Title:  Method of treating skin disorders with high-strength retinoids

United States Patent:  6,228,887

Appl. No.:  567792

Various skin disorders, excluding acne are treated by topical application to the skin of a retinoid-composition including a retinoid in a dermatologically acceptable vehicle at such a concentration and applied in such a way as to induce desquamation of the skin to ameliorate the disorder. Preferably, the compositions contain greater than 0.1 weight percent tretinoin, and more preferably at least 0.2 weight percent tretinoin. The vehicle is preferably a solvent for the retinoid such as an alcohol/glycol or hydroalcoholic vehicle, but it is also possible to apply the retinoid in a non-solvent vehicle such as emulsifying or suspending the retinoid in a cream, dressing, gel, ointment or liquid polymer, with or without penetration enhancers. The treatment achieves rapid amelioration of skin disorders such as photodamaged skin, hyperpigmentation, rosacea, premalignant cancers including actinic keratoses, wrinkles, superficial scarring, epidermal atrophy and atypia, and keratosis pilaris, by daily or every other day application for about one to two months. Thereafter, the high strength applications may be tapered off, and the treated skin maintained with more conventional lower concentration compositions.

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 other effects. Accordingly, as used herein for purposes of the present invention, the term "retinoid" will be understood to include any of the foregoing compounds. Examples of suitable retinoids for use in the present invention which are presently commercially available or in clinical trials include: 13-cis retinoic acid (isotretinoin), 9-cis retinoic acid, tazarotene (an acetylinic or RAR specific retinoid from Allergan, Inc.), and adapalene (a naphthoic acid derivative from Galderma Laboratories, Inc.)

There are preferably no other active ingredients in the retinoid compositions used in this invention, particularly no other active ingredients or components with known activity in treating skin disorders by chemical skin peeling, e.g., alpha hydroxy acids, salicylic acid, trichloroacetic acid, resorcinol and the like. However, steroids or other drugs may be used concurrently to offset side affects, where present or appropriate.

The retinoid used in this invention is applied to the skin being treated in a composition or formulation suitable for topical application, i.e., directly dabbing or spreading on the epidermis. The retinoid composition includes a carrier or vehicle, preferably a liquid vehicle that is a solvent for the retinoid and is dermatologically acceptable. The term "dermatologically acceptable" means suitable for use in contact with skin tissue without undue toxicity, incompatibility, instability or adverse reaction with the skin or the active ingredient, e.g. tretinoin.

Tretinoin and other retinoids are substantially insoluble in aqueous vehicles. Therefore, organic solvent vehicles are preferred as the liquid carrier. Alcoholic vehicles such as ethanol and isopropanol are preferred, with ethanol being most preferred. Other suitable solvent vehicles to form a solution of a retinoid include, for example, acetone, diethyl ether, liquid glycols or glycol derivatives, and hydroalcoholic vehicles.

The solvent vehicle may also be a mixture of such components. A particularly suitable solvent vehicle carrier for tretinoin comprises an alcohol selected from the group consisting of ethanol and isopropanol and a suitable liquid glycol or glycol derivative. Examples of suitable glycols are liquid polyethylene glycols, such as polyethylene glycol 400, propylene glycol and liquid polypropylene glycols. Of these, polyethylene glycols and propylene glycols are preferred. Examples of suitable liquid glycol derivatives include ethylene glycol ethers, such as mono-, di- and triethylene glycol monomethyl ethers and mono- di- and triethylene glycol monoethyl ethers.

A preferred solvent vehicle for tretinoin comprises from about 20 to 80% by weight of ethanol or isopropanol and the balance being a liquid glycol, preferably polyethylene glycol.

Instead of a solvent carrier, the retinoid may be suspended or emulsified in a non-solvent vehicle, such as any of various formulations known or available in the art, including creams, dressings, gels, ointments and liquid polymers. Whatever the vehicle or carrier selected for the retinoid, it is important that it be one which promotes good contact with and penetration into the skin, not only into the epidermis, but preferably also into the dermis. Thus, vehicles are preferred which drive the highest concentration across the stratum corneum as possible. Alcoholic vehicles are particularly useful in this regard, whereas polymers, sponges and other vehicles which may retard or sequester release of the active agent are not preferred. Although tretinoin, for example, is in itself a good penetration enhancer, additional penetration enhancing agents may be helpful in some circumstances, and such agents are generally known to those of ordinary skill in the art.

The retinoid concentration in the vehicle is such that the topical application will cause desquamation of the skin, including superficial and/or subclinical peeling. In the case of tretinoin the concentration is preferably greater than 0.1% by weight, e.g., at least about 0.12% by weight, and more preferably at least about 0.2% by weight tretinoin in the vehicle. Concentrations greater than about 0.3 to 0.5% by weight are unnecessary and not preferred. A particularly preferred formulation contains about 0.25% by weight tretinoin in a liquid carrier comprising ethanol and polyethylene glycol 400. These concentrations of tretinoin are percent by weight based on the total weight of the formulation. Such concentration are referred to herein as "high-strength" in contrast to lower strength concentrations, i.e. up to about 0.1% by weight, which for most people will not cause intensive inflammation and/or peeling. In the case of other retinoids, the concentration sufficient to cause desquamation may be different from that of tretinoin, but can be determined by one skilled in the art without undue experimentation.

The topical retinoid formulations of this invention are preferably solutions in which the retinoid is completely dissolved. The formulations may also contain other dermatologically acceptable adjuvants, such as antioxidants or other formulation stabilizers that provide increased shelf life, thickening agents, and other conventional skin care formulation additives, e.g., sunscreens or sun blocks.

