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WO2002094269A1 - Substances actives hydrophobes a encapsulation liposomale presentant une teneur elevee en substances actives $m(g) 50% et procede pour produire des preparations pharmaceutiques renfermant des substances actives hydrophobes a encapsulation liposomale - Google Patents

Substances actives hydrophobes a encapsulation liposomale presentant une teneur elevee en substances actives $m(g) 50% et procede pour produire des preparations pharmaceutiques renfermant des substances actives hydrophobes a encapsulation liposomale

Info

Publication number
WO2002094269A1
WO2002094269A1 PCT/DE2002/001916 DE0201916W WO02094269A1 WO 2002094269 A1 WO2002094269 A1 WO 2002094269A1 DE 0201916 W DE0201916 W DE 0201916W WO 02094269 A1 WO02094269 A1 WO 02094269A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
liposomally encapsulated
camptothecin
hydrophobic
active substance
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.)
Ceased
Application number
PCT/DE2002/001916
Other languages
German (de)
English (en)
Inventor
Regina Reszka
Peter Scherrer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
G O T Therapeutics GmbH
Original Assignee
G O T Therapeutics GmbH
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 G O T Therapeutics GmbH filed Critical G O T Therapeutics GmbH
Publication of WO2002094269A1 publication Critical patent/WO2002094269A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers

Definitions

  • the invention relates to liposomally encapsulated hydrophobic active ingredients, preferably liposomally encapsulated camptothecin or analogs of camptothecin, the liposomes having a high active ingredient content of> 50%. Furthermore, the invention relates to pharmaceutical preparations which comprise liposomally encapsulated hydrophobic active substances, preferably liposomally encapsulated camptothecin or analogues of camptothecin. They are produced by high-pressure homogenization, preferably with the prior formation of a liposome gel into which the active ingredient diffuses in solution or with the formation of aerosols.
  • the present invention provides highly stable, pharmaceutically active preparations of hydrophobic active substances which are intrinsically difficult to use. They are preferably camptothecin preparations which, after their liposomal encapsulation, are water-soluble and which are suitable for the treatment of various forms of cancer.
  • Camptothecin is a plant alkaloid. It is thought to inhibit cancer cells through interactions with the topoisomerase enzyme. So far, its anti-tumor efficacy has been demonstrated on colon cancer, lung cancer and breast cancer, among others.
  • Camptothecin and many of its analogues e.g. 9-aminocamptothecin, 10-hydroxy camptothecin, 10,11-methylenedioxycamptothecin, 9-nitro-10, l 1-methylenedioxy-camptothecin, 9-chloro-10, 11-methylenedioxycamptothecin, 9-amino-10, 11-methylene-dioxycamptothecin, 9 -Nitrocamptothecin and others are hydrophobic and show little or no solubility, which in turn limits their use as a pharmaceutical preparation.
  • a chemical modification to increase their water solubility leads to a reduction in anti-tumor activity.
  • camptothecin and its analogs as medicaments has been described, for example, in US Pat. No. 5,736,156.
  • the liposomal preparations shown there have the major disadvantage that the inclusion rate for the active ingredient camptothecin or its analogs in the liposomes is below 20%.
  • the object of the invention was therefore to provide hydrophobic active substances, in particular camptothecin or its analogs, in a pharmaceutical dosage form which enables effective, effective application.
  • liposome gels are first produced by means of high-pressure homogenization.
  • the hydrophobic active ingredients are then allowed to diffuse into the gels in aqueous or alcoholic solution.
  • the buffer solutions (pH, salts, ions, ion length), which ensure optimal stability of camptothecin, are preferably in the weakly acidic range.
  • the charge on the liposome gels can be increased by increasing the temperature.
  • the liposome gel formed contains in or on the membrane of the vesicles a polymer, preferably polyethylene glycol (MW 2000-10000), which protects the active substance on the liposome surface from inactivity with blood components.
  • a polymer preferably polyethylene glycol (MW 2000-10000), which protects the active substance on the liposome surface from inactivity with blood components.
  • the liposome gel can be sterilized (e.g. in an autoclave) in the absence of the active ingredient, which protects the active ingredient and also prevents active ingredient / lipid degradation.
  • the active ingredient is not exposed to extreme loads (physical or high temperatures) during high pressure homogenization.
  • a depot application with slow release on liposomes is possible.
  • the dosage of active substance can be varied with a constant lipid dose.
  • the bioavailability should therefore be independent of the drug dosage.
  • the Geldepot enables the active ingredient to be released slowly (high permeability).
  • the drug release rate can be regulated by adjusting the lipid composition in the liposomes.
  • compositions comprising encapsulated camptothecin and its analogs according to the invention are applied in particular to melanoma, colon cancer, small cell & non-small cell lung cancer, stomach cancer, leukemia, breast cancer and others.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des substances actives hydrophobes à encapsulation liposomale, de préférence de la camptothécine à encapsulation liposomale ou des analogues de camptothécine. Les liposomes présentent une teneur élevée en substances actives qui est >/= 50%. La présente invention concerne également des préparations pharmaceutiques qui renferment des substances actives hydrophobes à encapsulation liposomale, de préférence de la camptothécine à encapsulation liposomale ou des analogues de camptothécine. Ces préparations sont produites par homogénéisation sous haute pression, de préférence avec formation préalable d'un gel liposomal dans lequel la substance active se diffuse en solution ou avec formation d'un aérosol.
PCT/DE2002/001916 2001-05-25 2002-05-27 Substances actives hydrophobes a encapsulation liposomale presentant une teneur elevee en substances actives $m(g) 50% et procede pour produire des preparations pharmaceutiques renfermant des substances actives hydrophobes a encapsulation liposomale Ceased WO2002094269A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10157994.2 2001-05-25
DE2001157994 DE10157994A1 (de) 2001-05-25 2001-05-25 Liposomal verkapselte hydrophobe Wirkstoffe mit hohem Wirkstoffgehalt >50% sowie Verfahren zur Herstellung pharmazeutischer Zubereitungen, die liposomal verkapselte hydrophobe Wirkstoffe umfassen

