Stable topical retinoid compositions

Details Stable topical retinoid compositions Stable topical retinoid compositions

1995-12-28

1997-11-25

Mosley, Terressa

Drug, bio-affecting and body treating compositions

Topical body preparation containing solid synthetic organic...

424 7803, 514725, A61K 3174

Patent

active

056909233

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to aqueous pharmaceutical and cosmetic compositions, comprising a retinoid, for topical application to the skin.


BACKGROUND OF THE INVENTION

Topical compositions, comprising a retinoid in an aqueous vehicle, are known.
Vitamin A acid or retinoic acid, IUPAC name 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid, has been used topically for the treatment of acne vulgaris and recently also for the treatment of ageing skin. The naturally occurring form is the all-trans compound or tretinoin, but cis compounds are also known. The 13-cis compound or isotretinoin is also used as a keratolytic agent. Both isomers and derivatives thereof, such as salts, esters and amides, and structural analogues, such as etretinate, belong to the group of the retinoids.
WO 90/14833 (Bazzano) discloses a stable, aqueous composition for topical application to the skin, comprising a retinoid. Said composition may also comprise 0.1 to 20 wt % of a solubilising agent (ethanol) and a surfactant, the last mentioned ingredient being added in order to have the dual benefit of helping to maintain the active ingredient in uniform suspension in the formulation, while enhancing the bioavailability of the active ingredient.
However, the stability of the compositions is still rather limited: table II at page 17 mentions the percentage decomposition of tretinoin in 7 formulations, said percentage ranging from 3 to 13% after 10 months' storage. Furthermore, all examples show compositions comprising a substantial amount of the solubilising agent ethanol. It, thus, is to be expected that said compositions, due to the presence of said solubilising agent, still cause irritation and inflammation of the skin.
EP-A-393904 (Maxam) discloses a water-based, alcohol-, oil- and fat-free formulation comprising tretinoin in a not completely solvated form, a gelling agent and a proteinaceous material for stabilising the gelling agent. The formulation may further comprise one or more of an antioxidant, a preservative and glycerin. A surfactant, the choice of which does not seem to be critical, may also be incorporated in the formulation to allow good dispersion of the active ingredient and to enhance skin penetration. The compositions are said to be physically and chemically stable. However, it is well-known that proteinaceous materials, such as proteins, polypeptides, peptides, amino acids and mucopolysaccharides as mentioned in the specification, are prone to microbial attack and/or chemical degradation, especially in aqueous vehicles. Therefore, the stabilising effect exerted by said materials will be limited.
Reference is made further to U.S. Pat. Nos. 4,022,913 and 4,532,133 which both disclose compositions comprising vitamin-A alcohol esters for uses like high potency vitamin preparations and additives in animal feed.
The compositions of the present invention comprise compounds derived from vitamin-A acid which are not the subject of above references.
Retinoids are insoluble or at most very slightly soluble in water, but readily soluble in e.g. ethanol. Therefore retinoid containing preparations have been most effectively applied using an alcohol containing solvent system, which causes an uncomfortable burning sensation by itself. Said sensation is amplified when applied to skin which was previously or is simultaneously treated with retinoic acid. Cream formulations were found to be generally more acceptable to patients, but they were found to have other disadvantages, such as a reduced clinical effectiveness as compared with alcoholic compositions containing the same amount of retinoic acid and sometimes a comedogenic effect due to fats and oils, used in the formulations. Aqueous retinoic acid preparations containing no alcohol and no fats have not shown to be clinically very effective, due to the fact that the active ingredient is not dissolved and, thus, not available for exerting the desired effect.
There, thus, exists a need for a composition comprising a retinoid, which composition: said r

REFERENCES:
patent: 4532133 (1985-07-01), Schmidt
patent: 5043356 (1991-08-01), Fulton, Jr.

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