Topical composition for fungal treatment

A topical pharmaceutical composition having penetration enhancing properties for treating fungal dermatological conditions comprising a pharmaceutically active topical antifungal agent selected from the group consisting of sulconazole and natifine with an acetate penetration enhancing compound.

FIELD OF THE INVENTION 
This invention relates to a topical pharmaceutical composition having 
penetration enhancing properties for treating fungal dermatological 
conditions. Particularly, the composition has an enhanced ability to 
penetrate finger nails, toe nails, and the stratum cornea beneath nails. 
BACKGROUND OF THE INVENTION 
The risks associated with parenteral treatments, the concerns associated 
with variable rates of absorption and metabolism inherent in oral 
treatments, and difficulties in maintaining the continuity of drug 
administration can be avoided by relying upon efficacious topically 
applied compounds to treat certain maladies. Topical delivery allows 
effectively treating conditions which are local in nature, or which 
exhibit local manifestations, systemically, as well as locally with the 
same treatment regimen. 
Dermatological pharmaceutically active agents are frequently applied 
topically to obtain desired results. Topical application in the form of 
creams, lotions, gels, and solutions, for example, may avoid systemic side 
effects and permits the application of high concentrations of the 
pharmaceutically active agent at the site of action. Some dermatological 
agents are applied topically for achieving a systemic effect and others 
are applied topically for achieving a situs effect. 
Conditions such as onychomycosis pose serious problems in dermatology. 
Onychomycosis is a condition recognized by discoloration beneath toe nails 
and finger nails along with pain when pressure is placed near or at the 
site of discoloration. Various fungi, classified as white superficial 
fungi, cause the condition. Frequently the condition is treated by the 
combination of nail avulsion and pharmaceutical agent, as presently 
available topical anti-fungal formulations for treating onychomycosis have 
been met with limited success. This is primarily due to the limited 
ability of such compounds to penetrate into the nail plate, which is 
hyperkeratotic. The treatment of the condition is further problematic in 
geriatric patients where therapeutic options are often limited due to 
possible drug interactions, systemic side effects of treatment, and 
contra-indications secondary to other medical ailments. 
Compounds known as penetration or permeation enhancers produce an increase 
in the permeability of skin or other body membranes to a pharmacologically 
active agent. The increased permeability allows an increase in the rate at 
which the drug permeates through the skin and enters the blood stream. 
Penetration enhancers have been successful in overcoming the 
impermeability of pharmaceutical agents through the skin. However, the 
thin stratum corneum layer of the skin, which is about 10 to 15 cells 
thick and is formed naturally by cells migrating toward the skin surface 
from the basal layer, has been found to be easier to penetrate than nails. 
Penetration enhancers have been primarily categorized according to their 
ability to enhance permeation via three pathways. The first is the 
continuous polar or aqueous pathway composed of proteins. The second 
pathway is a continuous non-polar pathway consisting of lipids. The third 
pathway is a heterogenous polar-non-polar multilaminate of lipids and 
proteins. 
Binary penetration systems comprising N-(2-hydroxyethyl) pyrrolidone in 
combination with a cell envelope disordering compound, such as oleic acid, 
enhances the penetration and percutaneous delivery of pharmaceutically 
active agents to human and animal tissue and systems. U.S. Pat. No. 
4,537,776, Cooper, Aug. 27, 1985. 
Anti-microbial compositions for controlling bacterial and fungal infections 
comprising a metal chelate of 8-hydroxyquinoline and an alkyl benzene 
sulfonic acid have been shown to be efficacious due to the increased 
ability of the oleophilic group to penetrate the lipoid layers of 
microcells. The compounds however, do not effectively increase the ability 
to carry the pharmaceutically active anti-fungal through the cornified 
layer or stratum corneum of the skin. U.S. Pat. No. 4,602,011, West et 
al., Jul. 22, 1986; U.S. Pat. No. 4,766,113, West et al., Aug. 23, 1988. 
Percutaneous absorption accelerators containing glycerols or polyglycerols 
and alcohols as essential components are known. U.S. Pat. No. 4,859,696, 
Kamiya et al., Aug. 22, 1989; U.S. Pat. No. 4,948,588, Kamiya et al., Aug. 
14, 1990. The percutaneous absorbent preparations may be formulated by 
incorporating pharmaceutically effective anti-fungal components with the 
percutaneous absorbent accelerator. The percutaneous absorption 
accelerator can be advantageously used for many preparations of topical 
agents which are expected to exhibit the pharmacological effect to be 
absorbed from, for example, a liquid spraying agent, a lotion, an 
ointment, a cream, a gel, a sol, and aerosol, a cataplasm, a plaster, a 
tape preparation, and the like. 
Other penetration enhancing pharmaceutical compositions for topical 
transepidermal and percutaneous application may contain an active 
pharmaceutical permeant, including hydrophilic salt forms. The hydrophilic 
salts are contained in a penetration enhancing vehicle comprising a cell 
envelope disordering compound. The formulation enhances the penetration of 
pharmaceutically active agents through the integument. U.S. Pat. No. 
