FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "PHARMACEUTICAL COMPOSITIONS FOR TOPICAL APPLICATION"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(Section 10 and rule 13)
PHARMACEUTICAL COMPOSITIONS FOR TOPICAL APPLICATION
APPLICANT
Macleods Pharmaceuticals Ltd,
304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road,
Andheri (East), Mumbai - 400 059, Maharashtra, India
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The invention relates to a topical gel pharmaceutical composition of amorolfine or a pharmaceutically acceptable salt thereof, and methods of using such composition in treating fungal infections of nails and/or skin by topically administering such composition, and a method of preparing such composition.
The invention specifically relates to a topical gel pharmaceutical composition of amorolfine hydrochloride for the treatment of nail onychomycosis and fungal infection of the skin.
BACKGROUND OF THE INVENTION
Nail tinea (onychomycosis) is one of fungal infections and known as an intractable disease. A treatment with an external preparation or an oral preparation is performed as a treatment method for the nail tinea at present, and, since there are many patients who cannot be treated with the oral preparation due to problems of adverse side effects and drug interaction of the treatment with oral preparation, such patients are treated with the external preparation.
It is desirable to treat this disease topically due to the potential for side effects which have been associated with some of the oral treatment regimens. One reason for the absence of a topical treatment is that in this disease, the symptomatic thickened nail plate prevents topical agents from reaching the site of the infection. The target sites for the treatment of onychomycosis reside in the nail plate, nail bed and nail matrix.
The nail plate is thick, hard, dense, and represents a formidable barrier for drugs to be able to penetrate in a therapeutically required quantity. Although nail material is similar to the stratum corneum of the skin, being derived from epidermis, it is composed primarily of hard keratin, which is highly disulfide-linked, and is

approximately 100-fold thicker than stratum corneum. In order to deliver a sufficient amount of drug into the nail plate, the permeability of the nail plate to the drug must be enhanced. This is particularly true in fungal diseases where a common symptom of the disease is thickened nail plate.
Nail plates have high sulphur content in the form of disulfide bonds. U.S. Pat. No. 5,696,164 (Sun et al., 1997) discloses the use of thio-containing amino acids and its derivatives (i.e., sulfhydryl-containing amino acids), such as cysteine and N-acetyl cysteine, and urea to increase drug permeability in a nail plate, by breaking disulfide bonds in nail keratin to increase drug penetration into and through the nail. It was shown that a significant enhancement in topical drug delivery through nail was achieved. European Patent Application EP 503988 Al (1992) discloses a composition to treat onychomycosis, comprising nail-penetration agents, such as glycols, glycol ethers, dimethyl sulfoxide, caprolactam, and other hydrophilic compounds to facilitate the penetration of allylamine fungicides into the nail.
Nail lacquers containing therapeutic agents have been known in the past. For example, U.S. Pat. No. 4,957,730 (1990) describes a nail varnish containing a water-insoluble film-forming substance and antimycotic compound. U.S. Pat. No. 5,120,530 (1992) describes a antimycotic nail varnish containing amorolfine in quaternary ammonium acrylic copolymer. The water-insoluble film former is a copolymerizate of acrylic acid esters and methacrylic acid esters having a low content of quaternary ammonium groups. U.S. Pat. No. 5,264,206 (1993) describes a nail lacquer with antimycotic activity, which contains an antimycotic agent and water-insoluble film formers including polyvinyl acetate, a copolymer of polyvinyl acetate and acrylic acid, copolymers of vinyl acetate and crotonic acid, monoalkyl maleate, etc.
U.S. Pat. No. 9,668,987 discloses liquid compositions comprising at least one active agent, at least one volatile solvent, at least one film-forming ingredient, at

