WO1985000968A1 - Procede d'administration de liposomes servant a diminuer la toxicite d'un medicament antitumoral - Google Patents

Procede d'administration de liposomes servant a diminuer la toxicite d'un medicament antitumoral Download PDF

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Publication number
WO1985000968A1
WO1985000968A1 PCT/US1984/001431 US8401431W WO8500968A1 WO 1985000968 A1 WO1985000968 A1 WO 1985000968A1 US 8401431 W US8401431 W US 8401431W WO 8500968 A1 WO8500968 A1 WO 8500968A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
alpha
tocopherol
liposomes
toxicity
Prior art date
Application number
PCT/US1984/001431
Other languages
English (en)
Inventor
Eric Mayhew
Youcef M. Rustum
Fred C. Olson
David E. Maslow
Francis C. Szoka
Original Assignee
Health Research, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Health Research, Inc. filed Critical Health Research, Inc.
Publication of WO1985000968A1 publication Critical patent/WO1985000968A1/fr

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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

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.
PCT/US1984/001431 1983-09-06 1984-09-06 Procede d'administration de liposomes servant a diminuer la toxicite d'un medicament antitumoral WO1985000968A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52989083A 1983-09-06 1983-09-06
US529,890 1983-09-06

Publications (1)

Publication Number Publication Date
WO1985000968A1 true WO1985000968A1 (fr) 1985-03-14

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1984/001431 WO1985000968A1 (fr) 1983-09-06 1984-09-06 Procede d'administration de liposomes servant a diminuer la toxicite d'un medicament antitumoral

Country Status (2)

Country Link
EP (1) EP0153955A1 (fr)
WO (1) WO1985000968A1 (fr)

Cited By (40)

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US4769250A (en) * 1985-10-15 1988-09-06 Vestar, Inc. Antracycline antineoplastic agents encapsulated in phospholipid vesicle particles and methods for using same for tumor therapy
US4861580A (en) * 1985-10-15 1989-08-29 The Liposome Company, Inc. Composition using salt form of organic acid derivative of alpha-tocopheral
US4923854A (en) * 1986-01-22 1990-05-08 The Liposome Company, Inc. Solubilization of hydrophobic materials using lysophospholipid
US4946683A (en) * 1987-11-18 1990-08-07 Vestar, Inc. Multiple step entrapment/loading procedure for preparing lipophilic drug-containing liposomes
US4981690A (en) * 1987-10-27 1991-01-01 Board Of Regents, The University Of Texas System Liposome-incorporated mepartricin
US5041278A (en) * 1985-10-15 1991-08-20 The Liposome Company, Inc. Alpha tocopherol-based vesicles
US5049392A (en) * 1989-01-18 1991-09-17 The Liposome Company, Inc. Osmotically dependent vesicles
EP0464135A1 (fr) * 1989-03-13 1992-01-08 Kenneth Naoyuki Matsumura Procede de reduction des effets secondaires d'un medicament.
US5082664A (en) * 1987-05-22 1992-01-21 The Liposome Company, Inc. Prostaglandin-lipid formulations
US5132290A (en) * 1988-01-19 1992-07-21 The Board Of Regents, The University Of Texas System Esters of 3'-deaminodoxorubicin and liposomal compositions thereof
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
US5262168A (en) * 1987-05-22 1993-11-16 The Liposome Company, Inc. Prostaglandin-lipid formulations
US5364631A (en) * 1987-10-19 1994-11-15 The Liposome Company, Inc. Tocopherol-based pharmaceutical systems
EP0655239A1 (fr) * 1993-11-25 1995-05-31 Lipotec, S.A. Liposomes encapsulant de la doxorubicine
US5556580A (en) * 1987-04-16 1996-09-17 The Liposome Company, Inc. Liposome continuous size reduction method and apparatus
US5614214A (en) * 1993-05-21 1997-03-25 The Liposome Company, Inc. Reduction of liposome-induced adverse physiological reactions
US5616334A (en) * 1987-03-05 1997-04-01 The Liposome Company, Inc. Low toxicity drug-lipid systems
US5616341A (en) * 1987-03-05 1997-04-01 The Liposome Company, Inc. High drug:lipid formulations of liposomal antineoplastic agents
WO1999027908A1 (fr) * 1997-12-04 1999-06-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Traitement chimio et immunotherapeutique combine a l'aide de medicaments et de cytokines encapsules dans des liposomes
US5925375A (en) * 1987-05-22 1999-07-20 The Liposome Company, Inc. Therapeutic use of multilamellar liposomal prostaglandin formulations
US5948441A (en) * 1988-03-07 1999-09-07 The Liposome Company, Inc. Method for size separation of particles
US6406713B1 (en) 1987-03-05 2002-06-18 The Liposome Company, Inc. Methods of preparing low-toxicity drug-lipid complexes
EP1435231A1 (fr) * 2002-12-31 2004-07-07 Bharat Serums & Vaccines Ltd. Liposomes non-pegylés à longue durée de circulation
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
US7153490B2 (en) 2000-10-10 2006-12-26 Lipotec, Sa Liposomes encapsulating anticancer drugs and use thereof in the treatment of malignant tumors
US9107824B2 (en) 2005-11-08 2015-08-18 Insmed Incorporated Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally
US9114081B2 (en) 2007-05-07 2015-08-25 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9119783B2 (en) 2007-05-07 2015-09-01 Insmed Incorporated Method 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
US9402845B2 (en) 2005-12-08 2016-08-02 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9566234B2 (en) 2012-05-21 2017-02-14 Insmed Incorporated Systems for treating pulmonary infections
US9827317B2 (en) 2002-10-29 2017-11-28 Insmed Incorporated Sustained release of antiinfectives
US9895385B2 (en) 2014-05-15 2018-02-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US9925205B2 (en) 2007-05-04 2018-03-27 Insmed Incorporated Compositions of multicationic drugs for reducing interactions with polyanionic biomolecules and methods of use thereof
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
US10363226B2 (en) 2015-08-12 2019-07-30 North Carolina State University Platelet membrane-coated drug delivery system
US11291644B2 (en) 2012-09-04 2022-04-05 Eleison Pharmaceuticals, Llc Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products

