WO1997015289A1 - Solubilisation methods - Google Patents

Solubilisation methods Download PDF

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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
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WO
WIPO (PCT)
Prior art keywords
agent
amphiphile
solulan
medicament
common solvent
Prior art date
Application number
PCT/GB1996/002609
Other languages
French (fr)
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 NZ320442A priority Critical patent/NZ320442A/en
Priority to EP96935083A priority patent/EP0857061A1/en
Priority to BR9611343-0A priority patent/BR9611343A/en
Priority to AU73178/96A priority patent/AU704292B2/en
Priority to JP9516406A priority patent/JP2000502990A/en
Priority to KR1019980702965A priority patent/KR19990067028A/en
Publication of WO1997015289A1 publication Critical patent/WO1997015289A1/en
Priority to NO981864A priority patent/NO981864L/en

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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
    • A61K9/14—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.

Abstract

Improved methods for solubilising biologically active materials, e.g. proteins, in a hydrophobic solvent are provided.

Description

SOLUBILISATION METHODS
The present invention relates to methods of solubilising an agent, eg biologically active materials, in an amphiphile. In particular the invention relates to methods of bringing biologically active substances used for topical administration into association with permeation aids.
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 methods disclosed in the above-noted patent publications and applications include steps whereby the biologically active material is brought into association with an amphiphile . There are also circumstances where it would be desirable to achieve higher degrees of solubilisation of biologically active molecules, particularly water-soluble ones, in amphiphiles. Examples include:
i) to improve dissolution characteristics in aqueous media, eg. to aid in achieving rapid dissolution;
ii) to aid incorporation into low HLB systems such as oil mixtures; and iii) to bring about association between biologically active substances and permeation aids, which are often amphiphiles, for topical use.
Thus, in a first aspect, the present invention provides a method of solubilising an agent in an amphiphile which method includes the steps of:
(i) bringing the agent and amphiphile into association with each other in a common solvent;
(ii) removing the common solvent; and
(iii) heating the residue from step (ii) ;
In 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.
Suitably, in the above methods 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.
A wide variety of macromolecules is suitable for use in the present invention. In general, 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. Examples of 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.
Examples of particular proteins which may be successfully solubilised by the method of the present invention include insulin, calcitonin, haemoglobin, cytochrome C, horseradish peroxidase, aprotinin, mushroom tyrosinase, erythropoietin, somatotropin, growth hormone, growth hormone releasing factor, galanin, urokinase, Factor IX, tissue plasminogen activator, superoxide dismutase, catalase, peroxidase, ferritin, interferon, Factor VIII and fragments thereof (all of the above proteins can be from any suitable source) . Other macromolecules may be used are FITC-labelled dextran and RNA extract from Torulla yeast .
10
It seems that there is no upper limit of molecular weight for the macromolecular compound since dextran having a. molecular weight of about 1,000,000 can easily be solubilised by the process of the present invention.
15
In addition to macromolecules, the process of the present invention is of use in solubilising smaller organic molecules. Examples of small organic molecules include glucose, carboxyfluorescin and many pharmaceutical
20 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. In addition, compounds such as calcium chloride and sodium
25. phosphate can also be solubilised using this process. Indeed, 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
30 varied, for example to increase bioavailability.
Another type of species which may be included in the hydrophobic compositions of the invention is an inorganic material such as a small inorganic molecule or a colloidal substance, for example a colloidal metal. The process of the present invention enables some of the properties of a colloidal metal such as colloidal gold, palladium, platinum or rhodium, to be retained even in hydrophobic solvents in which the particles would, under normal circumstances, aggregate. This could be particularly useful for catalysis of reactions carried out in organic solvents.
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 (ZnAc2) .
Particularly suitable amphiphiles are those which are solid at room temperature, eg Solulan 16 and Solulan C24.
In other aspects the present invention provides:
i) a 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
ii) the use of a 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 ZnAc2.
Preferred features of each aspect of the invention are as for each other aspect mutatis mutandis . The invention will now be described with reference to the following examples, which should not be construed as in any way limiting the invention.
