WO1992005769A1 - Prevention or treatment of sunburn using the s(+) isomer of ketoprofen - Google Patents

Abstract

Ultraviolet radiation induced erythema is prevented or treated in a human mammal in need of such prevention or treatment, i.e., a mammal suffering from or seeking to avoid sunburn, by topically administering thereto a unit dosage erythema-preventing or treating effective amount of the S(+) ketoprofen enantiomer, said enantiomer being substantially free of its R(-) ketoprofen antipode.

Description

PREVENTION OR TREATMENT OF SUNBURN USING THE S(+) ISOMER OF KETOPROFEN

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to the use of topically administered S(+) ketoprofen to prevent or treat erythema induced by ultraviolet irradiation in mammalian organisms in need of such prevention or treatment, and to certain topical pharmaceutical compositions comprising unit dosage effective amounts of S(+) ketoprofen.

Description of the Art:

Ketoprofen, also known as DL-2-(3-benzoylphenyl) propionic acid, has the structural formula

The compound is well-known as a nonsteroidal anti- inflammatory drug having analgesic and antipyretic activity. In the United States, ketoprofen is marketed under the tradename Orudis^R. Other tradenames or codenames include RP 19583, Alrheumat, Alrheumun, Capisten, Fastum, Iso-K, Ke enid, Ketσpron, Lertus, Meprofen, Oruvail and Profenid. As Orudis^R, the drug is available by prescription in the U.S. as capsules containing 25 mg, 50 mg or 75 mg of ketoprofen, indicated for the acute or long-term treatment of the signs and symptoms of rheumatoid arthritis or osteoarthritis. Orudis^R is recommended at a daily dose of 150 to 300 mg, divided in three or four doses. It is recommended that drug treatment begin at 75 mg three times or 50 mg four times a day. Small people may need smaller doses. Daily dosages should not exceed 300 mg per day. See also Physician's Desk Reference, 41st edition, 1987, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, NJ 07649, pp. 2179- 2181. For mild to moderate pain and dysmenorrhea, a dose of 25 mg to 50 mg every 6 to 8 hours as needed was recently approved by the Food and Drug Administration ("F.D.A.") .

As is apparent from its chemical nomenclature, ketoprofen is a racemic mixture. It is only the racemic mixture which has in fact ever been marketed. There have, however, been a few studies of the individual S(+) and R(-) isomers reported in the literature.

The prior art groups the 2-arylpropionic acids together as a class. These possess a chiral center at the carbon atoms alpha to the carboxyl function. According to the prior art, many 2- arylpropionic acids are believed to have a metabolic chiral inversion of their asymmetric center, with partial or complete conversion in nonhuman mammals of the R to the S iso er. The rate and extent of that conversion has been known to vary as noted by Hutt et al, J. Pharm. Pharmacol.. 35, 693-704 (1983). This metabolic inversion of the chiral center, with no other covalent change to the drug, is thus far unique to the 2-arylpropionic acids. Caldwell et al., "The Metabolic Inversion and Dispositional Enantioselectivity of the 2-Arylpropionic Acids and their Biological Consequences", Biochem. Pharmacol.. 37, 105-114 (1988) . Generally, if an optically active compound has two isomers, there is an argument for resolving what is believed to be the optically active and therapeutically desirable isomer. However, many of the 2-arylpropionic non-steroidal anti-inflammatory drugs (NSAIDs) are unique and run contrary to that argument because of the teachings of the prior art relating to the conversion of the R(-) to the S(+) isomer. Thus, the argument for resolving the 2-arylpropionic acids to improve their clinical effect is not as clear as with other classes of racemic drugs. In many instances, the prior art actually teaches away from such a resolution by leading one of ordinary skill in the art to believe that there would be clinical or near clinical equivalence between the S(+) form and the racemic mixture. That is, the conversion of the R(-) isomer to the S(+) form is believed to progress at such a rate and to such an extent that a substantially equivalent clinical effect would result.

The majority of the prior art was too inconclusive to yield an accurate estimate of the extent of the possible conversion of the R(-) to the S(+) form of ketoprofen in man. Moreover, among the members of that class of NSAID's, comparatively few studies appear to have been conducted on ketoprofen. However, conversion in man would be assumed by one of ordinary skill in the art since in addition to the ketoprofen specific evidence from studies cited in the specification, several members of the 2-arylpropionic acid classes of NSAID's, e.g., ibuprofen, were known to undergo substantial chiral inversion of the R to the S enantiomer in man.

Indeed, Hutt et al concluded that there was no advantage in administering the pure S(+) form of ketoprofen since a rapid .in vivo conversion of the R(-) in the racemic mixture to the S(+) form would be expected, based on the fact that ketoprofen has a chiral center and it is known to be incorporated into triglycerides. Ketoprofen, like fenoprofen, has • been reported to be incorporated into triglycerides, and, in addition, a study using [³H-α- methyl] drug in man found increasing quantities of circulating radioactivity due to tritiated water. One means of loss of ³H from the α-methyl group would be that proposed for the loss of deuterium from d^ibuprofen during the chiral inversion process.

Hutt et al, "Review - The Metabolic Chiral Inversion of 2-Arylpropionic Acids - A Novel Route with Pharmacological Consequences," J. Pharm. Pharmacol.. Vol. 351, pp. 693-674 at 703 (1983). Thus, Hutt et al recognized that evidence existed supporting chiral inverion of the R(-) to the S(+) isomer for ketoprofen.

It has recently been noted that contrary to the expectations of the prior art, there is no conversion of R(-) to S(+) ketoprofen in man.

Interestingly, the R-enantiomer of some of these agents (e.g.. ibuprofen, fenoprofen, and benoxaprofen) may undergo a unique in vivo irreversible inversion to the S-enantiomer. This inversion is not a universal occurrence, as, at least in humans, it does not occur to any significant extent with tiaprofenic acid, indoprofen, carprofen, and perhaps ketoprofen. Jamali et al, "Stereoselective Pharmacokinetics of Flurbiprofen in Humans and Rats," Journal of Pharmaceutical Sciences, Vol. 77, No. 8, pp. 666-69 (August 1988) .

