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United States Patent (19) 11 Patent Number: 5,854,246 Francois Et Al

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United States Patent (19) 11 Patent Number: 5,854,246 Francois Et Al USOO5854246A United States Patent (19) 11 Patent Number: 5,854,246 Francois et al. (45) Date of Patent: Dec. 29, 1998 54 TOPICAL KETOCONAZOLE EMULSIONS 52 U.S. Cl. .......................... 514/252; 514/852; 514/881; 252/106; 252/172; 252/174.11; 252/544; 75 Inventors: Marc Karel Jozef Francois, 252/547; 252/551; 252/555; 252/399 Kalmthout; Eric Carolus Leonarda 58 Field of Search ..................................... 252/106, 173, Snoeckx, Beerse, both of Belgium 252/124.11, 124.23, 544, 547, 551, 555, 399; 514/257, 852, 881 73 Assignee: Janssen Pharmaceutica, N.V., Beerse, Belgium 56) References Cited U.S. PATENT DOCUMENTS 21 Appl. No.: 793,359 4,335,125 6/1982 Heeres et al. ........................... 424/250 22 PCT Filed: Aug. 25, 1995 4.942,162 7/1990 Rosenberg et al. ..................... 514/252 86 PCT No.: PCT/EP95/03366 4,976,953 12/1990 Orr et al. ........ ... 424/47 5,002,974 3/1991 Geria .............. ... 514/782 S371 Date: Feb. 24, 1997 5,215,839 6/1993 Kamishita et al ... 424/45 5,456,851 10/1995 Lin et al. ................................ 252/106 S 102(e) Date: Feb. 24, 1997 Primary Examiner Keith D. MacMillan 87 PCT Pub. No.: WO96/06613 Attorney, Agent, or Firm Mary Appollina 57 ABSTRACT PCT Pub. Date: Mar. 7, 1996 The invention concerns Stable emulsions comprising keto 30 Foreign Application Priority Data conazole having a pH in the range from 6 to 8, characterized Sep. 1, 1994 EP European Pat. Off. ............ 942O2SOS in that the emulsions lack Sodium Sulfite as an antioxidant; process of preparing Said emulsions. 51) Int. Cl. ........................ A61K 31/495; A61K 31/50; A61K 31/215; A61K 47/00 7 Claims, No Drawings 5,854.246 1 2 TOPCAL KETOCONAZOLE EMULSIONS on the total weight of the formulation. Similarly, ratios are CROSS-REFERENCE TO RELATED intended to define weight-by-weight ratios. APPLICATIONS The concentration of ketoconazole in the emulsions This application claims priority from PCT/EP95/03366, according to the invention may range from 0.1% to 10%, filed on Aug. 25, 1995, which in turn claimed priority from preferably from 0.5% to 5%, more preferably from 1% to EP 94.202.505.7, filed on Sep. 1, 1994. 3% and in particular it is about 2%. Up to 99% or more of The Subject invention furnishes Stable ketoconazole emul the ketoconazole may be in Suspension in the emulsions, the Sions for topical use lacking Sodium Sulfite, thus reducing remainder (if any) being dissolved. the potential of Skin irritation or Sensitization by this agent. The emulsions of the present invention consist of an The Subject compositions display a shelf life comparable aqueous phase and an oil phase. The compositions may take with the art cream formula, but with a significant improve the form of a water-in-oil emulsion or, preferably, an oil ment in tolerability. Ketoconazole, the preparation thereof in-water emulsion. Suitably, the emulsions comprise from and its utility as an antifungal have been described in U.S. 50 to 80% water. The oil phase of the emulsion may Pat. No. 4,335,125. A 2% ketoconazole dermal cream, comprise, for example, paraffin oil, fractionated coconut oil, containing ketoconazole, propylene glycol, 1-octadecanol, 15 isopropyl myristate; fatty alcohols Such as cetyl 1-hexadecanol, Sorbitan monoStearate, polySorbate 60, (hexadecanol), Stearyl alcohol (octadecanol) and the like; polySorbate 80, isopropyl myristate, Sodium Sulfite and fatty acid esterS Such as Sorbitan monoStearate and the like. water is commercially available Since many years in Several The emulsions may be applied in the form of conventional countries. Although this cream is efficacious in the treatment products Such as creams, emulsion gels, lotions and the like. of mycotic infections of the skin, it was desired to improve The formulations can be packaged in Suitable, art-known the tolerability of the composition while maintaining a containerS Such as plastic, glass or ceramic pots, tubes, e.g. Satisfactory shelf life. Ketoconazole is Subject to degrada PVC-covered aluminum tubes or bottles with a spraying tion by Oxidation. The art ketoconazole dermal cream was device. Stabilized by Sodium Sulfite, which is a common antioxidant. 