U.S. patent application number 10/291765 was filed with the patent office on 2003-12-18 for antifungal nail lacquer and method using same.
This patent application is currently assigned to MacroChem Corporation. Invention is credited to Samour, Carlos M..
Application Number | 20030232070 10/291765 |
Document ID | / |
Family ID | 24003208 |
Filed Date | 2003-12-18 |
United States Patent
Application |
20030232070 |
Kind Code |
A1 |
Samour, Carlos M. |
December 18, 2003 |
Antifungal nail lacquer and method using same
Abstract
A nail lacquer for the treatment or prevention of fungal
infections, such as, onychomycosis, includes fungicidally effective
amount of ciclopirox, econazole, or other antifungal agent in a
compatible film-forming lacquer vehicle which includes a
water-insoluble film-forming polymer; pentadecalactone, or similar
cyclic lactone compound or derivative thereof, and volatile
solvent. The pentadecalactone functions as a plasticizer for the
film-forming polymer and as a penetration enhancer for the
antifungal agent. The composition, when applied to the nails
provides a hard, clear, water-resistant film containing the
antifungal agent. The compositions are used for the treatment of
onychomycosis.
Inventors: |
Samour, Carlos M.; (Bedford,
MA) |
Correspondence
Address: |
PILLSBURY WINTHROP, LLP
P.O. BOX 10500
MCLEAN
VA
22102
US
|
Assignee: |
MacroChem Corporation
Lexington
MA
|
Family ID: |
24003208 |
Appl. No.: |
10/291765 |
Filed: |
November 12, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10291765 |
Nov 12, 2002 |
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09503715 |
Feb 14, 2000 |
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6495124 |
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Current U.S.
Class: |
424/443 ;
524/107 |
Current CPC
Class: |
A61K 31/5375 20130101;
A61K 9/7015 20130101; A61K 8/8147 20130101; A61K 31/4174 20130101;
A61K 8/4973 20130101; A61Q 3/02 20130101; A61K 31/4412
20130101 |
Class at
Publication: |
424/443 ;
524/107 |
International
Class: |
A61K 009/70; C08K
005/15 |
Claims
What we claim is:
1. A composition comprising: a plasticizing and penetration
enhancing effective amount of a compound of the following formula
(I): 10A is is group having the structure 11m 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.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6, each, independently, represent
hydrogen or a straight or branched chain alkyl group having from 1
to 6 carbon atoms, with the proviso that only one of R.sub.1 to
R.sub.6 may be said alkyl group, and with the further proviso that,
when p, q and r have a value of 0, m+n is at least 11;
water-insoluble, film-forming polymer; and, volatile solvent; the
composition forming, upon evaporation of the volatile solvent, a
hard, water-resistant film.
2. The composition of claim 1 wherein the film-forming polymer
comprises a water-insoluble film-forming polymer selected from the
group consisting of acrylate polymers, methacrylate polymers, and
copolymers of alkyl vinyl ether and maleic anhydride.
3. The composition of claim 1 wherein the film-forming polymer
comprises an acrylic copolymer.
4. The composition of claim 1 wherein the compound of formula (I)
comprises pentadecalactone.
5. The composition of claim 1 which comprises: from about 0.5 to
about 35 percent compound of formula (I); from about 0.5 to about
40 percent film-forming polymer; and from about 10 to about 70
percent volatile solvent.
6. The composition of claim 5 wherein the compound of formula (I)
comprises pentadecalactone.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of application Ser. No.
09/503,715, filed Feb. 14, 2000, (now allowed) and is incorporated,
in its entirety, herein by reference.
FIELD OF INVENTION
[0002] 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.
STATE OF THE PRIOR ART
[0003] 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, including yeast or
molds. Thus, for example, onychomycosis serves as a reservoir for
dermatophytes and contributes to treatment failure and recurrence
of tinea pedis.
[0004] Most common causes of tinea unguium are Trichophyton rubrum
(most frequent), T. mentagrophytes, and Epidermophytonfloccusum.
Onychomycosis due to nondermatophytes is usually caused by Candida
species.
[0005] 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. patents can be mentioned: U.S. Pat. No.