least one phospholipid. Such compositions are applied to the nail or skin treated surfaces as solutions that are in the form of a lacquer. After the compositions are applied, rapid drying of the volatiles results in a film on the treated surface, which film exhibits a web-like structure containing the active agent. These structured arrangements exhibit sustained and improved delivery of the active agent to the treated nail or skin.
Another topical form proposed is a patch containing an antifungal agent, in particular a patch containing amorolfine (WO 2005/092299), the effectiveness of which remains conditional on good penetration of the antifungal agent through the nail.
Amorolfine is a morpholine derivative with antifungal and fungistatic activity, introduced in 1981. It inhibits ergosterol synthesis on two levels: by inhibiting delta 14 reductase and delta 7-8 isomerase, which affects pathogen membrane synthesis, depletes ergosterol and causes non-typical spherical sterols to accumulate in the fungal cytoplasmic membranes.
Amorolfine is effective against dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton spp.), yeasts (Candida spp., Cryptococcus spp., Malassezia spp.), some molds (Alternaria spp., Hendersonula spp., Scopulariopsis spp.) and other pathogenic fungi (Cladosporium, Coccidioides, Histioplasma, Sporothrix) but not against bacteria except Actinomyces. Amorolfine nail lacquer 5% (Loceryl or Curanail) are commercially available OTC products in the UK for the treatment of serious fungal nail infections; as 0.25% cream, 5% nail lacquer and as 0.25% amorolfine spray in India, for the treatment of fungal nail infections and fungal skin infections.
Loceryl® is one example of a lacquer composed of amorolfine (5%), of Eudragit RL 100, of glycerol triacetate, of butyl acetate, of ethyl acetate and of

ethanol. The lacquer is applied to the horny plate of the nail and dried for a few minutes so as to evaporate off the solvents and leave a waterproof film of polymer on the surface of the nail. The active ingredient is subsequently released from the film and diffuses through the horny plate of the nail.
Loceryl® is applied one or two times a week, for six months for the nails of the hands and nine to twelve months for the nails of the feet. The duration of treatment depends essentially on the intensity, the localization of the infection and the nail surface affected.
Treatment of the nails with a lacquer thus proves to be relatively restricting since it is repetitive, requires maintenance of the nail before each application and demands particular attention in order to avoid any contamination of the unaffected nails.
The problem shared by all the topical antifungal agents used to treat onychomycosis, and the reason for the poor effectiveness thereof, is the very weak penetration of the active ingredients through the nail in order to reach the reservoir of the infectious agent, i.e., the nail bed.
Conventional antifungal compositions, however, exhibit poor to marginal efficacy against nail fungal infections, and there is clearly an unmet need for antifungal compositions with improved efficacy in the treatment of nail fungal infections. There is a need for improved compositions for topical delivery of antifungal agents.
It has now been surprisingly found that a topical composition of amorolfine, containing amorolfine as the sole active ingredient, together with a polymeric gelling agent and a solvent system, is effective in the treatment of treat nail and skin diseases.

SUMMARY OF THE INVENTION
The present invention relates to a topical gel pharmaceutical composition of amorolfine or a salt thereof, and a method of treating a fungal disease of nail and skin. Specifically the invention relates to a topical pharmaceutical composition for treating nail fungal i.e. onychomycosis.
In particular, the invention relates to a stable topical gel formulation useful for the treatment of a nail fungal disease, comprising amorolfine or a salt thereof, and one or more pharmaceutically acceptable excipients sufficient to form a gel capable of delivering the antifungal through the nail barrier.
Particularly, the invention relates to topical gel pharmaceutical compositions comprising amorolfine or a salt thereof, at least one polymeric gelling agent, a solvent system, at least one acidifying agent, and one or more other pharmaceutically acceptable excipient, having a consistency sufficient to adhere to the surface of a nail so that the antifungal is delivered through the nail plate.
The present invention also relates to a method of treating disease infected human nails or skin by topically applying a topical gel compositions comprising amorolfine or a salt thereof, at least at least one polymeric gelling agent, a solvent system, at least one acidifying agent, and one or more other pharmaceutically acceptable excipient.
The present invention further relates to process of preparing topical gel compositions of amorolfine or a salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides topical gel compositions comprising amorolfine or a salt thereof as the active agent which allows for improved delivery of the active agent to the treated nail or skin.

