WO2012070798A2

WO2012070798A2 - Topical antifungal composition comprising terbinafine or its salt

Info

Publication number: WO2012070798A2
Application number: PCT/KR2011/008684
Authority: WO
Inventors: Min-Ah Sung; Dong-Hun Lee; Mi-Young Kim; Yoong-Sik Park
Original assignee: Yuhan Corp
Current assignee: Yuhan Corp
Priority date: 2010-11-24
Filing date: 2011-11-15
Publication date: 2012-05-31
Anticipated expiration: 2013-05-24
Also published as: KR20120056314A; WO2012070798A3

Abstract

The present invention provides a topical antifungal having excellent properties in skin penetration and retention in the skin. Specifically, the present invention provides a topical antifungal composition comprising terbinafine or its salt; a film-forming agent; a solvent; and one or more selected from the group consisting of urea, 1-dodecylurea, and 1,3-didodecylurea as an agent for increasing retention of terbinafine or its salt in an applied skin.

Description

TOPICAL ANTIFUNGAL COMPOSITION COMPRISING TERBINAFINE OR ITS SALT

The present invention relates to a topical antifungal composition comprising terbinafine or its salt as an active ingredient, which has excellent properties in both skin penetration and retention in the skin.

As antifungal agents, there are widely used allylamine derivatives such as butenafine hydrochloride, naftifine hydrochloride, and terbinafine hydrochloride; imidazole derivatives such as veroconazole nitrate, clotrimazole, econazole nitrate, ketoconazole, miconazole nitrate, and oxiconazole nitrate; and triazole derivatives such as itraconazole and fluconazole in clinical application. Among them, terbinafine, one of the allylamine derivatives, is very useful against the dermatophytes causing fungal infection, through forming colonies in keratinous tissues such as stratum corneum, nail (or toenail), and hair. Most of antifungal agents including terbinafine, are sparingly soluble in water and thus have very low water-solubility.

Generally, the antifungal agents are used in forms of a solid formulation for oral administration or a topical formulation for external application. In designing a topical antifungal formulation for external application, it is necessary both to improve the low water-solubility of an antifungal agent (e.g., terbinafine) and to increase skin penetration thereof, for accomplishing a desired efficacy. For example, the prior arts such as WO 95/16465 and EP 515,310, and EP 513,988 have disclosed solubilization of active ingredients using a certain solubilizing agent. And also, WO 02/062336 has disclosed a formulation for external use comprising fluconazole and a base material, in which fluconazole is solublized by using fatty acid, fatty alcohol, higher fatty acid ester or lower alcohol. In addition, US 5,262,150 has disclosed an antifungal composition in the form of a dry powder spray, which comprises an antifungal agent (e.g., terbinafine), a noncyclized silicone polymer, and a propellant, in an aerosol container. Both US 6,005,001 and US 6,455,592 also disclosed the use of a solubilizing agent for improving the water-solubility of terbinafine.

Meanwhile, conventional topical antifungal formulations for external application are applied once or twice daily for treating the infection. However, since these topical antifungal formulations require a treatment regimen over one to several weeks, fully complying with the regimen to a successful treatment is difficult (i.e., the conventional formulations show very low drug compliance) and premature terminations of the treatment are common. In order to address the problem of drug compliance, WO 07/039533 has disclosed a topical antifungal composition comprising an antifungal agent, a film-forming agent, and a solvent. When the topical antifungal composition is applied on the skin, it can stay the antifungal agent (e.g., terbinafine) on the skin for at least 48 hours, thereby treating fungal infections in the skin. The film-forming agent includes acrylate polymers, acrylate copolymers, alkyl olefinic acid, alkyl olefinic acid ester copolymers, amide/olefinic acid, amide/olefinic acid copolymers, polyvinyl acetate, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, hydroxyalkyl cellulose, alkyl cellulose, etc. The composition according to WO 07/039533 may improve the patients' drug compliance. However, since the release of drug from the film-forming agent (e.g., acrylate-based film forming agents) is not easy, the absorption of drug into the skin tissue is limited and the skin penetration at early phase is very low. In addition, the amount deposited in the skin is very low, thereby showing unsatisfactory antifungal effect.

In addition, WO 10/110518 has disclosed an antifungal composition improving skin penetration using a silicon-based film-forming agent such as trimethylsiloxysilicate.

