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United States Patent 19 3,966,924 Fredriksson 145 June 29, 1976

(54) COMPOSITION AND METHOD FOR Stroughton et al., “Psoriasis", Proc. Int. Symp. (1971) TREATING PSORASS pp. 367-375, CA. vol. 79, Par. 38,717h. Tissot ct al., "Acta Dermato-Venereol', vol. 46(5), 75 Inventor: Torsten Fredriksson, Vasteras, (1966) pp. 447-452, Abstracted CA. vol. 66 (1967) Sweden p. 9621 v. 73 Assignee: Allergan Pharmaceuticals, Irvine, Calif. Primary Examiner-Elbert L. Roberts 22 Filed: Nov. 13, 1974 Attorney, Agent, or Firm-Martin A. Voct 21 Appl. No.: 523,241 57 ABSTRACT A composition and method for treating psoriasis in hu 52 U.S. Cl...... 424/240 mans comprising the topical administration to a 151 int. Cl...... A61K 31/56 human suffering from psoriasis of an cffective dose for 58) Field of Search...... 260/.397.45; 424/240 treating psoriasis of a composition comprising from about 0.01 to about 5% of a and prefer 56 References Cited . ably a halogenated corticosteroid and from about 0.05 OTHER PUBLICATIONS to about 10% of 5-fluorouracil together with a suitable Fisher et al., “Psoriasis", Proc. int. Symp. (1971) pp. topical carrier. 335-345, CA. Vol. 79, pp. 49, 360m abstracted. 4 Claims, No Drawings 3.966,924 2 - thasone benzoate, Valerate and dipropionate, chloro COMPOSITION AND METHOD FOR TREATING acetate, descinalone acetonide, , PSORASS , :acetate, , flucloronide, flumethasone, acetate, fluo BACKGROUND OF THE INVENTION cinolone acetonide, , , fluor Field of the Invention ometholone, fluperoline acetate, valer The present invention relates to the therapeutic ate, , methyl , parametha treatment of proliferation-type skin diseases. More sone acetate, prednisolomate, , particularly, the present invention relates to the use of butylacetate and phosphate sodium, and in combination with 5-fluorouracil in O acetonide, hexacetonide, diacetate, the treatment of skin conditions such as psoriasis. butyrate, flumethasone pivalate, halcininide and Psoriasis is a common, chronic, relapsing disease of propionate. unknown etiology which consists of elevated, silvery, The amount of corticosteroid which may be used in dry lesions which are known as plaques. Pathologically, the present invention varies from about 0.01 to about there are three obvious changes associated with the 5 5% and preferably about 0.025 to about 0.1% by disease: (1) increase in the rate of cell division of the weight of the composition. epidermis, (2) striking increase in the thickness of the Conventional topical formulations may be used with cornified epithelium, and (3) proliferation of the sub the foregoing ingredients. For example, a typical for epithelial capillaries. . . . is ...... mulation may contain non-ionic emulsifying waxes Corticosteroids and especially halogenated cortico such as Polawax or fatty alcohols, glycol ethers or es have been successfully used in the topical ters of fatty acids, other wax-like emulsifiers or self treatment of psoriasis to temporarily alleviate the signs emulsifying fatty alcohol blends; emollients, such as and symptoms of the disease. This effect is probably isopropyl myristate or other isopropyl esters of fatty due to influence on the nucleic acid metabolism of the 25 acids, butyl esters of fatty acids, glycerin, propylene epidermis. The effect, which is most striking when glycol, alcohols, dimethyl sulfoxide, dimethyl form occlusive dressings are used, is now well documented amide, propylene glycol carbonate and other carbox and accepted. However, there are several disadvan ylic acid esters; an oil phase such as mineral oil, petro tages with this type of treatment: occlusion must go on leum oil, oil extracts from animal sources, e.g. shark for periods of up to 2-3 weeks before lesions are 30 oil, lanolin and oil extracts from vegetable sources, e.g. cleared; and the recurrence rate is high, that is, the peanut oil. The formulation may also include stabilizers lesions return within a few weeks to a few months after including, for example, EDTA, 8-OH quinoline and withdrawal of therapy. conventional antioxidants and preservatives. 5-Fluorouracil has also been used in the topical treat A typical formulation for topical use contains the ment of psoriatic lesions under occlusion. However, 35 following ingredients per gram: when used alone erosions must be produced in order to have a lasting effect (Tsuji and Sugai, Arch. Derm., Mg 105:208, 1973), and these erosions are painful to the halogenated corticosteroid patient. 