JP6634703B2 - External composition - Google Patents

Description

  The present invention relates to an external composition containing an antifungal agent.

  Creams and lotions containing terbinafine hydrochloride are commercially available as remedies for athlete's foot and caterpillar (hereinafter abbreviated as “formulations” as appropriate). The O / W emulsion technology is widely used in creams and lotions because water-soluble drugs and fat-soluble drugs can be mixed in the aqueous phase and the oil phase, and the feeling of use is good.

Trichophyton, which causes athlete's foot and scabies, develops by infesting the stratum corneum of the skin. Therefore, it is effective to efficiently deliver the antifungal agent to the stratum corneum. In addition, when a therapeutic agent is applied to an affected area, the preparation is removed from the skin due to contact with sweat, water, or clothing, and there is a problem that the therapeutic effect is reduced. Therefore, in order to enhance the therapeutic effect of the therapeutic agent, it is important that the antifungal agent, which is an active ingredient, is retained on the skin for a long time, penetration into the stratum corneum is increased, and drug efficacy is maintained for a long time. It is also known that a therapeutic agent is applied not only to a part of an affected part but also to a wide area around the affected part to enhance the therapeutic effect.
On the other hand, a technique in which a carboxyvinyl polymer is blended (Patent Document 1), a technique in which xanthan gum is blended (Nizoral lotion 2%: Janssen Pharma Co., Ltd.), a composition in which polyvinyl alcohol is blended with a carboxyvinyl polymer (Patent Document 1) 2) A composition containing carrageenan, locust bean gum, glucomannan, tamarind seed gum, and gellan gum (Patent Document 3) has been reported, but none of them has been able to exhibit a sufficient effect with respect to adhesion retention. .
In general, when the preparation is hardened to increase the adhesion retention property, it becomes difficult to spread the preparation over a wide range. Conversely, if the preparation is made liquid to be applied over a wide range, the usability such as liquid dripping will be reduced. Therefore, it is desired to provide a preparation having a suitable viscosity, good usability, and excellent adhesion retention.
In addition, as a method of increasing drug permeability into the stratum corneum, blending of an absorption enhancer, ODT,
(Occlusive Dressing Technique) Treatment, carrier effect of nanoparticles etc., physical acceleration methods such as heat and friction treatment, etc. are known, but formulation design considering the balance between safety and permeability is necessary .

No. 3800232 JP 2008-19197 A JP 2012-162511 A

  An object of the present invention is to provide a composition for external use having an improved antifungal agent retention property and excellent keratin permeability.

The present inventors have conducted intensive studies to solve the above problems, and as a result, when a carboxyvinyl polymer and xanthan gum are combined with a specific antifungal agent, the adhesion retention property of the antifungal agent is improved, and excellent keratin permeability is improved. They have found that the present invention has been completed.
The aspects of the present invention obtained from such findings are as follows.
(1) (a) an antifungal agent having formed a pharmaceutically acceptable salt,
(B) a carboxyvinyl polymer, and (c) a composition for external use, which comprises xanthan gum;
(2) The external composition according to (1), wherein the pharmaceutically acceptable salt of (a) is a hydrochloride or a nitrate.
(3) The composition for external use according to (1), wherein the antifungal agent is an allylamine antifungal agent, an imidazole antifungal agent, or a benzylamine antifungal agent.
(4) The composition for external use according to (3), wherein the allylamine antifungal agent having formed a pharmaceutically acceptable salt is terbinafine hydrochloride.
(5) The imidazole antifungal agent which has formed a pharmaceutically acceptable salt is miconazole nitrate, econazole nitrate, oxyconazole nitrate, neticonazole hydrochloride, croconazole hydrochloride, isoconazole nitrate, sulconazole nitrate, fenticonazole nitrate An external composition according to (3), which is butconazole nitrate or omoconazole nitrate;
(6) The composition for external use according to (3), wherein the benzylamine antifungal agent having formed a pharmaceutically acceptable salt is butenafine hydrochloride.
(7) The composition for external use according to any of (1) to (6), which is a liquid, lotion, gel, emulsion or cream.
(8) The composition for external use according to any one of (1) to (7), which is an emulsion composition.
(9) The content of (b) the carboxyvinyl polymer is 0.01 to 10.0 parts by mass based on 1 part by mass of the antifungal agent (a) which has formed a pharmaceutically acceptable salt. An external composition according to the above,
(10) The content of (c) xanthan gum is (a) 0.1 to 5.0 parts by mass with respect to 1 part by mass of an antifungal agent which forms a pharmaceutically acceptable salt. Topical composition,
It is.

  ADVANTAGE OF THE INVENTION By this invention, it became possible to improve the adhesion retention property of a specific antifungal agent, and to have excellent keratin penetration.

  The antifungal agent that forms the pharmaceutically acceptable salt of the present invention is not particularly limited, but preferred are hydrochloride and nitrate, and compounds that are hardly soluble in water. Here, “slightly soluble in water” means that the amount of solvent required to dissolve 1 g of solute at 20 ° C. ± 5 ° C. is about 30 mL.