The present invention provides a topical formulation for external application, which is capable of maintaining efficacy for long duration so as to improve patients' drug compliance, and also which is capable of increasing skin penetration as well as the amount of an antifungal agent deposited in the skin so as to show excellent efficacy.

That is, it is an object of the present invention to provide a topical antifungal composition having excellent properties in skin penetration as well as retention in the skin.

In accordance with an aspect of the present invention, there is provided a topical antifungal composition comprising terbinafine or its salt; a film-forming agent; a solvent; and one or more selected from the group consisting of urea, 1-dodecylurea, and 1,3-didodecylurea as an agent for increasing retention of terbinafine or its salt in an applied skin.

In the topical antifungal composition of the present invention, the agent for increasing retention may be present in an amount ranging from 0.5 to 10 wt% based on the total weigh of the composition.

In an embodiment of the present invention, the salt of terbinafine may be terbinafine hydrochloride.

The film-forming agent may be one or more copolymer selected from the group consisting of a copolymer of methyl vinyl ether and maleic acid, a copolymer of methyl vinyl ether and ethyl maleate, a copolymer of methyl vinyl ether and isopropyl maleate, a copolymer of methyl vinyl ether and butyl maleate, a copolymer of acrylic acid ester and methacrylic acid ester, a copolymer of methacrylic acid and methacrylic acid ester, a copolymer of 2-(dimethylamino)ethyl methacrylate and methacrylic acid ester, a copolymer of 2-(trimethylamino)ethyl methacrylate and methacrylic acid ester, and a copolymer of octyl acrylamide , butylaminoethyl methacrylate, and acrylate. Preferably, the film-forming agent may be one or more copolymer selected from the group consisting of a copolymer of methyl vinyl ether and maleic acid, a copolymer of methyl vinyl ether and ethyl maleate, a copolymer of methyl vinyl ether and isopropyl maleate, and a copolymer of methyl vinyl ether and butyl maleate. The film-forming agent may be present in an amount ranging from 1 to 20 wt% based on the total weigh of the composition.

And also, the solvent may be ethanol or an ethanol solution, the ethanol or the ethanol solution containing 1 to 10 wt% of glycerin or propylene glycol based on the total weigh of the composition.

The composition may be in a form of gel, cream, lotion, solution, or ointment.

The topical antifungal composition according to the present invention can remarkably increase the penetration of terbinafine or its salt into the skin, especially skin penetration thereof at the early phase, while minimizing any skin irritation through avoiding the use of a surfactant. In addition, the topical antifungal composition according to the present invention can increase the amount of terbinafine or its salt deposited in the skin remarkably (e.g., more than about 3 to 6 times in comparison with conventional formulations), thereby expecting excellent efficacy. And also, the use of a certain copolymer, e.g., methyl vinyl ether-containing copolymers, as a film-forming agent makes it possible to effectively increase the release of terbinafine or its salt from the composition. Therefore, the topical antifungal composition according to the present invention is capable of maintaining efficacy for long duration (e.g., at least for 48 hours, preferably at least for 72 hours, by single application), thereby improving patients' drug compliance and expecting excellent efficacy.

FIG. 1 shows results of the transdermal penetration test performed with the antifungal formulation of the present invention (Example 1) and the control formulation (Lamisil Once^®).

The present invention provides a topical antifungal composition comprising terbinafine or its salt; a film-forming agent; a solvent; and one or more selected from the group consisting of urea, 1-dodecylurea, and 1,3-didodecylurea as an agent for increasing retention of terbinafine or its salt in an applied skin.

The composition according to the present invention is a unit dosage form capable of convenient long-term therapy and has high efficacy in curing or treating fungal infection in the skin, which makes it possible to increase patients' drug compliance.

Said urea, 1-dodecylurea, and/or 1,3-didodecylurea which are used as an agent for increasing retention of terbinafine or its salt in an applied skin (hereinafter, also referred to "a skin-retaining agent"), in the composition according to the present invention, can make the stratum corneum softer so as to facilitate the penetration of the active ingredient, thereby not only reducing retardation time during the skin penetration of the drug but also increasing the amount of the drug deposited in the skin. And also, since the composition of the present invention can avoid using penetration enhancers such as a surfactant (they are known to induce irritation to the skin), the composition of the present invention can minimize any potential skin irritation. Further, through skin-moisturizing effect of the skin-retaining agent, it is possible to additionally minimize any potential skin irritation by the composition. Therefore, in an embodiment, the composition of the present invention may be a surfactant-free topical antifungal composition comprising terbinafine or its salt; a film-forming agent; a solvent; and one or more selected from the group consisting of urea, 1-dodecylurea, and 1,3-didodecylurea as an agent for increasing retention of terbinafine or its salt in an applied skin.