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Cited By (78)

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US5330689A (en) * 1985-10-15 1994-07-19 The Liposome Company, Inc. Entrapment of water-insoluble compound in alpha tocopherol-based vesicles
US4861580A (en) * 1985-10-15 1989-08-29 The Liposome Company, Inc. Composition using salt form of organic acid derivative of alpha-tocopheral
US4769250A (en) * 1985-10-15 1988-09-06 Vestar, Inc. Antracycline antineoplastic agents encapsulated in phospholipid vesicle particles and methods for using same for tumor therapy
US5041278A (en) * 1985-10-15 1991-08-20 The Liposome Company, Inc. Alpha tocopherol-based vesicles
EP0460720A2 (fr) * 1985-10-15 1991-12-11 The Liposome Company, Inc. Procédé pour extruder des liposomes
EP0460720A3 (en) * 1985-10-15 1992-01-02 The Liposome Company, Inc. A method of extruding liposomes
US5234634A (en) * 1985-10-15 1993-08-10 The Liposome Company, Inc. Method for preparing alpha-tocopherol vesicles
US4756910A (en) * 1985-11-29 1988-07-12 Kabushiki Kaisha Vitamin Kenkyusyo Adriamycin-entrapping 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
US5376452A (en) * 1986-06-16 1994-12-27 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
US5616341A (en) * 1987-03-05 1997-04-01 The Liposome Company, Inc. High drug:lipid formulations of liposomal antineoplastic agents
US5795589A (en) * 1987-03-05 1998-08-18 The Liposome Company, Inc. Liposomal antineoplastic agent compositions
US6083530A (en) * 1987-03-05 2000-07-04 The Liposome Company, Inc. High drug:lipid formulations of liposomal-antineoplastic agents
US5744158A (en) * 1987-03-05 1998-04-28 The Liposome Company, Inc. Methods of treatment using high drug-lipid formulations of liposomal-antineoplastic agents
US5616334A (en) * 1987-03-05 1997-04-01 The Liposome Company, Inc. Low toxicity drug-lipid systems
US6406713B1 (en) 1987-03-05 2002-06-18 The Liposome Company, Inc. Methods of preparing low-toxicity drug-lipid complexes
US5556580A (en) * 1987-04-16 1996-09-17 The Liposome Company, Inc. Liposome continuous size reduction method and apparatus
US5262168A (en) * 1987-05-22 1993-11-16 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
US5082664A (en) * 1987-05-22 1992-01-21 The Liposome Company, Inc. Prostaglandin-lipid formulations
US5364631A (en) * 1987-10-19 1994-11-15 The Liposome Company, Inc. Tocopherol-based pharmaceutical systems
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
US5132290A (en) * 1988-01-19 1992-07-21 The Board Of Regents, The University Of Texas System Esters of 3'-deaminodoxorubicin and liposomal compositions thereof
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
EP0464135A1 (fr) * 1989-03-13 1992-01-08 Kenneth Naoyuki Matsumura Procede de reduction des effets secondaires d'un medicament.
EP0464135A4 (en) * 1989-03-13 1992-04-01 Kenneth Naoyuki Matsumura Method for reducing side effects of a drug
US5614214A (en) * 1993-05-21 1997-03-25 The Liposome Company, Inc. Reduction of liposome-induced adverse physiological reactions
US5662930A (en) * 1993-05-21 1997-09-02 The Liposome Company, Inc. Reduction of liposome-induced adverse physiological reactions
WO1995014459A1 (fr) * 1993-11-25 1995-06-01 Lipotec, S.A. Liposomes d'encapsulation de la doxorubicine
EP0655239A1 (fr) * 1993-11-25 1995-05-31 Lipotec, S.A. Liposomes encapsulant de la doxorubicine
ES2072223A1 (es) * 1993-11-25 1995-07-01 Lipotec Sa Liposomas encapsulando doxorubicina.
US5605703A (en) * 1993-11-25 1997-02-25 Lipotec, S.A. Liposomes encapsulating doxorubicin
WO1999027908A1 (fr) * 1997-12-04 1999-06-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Traitement chimio et immunotherapeutique combine a l'aide de medicaments et de cytokines encapsules dans des liposomes
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
US7153490B2 (en) 2000-10-10 2006-12-26 Lipotec, Sa Liposomes encapsulating anticancer drugs and use thereof in the treatment of malignant tumors
US9827317B2 (en) 2002-10-29 2017-11-28 Insmed Incorporated Sustained release of antiinfectives
EP1435231A1 (fr) * 2002-12-31 2004-07-07 Bharat Serums & Vaccines Ltd. Liposomes non-pegylés à longue durée de circulation
AU2003303368B2 (en) * 2002-12-31 2010-06-17 Zydus Bsv Pharma Private Limited Non-pegylated long-circulating liposomes
US9107824B2 (en) 2005-11-08 2015-08-18 Insmed Incorporated Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally
US9402845B2 (en) 2005-12-08 2016-08-02 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
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EP4122470A1 (fr) 2014-05-15 2023-01-25 Insmed Incorporated Méthodes de traitement d'infections pulmonaires mycobactériennes non-tuberculeuses
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

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