4,863,970, Patel et al., Sep. 5, 1989. It is also known to use 
compositions including diethylene glycol monoethyl or monomethyl ether in 
addition to an ester component to enhance the absorption of 
pharmaceutically active agents through the skin. U.S. Pat. No. 5,053,227, 
Chiang et al., Oct. 1, 1991. 
Other compositions known for enhancing the transdermal delivery of 
pharmaceutically active agents may contain a polar solvent material and a 
polar lipid material. U.S. Pat. No. 5,026,556, Drust et al., Jun. 25, 
1991. Compositions for carrying physiologically active agents through skin 
and for retaining these agents in body tissues may use a wide range of 
alkyl compounds to enhance penetration of such formulations. U.S. Pat. No. 
5,162,315, Nov. 10, 1992. 
The penetration enhancers discussed have been found to have limited 
potential for improving the permeability of finger nails and toe nails to 
pharmaceutically active agents. In order to overcome the highly 
impermeable nature of finger and toe nails, specifically selected vehicles 
or carriers to aid in the penetration of such compounds through nails must 
be found or developed. The successful treatment of persistent 
dermatological and other conditions which develop beneath nails will 
depend upon the ability of a penetration enhancer to allow a 
pharmaceutically active agent to pass through the thick, keratinized cell 
layers of the nails to attack the cause of the condition. 
SUMMARY OF THE INVENTION 
The present invention provides a topical pharmaceutical composition having 
penetration enhancing properties for treating fungal dermatological 
conditions, particularly the subungual condition known as onychomycosis. 
The composition comprises a pharmaceutically active topical antifungal 
agent hereinafter sometimes referred to as antifungal agent and a 
penetration enhancing compound. 
Preferably the pharmaceutically active topical antifungal agent is 
naftifine hydrochloride. In alternate embodiments, sulconazole nitrate may 
be used. In yet other embodiments, the antifungal agent may be selected 
from the group of compounds consisting essentially of morpholines, 
allylamines, triazoles, and combinations thereof. The antifungal agent is 
often present in a gel or other carrier at an effective strength in the 
composition for topical application. 
The preferred penetration enhancing compound is methyl acetate and is 
prepared in an amount of approximately 1 to 4 drops per 1 ounce of the 
topical antifungal agent. Acetate compounds that may be used as 
penetration enhancing compounds such as butylacetate, ethylacetate, 
isobutyl acetate, isopropyl acetate, propyl acetate or mixtures thereof. 
Other acetates may be used that are effective as penetration enhancers 
according to this invention. The penetration enhancing compound may be 
present in the pharmaceutically active topical anti-fungal in 
approximately 0.067% to 0.67% by weight of the pharmaceutically active 
topical anti-fungal. The topical pharmaceutical composition is preferably 
applied to a fungus affected nail area on a toe or finger or other 
affected area two times per day. 
The penetration enhancing compound of the topical pharmaceutical 
composition improved the penetration ability of the pharmaceutically 
active topical antifungal agent through the finger and toe nails of 
patients. The improved penetration resulted in a greater amount of the 
antifungal reaching the situs of fungi causing the onychomycosis 
condition. Thus, the condition cleared more completely and during a 
shorter period of time than with other topical treatments.

DETAILED DESCRIPTION OF THE INVENTION 
A topical pharmaceutical composition having penetration enhancing 
properties for treating fungal dermatological conditions was prepared by 
adding a penetration enhancing compound to a pharmaceutically active 
topical antifungal agent. The penetration enhancing composition is an 
acetate which can include methylacetate, ethylacetate, propylacetate, 
isopropylacetate, butylacetate or mixtures thereof. The preferred 
composition comprises four drops of the preferred penetration enhancing 
compound, methyl acetate, per one ounce of antifungal agent. The acetate 
is mixed into the antifungal agent until evenly dispersed therein. In 
alternate embodiments of the composition, one drop to 4 drops of the 
acetate may be added per one ounce of antifungal agent. The preferred 
range of acetate in the antifungal agent is from approximately 
0.067%-0.67% by weight. 
For the purpose of illustrating the present invention metylacetate was used 
in the studies presented. Methyl acetate was obtained from Spectrum 
Chemical Manufacturing Corporation, 14422 South San Pedro St., Gardena, 
Calif. 90249-9985. The preferred antifungal agent is naftifine 
hydrochloride 1% gel, having the chemical name 
(E)-N-Cinnamyl-N-methyl-1-naphthalene-methylamine hydrochloride. The 
pharmaceutical product NAFTIN.RTM. Gel, 1% (Allergan, Inc.) is preferred 
for use. In an alternate embodiment of the composition, sulconazole 
nitrate solution, 1%, having the chemical name 
(.+-.)-1-[2,4-dichloro-.beta.-[(p-chlorobenzyl)thiol]-phenethyl] imidazole 
mononitrate, may be used. This compound is available as the product 
EXELDERM.RTM. solution, 1% (Westwood-Squibb). 