The retinoid composition of this invention is initially applied to the skin to be treated either daily, or every other day or every third day, with single applications every day or every second day being preferred. For treatment of facial skin, the composition is applied to the entire face, i.e., the forehead, cheeks, around crows feet areas, the lower eyelids, the nose, the upper lip and the chin. Other areas of the skin, such as dorsal forearms, hands, upper chest, upper back, neck, and scalp, may be treated in the same way as facial skin. Preferably, the composition is applied at night prior to the individual going to bed. Application of the retinoid composition may be made by conventional means, e.g., a cotton-tipped applicator, a gauze pad, or the like. After each application of the retinoid composition, the composition is allowed to dry on the skin by at least partial evaporation of the vehicle.

In the case of the treatment of actinic keratoses, it may be desired to apply the retinoid composition twice a day, in a manner similar to the conventional treatment of actinic keratoses with 5-fluorouracil. This is particularly the case with treatment of thicker hypertrophic actinic keratoses or with treatment of the forearms, hands and other parts of the body which may be more tolerant to irritation than the face, and may require more intensive treatment to effect desquamation. Further, treatment of actinic keratoses and other skin disorders besides photoaging may be by spot application to visible lesions or affected areas of the skin, instead of by general application to the skin.

During the initial 1-2 weeks of treatment, the high concentration of retinoid present in the composition results in an intensive inflammation or irritation to the skin that is nevertheless generally at an acceptable or tolerable level for most individuals, when the preferred application rate of every night or every other night is used. The skin irritation is observable as a flushing or diffuse reddening of the skin on which the retinoid formulation is applied. For most individuals, erythema and desquamation (peeling) develop in about 7-10 days after initiation of treatment and subside in about another 7-10 days. Thus, in most cases, depending on the individual treated and the concentration and/or frequency of application, a superficial chemical skin peel, as well as subclinical peeling, is effected by the high-strength retinoid treatment. After the initial peeling, the patient's skin accommodates to the high dose, probably due to down-regulation of the cells, so that further treatment is more easily tolerated.

If desired, a bland moisturizer may be used during the time of peeling, typically over the first two weeks of treatment, which makes the irritation and peeling that occurs during this period more tolerable to the treated individuals. For individuals with more sensitivity to the irritating sensation, application of the retinoid tretinoin composition may be made every three days instead of the preferred application every one or two days. For individuals with more extensive photodamage, particularly elderly individuals who typically have a dampened inflammatory response, the tretinoin composition may be applied daily, rather than every other day.

After the initial two to three weeks of treatment, the retinoid composition may be applied daily since the irritation response subsides for most treated individuals. The treatment is continued for a total period of time of about 1-2 months, preferably about 4-6 weeks. Generally after about 3-4 weeks, the treated individuals report significant improvement in the treated skin such as smoothing, more suppleness and softness to the skin, diminution of fine lines, decreased sallowness (yellow color) and more vascularity as evidenced by a rosier glow to the skin. These results may be corroborated by photographic analysis of the treated individual both pre- and post-treatment. Treated individuals typically find that makeup (foundation) is easier to apply since the dry surface of photodamaged skin has been eliminated and replaced with an increase in skin moisturization, e.g., as measured by conductance using a Novameter.

Examination of skin biopsy specimens by histology confirms that reversal of photodamage is seen early in the course of the treatment of this invention. Such skin improvement includes normalization of epidermal atypia, thinning of the stratum corneum, acanthosis of the stratum germinativum, increased rete ridge patterns, dispersal of pigment granules, increased collagen fiber synthesis in the papillary dermis, and increase vascularity, as well as improved skin elasticity and increased skin moisturization.

After completion of the treatment of photoaging according to the method of this invention, the improvement in skin condition and appearance may be maintained by use of conventional skin treatment protocols, e.g., treatment with low strength (0.05%) tretinoin emollient creams, or other retinoid compositions, such as retinol or isotretinoin formulations.

The present invention is not only useful for treating individuals with photodamaged or photoaged skin, but also may be used with individuals who have other skin disorders including rosacea, hyperpigmentation (melasma), premalignant skin cancers (including actinic keratoses), wrinkles, superficial scarring, epidermal atrophy and/or atypia, and keratosis pilaris.

The retinoid treatment of this invention is surprisingly well tolerated by individuals being treated and results in rapid improvement of skin condition and appearance. Fine lines and wrinkles are reduced, blotchiness is diminished, and rough scaling is replaced by a smooth skin surface. Increased skin firmness is evident by palpation, and this may be confirmed by physical measurements of elasticity. The increased smoothness and improved texture of the skin that results may be confirmed by Silflo replicas. The increased hygroscopicity and water holding capacity in the stratum corneum of the treated skin may be confirmed by impedance measurements using a Novameter. The cosmetic benefits that result from the treatment method of this invention are noteworthy for treated individuals whose skin initially exhibits fine line wrinkles, mottled hyperpigmentation, skin roughness, and other symptoms associated with photoaging and photodamage.

In the case of the treatment of premalignancies such as actinic keratoses, it is believed that retinoids can drive apoptosis. Thus, while applicants do not wish to be bound by any particular theory, it is believed that the noraml killing off of cells that are aberrant (apoptosis) is interrupted by the premalignancies, so that the aberrant cells continue to divide and multiply. Retinoids appear to have the ability to stop the aberrant cell division by reinstituting a sort of apoptosis program so that the premalignant cells are killed off.

Claim 1 of 11 Claims

We claim:

1. A method for treating a skin disorder excluding acne, comprising topically applying to skin to be treated a retinoid-containing composition comprising a retinoid in a dermatologically acceptable vehicle, the concentration of retinoid in the composition and the topical application being effective to induce desquamation of the skin to ameliorate the disorder.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.