In the topical antifungal composition of the present invention, the skin-retaining agent may be present in an amount ranging from 0.5 to 10 wt%, preferably from 0.75 to 7 wt%, more preferably from 1 to 5 wt%, most preferably from 2 to 4 wt%, based on the total weigh of the composition.

The salt of terbinafine includes any pharmaceutically acceptable salts thereof, such as terbinafine hydrochloride, terbinafine lactate, terbinafine ascorbate, etc. Preferably, the salt of terbinafine may be terbinafine hydrochloride. Terbinafine or its salt may be present in a therapeutically effective amount in the composition of the present invention. For example, terbinafine or its salt may be present in an amount ranging from 0.5 to 30 wt%, preferably from 0.75 to 20 wt%, more preferably from 0.9 to 15 wt%, most preferably from 1 to 10 wt%, based on the total weigh of the composition.

The film-forming agent may be one or more copolymer selected from the group consisting of a copolymer containing methyl vinyl ether; a copolymer containing methacrylate; and a copolymer containing octylacrylamide, butylaminoethyl methacrylate, and acrylate (e.g., Amphomor^TM). The copolymer containing methyl vinyl ether includes a copolymer of methyl vinyl ether and maleic acid (e.g., Gantrez AN^TM), a copolymer of methyl vinyl ether and ethyl maleate (e.g., Gantrez ES 225^TM), a copolymer of methyl vinyl ether and isopropyl maleate (e.g., Gantrez ES 335^TM), a copolymer of methyl vinyl ether and butyl maleate (e.g., Gantrez ES 425^TM), etc. The copolymer containing methacrylate includes a copolymer of acrylic acid ester and methacrylic acid ester (e.g., Dialhole EX-55t^TM), a copolymer of methacrylic acid and methacrylic acid ester (e.g., Eudragit L^TM or Eudragit S^TM), a copolymer of 2-(dimethylamino)ethyl methacrylate and methacrylic acid ester (e.g., Eudragit E^TM), a copolymer of 2-(trimethylamino)ethyl methacrylate and methacrylic acid ester (e.g., Eudragit RL^TM or Eudragit RS^TM), etc.

It is newly found by the present invention that, when compared to copolymers containing acrylate, the above-described film-forming agents (i) are less sticky to the skin, (ii) form a flexible film layer having excellent skin-adhesibility and elasticity when applied on the skin, (iii) show excellent solubilization of the active ingredient, (iv) are able to increase the release rate and the amount of penetration, and (v) provide a reservoir of the drug (i.e., terbinafine or its salt) available to achieve an antifungal effect for long duration.

In addition, it is found that the polymers having polyurethane and carboxylic acid functional group (the polymers are obtained by addition polymerization) show very low adhesibility to the skin. However, it is found by the present invention that, when the above-described film forming agent are used, the resulting film is strongly adhered to the skin, thereby being able to stay for a required period of time even when exposed to typical hygienic cleaning cycles. Among the above-described film-forming agents, a copolymer containing methyl vinyl ether may be preferably used. More preferably, the film-forming agent used in the present invention may be one or more copolymer selected from the group consisting of a copolymer of methyl vinyl ether and maleic acid, a copolymer of methyl vinyl ether and ethyl maleate, a copolymer of methyl vinyl ether and isopropyl maleate, and a copolymer of methyl vinyl ether and butyl maleate.

The film-forming agent may be present in an amount ranging from 1 to 20 wt%, preferably from 1 to 10 wt%, more preferably from 3 to 7 wt%, based on the total weigh of the composition. When the amount of the film-forming agent is less than 1 wt% of the total weight of the composition, it may be difficult to form a film layer on the skin. And also, when the amount of the film-forming agent exceeds 20 wt% of the total weight of the composition, drying the resulting film may be delayed so as to cause unpleasant feeling of application.

