Compositions for regulating skin wrinkles and/or skin atrophy.

COMPOSITIONS FOR SKIN AND / OR ATROPHY WRINKLE CONTROL

OF THE SKIN

Technical Field

The present invention relates to the field of anti-aging skin. Specifically, the invention relates to novel compositions for vanishing and preventing wrinkles from mammalian skin.

Mod. 71 - 20,000 ex. - 90) 08

General Framework of the Invention

The skin is subjected to maltreatment by many extrinsic (environmental) factors as well as many intrinsic (chrono-aging) factors. A common extrinsic factor is exposure to ultraviolet radiation. Whether extrinsic or intrinsic, maltreatment results in the formation of skin wrinkles, for many people skin wrinkles are a permanent reminder of the disappearance of youth. As a result, the elimination of wrinkles has become a booming business in societies that value the youthful aspect. Treatments range from cosmetic creams and moisturizers to various forms of cosmetic surgery.

Chrono-aging results in thinning and general skin degradation. When the skin ages naturally, there is a reduction in the cells and blood vessels that feed the skin. There is also a flattening of the dermis-epidermis junction which results in the weaker mechanical strength of this junction. As a consequence, older people are more susceptible

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Mod. 71 · 20,000 οχ.-90/08 blistering in cases of mechanical trauma or disease-induced processes (see Oikarinen (1990), The Aging of Skin: Chronoaging Versus Photoaging, Photodermatal., Photoimmunol. Photomed ., Vol. 7, pages 3 and 4).

It is known that salicylic acid can be used for the treatment of acne; for example, U.S. Patent Nos. 4,891,227 and 4,891,228 issued to Thaman et al., both published January 2, 1990, the disclosures of which are incorporated herein. . In addition, salicylic acid has been used for the elimination of warts, calluses and corns; for the treatment of psoriasis, seborrheic dermatitis and dandruff; and for the topical treatment of infections caused by tinea. A list of commercially available products containing salicylic acid is found in Physician's Desk Reference, 45^§ Edition, 1991, page 323. However, these prior art uses of salicylic acid have generally comprised short-term treatments in which relatively large doses of acid are applied (this is sufficient to cause significant irritation and often scaling of the skin). ) in order to cure or treat the particular condition such as the elimination of comedones as opposed to the persistent treatment of normal skin aging.

Objectives of the present invention

It is an object of the present invention to provide compositions for regulating the presence of wrinkles and / or skin atrophy of mammals comprising a safe and effective amount of an anti-wrinkle / anti-atrophy agent.

Summary of the Invention

The present invention relates to make up = 3 =

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476

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Mod. 71 - 20,000 οχ. 90/90/0008/0008/0001/0001/0001/0001/0001/0001/0001/0001/0001/0001/0001/0001/0008/0008/0008/0008. This is a condition for regulating the presence of wrinkles and / or skin atrophy of mammals comprising a safe and effective amount of salicylic acid together with other active agents selected from the group consisting of a safe and effective amount of a salicylic acid. absorption of solar radiation an anti-inflammatory agent, a vitamin, an anti-oxidant agent, a chelating agent, a retinoid agent, a benzofuran derivative, an N-acetyl-L-cysteine ​​derivative and a skin protection agent, its derivatives and mixtures thereof.

All percentages and proportions given herein are by weight and all determinations are made at 25 ° C unless otherwise indicated.

Detailed Description of the Invention

As used herein, the term "alkyl" means an unsubstituted, preferably straight or branched, more preferably straight, saturated, monounsaturated (i.e., double or triple bonded chain) chain containing carbon atoms. ) or polyunsaturated (i.e., with two or more double bonds in the chain, two or more triple bonds in the chain, one or more double bonds and one or more triple bonds in the chain), preferably saturated.

As used herein, the term "topical application" means direct application to the skin or spreading on the outer skin.

As used herein, the term pharmaceutically acceptable means that drugs, drugs or ingredients

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Mod. 71 -20,000 ex. - 90/08 The term "inert" described is suitable for use in contact with human and lower animal tissues without undue toxicity, incompatibility, instability, irritation, allergic response and similar phenomena, consistent with a reasonable benefit / risk ratio. .

As used herein, regulating the presence of wrinkles means preventing, retarding, stopping or reversing the process of wrinkling in mammalian skin.

As used herein, the term "skin atrophy regulation" means the thinning and / or general degeneration of the dermis often characterized by a decrease in collagen and / or elastin as well as a decrease in number, size and doubling potential of fibroblastic cells. Skin atrophy is a natural result of aging. Skin atrophy is often an undesirable side effect resulting from corticosteroid treatment.

As used herein, the term skin atrophy regulation means avoiding, delaying, stopping or reversing the process of mammalian skin atrophy.

As used herein, the term safe and effective amount means an amount of compound or composition sufficient to significantly cause a positive change in the condition to be treated, but small enough to avoid serious side effects (with reasonable benefit ratio). / risk), within the scope of the correct judgment of the physician. The safe and effective amount

V

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Mod. 71 - 20,000 ex. The ability of the compound or composition to vary with the particular condition to be treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of the therapy simultaneously performed, the specific compound. or the composition employed, the particular pharmaceutically acceptable carrier employed and similar factors which are known and experienced by the attending physician.

As used herein, chronic treatment means continuous treatment with an active agent for a long period of a patient's life, preferably for at least about three weeks, more preferably between about three months and about twenty years, more preferably between about six months and about ten years, and most preferably between about one year and about five years.

As used herein, all percentages are by weight unless otherwise specified.

Salicylic Acid as an Active Ingredient Salicylic acid used as an active ingredient may be salicylic acid alone, salicylic acid derivatives and salicylic acid in combination with other active ingredients described below. Most preferred is salicylic acid in the form of a hydroalcoholic solution.

Salicylic acid is a well-known active ingredient and is generally described in U.S. Patent No. 4,514,385, issued to Damani et al., assigned to Alcon Laboratories, and published at 30 = 6 =

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Mod. 71 20,000 αχ. - April 8, 1985, 1985.

