EP0153955A1 - Liposome delivery method for decreasing the toxicity of an antitumor drug - Google Patents
Liposome delivery method for decreasing the toxicity of an antitumor drugInfo
- Publication number
- EP0153955A1 EP0153955A1 EP19840903412 EP84903412A EP0153955A1 EP 0153955 A1 EP0153955 A1 EP 0153955A1 EP 19840903412 EP19840903412 EP 19840903412 EP 84903412 A EP84903412 A EP 84903412A EP 0153955 A1 EP0153955 A1 EP 0153955A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- drug
- alpha
- tocopherol
- liposomes
- toxicity
- 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.)
- Withdrawn
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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
Definitions
- the method comprises trapping the drug and a drug-protective compound, at a selected ratio, in the same lipid bilayer vesicles.
- the drug-protective compound is one which itself decreases the toxicity of the drug when both compounds are administered in free form.
- the anti-tumor drug is AM
- the drug-protective compound is alpha-tocopherol
- the toxicity of AM when encapsulated in liposomes containing alpha-tocopherol is decreased more than about 60% over that of AM entrapped in vesicles containing no alpha-tocopherol. It is one object of the invention, therefore, to provide a novel method for reducing the toxicity of drugs.
- a more particular object of the invention is to provide a method for reducing the toxicity of an anti-tumor drug, such as AM. by including the drug in liposomes also containing a drug-protective compound, such as alpha-tocopherol.
- Still another object of the invention is to provide such a method which is applicable to a wide range of drugs and drug-protective compounds, both soluble and lipophilic.
- a further object of the invention is to provide a therapeutic agent comprising liposomes containing an entrapped anti-tumor drug, such as AM, and a coentrapped drug-protective compound. 5
- Multilamellar liposomes were made by first mixing 60 ⁇ oles of a 1:4:4 molar ratio mixture of phosphatidylglycerol; phophatidylcholine and cholesterol (in chloroform) with 1.5 mg AM (in methanol) and 0.6
- the therapeutic effects of AM were tested using DBA 2J mice injected intraperitoneally with 10 L1210 leukemia cells.
- the animals were treated one day later by intravenous injection of AM, either in the form of free AM, liposomes entrapping AM only (AM/liposomes). or liposomes entrapping both AM and alpha-tocopherol (AM-aT/liposomes) .
- the dosages of AM administered expressed in milligrams AM per kilogram animal body weight, are given at the left in Table I below.
- the day of death of the animals was recorded, and the mean survival time of each group was calculated. Each group contained from between 6 and 10 mice. The mean survival time and calculated standard deviations are shown at the three columns at the right in Table I.
- AM-aT/liposomes in doses of 2, 5, 10, 15, 20, 25, 30. 50, 75, 100 mg AM per kg animal body weight.
- the data are expressed in terms of LD ⁇ o , i.e., the dosage (in mg drug per kilogram of animal body weight) which produces death in half the animals receiving the drug.
- the upper row in Table II gives the D 5 _ data for mice dying within 14 days after drug administration (acute), the lower row, for mice dying between 50 and 120 days after drug administration (chronic).
- the number of mice available for determination of chronic toxicity (survival of acute toxicity) varied from between about 2 and 10 mice per group.
- Mean LD 5 _ (mg/kg) +.S.D. free AM AM/liposomes AM-aT/liposomes acute 20 +5 45 ⁇ 5 >75 chronic 12 +5 30 +5 50
- drug-protective liposomes described herein had an alpha-tocopherol to total lipid ratio of about 1:100.
- the ratio of alpha-tocopherol to total liposome lipids can be made much greater, preferably in the molar ratio range of 1:20 to 1:5, i.e.. between about 5 and 20 mole percent alpha-tocopherol.
- a preferred therapeutic agent of the invention comprises liposomes containing phospholipid.
- cholesterol, alpha-tocopherol succinate and AM at molar percentages of between about 30% and 70%, 20% and 50%, 5% and 20% and 0.2% and 15%, respectively.
- the data supports the concept of using liposomes to carry more than one agent simultaneously, where one of the agents is a drug and the other agent is either a drug-protective compound, such as disclosed herein, or a drug-potentiating compound which promotes the action of the drug at the site of drug delivery.
- examples of other drug-protective compounds which have been shown to reduce anthracycline cardiac toxicity when administered in free form, include hydroxybutylated toluene, N-acetylcysteine (reference 15) and niacin and isocitrate (reference 16). In practicing the method of the present invention, these compounds would be coentrapped, for example, at encapsulated concentrations of between about 5-100 mg/ml in anthracycline-containing liposomes. to produce an enhanced reduction in drug toxicity.
