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WO1997015289A1 - Procedes de solubilisation - Google Patents

Procedes de solubilisation Download PDF

Info

Publication number
WO1997015289A1
WO1997015289A1 PCT/GB1996/002609 GB9602609W WO9715289A1 WO 1997015289 A1 WO1997015289 A1 WO 1997015289A1 GB 9602609 W GB9602609 W GB 9602609W WO 9715289 A1 WO9715289 A1 WO 9715289A1
Authority
WO
WIPO (PCT)
Prior art keywords
agent
amphiphile
solulan
medicament
common solvent
Prior art date
Application number
PCT/GB1996/002609
Other languages
English (en)
Inventor
Roger Randal Charles New
Original Assignee
Cortecs (Uk) Limited
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 Cortecs (Uk) Limited filed Critical Cortecs (Uk) Limited
Priority to KR1019980702965A priority Critical patent/KR19990067028A/ko
Priority to JP9516406A priority patent/JP2000502990A/ja
Priority to AU73178/96A priority patent/AU704292B2/en
Priority to BR9611343-0A priority patent/BR9611343A/pt
Priority to NZ320442A priority patent/NZ320442A/en
Priority to EP96935083A priority patent/EP0857061A1/fr
Publication of WO1997015289A1 publication Critical patent/WO1997015289A1/fr
Priority to NO981864A priority patent/NO981864L/no

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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to methods of solubilising an agent, eg biologically active materials, in an amphiphile.
  • an agent eg biologically active materials
  • the invention relates to methods of bringing biologically active substances used for topical administration into association with permeation aids.
  • solubilisation it is a continuing objective of the pharmaceutical industry to achieve high degrees of solubilisation of biologically active materials in a variety of solvents. There are several reasons for this need to achieve solubilisation. For instance, achieving solubilisation in particular solvents may improve bioavailibility. An example of this would be the solubilisation of biologically active materials in oils. Examples of methods to achieve this can be found , for example, in WO 95/13795, WO 96/17593 and WO 96/17594.
  • the present invention provides a method of solubilising an agent in an amphiphile which method includes the steps of:
  • step (iii) heating the residue from step (ii) ;
  • step (i) the agent and the amphiphile can suitably be brought into association with each other by firstly dissolving each one separately in the common solvent, followed by mixing of the two resultant solutions.
  • the removal of the solvent should be carried out at a temperature such that the amphiphile/agent residue which remains is in the solid state.
  • the heating step should then be sufficient to melt the solid amphiphile, and also to convert the amphiphile/agent array from an "open" form to one which is more condensed.
  • the common solvent can be water, for example, and it can be removed in step (ii) by, e.g. freeze drying, centrifugal vacuum drying or any other suitable method.
  • the amphiphile will be a phospholipid, for instance lecithin, a glycolipid, a polyoxyethylene containing surfactant, a lipophilic sulphate, betaine, a sarcosine containing surfactant, Solulan 16, Solulan C24 , polyoxyethylene 40 stearate, one of the Tween series of surfactants, one of the Span series of surfactants or a pegolated castor oil derivative, e.g. Cremaphor EL35.
  • the "agent” is suitably a hydophilic species which is generally soluble in aqueous solvents but insoluble in hydrophobic solvents.
  • the range of hydrophilic species of use in the present invention is diverse but hydrophilic macromolecules represent an example of a species which may be used.
  • macromolecules are suitable for use in the present invention.
  • the macromolecular compound will be hydrophilic or will at least have hydrophilic regions since there is usually little difficulty in solubilising a hydrophobic macromolecuie in oily solutions.
  • suitable macromolecules include proteins and glycoproteins, oligo and polynucleic acids, for example DNA and RNA, polysaccharides and supramolecular assemblies of any of these including, in some cases, whole cells or organelles. It may also be convenient to co-solubilise a small molecule such as a vitamin in association with a macromolecuie, particularly a polysaccharide such as a cyclodextrin. Small molecules such as vitamin B12 may also be chemically conjugated with macromolecules and may thus be included in the compositions.
  • Other macromolecules may be used are FITC-labelled dextran and RNA extract from Torulla yeast .
  • the process of the present invention is of use in solubilising smaller organic molecules.
  • small organic molecules include glucose, carboxyfluorescin and many pharmaceutical
  • agents for example anti-cancer agents, but, of course, the process could equally be applied to other small organic molecules, for example vitamins or pharmaceutically or biologically active agents.
  • compounds such as calcium chloride and sodium
  • phosphate can also be solubilised using this process.
  • the present invention would be particularly advantageous for pharmaceutically and biologically active agents since the use of non aqueous solutions may enable the route by which the molecule enters the body to be
  • an inorganic material such as a small inorganic molecule or a colloidal substance, for example a colloidal metal.
  • a colloidal metal such as colloidal gold, palladium, platinum or rhodium
  • the above-described method is particularly suitable for achieving association between an agent which is for topical administration and a permeation aid.
  • An example of the former is Zinc Acetate (ZnAc 2 ) .
  • amphiphiles are those which are solid at room temperature, eg Solulan 16 and Solulan C24.
  • the present invention provides:
  • composition comprising an agent solubilised in an amphiphile obtainable by any of the methods described herein, particularly an agent for topical administration solubilised in an aphiphile which is a permeation aid; and
  • composition of the invention in the preparation of a medicament for topical administration, particularly a composition for use in the treatment of inflammation and/or arthritis wherein the active agent is ZnAc 2 .
  • a solution of zinc acetate at a concentration of lOOmg/ml was prepared by addition of lOOmg of ZnAc 2 to 1ml of distilled water, and mixing at RT until dissolution was achieved.
  • a solution of Solulan 16 at a concentration of lOOmg/ml was prepared by addition of 500mg of Solulan to 4.5ml of distilled water and mixing at 60°C until dissolution was achieved.
  • a solution of Solulan C24 at a concentration of lOOmg/ml was prepared by addition of 500mg of Solulan C24 to 4.5ml of distilled water and mixing at 60°C until dissolution was achieved.
  • a virus suspension (Sabin strains, Types 1, 2, 3) containing 5xl0 8 particles/ml (spun to remove contaminating protein) was diluted 50-fold by addition of 200 ⁇ l of the suspension to 9.9ml of distilled water, yielding a concentration of 10 7 particles/ml.
  • the suspension was divided into four equal aliquots of 2.5ml, and dispensed into 7ml screw-capped glass vials.
  • 2.5ml of distilled water was added to one aliquot of virus particles and this group was labelled "W” .
  • 2.5ml of Solulan C24 (lOOmg/ml) was added to another aliquot and mixed gently. This group was labelled "S”.
  • the suspensions prepared as described herein were used to perform 10-fold dilutions in Vero cell cultures,to measure the viability of the polio virus present. The results were expressed as the highest dilution at which 50% cytopathic effects were observed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Steroid Compounds (AREA)