The terms "topical" used herein in the broadest sense to refer to mean application of a topical drug or pharmacologically active agent to the skin or nail.
The term "amorolfine" means the amorolfine base. The term "pharmaceutically acceptable salts" means salts that are compatible with the integuments, and preferably with the skin and/or the mucous membranes. According to the preferred embodiment, the pharmaceutically acceptable salts of amorolfine is the hydrochloride salt (amorolfine HC1).
As used herein, the term "about" when used to refer to weight % in a composition means ±10% of the reported weight %. As used herein, the term "about" when used to refer to measured characteristics of the composition means ±20% of the reported value.
Amorolfine HC1 or amorolfine hydrochloride denotes the hydrochloride salt of cis-4-[3-[4-(l,l-dimethylpropyl)phenyl]-2-methylpropyl]-2,6-dimethylmorpholine represented by formula (1):

Amorolfine exerts a fungistatic and fungicidal activity by inhibiting the synthesis of the cell membrane sterols of fungi such as yeasts, dermatophytes, moulds and dematiaceous fungi (black fungi).
The topical gel compositions according to the present invention comprises about 0.1% to about 10% of amorolfine. Preferably, the topical gel compositions

comprises about 0.1% to about 5%, by weight of amorolfine, for example in the form of amorolfine hydrochloride, as therapeutically active antifungal agent.
The topical gel compositions according to the present invention are intended for application to the nails and/or skin of a patient.
The topical compositions according to present invention comprises amorolfine HC1, at least one at least one polymeric gelling agent, a solvent system, at least one acidifying agent, and one or more other pharmaceutically acceptable excipient.
The polymeric gelling agent which is used in the formulation of the present invention may include, but are not limited to, naturally-occurring polymeric materials such as, locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum sodium alginate, xanthan gum, quince seed extract, tragacanth gum, starch, chemically modified starches and the like, semi-synthetic polymeric materials such as cellulose ethers (e.g. hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose), micro-crystalline cellulose and compositions (Avicel types) manufactured by FMC, polyvinylpyrrolidone, polyvinylalcohol, guar gum, hydroxypropyl guar gum, soluble starch, cationic celluloses, cationic guars and the like and synthetic polymeric materials such as carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers and the like. Optionally, mixtures of the above compounds are contemplated.
The polymeric gelling agent, which is preferably a cellulose polymer is selected from hydroxy- or carboxy-alkyl celluloses. More preferably, the polymeric gelling agent is selected from the group of carboxymethylcellulose, hydroxyethylcellulose, hydroxypropycellulose and hydroxypropylmethylcellulose,

combinations thereof and the like. Most preferably, the polymeric gel forming agent is hydroxyethylcellulose. Cellulose polymers may be used as gelling agents as they act as suspending agents, viscosity builders, and thickeners.
The polymeric gelling agent in the compositions is ranged from about 0.1% to about15%, preferably from about 0.5% to about 5%, and more preferably between from about 0,5% to about 3%.
According to the present invention, a solvent system is a mixture of a water-miscible organic solvent and water.
An example of a preferred organic solvent for the gel composition of the invention is a polyol, also known as a polyhydric alcohol. Representative examples of polyols include glycols and sugar alcohols. Preferred polyols for the gel composition of the invention include polyether glycols, such as ethoxydiglycol, and propylene glycol. Propylene glycol is among the preferred polyols. The polyol concentration (e.g., the propylene glycol concentration) ranges from about 5 wt% to about 70 wt%, e.g., from about 15 wt% to about 50 wt%, most preferably from about 15% to about 40%.
The topical gel composition of the present invention contains water ranging from about 1% to 80% by weight, preferably from about 10% to 60% by weight, relative to the total weight of the composition. The water used in the composition according to the invention will preferably be purified water.
In one or more embodiment solvent system comprises a mixture of propylene glycol- and water.
In a preferred embodiment; the present invention provides a topical gel composition comprising propylene glycol-water solvent mixture in amounts such that the composition forms a clear, aqueous dispersion. In one or more embodiment

