KR20000059789A - dermal pharmaceutical composition of antifungal agent and process for the preparation thereof - Google Patents

Abstract

PURPOSE: An antifungal pharmaceutical composition for external application is provided which has an excellent skin permeability and also, a producing method thereof is provided. CONSTITUTION: The antifungal pharmaceutical composition for external application contains emulsion concentrate comprising 0.1 to 10 wt.% of antifungal agent, 0.1 to 30 wt.% of biphilic solvent having 100 deg. C or higher boiling point, 1 to 40 wt.% of surfactant and 1 to 40 wt.% of oil; hydrogel comprising 0.1 to 10 wt.% of gelation agent and 0.1 to 90 wt.% of purified water; and 0.01 to 5 wt.% of alkalifying agent, in which antifungal agent is butenafine-HCl, naftifine-HCl, terbinafine-HCl, and biphilic solvent is diethyleneglycol monoethylether, dimethylisosorbid, N-methyl-2-pyrrolidine, 1,2-propyleneglycol or propylenecarbonate. The method for producing antifungal pharmaceutical composition comprises the steps of: preparing emulsion pre-concentrate by mixing antifungal agent, biphilic solvent, surfactant, and oil; producing hydrogel by adding gelation agent into purified water; and mixing emulsion pre-concentrate and hydrogel and adding alkalifying agent to adjust pH.

Description

External pharmaceutical composition of antifungal agent and preparation method thereof

The present invention relates to a novel external pharmaceutical composition containing a poorly soluble antifungal agent as an active ingredient and a method for preparing the same.

Antifungal agents currently widely used include allylamine antifungal agents such as butenapine-hydrochloric acid (Butenafine-HCl), naphtipine-hydrochloric acid (Naftifine-HCl), terbinafine-hydrochloric acid (Terbinafine-HCl); Imidazole antifungal agents such as betoconazole nitrate, clotrimazole, econazol nitrate, ketoconazole, myconazole nitrate and oxyconazole nitrate; And triazole-based antifungal agents such as itraconazole and fluconazole, which have poor solubility in water.

These drugs are conventionally prepared as solid preparations and orally administered and have clinically excellent effects, but problems such as systemic side effects and gastrointestinal irritation occur when prolonged administration.

In order to enhance the efficacy of topical lesions without causing side effects of such oral administration, recent attempts have been made to formulate these drugs into external preparations. Solvents have been used to dissolve poorly soluble antifungal agents in the external preparations, and examples thereof include WO 9516465, EP 515310, EP 503988, and the like. The use of such a dissolving agent has improved the conventional solubility problem by formulating a poorly soluble antifungal agent in a dissolved state, but this external preparation does not have an effective absorption of the drug into the skin and thus has no antifungal effect. There is a fear that low boiling alcohol is volatilized and the composition is changed at the time of administration.

Accordingly, an object of the present invention is to provide an antifungal drug composition for external use that has no side effects of oral administration and has excellent solubility and skin permeability of the drug.

It is another object of the present invention to provide a method for producing the composition.

1 is a graph showing the transdermal permeation test results of the external preparation and the control drug ramisyl cream according to the present invention.

According to the above object, in the present invention

(A) an emulsion preconcentrate consisting of an antifungal agent as an active ingredient, an amphiphilic solvent having a boiling point of 100 ° C. or higher as an auxiliary solvent, a surfactant and an oil;

(B) a hydrogel consisting of a gelling agent and purified water; And

(C) It provides an antifungal drug composition for external use, comprising an alkalizing agent which is a pH adjusting agent.

In addition, in the present invention

(A) an emulsion preconcentrate is prepared by mixing an antifungal agent as an active ingredient, an amphiphilic solvent having a boiling point of 100 ° C. or higher as an auxiliary solvent, a surfactant and an oil;

(B) adding a gelling agent to purified water to prepare a hydrogel;

(C) It provides a method for producing an antifungal drug composition for external use comprising mixing (A) and (B) and adjusting the pH by adding an alkalizing agent.

Hereinafter, the present invention will be described in detail.

