SKIN COMPOSITION TO REPAIR THE EFFFECTS OF PHOTOAGING

Abstract: The effects of photoaging or sun damage of skin including loss of collagen fibers and deterioration of small blood vessels in the dermis of the skin are repaired by applying topically to the epidermis effective amounts of a compound having structure (I), wherein R1, R2, R3, R4 and R5 are independently selected from the group consisting of H, Cl, OR6, straight or branched alkyl of 1 to 10 carbon atoms, NO2, COOR6, CN, OR6, NR6R7, NR6C(=S)NR7R8, NR6COR7, SO2NR6R7, CH(CH3)COOH, CONR6R7, COR6, OCONR6R7, NR6COONR7, R9OR6, NR6SO2R7, Si(CH3)3, and NR6CONR7R8, R3 together with R4 forms a benzo ring or taken together with R2 forms a benzo or tetrahydrobenzo ring or together with R2 and R1 forms a (1) moiety or together with R2 forms a (2) moiety or R2 together with R1 forms a benzo ring or R2 together with R3 forms a (3) or (4) or (5) or (6) moiety, or R1 is independently selected from the group consisting of (7), (8) moiety, R6, R7 and R8 are independently selected from the group consisting of straight or branched alkyl containing from 1 to 10 carbon atoms, aryl containing from 6 to 10 carbon atoms and hydrogen, and R9 is alkylene of 1 to 6 carbon atoms, and iron carbonyl complexes thereof, to an area of the skin in an amount sufficient to repair the effects of elastosis in the skin. Lines and wrinkles due to aging are reduced and prevented.

Description: SKIN COMPOSITION TO REPAIR THE EFFECTS OF PH0T0A6ING Cross-Referencβ to Related Applications This application is a Continuation-In-Part of copending U.S. Application Serial No. 384,949 filed on July 25, 1989. Field of the Invention This invention relates to a method of repairing the effects of aging of the skin, particularly human facial skin, by topical application of specific polyene compositions. Background of the Invention Excessive exposure of human skin to sunlight causes damage, resulting in a number of gross cutaneous changes. These include wrinkling, leather- iness, yellowing, looseness, roughness, dryness, mottling (pigment spots) and benign and malignant skin tumors. A person exhibiting these signs looks prematurely aged. Photoaging is most prominent in light skinned persons who brown easily and tan poorly. The effects of sunlight are cumulative. As a result, this sunlight-induced skin damage has been referred to as photoaging. The majority of signs of photoaging can be prevented by judicious use of topically applied sunscreen agents. It is important to use sunscreens early in life, for example, as soon as a child begins to spend a significant amount of time outdoors. Many persons will neglect to use sunscreens, and worse, some will intentionally overexpose them¬ selves to natural or artificial sunlight to benefit from cosmetic attributes of tanned skin. Later in life, they will seek medical care in the hope of alleviating the skin damage, for instance, by under- going cosmetic surgery. A pharmaceutical composition that can promote the repair of photoaged skin is an alterna¬ tive treatment to patients who neglect to use sun¬ screens and do not prefer cosmetic surgery. Topi— cally applied all-trans retinoic acid is reported to improve the appearance of photoaged skin in open and double—blind studies. The beneficial changes were clinically significant to the investigators and the patients. These included effacement of fine wrinkles, reduced skin roughness, increased pinkening of the skin and lightening of pigmented sessions (lentigines, solar—induced freckles). In the double—blind study, it was reported that 92 percent of patients experienced a dermatitis characterized by patchy erythema, localized swelling, xerosis, and mild scaling. Eleven of the patients needed potent topical steroids to alleviate the dermatitis. Three patients withdrew from the study because of the severity of retinoid—induced dermati— tis. It has been sought to provide a method for the treatment of photoaged skin, but without the adverse effects of dermatitis as noted with all-trans retinoic acid treatment. The use of 13—cis—retinoic acid as a treat¬ ment for the adverse effects of elastosis is des¬ cribed in Australian Patent AU-A-83027187 by Hoffman—La Roche and European Patent Application Publication 0253393. In U.S. Patent 4,595,696 certain polyenes are described as being useful in treating inflamma¬ tory or allergic conditions. These conditions, of course are far afield of photoaging and