4,957,730 (1-hydroxy-2-pyridone in water-insoluble
film-former);
[0006] U.S. Pat. No. 5,120,530 (amorolfine in quaternary ammonium
acrylic copolymer);
[0007] U.S. Pat. No. 5,264,206 (tioconazole, econazole,
oxiconazole, miconazole, tolnaftate, naftifine hydrochloride, in
water-insoluble film-former); U.S. Pat. No. 5,346,692 (with urea
and dibutyl phthalate plasticizer); U.S. Pat. No. 5,487,776
(griseofulvin as colloidal suspension).
[0008] Other U.S. patents which relate to antifungal products
include, for example, U.S. Pat. Nos. 4,636,520, 5,002,938,
5,110,809, 5,219,877, 5,391,367, 5,464,610, 5,696,105.
[0009] 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.
[0010] 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.
[0011] 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,
are also 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
[0012] The present invention provides an antifungal nail lacquer
composition which will provide clear, hard, films adherent to nail
surfaces.
[0013] 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.
[0014] In particular, the present invention provides a composition
effective for the treatment or prevention of fungal infections of
nails, comprising:
[0015] (a) at least one antifungal agent effective in the treatment
or prevention of onychomycoses;
[0016] (b) a plasticizing and penetration enhancing agent selected
from compounds of the following formula (I): 1
[0017] wherein
[0018] A is is group having the structure 2
[0019] m and n are integers having a value from 1 to 20 and the sum
of m+n is not greater than 25,
[0020] p is an integer having a value of 0 or 1,
[0021] q is an integer having a value of 0 or 1,
[0022] r is an integer having a value of 0 or 1,
[0023] R represents hydrogen or a straight or branched chain alkyl
group having from 1 to 6 carbon atoms, and,
[0024] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6,
each, independently, represent hydrogen or a straight or branched
chain alkyl group having from 1 to 6 carbon atoms, with the
provisos that
[0025] (i) only one of R.sub.1 to R.sub.6 may be said alkyl group,
and
[0026] (ii) when p, q and r have a value of 0, m+n is at least
11,
[0027] (c) water-insoluble, film-forming polymer; and,
[0028] (d) volatile solvent.
[0029] 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.
[0030] 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).
[0031] 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
[0032] +P2
[0033] 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.
[0034] 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").
[0035] The preferred PSPE's for use in the present invention are
the cyclic lactones of formula (I): 3
[0036] wherein
[0037] A is is group having the structure 4
[0038] m and n are integers having a value from 1 to 20 and the sum
of m+n is not greater than 25,
[0039] p is an integer having a value of 0 or 1,
[0040] q is an integer having a value of 0 or 1,
[0041] r is an integer having a value of 0 or 1,
[0042] R represents hydrogen or a straight or branched chain alkyl
group having from 1 to 6 carbon atoms, and,
[0043] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6,
each, independently, represent hydrogen or a straight or branched
chain alkyl group having from 1 to 6 carbon atoms, with the
provisos that
[0044] (i) only one of R1 to R6 may be said alkyl group, and
[0045] (ii) when p, q and r have a value of 0, m+n is at least
11.
[0046] Examples of the alkyl group for R and R.sub.1 to R.sub.6
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, amyl, hexyl, and the like.
[0047] Preferably, each of R and R.sub.1 to R.sub.6 are hydrogen
atoms. These preferred compounds of formula (I) are, therefore,
cyclic lactones.
[0048] Another preferred class of compounds of formula (I) may be
represented by the following general formula (I-A): 5
[0049] wherein X, Y, R, A, m, n, p, q and r, are as defined
above.
[0050] Preferably, in formula (I-A), R is hydrogen.
[0051] The amount of enhancer compound is selected to provide the
desired plasticization of the film-forming polymer and the desired
delivery rate for the active compound but, taking into
consideration such additional factors as, product stability, side
effects, carrier system and the like. Generally, depending on the
particular antifungal agent and film-forming polymer, amounts of
the PSPE compound in the range of from about 0.5 to 35%, preferably
from about 2 or 3 up to about 25 or 30 percent, especially from
about 5 to 20 or 25 percent, most especially, from about 8 to 20%
by weight of the total composition, will be compatible with the
other ingredients of the lacquer composition and should provide
transungal delivery of the active principle over the duration of
the film on the nail. Within these ranges, the desired results
(flexibility, release and skin permeation characteristics) may
usually be achieved without incorporating additional co-solvents or
plasticizers.
