sign in sign up
<<
Home , Clobetasol

USOO6352686B2 (12) United States Patent (10) Patent No.: US 6,352,686 B2 Bohn et al. (45) Date of Patent: *Mar. 5, 2002

(54) ANTIPSORIATIC NAIL POLISH 5,120,530 A 6/1992 Ferro et al...... 424/61 5,258,186 A 11/1993 Ohmura et al...... 424/497 (75) Inventors: Manfred Bohn, Hofheim; Karl 5,264.206 A 11/1993 Bohn et al...... 424/61 Theodor Kraemer, Langen, both of 5,275,807 A * 1/1994 Pappas et al...... 424/61 (DE) FOREIGN PATENT DOCUMENTS (73) Assignee: Aventis Pharma Deutschland GmbH, DE 2 423849 12/1974 Frankfurt am Main (DE) DE 195 29 O85 A1 2/1997 EP O 226 984 12/1986 EP O 226 984 A1 7/1987 (*) Notice: This patent issued on a continued pros EP O 515 312 A2 11/1992 ecution application filed under 37 CFR GB 2 188844 A 10/1987 1.53(d), and is subject to the twenty year WO WO 87/O2580 5/1987 patent term provisions of 35 U.S.C. WO WO95/03838 2/1995 154(a)(2). WO WO-96/14048 A * 5/1996 WO WO 96/36311 * 11/1996 Subject to any disclaimer, the term of this WO WO 97/43644 5/1997 patent is extended or adjusted under 35 WO WO 97/34644 9/1997 U.S.C. 154(b) by 0 days. WO WO-97/34644 A1 * 9/1997 OTHER PUBLICATIONS (21) Appl. No.: 09/135,657 Wilkinsin, et al., Eds., Harry's Cosmeticology, 7th Ed., (22) Filed: Aug. 18, 1998 Chemical Publishing, New York (1982), pp. 375–379 and (30) Foreign Application Priority Data 383-385. Derwent Abstract No. 85-021807 corresponding to JP Aug. 21, 1997 (DE) ...... 19736. 112 59-216822A. (51) Int. Cl." ...... A61K 7/043; A61K 31/56; * cited by examiner A61K 31/785 Primary Examiner Diana Dudash (52) U.S. Cl...... 424/61; 424/78.05; 514/169 Assistant Examiner Alysia Berman (58) Field of Search ...... 424/61, 78.05; (74) Attorney, Agent, or Firm Finnegan, Henderson, 514/169 Farabow, Garrett & Dunner, LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS This invention relates to a nail polish comprising one or 3,861,932 A 1/1975 Kabacoff et al...... 106/187 more useful in treating nails which Show 4,210,633 A 7/1980 Takruri et al...... 424/80 changes due to the Syndrome of pSoriasis. 4,250,164 A 2/1981 Bernstein ...... 424/61 5,091,171 A 2/1992 Yu et al...... 424/642 28 Claims, No Drawings US 6,352,686 B2 1 2 ANTIPSORATIC NAL POLISH WO 97/43644 discloses a topical formulation suitable for the treatment of nail pSoriasis comprising at least one The involvement of the finger nails and toe nails in the , at least one spreading Solvent, at least one pSoriasis Syndrome is widespread. According to literature readily Volatile Solvent and a film-forming agent. This references, up to 50% of all pSoriasis patients also show topical formulation has the disadvantage that a spreading changes to the nails in addition to the characteristic skin Symptoms. The nail changes are found more frequently on Solvent is necessary. This additional spreading Solvent the fingers than on the toes and are identified in the order of increases the price of the formulation and Since It is not clear their frequency by the following Symptoms: if this spreading Solvent is physiologically acceptable, the Pitting (punctate or irregularly shaped depressions approval of the formulation becomes more complicated or arranged on the Surface of the body of the nail in a certain even impossible. pattern or alternatively irregularly), discoloration of the nail The invention aims to make available a glucocorticoid bed, onycholysis (detachment of the body of the nail from containing formulation which does not have the disadvan the nail bed), Subungual keratosis, or anomalies of the body tages described above or only has them to a minor extent. In of the nail. particular, the formulation should guarantee a good penetra For treatment of the nails affected by psoriasis, the 15 following four methods were used until now, but without tion of the nail by the glucocorticoid and thus a good Sweeping Success, in addition to PUVA phototherapy: bioavailability though a water-insoluble film-forming agent One treatment method, the Systemic method, consists in is used. administering methotrexate, retinoids or cyclosporin A The invention further aims to make available a gluco orally. This necessitates a long-term treatment, which corticoid formulation, which does guarantee a good pen according to experience can lead to intoxication. etration of the nail by the glucocorticoid and thus a good Another method consists in injecting intralesional corti bioavailability, comprising no additional spreading or pen costeroids. This method is naturally very painful, So that the etration promoting Solvent or Substance. patients are only initially ready to cooperate initially, but The object is achieved by the nail polish according to the later refuse treatment. 