CA2196304A1 - Controlled local delivery of chemotherapeutic agents for treating solid tumors - Google Patents
Controlled local delivery of chemotherapeutic agents for treating solid tumorsInfo
- Publication number
- CA2196304A1 CA2196304A1 CA002196304A CA2196304A CA2196304A1 CA 2196304 A1 CA2196304 A1 CA 2196304A1 CA 002196304 A CA002196304 A CA 002196304A CA 2196304 A CA2196304 A CA 2196304A CA 2196304 A1 CA2196304 A1 CA 2196304A1
- Authority
- CA
- Canada
- Prior art keywords
- chemotherapeutic agent
- composition
- tumor
- effective
- biodegradable
- 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.)
- Granted
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract 14
- 229940127089 cytotoxic agent Drugs 0.000 title claims abstract 14
- 206010028980 Neoplasm Diseases 0.000 title claims abstract 10
- 238000000034 method Methods 0.000 claims abstract 11
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims abstract 3
- 229930012538 Paclitaxel Natural products 0.000 claims abstract 3
- 230000008499 blood brain barrier function Effects 0.000 claims abstract 3
- 210000001218 blood-brain barrier Anatomy 0.000 claims abstract 3
- 229940127093 camptothecin Drugs 0.000 claims abstract 3
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims abstract 3
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims abstract 3
- 238000001802 infusion Methods 0.000 claims abstract 3
- 229960001592 paclitaxel Drugs 0.000 claims abstract 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims abstract 3
- 239000007943 implant Substances 0.000 claims abstract 2
- 238000001727 in vivo Methods 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims 10
- 239000011159 matrix material Substances 0.000 claims 8
- 150000001875 compounds Chemical class 0.000 claims 4
- 229920000642 polymer Polymers 0.000 claims 4
- 230000012010 growth Effects 0.000 claims 3
- 102000004127 Cytokines Human genes 0.000 claims 2
- 108090000695 Cytokines Proteins 0.000 claims 2
- 239000004952 Polyamide Substances 0.000 claims 2
- 229920002732 Polyanhydride Polymers 0.000 claims 2
- 229920001273 Polyhydroxy acid Polymers 0.000 claims 2
- 229920001710 Polyorthoester Polymers 0.000 claims 2
- 108010076039 Polyproteins Proteins 0.000 claims 2
- 239000004037 angiogenesis inhibitor Substances 0.000 claims 2
- 239000003242 anti bacterial agent Substances 0.000 claims 2
- 239000000604 anti-edema agent Substances 0.000 claims 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims 2
- 230000000259 anti-tumor effect Effects 0.000 claims 2
- 229940088710 antibiotic agent Drugs 0.000 claims 2
- 239000003443 antiviral agent Substances 0.000 claims 2
- 229940121357 antivirals Drugs 0.000 claims 2
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 claims 2
- 229920001577 copolymer Polymers 0.000 claims 2
- 239000005038 ethylene vinyl acetate Substances 0.000 claims 2
- 150000004676 glycans Chemical class 0.000 claims 2
- 229940051026 immunotoxin Drugs 0.000 claims 2
- 239000002596 immunotoxin Substances 0.000 claims 2
- 231100000608 immunotoxin Toxicity 0.000 claims 2
- 230000002637 immunotoxin Effects 0.000 claims 2
- 150000002632 lipids Chemical class 0.000 claims 2
- 229940026778 other chemotherapeutics in atc Drugs 0.000 claims 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims 2
- 229920002627 poly(phosphazenes) Polymers 0.000 claims 2
- 229920002647 polyamide Polymers 0.000 claims 2
- 229920000728 polyester Polymers 0.000 claims 2
- 229920001282 polysaccharide Polymers 0.000 claims 2
- 239000005017 polysaccharide Substances 0.000 claims 2
- 230000008685 targeting Effects 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- 229920000249 biocompatible polymer Polymers 0.000 claims 1
- 230000000973 chemotherapeutic effect Effects 0.000 claims 1
- 238000002513 implantation Methods 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 230000005855 radiation Effects 0.000 claims 1
- 238000007910 systemic administration Methods 0.000 claims 1
- 230000004614 tumor growth Effects 0.000 claims 1
- 229920002988 biodegradable polymer Polymers 0.000 abstract 2
- 239000004621 biodegradable polymer Substances 0.000 abstract 2
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 229960004562 carboplatin Drugs 0.000 abstract 1
- 190000008236 carboplatin Chemical compound 0.000 abstract 1
- 238000000748 compression moulding Methods 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- 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
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A method and devices for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability and/or short half-lives in vivo, are described. The devices consist of reservoirs which release drug over an extended time period while at the same time preserving the bioactivity and bioavailability of the agent. In the most preferred embodiment, the device consists of biodegradable polymeric matrixes, although reservoirs can also be formulated from non-biodegradable polymers or reservoirs connected to implanted infusion pumps. The devices are implanted within or immediately adjacent the tumors to be treated or the site where they have been surgically removed. The examples demonstrate the efficacy of paclitaxel, camptothecin, and carboplatin delivered in polymeric implants prepared by compression molding of biodegradable and non-biodegradable polymers, respectively. The results are highly statistically significant.