A considerable amount of effort has been spent in the search for a method to prevent the occurrence of, or alternatively, to treat sunburn. Sunburn is caused by certain wavelengths of ultraviolet (UV) radiation striking the skin. The ultraviolet light alters the keratinocytes in the basal layer of the epidermis. A slight alteration results in erythema, and a severe alteration causes bullae to form from the fluid collected in the epidermis. To produce a suntan, ultraviolet light stimulates the melanocytes in the germinating layer to generate more melanin and oxidizes melanin already in the epidermis. Both of these processes serve as protective mechanisms by diffusing and absorbing additional UV radiation. The effects of the sun on the skin usually begin to appear anywhere from 1 to 24 hours after exposure and range from mild erythema to tenderness, pain, and edema.

Severe reactions due to excessive exposure involve the development of vesicles or bullae as well as the constitutional symptoms of fever, chills, weakness, and shock. Energy emissions from the sun include radiation wavelengths ranging from 200 nm to more than 18,000 nm. Ultraviolet radiation is in the 200-400 nm range, and this spectrum is subdivided into three bands.

UV-A (320-400 nm) radiation can cause tanning of the skin, but is weak in causing mild sunburn of the skin. Erythemic activity (producing redness) is relatively weak at this wavelength. The primary action of UV-A is the development of a slow natural tan. At this UV level, radiation produces some immediate pigment darkening. In addition, UV-A represents the range in which most photosensitizing chemicals are active. It is also believed that UV-A may augment the effects of UV-B.

UV-B (290-320 n ) radiation causes sunburn reaction, which also stimulates pigmentation (tanning) of the skin. It is the most effective UV radiation wavelength for producing erythema, which is why it is called sunburn radiation. It triggers new pigment formation as well as vitamin D production. In addition, it is thought to be responsible for inducing skin cancer.

UV-C (200-290 nm) radiation from sunlight does not reach the earth's surface, but artificial UV sources can emit this radiation. It does not tan the - skin, but it can burn it. UV-C radiation from the sun does not reach the surface of the earth. However, UV-C is emitted by artificial ultraviolet sources. Although it will not stimulate tanning, it causes some erythema.

Other wavelengths of light also are absorbed and, if intense enough, produce erythema and burning.

This type of burning differs from sunburn in that it is due to generated heat rather than a photochemical reaction. Thus, it has been well documented that excessive exposure to ultraviolet light will cause erythema, edema, blister formation and sloughing of the skin due to cellular damage. Ultraviolet light injury includes epidermal cell death, increase in mitotic index, hyperplasia, as well as the vascular responses of vasodilation, altered permeability and cellular exudation.

The vascular changes that occur secondary to exposure to ultraviolet light are biphasic. The immediate erythema reaction is a faint, transient reddening of the skin beginning shortly after exposure to ultraviolet light and fading within 30 minutes after the exposure ends. A delayed erythema reaction appears after 2-6 hours and peaks 10-24 hours after ultraviolet-light exposure. This erythema gradually subsides over the next 2-4 days. Peeling follows 4-7 days after a moderate to severe sunburn. The mechanisms by which these two types of erythema are produced are not understood completely. Kinins, histamine, prostaglandins, other vasoactive substances, hydrolytic enzymes, and free radicals have been implicated as mediators of the erythema caused by sunlight. Prostaglandins have been shown to increase in erythematous skin exposed to ultraviolet B radiation. Aspirin and indomethacin which are nonsteroidal anti- inflammatory agents have been shown to inhibit the prostaglandin synthetase system in skin. Snyder et al, "Intradermal Anti-Prostaglandin

Agents and Sunburn," The Journal of Investigative Dermatology. Vol. 62, No. 1, 47-50 (1974) discussed the intradermal administration of indomethacin as well as aspirin to guinea pigs. The administration of each of those drugs was shown to decrease the intensity and delay the development of ultraviolet radiation induced erythema. Snyder et al, "Topical Indomethacin and ^" Sunburn," British Journal of Dermatology, pp. 90-91 (1974) , further demonstrated that the topical application of indomethacin in humans produced a reduction in redness, skin temperature and pain perception. It was suggested that indomethacin may be affecting sunburn by preventing biosynthesis of prostaglandins.

Likewise, several nonsteroidal anti- inflammatory drugs have been administered orally to human subjects and have been demonstrated to be effective in reducing erythema after exposure to ultraviolet radiation. In particular, Edwards et al, "Reduction of the Erythema Response to Ultraviolet Light by Nonsteroidal Anti-inflammatory Agents," Arch. Dermatol. Res. , Vol. 272, pp. 263-267, studied the effect of orally administered aspirin, indomethacin and ibuprofen on ultraviolet B induced erythema in human subjects. All three drugs were comparable in reducing the sunburn response to ultraviolet radiation.

Gomez et al, "Effect of Topical Diflumidone on Ultraviolet-Light-Induced Erythema," Dermatologica, Vol. 162, pp. 175-182 (1981) studied the topical efficacy of indomethacin and diflumidone for the suppression of ultraviolet-light-induced erythema in humans. Both indomethacin and diflumidone were found to inhibit the development of erythema; however, the indomethacin treated sites had significantly less erythema 24 hours after application. Greenbercj et al, "Orally Given Indomethacin and Blood Flow Response to UVL," Arch. Dermatol., Vol. Ill, pp. 328-330 (March 1975), demonstrated that orally administered indomethacin reduced the increase in blood flow produced by ultraviolet light irradiation by one- third.