The composition of the present invention is an oil-based hydrogel in which an emulsion containing an antifungal agent as an active ingredient is uniformly dispersed in a hydrogel in a particulate state, and an oily emulsion containing the same has an excellent ability to dissolve antifungal agents as an auxiliary solvent. It is characterized by the use of an amphiphilic solvent having a boiling point of 100 ° C. or higher, which allows it to be uniformly dispersed in the.

Hereinafter, the characteristic and the kind of each component used for the composition of this invention are demonstrated.

(1) antifungal agents

As the active ingredient used in the composition of the present invention, any poorly soluble antifungal agent can be used. For example, allylamine antifungal agents, such as butenapine-hydrochloric acid, naphthypine-hydrochloric acid, terbinaphine-hydrochloric acid; Imidazole antifungal agents such as betoconazole nitrate, clotrimazole, econazol nitrate, ketoconazole, myconazole nitrate and oxyconazole nitrate; And triazole-based antifungal agents such as itraconazole and fluconazole, and allylamine antifungal agents are preferable. The active ingredient in the composition of the present invention is used in an amount of 0.1 to 10% by weight based on the total weight of the composition, 0.5 to 5% by weight is preferred.

(2) amphiphilic solvent

Cosolvents that can be used in the compositions of the present invention are amphiphilic (both hydrophilic and lipophilic) solvents having a boiling point of 100 ° C. or higher, and any solvent can be used as long as the oily emulsion can be easily dispersed in the hydrogel. . The amphiphilic solvent not only provides the solubility suitable for formulation to the active ingredient, but also has both amphiphilic and lipophilic properties in terms of physical properties, thus aiding in emulsification of the formulation, and thus the active ingredient is uniformly dispersed in the hydrogel. Unlike lower alcohols, which are highly volatile, they have a boiling point higher than 100 ° C, so they do not change over time during formulation and storage, and provide the advantage of ensuring uniformity of the composition. There is no dual effect of maintaining a constant composition and increasing the solubility of the active ingredient. Amphiphilic solvents that meet these objectives include transcutol (diethylene glycol monoethyl ether, boiling point = 196 ° C), dimethylisosorbide (boiling point = 234 ° C), and N-methyl-2-pyrrolidone (boiling point). = 202 ° C), 1,2-propylene glycol (boiling point = 188 ° C) and propylene carbonate (boiling point = 242 ° C), each of which can be used alone or in combination. Of these, propylene carbonate is preferred. Amphiphilic solvents in the compositions of the present invention are used at 0.1 to 30% by weight based on the total weight of the composition, with 1 to 20% by weight being preferred.

(3) surfactant

Surfactants used in the present invention are pharmaceutically acceptable anionic, cationic, nonionic or amphoteric interfaces which stably emulsify lipophilic oil components and amphiphilic solvents in hydrogels to form uniform emulsions. Various surfactants can be used, including active agents.

Specifically, for example (i) the reaction product of natural or hydrogenated vegetable oil with ethylene glycol, ie polyoxyethylene glycolated natural or hydrogenated vegetable oil, for example polyoxyethylene glycolated natural or hydrogenated castor oil (Brand name: Cremophor, a manufacturer: BASF),

(ii) polyoxyethylene-sorbitan-fatty acid esters, ie esters of mono or trilauryl, palmityl, stearyl or oleyl (trade name: Tween, manufacturer: ICI),

(iii) polyoxyethylene fatty acid esters, ie polyoxyethylene stearic acid ester (trade name: Myrj, manufacturer: ICI),

(iv) polyoxyethylene-polyoxypropylene block copolymer (trade name: Poloxamer, manufactured by BASF),

(v) sodium dioctylsulfosuccinate or sodium lauryl sulfoate,

(vi) phospholipids,

(vii) propylene glycol mono or di-fatty acid esters, such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinolate or trade name migliol Propylene Glycol Caprylic-Capric Acid Diester, marketed as 840 (Miglyol 840, manufactured by Huls),

(viii) trans-esterification products of natural vegetable oil triglycerides with polyalkylene polyols (trade name: Labrafil M, manufactured by Gattefosse),

(ix) sorbitan fatty acid esters such as sorbitan monolauryl, sorbitan monopalmityl, sorbitan monostearyl, and the like sold under the trade name Span.