[0052] The PSPE's are, generally speaking, compatible with acrylate
and methacrylate copolymers. Compatibility between the film-forming
polymer and the PSPE compounds may be readily determined by one of
ordinary skill in the art, such as, for example, by formation of a
single homogenous phase when the polymer and PSPE are mixed
together, and, more particularly, by formation of a clear film upon
evaporation of solvent.
[0053] As will be appreciated by those skilled in the art, various
factors, such as, for example, polarity of "mer" units of the
polymer, molecular weight, and the like, will be considered for
compatibility.
[0054] It is expected that the plasticizing and adhesion promoting
functions of the subject PSPE compounds may also be exhibited with
the below-described film-forming polymers, for virtually any drug
which may be dissolved in the polymer/enhancer compound matrix,
with or without the assistance of solvents or co-solvents. Thus,
drugs which may be topically administered to the skin as well as
drugs which are adapted for use in treating nails for onychomycoses
or other ailments, may be incorporated into the nail and
skin-adherent polymer plus enhancer compound film-forming
composition of this invention.
[0055] The film-forming polymers which may be used in the present
invention are not particularly limited and may be chosen from among
any of the film-forming polymers previously used in or useful for
nail lacquer film-forming polymers and which are compatible with
the PSPE and which have good adhesion to nail keratin (and/or skin)
and form water-insoluble and/or water-resistant films which permit
release of the antifungal agent and also the steroidal
antiinflammatory agent, if present.
[0056] Examples of water-insoluble, film-forming polymers which may
be used in the nail lacquer compositions of this invention,
include, for example, polyvinyl acetate, mixed polymers (or
copolymers) of vinyl acetate with acrylic or methacrylic acid,
copolymers of (meth)acrylic acid and (meth)acrylate esters,
copolymers of (meth)acrylic acid esters with amino group and/or
quaternary ammonium group-containing comonomers, and the like.
These polymers may be used alone or in mixtures with each other or
with other film-forming polymers that will not impair the
objectives of this invention.
[0057] As used in this application, the term "lower" in connection
with "alkyl", etc., refers generally to carbon chain lengths of up
to 6 carbon atoms, however, the preferred lower alkyl groups
typically have from 1 to 4 carbon atoms.
[0058] Especially preferred film-forming polymers include acrylate
(co)polymers, methacrylate (co)polymers, and copolymers of alkyl
vinyl ether and maleic anhydride. For example, a preferred acrylic
copolymer comprises recurring units of at least one of the
following moieties (IV) and (V): 6
[0059] wherein R.sup.1 represents H or CH.sub.3; and R.sup.2
represents an alkyl group of from 1 to about 12 carbon atoms,
preferably from about 2 to about 12 carbon atoms, especially
preferably, from about 4 to about 10 carbon atoms. The alkyl group
may be linear or branched. Examples of alkyl groups for R.sup.2
include methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl,
n-butyl, n-pentyl, 4-methyl-n-pentyl, n-hexyl, n-heptyl, n-octyl,
2-methyloctyl, n-nonyl, n-decyl, n-dodecyl, and the like.
[0060] Another useful acrylic copolymer comprises recurring units
of a moiety of formula (VI) 7
[0061] wherein R.sup.3 represents an alkyl group, such as, for
example, the alkyl groups described above for R.sup.2; preferably
an alkyl group of at least two and up to about 12 carbon atoms,
especially preferably C.sub.4 to C.sub.10 alkyl.
[0062] Acrylic copolymers which comprise recurring units of formula
(V) or formula (VI) or both formulas (V) and (VI), and, optionally,
recurring units of formula (IV), as defined above, wherein at least
one of R.sup.2 and R.sup.3 represents an alkyl group having at
least 4 carbon atoms, are particularly preferred.
