Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-10-04
2002-09-24
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S724000
Reexamination Certificate
active
06455592
ABSTRACT:
The present invention concerns the use of hydrophilic penetration agents in dermatological compositions for the treatment, in both man and animals, of onychomycoses mainly due to dermatophytes or Candida, and dermatological compositions containing such penetration agents.
Zaias et al. [Clinical Experimental Dermatology 1989, 14, 120-123] have described the treatment of onychomycoses-due to Trichophyton rubrum by peroral administration of terbinafine. This antifungal agent, whose structure and activity against dermatophytic fungi are original, shows low toxicity via the oral route and can be used successfully for the long-term treatment of onychomycoses. It was found that the most effective treatment consists in the peroral administration of terbinafine 250 mg/day for 6 months. This represents an advance compared with previously known medicaments such as ketoconazole and griseofulvin. However, the administration of terbinafine shows disadvantages, namely that on the one hand the duration of the treatment is very prolonged, which carries a high risk of non-compliance, and on the other hand the cost of the treatment is extremely high, being linked to its duration and the daily assumption of terbinafine 250 mg.
For those reasons, it has long been desired to treat onychomycoses via the transungual route. The problem that then arises is to ensure that the antifungal agents will penetrate into and beneath the nail. Such antifungal agents could then advantageously consist of those belonging to the allylamine family, of which terbinafine is one, the latter being at present the only compound among the family that can be used via the oral route.
In this context, it was proposed in European Patent EP-A-0 064 830 to administer, via the transungual route, concentrated solutions of liposoluble antifungal agents belonging to the imidazole family, dissolved in fatty acids with C
8
-C
20
, such as undecylenic acid, these solutions being further solubilized in a solvent chosen from among the lower alcanols, such as ethanol and isopropanol, esters such as ethyl acetate, and ketones such as acetone and butanone-2. The C
8
-C
20
fatty acids mentioned play the part of transungual penetration agents, while undecylenic acid also serves to potentiate the antifungal properties of the imidazoles. A composition of this type is marketed under the name “TROSYD solution”, and contains 28% tioconazole; it is used to supplement oral treatments with griseofulvin.
Also known from the French patent FR-B-2 523 447, are antimycotic therapeutic preparations based on a cream or ointment containing one or more active antimycotic ingredients, together with 5-20% by weight of urea relative to the total weight of the preparation.
It is also apparent from the state of the art that, still in the attempt to increase the penetration of antifungal agents, which do not in their own right diffuse easily in the nails, compositions of the “nail varnish” type have been proposed. These contain a polymeric component and are intended to release the active agent at a programmed rate.
For example, Japanese patent JP-01-110 620 describes an antifungal composition intended for use on the nails, which contains polyvinyl acetate, an antifungal agent, preferably an imidazole, long-chain C
8
-C
20
fatty acid esters and/or higher alcohols, and a volatile solvent.
European patent EP-A-319 964 also describes antifungal preparations of the film-forming type for external application, containing approximately 0.1-1.5% of tolnaftate, about 10-20% of a methacrylate copolymer of dimethylaminoethyl methacrylic acid ester, and about 0.5-10% of a medium-chain fatty acid ester, in an alcohol solvent containing almost no water. The tolnaftate is released progressively from the polymeric matrix and penetration is favoured by the fatty acid ester in an anhydrous medium.
In addition, German patent DE-A-3 544 983 describes antimycotic nail varnishes containing a film-former insoluble in water, an antifungal agent from the hydroxy-1-pyridone-2 series, such as cyclopirox or octopirox, and an exclusively anhydrous solvent.
International patent application WO 87/02580 discloses a pharmaceutical vehicle capable of supplying an active ingredient to the nails. This consists of a hydrophilic polymer and a pharmaceutically acceptable solvent for the hydrophilic polymer. Example 2 mentions the association of an antifungal agent with a hydrophilic polymer, in a vehicle based on ethanol and water. The antifungal agent should preferably have a molecular weight lower than 300 and a solubility in water-of at least 0.01% by weight.
German patent application DE-A-3 720 147 also discloses varnishes for the treatment of onychomycoses, containing a water-insoluble polymeric film-former, an antifungal substance of the imidazole type, tolnaftate, naftifine hydrochloride, and a solvent for the film-forming polymer chosen from among the organic solvents commonly used in the field of cosmetics to manufacture nail varnishes, with a low boiling point of less than 100° C. Example 8 of that patent application concerns a varnish containing an antifungal agent of the allylamine family (naftifine hydrochloride), 4% of water, polyvinylbutyrate as the film-forming polymer, nitrocellulose and ethyl acetate.
Thus, the state of the art comprises compositions based on a low-molecular-weight antifungal agent, in a water-alcohol mixture in which the said antifungal agent can be dissolved, to which is added a hydrophilic polymer as in the case of international patent application WO 47/02580, or a water-insoluble polymer as in the case of patent application DE-A-3 720 147. However, none of these compositions gives really good results. Formulations such as those described in example 8 of German patent application DE-A-3 720 147 have a number of disadvantages which do not allow the desired results to be achieved in the treatment of onychomycoses:
in the first place, the polymers used hinder the release of the active ingredient: when the solvents have evaporated, the polymer network retains the naftifine and hinders its penetration into the stratum corneum;
during a second application, there is an accumulation of the couple polymer+active ingredient at the surface of the first layer, which accounts for the non-penetration of the active ingredient;
nitrocellulose is a powerful oxidizing agent and naftifine is chemically unstable in this medium, and is therefore rendered inactive; and
ethyl acetate is well known to dehydrate the nails and so slow down the penetration of the antifungal agent; in effect, it is a lipophilic solvent which counteracts the desired effect.
In searching for a solution to the problem posed, the applicant Company discovered that the hydrophilic penetration agents used to promote the transcutaneous penetration of active ingredients possess the property of considerably increasing the concentration of antifungal agent in and beneath the nail.
This result is completely unexpected, because numerous scientific studies have demonstrated that nails are hydrophilic in character, i.e. they behave as a hydrogel in contrast to the stratum corneum of the skin, which is lipophilic and behaves as a water barrier. Because of this, it is surprising that the penetration agents currently used to pass through the stratum corneum favour the penetration of antifungal agents into the nails, as shown in example 10 below.
The first aim of the present invention is thus to use hydrophilic penetration agents of the type usually used for the transcutaneous penetration of active ingredients, to improve the penetration of antifungal agents through the nails, in dermatological compositions intended for the treatment of onychomycoses.
The present invention also concerns a dermatological composition intended for the treatment of onychomycoses, presented in the form of a solution and containing, on the one hand, an effective quantity of at least one antifungal agent, and on the other hand, an effective quantity of at least one agent that favours the penetration of the said antifungal agent(s) into
Laugier Jean-Pierre
Rigenbach François
Rude Marie-France
Touzan Philippe
Loeschorn Carol A.
Novartis AG
Weddington Kevin E.
LandOfFree
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