Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-05-09
2001-05-08
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S725000
Reexamination Certificate
active
06228887
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention is directed to the treatment of various skin disorders with high-strength tretinoin (also known as vitamin A acid or all-trans retinoic acid) or other retinoids. More particularly, the invention is directed to the treatment of skin disorders, especially of human facial skin, with amounts of retinoid sufficient to ameliorate the disorder.
Caucasians who have had a good deal of sun exposure in childhood will show the following gross cutaneous alternations in adult life: wrinkling, leatheriness, yellowing, looseness, roughness, dryness, mottling (hyperpigmentation) and various premalignant growths (often subclinical). These changes are most prominent in light-skinned persons who burn easily and tan poorly. The baleful effects of sunlight are cumulative, increasing with time and often referred to as “photoaging”. Although the anatomic degradation of the skin is most advanced in the elderly, the destructive effects of excessive sun exposure are already evident by the second decade. Serious microscopic alterations of the epidermis and dermis occur decades before these become clinically visible. Wrinkling, yellowing, leatheriness, loss of elasticity are very late changes.
Retinoids (e.g., Vitamin A and its derivatives) are substances which are known to have a broad spectrum of biological activity. More specifically, these substances affect cell growth, differentiation and proliferation. Retinoids affect the differentiation, maintenance, and proliferation of many types of cells whether they are of ectodermal, endodermal or mesodermal origin; whether they are epithelial, fibroblastic or mesenchymal; or whether they are neoplastic, preneoplastic or non-neoplastic. Retinoids have found clinical utility in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Possible uses of retinoids are being explored in the prophylaxis and treatment of cancer. For a recent review of developments in the uses of retinoids, see Orfanos et al., “Current Use and Future Potential Role of Retinoids in Dermatology,”
Drugs
53:358-380 (March 1997).
Other older reviews of the uses of retinoids in research and clinical medicine can be found in the publication of a symposium held in Geneva: J. H Saurat, Editor, “Retinoids: New Trends in Research and Therapy”, Karger Publishing Co. (1985); Pawson, B. A. et al., “Retinoids at the Threshold: Their Biological Significance and Therapeutic Potential”,
Journal of Medicinal Chemistry
25: 1269-1277 (1982); and Thomas, J. R., et al., “The Therapeutic Uses of Topical Tretinoin”,
Journal of American Academy of Dermatology
4:505-516 (1981).
It is known to use tretinoin topically for treatment of acne as set forth in U.S. Pat. No. 3,729,568 of A. M. Kligman. That patent discloses the treatment of acne with tretinoin in alcohol/glycol vehicles at concentrations sufficient to cause irritation including inflammation and peeling, such concentrations ranging as high as 0.5 weight percent, preferably 0.05 to 0.25 weight percent.
U.S. Pat. Nos. 4,603,146; 4,877,805 and 4,888,342 of A. M. Kligman disclose long term methods for treating sun-damaged human skin topically with low concentrations of tretinoin and other retinoids in an emollient vehicle, such amounts of retinoids being essentially non-irritating to the skin. This treatment requires periodic applications for several months before improvement is achieved, and this factor often leads to the treated individual discontinuing treatment before positive results are obtained.
SUMMARY OF THE INVENTION
According to the method of the present invention, skin disorders, excluding acne, are treated by topical application to the affected skin of a retinoid composition comprising a retinoid in a dermatologically acceptable vehicle, wherein the concentration of the retinoid in the composition and the topical application are effective to induce desquamation of the skin to ameliorate the disorder. The concentration of the preferred retinoid, tretinoin, in the composition is preferably greater than 0.1 weight percent, and more preferably at least about 0.2 weight percent tretinoin.
The vehicle may be a solvent for the retinoid, such as ethanol, isopropanol, acetone, diethyl ether, propylene gylcol, polyethylene glycol and hydroalcoholic solvents, with mixtures of ethanol and polyethylene glycol being preferred. Is also possible to emulsify or suspend the retinoid in non-solvent vehicles, such as creams, dressings, gels, ointments and liquid polymers. The composition may also contain a penetration enhancing agent.
The retinoid-containing composition may be applied to facial skin, forearms, hands, upper chest, upper back, neck and scalp, in particular, or wherever the skin disorder is externally visible and of concern to the patient being treated. The composition is initially applied to the skin on the average of from about every day up to about one month to every other day for up to about two months. After the initial application regimen, the treatment may be tapered off to a lower concentration composition containing a retinoid for maintenance of the treated skin.
In its broadest aspects, the treatment of the present invention may be applied to skin affected with various disorders, including photodamaged skin, hyperpigmentation, rosacea, premalignant skin cancers including actinic keratoses, wrinkles, superficial scarring, epidermal atrophy and atypia, and keratosis pilaris. In one preferred embodiment, the present invention is directed to treatment of aging changes in the skin by topical application of high-strength retinoid in an alcoholic carrier or other suitable vehicle. Photoaging skin changes (sun damage) first become evident clinically in young to middle aged adults and are most evident in exposed portions of the body, particularly facial skin. Certain anatomic alterations associated with photoaging can be treated in a relatively short time using this invention, resulting in improvement in the appearance of the skin. Such skin abnormalities are corrected and modified to the extent that the structure and function of the skin acquires the characteristics of younger (undamaged) skin. This invention is particularly useful for providing rapid improvement in the treated skin, and such improvement can be maintained afterwards through conventional skin treatment programs.
In another preferred embodiment, the present invention is directed to the treatment of actinic keratoses (also known as solar keratoses). These are premalignancies which start in the basal cells of the epidermis, which left untreated may work down into the dermis and become malignancies. The treatment of actinic keratoses according to the present invention may require or benefit from twice daily application of the retinoid at the start of treatment, particularly for actinic keratoses of the hands, arms and other parts of the body.
DETAILED DESCRIPTION OF THE INVENTION
A retinoid is used as the active ingredient in this invention. A preferred retinoid is tretinoin, also known as vitamin A acid or all-trans retinoic acid.
Retinoids have been defined narrowly as comprising simply vitamin A (retinol) and its derivatives, such as vitamin A aldehyde (retinal), vitamin A acid (retinoic acid), comprising the so called natural retinoids. However, subsequent research has resulted in a much larger class of chemical compounds that are termed retinoids due to their biological similarity to vitamin A and its derivatives. Thus, there are now a number of so-called retinoic acid receptor (RAR)-specific retinoids which have been found to react with retinoid receptors despite having quite different structures from Vitamin A.
Compounds useful in the present invention include all natural and/or synthetic analogues of vitamin A or retinol-like compounds, as well as RAR-specific retinoids, which possess the biological activity of vitamin A in the skin, such as the control of epithelial cell differentiation of keratinocytes in the epidermis and/or stimulation of fibroplasia or new collagen synthesis in the dermis among o
Kligman Albert M.
Kligman Douglas E.
Akin Gump Strauss Hauer & Feld L.L.P.
Henley III Raymond
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