CA2033725C - Pharmaceutical and cosmetic compositions containing a salt of cholanic acid - Google Patents
Pharmaceutical and cosmetic compositions containing a salt of cholanic acid Download PDFInfo
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- CA2033725C CA2033725C CA002033725A CA2033725A CA2033725C CA 2033725 C CA2033725 C CA 2033725C CA 002033725 A CA002033725 A CA 002033725A CA 2033725 A CA2033725 A CA 2033725A CA 2033725 C CA2033725 C CA 2033725C
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- solution
- cholanic acid
- acid
- lecithin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0291—Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
- A61K8/553—Phospholipids, e.g. lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/678—Tocopherol, i.e. vitamin E
-
- 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
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
Abstract
Pharmaceutical and cosmetic preparations for topical administration, contain a salt of a cholanic acid, a lipid and optionally a pharmaceutical or cosmetic active substance.
Description
~~~~'7'~.' i The present invention is concerned with pharmaceutical and cosmetic preparations for topical administration, which contain a salt of a cholanic acid, a lipid and optionally a pharmaceutical or cosmetic active substance.
As cholanic acid salts there come into consideration in the present preparations the salts of cholanic acids or cholanic acid derivatives which are mentioned in DE-OS
As cholanic acid salts there come into consideration in the present preparations the salts of cholanic acids or cholanic acid derivatives which are mentioned in DE-OS
2 730 570, especially cholates, glycocholates, deoxy-cholates and taurocholates, especially the alkali salts such as the sodium salts. Na glycocholate is especially preferred.
As lipids there come into consideration especially phosphatidylcholines, e.g. natural lecithins or synthetic lecithins having modified side-chains (e. g. those which are described in European Patent Application A2-0154977).
Natural lecithins such as egg lecithin or soya lecithin are preferred.
The molar ratio between lipid and cholanic acid salt conveniently lies in the order of 0.1:1 to 2:1, Mixture ratios of 0.1:1 to 1.5:1 are preferred.
As active substances for the preparations in accordance with the invention there come into consideration all therapeutically and cosmetically active substances which ate suitable for application to skin and mucous membrane, including the eyes.
Examples of such active substances are corticosteroids such as hydrocortisone: hydrocortisone acetate predni-Grn/14.11.90 - z - 20:~~'r2 a solone, fluorocortolone, triamcinolone acetate; sex hormones such as estriol, estradiol, estradiol benzoate;
antiphlogistics such as indomethacin. bufexamac, salicylic acid, salicylamide: immunosuppressives such as cyclosporin A, FK 506 and immunosuppressive retinoids such as (all-E)--3.7-dimethyl-9-(2-trifluoromethyl)-6-nonyloxyphenyl--2.4,6.8-nonatetraenoic acid: antibiotics such as neo-mycin, gentamycin, polymyxin B. bacitracin, gramidicin.
tyrothricin, erythromycin, clindamycin. tetracyclins.
chloramphenicol, fusidic acid, nitrofural; antimycotics such as tolnaftate, imidazole derivatives (e. g. micona-zole. econazole). amorolfin, nystatin, amphotericin B.
flucytosine, griseofulvin; virustatics and cytostatics such as idoxuridine, tromantadine, acylovir, podophyllin.
5-fluorouracil; antipsoriatics such as anthralin and psoralens; retinoids such as tretinoin, isotreticioin.
arotinoids; sunscreen agents such as p-aminobenzoic acid derivatives, benzimidazole derivatives, cinnamic acid derivatives; skin care agents such as panthenol; vitamins such as tocopherol: moisturizing agents such as pyrrolidonecarboxyiic acids and their Na salts, lactic acid and its Na salts, perfusion-promoting agents such as nicotinic acid derivatives and capsicides. Further examples of active substances ate heparin, PAF
antagonists, leukotriene antagonists, antihistamines, mast cell blockets, local anaesthetics, peptides and proteins, especially cytokines, e.g. interferon and interleukin.
Solutions, lotions. sprays, creams, gels, salves and foams are examples of topical application forms.
The manufacture of the preparations in accordance with the invention can be effected using technology which is known per se in galenics, with the active substance or the active substances being used in the form of an aqueous solution of cholanic acid salt-lipid-mixed micelles.
2(1~33'~~~
Gels are obtained from these solutions by adding one or more anionic (e. g. carbomer, carboxymethylcelluloses and their salts, xanthanes, bentonite, montmorillonite), cationic (e. g. polyquaternium) or non-ionic gel formers.
However, non-ionic gel formers such as: methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxy-propylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohols and their copolymers, e.g. with vinyl acetate.
are preferably used.
Foams can be present as ethanol-containing aqueous mixed micelle solutions in pressurized containers, which contain about 10 wt.% of propellant, e.g. FKW 126114 (40:60), or can be produced by spraying from such pressurized containers. Sprays can be produced from the solution using a conventional spray nozzle.
For the preparation of creams and salves, an aqueous miceliar active substance solution is prepared, e.g, as described in DE-OS 2730570. This solution is incorporated in a conventional cream or salve base. Any conventional cream or salve base is suitable for this purpose. Such bases can be prepared on the basis of known adjuvants such as polyethylene glycols, paraffins, waxes, fats and fat-like substances and can be present as an oil-in-water or as a water-in-oil type.
The preparations in accordance with the invention can contain adjuvants and additives, especially penettation--enhancers such as unsaturated fatty acids, e.g, oleic acid: furthermore conventional preservatives (e. g.
p-hydroxybenzoic acid esters, benzyl alcohol, phenoxy-ethanol, chlorhexidine salts); antioxidants (BHT,'BHA, tocopherol, ascorbic acid): complexing agents (Na2 EDTA); buffers (citric acid, phosphoric acid):
moisturizing agents (propylene glycol, glycerol, sugars - ~t)~3'~~
and sugar alcohols, e.g. sorbitol) as well as water and other solvents such as ethanol, DMSO or organic amides.