Lim et al, "Effect of Indomethacin on Alteration of ATPase-Positive Langerhans Cell Density and Cutaneous Sunburn Reaction Induced by Ultraviolet-B Radiation," Journal of Investigative Dermatology . Vol. 81, No. 5, pp. 455-458 (1983) , showed that indomethacin topically applied prior to ultraviolet-B irradiation in humans resulted in protection from the sun. Topical application of indomethacin after ultraviolet-B irradiation resulted in a decrease in erythema. The protective effect of topical indomethacin applied prior to radiation may be explained by its .in vitro absorption of ultraviolet-B irradiation. The application of indomethacin after irradiation resulting in decreased erythema was probably related to its effect on prostaglandin synthetase inhibition. The authors concluded that indomethacin applied topically could be useful as a sunscreen agent. Its clinical safety and efficacy, however, remain to be determined. Flowers et al, "A Comparative Study of the

Effect of Flurbiprofen and Indomethacin on Sunburn," Current Therapeutic Research, Vol. 36, No. 4, pp. 787- 791 (October 1984) , evaluated the efficacy of ultraviolet-B induced erythema in humans when the subjects were treated with a test solution containing 2.5% indomethacin, 2.5% flurbiprofen or vehicle alone. The authors concluded that flurbiprofen showed more promise than indomethacin in the suppression of early ultraviolet-B irradiation induced erythema. Tas et al, "Effect of Topically Applied Flurbiprofen on Ultraviolet-Induced Erythema," Drug Intelligence and Clinical Pharmacy, Vol. 20, 496-499 (1986) , studied the effect of flurbiprofen on ultraviolet-B induced erythema in humans. The authors concluded that topical flurbiprofen decreased the dermal symptoms of sunburn. The optimum maximum concentration of flurbiprofen appeared to be approximately 3% and more than two applications appeared to have no added advantage.

In summary, the current state of the art now teaches that there is no conversion of R(-) to S(+) ketoprofen in humans and that the S(+) form is the active enantiomer of ketoprofen. However, there do not appear to be any human experiments on the efficacy of the separate enantiomers reported in the literature. The prior art, moreover, is conspicuously silent in respect to any prevention or alleviation of sunburn utilizing any particular optical isomer of the ketoprofen drug species.

SUMMARY OF THE INVENTION

Surprisingly, the present inventors now find that S(+) ketoprofen can be advantageously topically administered to mammals, especially humans, to prevent or treat ultraviolet radiation-induced erythema and to evoke such prevention or treatment more effectively than possible by administration of the same dose of ketoprofen in its racemic form. S(+) ketoprofen is more potent than an equal amount of the racemic mixture.

This is particularly surprising in light of the art's failures to attribute any difference in activity for S(+) ketoprofen versus the racemic mixture.

In one aspect, the present invention thus provides a method for preventing ultraviolet radiation- induced erythema in a mammal, said method comprising topically administering to a mammal exposed to ultraviolet radiation an amount effective to prevent ultraviolet radiation of S(+) ketoprofen substantially free of R(-) ketoprofen. In another aspect, the present invention provides a method for treating ultraviolet radiation- induced erythema in a mammal, said method comprising topically administering to a mammal in need of such treatment an amount effective to treat ultraviolet radiation-induced erythema of S(+) ketoprofen substantially free of R(-) ketoprofen.

In yet another aspect, the present invention provides a pharmaceutical composition of matter for use in preventing or treating ultraviolet radiation-induced erythema in mammals, especially humans, said composition comprising an amount effective to prevent or treat ultraviolet radiation-induced erythema of S(+) ketoprofen substantially free of R(-) ketoprofen. Typically, S(+) ketoprofen is associated with a nontoxic topical pharmaceutically acceptable inert carrier or diluent therefor.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The term "ketoprofen" or "racemic ketoprofen" as used herein is intended to encompass not only DL-2- (3-benzoylphenyl)propionic acid itself but also any pharmaceutically acceptable salt thereof. The term "S(+) ketoprofen" as used herein is intended to encompass not only the dextrorotatory or S(+) isomer of 2-(3-benzoylphenyl)propionic acid but also any pharmaceutically acceptable, antierythematously effective salt thereof. The expression "substantially free of R(-) ketoprofen" as used in conjunction with the term "S(+) ketoprofen" means that the S(+) ketoprofen is sufficiently free of R(-) ketoprofen [which is the levorotatory form or R(-) isomer of 2-(3-benzoylphenyl)-propionic acid or salt thereof] to exert the desired antierythema effect. Practically speaking, this means that the active ingredient should contain at least 90% by weight S(+) ketoprofen and 10% or less by weight R(-) ketoprofen. Preferably, the weight ratio of S(+) ketoprofen to R(-) ketoprofen is greater than or equal to 20:1, more preferably greater than 97:3. Ideally, the S(+) keto¬ profen is 99 or more % by weight free of R(-) ketoprofen, i.e., the weight ratio of S to R is approximately equal to or greater than 99:1. At the present time, a 20:1 ratio of S(+) to R(-) is readily obtainable from racemic ketoprofen by literature methods and eminently useful in the practice of the present invention. Where specific amounts of S(+) ketoprofen are set forth below, it should be understood that, unless otherwise specified, the amounts are given in mg of the acid, not of a salt. Moreover, unless otherwise specified, for simplicity's sake the amounts given represent total ketoprofen content, most of which is in the S(+) form. For example, "50 mg S(+) ketoprofen" means 50 mg total ketoprofen at least 90% of which is in the S(+) form, preferably at least 95%, more preferably at least 97% and most preferably 99% or more.

Topical S(+) ketoprofen, in accord with the present invention, produces the following unexpected results:

(1) the S(+) isomer of ketoprofen is more potent than racemic ketoprofen for topical administration on a mammal since the ketoprofen is substantially, or in large part, in the active form; and

(2) in the case of ketoprofen, the R(-) isomer is not active and would not substantially overcome the effects of ultraviolet-induced erythema or sunburn because there would probably be little if any chiral conversion in the skin.

These unexpected results can be achieved in the treatment of sunburn responsive to an NSAID (non¬ steroidal anti-inflammatory drug) .