materials useful for the treatment of inflammatory conditions are not expected to be useful in the treatment of photoaging and vice versa. In U.S. Patent 4,603,146 it is disclosed that all—trans retinoic acid (retin A) is useful in the treatment of photoaging. However, this treatment also results in great irritation to the skin, which severely limits its usefulness. Summary of the Invention The present invention relates to the use of specific polyenes in repairing the aging changes of exposed areas of the skin, especially the face. These polyenes retard and reverse the loss of collagen fibers and deterioration of small blood vessels without substantially adversely affecting the patient. The method of the invention comprises the repairing of sun-damaged skin comprising topically administering a compound having the structure: wherein R^ and Re are independently selected from the group consisting of H, Cl, 0 6 , straight or branched alkyl of 1 to 10 carbon atoms, N0 2 , C00R 6 , CN, OR^, N ^R 7 , NR 6 C(=S)NR 7 R g , NR 6 C0R 7 , S0 2 NR 6 R ? , CH(CH 3 )C00H, C0NR 6 R ? , C0R 6 , 0C0N 6 R ? , NR 6 C00NR ? , 9 OR 6 , N 6 S0 2 R y , Si(CH 3 ) 3 , and NR 6 C0NR 7 g , R together with ^ forms a benzo ring or taken together with R 2 forms a benzo or tetrahydrobenzo ring or together with 2 and -i forms a: I i Y moiety or together with R 2 forms a NHCOR, I 6 moiety or R 2 together with R, forms a benzo ring or R 2 together with R 3 forms a moiety, or R, is independently selected from the group consisting of moiety, R & , R 7 and R g are independently selected from the group consisting of straight or branched alkyl containing from 1 to 10 carbon atoms, aryl containing from 6 to 10 carbon atoms and hydrogen, and R Q is alkylene of 1 to 6 carbon atoms, and iron carbonyl complexes thereof, to an area of the skin in an amount sufficient to repair the effects of elastosis in the skin. Lines and wrinkles due to aging are reduced and prevented. The polyenes may be applied to the skin in any non-toxic, dermatologically acceptable vehicle, preferably a non—volatile emollient or lubricating vehicle in varied concentrations which is more fully described hereinbelow. Detailed Description of the Preferred Emobidments The treatment of skin with the polyenes of the present invention moderate and retard the aging changes in the skin to both the dermis and the epidermis. As age and exposure to sunlight increases, the skin's cells divide at a slower rate. The thickness of the epidermis decreases and the horny layer which protects against water loss sheds cells in large groups, resulting in rough, dry and scaling skin. The cells which make up the fiber of the dermis become smaller with increasing age with a loss of collagen fibers. The degradation of these fibers contributes to wrinkling and loss of elasti¬ city. The polyene compounds useful in the present invention have the structure: wherein R, , R 2 , R 3 , R^ and R. are independently selected from the group consisting of H, Cl, OR,, straight or branched alkyl of 1 to 10 carbon atoms, for which examples are provided hereinbelow, N0 2> C00 6 , CN, 0R 6 , N & R 7 , NR 6 C(=S)NR 7 Rg, NR 6 C0R y , S0 2 NR 6 R ? , CH(CH 3 )C00H, C0NR 6 R 7 , C0R 6 , OCON ^, NR 6 C00NR ? , RgOR 6 , NR 6 S0 2 R ? , Si(CH 3 ) 3 , and NR 6 C0 R 7 R g , R 3 together with R, forms a benzo ring or taken together with R 2 forms a benzo or tetrahydrobenzo ring or together with R 2 and R*. forms a: • moiety or together with R 2 forms a NHCOR, I 6 moiety or R 2 together with R, forms a benzo ring or R 2 together with R 3 forms a moiety, or R, is independently selected from the group consisting of moiety, R 6 , R 7 and R g are independently selected from the group consisting of straight or branched alkyl containing from 1 to 10 carbon atoms, for which examples are provided hereinbelow, and aryl containing from 6 to 10 carbon atoms and hydrogen, for which examples are provided hereinbelow, and R Q is alkylene of 1 to 6 carbon atoms, such as methylene, propylene, butylene, trimethylene, etc. and iron carbonyl complexes thereof such as For the purposes of this invention, examples of alkyl of 1 to 10 carbon atoms are methyl, butyl, pehtyl, octyl, ethyl, tertiary—butyl, benzyl, isopropyl, chloroethyl, chloropropyl, hydroxypropyl, carboxyethyl, carboxymethyl, phenynyl, cyanoethyl, and 2-ethylhexyl and aryl of 6 to 10 carbon atoms are exemplified by phenyl and napthyl. The method of preparing these polyenes