In other alternate embodiments, fungicidal agents from the groups of 
compounds known as morpholines, allylamines, and triazoles may be used for 
the antifungal in the composition. These compounds have been shown to have 
promise in treating dermatological fungal conditions, including 
onychomycosis. Mixtures of the antifungal agents can be used in 
pharmaceutically active strengths. The compounds have effective fungicidal 
activity such that in the appropriate formulation which would allow the 
compound to reach the site of action, they may be effective in eradicating 
or controlling fungal conditions. Antifungal agents in the preferred and 
alternate embodiment may be used in liquid, lotion, ointment, cream, gel, 
aerosol, and other forms. 
The efficacy of the preferred composition was observed and evaluated during 
a clinical study of 92 patients having onychomycosis. 45 of the patients 
were male and 47 were female. 46 of the patients were considered geriatric 
patients, being at least 60 years of age. Geriatric patients were sought 
to evaluate the effectiveness of treatment with the geriatric population 
due to the high incidence of dermatological conditions particularly, 
onychomycosis occurring in that group. Also, geriatric patients will 
frequently have thicker toe nails due to increased layers of keratinized 
cells, thereby making it even more difficult for topical preparations to 
penetrate. 
Patients were initially selected for the study based upon clinical 
observation of the onychomycosis condition. Patients demonstrating the 
typical discoloration beneath toe nails associated with onychomycosis were 
tested to determine the presence of fungus. Toe nail scrapings were taken 
to identify the presence of the classification of fungus referred to as 
white superficial fungus, on and under the toe nails of the patients. 
Toe nail scrapings were obtained using standard clinical procedures known 
to those skilled in the art. The scrapings were treated with potassium 
hydroxide (KOH) to dissolve the skin cells, leaving the fungal organisms. 
The KOH treated scrapings were viewed under microscopic conditions to 
verify the presence of the white superficial fungus. The procedures for 
performing the KOH evaluation are known to those in the art. Patients with 
a positive fungal presence were designated KOHT.sup.+. 
The patients having toe nail scrapings testing KOH.sup.+ were selected to 
participate in clinical observations to evaluate the effectiveness of the 
preferred embodiment of the composition. The toe nail scrapings were not 
cultured to identify specific fungal organisms. 
The patients were instructed to apply two times per day the preferred 
composition of four drops of methyl acetate that had been mixed well in 
one ounce of the preferred antifungal agent naftifine hydrochloride-1% 
gel. The composition was massaged into the surface, particularly the nail, 
of the affected toes. The composition of the invention can be applied once 
every twenty-four hours to about twenty-four times every twenty-four 
hours. Application intervals of every 4 hours to every 12 hours are 
preferred. However, any treatment regimen which allows a safe and 
effective amount of the selected pharmaceutically active antifungal agent 
to reach the afflicted situs can be employed while using the compositions 
of this invention. 
After 90 days of treatment, the onychomycosis was found to be fully cleared 
in the distal subungual of 66 patients (30 males and 36 females). The 
patients not showing complete clearing of the condition showed a visible 
improvement in the white superficial fungus condition of approximately 
50%. It was observed that the condition cleared the sooner and to a 
greater extent in the female patients. No conclusion drawn from this 
observation. 
The results observed with patients treated with the preferred embodiment of 
the composition comprising the pharmaceutically active topical antifungal 
agent and methyl acetate as the penetration enhancing vehicle were 
superior to those typically observed when onychomycosis is treated with 
known antifungal agents without methyl acetate. The antifungal agent with 
methyl acetate cleared the condition in 66 of the 100 patients completely 
in a shorter time than previously observed for partial clearing with other 
fungal agents not including methyl acetate. Results obtained with known 
onychomycosis treatment regimens are discussed in Riordan et al., Current 
Treatment of Onychomycosis, J. Geriatric Derm., Vol. 2, No. 5 (Sept./Oct. 
1994). 
The percutaneous and subungual absorbability of pharmaceutically-effective 
antifungal compounds and such preparations is unsatisfactory. It is often 
difficult for a base alone, used for conventional topical agents, to 
attain percutaneous absorption sufficient for the pharmaceutically active 
components to be effective in completely or nearly completely eradicating 
fungal conditions in a short period of time. Previously available 
penetration enhancers have improved the penetration ability of 
pharmaceutical compounds through skin and other membranes, but have had 
limited success in improving the penetration of such compounds through 
nails. 
It appears that the methyl acetate of the preferred embodiment of the 
topical pharmaceutical composition improved the penetration of the 
pharmaceutically active topical antifungal agent through the toe nails of 
patients. The improved penetration resulted in a greater amount of the 
antifungal reaching the situs of fungi causing the onychomycosis 
condition. Thus, the condition was cleared faster than with other topical 
treatments. The mechanism by which the methyl acetate improves the 
penetration of the antifungal agent through the toe nail is not known. 
In any form of medical practice, there are many variables which affect the 
particular treatment regimen. In that regard, the final diagnosis and 
treatment of fungal conditions is left to the expertise of the 
practitioner and patient. A practitioner skilled in the art will be able 
to determine the application parameters of specific formulation and 
application based on the needs of the patient. 
It will be obvious to those skilled in the art that the invention may be 
varied in many ways. Such variations are not to be regarded as a departure 
from the spirit and scope of the invention, and all such modifications as 
would be obvious to one skilled in the art are intended to be included 
within the scope of the claims.