In a group responsive to a given dose of the racemate, it is believed that S(+) ketoprofen applied in the same amount as racemic ketoprofen would provide a better response for preventing or treating ultraviolet radiation-induced erythema. S(+) ketoprofen would be at least twice as potent. The precise amount of topical S(+) ketoprofen for use in accord with the present invention will vary depending, for example, on the size and kind of the mammal and the condition for which the drug is administered. For use in humans, the amount effective to prevent or treat ultraviolet radiation-induced erythema of S(+) ketoprofen will typically be from about 0.5 wt. % to about 10 wt. % although greater amounts (e.g., 15 wt. %) may be employed if needed or if tolerated by the patient. The preferred composition contains about 1 wt. % to about 5 wt. %, more preferably about 2.5 to 3.5 wt. % ketoprofen. The most preferred composition would likely contain about 3.0 wt. % ketoprofen. It should be noted, however, that lesser amounts may be useful on patients with particularly sensitive skin and/or on the skin of children. The S(+) ketoprofen of the present invention may be applied in any vehicle or in any fashion suitable for topical administration. Topical preparations typically include solutions, .e.g. , clear or milky lotions, gels, creams, ointments, sprays, lip balm, clothwipe, impregnated bandages and other topical and transdermal delivery devices.

According to the FDA advisory review panel, "[a]n ideal sunscreen vehicle would be stable, neutral, nongreasy, nondegreasing, nonirritating, nondehydrating, nondrying, odorless, and efficient on all kinds of human skin. It should also hold at least 50% water, be easily compounded of known chemicals, and have infinite stability during storage". Federal Register. 43, 38218 (1978). S(+) ketoprofen may be formulated with any suitable nontoxic topical pharmaceutically acceptable inert carrier material. Such topical carrier materials are well known to those skilled in the art of pharmaceutical formulations. For those not skilled in the art, reference is made to the text entitled

Remington's Pharmaceutical Sciences, 17th edition, 1985, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pennsylvania 18042. Suitable solvents or vehicles, for instance, for the topical S(+) ketoprofen composition of the present invention includes methanol, ethanol, propyl alcohol, acetone, n-butyl alcohol, isobutyl alcohol and the like.

The primary uses of sunscreens are to prevent sunburn and aid in the development of a tan. Secondarily, they serve to protect exposed areas of the body in susceptible individuals from the long-term hazards of skin cancer and premature aging. In addition, sunscreens can be used to protect against drug-related ultraviolet-induced photosensitivity.

For purposes of the present invention, the term "sunscreen agent" shall refer to the use of S(+)- ketoprofen as a sunscreen-sunburn preventive agent, a sunscreen-suntanning agent and/or a sunscreen-opaque sunblock agent. Each of those type of agents has been defined by the FDA advisory review panel as nonprescription topical analgesic, antirheumatic, otic, burn and sunburn prevention and treatment drug products as follows:

A sunscreen-sunburn preventive agent contains an active ingredient that absorbs 95% or more of the radiation in the ultraviolet range at wavelengths from 290-320 nm and thereby removes the sunburning rays;

A sunscreen-suntanning agent contains an active ingredient that absorbs at least 85% of the radiation in the ultra-violet range at wavelengths from 290-320 nm, but transmits ultraviolet wavelengths longer than 320 nm (such agents permit tanning in the average individual and also permits some erythema without pain) ; A sunscreen-opaque sunblock agent has an opaque agent that reflects or scatters all radiation in the ultraviolet and visible range from 290-777 nm and thereby prevents or minimizes suntan and sunburn. The following pharmaceutically acceptable topical ingredients are present in commercial sunscreens or sunblocks: titanium dioxide, petrolatum, red petrolatum, benzophenone-3, isopropyl myristate, aloe vera extract, synthetic beeswax, cetyl palmitate, ceresin, lanolin, cetyl alcohol, alcohol, oleth-3 phosphate, synthetic spermaceti, glycerin, mineral oil, lanolin alcohol, cetyl stearyl glycol, lanolin oil, triethanolamine, carbomer 934, benzyl alcohol, menthol, camphor, essential oils, acrylic-acrylate copolymer, ammonium hydroxide, carbomer 934P, dimethicone, quaternium-15, stearic acid, stearyl alcohol, water, xanthan gum, SD alcohol 40, animal protein derivative, hydroxyethyl cellulose, choleth-24, hydroxypropyl cellulose, PPG-15 stearyl ether, propylene glycol dioctanoate, stearic acid, ozokerite, PEG-4 dilaurate, propylparaben, dihydroxyacetone, hydrocarbon oil, ointment base zinc oxide, opaque base, water-repellent cream base, caramel, perfume and flavors. It would be advantageous for the topical composition of the present invention to have sufficient substantivity to withstand exposure of the skin to swimming, high humidity and sweating.

Generally, sunscreens should be applied approximately 30 minutes before exposure to the sun. However, there are exceptions, for instance, aminobenzoic acid and its esters are more effective if applied two hours before exposure. Pre-application of the topical S(+) ketoprofen composition prior to sun exposure to the skin is advantageous because it allows the S(+) ketoprofen to penetrate and perhaps bind with the skin. The amount of S(+) ketoprofen useful in the topical preparations of the present invention is an amount sufficient to prevent or treat ultraviolet radiation-induced erythema.

Typical unit dosage forms for topical administration will contain about 0.5 wt. % to about 10 wt. %, preferably about 1 wt. % to about 5 wt. %, most preferably about 2.5 wt. % to about 3.5 wt. %, S(+) ketoprofen based on the entire weight of the composition per topical unit dose application. If the composition is intended for sustained release such as by using microcapsules or microspheres, much larger amounts of the active ingredient would of course be incorporated into an individual unit. As noted earlier, the composition and the method of the present invention is "substantially free of the R(-) ketoprofen."

