JP2021161037A - Pharmaceutical composition for external use - Google Patents

Abstract

To provide a pharmaceutical composition for external use excellent in stability.SOLUTION: There is prepared a pharmaceutical composition for external use which comprises (A) one or more selected from the group consisting of terbinafine and a pharmaceutically acceptable salt thereof, (B) a local anesthetic, (C) one or more selected from the group consisting of chlorpheniramine and a pharmaceutically acceptable salt thereof and (D) isopropyl methylphenol.SELECTED DRAWING: None

Description

The present invention relates to an external pharmaceutical composition. More specifically, it relates to an external pharmaceutical composition containing an antifungal agent.

For pharmaceutical compositions, it is important to ensure long-term stability in the manufacturing process, market distribution process, and after opening. In addition, the influence on the quality of the decomposition of the contained components and the coloring of the pharmaceutical product, which occur when the product is stored in a heated state or when it is exposed to light, cannot be ignored. Therefore, there is a demand for a method of stably storing a pharmaceutical product for a long period of time by preventing deterioration of the pharmaceutical product due to heat or light. (Patent Document 1).

Japanese Unexamined Patent Publication No. 2015-10059

Antifungal agents that block the growth of fungi are widely used to treat, prevent, and ameliorate various diseases and symptoms caused by fungal infections, but are exposed to heat and light during distribution and storage. In that case, the formulation may be altered and colored.

The present invention has been made in view of the above, and an object of the present invention is to provide a highly stable external pharmaceutical composition containing an antifungal agent.

The present inventors have selected at least one selected from the group consisting of (A) terbinafine and a pharmaceutically acceptable salt thereof, (B) a local anesthetic, (C) chlorpheniramine and its pharmaceutically acceptable salt. It has been found that a stable external pharmaceutical composition can be obtained by containing one or more selected from the group consisting of the salts to be obtained and (D) isopropylmethylphenol, and the present invention has been completed.

That is, the present invention provides the following external pharmaceutical compositions.
Item 1.
(A) At least one selected from the group consisting of terbinafine and its pharmaceutically acceptable salts;
(B) Local anesthetic;
(C) One or more selected from the group consisting of chlorpheniramine and a pharmaceutically acceptable salt thereof; and (D) an external pharmaceutical composition containing isopropylmethylphenol.
Item 2.
Item 2. The external pharmaceutical composition according to Item 1, further comprising (E) water.
Item 3.
One or two local anesthetics selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and their pharmaceutically acceptable salts, and ethyl aminobenzoate. Item 2. The external pharmaceutical composition according to Item 1 or 2, which is more than a species.
Item 4.
Item 4. The external pharmaceutical composition according to any one of Items 1 to 3, which is a liquid agent, a gel agent, a cream agent, or an aerosol agent.

The present invention further relates to the following stability improvers and methods for improving stability.
Item 5.
A stability improver for an external pharmaceutical composition containing (A) at least one selected from the group consisting of terbinafine and a pharmaceutically acceptable salt thereof, and (B) a local anesthetic. , (C) One or more selected from the group consisting of chlorpheniramine and a pharmaceutically acceptable salt thereof, and (D) Stability for an external pharmaceutical composition. Improver.
Item 6.
A method for improving the stability of an external pharmaceutical composition containing (A) at least one selected from the group consisting of terbinafine and a pharmaceutically acceptable salt thereof, and (B) a local anesthetic. Improves the stability of an external pharmaceutical composition, characterized in that one or more selected from the group consisting of (C) chlorpheniramine and a pharmaceutically acceptable salt thereof and (D) isopropylmethylphenol coexist. How to make it.

According to the present invention, it is possible to suppress the coloring of an external pharmaceutical composition containing an antifungal agent that may occur when exposed to heat or light.

[External pharmaceutical composition]
The present invention is at least one selected from the group consisting of (A) terbinafine and pharmaceutically acceptable salts thereof, (B) local anesthetics, (C) chlorpheniramine and pharmaceutically acceptable thereof. One or more selected from the group consisting of salts; and (D) an external pharmaceutical composition containing isopropylmethylphenol. The external pharmaceutical composition of the present invention has good stability against heat and light.