Publications (1)

Publication Number Publication Date
WO2002094269A1 true WO2002094269A1 (fr) 2002-11-28

Family

ID=7707025

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2002/001916 Ceased WO2002094269A1 (fr) 2001-05-25 2002-05-27 Substances actives hydrophobes a encapsulation liposomale presentant une teneur elevee en substances actives $m(g) 50% et procede pour produire des preparations pharmaceutiques renfermant des substances actives hydrophobes a encapsulation liposomale

Country Status (2)

Country Link
DE (1) DE10157994A1 (fr)
WO (1) WO2002094269A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102024112307A1 (de) * 2024-05-02 2025-11-06 INM - Leibniz-Institut für Neue Materialien gemeinnützige Gesellschaft mit beschränkter Haftung Kompositpartikel

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008986A1 (fr) * 1993-09-27 1995-04-06 Smithkline Beecham Corporation Compositions de camptothecine
WO1996015774A1 (fr) * 1994-11-18 1996-05-30 Aphios Corporation Procedes et dispositifs de confection de liposome contenant des medicaments hydrophobes
US5736156A (en) * 1995-03-22 1998-04-07 The Ohio State University Liposomal anf micellular stabilization of camptothecin drugs
WO1999013816A2 (fr) * 1997-09-16 1999-03-25 Nexstar Pharmaceuticals, Inc. Compositions a base de liposomes renfermant de la camptothecine
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
US6090407A (en) * 1997-09-23 2000-07-18 Research Development Foundation Small particle liposome aerosols for delivery of anti-cancer drugs

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008986A1 (fr) * 1993-09-27 1995-04-06 Smithkline Beecham Corporation Compositions de camptothecine
WO1996015774A1 (fr) * 1994-11-18 1996-05-30 Aphios Corporation Procedes et dispositifs de confection de liposome contenant des medicaments hydrophobes
US5736156A (en) * 1995-03-22 1998-04-07 The Ohio State University Liposomal anf micellular stabilization of camptothecin drugs
WO1999013816A2 (fr) * 1997-09-16 1999-03-25 Nexstar Pharmaceuticals, Inc. Compositions a base de liposomes renfermant de la camptothecine
US6090407A (en) * 1997-09-23 2000-07-18 Research Development Foundation Small particle liposome aerosols for delivery of anti-cancer drugs
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

Also Published As

Publication number Publication date
DE10157994A1 (de) 2003-01-02

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