The topical S(+) ketoprofen composition of the present invention may further be combined with other types of sun-protective and/or antierythema topical agents. Such agents may absorb 95 percent or more of the ultraviolet B radiation and thereby prevent or minimize the deleterious effects on human skin caused by excessive exposure to ultraviolet B (290 to 320 nm) and ultraviolet A (320 to 400 nm) radiation. Protection is afforded by the active chemical ingredients of a sunscreen through absorption, reflection and scattering of solar radiation impinging on the skin. Topical sunscreens can fall within one of two categories: (1) chemical, and (2) physical sunscreens. Chemical sunscreens contain one or more UV-absorbing chemicals, and upon application of a thin and invisible film, act as filters and do not allow the penetration of ultraviolet radiation to the viable cells of the epidermis. Chemical sunscreens are usually colorless because they do not contain any visible light-absorbing chemicals and are, therefore, cosmetically acceptable to most persons provided they are a nonirritant to the skin and eyes, nonphotosensitizing, stable, nonvolatile, and nonstaining to skin and clothes. Most of the commercial topical sunscreens contain one or more ultraviolet B absorbing chemicals in a moisturizing base. More recently, many leading brand-name sunscreens also contain ultraviolet A absorbing chemicals, especially the different benzophenones. The most widely used chemical sunscreens contain para- aminobenzoic acid (PABA) , PABA esters (a yldimethyl

PABA and octyldimethyl PABA) , benzophenones (oxybenzone and sulisobenzone) , cinnamates (octylmethoxy cinnamate and cinoxate) , salicylates (homomenthyl salicylate) , and anthranilates. To date, more than 21 such chemicals have been declared by the U.S. FDA as safe, effective agents in protecting skin against sunburn (see Table 1) , and are listed under Category I (safe and approved) . Table 1

SUNSCREEN AGENTS

Dose

Compound p-aminobenzoic acid glyceryl a inobenzoate amyl p-dimethylamino benzoate (Padimate A) 2-ethylhexyl-p-dimethylamino benzoate (Padimate O) 2-ethoxy-ethylhexyl-p-methoxy cinnamate (cinnoxate) diethanolamine-p-methoxycinnamate ■ethylhexyl-p-methoxycinnamate 2,2-dihydroxy-4-methoxybenzophenone (dioxybenzone)

2-hydroxy-4-methoxybenzophenone

(oxybenzone) 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid (sulisobenzone) 2-ethyl-hexyl-2-cyano-3,3-diphenylacrylate ethyl-4rbis-(hydroxypropyl)-amino benzoate digalloyl trioleate 2-ethylhexyl-salicylate lawsone + dihydroxyacetone 3,3,5-trimethylcyclohexyl salicylate (homosalate) methylanthranilate

2-phenyl-benzimidazole-5-sulfonic acid triethanolamine salicylate red veterinary petrolatum titanium dioxide

Several European sunscreen manufacturers often use p-methoxy-2-ethylhexylcinnamate, 2-phenylbenzimidazole-5-sulfonic acid, 2-phenyl-5- methoxybenzophenone, and 4-tert-butyl-4'-methoxy- dibenzoylmethane as ultraviolet A and B absorbing filters. The recommended concentration for each chemical may vary and is based on not only the solubility of the chemical in a given vehicle, but also the anticipated use of the sunscreen product as a total or partial block for the prevention of sunburn or acquisition of suntan responses. The formulation base (vehicle) used include alcohol plus glycerol or glycol, oil-in-water or water-in-oil lotion, cream, or ointment. The vehicle in which the ultraviolet radiation absorbing chemical is incorporated can determine whether a sunscreen remains effective under the general use condition involving prolonged sunbathing, sweating (sporting activities) , and swimming. This adherent property to skin, known as "substantivity," varies considerably among commercially available sunscreen formulations, some of which are retained on the skin and others of which are washed off easily after sweating or swimming.

Table 2 identifies several commercial chemical sunscreen preparations along with their ingredients and type of composition.

Table 2

Type of

Trade name Ingredients sunscreen

PABA sunscreens:

PreSun-15 Clear lotion Pabanol 5% PABA in 50%-70% Clear lotion Sunbrella ethyl alcohol Clear lotion PreSun-15 Gel

PABA ester sunscreens:

Block out 3.3% isoamyl-p-N,N- Lotion/gel di ethyl a ino- benzoate (padimate-A)

PABAFILM 3.3% isoamyl-p-N,N- Lotion/gel dimethyl amino- benzoate (padimate-A)

Sundown 3.3% isoamyl-p-N,N- Lotion dimethyl amino- benzoate (padimate-A)

Original 3.5% padimate-A + 3.0% Lotion

Eclipse octyldimethyl PABA Aztec 5.0% homomenthyl Lotion salicylate + 2.5% amyl-p-dimethyl aminobenzoate

Sea & Ski 3.3% octyldimethyl Cream PABA Marbert Sun benzyliden-camphor Cream Cre e phenylbenzi idazole-

5-sulfonic acid + iεopropyl dibenzoyl methane

PABA-ester combination sunscreens:

Coppertone 7% octyldimethyl PABA Milky lotion

Super Shade-15 + 3% oxybenzone Total Eclipse- 2.5% glyceryl PABA Milky lotion

15 + 2.5% octyldimethyl

PABA + 2.5% oxybenzone

MMM-What-A-Tan! 3.0% octyldimethyl Milky lotion

PABA+ 2.5% benzophenone-3

PreSun-15 8% padimate-O + Milky lotion (water- 3% oxybenzone resistant) Clinique-19 phenyl-benzimidazole- Milky lotion 5-sulfonic acid + 2.5% octyldimethyl PABA

Sundown-15 7% padimate-O + 5% Milky lotion (sunblock) octylsalicylate + 4% oxybenzone

Bain de Soleil 7.0% padimate-O + White cream 2.5% oxybenzone + 0.5% dioxybenzone

Elizabeth Arden padimate-O + oxy¬ White cream

Suncare benzone

Creme-15 Estee Lauder-15 phenyl-benzimidazole- White cream

5-sulfonic acid + dimethyl PABA

Rubenstein Gold ethyl-hexyl-p- Yellow gel Beauty-15 methoxycinnamate

+ octyldimethyl PABA

Block Out-15 7% octyldimethyl PABA Creamy lotion

+ 3% oxybenzone

Shiseido-15 6.5% titanium dioxide Lotion

+ 2.5% octyldimethyl

PABA + 0.3% benzophenone-3

Non-PABA sunscreens:

Piz Buin-8 5% ethyl-hexyl-p- Cream methoxycinnamate + 3% 2-hydroxy-4- methoxybenzophenone + 4% 2-phenyl-benzimidazole sulfonic acid Piz Buin-8 5% ethyl-hexyl-p- Milky lotion TIScreen-15 methoxycinnamate +