25 invention, comprising one or more glucocorticoids, a physi With a further method of Surgically removing the ologically tolerable, preferably readily Volatile, Solvent or affected nails, good treatment results can indeed be Solvent mixture and one or more water-insoluble film achieved, but intervention is only temporary because within forming agents. one week after regeneration of the body of the nail pSoriasis Antipsoriatic glucocorticoids are, for example: alclom may return. A fourth, gentler, method consists in treating the nails etaSone dipropionate, , beclomethasone locally with Specific, antipsoriatic Substances Such as dipropionate, bendacort, benzoate, dithranol, Vitamin D analogs, or . In this betamethasone dipropionate, , context, all Sorts of treatment methods have been attempted. bude Sonide, chlorquinaldol, clioquinol, clobetasol Thus, in a combined treatment the nails are first treated with 35 propio nate, clobe tas one buty rate, de Sonide, Solutions of the antipsoriatic Substances. Then cream dress , , , difiorasone ings are applied at night. Even this treatment method is diacetate, Valerate, , , naturally very unpleasant and psychologically distressing flucinolone ace to nide, ace to nide, for the patient. First, the treatment of the nails with solutions fluidroxycortide, flumethasone pivalate, is necessary Several times daily. Second, the treated nails 40 acetonide, , , , must be covered with dressings at night. flupamesone, flu prednidene, flu prednidene acetate, This leads to the results that the treatment of patients, flu rand re no lide, halcino nide, halo me taSone, usually for many months, is often not completed. Patients , butyrate, methylpredniso become disheartened and negligent and thus no therapeutic lone aceponate, furoate, , result materializes. The Success of treatment in this method 45 , , , is furthermore adversely affected because the Solutions and acetonide. creams are usually miscible with water or are hydrophilic The glucocorticosteroids can be present either as free and can therefore be removed from the nail Surface or alcohols or in the form of their esters. dissolved out of the nail by Washing, bathing and showering Suitable water-insoluble film-forming agents are, for and thus consequently then have to be reapplied again. AS a 50 example, cellulose derivatives Such as cellulose nitrate or result of this, the treatment with these topical agents is ethylcellulose or physiologically acceptable polymerS Such ineffective and, moreover, highly uneconomical. as are customary, for example, in cosmetics. Mention may High hopes have therefore been placed in another be made, for example, of poly(Vinyl acetate), and partially method, namely in the treatment of the affected nails with a hydrolyzed poly(Vinyl acetate); copolymers of vinyl acetate 50:50 mixture of commercially available 55 with acrylic acid or crotonic acid or monoalkyl maleate; containing lotions, creams or ointments with commercially ternary copolymers of vinyl acetate with crotonic acid and available clear cosmetic varnishes (U.S. Pat. No. 4,250,164). Vinyl neodecanoate, or crotonic acid and Vinyl propionate; This method, however, although already known for a long copolymers of methyl vinyl ether and monoalkyl maleates, time, has not generally found its way into therapy Since a and in particular monobutyl maleate; copolymers of fatty Satisfactory result from these-naturally physically 60 acid Vinyl esters and acrylic acid or methacrylic acid; unstable-mixtures do not appear, presumably for lack of copolymers of N-Vinylpyrrolidone, methacrylic acid and sufficient bioavailability of the active compound from the alkyl methacrylates, copolymers of acrylic acid and meth Solid System present after the drying of the mixture. acrylic acid or alkyl acrylates or alkyl methacrylates, in Therefore, many cases, in particular the Severe cases, particular containing quaternary ammonium groups; or have been treated as before using the Surgical method 65 polymers, copolymers or mixtures comprising ethyl described above or using painful intralesional injections or acrylate, methyl methacry ate or trimethylammonioethyl using combined Solution and cream therapy. methacrylate chloride or polyvinyl acetals and polyvinyl US 6,352,686 B2 3 4 butyrals, alkyl-substituted poly-N-vinylpyrrolidone, alkyl EXAMPLE 1. esters of copolymers of olefins and maleic anhydride, reac tion products of colophony with acrylic acid and also benzoins. In the esters, the alkyl radicals are usually short Clobetasol-17-propionate 8.0% chain and mostly do not have more than four carbon atoms. 