5-Fluorouracil is a known inhibitor of thimydy 5-fluorouracil O late synthetase and through this inhibition also inter 40 inert carrier 989 feres with the nucleic acid metabolism, SUMMARY OF THE INVENTION In carrying out the novel method employing the topi It has now been discovered that corticosteroids and cal route, the active ingredient formulated, for exam especially halogenated corticosteroids in combination 45 ple, as an ointment or solution, as indicated above, is with 5-fluorouracil and a suitable topical pharmaceuti applied to a psoriatic lesion at a rate varying from 1 mg cal carrier provide a synergistic formulation which is per Square cm. of skin surface per day up to 10 mg per more effective than the compounds used alone and Square cm. of skin surface per day until the appearance which provides a substantial improvement in recur of the psoriatic skin has returned to normal. The oint rence. That is, the claimed formulation temporarily 50 ment or solution is generally applied daily for one alleviates the symptoms of psoriasis, that is, improves week, preferably using a continuous occlusive dressing. the appearance of psoriatic skin by eliminating the With the foregoing concentration, a dose of about psoriatic plaques with fewer side effects and a longer 10-150 mg of the composition per square cm./per remission time than the compounds used alone. week of skin surface readily supplies the amount of 55 active ingredient specified above. DETALED DESCRIPTION OF THE INVENTION To illustrate the manner in which the invention is 5-Fluorouracil is a known compound and is commer made, the following examples are given. It is under cially available. The amount of 5-fluorouracil which stood, however, that the examples are for purposes of may be used in the present invention varies from about illustration and the invention is not to be regarded as 0.05 to about 10% and preferably about 1 to about 5% 60 limited to any of the specific materials or conditions by weight of the composition. therein. Corticosteroids including halogenated corticoster EXAMPLE oids are also known and are commercially available. Typical examples include , hydrocortisone Method and derivatives thereof including cortodoxone, fluceto 65 Ninety subjects with nummular and extensive psoria nide, acetate, flurandrenolone aceto sis were selected from a clinical pool. All were hospital nide, ; prednisone, prednisolone and deriva ized for 7 to 9 days to control the treatment method tives thereof including , , betame and period. Psoriatic-involved portions of the body 3,966,924 3 4 were divided into comparable separate areas and were (b) Recurrence within three months in 26 out of 26 treated with the following formulations, respectively, patients (100%). twice a day for 7 days. All treated areas were occluded Comparing the foregoing formulations, it is apparent that formulations l and 2 are synergistic in that 24 hours per day. Sixty of the ninety treated patients (1) they are far more effective than formulations 3, 4 were able to be evaluated three months after the end of 5 and 5 (85% clearing of plaques in 7 days vs. 52% the treatment. and 43% clearing of plaques in 21 days); and Formu- 5-Fluoro (2) they result in a far lower recurrence rate than lation uracil Corticosteroid Corticosteroid formulations 3, 4 and 5 (43% recurrence vs. 100% O recurrence). 1% 0.025% mo I claim: 2 1. - 0. 3 ar - 1. A method for treating psoriasis in humans com 4 0.025% prising the topical administration to a human suffering 5 --- 0.1% from psoriasis of an effective dose for treating psoriasis Fluoroplex, Altergan Pharmaceuticals. 15 of a composition comprising as active ingredients, from Commercially available hologenated corticosteroid formulation synalar (ac tive acetonide). about 0.025 to about 0.1% by weight of 6- * Commercially available hologenated corticosteroid formulation valisone valerate and about 1 to about 5% of 5-fluorouracil. 0.1% (active steroid beta-methasone waterale). 2. A method for treating psoriasis in humans com prising the topical administration to a human suffering Results of the foregoing tests were as follows: from psoriasis of an effective dose for treating psoriasis Formulations 1 and 2 20 of a composition comprising as active ingredients, from (a) Complete clearing of plaques in 7 days in 51 out about 0.025 to about 0.1% by weight of fluocinolone of 60 patients (85%). acetonide and about 1 to about 5% of 5-fluorouracil. (b) Recurrence within three months 22 out of 51 3. A composition for treating psoriasis in humans patients (43%). comprising as active ingredients, from about 0.025 to Formulation 3 25 about 0.1% by weight of g-methasone valerate and (a) Complete clearing of plaques in 21 days in 31 out about 1 to about 5% of 5-fluorouracil. of 60 patients (52%). 4. A composition for treating psoriasis in humans (b) Recurrence within three months 31 out of 31 comprising as active ingredients, from about 0.025 to patients (100%). 30 about 0.1% by weight of and Formulations 4 and 5 about 1 to about 5% of 5-fluorouracil. (a) Complete clearing of plaques in 21 days in 26 out of 60 patients (43%).

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