3% 2-hydroxy-4- methoxybenzophenone

Piz Buin-4 4.5% ethyl-hexyl-p- Milky lotion methoxycinnamate UVAL 10% 2-hydroxy-4- Milky lotion methoxybenzophenone-

5-sulfonic acid

Coppertone 8% homomenthyl- Lotion salicylate

Ultra Vera-20 octylmethoxycinnamate Milky lotion (Cheesebrough- + 2-hydroxy-4- Ponds) metlioxybenzophenone

Piz Buin cinnamide + dibenzoyl- Yellow lotion Gletscher methane Creme-15

Piz Buin-12 4.5% octyl-methoxy- Milky lotion cinnamate + 4.5% zinc oxide + 4.5% talc + 2.2% benzophenone-3

Physical sunscreens are usually opaque formulations and contain ingredients particulate in nature that do not selectively absorb ultraviolet radiation, but, when applied as a thin film, primarily reflect and scatter ultraviolet and visible radiation because of the size of the particles and the thickness of the film. These include titanium dioxide (5% to 20%) , talc (magnesium silicate) , magnesium oxide, zinc oxide, kaolin, ferric chloride, and ichthyol (ichthammol) . Zinc oxide appears to be the most effective. These formulations are cosmetically unpleasing, unacceptable to many patients, and are often occlusive and messy to use. Physical sunscreens are, however, essential for those patients who are unusually sensitive to ultraviolet radiation as well as visible radiation; these are usually applied to limited areas such as the nose, lips, or helix of the ear. Table 3 identifies several commercial physical sunscreen preparations along with their ingredients and type of composition.

Table 3 Physical sunscreens

Tradename Ingredients Type of Sunscreen

A-Fil titanium dioxide + Cream

RV Paque oxide + talc, Cream

Shadow kaolin, iron oxide, Cream

Reflecta or red veterinary Cream

Covermark petrolatum Cream

Clinique Cream

S(+) ketoprofen may be combined along with any of the compounds identified in any of the Tables identified above as a topical vehicle for administration.

For cosmetic rather than therapeutic needs, the patient may desire a suntan product. In many cases, suntan products differ from sunscreens only by having a lower concentration of the sunscreen agent. The concentration of the active ingredient is an important factor in judging the use and effectiveness of a product. For example, SunDare Lotion, a suntan product, contains 1.75% cinoxate, while Maxafil Cream, a sunscreen product, contains 4% (about twice as much as the suntan product) and 5% menthyl anthranilate, a second sunscreen.

Further, the sunburn/sunscreen product of the present invention may include a burn or sunburn treatment component such as an anesthetic, antimicrobial or another ingredient.

The anesthetic component of commercial products presently include: benzocaine, lidocaine hydrochloride, buta ben picrate, dibucaine, tetracaine hydrochloride, tripelennamine, and menthol benzocaine.

The antimicrobial component of commercial products currently include: benzethonium chloride, benzalkonium chloride, povidone-iodine, chloroxylenol, chlorobutanol, 8-hydroxyquinoline, phenol, 8-hydroxyquinoline sulfate, cresol-camphor complex, chlorothymol, methylbenzethonium chloride, triclosan, benzyl alcohol, and parahydracin.

The S(+) ketoprofen for use in the method and compositions of the present invention can be prepared by a variety of methods, such as by resolution of racemic ketoprofen.

Farge et al, United States Patent No. 3,641,127 describes the preparation of racemic ketoprofen and related compounds; see, in particular, Example V thereof. The Farge et al patent also describes a method for preparing the individual D- and L-isomers by oxidation of the corresponding optically active (3-benzylphenyl)^'alkanoic acids; see column 3, lines 22-40.

Abas et al, J. Pharmacol. EXP. Ther. 240(2) . 637-641 (1987) , have resolved racemic ketoprofen using a modification of the method of Blazevic et al, Acta Pharmacol. Jugoslav. 25. 155-164 (1975) . Abas et al prepared the diastereoisomeric amides of R(-) and S(+) ketoprofen with (+)-R-1-methylbenzylamide from racemic ketoprofen, via the acid chlorides using thionyl chloride. The diastereoisomeric amides were separated by the HPLC (high performance liquid chromatographic) method of Sallustio et al. Journal of Chromatography 374. 329-337 (1986), but using a 7.8 mm x 300 mm preparative column. The pure amides were then separately converted to nitroso derivatives with dinitrogen tetroxide, and the nitroso derivatives were thermally decomposed to the respective ketoprofen enantiomers as described by Balzevic et al. Purification of the R and S enantiomers by silica gel chromatography, recrystallization from diethyl ether/cyclohexane and HPLC analysis according to Sallustio et al's method afforded the R and S enantiomers with enantiomeric purities of 98% and 95%, respectively.

HPLC methods other than Sallustio et al's for resolving enantiomers of NSAID's such as ketoprofen and fenoprofen, and likely adaptable to resolution of ketoprofen, include the method of Doyle et al, Phar . Technol. 9 2) . 28-32 (1985) , which utilizes conversion of the race ate to its amide derivatives for effective resolution; and that of Wainer et al, J. Chromatogr. 284fl) , 117-124 (1984) , which utilizes conversion of the drug to 1-naphthalenemethylamide derivatives.

A method for derivatizing ketoprofen, fenoprofen and other nonsteroidal anti-inflammatory drugs with optically active amphetamine (α- methylbenzeneethanamide) has been described by Singh et al, J. Chromatogr. Biomed. Appln.. 378. 125-135 (1986) . Those authors also provide a summary of the usual methods for resolving enantiomers, i.e. (1) by direct separation or chiral HPLC or GC (gas chromatographic) columns, or (2) by diastereoisomer formation, by reaction with an optically pure resolving agent, followed by chromatographic separation on an optically inactive column. Singh et al's method is a new version of the second approach, using optically active amphetamine as the resolving agent, followed by separation of the diastereoisomers by capillary gas chromatography with nitrogen-phosphorus detection. (The acid, now in optically pure form, could of course then be regenerated from the salt as is well-known.) The usual method in the art- utilizes optically active α-methylbenzylamine and involves preparation of the diastereoisomeric NSAID-α-methylbenzylamide directly by means of a coupling agent (e.g. 1,1'- carbonyldiimidazole) or via the NSAID acid chloride (prepared with thionyl chloride) .

