Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1995-02-27
1997-07-01
Dodson, Shelley A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514182, 514552, 514558, 514625, 514847, A61K 3159, A61K 3123, A61K 3120, A61K 3116
Patent
active
056438990
DESCRIPTION:
BRIEF SUMMARY
This invention resides in the area of topical formulations for application to skin. Among the various effects sought by the administration of such formulations are emolliation and hydration, as well as repair of the epidermal barrier function. In particular, this invention relates to the application of lipids and lipid formulations and to the treatment of subjects suffering from skin or mucous membrane diseases or disorders which display epidermal hyperproliferation and disruptions of the barrier function.
BACKGROUND OF THE INVENTION
The skin is the largest organ of the body and protects mammalian organisms from both aqueous and xerotic ambient environments. The maintenance of a barrier against excessive transcutaneous water loss to the environment is critical to survival of all terrestrial animals. In mammals, this barrier is formed by the anucleate, cornified, outermost layers of the epidermis, collectively known as the stratum corneum. Both the surfaces of mucous membranes and the deepest layers of the stratum corneum contain high concentrations of glycosphingolipids which are metabolized progressively to ceramides as the stratum granulosum becomes anucleate with outward maturation. Localized or generalized perturbations of the epidermal barrier occur in a variety of diseases and conditions of the skin and mucous membrane. These perturbations not only contribute significantly to the morphology of the cutaneous lesions, but also activate certain skin diseases, for example the Koebner phenomenon in psoriasis. Common moisturizers and emollients also cause disruptions of the barrier function.
It is now generally accepted that the intercellular, lamellar bilayer sheets of stratum corneum lipids are the key constituents for a functional barrier. The epidermal lipids consist of a mixture of polar and nonpolar species. The three dominant lipids by weight are ceramides (40%), cholesterol (20-25%) and free fatty acids (20-25%). The latter group include the essential fatty acid, linoleic acid, as well as additional nonessential fatty acids. The human epidermis further contains a unique acylsphingolipid whose molecular structure includes a sphingoid backbone with a 30-carbon, .alpha.-hydroxy acid residue joined to the backbone through an amide linkage, the residue itself being .omega.-esterified with linoleic acid.
Although each of the lipid species is important for stratum corneum homeostasis, ceramides are of particular importance because of their large weight contribution and structural characteristics. The moisturization properties of ceramides are known. A published Japanese patent application of Kao Company Limited (No. 24391-1987) discloses a formulation containing bovine ceramide with a sphingoid base of 10 to 26 carbon atom length and one or more of any of the other stratum corneum lipids. The purpose of this formulation is to increase water retention and improve skin roughness (moisturization).
Despite the potential efficacy of lipids as moisturizer ingredients, studies have demonstrated that many of the individual lipids, including ceramides and lipid combinations which are disclosed in the Kao disclosure for their moisturization properties, actually impede rather than facilitate barrier repair when applied to damaged skin. Formulations of this kind will therefore worsen the lesions of skin and mucous membrane diseases because an acute or chronically damaged epidermal barrier responds differently than either normal skin or merely dry, rough skin when epidermal lipids are applied.
While substances which effect barrier repair are all effective as moisturizers as well, the converse is not true. For example, scaling and roughness of the skin are a manifestation of an abnormally desquamating stratum corneum, but often these conditions do not correlate with the function of the stratum corneum barrier. Patients suffering from atopic dermatitis, for example, have skin with an incompetent barrier, as measured by trans-epidermal water loss, but no visible scaling.
Moisturizers are defined as substances which in
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William Abraham, et al., "Effect of Epidermal Acylglucosylceramides and Acylceramides on the Morphology of Liposomes Prepared From Statum Corneum Lipdis, Biochimica et Biophysica Acta 939", 403-408, (1988) Elsevier.
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Elias Peter M.
Feingold Kenneth R.
Thornfeldt Carl R.
Cellegy Pharmaceuticals Inc.
Dodson Shelley A.
The Regents of the University of California
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