Preferred topical carrier for salicylic acid used as an active ingredient comprises a hydroalcoholic solution at pH of 2 to 4 salicylic acid as an anti-acne active ingredient together with a specific anionic surfactant component. More preferably, such a composition is a stable hydroalcoholic composition having a pH of from 2 to 4 and containing from about 0.2 to about 5% by weight of salicylic acid and from about 0.2 to about of 5% by weight of sodium methyl cocoyl taurate and / or sodium methyl oloyl taurate as anionic surfactant component. Generally, a sufficient amount of a cosmetically acceptable alkaline component (i.e. alkalizing agent) is included to provide and maintain the composition at a pH of from about 2 to about 4.

As the alcoholic component of the hydroalcoholic solvent, from about 10 to about 60% by weight of ethyl alcohol, expressed as total C content, is preferred.₂Hc-OH, although an equal amount of isopropyl alcohol (Ο ^ ΗγΟΗ) may also be used beneficially. From about 30 to about 80% by weight of water as an aqueous component of the hydroalcoholic solvent is also required.

anionic surfactant which is a component of this active composition, i.e. the taurate surfactant component, is specifically directed to sodium methyl cocoyl taurate and sodium methyl oleyl taurate, both of which are readily obtainable in various commercial suppliers, as indicated in The Cosmetic, Toiletry and Fragrance Association (CTFA), Cosmetic Ingredient Dictionary ”, 3- Edition, 1982, pages 186 - 287.

= 7 =

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Although it is preferred to use the taurate surfactant as the sole surfactant in the compositions according to the present invention, other surfactants, preferably non-ionic ones, may also be included. of anionic type because of their relative non-irritating characteristics. Cationic surfactants, which are more irritating to the skin, are less preferred because of their high susceptibility to hydrolysis at the small acidic pH value of the compositions according to the present invention.

The pH value of the preferred active component, from about 2 to about 3.5, can be achieved by using the appropriate cosmetically acceptable primary or double buffer systems. In most cases, the resulting pH of the hydroalcoholic salicylic acid solution is slightly lower or belongs to the lower end of the indicated range and all that is required to adjust the pH to the highest desired value within the indicated range is to add an alkaline additive as commonly used in cosmetic formulations for this purpose. Although sodium carbonate is preferred, other suitable alkalizing agents include potassium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine and the like. If it is deemed necessary to modify or adjust the pH to a lower value, an appropriate cosmetically acceptable acidulant such as citric acid may be employed.

Active Ingredient Combinations

A. Sun Absorption Agents and Solar Blockers______________

Optimum setting of = 8 = t can be obtained

i

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Mod. 71 - 20,000 ex. The formation of skin wrinkles as a result of exposure to ultraviolet light using a combination of the active ingredient of salicylic acid according to the present invention together with sunlight absorbing substances or sunscreens. Useful sunlight absorbing agents include, for example, zinc oxide and titanium dioxide.

Photodanification is the predominant cause of skin wrinkling. Thus, in order to prevent the formation of wrinkles, the combination of the active compound with a UVA and / or UVB absorbing agent is most desirable. The inclusion of sunlight-absorbing substances in the compositions of the present invention provides immediate protection against acute UV damage. Thus, the sunlight absorbing agent prevents further wrinkling caused by UV radiation, while the active compound regulates existing wrinkles and skin atrophy.

A wide variety of conventional sunlight absorbing agents are suitable for use in combination with the active compound. Segarin et al., In Chapter VIII, page 189 et seq. Of Cosmetics Soience and Technology, report numerous appropriate agents. Suitable specific light-absorbing agents include, for example, p-amino benzoic acid, its salts and derivatives (ethyl esters, isobutyl, glyceryl; p-dimethylamino benzoic acid); anthranilates (i.e. o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenylethyl, linalino, terpinyl and cyclohexenyl esters); salicylates (amyl, phenyl, benzyl, menthyl, glyceryl and dipropylene glycol esters); cinnamic acid derivatives (methyl and benzyl esters, alpha-phenyl cinamonitrile; cinnamoyl = 9 =

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butyl pyruvate); dihydroxy-cinnamic acid derivatives (umbeliferone, methyl umbeliferone, methyl acetate umbeliferone); trihydroxy cinnamic acid derivatives (esculetin, methyl esculetin, daffnetin and the esculin and daffin glucosides); hydrocarbons (diphenyl butadiene, stilbene); dibenzalacetone and benzalacetophenone; naphthol sulfonates (sodium salts of 2-naphthol-3,6-disulfonic acids and 2-naphthol-6,8-disulfonic acids), dihydroxy naphthoic acid and its salts; o-hydroxy biphenyl disulfonates and p-hydroxy biphenyl disulfonates; coumarin derivatives (7-hydroxy, 7-methyl, 3-phenyl); diazols (2-acetyl-3-bromoimidazole, phenyl benzoxazole, methyl naphthoxazole, various aryl benzothiazoles); quinine salts (bisulfate, sulfate, chloride, oleoate and tanate); quinoline derivatives (8-hydroxy-quinoline, 2-phenyl-quinoline salts); hydroxy or methoxy substituted benzophenones; uric and villuic acids; tannic acid and its derivatives (for example hexahyethyl ether); butyl carbbotol-6-propyl piperonyl ether; hydroquinone; benzophenones (oxybenzene, sulisobenzone, dioxibenzone, benzoresorsinol, 2,2 ', 4,4'-tetrahydroxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, octabenzone 4-isopropyl dibenzoyl methane, butyl methoxy dibenzoyl methane, ethoorylene and 4-isopropyl dibenzoyl methane.

Preferred sunlight-absorbing agents useful in the compositions according to the present invention are 2-ethylhexyl p-methoxy cinnamate, butyl methoxy dibenzoyl methane, 2-hydroxy-4-methoxy benzophenone, octyl acid -dimethyl-p-aminobenzoic acid and mixtures thereof.

In compositions according to the present invention, a safe amount and

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Mod. 71 - 20,000 οχ. - Effective 90/08 sunlight absorbing agents. The sunlight absorbing agent should be compatible with the active compound. Generally, the composition may comprise from about 1 to about 20, preferably from about 2 to about 10% of a sunlight absorbing agent. Exact amounts vary depending on the sunlight protection agent chosen and the desired sunlight protection factor (SPF).