Among them, the polyoxy of the vegetable oil marketed under the trade name Cremophor (BASF), the esterification product of the natural vegetable oil and the polyoxyethylene glycol marketed under the trade name Labrafil (Gattefosse) Ethylene products, fatty acid esters of sorbitan sold under the trade name Span (ICI), and the like. In the composition of the present invention, the surfactant is used at 1 to 40% by weight based on the total weight of the composition, with 2 to 25% by weight being preferred.

(4) oil

Oils that can be used in the present invention can be selected as long as they have a good ability to dissolve antifungal agents and are suitable for emulsifying the formulation. Intermediate fatty acid triglycerides such as for example caprylic acid / capric mono, diglycerides, caprylic acid / capric triglycerides; Corn oil, coconut oil, cotton seed oil, soybean oil, rapeseed oil, safflower oil, sunflower oil, castor oil Natural vegetable oils); And animal oils such as fish oil. Preferred is a double caprylic acid / capric mono, diglyceride mixture (trade name: Capmul MCM, manufactured by Abitec). In the compositions of the present invention the oil is used at 1 to 40% by weight, based on the total weight of the composition, with 2 to 25% by weight being preferred.

(5) gelling agent

In the composition of the present invention, any gelling agent may be used as an additive capable of forming a gel by contact with water, and generally hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium-carboxymethylcellulose Cellulose derivatives such as (Na-CMC), carboxyvinyl polymer (trade name: Carbopol, BF Goodrich Chemical), polyoxyethylene-polyoxypropylene copolymer (trade name: Pluronic, manufacturer: BASF ), Of which carboxyvinyl polymer is preferred. The gelling agent in the composition of the present invention is used at 0.1 to 10% by weight, based on the total weight of the composition, 0.1 to 5% by weight is preferred.

(6) purified water

As the purified water in the composition of the present invention, water of a pharmaceutically acceptable grade is used. Purified water in the composition of the present invention is used at 0.1 to 90% by weight, based on the total weight of the composition, 30 to 80% by weight is preferred.

(7) alkalizing agent

The alkalizing agent for adjusting pH suitably is added to the composition of this invention. The pH value of the composition of the present invention may vary depending on the type of the ingredient added to the composition, especially the antifungal agent, which is the active ingredient, but generally a pH range of 3 to 9 is preferred. The alkalizing agent for pH adjustment includes inorganic alkaline substances such as Na ₂ HPO ₄ , NaHCO ₃ , Na ₂ CO ₃ , NaOH; And organic alkaline substances such as amines such as amino acids and triethanolamines. In the present invention, the alkalizing agent is used at 0.01 to 5% by weight based on the total weight of the composition, preferably 0.01 to 3% by weight.

In addition, a preservative can be added to the composition of this invention within the range which does not impair the effect of this invention. As the preservative, any component having a pharmaceutically acceptable preservative may be used, for example benzyl alcohol, parabens, sodium benzoate, and the like.

The composition according to the invention can be prepared as follows.

First, an antifungal agent as an active ingredient is dissolved in an amphiphilic solvent, and then a surfactant and an oil are added thereto and mixed to prepare an emulsion preconcentrate (A). In addition, the gelling agent is added to purified water and uniformly stirred to dissolve to prepare a hydrogel (B). The emulsion preconcentrate (A) and the hydrogel (B) are mixed to obtain an emulsion, and an alkalizing agent is added thereto to adjust to the desired pH range to prepare an oil-based hydrogel formulation containing the emulsion according to the present invention.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1

The homogenous emulsion preconcentrate was prepared by mixing and dissolving the component (A) having the following composition.

(A) emulsion preconcentrate

Terbinafine Hydrochloride 10mg

Propylene Carbonate 21mg

Cremophor EL 21mg

Labrafil M 1944 CS 83.8mg

Span 80 21mg

Caprylic Acid / Capric Triglycerides 42mg

Caprylic Acid / Capric Mono, Diglycerides 21mg

Castor Oil 73mg

Benzyl Alcohol 15.7mg

On the other hand, Carbopol 934 and the preservatives described in (B) was uniformly dissolved in purified water to prepare a hydrogel.