- Compounds that potentiate anthracycline activity include agents that block calcium uptake, such as verapamil (reference 17). compounds that interfere with calcium mobilization from an intracellular store, such as 8-(N,N-diethylamino)-octyl-3. 4,5-trimethoxy- benzoate (TMB-8) (reference 18), or compounds that interfere with calcium binding to the protein
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Procédé visant à diminuer la toxicité d'un médicament antitumoral. Le médicament est emprisonné dans des liposomes contenant également un composé protecteur contre les effets secondaires du médicament.A method of decreasing the toxicity of an anti-tumor drug. The drug is trapped in liposomes also containing a protective compound against the side effects of the drug.
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52989083A | 1983-09-06 | 1983-09-06 | |
US529890 | 1995-09-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0153955A1 true EP0153955A1 (en) | 1985-09-11 |
Family
ID=24111649
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19840903412 Withdrawn EP0153955A1 (en) | 1983-09-06 | 1984-09-06 | Liposome delivery method for decreasing the toxicity of an antitumor drug |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP0153955A1 (en) |
WO (1) | WO1985000968A1 (en) |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4861580A (en) * | 1985-10-15 | 1989-08-29 | The Liposome Company, Inc. | Composition using salt form of organic acid derivative of alpha-tocopheral |
IE58981B1 (en) * | 1985-10-15 | 1993-12-15 | Vestar Inc | Anthracycline antineoplastic agents encapsulated in phospholipid micellular particles |
US5041278A (en) * | 1985-10-15 | 1991-08-20 | The Liposome Company, Inc. | Alpha tocopherol-based vesicles |
JPH0617309B2 (en) * | 1985-11-29 | 1994-03-09 | 株式会社ビタミン研究所 | Adriamycin embedded liposome preparation |
US4923854A (en) * | 1986-01-22 | 1990-05-08 | The Liposome Company, Inc. | Solubilization of hydrophobic materials using lysophospholipid |
US5204112A (en) * | 1986-06-16 | 1993-04-20 | The Liposome Company, Inc. | Induction of asymmetry in vesicles |
US5252263A (en) * | 1986-06-16 | 1993-10-12 | The Liposome Company, Inc. | Induction of asymmetry in vesicles |
MX9203808A (en) * | 1987-03-05 | 1992-07-01 | Liposome Co Inc | HIGH DRUG CONTENT FORMULATIONS: LIPID, FROM LIPOSOMIC-ANTINEOPLASTIC AGENTS. |
US6406713B1 (en) | 1987-03-05 | 2002-06-18 | The Liposome Company, Inc. | Methods of preparing low-toxicity drug-lipid complexes |
US5616334A (en) * | 1987-03-05 | 1997-04-01 | The Liposome Company, Inc. | Low toxicity drug-lipid systems |
JPH02502978A (en) * | 1987-04-16 | 1990-09-20 | ザ リポソーム カンパニー,インコーポレイテッド | Method and device for continuous size reduction of liposomes |
US5082664A (en) * | 1987-05-22 | 1992-01-21 | The Liposome Company, Inc. | Prostaglandin-lipid formulations |
US5925375A (en) * | 1987-05-22 | 1999-07-20 | The Liposome Company, Inc. | Therapeutic use of multilamellar liposomal prostaglandin formulations |
US5262168A (en) * | 1987-05-22 | 1993-11-16 | The Liposome Company, Inc. | Prostaglandin-lipid formulations |
MX9203804A (en) * | 1987-10-19 | 1992-07-01 | Liposome Co Inc | PHARMACEUTICAL SYSTEMS BASED ON TOCOPHEROL. |
US4981690A (en) * | 1987-10-27 | 1991-01-01 | Board Of Regents, The University Of Texas System | Liposome-incorporated mepartricin |
US4946683A (en) * | 1987-11-18 | 1990-08-07 | Vestar, Inc. | Multiple step entrapment/loading procedure for preparing lipophilic drug-containing liposomes |
WO1989006654A1 (en) * | 1988-01-19 | 1989-07-27 | Board Of Regents, The University Of Texas System | Glycosides, liposomal compositions thereof, and methods for their use |
US5948441A (en) * | 1988-03-07 | 1999-09-07 | The Liposome Company, Inc. | Method for size separation of particles |
US5049392A (en) * | 1989-01-18 | 1991-09-17 | The Liposome Company, Inc. | Osmotically dependent vesicles |
DE69027598T2 (en) * | 1989-03-13 | 1996-10-31 | Kenneth N Matsumura | COMPOSITION TO REDUCE THE SIDE EFFECTS OF A MEDICINAL PRODUCT |