The preparations in accordance with the invention can be applied to the skin, to mucous membranes, e.g. buccally or nasally as a gel, solution, chewable capsule or buccal tablet; to the eyes as a cream, salve, gel or solution;
and to the respiratory tract as a spray.
Mixed micelle solutions of pharmaceutical active substances can also be used in transdermal application systems. The preparations in accordance with the invention therefore also embrace transdermal preparations in which the combination of active substance, cholanic acid (salt) and lipid is present as a solution or in dried, e.g, in lyophilized, form, Compared With conventional formulations, the prepara-tions in accordance with the invention have advantageous properties, for example an improved penetration of the active substance and its improved distribution in the skin, not only for hydrophilic active substances, but also for lipophilic active substances. In the case of the latter there is an additional advantage that the use of organic solvents which have a poor compatibility can be dispensed with. The preparations in accordance with the invention are distinguished e.g. vis-a-vis liposomal formulations by an improved physical stability and an industrially less costly manufacture.
The preparations are well tolerated by the skin, the mucous membranes and the eyes.
Primary eye and skin irritation tests with active substance-free mixed micelle formulations were carried out in accordance with the OECD guidelines. The preparations ~0~3~~J
in accordance with the invention were all found to be "non-irritating" in contrast to conventional solubilizates (e. g. with sodium lauryl sulphate).
It has been found that topical formulations, which except for cholanic acid salt/lipid mixed micelles contain no pharmaceutical active substance, have an antimycotic activity. The invention is therefore also concerned with preparations for topical administration which contain except for cholanic acid salt/lipid-mixed micelles no pharmaceutical active substances.
The inventian is illustrated further by the following Examples:
All operations ate carried out under an inert. gas; the solvents are freed from oxygen by the introduction of inert gas.
Examine 1 1.75 g of glycocholic acid. 1.50 g 'of soya lecithin.
0.278 g of amorolfin HC1 and 1.0 g of benzyl alcohol are dissolved clear in 10.0 g of ethanol (or another suitable organic solvent) at about 45-50°C (solution A). 3.75 ml of a IN NaOH solution are added to 80 ml of deionized water.
This solution is added to solution A while stirring and the mixture is made up to 100.0 g with water.
Example 2 1.75 g of glycocholic acid are suspended in about 50 g of deionized water and dissolved by adding NaOH. After adjusting to a pH value of 6.0 1.50 g of Soya lecithin, 0.278 g of amorolfin HCl and 1.0 g of benzyl alcohol are dissolved in succession (solution A). The dissolution operation can be accelerated by ultrasonics and/or warming. 1.60 g of methylcellulose 4000 cP are suspended in 5.0 g of propylene glycol and added to solution A while stirring. The mixture is made up to 100.0 g with water and the gel is stirred slowly at 5°C until the methylcellulose has swollen completely.
Example 3 ip Gels for the topical administration of amorolfin having the following compositions can be manufactured in analogy to the Examples set forth above:
3a 3b 3c Amorolfin HC1 0.278 0.278 0.278 g Benzyl alcohol 1.00 1.00 1.00 g Propylene glycol 5.00 5.00 5.00 g Lecithin 1.50 1.5 7.45 g Glycocholic acid 1.75 1.75 5.38 g NaOH ad pH 6.0-6.2 q.s. q.s. q.s.
Methylcellulose 1.6 - - g Hydroxyethylcellulose - 1.80 1.80 g Ethanol - 10.0 - g Water ad 100.0 100.0 100.0 g The penetration data show that with the cholanic acid salt/lecithin systems much higher active substance concentrations are achieved not only in the cornea but also in the lower layers of the skin as compared to the administration by classical creams.
_ ~ _ ~cd~J~3'~~:
i Formulation Dosage Time Skin Str. Remaining Chamber (h) surfacecorneum skin fluid _ Gel of 0.257L 16 9.99 1.74 3.22 ) 0.05 (ug/cm Ex. 3a 156.6 11.6 21.5 0.3 (76) ~
of 0.257 16 5.04 3.71 6.21 ) Gel 0.04 (ug/c ,Ez. 3b 33.6 24.7 41.4 0.3 (X) Gel of 0.25x 16 11.92 1.41 1.65 ) 0.02 (ug/cm Ex. 3c 79.4 9.4 11.0 0.1 (x) Cre am 0.2576 16 14.19 0.32 0.48 0.01 (1tg/cm ) 94.6 2.1 3.2 0.1 ('JG) Example 4 A mixed micelle~solution of isotretinoin can have the following composition:
Isotretinoin 50 mg dl-a-To,copherol 10 mg Na2 EDTA 30 mg Lecithin 16.9 g Glycocholic acid 8.85 g Benzyl alcohol 1.0 g NaOH ad pH 6 q.s.
Water ad 100.0 g This mixed micelle solution can be processed to a gel analogously to Example 2.
2U~:~'~ i _8_ The gel can he used fot topical treatment e.g. of acne.
Example 5 A mixed micelle solution of tretinoin can have the following composition:
Tretinoin 20 mg dI-a-Tocopherol 10.0 mg . .
Lecithin 16.9 g Glycocholic acid 8.85 g NaOH ad pH 6 q.s.
Benzyl alcohol 1.0 g Water ad 100.0 ml This mixed micelle solution can be ocessed.to a gel pr as described in Example 2. The gel so be used for can al topical treatment e.g. of acne.