In the topical antifungal composition of the present invention, any solvent may be used as long as it can solubilize or suspend terbinafine or its salt, is compatible with the skin-retaining agent, and is easily evaporable when applied on the skin. For example, the suitable solvent includes a lower alcohol such as ethanol, isopropyl alcohol, methanol, etc; a polyhydric alcohol such as propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin, hexylene glycol, polyethylene glycol, etc; and a mixture thereof. Preferably, the solvent may be ethanol or an ethanol solution (e.g., 95 wt% ethanol solution), optionally further comprising one or more polyhydric alcohols, for example propylene glycol and/or glycerin. Preferably, the solvent may be ethanol or an ethanol solution, the ethanol or the ethanol solution containing 1 to 10 wt% of polyhydric alcohol (glycerin or propylene glycol) based on the total weigh of the composition. In an embodiment, the solvent may be a mixed solvent containing propylene glycol and/or glycerin in an amount ranging from 1 to 10 wt%, preferably about 3 wt%, based on total weigh of the composition, in 95 wt% ethanol solution as a major solvent. The propylene glycol and/or glycerin also function as an agent to facilitate both forming a film and increasing penetration of the drug.

The topical antifungal composition of the present invention may further comprise one or more conventional excipients used in the field of pharmaceutics. For example, the excipients include, but not limited to, a thickening agent such as hydroxypropyl cellulose, ethyl cellulose, polyvinylpyrrolidone, etc; a refreshing agent such as menthol or its derivatives, terpenes (e.g., limonene); and an antioxidant.

The topical antifungal composition of the present invention may be applied to external area (i.e., skin) of the human body except for nail (or toenail) and cornea.

The antifungal composition of the present invention may be formulated to a suitable topical dosage form for external application, for example to a form of gel, cream, lotion, solution, or ointment; preferably to a form of solution. The topical antifungal composition of the present invention may be topically applied to the infected skin area with single administration, or with multiple administrations if necessary. After the topical application, the antifungal activity thereof may be maintained for at least 72 hours.

The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Examples 1 to 6

Antifungal formulations for external application in the form of solution were prepared according to the components and amounts shown in Table 1. The amounts of Table 1 represent % by weight (wt%) of each components. The film-forming agent was dissolved in 95 wt% ethanol to obtain a solution. And then, the remaining components were completely dissolved in the previously obtained solution, to obtain the antifungal formulations for external application in the form of solution.

Table 1

	Component	Example
	Component	1	2	3	4	5	6
Active ingredient	Terbinafine hydrochloride	1.125	1.125	1.125	1.125	1.125	1.125
Film-forming agent	Copolymer of methyl vinyl ether and ethyl maleate (Gantrez ES 225^TM)	3.00	5.00	-	10.0	-	5.00
	Copolymer of methyl vinyl ether and maleic acid (Gantrez AN^TM)	-	-	5.00	-	-	-
	Copolymer of 2-(dimethylamino)ethyl methacrylate and methacrylic acid ester (Eudragit E^TM)	-	-	-	-	5.00	-
Skin-retaining agent	Urea	2.00	2.00	2.00	1.00		2.00
Skin-retaining agent	1-Dodecyl urea	-	-	-	-	2.00	-
Solvent(Co-solvent)	95 wt% Ethanol	87.375	85.375	81.375	76.375	81.375	85.075
	Glycerin	3.00	-	3.00	3.00	3.00	-
	Propylene glycol	-	3.00	-	-	-	3.00
Excipient	Hydroxypropyl cellulose	2.50	2.50	1.50	2.50	1.50	2.80
	Ethyl cellulose	-	-	5.00	-	5.00	-
	Polyvinylpyrrolidone	-	-	-	5.00	-	-
	L-menthol	1.00	1.00	1.00	1.00	1.00	1.00

Comparative Examples 1 and 2

Antifungal formulations for external application in the form of solution were prepared according to the components and amounts shown in Table 2. The amounts of Table 2 represent % by weight (wt%) of each components. The film-forming agent was dissolved in 95 wt% ethanol to obtain a solution. And then, the remaining components were completely dissolved in the previously obtained solution, to obtain the antifungal formulations for external application in the form of solution.

Table 2

	Component	Comparative Example 1	Comparative Example 2
Active ingredient	Terbinafine hydrochloride	1.125	1.125
Film-forming agent	Copolymer of methyl vinyl ether and ethyl maleate (Gantrez ES 225^TM)	3.00	-
Film-forming agent	Copolymer of octylacrylamide and acrylate(Dermacryl 79^TM)	-	3.50
Solvent(Co-solvent)	95 wt% Ethanol	89.375	89.375
Solvent(Co-solvent)	Glycerin	3.00	2.50
Excipient	Hydroxypropyl cellulose	2.50	2.50
Excipient	L-menthol	1.00	1.00

Experimental Example 1: In vitro skin penetration test using hairless mice

An in vitro skin penetration test was performed on the formulations obtained in Example 1 and Comparative Examples 1 and 2. And also, Lamisil^®Once 1% cutaneous solution (Norvatis AG) was used as a control formulation.