Also particularly useful in the compositions according to the present invention are the sun-absorbing agents which are described in Sabatelli Serial Number 054 085 (filed June 2, 1987) and U.S. Patent Application Serial Number 054 046 (filed June 2, 1987) by Sabattelli et al. The sunlight-absorbing agents referred to therein have in a single molecule two distinct chromophoric clusters having different ultraviolet radiation absorption spectra. One of the chromophores group absorbs predominantly in the UVB radiation zone and the other strongly absorbs in the UVA radiation zone.

An agent may also be added to any of the compositions of the present invention to improve the substantivity of the skin of such compositions, particularly to increase their strength and to be water-worn or to be rubbed off. A preferred agent providing this benefit is an ethylene and acrylic acid copolymer. Compositions comprising this copolymer are described in Brock U.S. Patent No. 4,663,157, issued May 5, 1987, which is incorporated herein by reference.

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B. Anti-Inflammatory Agents

A preferred wrinkle and atrophy regulating composition according to the present invention includes an anti-inflammatory agent as active agent together with the active compound. The inclusion of the anti-inflammatory agent enhances the benefits of regulating the presence of wrinkles in the compositions. 0 anti-inflammatory agent protects strongly in the UVA radiation spectrum (although it also provides some protection against UVB), thereby preventing further wrinkling caused by ultraviolet radiation, while the active compound regulates existing wrinkles and skin atrophy. Thus, the combination provides broad protection. Topical use of antiinflammatory agents reduces photoaging of the skin resulting from chronic exposure to ultraviolet radiation. (See U.S. Patent No. 4,847,071 to Bissett, Bush, and Chatterjee, issued July 11, 1989, which is incorporated herein by reference; and U.S. Patent No. No. 4,847,069 to Bissett and Chatterjee, issued July 11, 1989, incorporated herein by reference.

A safe and effective amount of an antiinflammatory agent according to the present invention preferably comprises from about 0.1% to about 10, more preferably from about 0.5% to about 5% of the composition. The exact amount of anti-inflammatory agent to be used in the compositions according to the present invention depends on the particular anti-inflammatory agent used as the potency of these agents varies within wide limits.

Anti-inflammatory agents may be used.

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Case 4534 steroidal materials, including - but not limited to corticosteroids such as hydrocortisone, hydroxyl triamcinolone, alpha-methyl dexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valeriate, desonide, deoxy corticosterone, difoxas ketone -metasone, dexamethasone acetate, dichlorisone, diflucortolone diavaleriate, fluadrenelone, fluclorolone acetonide, fludrocortisone, flumetasone pivalate, fluosinolone acetonide, fluocinonide, flucortin butyl ester, fluocortolone, flupredidene acetate (fluprednilidene), fluran-drenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, triam15 cinolone acetonide, cortisone, cortodoxone, fluceMod. 71 · 20,000 ex. - 90/03 tonus, fludrocortisone, difluorosone diacetate, fluradrenolone-acetonide, medrisone, amcinafel, amcinafide, betamethasone and the remainder of its esters chloroprednisone, chloroprednisone acetate, clocor20 tolone, clescinolone, dichloroisone, dichloridone, , fluperolone, fluprednisolone, hydrocortisone valereate, hydrocortisone cyclopentyl propionate, hydrocortamate, meprednisone, parametasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone and mixtures thereof. The preferred steroidal anti-inflammatory agent for use in the compositions according to the present invention is hydrocortisone.

A second class of antiinflammatory agents which is useful in the compositions according to the present invention includes non-steroidal antiinflammatory agents. The wide variety of compounds within this group is well known to those skilled in the art. For a detailed description of chemical structure, synthesis, side effects, etc. of anti-inflammatory agents =

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non-steroidal conditions, reference is made to the usual textbooks, which include Antiinflammatory and Anti-Rheumatic

Drugs, KD Rainsford, Vol. I-III, CRC Press, Boca Raton (1985) and Anti-inflammatory Agents, Chemistry and Pharmacology, 1, RA Scherrer et al., Academic Press, Nova

York (1974).

Specific non-steroidal anti-inflammatory agents useful in the compositions of the present invention include (not limited to the compounds cited):

1) oxycames such as piroxicam, isoxicam, tenoxicam, sudoxicam and CP-14,304;

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2) salicylates such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal and fendosal;

3) acetic acid derivatives such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, thiopinac, zidometacin, acematacin, fentiazae, zomepiract, clidanac, oxepinac and felbinac;

4) fenoma such as mefenamic, meclofenamic, flufenamic, niflumic and tolfenamic acids;

5) propionic acid derivatives such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, priprofen, carprofen, oxaprozin, pranoprofen, miroprofen, thio14 =

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xaprofen, suprofen, alaminoprofen and thiaprofen; and

6) pyrazoles such as phenibutazone, oxyphenbutazone, feprazone, azapropazone and trimetazone.

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Mixtures of these non-steroidal anti-inflammatory agents as well as their pharmaceutically acceptable salts and esters may also be employed. For example, particularly useful for topical application is etophenamate, a derivative of flufenamic acid. Of the non-steroidal anti-inflammatory agents, preferred are ibuprofen, naproxen, flufenamic acid, mefenamic acid, meclofenamic acid, piroxicam and felbinac; most preferred are isoprofen, naproxen and fenamic acid.

Another class of antiinflammatory agents which are useful in the compositions according to the present invention are the antiinflammatory agents referred to in U.S. Patent No. 4,708,966 to Loomans et al., Issued November 24, 1987 · This patent relates to a class of non-steroidal anti-inflammatory compounds comprising specifically substituted phenyl compounds, especially substituted 2,6-di-tertiary butyl phenol derivatives. For example, compounds selected from 4- (4'-pentin-3'-one) -2,6-di-t-butyl-phenol are useful according to the present invention; 4- (5'-hexinoyl) -2,6-di-t-butyl-phenol; 4 - [(S) - (-) - 3'-methyl-5'-hexynoyl] -2,6-di-t-butyl phenol; 4 - [(R) - (+) - 3'-methyl-5'-hexynoyl] -2,6-di-t-butyl phenol; and 4- (3 ', 3'-dimethoxypropionyl) -2,6-di-t-butylphenol.

Another class of anti-inflation agents

15=

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Mod. 71 · 20,000 - 90 (08 materials useful in accordance with the present invention are those described in Mueller U.S. Patent No. 4,912,248, issued March 27, 1990. This patent discloses diastereomeric compounds and mixtures of specific 2-naphthyl ester compounds, especially compounds of naproxen esters and naproxol esters having two or more chiral centers.