Examule 6 A mixed micelle~solution for topical use in psoriasis can have the following composition:
Methyl p-[2-(5,6,7,8-tetrahydro--5,5,8,8-tetramethyl-2-naphthyl)-propyl]phenylsulphone 0.05 g Lecithin 16.90 g Glycocholic acid 8.85 g NaOH ad pH 5.0 q.s.
Benzyl alcohol 1.00 g Water ad 100.00 g The solution can be converted into gel in analogy to a Example 2.
~:~;~~'~~ a _ g _ Example 7 Mixed micelle solutions for the manufacture of a hydrocortisone spray can have the following composition:
(a) (b) Hydrocortisone 0.25 0.50 g Lecithin 8.00 10.58 g Glycocholic acid 5.00 8.06 g NaOH ad pH 6.0 q.s. q.s.
Benzyl alcohol 1.00 1.00 g Water ad 100.00 100.00 g An improved tissue level of hydrocortisone in the skin can be achieved with mixed micelle solutions, which can be used as a spray, than when liposomal carriers are applied:
Bormulation Dosage Time Skin Str. btemaining Chamber (h) surface corneum skin fluid Xixed 0.25x 6 12.39 1.48 1.04 0.09 (ug/c~az) taicelle 82.6 9.9 6.9 0,6 (x) solution (a) of E:. 7 Liposome 0.2576 6 13.46 0.68 0.84 0.02 (ug/cm2) sol. 89.7 4.5 5.6 0.1 (x) The hydrocortisone liposomes were prepared analogously to a procedure of Wholrab and Lasch (Dermatologica 174. 18 ~U:~~3'~~:5 - to -(1987)).
Solutions 7a and 7b can be used as sprays for topical application in the case of inflammatory skin disorders.
Example 8 A mixed micelle solution of panthenol can have the following composition:
n-Panthenol 0.50 g Lecithin 8.00 g Glycocholic acid 5.00 g paOH ad pH 6.0 g.s.
Benzyl alcohol 1.00 g Water ad 100.00 a The solution can be used as a spray for the treatment 2p of damaged skin.
As a comparison of the in vitro penetration data shows, clearly higher panthenol concentrations in the skin are achieved than with a conventional salve:
~'~~~3'~~:, FormulationPanthenolTimeSkin Str. EemainingChamber content (h) surface corneumskin fluid 5076 b 222.6 51.99 22.44 2.9 ) 0 ('~g7cm Solution .
2 17.3 7.5 1.9 (R) of Ez. 8 .
6 9 7.70 2.98 0.43 tug7cm2) Conven- 0.508 .
As lipids there come into consideration especially phosphatidylcholines, e.g. natural lecithins or synthetic lecithins having modified side-chains (e. g. those which are described in European Patent Application A2-0154977).
Natural lecithins such as egg lecithin or soya lecithin are preferred.
The molar ratio between lipid and cholanic acid salt conveniently lies in the order of 0.1:1 to 2:1, Mixture ratios of 0.1:1 to 1.5:1 are preferred.
As active substances for the preparations in accordance with the invention there come into consideration all therapeutically and cosmetically active substances which ate suitable for application to skin and mucous membrane, including the eyes.
Examples of such active substances are corticosteroids such as hydrocortisone: hydrocortisone acetate predni-Grn/14.11.90 - z - 20:~~'r2 a solone, fluorocortolone, triamcinolone acetate; sex hormones such as estriol, estradiol, estradiol benzoate;
antiphlogistics such as indomethacin. bufexamac, salicylic acid, salicylamide: immunosuppressives such as cyclosporin A, FK 506 and immunosuppressive retinoids such as (all-E)--3.7-dimethyl-9-(2-trifluoromethyl)-6-nonyloxyphenyl--2.4,6.8-nonatetraenoic acid: antibiotics such as neo-mycin, gentamycin, polymyxin B. bacitracin, gramidicin.
tyrothricin, erythromycin, clindamycin. tetracyclins.
chloramphenicol, fusidic acid, nitrofural; antimycotics such as tolnaftate, imidazole derivatives (e. g. micona-zole. econazole). amorolfin, nystatin, amphotericin B.
flucytosine, griseofulvin; virustatics and cytostatics such as idoxuridine, tromantadine, acylovir, podophyllin.
5-fluorouracil; antipsoriatics such as anthralin and psoralens; retinoids such as tretinoin, isotreticioin.
arotinoids; sunscreen agents such as p-aminobenzoic acid derivatives, benzimidazole derivatives, cinnamic acid derivatives; skin care agents such as panthenol; vitamins such as tocopherol: moisturizing agents such as pyrrolidonecarboxyiic acids and their Na salts, lactic acid and its Na salts, perfusion-promoting agents such as nicotinic acid derivatives and capsicides. Further examples of active substances ate heparin, PAF
antagonists, leukotriene antagonists, antihistamines, mast cell blockets, local anaesthetics, peptides and proteins, especially cytokines, e.g. interferon and interleukin.
Solutions, lotions. sprays, creams, gels, salves and foams are examples of topical application forms.
The manufacture of the preparations in accordance with the invention can be effected using technology which is known per se in galenics, with the active substance or the active substances being used in the form of an aqueous solution of cholanic acid salt-lipid-mixed micelles.
2(1~33'~~~
Gels are obtained from these solutions by adding one or more anionic (e. g. carbomer, carboxymethylcelluloses and their salts, xanthanes, bentonite, montmorillonite), cationic (e. g. polyquaternium) or non-ionic gel formers.
However, non-ionic gel formers such as: methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxy-propylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohols and their copolymers, e.g. with vinyl acetate.
are preferably used.