The skins excised from the back area of male hairless mice (5-7 weeks) were used in the test. The penetration amounts and rates were measured using a vertical diffusion cell. The excised fresh skins were inserted between the half-cells. In the donor cells contacted with the stratum corneum, the formulations of Example 1 and Comparative Examples 1 & 2, and the control formulation were respectively applied on 4.9 cm² of each skin surface. Each formulation was applied in the corresponding amount of 500 mg of terbinafine. To the receptor cell contacted with the dermis, 13±3 ml of the medium [40 %(v/v) ethanol solution] was added as a receptor solution. The contents of the receptor cells were stirred at 600 rpm, while maintaining the temperature at 37±0.5 ℃. After 2, 4, 6, 12, 24, 48, and 72 hours from the application, each sample was taken from the receptor cells, and then the same amount of the medium was supplemented thereto. The concentration in each sample was measured with a HPLC and then the amounts of skin penetration per unit area (accumulated amount, ㎍/cm²) and the penetration rates (accumulated rate, ㎍/cm²/hr) were calculated. The HPLC conditions were as follows:

- Column: Capcellpak C18 (4.6 mm x 150 mm, 5㎛)

- Mobile phase: Acetonitrile /pH 7.8 buffer /tetrahydrofuran (65:25:10)

- Flow rate: 2.0 ml/min

- Wavelength: 280 nm

- Injection volumn: 20 ㎕

The results are shown in the following tables 3 and 4. The profiles of the amounts of terbinafine penetrated to the skin according to the formulation of Example 1 and the control formulation are also shown in FIG. 1.

Table 3

Amount of skin penetration (㎍/cm²)

Time (hr)	Control Formulation	Example 1	Comparative Example 1	Comparative Example 2
2	1.86±0.23	101.36±32.98	8.78±2.19	3.17±1.48
4	5.07±2.94	181.05±52.24	37.62±21.02	8.37±3.60
6	17.58±13.08	205.74±54.23	60.00±33.07	16.15±10.08
12	38.12±24.55	276.01±58.70	141.22±49.43	36.68±14.48
24	173.48±52.62	448.65±38.37	307.16±26.03	95.50±21.47
48	217.03±64.33	544.65±133.61	498.02±31.72	184.83±10.93
72	232.73±52.32	656.27±28.50	575.19±25.77	288.88±48.82

Referring to Table 3, it can be seen that the formulation of the present invention shows remarkably higher (more than 55 times) amount of skin penetration for early 2 hours than the control formulation. And also, the formulation of the present invention shows much higher than the control formulation, in terms of the total amount of skin penetration for 72 hours. In addition, it can be seen that, in comparison with the formulations of Comparative Examples 1 and 2, the skin penetration at the early phase are remarkably increased in the solution of the present invention containing the skin retaining agent. Furthermore, it can be also seen that, in comparison with the formulation obtained by using the acrylate-based polymer, the formulation comprising the methyl vinyl ether-containing copolymer shows excellent skin penetration of the active ingredient and releases more active ingredient in continuous releasing manner.

Table 4

Skin penetration rate (㎍/cm²/hr)

Time (hr)	Control Formulation	Example 1	Comparative Example 1	Comparative Example 2
2	0.93	50.68	4.39	1.59
4	1.27	45.26	9.40	2.09
6	2.93	34.29	10.00	2.69
12	3.18	23.00	11.77	3.06
24	7.23	18.69	12.80	3.98
48	4.52	11.35	10.38	3.85
72	3.23	9.11	7.99	4.01

And also, referring to Table 4, it can be seen that the formulation of the present invention remarkably reduces the retardation time of skin penetration, while the control formulation show significant retardation time of skin penetration at the early phase. In addition, it can be seen that the formulation of the present invention shows remarkably faster (more than 55 times) skin-penetration rate for early 2 hours than the control formulation. And, the solution of the present invention also maintains faster skin-penetration rate for 72 hours than the control formulation.

From the above results, it can be seen that the composition of the present invention remarkably reduces the retardation time of skin penetration, thereby resulting in fast deliver of the active ingredient to the applied site. And also, the composition of the present invention can allow to penetrate higher amounts of the active ingredient and to continuously maintain the therapeutic effects thereof.