More generally speaking, the S(+) isomer can be separated from racemic ketoprofen by preparing a salt of ketoprofen with an alkaloid or similar resolving agent such as cinchonidine, then separating the products by fractional crystallization from a solvent in which the dextrorotatory isomer is least soluble. The d-salt can then be acid cleaved to yield S(+) ketoprofen. Compare, for example, Alvarez, United States Patent No. 3,637,767, issued January 25, 1972, which relates to resolution of naproxen and related compounds; and Kaiser et al, J. Pharm. Sci. 65(21 _r 269-273 (1976) , which relates to resolution of ketoprofen. While S(+) ketoprofen may be conveniently obtained by resolution of racemic ketoprofen, it may also be possible to utilize a chemical or microbiological synthetic process which will provide the S(+) enantiomer directly. One such chemical process is described in Farge et al. United States

Patent No. 3,641,127, as already mentioned hereinabove. Another chemical process is provided by Schloemer, United States Patent No. 4,542,237, which describes a process for preparing α-arylalkanoic acids utilizing novel a-hydroxy alkyl aryl ketals as intermediates. As taught in column 9 of the Schloemer patent, the process is advantageous in that the α-hydroxy ketal can be resolved by well-known methods and the optically active α-hydroxy ketal thus obtained can then be used in the subject process to ultimately afford the desired acid in optically pure form.

Alternatively, a microbiological process such as that described in SHELL INTERNATIONALE RESEARCH MAATSCHAPPIJ B.V. -s European Patent Appln. No. 86

200987.5, published under No. 0 205215 on December 17, 1986, may be employed. According to the European application, a pharmaceutically active compound of the type

or a pharmaceutically active salt or ester thereof, which most preferably is naproxen or ketoprofen but which may be ketoprofen or various other NSAIDs, is prepared in stereospecific form by subjecting a compound of the formula

to the action of an appropriate microorganism. The desired acid is obtained having at least 70% by weight in the S-configuration. Preferably, a microorganism is selected such that the acid which is formed is at least 90% by weight in the S-configuration. Use of this method has afforded naproxen with enantiomeric distributions of 98.9% S and 1.1% R in one instance, and distributions of 99.5% S and 0.5% R in another. Processes of this type may be utilized to prepare S(+) ketoprofen for use in the present invention if the S(+) isomer can be obtained in sufficient purity [ideally, at least 90% by weight S(+) isomer.]

When S(+) ketoprofen is to be employed in the form of a pharmaceutically acceptable, antierythematously active salt thereof, such salt may be conveniently prepared by direct salification of S(+) ketoprofen by known methods. See, for example, deVincentiis, United States Patent No. 4,440,787, which describes salts of (2• ,4'-difluoro-4-biphenyl)oxypro- pionic acid with metallic ions, such as sodium, potassium, magnesium and calcium, or with pharmaceutically acceptable organic bases, such as lysine, arginine and diethanolamine. Compare also Ar itage et al, United States Patent No. 4,501,727, issued February 26, 1985, which describes the N-methyl- D-glucamine salt of flurbiprofen. Such a salt may not only be used in oral or rectal compositions, but, if sufficiently soluble in water, may be useful in the preparation of aqueous solutions of S(+) ketoprofen for parenteral injection.

From the foregoing description, one of ordinary skill in the art can easily ascertain the essential characteristics of the instant invention, and without departing from the spirit and scope thereof, can make various changes and/or modifications of the invention to adapt it to various usages and conditions. As such, these changes and/or modifications are properly, equitably and intended to be within the full range of equivalents of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for preventing or treating ultraviolet radiation-induced erythema in a human mammal exposed to ultraviolet radiation or suffering from ultraviolet radiation-induced erythema and in need of such prevention or treatment, comprising topically administering to such mammal a composition comprising a unit dosage amount effective to prevent or treat ultraviolet radiation-induced erythema of the S(+) ketoprofen enantiomer, and said enantiomer being substantially free of its R(-) ketoprofen antipode.

2. The method according to Claim 1, wherein the weight ratio of S(+) ketoprofen to R(-) ketoprofen is greater than 9:1.

3. The method according to Claim 2, wherein the weight ratio of S(+) ketoprofen to R(-) ketoprofen is greater than 20:1.

4. The method according to Claim 3, wherein the weight ratio of S(+) ketoprofen to R(-) ketoprofen is greater than 97:3.

5. The method according to Claim 4, wherein the weight ratio of S(+) ketoprofen to R(-) ketoprofen is approximately equal to or greater than 99:1.

6. The method according to Claim 1, comprising topically administering to such mammal from about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

7. The method according to Claim 1, comprising topically administering to such mammal from about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

8. The method according to Claim 1, comprising topically administering to such mammal from about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

9. The method according to Claim 2, comprising topically administering to such mammal from about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

10. The method according to Claim 2, comprising topically administering to such mammal from about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

11. The method according to Claim 2, comprising topically administering to such mammal from about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition. '

12. The method according to Claim 3, comprising topically administering to such mammal from about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

13. The method according to Claim 3, comprising topically administering to such mammal from about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

14; The method according to Claim 3, comprising topically administering to such mammal from about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

15. The method according to Claim 4, comprising topically administering to such mammal from about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

16. The method according to Claim 4, comprising topically administering to such mammal from about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

17. The method according to Claim 4, comprising topically administering to such mammal from about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

18. The method according to Claim 5, comprising topically administering to such mammal from about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

19. The method according to Claim 5, comprising topically administering to such mammal from about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

20. The method according to Claim 5, comprising topically administering to such mammal from about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

21. The method according to Claim 1, wherein the S(+) enantiomer is topically administered as a lotion.

22. The method according to Claim 1, wherein the S(+) enantiomer is topically administered as a gel.

23. The method according to Claim 1, wherein the S(+) enantiomer is topically administered as a solution.

24. The method according to Claim 1, wherein said composition further comprises a unit dosage amount effective to prevent or treat ultraviolet radiation- induced erythema of an additional sunscreen.