DE1118326T1 (en) * | 1993-05-21 | 2002-04-18 | Liposome Co Inc | Reduction of physiological counter-reactions induced by liposomes |
ES2072223B1 (en) * | 1993-11-25 | 1996-03-16 | Lipotec Sa | LIPOSOMES ENCAPSULATING DOXORUBICIN. |
IL136343A0 (en) * | 1997-12-04 | 2001-05-20 | Yissum Res Dev Co | Combined chemo-immunotherapy with liposomal drugs and cytokines |
US6787132B1 (en) | 1997-12-04 | 2004-09-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Combined chemo-immunotherapy with liposomal drugs and cytokines |
ES2186484B1 (en) | 2000-10-10 | 2004-07-01 | Lipotec, S.A. | LIPOSOMES ENCAPSULATING ANTI-CANCER DRUGS AND USE OF THEM IN THE TREATMENT OF EVIL TUMORS. |
US7718189B2 (en) | 2002-10-29 | 2010-05-18 | Transave, Inc. | Sustained release of antiinfectives |
KR101171045B1 (en) * | 2002-12-31 | 2012-08-03 | 자이더스 비에스브이 파마 프라이빗 리미티드 | Composition Comprising A Long-Circulating Non-Pegylated Liposomes and Its Manufacture |
US9107824B2 (en) | 2005-11-08 | 2015-08-18 | Insmed Incorporated | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
CA2838111C (en) | 2005-12-08 | 2016-01-19 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
US20100196455A1 (en) | 2007-05-04 | 2010-08-05 | Transave, Inc. | Compositions of Multicationic Drugs for Reducing Interactions with Polyanionic Biomolecules and Methods of Use Thereof |
US9119783B2 (en) | 2007-05-07 | 2015-09-01 | Insmed Incorporated | Method of treating pulmonary disorders with liposomal amikacin formulations |
US9114081B2 (en) | 2007-05-07 | 2015-08-25 | Insmed Incorporated | Methods of treating pulmonary disorders with liposomal amikacin formulations |
US9333214B2 (en) | 2007-05-07 | 2016-05-10 | Insmed Incorporated | Method for treating pulmonary disorders with liposomal amikacin formulations |
CN108743537B (en) | 2012-05-21 | 2021-06-11 | 英斯麦德公司 | System for treating pulmonary infections |
MX2015002842A (en) | 2012-09-04 | 2015-08-12 | Eleison Pharmaceuticals LLC | Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin. |
CN104884047A (en) | 2012-11-29 | 2015-09-02 | 英斯梅德股份有限公司 | Stabilized vancomycin formulations |
MX2016014921A (en) | 2014-05-15 | 2017-07-28 | Insmed In Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections. |
US10363226B2 (en) | 2015-08-12 | 2019-07-30 | North Carolina State University | Platelet membrane-coated drug delivery system |
US11571386B2 (en) | 2018-03-30 | 2023-02-07 | Insmed Incorporated | Methods for continuous manufacture of liposomal drug products |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3993754A (en) * | 1974-10-09 | 1976-11-23 | The United States Of America As Represented By The United States Energy Research And Development Administration | Liposome-encapsulated actinomycin for cancer chemotherapy |
US4263428A (en) * | 1978-03-24 | 1981-04-21 | The Regents Of The University Of California | Bis-anthracycline nucleic acid function inhibitors and improved method for administering the same |
IL55431A (en) * | 1978-08-24 | 1982-07-30 | Yeda Res & Dev | Anthracycline type antibiotics,their preparation and pharmaceutical compositions comprising them |
US4241046A (en) * | 1978-11-30 | 1980-12-23 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4419348A (en) * | 1981-04-27 | 1983-12-06 | Georgetown University | Anthracycline glycoside compositions, their use and preparation |
-
1984
- 1984-09-06 EP EP19840903412 patent/EP0153955A1/en not_active Withdrawn
- 1984-09-06 WO PCT/US1984/001431 patent/WO1985000968A1/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO8500968A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1985000968A1 (en) | 1985-03-14 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Designated state(s): AT BE CH DE FR GB LI LU NL SE |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 19850807 |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: MASLOW, DAVID, E. Inventor name: SZOKA, FRANCIS, C. Inventor name: RUSTUM, YOUCEF, M. Inventor name: OLSON, FRED, C. Inventor name: MAYHEW, ERIC |