  As the type of the antifungal agent of the present invention, for example, an allylamine antifungal agent, an imidazole antifungal agent, a benzylamine antifungal agent or a morpholine antifungal agent is preferable. Examples of the pharmaceutically acceptable salt of the allylamine antifungal agent of the present invention include terbinafine hydrochloride. Pharmaceutically acceptable salts of the imidazole antifungal agents of the present invention include, for example, miconazole nitrate, econazole nitrate, oxyconazole nitrate, neticonazole hydrochloride, croconazole hydrochloride, isoconazole nitrate, sulconazole nitrate, fenticonazole Nitrate, butconazole nitrate, omoconazole nitrate and the like can be mentioned. Pharmaceutically acceptable salts of the benzylamine antifungal agent of the present invention include, for example, butenafine hydrochloride.

  Preferred as antifungal agents which form the pharmaceutically acceptable salts of the present invention are terbinafine hydrochloride, butenafine hydrochloride, isoconazole nitrate, econazole nitrate, oxyconazole nitrate or miconazole nitrate. The content of the antifungal agent which forms the pharmaceutically acceptable salt of the present invention is preferably 0.2 to 2% by mass, and more preferably 0.5 to 1.5% by mass of the whole external composition of the present invention. It is.

The carboxyvinyl polymer of the present invention means a copolymer of acrylic acid. For example, there are several types having different viscosities such as a 0.5% aqueous solution having viscosities of 4000 to 10000 mPa · s and 40,000 to 60,000 mPa · s. You can use them properly.
The content of the carboxyvinyl polymer is preferably from 0.01 to 10.0% by mass of the whole external composition of the present invention. The amount is preferably 0.01 to 10.0% by mass, more preferably 0.1 to 5.0% by mass, based on 1 part by mass of the antifungal agent of the present invention.

The xanthan gum of the present invention means a polysaccharide produced outside the cells by the microorganism Xanthomonas campestris fermenting glucose and the like.
The content of xanthan gum is preferably 0.1 to 5.0% by mass of the whole external composition of the present invention. Moreover, 0.1 to 5.0 mass% is preferable with respect to 1 mass part of antifungal agents of this invention, More preferably, it is 0.15 to 1.0 mass%.

  The dosage form of the composition for external use of the present invention is not particularly limited, and examples thereof include liquids, lotions, gels, emulsions, and creams.

  The viscosity of the composition for external use of the present invention is preferably 2.8 Pa · s or more (B-type viscometer) at 25 ° C. An external composition having the above viscosity can be obtained mainly by appropriately selecting the types and amounts of the carboxyvinyl polymer and xanthan gum. In this application, a B-type viscometer (TVB-10M / Toki Sangyo Co., Ltd.) or a viscous viscometer (VISCOMATE VM-100 / Yamaichi Electric Co., Ltd.) is used. The viscosity at 25 ° C. is measured according to.

  In the composition for external use of the present invention, optional components usually used in the composition for external use can be appropriately compounded within a range that does not impair the effects of the present invention. Such optional components include purified water, dissolution aids such as lower alcohols and polyhydric alcohols, hydrocarbons, glycerin fatty acid esters, wax components, surfactants, antioxidants, emulsion stabilizers, gelling agents, adhesives Agents, extracts from various animals and plants, pH adjusters, preservatives, chelating agents, fragrances, pigments, liquefied gases and the like. Further, in the emulsified composition of the present invention, for example, a bactericide, an analgesic, an antihistamine, an anti-inflammatory, a tissue repair, an antipruritic, a humectant, a vasoconstrictor, an antiallergic, a refreshing agent, an oxygen scavenger Pharmaceutical ingredients such as vitamins, ultraviolet absorbers, ultraviolet scattering agents and the like can be appropriately compounded within a range that does not impair the effects of the present invention.

  Further, the composition for external use of the present invention is preferably an emulsion type, and may be any of an O / W type and a W / O type.

  Hereinafter, the present invention will be described in more detail with reference to examples, comparative examples, and test examples, but the present invention is not limited to these examples.

Examples 1 to 4 and Comparative Examples 1 to 17
(Method of preparing each external composition)
In accordance with the formulations shown in Tables 1 to 5 below, each component was weighed, and after the components A and B were combined and heated to about 80 ° C., the component C was added and stirred. After stirring, the D phase heated to 85 ° C. was added, and then the E, F, and G phases were added in this order to obtain O / W emulsion compositions of Examples and Comparative Examples. The viscosity of the final composition was measured using a B-type viscometer (TVB-10M / Toki Sangyo Co., Ltd.) or a vibration viscometer (VISCOMATE VM-100 / Yamaichi Electric Co., Ltd.).
In addition, the compounding amount of the polymer of each composition is different because it is prepared in order to adjust the viscosity between each composition.