Abstract

Ces procédés améliorés permettent de solubiliser des substances biologiquement actives, des protéines par exemple, dans un solvant hydrophobe.
PCT/GB1996/002609 1995-10-25 1996-10-25 Procedes de solubilisation WO1997015289A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
KR1019980702965A KR19990067028A (ko) 1995-10-25 1996-10-25 가용화 방법
JP9516406A JP2000502990A (ja) 1995-10-25 1996-10-25 可溶化方法
AU73178/96A AU704292B2 (en) 1995-10-25 1996-10-25 Solubilisation methods
BR9611343-0A BR9611343A (pt) 1995-10-25 1996-10-25 Processo de solubilização d eum agente em um anfifìlico, composição, e, uso da mesma.
NZ320442A NZ320442A (en) 1995-10-25 1996-10-25 Solubilisation methods of biologially active material in an amphiphile
EP96935083A EP0857061A1 (fr) 1995-10-25 1996-10-25 Procedes de solubilisation
NO981864A NO981864L (no) 1995-10-25 1998-04-24 Oppl°sningsmetoder

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9521805.3 1995-10-25
GBGB9521805.3A GB9521805D0 (en) 1995-10-25 1995-10-25 Solubilisation methods

Publications (1)

Publication Number Publication Date
WO1997015289A1 true WO1997015289A1 (fr) 1997-05-01

Family

ID=10782854

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/002609 WO1997015289A1 (fr) 1995-10-25 1996-10-25 Procedes de solubilisation

Country Status (12)

Country Link
EP (1) EP0857061A1 (fr)
JP (1) JP2000502990A (fr)
KR (1) KR19990067028A (fr)
CN (1) CN1202818A (fr)
AU (1) AU704292B2 (fr)
BR (1) BR9611343A (fr)
CA (1) CA2235487A1 (fr)
GB (1) GB9521805D0 (fr)
NO (1) NO981864L (fr)
NZ (1) NZ320442A (fr)
WO (1) WO1997015289A1 (fr)
ZA (1) ZA969016B (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034581A1 (fr) * 1996-03-19 1997-09-25 Cortecs (Uk) Limited Procede de solubilisation de substances hydrophiles (par exemple des proteines) dans un solvant hydrophobe
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
US9526763B2 (en) 2005-02-03 2016-12-27 Intarcia Therapeutics Inc. Solvent/polymer solutions as suspension vehicles
US9539200B2 (en) 2005-02-03 2017-01-10 Intarcia Therapeutics Inc. Two-piece, internal-channel osmotic delivery system flow modulator
US9572889B2 (en) 2008-02-13 2017-02-21 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US9682127B2 (en) 2005-02-03 2017-06-20 Intarcia Therapeutics, Inc. Osmotic delivery device comprising an insulinotropic peptide and uses thereof
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
USD835783S1 (en) 2016-06-02 2018-12-11 Intarcia Therapeutics, Inc. Implant placement guide
US10159714B2 (en) 2011-02-16 2018-12-25 Intarcia Therapeutics, Inc. Compositions, devices and methods of use thereof for the treatment of cancers
US10231923B2 (en) 2009-09-28 2019-03-19 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
US10501517B2 (en) 2016-05-16 2019-12-10 Intarcia Therapeutics, Inc. Glucagon-receptor selective polypeptides and methods of use thereof
US10527170B2 (en) 2006-08-09 2020-01-07 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies for use therein
US10835580B2 (en) 2017-01-03 2020-11-17 Intarcia Therapeutics, Inc. Methods comprising continuous administration of a GLP-1 receptor agonist and co-administration of a drug
US10925639B2 (en) 2015-06-03 2021-02-23 Intarcia Therapeutics, Inc. Implant placement and removal systems
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0012115A1 (fr) * 1978-12-04 1980-06-11 Ciba-Geigy Ag Préparations pharmaceutiques pour le traitement topique d'infections virales
US4411882A (en) * 1978-12-21 1983-10-25 Sandoz Ltd. Galenical compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0012115A1 (fr) * 1978-12-04 1980-06-11 Ciba-Geigy Ag Préparations pharmaceutiques pour le traitement topique d'infections virales
US4411882A (en) * 1978-12-21 1983-10-25 Sandoz Ltd. Galenical compositions

