Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-24
1998-12-29
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514852, 514881, 252106, 252172, 25217411, 252544, 252547, 252551, 252555, 252399, A61K 31495, A61K 3150, A61K 31215, A61K 4700
Patent
active
058542469
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from PCT/EP95/03366, filed on Aug. 25, 1995, which in turn claimed priority from EP 94.202.505.7, filed on Sep. 1, 1994.
The subject invention furnishes stable ketoconazole emulsions for topical use lacking sodium sulfite, thus reducing the potential of skin irritation or sensitization by this agent. The subject compositions display a shelf life comparable with the art cream formula, but with a significant improvement in tolerability. Ketoconazole, the preparation thereof and its utility as an antifungal have been described in U.S. Pat. No. 4,335,125. A 2% ketoconazole dermal cream, containing ketoconazole, propylene glycol, 1-octadecanol, 1-hexadecanol, sorbitan monostearate, polysorbate 60, polysorbate 80, isopropyl myristate, sodium sulfite and water is commercially available since many years in several countries. Although this cream is efficacious in the treatment of mycotic infections of the skin, it was desired to improve the tolerability of the composition while maintaining a satisfactory shelf life. Ketoconazole is subject to degradation by oxidation. The art ketoconazole dermal cream was stabilized by sodium sulfite, which is a common antioxidant. Unexpectedly, it has been found that no significant degradation of ketoconazole was observed after omitting the antioxidant from the emulsion, if only the pH of the formula was maintained in a strict range.
In particular, the present invention concerns emulsions comprising ketoconazole and having a pH in the range from 6 to 8, characterized in that the emulsions lack sodium sulfite as an antioxidant.
The subject compositions should be applied topically, by covering the affected and immediately surrounding area The emulsions show the advantage that they allow a once-daily dosage schedule. It is evident that the dosage schedule may be altered depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compositions of the instant invention.
The term "stable" as used herein relates to compositions wherein the decrease in the ketoconazole content is less than 10%, preferably less than 5% and most preferably less than 2%, after storage at 40.degree. C. or below for up to 12 months.
Ketoconazole is the generic name of -ylmethoxy!phenyl!piperazine. The term "ketoconazole" as used herein comprises ketoconazole in the free base form, the pharmaceutically acceptable addition salts, the stereochemically isomeric forms thereof and the tautomeric forms thereof. The preferred ketoconazole compound is the (.+-.)-(cis) form of the free base form. The acid addition forms may be obtained by reaction of the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. The term addition salt as used hereinabove also comprises the solvates which ketoconazole as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
Hereinafter, the amounts of each of the ingredients in the compositions are expressed as percentages by weight based on the total weight of the formulation. Similarly, ratios are intended to define weight-by-weight ratios.
The concentration of ketoconazole in the emulsions according to the invention may range from 0.1% to 10%, preferably from 0.5% to 5%, more preferably from 1% to 3% and in particular it is about 2%. Up to 99% or more of the ketoconazole may be in suspension in the emulsions, the remainder (if any) being dissolved.
The emulsions of the present invention consist of an aqueous phase and an oil phase. The compositions may take the form o
REFERENCES:
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patent: 4942162 (1990-07-01), Rosenberg et al.
patent: 4976953 (1990-12-01), Orr et al.
patent: 5002974 (1991-03-01), Geria
patent: 5215839 (1993-06-01), Kamishita et al.
patent: 5456851 (1995-10-01), Lin et al.
Francois Marc Karel Jozef
Snoeckx Eric Carolus Leonarda
Appollina Mary
Janssen Pharmaceutica N.V.
MacMillan Keith D.
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