25 A first group of emulsions takes the form of a cream Unexpectedly, it has been found that no significant degra formulation (type I). The oil phase of these cream formulae dation of ketoconazole was observed after omitting the preferably comprises isopropyl myristate as its presence antioxidant from the emulsion, if only the pH of the formula results in a favourable Viscosity and spreadability of the was maintained in a strict range. cream, which improve the cosmetic acceptability of the In particular, the present invention concerns emulsions product. comprising ketoconazole and having a pH in the range from Certain skin types (e.g. greasy skin) and disease States, 6 to 8, characterized in that the emulsions lack Sodium Sulfite however, require formulations with a low content of fatty as an antioxidant. materials. Formulations with a limited greasiness also show The Subject compositions should be applied topically, by the advantage in that they are more easily applicable to covering the affected and immediately Surrounding area The 35 haired skin. A Second group of emulsions therefor takes the emulsions show the advantage that they allow a once-daily form of an emulsion gel (type II). These emulsions of type dosage Schedule. It is evident that the dosage Schedule may II contain only a minor amount of fatty materials. Fatty be altered depending on the response of the treated Subject materials as used herein comprise the oil phase Substances and/or depending on the evaluation of the physician pre mentioned hereinabove as well as, for example, fatty acids Scribing the compositions of the instant invention. 40 Such as Stearic acid, palmitic acid, myristic acid, and the like. The term “stable” as used herein relates to compositions Preferably, the concentration of the fatty materials in the wherein the decrease in the ketoconazole content is less than type II emulsions is from 1 to 10%, more preferably is about 10%, preferably less than 5% and most preferably less than 5%. Type II emulsions suitably comprise fractionated coco 2%, after storage at 40 C. or below for up to 12 months. nut oil as the oil phase. Ketoconazole is the generic name of 1-acetyl-4-4-2-(2, 45 The Subject emulsions may further comprise various 4-dichlorophenyl)-2-imidazol-1-ylmethyl-1,3-dioxolan-4- additives Such as emulsifiers, buffer Systems, wetting agents, ylmethoxyphenylpiperazine. The term "ketoconazole' as acids or bases, Stabilizing agents, antimicrobial used herein comprises ketoconazole in the free base form, preservatives, thickening agents and the like. Suitable emul the pharmaceutically acceptable addition Salts, the Stere Sifiers are, for example, anionic, cationic or, more ochemically isomeric forms thereof and the tautomeric 50 preferably, nonionic emulsifiers, Such as, for example, forms thereof. The preferred ketoconazole compound is the Sucrose esters, glucose esters, polyoxyethylated fatty esters, (+)-(cis) form of the free base form. The acid addition forms polyoxyethylated fatty alcohol ethers, glycerol esters, e.g. may be obtained by reaction of the base form with an glycerol monoStearate, Sorbitan esters, e.g. Sorbitan mono appropriate acid. Appropriate acids comprise, for example, palmitate (=Span 40E), Sorbitan monostearate (=-Span inorganic acids Such as hydrohalic acids, e.g. hydrochloric 55 600R); polyoxyethylene derivatives of Sorbitan esters, e.g. or hydrobromic acid, Sulfuric, nitric, phosphoric and the like polysorbate 40 (=-Tween 40(R), polysorbate 60 (=Tween acids, or organic acids Such as, for example, acetic, 60(R), cetyl dimethicon copolyol and the like. The cream propanoic, hydroxyacetic, lactic, pyruvic, Oxalic, malonic, compositions of type I preferably comprise as emulsifying Succinic, male ic, fumaric, malic, tartaric, citric, constituents Sorbitan monoStearate and polySorbate 60 in an methaneSulfonic, ethane Sulfonic, benzene Sulfonic, 60 amount of 0.5 to 10% each, preferably in an amount of 1 to p-toluenesulfonic, cyclamic, Salicylic, p-aminoSalicylic, 2% each. Examples of appropriate wetting agents are poly pamoic and the like acids. The term addition Salt as used oxyethylene derivatives of Sorbitan esters, e.g. polySorbate hereinabove also comprises the Solvates which ketoconazole 80 (=Tween 80B), polysorbate 20 (=Tween 2008), sodium as well as the salts thereof, are able to form. Such Solvates lauryl Sulfate, Sodium dioctyl SulfoSuccinate, and the like. are for example hydrates, alcoholates and the like. 65 Preferably, polysorbate 80 is used in an amount from 0.01 to Hereinafter, the amounts of each of the ingredients in the 1%, preferably in an amount from 0.1 to 0.2%. Buffer compositions are expressed as percentages by weight based Systems comprise mixtures of appropriate amounts of an 5,854.246 3 4 acid Such as phosphoric, Succinic, tartaric, lactic, or citric using a carbomer thickener in the present emulsions, little or acid, and a base, in particular Sodium hydroxide or disodium no emulsifying Substances are required to obtain stable hydrogen phosphate. Alternatively, the pH of the composi formulations. Particular emulsions of type II further com tion can be fixed upon addition of an acid Such as hydro prise a polyethylene oxide thickener in an amount from 0.1 chloric acid or a base Such as Sodium hydroxide and the like. to 1%, preferably in amount of approximately 0.2%. Acids and/or bases are included in the emulsion to maintain Preferably, the polyethylene oxide thickener has an average the pH of the formulation in the range from 6 to 8, more molecular weight of 200000. The use of polyethylene oxide preferably in the range from 6.5 to 7.5, most preferably at in the emulsion gels has cosmetic advantages in that a Soft about 7. feeling is experienced during rubbing in.
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