50% strength solution of a copolymer of methyl vinyl ether and 30.0% Suitable physiologically tolerable solvents are sub monobutyl maleate in isopropyl alcohol stances Such as hydrocarbons, halogenated hydrocarbons, Isopropyl alcohol 31.0% alcohols, ethers, ketones and esters which are customary in Ethyl acetate 31.0% cosmetics, in particular acetate esters of monohydric alco 1O hols Such as ethyl acetate and butyl acetate, optionally as a The percentage quantitative data are by weight. mixture with aromatic hydrocarbons Such as toluene and/or The nail polish is prepared by dissolving the various alcohols Such as ethanol or isopropanol. components in the Solvents. AS is known, the combination of the Solvents is of crucial importance for the drying time, spreading ability, and other 15 EXAMPLE 2 important properties of the varnish or of the varnish film. The Solvent System preferably consists of an optimal mix ture of low-boiling components (Solvents having a boiling Desoximetasone 5.0% point up to 100° C.) and medium-boiling components Ethyl acrylate/methyl methacrylate/trimethylammonioethyl 12.0% (Solvents having a boiling point up to 150 C.), optionally methacrylate chloride in a molar ratio of 1:2:0.2 with a Small proportion of high-boiling components (EUDRAGIT (R. RL 100) Ethanol 96% 60.0% (solvents having a boiling point up to 200° C.). Ethyl acetate 13.0% Readily volatile Solvents are understood as meaning Butyl acetate 10.0% compounds which have a boiling point which is below 80 C. 25 The nail polishes according to the invention can further EXAMPLE 3 contain additives customary in cosmetics, Such as plasticiz erS based on phthalate or camphor, colorants or color pigments, pearl luster agents, Sedimentation retardants, Sul Betamethasone dipropionate 5.0% fonamide resins, Silicates, aromatic Substances, lanolin Ethylcellulose 11.0% derivative S, SunScreenS Such as 2-hydroxy-4- Ethyl acetate 30.0% methoxybenzophenone, antimicrobial Substances, and Sub Butyl acetate 34.0% stances having keratolytic and/or keratoplastic action, Such Ethanol 96% 20.0% as ammonium Sulfite, esters and Salts of thioglycolic acid, urea, allantoin, enzymes, and Salicylic acid. 35 Using the nail polish according to the invention, one can EXAMPLE 4 achieve a drastic cure in the treatment of psoriatic nails, the nail usually growing again without deformation. In View of the poor therapeutic experiences until now, this is an 40 Prednicarbate 7.5% extremely important finding. Polyvinyl butyral 4.7% The nail polish according to the invention is also Suitable Cellulose nitrate 4.3% for prophylactic use against psoriatic nails, a Sufficiently Dibutyl phthalate O.6% Ethyl acetate 10.0% high active compound depot being achieved in the nail Such Ethanol 96% 72.9% that a possible recurrence does not break out. 45 The content of active compound in the nail polish according to the invention is dependent on the Structure of each active compound and thus on its release from the EXAMPLE 5 Varnish film, its penetration behavior in the nail, and its potency. 50 In the nail polish according to the invention, (i.e., the Halcinomide 2.0% Solvent-containing use form) the active compound is in Methacrylic acid/ethyl acrylate 1:1 copolymer 6.5% general contained in an amount from 0.5 to 20, preferably 2 Ethanol 96% 71.5% to 15, percent by weight. The minimum content of active Ethyl acetate 20.0% compound in the medicinal nail polishes (i.e., those for 55 treatment) is preferably 8 percent by weight; the nail pol ishes used for prophylaxis preferably contain 1 to 4 percent The action of the nail polish according to the invention is by weight of active compound. demonstrated in permeation tests on cowhorn platelets and Colored or pigmented nail polishes have the-advantage, in treatment experiments on Subjects. The permeation test on for example, that the preparation according to the invention 60 cowhorn platelets allows the release of an active compound can be tailored to the esthetic perception of the patient. from a certain preparation and the Subsequent permeation The nail polish is prepared in a customary manner by through keratin material to be tested. mixing together the individual components and-if At present, there are still no topical preparations known necessary-further processing tailored to the respective for the treatment of nail pSoriasis with glucocorticoids from preparation. 65 which the active compound is released in Sufficient amount, The nail polish according to the invention has the fol then penetrates into the nails and can thus act in a therapeutic lowing composition: dose on the underlying matrix or the nail bed. US 6,352,686 B2 S 6 AS a control example, the following was used: We claim: 1. A nail polish for treating psoriasis of the nail, compris ing one or more glucocorticoids, one or more physiologi cally tolerable Solvents, and one or more water-insoluble clobetasol-17-propionate 8.0% is dissolved film-forming agents comprising one or more quaternary in isopropyl alcohol 92.0%. ammonium groups to form a Stable nail polish. 