[0063] Another preferred class of acrylic copolymer comprises
recurring units of acrylic and/or methacrylic acid esters and
recurring units of a moiety containing a cationic amine and/or
quaternary ammonium group, such as, for example,
carboethoxy-t-butyl ammonium. As is well known in the art, the
cationic amine group may be quaternized by reaction of the amine
with an alkylating agent or other appropriate reagent to form a
salt.
[0064] For example, any of the water-insoluble quaternary ammonium
group containing acrylic copolymers disclosed in the aforementioned
U.S. Pat. No. 5,120,530, the disclosure of which is incorporated
herein by reference thereto, may be used as the film-forming
copolymer in the compositions of the present invention.
[0065] Another preferred example of the water-insoluble,
film-forming polymer comprises a copolymer of alkyl vinyl ether,
such as, for example, methyl vinyl ether or ethyl vinyl ether, and
at least one comonomer of a monoester of a dicarboxylic acid.
Examples of such comonomer of a monoester of a dicarboxylic acid
are shown by the following formula (VII): 8
[0066] wherein R.sup.4 represents a lower alkyl group, especially
an alkyl group of from 1 to 4 carbon atoms, such as, for example,
methyl, ethyl, propyl.
[0067] See also the film-forming polymers disclosed in the
aforementioned U.S. Pat. No. 5,264,206, and the other patents
mentioned above, which may also be used in this invention.
[0068] Film-forming polymers useful in the present invention are
commercially available, such as, for example, the acrylic
copolymers sold by National Starch Co. under the tradename
DERMACRYL, e.g., DERMACRYL 79, DERMACRYL LT; the amine or
quaternary ammonium group containing acrylic copolymers sold by
Rohm (a division of Huls Group) under the tradename EUDRAGIT, e.g.,
EUDRAGITs E, RS, RL; the methylvinyl ether copolymers sold by ISP
Corp. under the tradename GANTREZ, e.g., GANTREZ ES-3351, GANTREZ
ES-425, ES-435; the quaternary ammonium acrylic copolymers sold by
National Starch Co. under the tradename AMPHOMER, e.g., AMPHOMER
LV-71. Particularly good results have been obtained with each of
the following commercially available products: 9
[0069] The amount of film-forming polymer will depend on such
factors as, for example, the molecular weight of the polymer, the
desired thickness of the resulting film, the degree of
water-resistance and the intended duration and delivery rate of the
active agent(s), the compatibility with the other ingredients, and
the like. Usually, however, satisfactory results are obtained when
the amount of film-forming polymer is in the range of from about 10
to about 70 percent, preferably from about 15 to about 50 percent,
especially from about 20 to 40 percent by weight of the total nail
lacquer composition.
[0070] In terms of weight ratio between film-forming polymer and
penetration enhancing and plasticizing compound of formula (I),
suitable values of polymer:enhancer/plasticizer generally range
from about 4:1 to about 1:1, preferably from about 3:1 to about
1.2:1, especially preferably from about 2:1 to about 1.2:1. The
plasticizing function of the compounds of formula (I) is exhibited
over generally the same or somewhat higher concentrations as the
skin penetration enhancing function. Therefore, when other
plasticizing additives, as described below, are included in the
compositions of this invention, the ratio of polymer to enhancer
may be somewhat higher than the above ranges, for example, from
about 5:1 to about 1:1.
[0071] Conventional plasticizers compatible (e.g., forming a
homogenous solution and clear films) with film-forming polymers may
be included in the compositions of this invention to provide
additional flexibility to the dried polymer film upon evaporation
of the solvent, and/or additional releasability of the antifungal
agent as well as for the PSPE compound. Suitable plasticizers
include, for example, 1,2,3-propanetriol triacetate (triacetin),
dibutyl phthalate, dioctyl phthalate, dibutoxy ethyl phthalate,
diamyl phthalate, sucrose acetate isobutyrate, butyl acetyl
ricinoleate, butyl stearate, triethyl citrate, dibutyl tartrate,
polyethylene glycol, dipropylene glycol, polypropylene glycols,
propylene glycol, glycol fatty acid esters, such as, propylene
glycol dipelargonate, and the like.