(Test Example 1: Evaluation of adhesion retention property)
In order to evaluate the adhesion retention property of the composition, a test was performed by applying the paddle method described in the Japanese Pharmacopoeia using a dissolution tester. 0.8 g of the composition of each of Examples and Comparative Examples was applied on a glass plate in a range of 2.5 cm × 3.5 cm, and Examples 1, 3, and 4 and Comparative Examples 1 to 6 and 14 to 17 were left for 3 hours. After that, Example 2 and Comparative Examples 7 to 12 were allowed to stand for 2 hours and then tested under the following conditions using a dissolution tester (NTR-6100A / Toyama Sangyo Co., Ltd.).
Examples 1, 3 and 4, Comparative Examples 1 to 6 and 14 to 17
Test liquid: water, temperature: 25 ° C., paddle rotation speed: 100 rpm, stirring time: 15 minutes Example 2, Comparative Examples 7 to 12
Test solution: water, temperature: 40 ° C., paddle rotation speed: 50 rpm, stirring time: 15 minutes After stirring, terbinafine hydrochloride, butenafine hydrochloride or miconazole nitrate (hereinafter appropriately referred to as “terbinafine hydrochloride” or “butenafine hydrochloride” in the composition remaining on the glass plate). Abbreviated as "each antifungal agent"). The amount was measured using liquid chromatography (e2695 / Waters). The content of each applied antifungal agent is defined as 100%, and the remaining ratio% of each antifungal agent remaining on the glass plate after the test (hereinafter, abbreviated as "residual ratio" as appropriate) is retained. It was calculated as sex.
The results are shown in Tables 1 to 4. The unit of the compounding amount in the table is wt%.

  The composition of Example 1 was compared with Comparative Examples 1 to 6 having the same viscosity, and the composition of Example 3 was compared with Comparative Examples 14 and 15 having the same viscosity. The composition of No. 4 showed remarkable adhesion retention compared with Comparative Examples 16 and 17 having the same viscosity. In addition, even under severe conditions under heating, the composition of Example 2 showed remarkable adhesion retention compared with Comparative Examples 7 to 12. From the above results, it was found that the combination of the carboxyvinyl polymer and the xanthan gum was most suitable for the adhesion retention property of each antifungal agent without depending on the viscosity of the composition.

(Test Example 2: Silicon film migration test)
0.15 g of each of the compositions of Example 1 and Comparative Example 13 was spread on a silicone rubber film (2.5 cm × 2.5 cm × 0.5 mm) so as to spread over the entire surface, and immediately the thermostat (approximately 32 (° C, humidity). After 2 hours, the silicone rubber film was taken out of the thermostat, the formulation on the surface was thoroughly washed with water, and the moisture was thoroughly wiped off. This was immersed in acetonitrile and allowed to stand overnight, and terbinafine hydrochloride was extracted from the silicon membrane with an ultrasonic generator, and the content of terbinafine hydrochloride in the extract was measured by liquid chromatography (e2695 / Waters Corporation). ). The content of terbinafine hydrochloride applied was set to 100%, and the amount of terbinafine hydrochloride extracted from the silicon film was calculated as the percentage of transfer to the silicon film.
Table 5 shows the silicon film transfer rate% of Example 1 and Comparative Example 13. The unit of the compounding amount in the table is wt%.

As is evident from the results, the composition of Example 1 increased the transferability of terbinafine hydrochloride to the silicon film more than twice as compared with the composition of Comparative Example 13. Therefore, it became clear that the composition containing xanthan gum and the carboxyvinyl polymer had an effect of increasing the transferability of terbinafine hydrochloride to the silicon film. Since it is considered that there is a correlation between the ability to transfer to the silicon membrane and the skin permeability, it is considered that a composition having enhanced skin permeability can be provided by blending a carboxyvinyl polymer and xanthan gum with terbinafine hydrochloride.
In addition, the adhesion retention property of terbinafine hydrochloride and the excellent keratin permeability effect of the above results are presumed to be an effect due to the interaction between terbinafine hydrochloride and a high-molecular carboxyvinyl polymer and xanthan gum. Similar effects can be expected with other antifungal agents that form (ie, other antifungal agents that have formed pharmaceutically acceptable salts).

  ADVANTAGE OF THE INVENTION By this invention, the adhesion retention property of a specific antifungal agent was improved, and it became possible to provide the external application composition which had excellent keratin penetration. The composition for external use is useful as pharmaceuticals, quasi-drugs, cosmetics, and the like.

Claims (5)

(A) at least one antifungal agent selected from the group consisting of terbinafine hydrochloride, butenafine hydrochloride, and miconazole nitrate ;
An external composition comprising (b) a carboxyvinyl polymer and (c) xanthan gum. The topical composition according to claim 1, which is a solution, a lotion, a gel, an emulsion or a cream. The composition for external use according to claim 1 or 2 , which is an emulsion composition. The composition for external use according to claim 1, wherein the content of (b) the carboxyvinyl polymer is 0.01 to 10.0 parts by mass based on 1 part by mass of the antifungal agent (a). The composition for external use according to claim 1, wherein the content of (c) xanthan gum is 0.1 to 5.0 parts by mass based on 1 part by mass of (a) the antifungal agent.