is well known and is generally described in U.S. Patent 4,595,696(incorporated herein by reference). Generally, the compounds are formed by reaction of polyene acids with acetic anhydride, boron trifluoride, oxalkylene chloride, phosphorous trichloride or thionyl chloride and then further treated with phenolic compounds. Useful polyenes within the scope of the present invention include those with the following structures: I. ω ω H cπ o O in cπ <! <! H H H H <i H H H H CO CO l-J NJ I-" n o Cn O o -J- M M H H M CO Cπ O cπ -Ji H H < H CO cπ cπ cπ H 3 o o o CO W O CO NJ cπ o Cπ cπ ω CO NJ NJ l-» cπ o cπ O Ul O Cπ CO CO NJ Nϊ cπ o cπ O cπ Oi CO CO cπ o NJ NJ cπ Cπ Cπ The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically-acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain of clay and so forth. They may be administered orally in the form of solutions which may contain coloring or flavoring agents. When applied topically for treatment of photoaging, they may be provided in the form of dusting powders, aerosol sprays, ointments, aqueous compositions including solutions and suspensions, cream lotions and the like. In this regard, any of the commonly employed extending agents can be used depending on the nature of the product as is well—known in the art. The physician will determine the dosage of the present theraputic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermore, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circumstances is reached. The polyenes which are formulated in moisturi- zing bases such as creams or ointments are usually provided in low concentrations. For example, Compound I may be used in concentrations of about 0.001 percent to 10 percent and preferably about 0.01 percent to 5 percent by weight of the base. Other non—toxic, dermatologically acceptable vehicles or carriers in which the polyenes are stable will be evident to those of ordinary skill in the art. In general, emollient or lubricating vehicles, such as oleaginous substances, which help hydrate the skin are preferred. As used herein, the term ■■ emollient" will be understood to refer to the non—irritating character of the composition as a whole. That is, the nature of the vehicle and amount of polyene therein should be selected so as to provide a sub—irritating dose for topical applica¬ tion. Volatile vehicles which dry or otherwise harm the skin, such as alcohol and acetone, should be avoided. An ointment base (without water) is pre¬ ferred in the winter and in subjects with very dry skin. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions, such as Eucerin (Beiersdorf). In warm weather and often for younger persons, oil in water emulsion (cream) bases, are preferred. Examples of suitable cream bases are Nivea Cream (Beiersdorf), cold cream (USP), Purpose Cream (Johnson &. Johnson), hydrophilic ointment (USP), and Lubriderm (Warner-Lambert). The length of treatment of human skin can vary. Usually, there is little point in beginning the treatments of the present invention until young adult life or, more typically, in middle age, when the effects of aging begin to appear. The particular program of maintenance therapy according to the present invention will vary depending upon the individual and conditions being treated. Generally, depending upon the age and state of the skin when treatments begin, it has been found that once a day applications of polyenes for up to two months may be necessary to reduce and control the effects of aging which have already occurred. Once a stabilized skin control has been obtained, the frequency of applica- tion of the polyenes may be reduced, for example to two or three times a week, and in some cases only once a week for the rest of the person's life. That is, once the aging process has been controlled, a maintenance dose on the order of two applications per week is generally sufficient to maintain that state. The topical compositions of this invention can, if desired, contain suitable sunscreen agents. Any conventional sunscreen agent can be utilized in formulating the polyenes formulations which can be utilized in accordance with this invention. These topical compositions can contain any of the conventional excipients and additives commonly used in preparing topical compositions. Among the conventional additives or excipients which can be utilized in preparing these cosmetic compositions in accordance with this invention are preservatives, thickeners, perfumes