Finally, the so-called natural anti-inflammatory agents are also useful in accordance with the present invention. For example, candelilla wax, alpha-bisabolol, true aloe, manjistha (extracted from Rubia plants, particularly Rubia dordifolia) and guggal (extracted from Commiphora plants, particularly Commiphora mukul) can be used.

C. Anti-Oxidizing Agents / Eliminators

Radicals

Preferred compositions of the present invention for regulating the presence of wrinkles and skin atrophy include an anti-oxidant / radical scavenger as an active agent together with the active compound. The inclusion of the anti-oxidant / radical scavenger enhances the wrinkle-regulating benefits of the composition.

To the compositions according to the present invention a safe and effective amount of an antioxidant / radical scavenger may be added, preferably from about 0.1% to about 10%, more preferably from about 1%. ? and about 5% of the composition.

Antioxidants may be used / =

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I

Mod. 71 -20,000 οχ. - 90/00 / radical scavengers such as ascorbic acid (vitamin C) and its salts, tocopherol (vitamin E), tocopherol sorbate, other tocopherol esters, butylated hydroxy benzoic acids and their salts, 6-hydroxy acid -2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the tradename Trolox), gallic acid and its alkyl esters, especially propyl gallate, uric acid and their salts and esters of alkyl, sorbic acid and its salts, fatty acid ascorbyl esters, amines (e.g. β-diethylhydroxylamine, aminoguanidine), sulfhydryl compounds (e.g. glutathione) and dihydroxy fumaric acid and their salts,

D. Chelating Agents

In a preferred wrinkle and atrophy regulating composition according to the present invention, a chelating agent is included as an active agent together with the active compound. As used herein, the term chelating agent means a chelating agent capable of eliminating a metal ion from a complex forming system such that the metal ion cannot easily participate in chemical reactions or catalyze chemical reactions. The inclusion of the chelating agent enhances the wrinkle-regulating benefits of the composition.

A safe and effective amount of a chelating agent may be added to the compositions of the present invention, preferably from about 0.1% to about 10%, more preferably from about 1% to about 5%. of composition. Chelating agents useful in the compositions according to the present invention are described in the invention.

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Mod. 71 -20,000 ex. - U.S. Pat. No. 8,401,910 issued to Bissett, Bush, and Chatterjee, filed October 4, 1988, which is incorporated herein by reference. Preferred chelating agents used in the compositions according to the present invention are furyl dioxime and its derivatives and more preferably amphi-2-furyl dioxime.

E. Retinoid Agents

A preferred wrinkle and atrophy regulating composition according to the present invention includes a retinoid, preferably retinoic acid, as active agent together with the active compound. The inclusion of retinoid increases the benefits of regulating the presence of wrinkles in the composition. To the compositions according to the present invention a safe and effective amount of a retinoid may be added, preferably from about 0.001% to about 2%, more preferably from about 0.01 to about 1% of the retinoid. composition. As used herein, the term retinoid includes all natural and / or synthetic analogues of vitamin A or retinol-like compounds which have the biological activity of vitamin A on the skin, as well as geometric isomers and stereoisomers. -isomers of these compounds, such as all-trans-retinoic acid and 13-cis-retinoic acid.

F. Benzofuran Derivatives

A preferred wrinkle and skin atrophy regulating composition according to the present invention includes a benzofuran derivative, preferably amiodarone, as active agent together with com = 18 =

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Mod. 71 - 20,000 ex. -90/08 active post. The inclusion of the benzofuran derivative increases the wrinkle regulation benefits of the composition.

To the compositions according to the present invention, a safe and effective amount of a benzofuran derivative, preferably from about 0.01% to about 20%, more preferably from about 0.1% to about 20%, may be added. 10% of the composition. Benzofuran derivatives useful in accordance with the present invention are described in Chatterjee and Kapoor U.S. Patent Application No. 674,628, filed March 25, 1991, which is incorporated herein by reference .

G. N-Acetyl-L-Cysteine ​​Derivatives

In the compositions according to the present invention, also preferred are those compounds having the formula

<td colspan="3">3 0R °</td>

<td rowspan="2">0 !! R¹-Ç -</td><td></td><td> 3 = 0</td>

<td colspan="2">NH - CH - CH</td>

<td>l_</td><td></td><td>____ í .1</td>

or a pharmaceutically acceptable salt thereof.

R is selected from the group consisting of nothing and a C1 -C4 alkyl radical, preferably C1 -C6 alkyl, more preferably C1 -C6 alkyl and most preferably C1 -C4 alkyl.

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R is chosen from the group consisting of nothing, -H, C1 -C6 alkyl._O and ^{1 18}

- C - R; preferably means -H and C1 -C4 alkyl_1g more preferably still -H. In one embodiment, R² is preferably a C1 -C4 alkyl radical, more preferably C1 -C4 alkyl, more preferably C1 -C4 alkyl ^andEspecially preferably C1 -C4 alkyl.

R is selected from the group consisting of -H and C1 -C4 alkyl, preferably -H. In one embodiment, R 1 is preferably C 1 -C 4 alkyl, more preferably C 1 -C 4 alkyl, more preferably C 1 -C 4 alkyl, and especially preferably C 1 -C 4 alkyl.

x

R is a C1 -C4 alkyl radical, preferably C1 -C4 alkyl, more preferably C1 -C6 alkyl ^andMore preferably still alkyl in

In another embodiment both R symbols₁ and R₉ are nonexistent and the car atom¹ The carbonyl bond and the sulfur atom adjacent to R and R, respectively, are covalently linked to form a cyclic ring. Otherwise, R and R are different from nothing.

Preferred pharmaceutically acceptable salts of the active compound include - but are not limited to - sodium, potassium, magnesium, calcium, lithium, rubidium, strontium, aluminum, boron, silicon and zinc salts of the active compound.

The compositions according to the present

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Mod. 71 -20,000 ex. The invention comprises from about 0.01% to about 50% of active compound, preferably from about 0.1% to about 20%, and more preferably from about 2% to about 5%. $.

Zinc-forming zinc complexes and the active compound are useful in the compositions of the present invention.