solvent system comprises a mixture of from about 5 % to about 50 % by weight of propylene glycol and from about from about 1% to 75% by weight of water. In a preferred embodiment solvent system comprises a mixture of from about 5% to about 40% by weight of propylene glycol and from about from 1% to 60% by weight of water.
It has now been surprisingly found that a mixture of propylene glycol- and water in specific proportions are effective to solubilize drug, and thus are found suitable to be utilized in the preparation of novel, stable gel compositions of the invention.
As used herein the term "acidifying agent" refers to substances which are liquids having an apparent pH of < 1, or solids having a pKa<5. The preferred acidifiers are hydrochloric acid, sulfuric acid, o-phosphoric acid, nitric acid, acetic acid, L (+)-lactic acid, salicylic acid, and glycolic acid. The particularly preferred acidifier is hydrochloric acid. The acidifying agent is present in amount from about 0.05 % to about 1%, more preferably form about 0.05% to about 0.25%.
Suitable preservatives that can be used in the present invention include any preservatives that are suitable for topical application. Examples of the preservatives include, but are not limited to, sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea, or diazolidinyl urea. Additional examples of preservatives may include quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; alcoholic agents, such as, chlorobutanol; antibacterial esters, such as esters of parahydroxybenzoic acid etc. Preferably the preservative is phenoxyethanol.
According to present invention, the amount of the preservatives in the composition varies from about 0.5% to about 5%, preferably form about 0.5% to about 3% more preferably form about 0.5% to about 1% (w/w).

The topical gel composition may also include one or more additional ingredients or excipient such as moisturizing agent, humectant, neutralizing agent, emollient, and mixtures thereof.
The moisturizing agent includes but is not limited to glycerin, alkylene polyols and their derivatives, including propylene glycol, sorbitol, ethoxylated glycerol and mixtures thereof.
The humectant includes but are not limited to glycerin, sorbitol or trehalose (e.g., a,a- trehalose, p,p-trehalose, a,P-trehalose) or a salt or ester thereof (e.g., trehalose 6-phosphate).
The emollient includes but is not limited to, isostearic acid derivatives, isopropyl palmitate, lanolin oil, diisopropyl dimerate, maleated soybean oil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, hydrogenated coco-glycerides, isononyl isononanoate, isotridecyl isononanoate, myristal myristate, triisocetyl citrate, octyl dodecanol, sucrose esters of fatty acids, octyl hydroxystearate and mixtures thereof.
According to one embodiment of the present invention provides a topical gel composition that comprises amorolfine or a pharmaceutically salts thereof as the active agent, cellulose polymers as polymeric gelling agent, solvent system comprising a mixture of polyol and water, an acidifying agent, preservative and other optional pharmaceutically acceptable excipients.

According to another embodiment; there is provided a topical gel composition that comprises amorolfine hydrochloride, hydroxyethyl cellulose, solvent system comprising a mixture of propylene glycol and water, hydrochloric acid to adjust pH of the composition, phenoxyethanol and other optional pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides a topical gel composition that comprises from about 0.1% to about 5% of amorolfine hydrochloride, from about 0.5 to about 5% of hydroxyethyl cellulose, from about 5 wt% to about 50 wt% of propylene glycol, from about 40% to about 75% of water, from about 0.05 % to about 1% of hydrochloric acid, from about 0.5% to about 1% of phenoxyethanol and other optional pharmaceutically acceptable excipients.
In a most preferred embodiment, the present invention provides a topical gel composition consisting of about 0.25% of amorolfine hydrochloride, about 2% of hydroxyethyl cellulose, about 40% of propylene glycol, about 60% of water, about 0.25% of hydrochloric acid, about 1% of phenoxyethanol and other optional pharmaceutically acceptable excipients.
In another embodiment of this invention, there is also provided a process for preparing a composition of the invention as described above, which comprises the steps of preparing a drug phase, and a preservative phase and mixing both phases to form a homogeneous and transparent gel.
The composition of this invention may be, for example, filled and packaged into a container such as such as glass jars and aluminum and laminate tubes, a plastic or glass tube or jar or bottle, an airless pump and plastic squeeze bottle, appropriate for packaging topical formulations.
The product may further contain additional packaging such as a plastic or cardboard box for storing such container. In one embodiment, the product comprises