((A) At least one selected from the group consisting of terbinafine and its pharmaceutically acceptable salt)
At least one selected from the group consisting of terbinafine and its pharmaceutically acceptable salts has the function of inhibiting or suppressing the growth of fungi or killing fungi, and diseases and symptoms caused by fungal infections. Is used to treat, prevent and improve. At least one selected from the group consisting of terbinafine and its pharmaceutically acceptable salt is not particularly limited as long as it is a grade or grade used as a component of an external preparation in the field of pharmaceuticals or quasi-drugs.

(A) The total content of at least one selected from the group consisting of tervinafin and pharmaceutically acceptable salts thereof is based on the total amount of the external pharmaceutical composition from the viewpoint of exerting the effect of the present invention more prominently. , Preferably 0.01% by mass or more, more preferably 0.1% by mass or more, still more preferably 0.3% by mass or more, still more preferably 0.5% by mass or more, particularly preferably 0.8% by mass or more. That is all. (A) The total content of at least one selected from the group consisting of terbinafine and its pharmaceutically acceptable salt is based on the total amount of the external pharmaceutical composition from the viewpoint of exerting the effect of the present invention more prominently. It is preferably 10% by mass or less, more preferably 8% by mass or less, still more preferably 5% by mass or less, still more preferably 2% by mass or less, particularly preferably 1.5% by mass or less, and most preferably 1. It is 3% by mass or less. With respect to the total amount of the external pharmaceutical composition, the total content of at least one selected from the group consisting of (A) terbinafin and a pharmaceutically acceptable salt thereof is from the viewpoint of exerting the effect of the present invention more remarkably. , Preferably 0.01% by mass to 10% by mass, more preferably 0.1% by mass to 8% by mass, still more preferably 0.3% by mass to 5% by mass, still more preferably 0.5% by mass. It is ~ 2% by mass, particularly preferably 0.8% by mass to 1.5% by mass, and most preferably 0.8% by mass to 1.3% by mass. Among them, 1% by mass is the most preferable.

((B) Local anesthetic)
The local anesthetic (B) of the present invention is not particularly limited as long as it is a grade or grade used as a component of an external preparation in the field of pharmaceuticals or quasi-drugs. Local anesthetics include, for example, lidocaine, dibucaine, mepivacaine, bupivacaine, ropivacaine, levobupivacaine, and amide-type local anesthetics having amine and amide structures such as pharmaceutically acceptable salts thereof, procaine, chloroprocine. , Tetracaine, and ester-type local anesthetics having an amine and ester structure such as pharmaceutically acceptable salts thereof, ethyl aminobenzoate, oxypolyethoxydodecane and the like. Of these agents, amide-type local anesthetics having an amine and amide structure are preferable, but not limited to. From the viewpoint of exerting the effects of the present invention more prominently, preferably from procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobpibacaine, and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate. One or more selected from the group consisting of lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobpibacaine and pharmaceutically acceptable salts thereof. Particularly preferred is lidocaine or a pharmaceutically acceptable salt thereof.

All of these components (B) may be used alone or in any combination of two or more.

The total content of the component (B) is usually 0.001% by mass or more, preferably 0.01% by mass or more, more preferably, based on the total amount of the external pharmaceutical composition, from the viewpoint of exerting the effect of the present invention more remarkably. Is 0.05% by mass or more, more preferably 0.1% by mass or more, particularly preferably 0.2% by mass or more, still more preferably 0.5% by mass or more. The total content of the component (B) is preferably 10% by mass or less, more preferably 5% by mass or less, still more preferably 3 with respect to the total amount of the external pharmaceutical composition from the viewpoint of usability and ease of handling of the preparation. It is mass% or less, particularly preferably 2.5 mass% or less. The total content of the component (B) with respect to the total amount of the external pharmaceutical composition is usually 0.001 to 10% by mass, preferably 0.01 to 10% by mass, from the viewpoint of exerting the effect of the present invention more remarkably. It is more preferably 0.05 to 5% by mass, further preferably 0.1 to 3% by mass, particularly preferably 0.2 to 2.5% by mass, and even more preferably 0.5 to 2.5% by mass. ..

In the external pharmaceutical composition of the present invention, from the viewpoint of exerting the effect of the present invention more remarkably, the ratio of the component (B) to the component (A) is, for example, (1 part by mass of the total content of the component (A)). B) The total content of the components is preferably 0.001 to 1000 parts by mass, more preferably 0.01 to 100 parts by mass, more preferably 0.05 to 100 parts by mass, and further preferably 0.1 to 10 parts by mass. It is preferably 0.15 to 5 parts by mass, particularly preferably 0.2 to 3 parts by mass, and most preferably 0.25 to 2.5 parts by mass.

