/en not_active Expired - Fee Related
-
2002
- 2002-12-20 US US10/327,018 patent/US20030095995A1/en not_active Abandoned
-
2004
- 2004-09-02 US US10/933,971 patent/US20050048098A1/en not_active Abandoned
-
2005
- 2005-04-29 US US11/117,778 patent/US20050191334A1/en not_active Abandoned
- 2005-11-14 US US11/273,871 patent/US20060067966A1/en not_active Abandoned
-
2006
- 2006-01-30 JP JP2006020891A patent/JP2006192282A/en not_active Withdrawn
- 2006-05-12 US US11/432,952 patent/US20060204543A1/en not_active Abandoned
-
2007
- 2007-11-01 US US11/933,912 patent/US20080124377A1/en not_active Abandoned
-
2009
- 2009-02-10 US US12/368,807 patent/US20090148499A1/en not_active Abandoned
-
2010
- 2010-10-08 JP JP2010228763A patent/JP2011005300A/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2222889C (en) | Improved formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents | |
US6369116B1 (en) | Composition and method for treating glaucoma | |
US5443505A (en) | Biocompatible ocular implants | |
RU2357709C1 (en) | Microimplants for ophthalmologic introduction | |
US20050244461A1 (en) | Controlled release drug delivery systems and methods for treatment of an eye | |
US20090196905A1 (en) | Stabilization of mitochondrial membranes in ocular diseases and conditions | |
US20050244465A1 (en) | Drug delivery systems and methods for treatment of an eye | |
US20060280774A1 (en) | Compositions and methods for treating glaucoma | |
MXPA97009218A (en) | Improved formulation to control the release of drugs by the combination of hydrophilic and hydrophobic agents | |
AU731486B2 (en) | Biocompatible ocular implants |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
EEER | Examination request |
Effective date: 20111221 |
|
FZDE | Discontinued |
Effective date: 20140918 |