(B) hydrogel

Carbopol 940 10.5mg

670mg of purified water

Methyl paraben 0.5 mg

Subsequently, 10.5 mg of triethanolamine, an alkalizing agent, was added to the emulsion preconcentrate and hydrogel, which were mixed and homogeneously stirred, to adjust the pH to about 5.8 to prepare an emulsion-containing hydrogel.

Example 2

An oily hydrogel containing an emulsion was prepared in the same manner as in Example 1 using the following ingredients.

(A) emulsion preconcentrate

Terbinafine Hydrochloride 10mg

20 mg of propylene carbonate

Cremophor EL 20mg

Labrafil M 1944 CS 100mg

Caprylic Acid / Capric Mono, Diglycerides 70mg

Castor Oil 70mg

Benzyl Alcohol 10mg

(B) hydrogel

Carbopol 940 10mg

680mg of purified water

Sodium benzoate 0.15mg

(c) alkalizing agent

Triethanolamine 10mg

Example 3

An oily hydrogel containing an emulsion was prepared in the same manner as in Example 1 using the following ingredients.

(A) emulsion preconcentrate

Ketoconazole 20mg

Propylene Carbonate 30mg

Cremophor EL 20mg

Labrafil M 1944 CS 80mg

Span 80 20mg

Caprylic Acid / Capric Triglyceride 40mg

Caprylic Acid / Capric Mono, Diglycerides 40mg

Castor Oil 70mg

Benzyl Alcohol 10mg

(B) hydrogel

Carbopol 940 10mg

650 mg of purified water

Sodium benzoate 0.15mg

(c) alkalizing agent

Triethanolamine 10mg

Example 4

An oily hydrogel containing an emulsion was prepared in the same manner as in Example 1 using the following ingredients.

(A) emulsion preconcentrate

Econazol Nitrate 10mg

Methyl Pyrrolidone 50mg

Cremophor EL 30mg

Labrafil M 1944 CS 90mg

Caprylic Acid / Capric Triglyceride 50mg

Caprylic Acid / Capric Mono, Diglycerides 60mg

Benzyl alcohol 10mg

(B) hydrogel

Carbopol 940 10mg

680mg of purified water

Sodium benzoate 0.15mg

(c) alkalizing agent

Triethanolamine 10mg

Example 5

An oily hydrogel containing an emulsion was prepared in the same manner as in Example 1 using the following ingredients.

(A) emulsion preconcentrate

Terbinafine Hydrochloride 10mg

Transcutol 20mg

Cremophor EL 20mg

Labrafil M 1944 CS 80mg

Tween 20 20mg

Caprylic Acid / Capric Triglyceride 50mg

Caprylic Acid / Capric Mono, Diglycerides 50mg

Castor Oil 40mg

Benzyl Alcohol 10mg

(B) hydrogel

Carbopol 940 10mg

680mg of purified water

Sodium benzoate 0.15mg

(c) alkalizing agent

Triethanolamine 10mg

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

In order to measure the skin permeability of the external preparations according to the present invention, an in vitro transdermal penetration test was conducted using a hairless mouse as follows. In this test, an external preparation prepared in Example 1 was used as a test formulation, and a commercial lamisil cream (Novatis Co., Ltd.) was used as a control formulation.

The hairless mouse (5 weeks old, male) was anesthetized by subcutaneous injection of a 20% urethane solution in an amount of 1.2 g / kg, and then the skin of the abdomen was cut out to obtain a Franz cell (r = 0.75 cm, a receiver volume of 11 ml). Used as a membrane, 0.01M sodium chloride solution was used as the receiver solution. The topical preparation or lamisil cream prepared in Example 1 was applied on the skin of a hairless mouse with a corresponding amount of terbinapine-hydrochloric acid (4 mg), and then, after 24 hours under a condition of 600 rpm, 300 μl of a solution of the terbinafine hydrochloride was obtained. Was measured. In addition, the skin tissue was washed well with physiological saline, homogeneously pulverized with methanol, and the extracted methanol solution was dried, and then dissolved in 500 µl of mobile phase and subjected to high pressure liquid chromatography (HPLC) to analyze the terbinaphine-hydrochloric acid concentration. HPLC conditions used in this analysis are as follows.