Further, for example, when the component (B) is lidocaine or a pharmaceutically acceptable salt thereof, it is preferably 0.01 to 10% by mass, more preferably 0.01 to 10% by mass, from the viewpoint of exerting the effect of the present invention more remarkably. It is 0.1 to 8% by mass, more preferably 0.25 to 5% by mass, even more preferably 0.5 to 4% by mass, particularly preferably 1 to 3% by mass, and most preferably. Is 1.5 to 2.5% by mass.
In the external pharmaceutical composition of the present invention, from the viewpoint of exerting the effect according to the present invention more remarkably, the ratio of lidocaine or a pharmaceutically acceptable salt thereof to the component (A) is, for example, the total content of the component (A). The total content of lidocaine or a pharmaceutically acceptable salt thereof with respect to 1 part by mass is preferably 0.1 to 100 parts by mass, more preferably 0.25 to 10 parts by mass, and 0.5 to 5 parts by mass. It is more preferably 1 to 2.5 parts by mass, and particularly preferably 1 to 2.5 parts by mass.

((C) One or more selected from the group consisting of chlorpheniramine and its pharmaceutically acceptable salt)
One or more selected from the group consisting of (C) chlorpheniramine of the present invention and a pharmaceutically acceptable salt thereof is used as an antihistamine. One or more selected from the group consisting of chlorpheniramine and a pharmaceutically acceptable salt thereof is not particularly limited as long as it is a grade or grade used as a component of an external preparation in the field of pharmaceuticals or quasi-drugs. As chlorpheniramine and its pharmaceutically acceptable salt, chlorpheniramine and / or chlorpheniramine maleate is particularly preferable.

The total content of (C) is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, based on the total amount of the external pharmaceutical composition, from the viewpoint of exerting the effect of the present invention more remarkably. It is more preferably 0.1% by mass or more, and particularly preferably 0.3% by mass or more. The total content of (C) is preferably 2.5% by mass or less, more preferably 1.5% by mass or less, based on the total amount of the external pharmaceutical composition, from the viewpoint of exerting the effect of the present invention more remarkably. It is even more preferably 1% by mass or less, even more preferably 0.7% by mass or less, and particularly preferably 0.5% by mass or less. The total content of (C) is preferably 0.01 to 2.5% by mass, more preferably 0.05 to 1.5% by mass, still more preferably 0.1 to 1% based on the total amount of the external pharmaceutical composition. It is 1% by mass, particularly preferably 0.3 to 0.7% by mass, and even more preferably 0.3 to 0.5% by mass.

In the external pharmaceutical composition of the present invention, from the viewpoint of exerting the effect of the present invention more remarkably, the ratio of the component (C) to the component (A) is, for example, relative to 1 part by mass of the total content of the component (A). , (C) The total content of the component is preferably 0.03 to 50 parts by mass, more preferably 0.05 to 10 parts by mass, still more preferably 0.1 to 2 parts by mass, and particularly preferably 0.2. It is ~ 0.7 parts by mass, most preferably 0.3 to 0.5 parts by mass.

((D) Isopropylmethylphenol)
The (D) isopropylmethylphenol of the present invention is not particularly limited as long as it is a grade or grade used as a component of an external preparation in the field of pharmaceuticals or quasi-drugs.

The content of (D) is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, still more preferably 0.1% by mass or more, based on the total amount of the external pharmaceutical composition, from the viewpoint of exerting the effect of the present invention more remarkably. Is 0.3% by mass or more, more preferably 0.5% by mass or more, and particularly preferably 0.8% by mass or more. The content of (D) is preferably 10% by mass or less, more preferably 5% by mass or less, still more preferably 3% by mass, based on the total amount of the external pharmaceutical composition from the viewpoint of exerting the effect of the present invention more remarkably. Hereinafter, it is particularly preferably 1.5% by mass or less. The content of (D) is preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, still more preferably 0.3 to 3% by mass, and further, based on the total amount of the external pharmaceutical composition. It is more preferably 0.5 to 3% by mass, and particularly preferably 0.8 to 1.5% by mass.