and the like. In addition, the conventional antioxidants , such as butylated hydroxy- anisoles (BHA), ascorbyl palmitate, propyl gallate, citric acid butylated hydroxy toluene (BHT), ethoxy- quin and the like can be incorporated into these compositions. These topical compositions can contain conventional acceptable carriers for topical applica¬ tions which are generally utilized in these composi— tions. These compositions may contain thickening agents, humectants, emulsifying agents and viscosity stabilizers, such as those generally utilized. In addition, these compositions can contain flavoring agents, colorants, and perfume which are conventional in preparing cosmetic compositions. This invention is further illustrated by the following examples, which are illustrative only. Example A. Efficacy Tests Compound II was tested for its effect on the differentiation of epidermis and dermis in hairless mice and directly compared to all-trans retinoic acid. In the first test used, polyene compounds related to vitamin A, including all—trans retinoic acid, are highly effective in reducing the size of horn—filled utricles in hairless rhino mouse skin. The number of interutricular epidermal cells layers increases, coneomitantly, as the size of the utricles diminish. Increased numbers of epidermal cell layers are also prominent in human photoaged skin treated with all—trans retinoic acid. Hairless rhino mice (hr r hr r ) from Temple University Skin and Cancer Hospital were treated with 0.05 ml of Compound II, all—trans retinoic acid or the ethanol:acetone (1:1) vehicle on the dorsolateral skin once daily on five consecutive days, for four weeks. Mice were sacrificed by C0 2 on the third day after the last treatments. A 7/8" punch biopsy of skin was removed and bisected in half. One of the halves was placed in 0.5 percent acetic acid overnight at 4°C so that horizontal epidermal sheets could be removed from each biopsy. The following day, epidermal sheets were removed from the dermis by peeling with a metal spatula. These sheets were fixed in formalin, dehydrated with ethanol, and kept in xylene. The other half of the biopsy was placed in 10 percent buffered formalin and processed into hematoxylin and eosin (H&E)—stained vertical sections. To assess utricle diameter, each epidermal sheet was placed on a glass slide in a few drops of xylene. The diameter of 40 utricles was measured with an image analyzer. The epidermal thickness of the H&E-stained sections was measured on 15 inter- utricular areas of each section with an image analyzer. Tabie 1 Dose-Related Activity of Compound II and All—Trans Retinoic Acid on Rhino Mouse Skin Utricle Diameter Percent Con- Mean Percent centration, Diameter Reduction Treatment w/v um± S.D.* Vs . Vehicle Vehicle 138 ± 16 0 * 5 mice per group. As seen in Table 1, Compound II has marked activity over a wide concentration range, identical to all—trans retinoic acid. The interutricular epidermal thickness results are shown in Table 2 (on skin samples from the same rhino mice that have their data in Table 1) Table 2 Dose-Related Activity of Compound II and All—Trans Retinoic Acid on Rhino Mouse Skin Epidermal Thickness *5 mice per group Compound II was as effective as all—trans retinoic acid in increasing the interutricular epidermal thickness of rhino mice. This increase in epidermal thickness was due to an increase in the number of epidermal cell layers. Polyene compounds are also evaluated for their effects on epidermal differentiation when they are applied to a non—wrinkled strain of hairless mice (hrhr). These mice have fewer horn-filled utricles in their skin compared to rhino mice. A variety of polyene compounds induce an increase in the number of epidermal cell layers when a compound is applied once to dorsal skin. Hairless mice, obtained from Jackson Labs, had their dorsolateral skin treated twice, on Days 0 and 1, with 0.05 ml of Compound II, all—trans retinoic acid, or ethanol vehicle. At the peak of the epidermal hyperplasia, on Day 4, the mice were sacrificed by C0 2 and a 7/8" punch biopsy from the treated skin was removed and placed into 10 percent buffered formalin. H&E—stained vertical sections were prepared and the epidermal thickness in the mterfollicular areas was measured with an image analyzer. The results are shown in Table 3. Table 3 Epidermal Hyperplasis in Hairless Mouse Skin Induced by Compound II and All-Trans Retinoic Acid Percent Con- Epidermal Percent centration, Thickness Control Treatment w/v μm± S.D.