Example 1
(1). A solution of zinc acetate at a concentration of lOOmg/ml was prepared by addition of lOOmg of ZnAc2 to 1ml of distilled water, and mixing at RT until dissolution was achieved.
(2) 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.
(3) Solutions from steps 1 & 2 were dispensed into 4ml glass screw-capped vials as follows, and mixed well:
A B C
ZnAc2 (Vol) 0.2ml 0.3ml 0.4ml Solulan 16 (Vol) 1.8ml 1.7ml 1.6ml
ZnAc2 (wt) 20mg 30mg 40mg Solulan 16 (wt) 180mg 170mg 160mg
%Zn (wt:wt) 10 15 20 Ratio ιwt:wt) 9:1 5.7:1 4 :1
(4) The vials and contents were frozen in liquid nitrogen and lyophilised overnight with a condenser temperature of -40°C, and a vacuum of O.lmBar. (5) The following day, the lyophilates were incubated at +60°C on a heating block, to melt the solid cake of Solulan S16.
(6) Because of the fact that the solutions solidified at room temperature, dissolution or otherwise of ZnAc2 in Solulan 16 was assessed visually by examining the clarity or turbidity of the resulting liquid formulations, rather than by recording optical densities. Results of visual observations are recorded in the table below:
Sample Ratio S16:Zn Optical Appearance (wt:wt) Clarity
A 9:1 +++ Clear Solution
B 5.7:1 - Cloudy Paste
C 4:1 - Cloudy Paste
Example 2
(1) Solutions of Solulan 16 and ZnAc2 were prepared as above, and dispensed into 2ml glass screw-capped vials as follows:
A B C D E F G
S16(μl) 0 20 40 80 120 160 200
ZnAc2 (μl) 20 20 20 20 20 20 20
S16 (mg) 0 2 4 8 12 16 20
ZnAc2 (mg) 2 2 2 2 2 2 2
Ratio 0:1 1:1 2:1 4:1 6:1 8:1 10:1 S16:Zn
(2) After lyophilisation and heating to 60°C, the solubility of ZnAc2 in S16 was assessed visually as described in Example 1. The results of observations are given in the table below:
Sample A B C D E F G
Ratio (S16:Zn) 0 1 2 4 6 8 10
Observations * * * + + - - after heating
*= Samples remained as white solids += Samples turned to a viscous glassy fluid essentially clear free-flowing fluid
Example 3
(1) 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.
(2) 500mg CuAc2 was dissolved in 10ml of distilled water to give a concentration of 50mg/ml.
(3) 150μi of CuAc2 solution (7.5mg solid) and 925μl of Solulan C24 solution (92.5mg solid) were dispensed into a 4ml glass screw-capped vial. The vial contents were mixed well, frozen in liquid nitrogen and lyophilised overnight .
(4) lOmg of CuAc2 was dispensed into a 2ml glass vial and lOOmg of Solulan C24 was added. The vials was capped and heated to 60°C to melt the oil. The contents of the tube were vortexed to disperse the CuAc2 in the oil, then incubated at 60°C for eight hours. After incubation, the contents of the vial consisted of a colourless oil solution on top of solid undissolved crystals of CuAc2.
(5) The following day, the contents of the lyophilised tube was converted to a clear strong blue-coloured solution by incubating in a heating block for 2 minutes at 60°C.
(6) The vials from steps (4) and (5) were allowed to stand at room temperature to allow any undissolved CuAc2 to sediment, before the oil solidified.
(7) 20μg of solid oil was taken off the surface of each sample in step (6) , and dissolved in 180μl of distilled water.
(8) The optical densities of the aqueous solutions obtained in step (7) were measured at 650nm, and compared against reference solutions prepared by dilution of CuAc2 solution from step 2 in distilled water. The results are reported in the table below, where it is seen that a higher concentration of CuAc2 dissolved in the oil can be measured by following the lyophilisation procedure described above, than by simple mixing of the components.
Concentration in aqueous solution(mg/ml)
Measured Theoretical
After 6.7 7.5 lyophilisation
After simple 0.8 10.0 mixing
Example 4
A virus suspension (Sabin strains, Types 1, 2, 3) containing 5xl08 particles/ml (spun to remove contaminating protein) was diluted 50-fold by addition of 200μl of the suspension to 9.9ml of distilled water, yielding a concentration of 107 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".
200μl of each preparation was dispensed into 10 freeze- drying vials, and the remainder in lOOμl aliquots into other tubes as "pre-drying" controls. The controls were stored overnight at +4°C. The freeze-drying vials were placed in the centrifugal rotor of the freeze-dryer and lyophilised overnight.
On the following day lOOμl of culture medium was added to each vial in group "W" and mixed gently. The vials in group "S" were sealed and heated to 60°C in a hot water bath for 5 seconds to melt the Solulan C24, which resulted in a claer solution. Upon cooling to room temperature this material solidified. 90μl of medium was added to the vials of the "S" group to make the total volume up to lOOμl. lOμl of sample was then transferred from each of groups "S" and "W" to fresh 1ml vials and lml of medium was added to each and mixed well.
To fresh lml vials was added 4 x 20μl of samples from each of the pre-drying groups and lml of medium was added to each. The contents of each vial were mixed well.
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.
Nature of Sample Highest Dilution at which 50% CPΞ observed
Non-dried control + water 10"4/10"6 Non-dried control + Solulan C24 lO'VlO-5
Freeze-dried control + water 10"2/10"2
Freeze-dried control + Solulan C24 10'VlO"8