„Skin Protection Agents

In a preferred skin wrinkle and atrophy regulating composition according to the present invention, a safe and effective amount of a skin protecting agent may be added to the compositions according to the present invention; the skin protecting agent preferably comprises from about 0.001% to about 2%, more preferably from about 0.01% to about 1% of the composition. Useful skin protection agents are referred to in Federal Register, Vol. 48, No. 32 and include allantoin, aluminum hydroxide gel, bismuth subnitrate, boric acid, calamine, cocoa butter, cornstarch, dimethicone, glycerin, kaolin, live yeast cell derivatives, petroleum jelly, liver oil. shark, sodium bicarbonate, sulfur, tannic acid, white petroleum jelly, zinc acetate, zinc carbonate and zinc oxide and mixtures thereof.

Other useful components include hormones such as pregnenolone and estrogens. Also useful are alpha hydroxy acids or beta hydroxy acids or alpha keto acids or derivatives thereof, as disclosed in U.S. Patent No. 4,234,599, issued to Van Scott et al., Published on November 18, 1980, which is incorporated herein by reference.

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include -isobutyric, -hydroxyisovaleric, x -butyric acid, nyl-pyruvic acid, cturonic acid, -lactone, ronic, isopropyl, methyl pyruvate, saccharic acid, tartaric acid and tartronic acid

Useful members of this class of compounds alpha-hydroxyalphahydroxy-isocaproic acid, alpha-atrolactic acid, beta-phenyl-lactic acid, citric-ethyl pyruvate, glucoheptonic acid, gluconic acid, glucurono-lactone, lactic acid, alpha-hydroxy- butyric acid beta-hydroacid acid beta-facid acid galaglucoheptono-1,4 acid glucono-lactono-glucuacid acid, malic acid pyruvate, mandelic acid, pyruvic acid, saccharic acid ac1,4-lactone, tarMod. 71 - 20,000 ex. - 90/08

I. Vitamins

In the compositions according to the present invention, it is also possible to include various vitamins. For example, vitamin A, ascorbic acid, vitamin B, biotin, pantothenic acid, vitamin D, vitamin E and mixtures and derivatives thereof may be used.

Pharmaceutical Carrier Substances

In a preferred embodiment, the treatment employs the use of a topical pharmaceutical composition comprising the active compound and a pharmaceutically acceptable carrier. The term pharmaceutically acceptable carrier as used herein means one or more compatible solid diluents or liquid fillers or microencapsulating substances that are suitable for administration to humans or lower animals. Pharmaceutically acceptable carriers must have a sufficiently high purity and a sufficient toxicity.

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Mod. 71 -20,000 ex-90/08 low enough to make them suitable for administration to humans or animals to be treated. A safe and effective amount of carrier is from about 50% to about 99.99%, preferably from about 00.9% to about 80, and most preferably from about 98% to about 100%. 95% of the composition.

Variations in the formulation of these carriers result in a wide variety of products falling within the scope of the present invention.

Topical pharmaceutical compositions according to the present invention may be made in a wide variety of product types. These include - but are not limited to - solutions, lotions, creams, beach products, gels, lipsticks, sprys, pads, ointments, pastes, foams, and cosmetics. These types of products may comprise various types of vehicle systems including - but not limited to - solutions, emulsions, gels and solid products.

Topical pharmaceutical compositions according to the present invention as solutions typically include a pharmaceutically acceptable aqueous or organic solvent. The terms pharmaceutically acceptable aqueous solvent and pharmaceutically acceptable organic solvent refer to solvents capable of keeping the active compound dispersed or dissolved and having acceptable safety properties (e.g., irritation and sensitization characteristics). Water is a topical aqueous solvent. Examples of suitable organic solvents include propylene glycol, butylene glycol, polyethylene glycol (200 - 600), polypropylene glycol (425 - 2.025), glycerol, 1,2,4-butanotriol, sorbitol esters, 1,2 , 6-hexanetriol, ethanol, isoprop = = 23 = r

&gt;

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<img file="PT101089A_D0023.tif" />

Mod. 71 -20,000 ex. - 90/08 panol, butanediol and mixtures thereof. Preferably, these solutions contain from about 0.01% to about 50% active compound, more preferably from about 20% 0.1% to about 20%; and from about 1% to about 80% of acceptable aqueous or organic solvent, and more preferably from about 1% to about 40%.

If the topical pharmaceutical compositions according to the present invention are formulated as an aerosol and are applied to the skin in spray form, a propellant is added to the solution solution composition. A more complete reference to the propellants useful in accordance with the present invention can be found in Sagarin, Cosmetics Science and Technology, 2nd Edition, Vol. 2, pages 443-465 (1972).

Topical pharmaceutical compositions according to the present invention may be formulated as a solution comprising an emollient agent. An example of a composition formulated in this manner may be a product containing sunlight absorbing agents. Preferably, these compositions contain from about 0.1% to about 50% of the active compound and from about 2% to about 50% of a pharmaceutically acceptable topical emollient agent.

As used herein, the term "emollients" refers to materials used to prevent or eliminate dryness of the skin as well as to protect the skin. A wide variety of suitable softening agents are known which may be used in accordance with the present invention. Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pages 32-43 (1972), which is incorporated herein, contains numerous examples of suitable materials.

= 24 = &gt;

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<img file="PT101089A_D0024.tif" />

Mod. 71 -20,000 ex-90/08

A solution may be prepared from a carrier system in the form of a solution. Lotions preferably comprise from about 0.1% to about 2055, more preferably from about 1% to about 5% of active compound; from about 15 to about 20%, preferably from about 5% to about 1055 of softening agent; and from about 50% to about 90% preferably from about 60% to about 80% water.

Another type of product that can be formulated from a carrier system in solution form is a cream. A cream according to the present invention preferably comprises from about 0.1% to about 20%, more preferably from about 1% to about 5% of active compound; between about 5 $ and

<td colspan="2">fence</td><td>in</td><td> 50</td><td>$ preferably between</td><td>fence</td><td colspan="2">$ 10 and about</td>

<td>in</td><td> 20</td><td> $</td><td>in</td><td>softening agent; and between</td><td>fence</td><td>from 45</td><td>55 and</td>

<td>oa</td><td>in</td><td> 85</td><td> 1^The 1</td><td>preferably between</td><td>fence</td><td>$ 50</td><td>and about</td>

<td>in</td><td> 75</td><td> $</td><td>in</td><td>Water.</td><td></td><td></td><td></td>

Another type of product that can be formulated from a solution-shaped carrier system is an ointment. An ointment may comprise a simple base of animal or vegetable oils or semi-solid (oilseed) hydrocarbons. Ointments may also comprise absorption ointment bases that absorb water to form emulsions. Carriers of ointment should be water soluble. An ointment may also comprise from about 2% to about 10% of an emollient agent and from about 0.1% to about 2% of a thickening agent. A more complete description of thickeners useful in accordance with the present invention can be found in Segarin, Cosmetics, Science and Technology, 33 Edition, Vol. 1, pages 72 and 73 (1972).