[0072] Particularly preferred plasticizers are glycols, such as
propylene glycol and dipropylene glycol, glycol esters, phthalate
esters, citrate esters, polyethylene glycols, and polypropylene
glycols.
[0073] The type and amount of additional plasticizer, when present
in the formulation, affects resistance of the dried polymer film to
water and may also affect the release rate of the active drug
ingredients as well as that of the PSPE compound. Those skilled in
the art will recognize that the degree of water resistance can also
be controlled by the type and amount of the plasticizer(s), the
nature of the active principles, the choice of polymer (e.g.,
amount of acid groups in the polymer, etc.), the, amount of the
polymer, and the like.
[0074] When additional plasticizer is present it will generally be
used in amounts which depend on the types and amounts of the
film-forming polymer and the PSPE, most usually in the range of
from about 0.5 to about 20 percent, preferably from about 2 to 10
percent, especially, from about 4 to 8 percent, based on the total
weight of the composition.
[0075] While additional plasticizers may be incorporated in the
invention compositions, as noted above, sufficient flexibility and
adhesion, as well as compatibility (both wet and dry) between the
respective ingredients, will usually be achieved without the
addition of conventional plasticizers.
[0076] Solvents which may be used in the nail lacquer compositions
of this invention are also not particularly critical but may be
selected from among the usual physiologically safe organic solvents
for lacquer compositions, so long as the active principles and
film-forming polymers are soluble therein and so long as the
lacquer is easy to apply and sufficiently volatile to provide
acceptable drying times, usually dry to the touch in less than
about 5 minutes, preferably less than about 2 minutes. As examples
of such solvents mention may be made of lower alkanols, e.g.,
ethanol, propanol, isopropanol, butanol, isobutanol; lower alkyl
esters of lower carboxylic acids, e.g., ethyl acetate, propyl
acetate, n-butyl acetate, n-amyl acetate; lower alkyl ethers, e.g.,
methyl ether, methyl ethyl ether; lower alkyl ketones, e.g., methyl
ethyl ketone; halogenated hydrocarbons, e.g., methylene chloride,
methyl chloroform; aromatic hydrocarbons, e.g., toluene; cyclic
ethers, such as, tetrahydrofuran, 1,4-dioxane; and mixtures
thereof. Anhydrous ethanol (EtOH) is especially preferred.
[0077] The solvents used in the nail lacquer formulations of this
invention are generally and preferably non-aqueous. However, in
some cases small amounts of water, generally less than about 10%,
preferably less than about 5% by weight of total solvents, may be
used if not substantially impairing the homogeneity, clarity and
solubility of the various ingredients in the lacquer solution. For
example, ethanol when used may sometimes be added in the form of a
95% ethanol solution.
[0078] Again, in view of the good compatibility between the
film-forming polymer and the enhancer/plasticizer compounds of
formula (I), use of co-solvents, such as propylene glycol, in
addition to solvent, e.g., ethanol, are usually not required and,
therefore, may be omitted.
[0079] On the other hand, however, it may be desirable and, in some
cases, preferred, to decrease the water-resistance of the dried
polymer film, for example, to facilitate removal of the film after
release of all or most of the active ingredients. Thus, in addition
to a lacquer film from which the active ingredients are released
over periods of several days to about 1 week or longer, lacquer
films from which the active ingredient is at least substantially
released over shorter periods of time, such as one day, may be
desirable since many individuals are accustomed to and prefer
treatments requiring applications of a drug on a daily basis.
[0080] Techniques for increasing the availability of the active
ingredients for transungual delivery have been described above.
When the release rate of active ingredient becomes low the film may
be removed by application of suitable solvents, such as those
described above, e.g., alcohols, acetone, ketones, etc., and/or by
scraping or brushing, as also well known in the nail lacquer
art.
[0081] Often, mixtures of volatile solvents of different boiling
points, usually a low boiling solvent in the range of from about
40.degree. C. to about 100.degree. C. with a medium boiling solvent
(boiling point up to about 150.degree. C.) may be selected to
provide drying times of no more than a few minutes or less, with
uniform evaporation rates, good flow and viscosity characteristics
and other desirable lacquer parameters, as well known in the
cosmetic art. In some cases, high boiling point solvents, such as,
for example, cellosolve, butylcellosolve acetate, butyl cellosolve,
ethyl cellosolve, and the like, may be added in small amounts
provided they do not impede the fast drying property and other
desired characteristics.