Foams can be present as ethanol-containing aqueous mixed micelle solutions in pressurized containers, which contain about 10 wt.% of propellant, e.g. FKW 126114 (40:60), or can be produced by spraying from such pressurized containers. Sprays can be produced from the solution using a conventional spray nozzle.
For the preparation of creams and salves, an aqueous miceliar active substance solution is prepared, e.g, as described in DE-OS 2730570. This solution is incorporated in a conventional cream or salve base. Any conventional cream or salve base is suitable for this purpose. Such bases can be prepared on the basis of known adjuvants such as polyethylene glycols, paraffins, waxes, fats and fat-like substances and can be present as an oil-in-water or as a water-in-oil type.
The preparations in accordance with the invention can contain adjuvants and additives, especially penettation--enhancers such as unsaturated fatty acids, e.g, oleic acid: furthermore conventional preservatives (e. g.
p-hydroxybenzoic acid esters, benzyl alcohol, phenoxy-ethanol, chlorhexidine salts); antioxidants (BHT,'BHA, tocopherol, ascorbic acid): complexing agents (Na2 EDTA); buffers (citric acid, phosphoric acid):
moisturizing agents (propylene glycol, glycerol, sugars - ~t)~3'~~
and sugar alcohols, e.g. sorbitol) as well as water and other solvents such as ethanol, DMSO or organic amides.
The preparations in accordance with the invention can be applied to the skin, to mucous membranes, e.g. buccally or nasally as a gel, solution, chewable capsule or buccal tablet; to the eyes as a cream, salve, gel or solution;
and to the respiratory tract as a spray.
Mixed micelle solutions of pharmaceutical active substances can also be used in transdermal application systems. The preparations in accordance with the invention therefore also embrace transdermal preparations in which the combination of active substance, cholanic acid (salt) and lipid is present as a solution or in dried, e.g, in lyophilized, form, Compared With conventional formulations, the prepara-tions in accordance with the invention have advantageous properties, for example an improved penetration of the active substance and its improved distribution in the skin, not only for hydrophilic active substances, but also for lipophilic active substances. In the case of the latter there is an additional advantage that the use of organic solvents which have a poor compatibility can be dispensed with. The preparations in accordance with the invention are distinguished e.g. vis-a-vis liposomal formulations by an improved physical stability and an industrially less costly manufacture.
The preparations are well tolerated by the skin, the mucous membranes and the eyes.
Primary eye and skin irritation tests with active substance-free mixed micelle formulations were carried out in accordance with the OECD guidelines. The preparations ~0~3~~J
in accordance with the invention were all found to be "non-irritating" in contrast to conventional solubilizates (e. g. with sodium lauryl sulphate).
It has been found that topical formulations, which except for cholanic acid salt/lipid mixed micelles contain no pharmaceutical active substance, have an antimycotic activity. The invention is therefore also concerned with preparations for topical administration which contain except for cholanic acid salt/lipid-mixed micelles no pharmaceutical active substances.
The inventian is illustrated further by the following Examples:
All operations ate carried out under an inert. gas; the solvents are freed from oxygen by the introduction of inert gas.
Examine 1 1.75 g of glycocholic acid. 1.50 g 'of soya lecithin.
0.278 g of amorolfin HC1 and 1.0 g of benzyl alcohol are dissolved clear in 10.0 g of ethanol (or another suitable organic solvent) at about 45-50°C (solution A). 3.75 ml of a IN NaOH solution are added to 80 ml of deionized water.
This solution is added to solution A while stirring and the mixture is made up to 100.0 g with water.
Example 2 1.75 g of glycocholic acid are suspended in about 50 g of deionized water and dissolved by adding NaOH. After adjusting to a pH value of 6.0 1.50 g of Soya lecithin, 0.278 g of amorolfin HCl and 1.0 g of benzyl alcohol are dissolved in succession (solution A). The dissolution operation can be accelerated by ultrasonics and/or warming. 1.60 g of methylcellulose 4000 cP are suspended in 5.0 g of propylene glycol and added to solution A while stirring. The mixture is made up to 100.0 g with water and the gel is stirred slowly at 5°C until the methylcellulose has swollen completely.
Example 3 ip Gels for the topical administration of amorolfin having the following compositions can be manufactured in analogy to the Examples set forth above:
3a 3b 3c Amorolfin HC1 0.278 0.278 0.278 g Benzyl alcohol 1.00 1.00 1.00 g Propylene glycol 5.00 5.00 5.00 g Lecithin 1.50 1.5 7.45 g Glycocholic acid 1.75 1.75 5.38 g NaOH ad pH 6.0-6.2 q.s. q.s. q.s.
Methylcellulose 1.6 - - g Hydroxyethylcellulose - 1.80 1.80 g Ethanol - 10.0 - g Water ad 100.0 100.0 100.0 g The penetration data show that with the cholanic acid salt/lecithin systems much higher active substance concentrations are achieved not only in the cornea but also in the lower layers of the skin as compared to the administration by classical creams.
_ ~ _ ~cd~J~3'~~:
i Formulation Dosage Time Skin Str. Remaining Chamber (h) surfacecorneum skin fluid _ Gel of 0.257L 16 9.99 1.74 3.22 ) 0.05 (ug/cm Ex. 3a 156.6 11.6 21.5 0.3 (76) ~
of 0.257 16 5.04 3.71 6.21 ) Gel 0.04 (ug/c ,Ez. 3b 33.6 24.7 41.4 0.3 (X) Gel of 0.25x 16 11.92 1.41 1.65 ) 0.02 (ug/cm Ex. 3c 79.4 9.4 11.0 0.1 (x) Cre am 0.2576 16 14.19 0.32 0.48 0.01 (1tg/cm ) 94.6 2.1 3.2 0.1 ('JG) Example 4 A mixed micelle~solution of isotretinoin can have the following composition:
Isotretinoin 50 mg dl-a-To,copherol 10 mg Na2 EDTA 30 mg Lecithin 16.9 g Glycocholic acid 8.85 g Benzyl alcohol 1.0 g NaOH ad pH 6 q.s.