Claims
1. A chemotherapeutic composition comprising a biocompatible polymeric matrix incorporating an effective amount to inhibit tumor growth when released in vivo at the site of the tumor of a relatively water insoluble, relatively lipid insoluble chemotherapeutic agent, wherein the chemotherapeutic agent does not cross the blood-brain barrier in an amount effective to inhibit growth of a solid tumor when administered systemically and is not paclitaxel.
3. The composition of claim 1 wherein the chemotherapeutic agent is camptothecin or a functionally effective derivative.
4. The composition of claim 1 wherein the polymer matrix is biodegradable.
7. The composition of claim 4 wherein the polymeric matrix is formed of a polymer selected from the group consisting of polyanhydrides, polyhydroxy acids, polyphosphazenes, polyorthoesters, polyesters, polyamides, polysaccharides, polyproteins and copolymers and blends thereof.
8. The composition of claim 1 wherein the polymeric matrix is formed of ethylene vinyl acetate.
9. The composition of claim 1 further comprising biologically active compounds selected from the group consisting of other chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof.
10. A method of administering to a patient in need of treatment a relatively water insoluble, relatively lipid insoluble chemotherapeutic agent comprising administering an amount of the chemotherapeutic agent effective to inhibit growth of a solid tumor locally near or in the tumor, wherein the systemic administration of the same dosage of chemotherapeutic agent is not effective to treat tumors and wherein the chemotherapeutic agent does not cross the blood-brain barrier in an amount effective to inhibit growth of a solid tumor when administered systemically and is not paclitaxel.
12. The method of claim 10 wherein the chemotherapeutic agent is camptothecin or a functionally effective derivative.
13. The method of claim 10 wherein the chemotherapeutic agent is locally delivered by direct infusion to the tumor from a reservoir.
14. The method of claim 10 wherein the chemotherapeutic agent is locally delivered by implantation of a biocompatible polymer matrix incorporating the chemotherapeutic agent.
15. The method of claim 14 wherein the polymer matrix is biodegradable.
16. The method of claim 15 wherein the polymeric matrix is formed of a polymer selected from the group consisting of polyanhydrides, polyhydroxy acids, polyphosphazenes, polyorthoesters, polyesters, polyamides, polysaccharides, polyproteins, and copolymers and blends thereof.
17. The method of claim 14 wherein the polymeric matrix is formed of ethylene vinyl acetate.
18. The method of claim 10 further comprising administering radiation in combination with the composition.
19. The method of claim 19 further comprising administering with the chemotherapeutic agent biologically active compounds selected from the group consisting of other chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof.
20. The method of claim 10 wherein the composition is in the form of micro-implants and are administered by injection or infusion.
3. The composition of claim 1 wherein the chemotherapeutic agent is camptothecin or a functionally effective derivative.
4. The composition of claim 1 wherein the polymer matrix is biodegradable.
7. The composition of claim 4 wherein the polymeric matrix is formed of a polymer selected from the group consisting of polyanhydrides, polyhydroxy acids, polyphosphazenes, polyorthoesters, polyesters, polyamides, polysaccharides, polyproteins and copolymers and blends thereof.
8. The composition of claim 1 wherein the polymeric matrix is formed of ethylene vinyl acetate.
9. The composition of claim 1 further comprising biologically active compounds selected from the group consisting of other chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof.
10. A method of administering to a patient in need of treatment a relatively water insoluble, relatively lipid insoluble chemotherapeutic agent comprising administering an amount of the chemotherapeutic agent effective to inhibit growth of a solid tumor locally near or in the tumor, wherein the systemic administration of the same dosage of chemotherapeutic agent is not effective to treat tumors and wherein the chemotherapeutic agent does not cross the blood-brain barrier in an amount effective to inhibit growth of a solid tumor when administered systemically and is not paclitaxel.
12. The method of claim 10 wherein the chemotherapeutic agent is camptothecin or a functionally effective derivative.
13. The method of claim 10 wherein the chemotherapeutic agent is locally delivered by direct infusion to the tumor from a reservoir.