[0082] In this connection, in its preferred embodiment, all of the
volatile and non-volatile ingredients are compatible with each
other and form upon mixing clear solutions which are stable against
phase separation over a wide temperature range above and below room
temperature, such as, for example, from temperatures within the
range of from about -10.degree. C. to about +135.degree. C.
[0083] Another important characteristic of commercially acceptable
products is that the films formed upon evaporation of the
solvent(s) and any other volatile components are strongly adherent
to the nail and are water-resistant, namely, capable of
withstanding repeated normal washing with soapy water for at least
1 day, usually up to about 5 or more days, preferably, at least one
week, depending on the amount of antifungal agent in the film and
upon the release rate of the active principles from the film. In
addition, the dry films, for cosmetic appearance, should be
substantially clear and transparent.
[0084] It is also within the scope of the invention to include
colorants, such as pigments and/or dyestuffs, nacreous agents,
pearlescent agents, fillers, and the like, to cover the nail, for
example, to hide any unsightly manifestations of the fungal, yeast
or other infection, or otherwise as may be cosmetically
desirable.
[0085] Other conventional additives customarily present in cosmetic
or medicinal nail lacquers may be included in the present
formulations in their usual amounts so long as they do not
interfere with the diffusion of the active principles and other
parameters of the lacquer composition and dried polymer-film.
Examples of such additives include, sedimentation retarders,
chelating agents, antioxidants, silicates, aroma substances,
wetting agents, lanolin derivatives, light stabilizers,
antibacterial substances, and the like.
[0086] The lacquer compositions of this invention, with or without
antifungal agent, may be prepared following any of the procedures
normally employed in the nail lacquer field, noting that most of
the ingredients are added as mobile liquids such that normal mixing
techniques are available, with no particular order of addition of
the respective ingredients being required. Generally, however, the
polymer film-former, if in powder form, should be added gradually
to some or all of the liquid components in such manner as to avoid
clumping and resulting protracted dissolution times. Other
ingredients may be added as convenient, as will be readily apparent
to the practitioner.
[0087] The antifungal agent films obtained from the nail lacquers
of this invention should be effective in treating onychomycoses and
other fungal infections. Usually, repeated applications of the
antifungal lacquer will be made over a period of several weeks to
several months, depending on the severity of the infection, the
amount of active agent, and the condition of the nails of the
patient. The antifungal agent containing film will contain
sufficient active principle to be diffused through the nail over a
period of at least 1 day, and up to about 7 days. Since the film
will remain in place usually for the entire period of diffusion,
applications of the antifungal nail lacquer need be repeated only
about once per day to about once per week. For example, it may be
desired to provide formulations for daily application during the
initial period of usage until the patient observes substantial
reduction in the degree and extent of infection and thereafter to
provide different formulations designed for less frequent
applications, such as every other day, weekly, etc.
[0088] In addition to treating an existing infection or fungal
infestation, the nail lacquers of this invention may also be
applied prophylactically to the nails of a healthy individual who
is or who believes he or she may be at risk for a mycotic
infection, as a result, for example, of occupation, geographical
location or otherwise. The manner of use is otherwise identical to
the use in treating an existing infection, however, smaller
dosages, but still at least above the MIC of the antifungal agent,
may be sufficient in many cases to prevent the onset of fungal
infection in the event of fungal contamination or infestation.
[0089] There is no particular limitation on the antifungal agents
used in the compositions of this invention; any of the agents known
to be effective for this purpose may be used and a listing of such
compounds may be found, for example, in any current edition of The
Merck Index under the headings "Antifungal (Antibiotic)" and
"Antifungal (Synthetic)" in the Therapeutic Category and Biological
Activity Index section.