Water ad 100.0 g This mixed micelle solution can be processed to a gel analogously to Example 2.
2U~:~'~ i _8_ The gel can he used fot topical treatment e.g. of acne.
Example 5 A mixed micelle solution of tretinoin can have the following composition:
Tretinoin 20 mg dI-a-Tocopherol 10.0 mg . .
Lecithin 16.9 g Glycocholic acid 8.85 g NaOH ad pH 6 q.s.
Benzyl alcohol 1.0 g Water ad 100.0 ml This mixed micelle solution can be ocessed.to a gel pr as described in Example 2. The gel so be used for can al topical treatment e.g. of acne.
Examule 6 A mixed micelle~solution for topical use in psoriasis can have the following composition:
Methyl p-[2-(5,6,7,8-tetrahydro--5,5,8,8-tetramethyl-2-naphthyl)-propyl]phenylsulphone 0.05 g Lecithin 16.90 g Glycocholic acid 8.85 g NaOH ad pH 5.0 q.s.
Benzyl alcohol 1.00 g Water ad 100.00 g The solution can be converted into gel in analogy to a Example 2.
~:~;~~'~~ a _ g _ Example 7 Mixed micelle solutions for the manufacture of a hydrocortisone spray can have the following composition:
(a) (b) Hydrocortisone 0.25 0.50 g Lecithin 8.00 10.58 g Glycocholic acid 5.00 8.06 g NaOH ad pH 6.0 q.s. q.s.
Benzyl alcohol 1.00 1.00 g Water ad 100.00 100.00 g An improved tissue level of hydrocortisone in the skin can be achieved with mixed micelle solutions, which can be used as a spray, than when liposomal carriers are applied:
Bormulation Dosage Time Skin Str. btemaining Chamber (h) surface corneum skin fluid Xixed 0.25x 6 12.39 1.48 1.04 0.09 (ug/c~az) taicelle 82.6 9.9 6.9 0,6 (x) solution (a) of E:. 7 Liposome 0.2576 6 13.46 0.68 0.84 0.02 (ug/cm2) sol. 89.7 4.5 5.6 0.1 (x) The hydrocortisone liposomes were prepared analogously to a procedure of Wholrab and Lasch (Dermatologica 174. 18 ~U:~~3'~~:5 - to -(1987)).
Solutions 7a and 7b can be used as sprays for topical application in the case of inflammatory skin disorders.
Example 8 A mixed micelle solution of panthenol can have the following composition:
n-Panthenol 0.50 g Lecithin 8.00 g Glycocholic acid 5.00 g paOH ad pH 6.0 g.s.
Benzyl alcohol 1.00 g Water ad 100.00 a The solution can be used as a spray for the treatment 2p of damaged skin.
As a comparison of the in vitro penetration data shows, clearly higher panthenol concentrations in the skin are achieved than with a conventional salve:
~'~~~3'~~:, FormulationPanthenolTimeSkin Str. EemainingChamber content (h) surface corneumskin fluid 5076 b 222.6 51.99 22.44 2.9 ) 0 ('~g7cm Solution .
2 17.3 7.5 1.9 (R) of Ez. 8 .
6 9 7.70 2.98 0.43 tug7cm2) Conven- 0.508 .
4 2.5 1.0 0.1 (R) tional .
salve Example 9 Cyclosporin A mixed micelle solutions can have the following composition:
Cyclosporin A 1.7 - 3.7 mg Lecithin 30.8 - 92.4 mg Na glycocholate 19.5 - 58.5 mg Water or buffer ad 1.0 ml Lecithin (Lipoid E PG, Lipoid KG), sodium glycocholate and cyclosporin are dissolved in 5 ml of chloroform/
methanol (1:1, v/v) in a round flask. The film which results after evaporation of the organic solvent (40°C) is dispersed in 1 ml of water and adjusted to pH 6.0 t 0.1 with 1N HC1. Buffer solutions such as phosphate buffer or polyalcohol solutions, e.g. mannitol solutions, can also be used for the hydration of the film.
~t3~~'i :0.i Example l0 A mixed micelle solution of vitamin A palmitate can have the following composition:
Vitamin A palmitate 5000 IU
Glycocholic acid 23.6 .mg Lecithin 35.0 mg Propylene glycol 50.0 mg Ethanol 50.0 mg NaOH ad pH 6.0 q.s. mg Benzyl alcohol 10.0 mg Water ad 1000.0 mg The glycocholic acid, the lecithin and the vitamin A
palmitate stabilized with tocopherol are dissolved in a mixture of propylene glycol, ethanol and benzyl alcohol to give a clear solution. The pH value of the solution is adjusted to 6.0 t 0.1 with NaOH.
Examvle 11 Tocopherol acetate mixed micelle solutions for topical use can have the following composition:
lla Formulations with Na glycocholate as the detergent al a2 -.-dl-a-Tocopherol acetate 2.0 5.0 g dl-a-Tocopherol 0.05 0.05 g Na glycocholate 2.0 - 3.39 5.0 g Lecithin 3.0 - 5.0 10.0 g Proplyene glycol 5.0 5.0 g Ethanol 5.0 5.0 g $enzyl alcohol 1.0 1.0 g Water ad 100.0 100.0 g The ethanol, tocopherol, tocopherol acetate, propylene glycol, benzyl alcohol, lecithin and Na glycocholate are added in succession and dissolved with slight warming to give a clear solution. Thereafter, the solution is treated with water and the pH value is adjusted to 6Ø
Formulations of tocopherol acetate (2%) based on lecithin-cholanic acid salt-mixed micelles are distin-guished, vis-a-vis conventional tocopherol acetate solubilizates, in that only physiological solubilizers are used. Moreover, the in vitro skin penetration from the mixed micelle solution is somewhat better than from an analogous conventional solubilizate using 10% PEG-36 castor oil.