= 25 =

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<img file="PT101089A_D0025.tif" />

Mod. 71 -20,000 βχ. - 90/03

If the carrier is emulsified, from about 1% to about 10% preferably from about 2% to about 5% of the carrier system comprises an emulsifying agent. Emulsifying agents may be nonionic, anionic or cationic. Suitable emulsifying agents are disclosed, for example, in U.S. Patent 3,755,560, issued August 28, 1973 and issued to Dickert et al., U.S. Patent No. 4,421,769, issued 20 December 1983 θ issued to Dixon et al; and in McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317- 324 (1986); which are incorporated herein by reference. Preferred emulsifying agents are anionic or nonionic, although the other types may also be used.

Lotions and creams may be formulated as emulsions and as solutions. Preferably, such lotions comprise from about 0.1% to about $, more preferably from about 1% to about $% of active compound; from about $ 1 to about $ 20, preferably from about $ 5 to about $ 10 of emollient agent; from about 25% to about 75%, preferably from about 45% to about 95% water; and from about 0.1% to about 10%, preferably from about 0.5% to about 5% emulsifying agent. Such creams preferably contain from about 0.1% to about 20%, more preferably from about 1% to about 5% active compound; from about 1% to about 20%, preferably from about 5% to about 10% softening agent; from about 20% to about 80%, preferably from about 30% to about 70% water; and from about $ 1 to about $ 10, preferably from about $ 2 to about $ 5 agent = 26: = *

i

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<img file="PT101089A_D0026.tif" />

Mod. 71 - 20,000 ex. - 90/03 emulsifier.

In the art of cosmetics, single emulsion skin care preparations such as oil-in-water and water-in-oil type lotions and creams are known and are useful in the compositions according to the present invention. In accordance with the present invention. In accordance with the present invention, multistage emulsion compositions such as water in oil in water type as referred to in U.S. Patent No. 4,254,105 issued to Fakuda et al. . and published March 3, 1981, which is incorporated herein by reference. In general, these single phase or multi phase emulsions contain water, softening agents and emulsifying agents as essential ingredients.

Triple emulsion carrier systems comprise an oil-in-water emulsion in silicone fluid, as described in U.S. Patent No. 4,960,764, issued to Figueroa and published October 2, 1990, are also useful according to the invention. with the present invention. Preferably, this triple emulsion carrier system may be from about 0.1% to about 20%, more preferably from about 1% to about 5% of aethyl compound to obtain the topical pharmaceutical composition according to the present invention.

Another emulsion-shaped carrier system useful in the topical pharmaceutical compositions according to the present invention is a microemulsion carrier system. This system comprises from about 9 l to about 15 l of squalane; between about $ 25 and about $ 40 of silicone oil; between about $ 8 and about $ 20 of a fatty alcohol; between about $ 15 and = 27 65,476

Case 4534

<img file="PT101089A_D0027.tif" />

Mod. 71 - 20,000 ex. About 30% polyoxyethylene sorbitan mono fatty acid ester (commercially available under the tradename Tweens) or other nonionic agents; and between about 7% and about 20% water. This carrier system is preferably combined with from about 1% to about 5% active compound.

If the topical pharmaceutical compositions according to the present invention are formulated as a gel or as a cosmetic lipstick, an appropriate amount of a thickening agent as indicated above is added to the cream or lotion formulation.

Topical pharmaceutical compositions according to the present invention may also be formulated as make-up products such as base ointments.

Topical pharmaceutical compositions according to the present invention may also be formulated as drug-containing pads. Suitable examples of such pads are fully described in U.S. Patent Nos. 4,891,227 and 4,891,228 issued to Thaman et al., Both published January 2, 1990, the disclosures of which are incorporated herein by reference.

The topical pharmaceutical compositions according to the present invention may contain, in addition to the aforementioned components, a wide variety of additional oil-soluble substances and / or water-soluble substances conventionally used in the topical compositions, with the levels of levels established by the art.

Various water soluble substances may also be present in the compositions according to a = '-28 =

65.476

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<img file="PT101089A_D0028.tif" />

Mod. 71 - 20,000. 90 (08). These include wetting agents, proteins and polypeptides, preserving agents and alkalizing agents. In addition, topical compositions according to the present invention may contain conventional cosmetic auxiliary agents such as colorants, opacifying agents (e.g. , titanium dioxide), pigments and perfumes.

Topical pharmaceutical compositions according to the present invention may also include a safe and effective amount of a penetration enhancing agent. The preferred amount of penetration enhancing agent is from about 1% to about 5% of the composition. A useful penetration enhancing agent according to the present invention is the nonionic polymer of the CTFA designation of polyacrylamide and isoparaffin and lauret 7, available as Sepigel from Seppic Corporation. Also useful is polyquaternium-32 and mineral oil known as SalCare SC92, available from Allied Colloids, Suffolk, VA, United States of America. A class of compounds is a class of cationic polymers which are generally described in U.S. Patent No. 4,628,078 issued to Glover et al., Issued December 9, 1986 and U.S. Patent No. 4 No. 599,379, issued to Flesher et al., And published July 8, 1986, both incorporated herein by reference.

Examples of useful penetration aids are useful, among others, in U.S. Patent Nos. 4,537,776 issued to Cooper, issued August 27, 1985; 4,552,872 issued to Cooper et al. and published November 12, 1985; 4,557,934 issued to Cooper and published December 10 “29 =

65.476

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Mod. 71 - 20,000 ax. - 90/08 of 1985; 4,130,667, issued to Smith and published December 19, 1978; 3,989,816 issued to Rhaadhyaksha and published November 2, 1976; No. 4,017,641 issued to Digiulio and published April 12, 1977; and European Patent Application 0043738, filed by Cooper et al. and published January 13, 1982.