[0090] As examples of suitable antifungal agents mention may be
made of, for example, polyenes, e.g., Natamycin, Nystatin;
allylamines, e.g., Naftifine, Terbinafine; imidazoles, e.g.,
Bifonazole, Chlotrimazole, Econazole, Fenticonazole, Ketocanazole,
Miconazole, Oxiconazole; triazoles, e.g., Fluconazole,
Itraconazole, Terconazole; tolnaftate, ciclopirox, undecylenic
acid, sulbentine, and morpholines, e.g., amorolfine, and the
related morpholines disclosed in the aforementioned U.S. Pat. No.
5,120,530. The 1-hydroxy-2-pyridone compounds disclosed in U.S.
Pat. No. 4,957,730, the disclosure of which is incorporated herein,
by reference thereto, may also be used, as may the antifungal
agents disclosed in any of the other patent documents discussed in
the Background of the Invention.
[0091] In the present invention, the antifungal agents are,
preferably, present in the free form, e.g., as acid or base, rather
than in the form of their salts. In this regard, the free form of
antifungal agent will usually have a higher diffusion rate through
the nail than a salt of the same agent; or, the salt form of a drug
may impair the water-resistance of the lacquer film.
[0092] The amount of the active antifungal agent or mixture of such
agents in the composition will depend on such factors as its
structure and antimicrobial activity, release rate from the polymer
film, diffusion characteristics and penetration behavior in the
nail. Generally, any amount effective to kill the infecting
microorganism, which will generally be several to several tens to
hundreds of times greater than the Mean Inhibitory Concentration
(MIC), may be included in the nail lacquer (as applied)
composition.
[0093] Typically, amounts of active antifungal agent in the range
of from about 0.5 to 20 percent by weight, preferably from about 1
to 10 percent, by weight, of the total composition (including
solvents, film-forming polymer, enhancer, etc.) will suffice for
compositions for treatment as well as compositions for prevention.
The amount of antifungal agent in the dried film will, therefore,
depend on the amount of agent in the lacquer solution and by the
thickness of the applied film. The thickness of the film can be
controlled by, for example, controlling the viscosity of the
lacquer solution, such as by the type and amount of polymer, types
and amounts of solvents, etc.
[0094] Conversely, on the basis of the non-volatile components of
the composition, the amount of active agent is generally about 1 to
50%, preferably about 2 to 35%, more preferably, from about 2 to
30%, especially preferably from about 5 to 20%, by weight of the
composition (film-forming polymer(s), active(s), PSPE, additional
plasticizer(s) and other non-volatile additives).
[0095] The antifungal nail lacquers according to this invention, by
virtue of the incorporation of the penetration
enhancer-plasticizer, as described above, may provide
therapeutically effective concentrations of antifungal agent deep
into the nail bed. The minimum value of the therapeutically
effective amount of antifungal agent will depend on several
factors, primarily the particular antifungal agent and the degree
and severity and cause of onychomycoses or other fungal
infection.
[0096] Generally concentrations of antifungal agent greater than at
least about 150 ppm in deep nail bed should be reached to attain
favorable clinical results.
[0097] The following examples illustrate the compatability of
various compositions containing pentadecalactone, as a
representative compound of formula (I) but the present invention is
not intended to and should not be construed to in any manner to be
limited to the compositions shown in these examples.
EXAMPLE 1-8
[0098] The nail lacquer compositions shown in the following Table
were prepared. Each nail lacquer composition was applied to a glass
substrate and allowed to dry in air for several hours and the state
(homogeneity) of the dried lacquer films were observed.
Visualization of crystals was by means of videomicrographs taken
under crossed polarizers. The results are also reported in the
following Table. Pentadecalactone used in these examples has the
following structure:
1 Ingredient Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8
Ciclopirox 8 8 8 8 8 8 8 8 Pentadecalactone 10 15 10 15 10 10 15 15
EUDRAGIT .RTM. -- -- -- -- 25 -- 25 -- RL.sup.a EUDRAGIT .RTM.
L.sup.b -- -- -- -- -- 25 -- 25 DERMACRYL .RTM. 25 25 -- -- -- --
-- LT.sup.c Ethanol 55 52 57 52 57 57 52 52 Appearance clear clear
clear clear cloudy clear crystals cloudy .sup.aCationic Acrylic
Polymer .sup.bAnionic acrylic polymer .sup.cAmphoteric acrylic
polymer
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