* Vs. Vehicle Vehicle 22.2 + 3.4 100 * 5 mice per group. At all three concentrations, Compound II caused the same degree of epidermal hyperplasia as the three equivalent concentrations of all-trans retinoic acid. All-trans retinoic acid is known to affect the differentiation of cells in the dermis of hair¬ less mouse skin, most effectively in the skin of mice that have been damaged by UV radiation. The forma¬ tion of a new zone of connective tissue is acceler¬ ated in photoaged hairless mouse skin by topical treatment with all—trans retinoic acid. This is due to an increased number of fibroblasts and an increase in their metabolic activity. As a result, new collagen bundles and elastic fibers are formed, which leads to a compression of the old, abnormal elastic fibers by the newly created dermal matrix. Fe ale hairless mice (Skh-HRl), six to eight weeks old, obtained from Temple University Skin and Cancer Hospital, had their dorsal skin irradiated with ultraviolet B (UVB) radiation on Monday, Wednes- day and Friday each week for ten weeks, using a bank of eight Westinghouse FS-40 sunlamps placed 16 cm above the back of the mice. During the first three weeks, the radiation dose per day was progressively increased from one minimal erythemal dose (MED) to four MED's. The 4-MED dose per day was then con¬ tinued for the last seven weeks . At the end of ten weeks, irradiation was stopped and starting at week eleven, treatment with a 0.05 ml of ethanol vehicle, all— rans retinoic acid, or Compound II was given to the dorsal skin once daily for five consecutive days for ten weeks. At the end of treatment, mice were sacri¬ ficed by cervical dislocation and dorsal skin was removed and placed in 10 percent buffered formalin. Parafin—embedded sections were cut at 10 μm thickness and stained with Luna's aldehyde fuchsin for elastic fibers . The dermal repair zone was measured microscopically and is defined as the area from the epidermal—dermal border to the top of the compressed elastotic material. The results in Table 4 show that Compound II was as effective as all—trans retinoic acid in causing increased repair of the connective tissue zone. Table 4 The Depth of the Dermal Repair Zone Induced in Photoaged Hairless Mouse Skin by Representative Compounds of Percent Dermal Repair Control 12 mice per group r I 291 282 260 277 223 210 229 264 Part IV Compound XXII 93.71 414 All Trans-Retinoic Acid, 96.16 425 0.1 percent Vehicle 22.6 0.1 percent B. Toxicitv Tests A rabbit model of skin irritation was used to assess the dermatitis produced by treatment with Compound II and all—trans retinoic acid. The rabbit is commonly used as a skin irritation model for predicting the potential local irritation of topically applied materials . New Zealand albino rabbits, from Beckens Farms, Sanborn, N.Y. , were clipped closely at four sites on the back with an electric hair clipper to give 4 cm X 4 cm square sites. Each rabbit received 0.2 ml of Compound II and all—trans retinoic acid, once daily for fourteen consecutive days. Each day, the degree of erythema, scaling and edema was assessed visually by using the Draize 0 to 4 grading method. The results were expressed as average daily Draize score, which was derived by taking the cumula¬ tive score over fourteen days, for each parameter, and dividing by fourteen. Table 5 shows a comparison of three doses of Compound II (0.1, 0.01 and 0.001 percent) to 0.01 percent all-trans retinoic acid. Table 5 Mean Daily Draize Score Averaged Over 14 Days ± S.D.* Treatment Global (percent) Erythema Scaling dema Irri a io Part I All-Trans Retinoic Acid, 0.01 1.86 ± 0.53 1.3 ± 0.70 0.63 ± 0.42 Compound II, 0.1 1.21 ± 0.54 0.8 ± 0.57 0.21 ± 0.34 0.01 0.83 ± 0.57 0.47 ± 0.48 0.11 ± 0.54 0.001 0.52 ± 0.33 0.17 ± 0.19 0 ± 0 *10 rabbits. Part II All-Trans Retinoic Acid, 0.1 6.6 Compound II 1.65 Compound XIX, 2.5 0.1 Compound XX, 4.5 0.1 Compound XXV, 3.3 0.1 Compound XXVI 3.3 0.1 Co pound XXVII, 6.6 0.1 Compound XXVIII, 6.6 0.1 Compound XXXI, 7.3 0.1 * 10 rabbits. The degree of irritation caused by Compound II even at ten times the dose of all—trans retinoic acid, is statistically lower than all—trans retinoic acid for erythema and scaling. Because of the variability associated with the edema scores, there were no statistically significant differences between any treatments, even though Compound II had numer¬ ically