After a penetration period of 6 h. the following distribution in the hog skin was determined:
Formulation with Skin Str. Remaining skin 2% tocopherol acetate surface corneum Mixed micelle solution 1) 88.8% 8.9% 2.3%
Conventional solubilizate 90.4% 7.8% 1.8%
1) 3.5% lecithin and 2.17% Na glycocholate llb Formulations with Na cholate as the detergent dI-a-Tocopherol acetate 2.0 g dl-a-Tocophe=ol 0.05 g Na cholate 2.5 g Lecithin 3.0 g Propylene glycol 5.0 g Ethanol 5.0 g Water ad 100.0 g ~c:d~~~'~~ i A solution of tocopherol acetate and tocopherol (2.0 +
0.05 g) in ethanol and the lecithin (3.0 g) dissolved in chloroform/methanol (1:1) are mixed and dried in a vacuum to a film. The film is dissolved in 5.0 g of ethanol and 5.0 g of propylene glycol in the warm. Subsequently, this solution is treated with an aqueous solution of 2.0 g of Na cholate, shaken and warmed. The pH value is adjusted to 6.0 t 0.1 with 1N HC1 and the solution is made up to 100 g with water. It is then stirred at RT until a clear solution is obtained (about 18 h.).
salve Example 9 Cyclosporin A mixed micelle solutions can have the following composition:
Cyclosporin A 1.7 - 3.7 mg Lecithin 30.8 - 92.4 mg Na glycocholate 19.5 - 58.5 mg Water or buffer ad 1.0 ml Lecithin (Lipoid E PG, Lipoid KG), sodium glycocholate and cyclosporin are dissolved in 5 ml of chloroform/
methanol (1:1, v/v) in a round flask. The film which results after evaporation of the organic solvent (40°C) is dispersed in 1 ml of water and adjusted to pH 6.0 t 0.1 with 1N HC1. Buffer solutions such as phosphate buffer or polyalcohol solutions, e.g. mannitol solutions, can also be used for the hydration of the film.
~t3~~'i :0.i Example l0 A mixed micelle solution of vitamin A palmitate can have the following composition:
Vitamin A palmitate 5000 IU
Glycocholic acid 23.6 .mg Lecithin 35.0 mg Propylene glycol 50.0 mg Ethanol 50.0 mg NaOH ad pH 6.0 q.s. mg Benzyl alcohol 10.0 mg Water ad 1000.0 mg The glycocholic acid, the lecithin and the vitamin A
palmitate stabilized with tocopherol are dissolved in a mixture of propylene glycol, ethanol and benzyl alcohol to give a clear solution. The pH value of the solution is adjusted to 6.0 t 0.1 with NaOH.
Examvle 11 Tocopherol acetate mixed micelle solutions for topical use can have the following composition:
lla Formulations with Na glycocholate as the detergent al a2 -.-dl-a-Tocopherol acetate 2.0 5.0 g dl-a-Tocopherol 0.05 0.05 g Na glycocholate 2.0 - 3.39 5.0 g Lecithin 3.0 - 5.0 10.0 g Proplyene glycol 5.0 5.0 g Ethanol 5.0 5.0 g $enzyl alcohol 1.0 1.0 g Water ad 100.0 100.0 g The ethanol, tocopherol, tocopherol acetate, propylene glycol, benzyl alcohol, lecithin and Na glycocholate are added in succession and dissolved with slight warming to give a clear solution. Thereafter, the solution is treated with water and the pH value is adjusted to 6Ø
Formulations of tocopherol acetate (2%) based on lecithin-cholanic acid salt-mixed micelles are distin-guished, vis-a-vis conventional tocopherol acetate solubilizates, in that only physiological solubilizers are used. Moreover, the in vitro skin penetration from the mixed micelle solution is somewhat better than from an analogous conventional solubilizate using 10% PEG-36 castor oil.
After a penetration period of 6 h. the following distribution in the hog skin was determined:
Formulation with Skin Str. Remaining skin 2% tocopherol acetate surface corneum Mixed micelle solution 1) 88.8% 8.9% 2.3%
Conventional solubilizate 90.4% 7.8% 1.8%
1) 3.5% lecithin and 2.17% Na glycocholate llb Formulations with Na cholate as the detergent dI-a-Tocopherol acetate 2.0 g dl-a-Tocophe=ol 0.05 g Na cholate 2.5 g Lecithin 3.0 g Propylene glycol 5.0 g Ethanol 5.0 g Water ad 100.0 g ~c:d~~~'~~ i A solution of tocopherol acetate and tocopherol (2.0 +
0.05 g) in ethanol and the lecithin (3.0 g) dissolved in chloroform/methanol (1:1) are mixed and dried in a vacuum to a film. The film is dissolved in 5.0 g of ethanol and 5.0 g of propylene glycol in the warm. Subsequently, this solution is treated with an aqueous solution of 2.0 g of Na cholate, shaken and warmed. The pH value is adjusted to 6.0 t 0.1 with 1N HC1 and the solution is made up to 100 g with water. It is then stirred at RT until a clear solution is obtained (about 18 h.).
Claims (8)
1. The use of mixed micelles from cholanic acid salts and lipids with a molar ratio lipid:cholanic acid salt of 0.1:1 to 2:1 in pharmaceutical or cosmetic preparations for topical administration.