14. The method of claim 10 wherein the chemotherapeutic agent is locally delivered by implantation of a biocompatible polymer matrix incorporating the chemotherapeutic agent.
15. The method of claim 14 wherein the polymer matrix is biodegradable.
16. The method of claim 15 wherein the polymeric matrix is formed of a polymer selected from the group consisting of polyanhydrides, polyhydroxy acids, polyphosphazenes, polyorthoesters, polyesters, polyamides, polysaccharides, polyproteins, and copolymers and blends thereof.
17. The method of claim 14 wherein the polymeric matrix is formed of ethylene vinyl acetate.
18. The method of claim 10 further comprising administering radiation in combination with the composition.
19. The method of claim 19 further comprising administering with the chemotherapeutic agent biologically active compounds selected from the group consisting of other chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof.
20. The method of claim 10 wherein the composition is in the form of micro-implants and are administered by injection or infusion.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US284,341 | 1994-08-02 | ||
US08/284,341 US5626862A (en) | 1994-08-02 | 1994-08-02 | Controlled local delivery of chemotherapeutic agents for treating solid tumors |
PCT/US1995/009805 WO1996003984A1 (en) | 1994-08-02 | 1995-08-02 | Controlled local delivery of chemotherapeutic agents for treating solid tumors |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2196304A1 true CA2196304A1 (en) | 1996-02-15 |
CA2196304C CA2196304C (en) | 2011-02-15 |
Family
ID=23089835
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2196304A Expired - Lifetime CA2196304C (en) | 1994-08-02 | 1995-08-02 | Controlled local delivery of chemotherapeutic agents for treating solid tumors |
Country Status (9)
Country | Link |
---|---|
US (4) | US5626862A (en) |
EP (1) | EP0774964B1 (en) |
JP (1) | JPH10505587A (en) |
AT (1) | ATE290860T1 (en) |
CA (1) | CA2196304C (en) |
DE (1) | DE69534080T2 (en) |
ES (1) | ES2243940T3 (en) |
PT (1) | PT774964E (en) |
WO (1) | WO1996003984A1 (en) |
Cited By (1)
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US11191853B2 (en) | 2014-08-15 | 2021-12-07 | The Johns Hopkins University | Post-surgical imaging marker |
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US5395850A (en) * | 1994-03-10 | 1995-03-07 | Bristol-Myers Squibb Company | 6,7-epoxy paclitaxels |
-
1994
- 1994-08-02 US US08/284,341 patent/US5626862A/en not_active Expired - Lifetime
-
1995
- 1995-08-02 EP EP95928721A patent/EP0774964B1/en not_active Revoked
- 1995-08-02 AT AT95928721T patent/ATE290860T1/en not_active IP Right Cessation
- 1995-08-02 WO PCT/US1995/009805 patent/WO1996003984A1/en active IP Right Grant
- 1995-08-02 ES ES95928721T patent/ES2243940T3/en not_active Expired - Lifetime
- 1995-08-02 JP JP8506742A patent/JPH10505587A/en active Pending
- 1995-08-02 CA CA2196304A patent/CA2196304C/en not_active Expired - Lifetime
- 1995-08-02 US US08/750,736 patent/US5846565A/en not_active Expired - Lifetime
- 1995-08-02 PT PT95928721T patent/PT774964E/en unknown
- 1995-08-02 DE DE69534080T patent/DE69534080T2/en not_active Revoked
-
1996
- 1996-06-14 US US08/663,711 patent/US5651986A/en not_active Ceased
-
1999
- 1999-07-29 US US09/363,519 patent/USRE37410E1/en not_active Expired - Lifetime
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11191853B2 (en) | 2014-08-15 | 2021-12-07 | The Johns Hopkins University | Post-surgical imaging marker |
Also Published As
Publication number | Publication date |
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EP0774964A1 (en) | 1997-05-28 |
PT774964E (en) | 2005-08-31 |
US5846565A (en) | 1998-12-08 |
USRE37410E1 (en) | 2001-10-16 |
DE69534080D1 (en) | 2005-04-21 |
ES2243940T3 (en) | 2005-12-01 |
JPH10505587A (en) | 1998-06-02 |
EP0774964B1 (en) | 2005-03-16 |
CA2196304C (en) | 2011-02-15 |
WO1996003984A1 (en) | 1996-02-15 |
US5626862A (en) | 1997-05-06 |
ATE290860T1 (en) | 2005-04-15 |
US5651986A (en) | 1997-07-29 |
DE69534080T2 (en) | 2006-04-13 |
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