2. A nail polish according to claim 1, which comprises a A) Permeation Test on Cowhorn Platelets glucocorticoid Selected from the group consisting of alclom The measurement of the active compound permeation is etaSone dipropionate, amcinonide, beclomethasone carried out by means of time-resolved ATR technique dipropionate, bendacort, , (time-resolved infrared attenuated total reflection-see betamethasone dipropionate, betamethasone Valerate, Th.M. Bayerl et al.; J. Invest. Dermatol. 105:291-295, bude Sonide, chlorquinaldol, clioquinol, clobetasol 1995): 100 ul of the test preparation (test preparation or control propio nate, clobe tas one buty rate, de Sonide, example) are applied to a defined area on the top of a deSoximetasone, dexamethasone, dichlorisone, cowhorn platelet of 0.5 mm thickness. After a drying 15 diacetate, , difluprednate, fluazacort, time of 15 minutes, the cowhorn platelet with the flucinolone ace to nide, fluclorolone ace to nide, Varnish layer was applied to the measuring crystal and fluidroxycortide, flumethasone pivalate, fluocinolone pressed on by an external device. The contact pressure acetonide, fluocinonide, fluocortolone, fluorometholone, and the penetration depth of the measuring beam were flupamesone, flu prednidene, flu prednidene acetate, selected here such that the IR spectrum did not record flu rand re no lide, halcino nide, halo me taSone, any portions of the cowhorn platelet. Spectra of the hydrocortamate, , methylpredniso varnish layer were recorded for 48 hours and the lone aceponate, mometaSone furoate, prednicarbate, decrease in the active compound bands which is to be prednisolone, prednisone, tiXocortol, triamcinolone attributed to the penetration of the active compound acetonide, and a mixture thereof. 25 3. A nail polish according to claim 1, which comprises a into the keratin material was investigated. glucocorticoid Selected from the group consisting of clobe It is seen here that the characteristic band of clobetasol tasol propionate, desoximetaSone, betame thaSone 17-propionate at 1660 cm decreases to approximately dipropionate, prednicarbate and . 60% of the starting value in the clear varnish film of the 4. A nail polish according to claim 1, comprising between nail polish according to the invention in the measure about 0.5% to about 20% by weight one or more glucocor ment period of 48 hours, while the active compound ticoids. precipitates almost quantitatively from the control 5. A nail polish according to claim 1, comprising between example on evaporating the Solvent and is thus no about 2% to about 15% by weight one or more glucocorti longer available for penetration into the keratin mate coids. rial. 35 6. A nail polish according to claim 1, where the gluco Moreover, it was possible to detect clobetasol-17 corticoids are in the form of free alcohols or esters. propionate qualitatively on the back of the cowhorn 7. A nail polish according to claim 1, wherein the content platelet employed after the application of the nail polish of glucocorticoid is at least 8% by weight. according to the invention, while after the application 8. A nail polish according to claim 1 wherein the gluco of the control preparation it was not possible to produce 40 corticoid is present in the amount of about 1% to about 4% this detection. by weight. Although in EP 0 226 984 similar penetration properties 9. A nail polish according to claim 1, which further of certain antimycotic hydroxypyridone compounds comprises a cellulose derivative as another water-insoluble from Solid varnish films are described, this is never film-forming agent. theless a Surprising finding, Since it was not to be 45 10. A nail polish according to claim 9, which further foreseen that glucocorticoids, which constitute a bulky, comprises cellulose nitrate, ethylcellulose, or mixtures rigid cyclopentanoperhydrophenanthrene four-ring thereof as another water-insoluble film-forming agent. system, are more bioavailable from the water-insoluble 11. A nail polish according to claim 1, which further Solid System present after the drying of the varnish comprises a poly(Vinyl acetate), partially hydrolyzed poly preparation and permeate into or through the keratin 50 (Vinyl acetate); copolymers of vinyl acetate with acrylic material better than from the isopropanolic Solution. acid, or crotonic acid or monoalkyl maleate; ternary poly B) Activity Testing mers of vinyl acetate with crotonic acids and vinyl neode 1) The antipsoriatic properties of the nail polish according canoate, ternary polymers of vinyl acetate with crotonic acid to the invention have been tested on 2 people with and Vinyl propionate, copolymers methyl ethyl Vinyl ether long-standing two-handed thumb nail pSoriasis. A daily 55 and monoalkyl maleates, copolymers of fatty acid vinyl treatment of the affected nails for only four months with esters and acrylic acid or methacrylic acid; copolymers of the nail polish