2. The use according to claim 1, characterized in that the cholanic acid salt is Na glycocholate and the lipid is phosphatidylcholine.
3. The use according to claim 2, characterized in that the lipid is natural lecithin.
4. The use according to any one of claims 1 to 3 for the topical administration of a retinoid.
5. The use according to any one of claims 1 to 3 for the topical administration of an antimycotic.
6. The use according to any one of claims 1 to 3 for the topical administration of pantenol.
7. The use according to any one of claims 1 to 6 in the form of a solution or a gel.
8. The use of mixed micelles from cholanic acid salts and lipids with a molar ratio lipid:cholanic acid salt of 0.1:1 to 2:1 as active substances in the manufacture of preparations for the topical treatment of mycoses.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH222/90 | 1990-01-24 | ||
| CH22290 | 1990-01-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2033725A1 CA2033725A1 (en) | 1991-07-25 |
| CA2033725C true CA2033725C (en) | 2001-05-29 |
Family
ID=4182066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002033725A Expired - Lifetime CA2033725C (en) | 1990-01-24 | 1991-01-07 | Pharmaceutical and cosmetic compositions containing a salt of cholanic acid |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5376646A (en) |
| EP (1) | EP0439042B1 (en) |
| JP (1) | JP3240330B2 (en) |
| AT (1) | ATE124253T1 (en) |
| AU (1) | AU636947B2 (en) |
| CA (1) | CA2033725C (en) |
| DE (1) | DE59105808D1 (en) |
| DK (1) | DK0439042T3 (en) |
| IE (1) | IE67504B1 (en) |
| NZ (1) | NZ236823A (en) |
| PH (1) | PH31460A (en) |
| ZA (1) | ZA91353B (en) |
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| US8846066B2 (en) | 2004-05-19 | 2014-09-30 | The Regents Of The University Of California | Methods and related compositions for reduction of fat and skin tightening |
| US9186364B2 (en) | 2009-03-03 | 2015-11-17 | Kythera Biopharmaceuticals, Inc. | Formulations of deoxycholic acid and salts thereof |
| US9683007B2 (en) | 2009-12-18 | 2017-06-20 | Kythera Biopharmaceuticals, Inc. | Methods for the purification of deoxycholic acid |
| US11344561B2 (en) | 2011-02-18 | 2022-05-31 | Allergan Sales, Llc | Treatment of submental fat |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2033714A1 (en) * | 1990-01-25 | 1991-07-26 | Alberto Ferro | Pharmaceutical preparations |
| US5958379A (en) * | 1994-09-30 | 1999-09-28 | Mika Pharma Gesellschaft Fuer Die Entwicklung Und Vermarktung Pharmazeutischer Producte Mbh | Pharmaceutical composition |
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| DE19522693A1 (en) * | 1995-06-22 | 1997-01-02 | Dianorm G Maierhofer Gmbh | Composition for the production of finely dispersed systems and process for their production |
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| FR2746009B1 (en) * | 1996-03-14 | 1998-05-29 | VITAMIN A ESTER EMULSION | |
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| IL122084A (en) * | 1997-10-31 | 1999-09-22 | Lurident Ltd | Formulation for personal care with mucoadhesive properties |
| GB9723669D0 (en) * | 1997-11-07 | 1998-01-07 | Univ Aberdeen | Skin penetration enhancing components |
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| US6221378B1 (en) | 1998-02-10 | 2001-04-24 | Generex Pharmaceuticals Incorporated | Mixed micellar delivery system and method of preparation |
| DE19823319A1 (en) * | 1998-05-26 | 1999-12-02 | Karl Engelhard, Fabrik Pharm.- Praeparate Gmbh & Co. Kg | Topical drug for the treatment of viral infections |
| DE19825856A1 (en) * | 1998-06-10 | 1999-12-16 | Labtec Gmbh | New topical formulation which includes active agent as liquid lipid nanoparticles in an oil-in-water emulsion |
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| DE10243437A1 (en) * | 2002-09-18 | 2004-04-29 | Pm-International Ag | Cosmetic formulation |
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Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5118501B2 (en) * | 1972-06-06 | 1976-06-10 | ||
| US4115313A (en) * | 1974-10-08 | 1978-09-19 | Irving Lyon | Bile acid emulsions |
| IT1202370B (en) * | 1976-07-12 | 1989-02-09 | Hoffmann La Roche | INJECTABLE SOLUTIONS IN WHICH THE EMOLITHIC LIFE OF NATURAL MICELLES TRAINING AGENTS IS AVOIDED BY THE ADDITION OF LIPOIDS AND RELATED PRODUCTS |
| JPS53107408A (en) * | 1977-02-28 | 1978-09-19 | Yamanouchi Pharmaceut Co Ltd | Micellar preparation for rectal infusion |
| IT1174680B (en) * | 1980-08-14 | 1987-07-01 | Francesca Candussi | PATENTS AND MARKS NOTARBATOLO & GERVASI VLE BIANCA MARIA 33 MILAN |
| LU83711A1 (en) * | 1981-10-23 | 1983-06-07 | Oreal | OIL COMPOSITIONS COMPRISING AN ACTIVE DERMATOLOGICAL PRINCIPLE FOR THE TREATMENT OF SCALP OR SKIN |