Column-Cosmosil C ₁₈ (5 μm, 4.6 mm x ₁₅ cm)

Detector-UV 280nm

Mobile Phase-Acetonitrile: Tetrahydrofuran: pH 7.8 Phosphate Buffer = 65:10:25

Flow rate-2.0 ml / min

Injection volume-20 μl

The result is shown in FIG. As shown in FIG. 1, the intradermal concentration of terbinapine-hydrochloric acid after 24 hours of the external preparation prepared in Example 1 is about 2 times higher than that of the commercially available lamisil cream.

On the other hand, the concentration of terbinafine-hydrochloric acid in the receiver solution was very slight below the quantitative sensitivity of the assay in both the external preparation prepared in Example 1 and the commercially available lamisil cream. Therefore, it can be seen that the poorly soluble antifungal agent is not penetrated until absorbed into the skin until the water-soluble receptor solution.

The antifungal drug composition for external use of the present invention has an excellent transdermal permeability by using an amphiphilic solvent having a boiling point of 100 ° C. or higher as an auxiliary solvent and allows the antifungal agent to reach the skin effectively.

Claims (9)

(A) an emulsion concentrate consisting of an antifungal agent as an active ingredient, an amphiphilic solvent having a boiling point of 100 ° C. or higher as an auxiliary solvent, a surfactant, and an oil; (B) a hydrogel consisting of a gelling agent and purified water; And (C) An antifungal drug composition for external use, comprising an alkalizing agent which is a pH adjusting agent. The method of claim 1, 0.1 to 10% by weight of the antifungal agent, 0.1 to 30% by weight of amphipathic solvent, 1 to 40% by weight of surfactant, 1 to 40% by weight of oil, 0.1 to 10% by weight of gelling agent, and 0.1 to 10% by weight, based on the total weight of the composition 90 wt% and 0.01-5 wt% of an alkalizing agent. The method according to claim 1 or 2, The antifungal agent is butenapine-hydrochloric acid, naphthypine-hydrochloric acid, terbinafine-hydrochloric acid, betoconazole nitrate, clotrimazole, echonasol nitrate, ketoconazole, myconazole nitrate, oxyconazole nitrate, itraconazole or fluconazole. Composition. The method according to claim 1 or 2, Wherein said amphiphilic solvent is diethylene glycol monoethyl ether, dimethylisosorbide, N-methyl-2-pyrrolidone, 1,2-propylene glycol or propylene carbonate. The method according to claim 1 or 2, The surfactant may be a reaction product of natural or hydrogenated vegetable oil with ethylene glycol, polyoxyethylene-sorbitan-fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, sodium dioctylsulfosuccinate, A composition characterized in that it is a sodium uric acid sulfoate, phospholipid, propylene glycol mono or di-fatty acid ester, a trans-esterification reaction product of a natural vegetable oil triglyceride with a polyalkylene polyol or sorbitan fatty acid ester. The method according to claim 1 or 2, Wherein said oil component is caprylic acid / capric mono, diglyceride. The method according to claim 1 or 2, Wherein said gelling agent is a cellulose derivative, a carboxyvinyl polymer or a polyoxyethylene-polyoxypropylene copolymer. The method according to claim 1 or 2, Wherein said alkalizing agent is triethanolamine. (A) an emulsion preconcentrate is prepared by mixing an antifungal agent as an active ingredient, an amphiphilic solvent having a boiling point of 100 ° C. or higher as an auxiliary solvent, a surfactant and an oil; (B) adding a gelling agent to purified water to prepare a hydrogel; (C) mixing the emulsion preconcentrate prepared in (A) and the hydrogel prepared in (B) and adjusting the pH by adding an alkalizing agent, the method for producing an antifungal drug composition for external use.