25. The method according to Claim 24, wherein said additional sunscreen is selected from the group consisting of p-aminobenzoic acid, amyldimethyl p- aminobenzoic acid, octyldimethyl p-aminobenzoic acid, octylmethoxy cinnamate, homomenthyl salicylate, glyceryl aminobenzoate, amyl p-dimethylamino benzoate 2- ethylhexyl-p-dimethylamino benzoate, 2-ethoxy-ethylhexyl- p-methoxy cinnamate, diethanolamine-p-methoxycinnamate, ethylhexyl-p-methoxycinnamate, 2,2-dihydroxy-4- methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2- hydroxy-4-methoxybenzophenone-5-sulfonic acid, 2-ethyl- hexyl-2-cyano-3 ,3-diphenylacrylate, ethyl-4-bis-

(hydroxypropyl)-amino benzoate, digalloyl trioleate, 2- ethylhexyl-salicylate, lawsone + dihydroxyacetone, 3,3,5- trimethylcyclohexyl salicylate, methylanthranilate, 2- phenyl-benzimidazole-5-sulforiic acid, triethanolamine salicylate, red veterinary petrolatum and titanium dioxide.

26. The method according to Claim 25, wherein said additional sunscreen is selected from the group consisting of para-aminobenzoic acid, amyldimethyl para- aminobenzoic acid, octyldimethyl para-aminobenzoic acid, 2-hydroxy-4-methoxybenzophenone and 2-hydroxy-4- methoxybenzophenone-5-sulfonic acid.

27. The method according to Claim 26, wherein said additional sunscreen is para-aminobenzoic acid.

28. A pharmaceutical composition of matter adapted for topical administration for preventing or treating ultraviolet radiation-induced erythema in a human mammal exposed to ultraviolet radiation or suffering from ultraviolet radiation-induced erythema, said composition comprising a unit dosage topically effective amount to prevent or treat ultraviolet radiation-induced erythema of the S(+) ketoprofen enantiomer, said enantiomer being substantially free of its R(-) ketoprofen antipode, and a nontoxic topical pharmaceutically acceptable carrier or diluent therefor.

29. The composition according to Claim 28, wherein the weight ratio of S(+) ketoprofen to R(-) ketoprofen is greater than 9:1.

30. The composition according to Claim 29, wherein the weight ratio of S(+) ketoprofen to R(-) ketoprofen is greater than 20:1.

31. The composition according to Claim 30, wherein the weight ratio of S(+) ketoprofen to R(-) ketoprofen is greater than 97:3.

32. The composition according to Claim 31, wherein the weight ratio^' of S(+) ketoprofen to R(-) ketoprofen is approximately equal to or greater than 99:1.

33. The composition according to Claim 28, comprising topically administering to such mammal from about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

34. The composition according to Claim 28, comprising topically administering to such mammal from about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

35. The composition according to Claim 28, comprising about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

36. The composition according to Claim 29, comprising about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of. the entire composition.

37. The composition according to Claim 29, comprising about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

38. The composition according to Claim 29, comprising about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

39. The composition according to Claim 30, comprising about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

40. The composition according to Claim 30, comprising about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

41. The composition according to Claim 30, comprising about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

42. The composition according to Claim 31, comprising about 0.5 wt. .% to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

43. The composition according to Claim 31, comprising about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

44. The composition according to Claim 31, comprising about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

45. The composition according to Claim 32, comprising about 0.5 wt. % to about 10 wt. % S(+) ketoprofen, based on the weight of the entire composition.

46. The composition according to Claim 32, comprising about 1.0 wt. % to about 5.0 wt. % S(+) ketoprofen, based on the weight of the entire composition.

47. The composition according to Claim 32, comprising about 2.5 wt. % to about 3.5 wt. % S(+) ketoprofen, based on the weight of the entire composition.

48. The composition according to Claim 28, wherein the S(+) enantiomer is topically administered as a lotion.

49. The composition according to Claim 28, wherein the S(+) enantiomer is topically administered as a gel.

50. The composition according to Claim 28, wherein the S(+) enantiomer is topically administered as a solution.

51. The composition according to Claim 28, wherein said composition further comprises a unit dosage amount effective to prevent or treat ultraviolet radiation-induced erythema of an additional sunscreen.

52. The composition according to Claim 51, wherein said additional sunscreen is selected from the group consisting of p-aminobenzoic acid, amyldimethyl p- aminobenzoic acid, octyldimethyl p-aminobenzoic acid, ^* pctylmethoxy cinnamate, homomenthyl salicylate, glyceryl aminobenzoate, _. a yl p-dimethylamino benzoate 2- ethylhexyl-p-dimethylamino benzoate, 2-ethoxy-ethylhexyl- p-methoxy cinnamate, diethanolamine-p-methoxycinnamate, ethylhexyl-p-methoxycinnamate, 2 , 2-dihydroxy-4- methoxybenzophenone, 2-hydroxy-4-*-methoxybenzophenone, 2- hydroxy-^*4-methoxybenzophenone-5-sulfonic acid, 2-ethyl- hexyl-2-cyano-3 , 3-diphenylacrylate, ethyl-4-bis- (hydroxypropyl)-amino benzoate, digalloyl trioleate, 2- ethylhexyl-salicylate, lawsone+ dihydroxyacetone, 3,3,5- trimethylcyclohexyl salicylate, methylanthranilate, 2- phenyl-benzimidazole-5-sulfonic acid, triethanolamine salicylate, red veterinary petrolatum and titanium dioxide.

53. The composition according to Claim 52, wherein said additional sunscreen is selected from the group consisting of para-aminobenzoic acid, amyldimethyl para-aminobenzoic acid, octyldimethyl para-aminobenzoic acid, 2-hydroxy-4-methoxybenzophenone and 2-hydroxy-4- methoxybenzophenone-5-sulfonic acid.

54. The composition according to Claim 53, wherein said additional sunscreen is para-aminobenzoic acid.