| CA1264162A (en) * | 1984-03-15 | 1990-01-02 | Manfred Breuninger | Glycerol ether phosphatides |
| GB8417895D0 (en) * | 1984-07-13 | 1984-08-15 | Marples B A | Pharmaceutical anti-fungal composition |
| US4826871A (en) * | 1985-03-13 | 1989-05-02 | Gressel Philip D | Topical ophthalmic compositions containing one or more retinoids |
| US4857514A (en) * | 1985-09-17 | 1989-08-15 | Yeda Research And Development Company, Ltd. | Virus inactivation |
| FR2591105B1 (en) * | 1985-12-11 | 1989-03-24 | Moet Hennessy Rech | PHARMACEUTICAL COMPOSITION, IN PARTICULAR DERMATOLOGICAL, OR COSMETIC, BASED ON HYDRATED LIPID LAMELLAR PHASES OR LIPOSOMES CONTAINING A RETINOIDE OR A STRUCTURAL ANALOG OF SUCH A RETINOID AS A CAROTENOID. |
| US5179079A (en) * | 1986-12-16 | 1993-01-12 | Novo Nordisk A/S | Nasal formulation and intranasal administration therewith |
| CA1319886C (en) * | 1987-02-03 | 1993-07-06 | Alberto Ferro | Mixed micelle solutions |
| DE3903753A1 (en) * | 1989-02-06 | 1990-08-23 | Schering Ag | METHOD FOR PRODUCING AQUEOUS MIXED MICRO SOLUTIONS |
| NZ232865A (en) * | 1989-03-21 | 1992-07-28 | Hoffmann La Roche | A mixed-micelle solution comprising a micelle former and an immunomodulator |
-
1991
- 1991-01-07 CA CA002033725A patent/CA2033725C/en not_active Expired - Lifetime
- 1991-01-14 DE DE59105808T patent/DE59105808D1/en not_active Expired - Lifetime
- 1991-01-14 DK DK91100372.1T patent/DK0439042T3/en not_active Application Discontinuation
- 1991-01-14 EP EP91100372A patent/EP0439042B1/en not_active Expired - Lifetime
- 1991-01-14 AT AT91100372T patent/ATE124253T1/en not_active IP Right Cessation
- 1991-01-17 ZA ZA91353A patent/ZA91353B/en unknown
- 1991-01-18 NZ NZ236823A patent/NZ236823A/en unknown
- 1991-01-21 AU AU69856/91A patent/AU636947B2/en not_active Expired
- 1991-01-21 JP JP01915791A patent/JP3240330B2/en not_active Expired - Lifetime
- 1991-01-23 IE IE23591A patent/IE67504B1/en not_active IP Right Cessation
-
1993
- 1993-06-16 US US08/077,811 patent/US5376646A/en not_active Expired - Lifetime
-
1994
- 1994-01-24 PH PH41891A patent/PH31460A/en unknown
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10058561B2 (en) | 2004-05-19 | 2018-08-28 | The Regents Of The University Of California | Methods and related compositions for reduction of fat and skin tightening |
| US8846066B2 (en) | 2004-05-19 | 2014-09-30 | The Regents Of The University Of California | Methods and related compositions for reduction of fat and skin tightening |
| WO2006086038A1 (en) * | 2005-02-08 | 2006-08-17 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Methods and related compositions for reduction of fat and skin tightening |
| US9186364B2 (en) | 2009-03-03 | 2015-11-17 | Kythera Biopharmaceuticals, Inc. | Formulations of deoxycholic acid and salts thereof |
| US10071105B2 (en) | 2009-03-03 | 2018-09-11 | Kythera Biopharmaceuticals, Inc. | Formulations of deoxycholic acid and salts thereof |
| US10500214B2 (en) | 2009-03-03 | 2019-12-10 | Allergan Sales, Llc | Formulations of deoxycholic acid and salts thereof |
| US11179404B2 (en) | 2009-03-03 | 2021-11-23 | Allergan Sales, Llc | Formulations of deoxycholic acid and salts thereof |
| US9683007B2 (en) | 2009-12-18 | 2017-06-20 | Kythera Biopharmaceuticals, Inc. | Methods for the purification of deoxycholic acid |
| US10005813B2 (en) | 2009-12-18 | 2018-06-26 | Kythera Biopharmaceuticals, Inc. | Methods for the purification of deoxycholic acid |
| US10472384B2 (en) | 2009-12-18 | 2019-11-12 | Allergan Sales, Llc | Methods for the purification of deoxycholic acid |
| US10981946B2 (en) | 2009-12-18 | 2021-04-20 | Allergan Sales, Llc | Methods for the purification of deoxycholic acid |
| US11344561B2 (en) | 2011-02-18 | 2022-05-31 | Allergan Sales, Llc | Treatment of submental fat |
| US8653058B2 (en) | 2011-04-05 | 2014-02-18 | Kythera Biopharmaceuticals, Inc. | Compositions comprising deoxycholic acid and salts thereof suitable for use in treating fat deposits |
| US10946030B2 (en) | 2011-04-05 | 2021-03-16 | Allergan Sales, Llc | Formulations of deoxycholic acid and salts thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ236823A (en) | 1993-08-26 |
| US5376646A (en) | 1994-12-27 |
| CA2033725A1 (en) | 1991-07-25 |
| ATE124253T1 (en) | 1995-07-15 |
| IE910235A1 (en) | 1991-07-31 |
| JPH04210927A (en) | 1992-08-03 |
| AU6985691A (en) | 1991-07-25 |
| AU636947B2 (en) | 1993-05-13 |
| IE67504B1 (en) | 1996-04-03 |
| EP0439042B1 (en) | 1995-06-28 |
| DE59105808D1 (en) | 1995-08-03 |
| PH31460A (en) | 1998-11-03 |
| JP3240330B2 (en) | 2001-12-17 |
| DK0439042T3 (en) | 1995-10-02 |
| ZA91353B (en) | 1991-09-25 |
| EP0439042A1 (en) | 1991-07-31 |
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