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034581A1 (fr) * 1996-03-19 1997-09-25 Cortecs (Uk) Limited Procede de solubilisation de substances hydrophiles (par exemple des proteines) dans un solvant hydrophobe
US8398967B2 (en) 2002-12-19 2013-03-19 Intarcia Therapeutics, Inc. Particle formulations for use in pharmaceutical compositions
US9724293B2 (en) 2003-11-17 2017-08-08 Intarcia Therapeutics, Inc. Methods of manufacturing viscous liquid pharmaceutical formulations
US8257691B2 (en) 2003-11-17 2012-09-04 Intarcia Therapeutics, Inc. Composition and dosage form comprising a particle formulation and suspending vehicle
US7964183B2 (en) 2003-11-17 2011-06-21 Intarcia Therapeutics, Inc. Composition and dosage form comprising a particle formulation and suspending vehicle
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
US9526763B2 (en) 2005-02-03 2016-12-27 Intarcia Therapeutics Inc. Solvent/polymer solutions as suspension vehicles
US9539200B2 (en) 2005-02-03 2017-01-10 Intarcia Therapeutics Inc. Two-piece, internal-channel osmotic delivery system flow modulator
US9682127B2 (en) 2005-02-03 2017-06-20 Intarcia Therapeutics, Inc. Osmotic delivery device comprising an insulinotropic peptide and uses thereof
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
US10363287B2 (en) 2005-02-03 2019-07-30 Intarcia Therapeutics, Inc. Method of manufacturing an osmotic delivery device
US10527170B2 (en) 2006-08-09 2020-01-07 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies for use therein
US9572889B2 (en) 2008-02-13 2017-02-21 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US10441528B2 (en) 2008-02-13 2019-10-15 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US10231923B2 (en) 2009-09-28 2019-03-19 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
US12042557B2 (en) 2009-09-28 2024-07-23 I2O Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
US10869830B2 (en) 2009-09-28 2020-12-22 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
US10159714B2 (en) 2011-02-16 2018-12-25 Intarcia Therapeutics, Inc. Compositions, devices and methods of use thereof for the treatment of cancers
US10583080B2 (en) 2014-09-30 2020-03-10 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
US10925639B2 (en) 2015-06-03 2021-02-23 Intarcia Therapeutics, Inc. Implant placement and removal systems
US11214607B2 (en) 2016-05-16 2022-01-04 Intarcia Therapeutics Inc. Glucagon-receptor selective polypeptides and methods of use thereof
US10501517B2 (en) 2016-05-16 2019-12-10 Intarcia Therapeutics, Inc. Glucagon-receptor selective polypeptides and methods of use thereof
US11840559B2 (en) 2016-05-16 2023-12-12 I2O Therapeutics, Inc. Glucagon-receptor selective polypeptides and methods of use thereof
USD835783S1 (en) 2016-06-02 2018-12-11 Intarcia Therapeutics, Inc. Implant placement guide
USD912249S1 (en) 2016-06-02 2021-03-02 Intarcia Therapeutics, Inc. Implant removal tool
USD962433S1 (en) 2016-06-02 2022-08-30 Intarcia Therapeutics, Inc. Implant placement guide
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
US10835580B2 (en) 2017-01-03 2020-11-17 Intarcia Therapeutics, Inc. Methods comprising continuous administration of a GLP-1 receptor agonist and co-administration of a drug
US11654183B2 (en) 2017-01-03 2023-05-23 Intarcia Therapeutics, Inc. Methods comprising continuous administration of exenatide and co-administration of a drug

Also Published As

Publication number Publication date
AU7317896A (en) 1997-05-15
BR9611343A (pt) 1999-12-28
KR19990067028A (ko) 1999-08-16
NZ320442A (en) 1999-10-28
NO981864D0 (no) 1998-04-24
CN1202818A (zh) 1998-12-23
ZA969016B (en) 1998-04-28
GB9521805D0 (en) 1996-01-03
JP2000502990A (ja) 2000-03-14
NO981864L (no) 1998-06-24
EP0857061A1 (fr) 1998-08-12
AU704292B2 (en) 1999-04-15
CA2235487A1 (fr) 1997-05-01

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