Claims

CLAIMS :
1. A method of solubilising an agent in an amphiphile which method includes the steps of:-
(i) bringing the agent and amphiphile into association with each other in a common solvent;
(ii) removing the common solvent; and
(iii) heating the residue from step (ii) ;
2. A method as claimed in claim 1 wherein the agent and the amphiphile "are brought into association with each other by firstly dissolving each one separately in the common solvent, followed by mixing of the two resultant solutions.
3. A method as claimed in claim 1 or claim 2 wherein the" common solvent is water.
4. A method as claimed in claim 3 wherein the water is removed in step (iii) by freeze drying, centrifugal vacuum drying or any other suitable method.
5. A method as claimed in any one of claims 1 to 4 wherein the amphiphile is lecithin, a glycolipid, a polyoxyethylene containing surfactant, a lipophilic sulphate, betaine, a sarcosine containing surfactant,
Solulan 16, Solulan C2 , 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.
6. A method as claimed in any one of claims 1 to 4 wherein the amphiphile is a permeation aid.
7. A method as claimed in any one of claims 1 to 6 wherein the agent is one administered topically.
8. A method as claimed in claim 7 wherein the agent is Zinc Acetate.
9. A method as claimed in claim 8 wherein the amphiphile is Solulan 16 or Solulan C24.
10. A method as claimed in any one of claims 1 to 5 wherein the agent is a macromolecuie, a small organic or inorganic molecule or a colloidal substance.
11. A method as claimed in claim 10, wherein the macromolecuie comprises a protein, glycoprotein, oligo- or polynucleic acid, polysaccharide or supramolecular assembly thereof.
12. A method as claimed in claim 11, wherein the protein is insulin, calcitonin, haemoglobin, cytochrome C, horseradish peroxidase, aprotinin, mushroom tyrosinase, erythropoietin, somatotropin, growth hormone, growth hormone releasing factor, galanin, urokinase, Factor IX, tissue plasminogen activator, superoxide dismutase, catalase, peroxidase, ferritin, interferon, Factor VIII or fragments thereof.
13. A method as claimed in any one of claims 10 to 12 wherein the agent is for oral administration.
14. A method as claimed in claim 13 wherein the agent is a virus .
15. A composition comprising an agent solubilised in an amphiphile obtainable by a method as defined in any one of claims 1 to 14.
16.. The use of a composition as defined in claim 15 in the preparation of a medicament for topical administration.
17. The use as claimed in claim 16 wherein the medicament is for the treatment or prevention of inflammation and/or arthritis.
18. The use of a composition as defined in claim 15 in the preparation of a medicament for manipulating the immune response.
19. The use as claimed in claim 18 wherein the medicament is a vaccine.
PCT/GB1996/002609 1995-10-25 1996-10-25 Solubilisation methods WO1997015289A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
NZ320442A NZ320442A (en) 1995-10-25 1996-10-25 Solubilisation methods of biologially active material in an amphiphile
EP96935083A EP0857061A1 (en) 1995-10-25 1996-10-25 Solubilisation methods
BR9611343-0A BR9611343A (en) 1995-10-25 1996-10-25 Solubilization process of an agent in an amphiphilic, composition, and use of it.
AU73178/96A AU704292B2 (en) 1995-10-25 1996-10-25 Solubilisation methods
JP9516406A JP2000502990A (en) 1995-10-25 1996-10-25 Solubilization method
KR1019980702965A KR19990067028A (en) 1995-10-25 1996-10-25 Solubilization Method
NO981864A NO981864L (en) 1995-10-25 1998-04-24 Upl ° sningsmetoder

Applications Claiming Priority (2)

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

Publications (1)

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

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

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WO1997034581A1 (en) * 1996-03-19 1997-09-25 Cortecs (Uk) Limited Method for solubilising hydrophylic materials (e.g. proteins) in a hydrophobic solvent
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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
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US8257691B2 (en) 2003-11-17 2012-09-04 Intarcia Therapeutics, Inc. Composition and dosage form comprising a particle formulation and suspending vehicle
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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
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US10159714B2 (en) 2011-02-16 2018-12-25 Intarcia Therapeutics, Inc. Compositions, devices and methods of use thereof for the treatment of cancers
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
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
US10925639B2 (en) 2015-06-03 2021-02-23 Intarcia Therapeutics, Inc. Implant placement and removal systems
US11840559B2 (en) 2016-05-16 2023-12-12 I2O 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
US11214607B2 (en) 2016-05-16 2022-01-04 Intarcia Therapeutics Inc. Glucagon-receptor selective polypeptides and methods of use thereof
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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

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CN1202818A (en) 1998-12-23
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AU7317896A (en) 1997-05-15
NZ320442A (en) 1999-10-28
NO981864D0 (en) 1998-04-24
ZA969016B (en) 1998-04-28
EP0857061A1 (en) 1998-08-12
AU704292B2 (en) 1999-04-15
GB9521805D0 (en) 1996-01-03
BR9611343A (en) 1999-12-28
CA2235487A1 (en) 1997-05-01
NO981864L (en) 1998-06-24

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