In accordance with the present invention, it is also possible to include other conventional additives for skin care products, for example, collagen, hyaluronic acid, elastin, hydrolysates, evening primrose oil, jojoba oil, epidermis growth factor may be used. , soybean saponins, mucopolysaccharides and mixtures thereof.

Cleaning Composigges

The skin cleansing compositions according to the present invention comprise, in addition to the active compound, a cosmetically acceptable surfactant. The term cosmetically acceptable surfactant ”refers to a surfactant that is not only an effective skin cleansing agent but can also be used without undue toxicity, irritation, allergic response and the like. In addition, the surfactant must be capable of being admixed with the active compound in such a way that there is no interaction that could substantially reduce the effectiveness of the composition in regulating skin wrinkles and / or skin atrophy.

The skin cleansing compositions of the present invention preferably contain from about 0.1% to about 20%, preferably from about 1% to about 5% of active compound and from about 1%. and about 90, more preferably from about 1% to about 10% of a surfactant cos = 30 =

<img file="PT101089A_D0029.tif" />

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Case 4534

Mod. 71 - 20,000 ex. - 90/08 metically acceptable.

The physical form of skin cleansing compositions is not critical. The compositions may be formulated, for example, as toilet bars, liquids, pawns, foams or pads.

The surfactant component of the compositions according to the present invention is chosen from anionic, nonionic, hybrid, amphoteric surfactants as well as mixtures of these surfactants. These surfactants are well known to those skilled in the detergent art.

The skin cleansing compositions of the present invention may optionally contain, at their levels established in the art, substances that are conventionally used in skin cleansing compositions.

Regulation of Wrinkles and / or Skin Atrophy of Mammals

The amount of active components and the frequency of treatment vary within a wide range, depending on the patient's existing level of wrinkling and / or skin atrophy, the rate of later wrinkling and / or atrophy and the level of regulation. intended.

Preferably, the composition is applied to the skin by chronic topical application of a safe and effective amount of the composition to regulate mammalian skin wrinkles and / or atrophy. The amount of active compounds and the frequency of topical application to the skin may vary within a wide range depending on personal needs but it is suggested as an example that the

65.476

Case 4534

<img file="PT101089A_D0030.tif" />

Mod. 71 20.0 'eg 90/08 Frequency of topical application ranges from about once a week to about ten times a day, preferably from about twice a week to four times a day, more preferably from about one week. three times a week and about three times a day, and especially preferably about once or twice a day.

The composition for topical application comprises from about 0.01% to about 50, preferably from about 0.1% to about 20%, more preferably from about 1% to about 5% active compound. By "chronic application" is meant herein that the period of topical application may be throughout the patient's life, preferably for a period of at least about three weeks, more preferably between about three months and about twenty years, more preferably between about six months and about ten years and most preferably between about one year and about five years, resulting in the regulation of wrinkles and / or skin atrophy of mammals.

In the case of compositions according to the present invention, a safe and effective amount of the active compound and a safe and effective amount of one or more auxiliary agents including sunlight absorbing agents, anti-inflammatory agents, vitamins, antioxidants / radical scavengers chelating agents, retinoid agents, N-acetyl-L-cysteine ​​derivative, skin protection agents and / or benzofuran derivatives simultaneously. As used herein, the term simultaneous application or the term simultaneously means that agents are applied to the skin therein = - 32 = *

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Case 4534

<img file="PT101089A_D0031.tif" />

Mod. 71 20.OCO ex. - 90/08 site of the body and approximately at the same time. Although this may be accomplished by applying the agents separately to the skin, preferably one with the position comprising all desired mixed agents is applied to the skin. The amount of sunlight absorbing agent applied generally ranges from about 0.02 mg to about 1 mg per square centimeter of skin. The amount of anti-inflammatory agent applied generally ranges from about 0.005 mg to 0.5 mg, preferably from about 0.01 mg to about 0.1 mg per square centimeter of skin. The amount of antioxidant / radical scavenger generally applied ranges from about 0.001 mg to about 1 mg, preferably from about 0.05 mg to about 0.5 mg per square centimeter of skin. The amount of chelating agent generally applied ranges from about 0.001 mg to about 1 mg, preferably from about 0.01 mg to about 0.5 mg, and most preferably from about 0.05 mg. about 0.1 mg per square centimeter of skin. The amount of retinoid applied generally ranges from about 0.00001 mg to about 0.02 mg per square centimeter of skin, preferably from about 0.001 mg to about 0.01 mg per square centimeter. The amount of benzofuran derivative applied generally ranges from about 0.001 mg to about 1 mg, preferably from about 0.01 mg to about 0.5 mg per square centimeter of skin per application. The amount of active compound applied generally ranges from about 0.001 mg to about 1 mg per square centimeter of skin per application, preferably between about 0.01 mg and about 0.5 mg per square centimeter of skin per application and more preferably from about 0.05 mg to about 0.25 mg per square centimeter of skin per application.

The following examples describe more = 33 ⁼

r.

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Case 4534

<img file="PT101089A_D0032.tif" />

Mod. 71 - 20,000 ex. 90/03 in detail and demonstrate preferred embodiments within the scope of the present invention. The examples are provided for illustration only and are not intended to serve as a limitation of the present invention, since many variations are possible without departing from their spirit and scope.

EXAMPLES

Example I

A cushion according to the present invention is prepared using the following ingredients:

Cushion Composition

Substrate A

Cellulose-based nonwoven fabric

Substrate B

Polyester (denier = 6)

Ώ

Orion (denier 8)

Styrene Butadiene Resin

Laminate

Polyethylene powder melt% by weight

100,0

45,0

15,0

40,0

100,0 = 34 =

<img file="PT101089A_D0033.tif" />

476

<img file="PT101089A_D0034.tif" />

4534

<img file="PT101089A_D0035.tif" />

<td>Active Composition</td><td>$ by weight</td>

<td>Salicylic acid</td><td> 2,0</td>

<td>Na methyl cocoyl taurate</td><td> 3,0</td>

<td>Ç₂H₅OH (95% ethanol)</td><td> 35,0</td>

<td>Bamamele Distillate</td><td> 5,0</td>

<td>Quaternium-22</td><td> 1,0</td>

<td>Menthol</td><td> 0,1</td>

<td>True Aloe Gel</td><td> 0,5</td>

<td>perfume</td><td> 0,05</td>

<td>Water</td><td>what</td>

Mod. 71 -20,000 οχ. -90/08

Obtained from James River as Airtex Spec 382.

