Drug – bio-affecting and body treating compositions – Manicure or pedicure compositions
Reexamination Certificate
2000-02-14
2002-12-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Manicure or pedicure compositions
C424S401000, C424S404000
Reexamination Certificate
active
06495124
ABSTRACT:
BACKGROUND OF THE INVENTION
(1). Field of Invention
This invention relates to antifungal nail lacquer compositions useful in the treatment of onychomycoses or other fungal infestations affecting toe nails or finger nails using the nail lacquer composition. More particularly, the invention relates to antifungal nail lacquers which may be applied to nails to form films from which the antifungal agent will be released and become available for nail penetration; and to the method for treating or preventing fungal infestations of animal nails by applying the antifungal composition to the infected nail or to the fungal susceptible nail.
(2). State of the Prior Art
Fungal infection of the nails, commonly referred to as onychomycosis, is most frequently caused by dermatophytes but also can be caused by molds and Candida. Mixed infections also occur. Onychomycosis includes dermatophyte infection of the nail plate and includes infection of nails by any fungus, ineluding yeast or molds. Thus, for example, onychomycosis serves as a reservoir for dermatophytes and contributes to treatment failure and recurrence of tinea pedis.
Most common causes of tinea unguium are
Trichophyton rubrum
(most frequent),
T. mentagrophytes
, and
Epidermophyton floccusum
. Onychomycosis due to nondermatophytes is usually caused by Candida species.
Nail lacquers for the treatment of onychomycoses and similar fungal infections affecting nails (toe nails and/or finger nails) of humans, in particular, or other animals, are known. Representative examples are described in the patent literature, of which the following U.S. Pat. Nos. can be mentioned:
4,957,730 (1-hydroxy-2-pyridone in water-insoluble film-former);
5,120,530 (amorolfine in quaternary ammonium acrylic copolymer);
5,264,206 (tioconazole, econazole, oxiconazole, miconazole, tolnaftate, naftifine hydrochloride, in water-insoluble film-former); 5,346,692 (with urea and dibutyl phthalate plasticizer);
5,487,776 (griseofulvin as colloidal suspension).
Other U.S. Pat. Nos. which relate to antifungal products include, for example, 4,636,520, 5,002,938, 5,110,809, 5,219,877, 5,391,367, 5,464,610, 5,696,105.
Effectiveness of nail lacquers as a delivery vehicle for topically administering the antifungal agent amorolfine is described by Jean-Paul L. Marty, J. of the European Academy of Dermatology and Venereology, 4(Suppl. 1), pp.S17-S21 (1995). As described by the author, the film-generating solution as the lacquer base for the active principle basically consists of volatile solvent (ethanol, ethyl/butyl/methyl acetate, methylene chloride, methyl ethyl ketone, isopropanol), and a non-water-soluble polymer (methacrylic acid copolymers, vinyl polymers) which leaves a thin continuous film following evaporation of the solvent. Plasticizers (triacetin, dibutyl phthalate) impart sufficient mechanical flexibility to prevent flaking and removal.
More recently, some of the present inventors developed highly effective antifungal nail lacquer formulations which incorporated 2-n-nonyl-1,3-dioxolane or related dioxolane, dioxane and acetal compounds as skin (nail) permeation enhancers (SPE) and also, surprisingly, discovered that the SPE compounds function as plasticizers for the film-forming polymer. Thus, the nail lacquer formulation containing the dioxolane, dioxane and acetal classes of skin penetration enhancing compounds were able to be formulated without additional plasticizer while still providing clear, hard, water-resistant films exhibiting good adherence to nails and from which the antifungal agent could be readily dispensed into the affected nail. These antifungal nail compositions are disclosed in WO 99/39680, published Aug. 12, 1999.
Based on this experience, the present inventors attempted to find other penetration enhancing compounds which would also be useful in formulating antifungal lacquer compositions and capable of functioning as plasticizer for the film forming polymers of lacquer formulations. As a result, it was discovered that the skin penetration enhancing cyclic lactones and derivatives thereof, as disclosed in U.S. Pat. Nos. 5,023,252 and 5,731,303, the disclosures of which, are incorporated herein, in their entireties, also are compatible with a range of lacquer formulations containing film-forming polymer, antifungal agent and solvent. The present invention is based on this discovery.
SUMMARY OF INVENTION
The present invention provides an antifungal nail lacquer composition which will provide clear, hard, films adherent to nail surfaces.
According to the present invention there is provided a nail lacquer formulation incorporating an antifungal agent, which formulation, when applied to nails may yield a substantially clear film, for use in the treatment or prevention of fungal infestations or infections on or associated with nails.
In particular, the present invention provides a composition effective for the treatment or prevention of fungal infections of nails, comprising:
(a) at least one antifungal agent effective in the treatment or prevention of onychomycoses;
(b) a plasticizing and penetration enhancing agent selected from compounds of the following formula (I):
wherein
A is is group having the structure
m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25,
p is an integer having a value of 0 or 1,
q is an integer having a value of 0 or 1,
r is an integer having a value of 0 or 1,
R represents hydrogen or a straight or branched chain alkyl group having from 1 to 6 carbon atoms, and,
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
, each, independently, represent hydrogen or a straight or branched chain alkyl group having from 1 to 6 carbon atoms, with the provisos that
(i) only one of R
1
to R
6
may be said alkyl group, and
(ii) when p, q and r have a value of 0, m+n is at least 11,
(c) water-insoluble, film-forming polymer; and,
(d) volatile solvent.
The composition, when applied to nails, forms, upon evaporation of the volatile solvent, a film lacquer from which the antifungal agent is releasable and becomes available to treat or prevent fungal infection.
The invention also provides lacquer compositions effective for providing long-lasting, water-resistant adherent films on animal (e.g., human) skin and nails comprising a substantially non-aqueous solution of water-resistant, film-forming polymer, and plasticizing effective amount of at least one compound of formula (I).
The resulting water-resistant, adherent films will be suitable as a delivery matrix for drugs, including antifungal agents and others. When such film with drug incorporated therein, is deposited on animal, especially human or other mammal, skin or nail, the drug can leach from the film and be capable of being absorbed by or transported into and through the skin or nail.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
The present invention provides antifungal nail lacquer compositions capable of forming films which will adhere to nails upon evaporation of the volatile solvent from the film-generating solution of nail lacquer composition. These films allow diffusion of active principle(s) included in the lacquer composition from the resulting film.
The cyclic lactones and related compounds as disclosed in the aforementioned U.S. Pat. Nos. 5,023,252 and 5,731,303, are described only as enhancers for penetration of various pharmacologically active principles through the skin. The compounds of formula (I), additionally, will provide a plasticizing effect for film-forming polymers of lacquer compositions and, therefore, are sometimes referred to hereinafter as PSPE's (“plasticizing skin penetration enhancers”).
The preferred PSPE's for use in the present invention are the cyclic lactones of formula (I):
wherein
A is is group having the structure
m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25,
p is an integer having a value of 0 or 1,
q is an integer having a value of 0 or 1,
r is an integer having a value of 0 or 1,
R represents hydrogen or a straight or branched chain
Howard S.
Macrochem Corporation
Page Thurman K.
Pillsbury & Winthrop LLP
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