a composition of the invention and contains instructions directing the user to apply the composition to the nail or skin.
The labeling instructions can come in the form of a pamphlet, a label applied to or associated with the packaging of the article of manufacture.
In an additional embodiment of this invention, there are provided methods of treatment of nail and skin fungal infections by topical administration of the compositions of the present invention to the afflicted area of nail or skin as a gel. More specifically, the method of treating a nail or skin fungal infection in a human in need thereof, comprising applying to the nail or skin a therapeutically effective dose of the composition of the invention and allowing the composition to dry.
In a preferred embodiment of this invention, the compositions are topical gel, to be applied evenly on the skin or nail with a brush, spatula, pipette, or an applicator capable of being applied to a nail or skin surface with a brush or a metered dose device. The invention further relates to a dispensing device with the composition of the present invention contained therein.
The application may be done once to multiple times daily and repeated as per physician's instructions. The composition should be applied evenly over the entire nail plate and surrounding skin.
Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art.
EXAMPLES
The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLE 1
Table 1: Manufacturing formula
Ingredients Weight Percent
Amorolfine Hydrochloride IP 0.25
Propylene Glycol IP 40.00
Hydroxyethyl Cellulose USP-NF 2.00
Phenoxyethanol IP 1.00
0.1N Hydrochloric Acid 0.25
Purified Water IP QS to l00%
Manufacturing process:
1. Preparation of drug phase
1.1. Weighed quantity of propylene glycol was added to a vessel followed by adding amorolfine hydrochloride slowly in small portions under continuous stirring until a clear solution was obtained.
1.2. Hydroxyethyl cellulose was added to the drug solution formed in step 1.1 under continuous stirring to obtain a uniform dispersion.
2. Preparation of preservative Phase
2.1. Phenoxyethanol was added to a vessel containing purified water under continuous stirring to get a clear solution.
3. Preparation of Gel
3.1. Preservative solution formed in step 2.1 was added to the drug dispersion formed in step 1.2 under continuous stirring to form a lump free uniform dispersion

and the dispersion was kept for 4-6 hrs with intermittent stirring at slow speed for complete swelling of hydroxyethyl cellulose, until a transparent gel was formed.
3.2. The pH of the gel formed in step 3.1 was adjusted with 0.1N hydrochloric acid and was stirred continuously under vacuum to obtain a uniform gel free of entrapped air.

EXAMPLE 2
Table 2: Manufacturing formula
Ingredients Weight Percent
Amorolfine Hydrochloride 0.25
Propylene Glycol 5.00
Diethylene glycol monoethyl ether (Teanscutol P®) 5.00
Hydroxyethyl Cellulose 2.00
Phenoxyethanol 1.00
0.1N Hydrochloric Acid 0.25
Purified Water QS to l00%
Manufacturing process:
1. Preparation of drug phase
1.1. Weighed quantities of propylene glycol and diethylene glycol monoethyl ether were added to a vessel followed by adding amorolfine hydrochloride slowly in small portions under continues stirring until a clear solution was obtained.
1.2. Hydroxyethyl cellulose was added to the drug solution formed in step 1.1 under continuous stirring to obtain a uniform dispersion.
2. Preparation of preservative Phase