Obtained from Eastern Chemical Company.

Obtained from American Cyanamid.

Obtained from Reichold as tylao 68-500 (80: 20 ratio of styrene to butadiene).

Obtained from Quantum Chemical microtene as powder.

substrate A has a base unit weight of about 65.9 grams per square meter (55 grams per square yard) and a thickness of about 0.89 millimeter (35 thousandths). Substrate B has a basis unit weight of about 77.8 grams per square meter (65 grams per square yard, and a thickness of about 1.78 to 2 millimeters (70 to 80 thousandths). The two materials are laminated together by applying a small polyethylene powder coating to substrate A and heating with infrared lamps. Substrate A and substrate B are then unified.

<img file="PT101089A_D0036.tif" />

65.476

Case 4534

<img file="PT101089A_D0037.tif" />

Mod. 71 - 20,000 ex. 90/00 to form a roll for compressing and bonding the materials. The resulting nonwoven fabric has a thickness of about 2.29 to 2.54 millimeters (90 to 100 milliseconds). The resulting material is then cut to an oval-shaped portion (5 x 7 cm). The active components are combined to form a solution and a pad is saturated with this solution.

This composition is useful for topical application to regulate skin wrinkles and / or skin atrophy. It is appropriate to use an amount of composition which deposits about 2 mg per square centimeter of skin of active compound.

Example II

A cushion according to the present invention is prepared by combining the following components as in Example I:

Cushion composition% by weight

Substrate A

100.0 Cellulose Based Nonwoven Fabric

Substrate B

Polyester (denier = 6) 45.0

Orion (denier = 8) 15.0

Styrene Butadiene Resin40,0

Laminate

100.0 Polyethylene Powder Melt

<img file="PT101089A_D0038.tif" />

65.476

Case 4534

Active Composition

<img file="PT101089A_D0039.tif" />

<td>Salicylic acid</td><td> 2,0</td>

<td>Ç₂H₅OH (95% ethanol)</td><td> 35,0</td>

<td>Glycerin</td><td> 2,0</td>

<td>True Aloe Gel</td><td> 1,0</td>

<td>Menthol</td><td> 0,05</td>

<td>Amine triethanol</td><td> 0,7</td>

<td>perfume</td><td> 0,15</td>

<td>Water</td><td>what</td>

Mod. 71 -20,000 οχ.-90/08

This composition is useful for topical application to regulate skin wrinkles and / or skin atrophy. It is appropriate to use an amount of composition which deposits about 2 mg / cm 2 of active compound on the skin.

Example III

A topical composition is prepared by combining the following components and using conventional mixing techniques:

<td>Active Composition</td><td>$ by weight</td>

<td>Salicylic acid</td><td> 1,25</td>

<td>Ascorbic acid</td><td> 5,00</td>

<td>Na methyl cocoyl taurate</td><td> 1,5</td>

<td>Ç₂H₅OH (95% ethanol)</td><td> 45,0</td>

<td>Hamamele distillate</td><td> 5,0</td>

<td>Quaternium-22</td><td> 1,0</td>

= 37 =

<img file="PT101089A_D0040.tif" />

65.476

Case 4534 (Continued)

Active Composition

<img file="PT101089A_D0041.tif" />

<td>Menthol</td><td> 0,05</td>

<td>perfume</td><td> 0,05</td>

<td>Water</td><td> 41,15</td>

This composition is useful for topical application in order to regulate skin wrinkles and / or skin atrophy. It is appropriate to use an amount of composition which deposits about 2 mg per square centimeter of active compound on the skin.

Example IV

Mod Zl -20,000 ex. -20/08

A topical composition is prepared by combining the following components and using conventional mixing technology;

<td>Ingredient</td><td>in weight / weight</td>

<td>Purified water</td><td> 54,0</td>

<td>SD 40 Alcohol</td><td> 40,0</td>

<td>Polyacrylamide and Isoparaffin</td><td></td>

<td>1 in C ^ 2 -]^and laurette-7</td><td> 4,0</td>

<td>Salicylic acid</td><td> 2,0</td>

<td>Add water</td><td>to a container of</td>

<td>appropriate size. While mixing</td><td>with a speed</td>

(300 revolutions per minute), add water, polyacrylamide isoparaffin and lauret 7. Separately, place the alcohol in a container and cover. Using one

65.476

Case 4534

<img file="PT101089A_D0042.tif" />

Lightnin 'mixer with a three-blade propeller blade, the salicylic acid is added to the alcohol and mixed at low speed (100 revolutions per minute) until all salicylic acid dissolves. Alcohol is slowly added to the aqueous phase to form the gel. The resulting gel is mixed at moderate speed until uniformity is achieved.

This composition is useful for topical application to regulate skin wrinkles and / or skin atrophy. The use of an amount of composition which deposits about 2 mg per square centimeter of active compound on the skin is appropriate.

Mod. 71 · 20,000 ex. - 50/03

Example V

A topical composition is prepared by combining the following components and using conventional mixing technology as in Example IV:

Ingredient

Water

SD 40 Alcohol

Salcare SC92¹

Salicylic acid

Menthol

M_g2EDTA

Glycerin% w / w

what

40,0

3,0

2,0

0,05

0,05

2,00

Salcare SC92 is an acylamide copolymer and a cationic acrylate obtainable from Allied Colloids.

= 39 = *&gt;€

<img file="PT101089A_D0043.tif" />

<img file="PT101089A_D0044.tif" />

476

Case 4534

This composition is useful for topical application to regulate skin wrinkles and / or skin atrophy. It is appropriate to use an amount of composition which deposits about 2 mg per square centimeter of active compound on the skin.

Lisbon, 2SFEVí^!

By RICHARDSON VICKS INC.

Mod. 71 -20,000 ex. - 90/08

<img file="PT101089A_D0045.tif" />

Age^r&lt;ie Of ^ ial

4a Prcp &lt;-idôO '· ~ ®^O Concetç®®, usm = 40 = «

<img file="PT101089A_D0046.tif" />

AND

<img file="PT101089A_D0047.tif" />