lower edema scores. For the purposes of this invention, Global Irritation score is defined as the sum of the erythema, edema and scaling scores. The toxicity induced by systemically administered Compound II was evaluated in albino mice. Vitamin A—related polyene compounds cause multiple signs of toxicity, referred to as the hypervitaminosis A syndrome, characterized by loss of body weight, skin scaling, hair loss and bone fractures. Albino CD—1 TM mice, from Charles River Laboratories, Wilmington, Ma., were administered Compound II and all—trans retinoic acid by intra- peritoneal injection in peanut oil, at 8 ml/kg, once daily for five consecutive days, for two weeks. Mice were graded daily during treatment for signs of hypervitaminosis A by the method of Bollag. An animal is defined as having hypervitaminosis A when addition of the grades for loss of body weight, skin scaling, hair loss and bone fractures totals at least three. The results are shown in Table 6. Compound II at 200 mg/kg, which was twice the highest dose of all-trans retinoic acid, did not cause hyper¬ vitaminosis A. In contrast, at 100 mg/kg, all-trans retinoic acid was so toxic that all ten of ten mice showed hypervitaminosis A and three mice treated with this dose died between Days 7 and 10. Table 6 Assessment of the Effects of All—Trans Retinoic Acid and Compound II on Hypervitaminosis A Signs in CD—1 Mice* Treatment All—Trans Retinoic Acid 100 mg/kg 50 mg/kg 10 mg/kg Peanut Oil Vehicle Untreated Compound II 200 mg/kg 50 mg/kg 20 mg/kg Peanut Oil Vehicle Untreated * Retinoid-treated groups had 10 mice. Untreated and vehicle—treated groups had 5 mice. Each retinoid was evaluated in separate studies . ** Based on 7 mice. Three mice died between Days 7 and 10. In comparative treatment with 13—cis retinoic acid it was found that Compound II was approximately twice as effective as 13-cis retinoic acid and also caused less dermal irritation. The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.

Claims: What is claimed is: 1. A method of repairing sun-damaged human skin comprising topically administering a compound having the structure: wherein '2' R, and R c are independently selected from the group consisting of H, Cl, OR., straight or branched alkyl of 1 to 10 carbon atoms, 0 2> C00R., CN, OR., NR R , NR 6 C(=S)NR 7 R g , NR 6 C0R ? , S0 2 N 6 R ? , CH(CΞ 3 )C00H, C0NR 6 R ? , C0R 6 , OCONR^, NR 6 C00NR ? , Rg0R 6 , NR 6 S0 2 R 7> Si(CH 3 ) 3 , and N gCON y g, R 3 together with R^ forms a benzo ring or taken together with R 2 forms a benzo or tetrahydrobenzo ring or together with R 2 and R*. forms a: moiety or together with 2 forms a NHC0R, \ _ moiety or R 2 together with R, forms a benzo ring or R 2 together with R 3 forms a • moiety, or R, is independently selected from the group consisting of moiety, R., R 7 and R g are independently selected from the group consisting of straight or branched alkyl containing from 1 to 10 carbon atoms, aryl containing from 6 to 10 carbon atoms and hydrogen, and R. is alkylene of 1 to 6 carbon atoms, and iron carbonyl complexes thereof, to an area of the skin in an amount sufficient to repair the effects of elastosis in the skin. 2. The method of claim 1 wherein R 2 and R, are independently selected from the group consisting of NR 6 C0R 7 , C0 R 6 R 7 , S0 2 NR 6 R ? , 0C0NR 6 R y , NR 6 C00R ? , NR 6 C0NR 7 R g , NR 6 S0 2 R y and NR 6 C(=S)NR 7 Rg. 3. A method according to claim 1 wherein R 3 is NHC0CH 3 and χ , R 2 and R^ are Ξ. CO cπ CO CO NJ NJ r-~ cπ o cπ O Cπ O π CO CO NJ NJ Cπ O Cπ O Cπ π to to Cπ 6. A method according to claim 1 wherein said skin is human facial skin. 7. A method according to claim 1 wherein said compound is applied in an emollient vehicle. 8. A method according to claim 1 wherein the compound is applied with a dermatologically acceptable carrier. 9. The method of claim 1 wherein the compound comprises about 0.001 to about 10 percent by weight of the mixture applied. 10. The method of claim 1 wherein the compound comprises about 0.01 to about 5 percent by weight of the mixture applied.

Inventors: GENDIMENICO GERARD JOSEPH, HALEY NEIL FREDERICK, NAIR XINA, SWANN R THOMAS, ZUSI F CHRISTOPHER, GENDIMENICO, GERARD, JOSEPH, HALEY, NEIL, FREDERICK, NAIR, XINA, SWANN, R., THOMAS, ZUSI, F., CHRISTOPHER
Applicants: EASTMAN KODAK CO, EASTMAN KODAK COMPANY
Application year: 1990
Main classification: A61K7
IPC codes: A61K8, A61K31, A61P17, A61Q19, C07D277, C07D455