2.1. Phenoxyethanol was added to a vessel containing purified water under continuous stirring to get a clear solution.
3. Preparation of Gel
3.1. Preservative solution formed in step 2.1 was added to the drug dispersion
formed in step 1.2 under continuous stirring to form a lump free uniform dispersion
and the dispersion was kept for 4-6 hrs with intermittent stirring at slow speed for
complete swelling of hydroxyethyl cellulose, until a transparent gel was formed.
3.2. The pH of the gel formed in step 3.1 was adjusted with 0.1N hydrochloric Acid
and was stirred continuously under vacuum to obtain a uniform gel free of entrapped
air.
EXAMPLE 3: Skin Permeation Study with amorolfine hydrochloride gel formulation
In-vitro release testing (IVRT) study was performed to compare the skin permeability of topical gel composition of amorolfine hydrochloride with currently marketed amorolfine hydrochloride topical cream compositions. In vitro permeation of amorolfine hydrochloride from topical gel compositions was performed using Franz diffusion cell method by utilizing a nylon membrane having a pore diameter of 0.45 µ and a receptor solution of methanol and a buffer solution having pH of about 3.0. Permeability data obtained from amorolfine hydrochloride cream 0.25% was compared with data derived from exemplary compositions according to the present invention (e.g., amorolfine hydrochloride gel 0.25%) as shown in table 3.
Table 3: Comparison of skin permeability of gel formulation versus cream formulations:

Time (Hr) Amorolfine Gel
0.25% w/w (% Release) Amorolfine Cream
0.25% w/w
FUNGICROS
(% Release) Amorolfine Cream
0.25% w/w
LIVAFIN
(% Release) Amorolfine Cream
0.25% w/w
AMROLMAC
(% Release)
0.5 62.7 2.4 4.9 4.4
1 81.8 3.4 7.7 7.9
2 88.3 6.2 11.4 12.0
3 86.3 8.2 13.2 14.9
4 84.3 9.4 15.5 18.0
As it is apparent from the data shown in Table 3, the rate and extent of permeation of amorolfine hydrochloride achieved from amorolfine hydrochloride 0.25% gel was greater than that achieved from amorolfine hydrochloride cream 0.25%.

I/We claim:
1. A topical gel pharmaceutical composition, for the treatment of nails or skin fungal
disease, comprising:
(a) amorolfme hydrochloride;
(b) at least one polymeric gelling agent;
(c) a solvent system comprising a mixture of a polyol and water;
(d) at least one acidifying agent;
(e) a preservative and optionally one or more of a pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1, wherein amorolfme is present in an amount from about 0.1% to about 5%, by weight of the composition.
3. The pharmaceutical composition of claim 1, wherein at least one polymeric gelling agent is hydroxyethyl cellulose.
4. The pharmaceutical composition of claim 1, wherein at least one polymeric gelling agent is present in an amount from about 0.5% to about 5% by weight of the composition.
5. The pharmaceutical composition of claim 1, wherein polyol is selected from ethoxydiglycol, and propylene glycol.
6. The pharmaceutical composition of claim 1, wherein at least one acidifying agent is selected from hydrochloric acid, sulfuric acid, o-phosphoric acid, nitric acid, acetic acid, and lactic acid.
7. The pharmaceutical composition of claim 1, wherein preservative is selected from sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea, or

diazolidinyl urea, benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride, chlorobutanol; esters of parahydroxybenzoic acid.
8. A topical gel composition, comprising:
(a) about 0.25% by weight of amorolfine hydrochloride;
(b) about 2% by weight of hydroxyethyl cellulose;
(c) a solvent system comprising a mixture of about 15% to about 40% by weight of propylene glycol and about 60% by weight of water;
(d) about 0.25% by weight of hydrochloric acid;
(e) about 1% by weight of phenoxyethanol and other optional pharmaceutically acceptable excipients.
9. A method of treating a nail or skin fungal disease, which comprises applying to
the surface of the nail or skin a topical gel composition according to claim 8.
10. The method of claim 9, wherein the nail disease is onychomycosis.