Experimental Example 2: In vitro skin deposition test using hairless mice

An in vitro skin deposition test was performed on the formulations obtained in Example 1 and Comparative Examples 1 and 2. And also, Lamisil^® Once 1% cutaneous solution (Norvatis AG) was used as a control formulation.

After completing the test of Experimental Example 1, each diffusion area was excised and then washed with a phosphate buffer so as to remove the drug on the skin surface. The stratum corneum layer was peeled off with a slide glass and then the weight of the resulting skin was measured. The resulting skin was cut with scissors into small fragments. The fragments were charged to an eppendorf tube, and then extracted with 2 ml of methanol for 24 hours. The resulting mixture was homogenized 4 times (each for 2-3 minutes) for grinding the skin tissue. The resultant was centrifuged at 12,000 rpm for 5 minutes so as to obtain the supernatant. The concentration of the drug in the supernatant was measured using a HPLC, according to the same method as in Experimental Example 1. The results are shown in Table 5.

Table 5

Amount deposited in the skin (㎍/mL)

Control Formulation	Example 1	Comparative Example 1	Comparative Example 2
32.73 ±14.62	187.14±21.87	60.34±14.42	66.70±5.86

Generally, it is known that dermatophytosis is caused by dermatophytes (e.g., Trichophyton rubrum, Trichophyton mentagrophytes, etc), yeast fungi (e.g., C. Spp., etc) and Aspergillus. The minimum inhibition concentration (MIC) of terbinafine hydrochloride against T. rubrum generally ranges from 0.0015 to 0.006 ㎍/mL. However, against 24% of the identified microorganisms, the MIC thereof is about 32 ㎍/mL. And also, the MIC against C. albicans ranges from 6.25 to 100 ㎍/mL (Antimicrobial agents and chemotherapy, vol.31, No. 9, Sept.1987,p1365-1368, Anais. Braseleiros de Dermatologia, vol.84, No.3, Rio de Janeiro, July.2009)

From the above results of Table 5, it can be seen that the solution of the present invention shows remarkably higher (more than 6 times) amount of skin deposition after 72 hours than the control formulation. Therefore, the formulation of the present invention has sufficient and effective antifungal activity against various microorganisms causing dermatophytosis, through retaining higher amount of the drug in the skin.

Claims

A topical antifungal composition comprising terbinafine or its salt; a film-forming agent; a solvent; and one or more selected from the group consisting of urea, 1-dodecylurea, and 1,3-didodecylurea as an agent for increasing retention of terbinafine or its salt in an applied skin.
The topical antifungal composition of claim 1, wherein the agent for increasing retention is present in an amount ranging from 0.5 to 10 wt% based on the total weigh of the composition.
The topical antifungal composition of claim 1, wherein the salt of terbinafine is terbinafine hydrochloride.
The topical antifungal composition of claim 1, wherein the film-forming agent is one or more copolymer selected from the group consisting of a copolymer of methyl vinyl ether and maleic acid, a copolymer of methyl vinyl ether and ethyl maleate, a copolymer of methyl vinyl ether and isopropyl maleate, a copolymer of methyl vinyl ether and butyl maleate, a copolymer of acrylic acid ester and methacrylic acid ester, a copolymer of methacrylic acid and methacrylic acid ester, a copolymer of 2-(dimethylamino)ethyl methacrylate and methacrylic acid ester, a copolymer of 2-(trimethylamino)ethyl methacrylate and methacrylic acid ester, and a copolymer of octyl acrylamide, butylaminoethyl methacrylate, and acrylate.
The topical antifungal composition of claim 4, wherein the film-forming agent is one or more copolymer selected from the group consisting of a copolymer of methyl vinyl ether and maleic acid, a copolymer of methyl vinyl ether and ethyl maleate, a copolymer of methyl vinyl ether and isopropyl maleate, and a copolymer of methyl vinyl ether and butyl maleate.
The topical antifungal composition of claim 1 or 2, wherein the film-forming agent is present in an amount ranging from 1 to 20 wt% based on the total weigh of the composition.
The topical antifungal composition of claim 1 or 2, wherein the solvent is ethanol or an ethanol solution, the ethanol or the ethanol solution containing 1 to 10 wt% of glycerin or propylene glycol based on the total weigh of the composition.
The topical antifungal composition of claim 1 or 2, wherein the composition is in a form of gel, cream, lotion, solution, or ointment.