according to the invention according to N-Vinylpyrrollidone, methacrylic acid, and alkyl methacry Example 1 led to the growing out of Symptom-free new lates, copolymers of acrylic acid and methacrylic acid, alkyl nail plates. acrylates, or alkyl methacylates as another water-insoluble 2) The antipsoriatic properties of the nail polish according 60 film-forming agent. to the invention have been tested on 14 people with nail 12. A nail polish according to claim 11, where Said other pSoriasis. A treatment two times a week of the affected water-insoluble film-forming agent is a copolymer of methyl nails for only six months with the nail polish according Vinyl ether and monobutyl maleate. to the invention according to Example 1 led to a lasting 13. A nail polish according to claim 1, which further improvement of the nail plates or to the growing out of 65 comprises a polymer, copolymer, or mixture comprising one symptom free new nail plates in 86% of the cases (12 or more of ethyl acrylate, methyl methacrylate, trimethy people out of 14). lammonioethyl methacrylate chloride, polyvinyl acetals, US 6,352,686 B2 7 8 polyvinyl butyrals, alkyl-substituted poly-N- 21. A nail polish according to claim 20, where the additive Vinylpyrrolidone, alkyl esters of copolymers of olefins and Sunscreen is 2-hydroxy-4-methoxybenzophenone. maleic anhydride, reaction products of colophony with 22. A nail polish according to claim 20, where the acrylic acid, and benzoins as another water-insoluble film keratolytic active Substance, the keratoplastic active forming agent. Substance, or both is ammonium Sulfite, esters and Salts of 14. A nail polish according to claim 1 where the water thioglycolic acid, urea, allantoin, enzymes, Salicylic acid, or insoluble film-forming agent comprises ethyl acrylate, mixtures thereof. methyl methacrylate, and trimethylammonioethyl methacry 23. A method of treating psoriasis of the nail, comprising late chloride in a molar ratio of 1:2:0.2. 15. A nail polish according to claim 1, where the physi applying an effective amount of one or more glucocorticoids ologically tolerable Solvent is Selected from the group con to a nail in need of Said treatment, together with one or more Sisting of hydrocarbons, halogenated hydrocarbons, physiologically tolerable Solvents and one or more water alcohols, ethers, ketones, esters, and mixtures thereof. insoluble film-forning agents. 16. A nail polish according to claim 15, where the 24. A nail polish according to claim 1 for treating psoriasis physiologically tolerable Solvent comprises acetate esters of 15 of the nail, wherein the nail polish is substantially free of monohydric alcohols. Water. 17. A nail polish according to claim 1, where the physi 25. A nail polish according to claim 24 for treating ologically tolerable Solvent is Selected from the group con pSoriasis of the nail, wherein the nail polish contains leSS Sisting of ethyl acetate, butyl acetate, mixtures thereof, than about 3% water by weight. mixtures with aromatic hydrocarbons, and mixtures with 26. A nail polish according to claim 1 for treating psoriasis alcohols. of the nail, wherein Said one or more glucocorticoids is 18. A nail polish according to claim 17 where the aromatic present in at least about 0.5% by weight. hydrocarbon is toluene. 27. A method for treating psoriasis of nails, comprising 19. A nail polish according to claim 17 where the alcohol applying an effective amount of a nail polish according to claim 1 to a nail of a host. is Selected from the group consisting of ethanol, 25 isopropanol, and a mixture thereof. 28. A nail polish of claim 1, wherein said water-insoluble 20. A nail polish according to claim 1, further comprising film-forming agent comprising one or more quaternary a phthalate-based plasticizer, a camphor-based plasticizer, a ammonium groups comprises a copolymer of fatty acid colorant or color pigment, pearl luster agents, Sedimentation Vinyl esters and acrylic acid or methacrylates, or a copoly retardants, Sulfonamide resins, Silicates, aromatic mer of acrylic acid and methacrylic acid, alkyl acrylates, or Substances, lanolin derivatives, SunScreens, antimicrobial alkyl methacylates. Substances, Substances having keratolytic activity, kerato plastic activity, or both, or mixtures thereof. UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 6,352,686 B2 Page 1 of 1 DATED : March 5, 2002 INVENTOR(S) : Bohnet al.

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Column 6 Line 28, “prednicarbate and” should read -- prednicarbate, and --. Line 59, "methacylates' should read -- methacrylates --.

Column 8 Line 30, “methacylates' should read -- methacrylates --.

Signed and Sealed this Twenty-ninth Day of October, 2002

Attest.

JAMES E ROGAN Attesting Officer Director of the United States Patent and Trademark Office