In the external pharmaceutical composition of the present invention, from the viewpoint of exerting the effect of the present invention more remarkably, the ratio of the component (D) to the component (A) is, for example, relative to 1 part by mass of the total content of the component (A). , The content of the component (D) is preferably 0.001 to 1000 parts by mass, more preferably 0.01 to 100 parts by mass, still more preferably 0.1 to 10 parts by mass, still more preferably 0.5. It is ~ 5 parts by mass, particularly preferably 0.3 to 3 parts by mass, and most preferably 0.3 to 1.5 parts by mass.

((E) water)
The external pharmaceutical composition of the present invention may optionally contain (E) water in addition to the components (A) to (D). The content of (E) is preferably 0.1% by mass or more, more preferably 1% by mass or more, based on the total amount of the external pharmaceutical composition, from the viewpoint of further enhancing the stability of the external pharmaceutical composition of the present invention. It is more preferably 5% by mass or more, and particularly preferably 10% by mass or more. The content of (E) is preferably 70% by mass or less, more preferably 50% by mass or less, still more preferably 30% by mass, based on the total amount of the external pharmaceutical composition from the viewpoint of exerting the effect of the present invention more remarkably. % Or less, particularly preferably 20% by mass or less. The content of (E) is preferably 0.1 to 70% by mass, more preferably 1 to 50% by mass, still more preferably 5 to 30% by mass, and particularly preferably 5 to 30% by mass, based on the total amount of the external pharmaceutical composition. It is 10 to 20% by mass. On the other hand, it is preferable because the effect of the present application can be obtained even in a mode containing no water.

The external pharmaceutical composition of the present invention may optionally contain alcohol in addition to the components (A) to (D). Examples of the alcohol include lower alcohols, higher alcohols and the like. Examples of the lower alcohol include monohydric lower alcohols such as ethanol, isopropanol, propanol, isobutanol and butanol, and examples of the higher alcohol include octyldodecanol, isostearyl alcohol, oleyl alcohol, stearyl alcohol and cetanol. , Behenyl alcohol and the like.

Here, in particular, in the external pharmaceutical composition of the present invention, it is preferable to use a monohydric lower alcohol, and it is more preferable to use ethanol.
The content of the monohydric lower alcohol is preferably 5% by mass or more, more preferably 30% by mass or more, still more preferably mass, based on the total amount of the external pharmaceutical composition from the viewpoint of exerting the effect of the present invention more remarkably. It is 50% or more, particularly preferably 70% by mass or more. The monohydric lower alcohol is preferably 97% by mass or less, more preferably 95% by mass or less, still more preferably 90% by mass or less, based on the total amount of the external pharmaceutical composition, from the viewpoint of exerting the effect of the present invention more remarkably. Is. The content of the monohydric lower alcohol is preferably 5 to 97% by mass, more preferably 30 to 95% by mass, still more preferably 50 to 90% by mass, and particularly preferably 70 to 70 to the total amount of the external pharmaceutical composition. It is 90% by mass.

In the external pharmaceutical composition of the present invention, from the viewpoint of exerting the effect of the present invention more remarkably, the ratio of the monovalent lower alcohol to the component (A) is, for example, relative to 1 part by mass of the total content of the component (A). The content of the monovalent lower alcohol is preferably 0.5 to 10000 parts by mass, more preferably 1 to 5000 parts by mass, still more preferably 10 to 1000 parts by mass, and even more preferably 10 to 100 parts by mass. , Especially preferably 50 to 95 parts by mass, and most preferably 70 to 90 parts by mass.

The external pharmaceutical composition of the present invention may optionally contain a polyhydric alcohol in addition to the components (A) to (D). Examples of the polyhydric alcohol include glycol ethers such as diethylene glycol monomethyl ether and diethylene glycol monoethyl ether; polyethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin, isoprene glycol and the like, preferably 1,3-. Butylene glycol can be mentioned.

The content of the polyhydric alcohol is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, still more preferably 0.1% by mass or more, based on the total amount of the external pharmaceutical composition, from the viewpoint of exerting the effect of the present invention more remarkably. Is 0.5% by mass or more, particularly preferably 1% by mass or more. From the viewpoint of exerting the effect of the present invention more remarkably, the polyhydric alcohol is preferably 30% by mass or less, more preferably 20% by mass or less, still more preferably 10% by mass or less, particularly, based on the total amount of the external pharmaceutical composition. It is preferably 5% by mass or less. The content of the polyhydric alcohol is preferably 0.01 to 30% by mass, more preferably 0.1 to 20% by mass, still more preferably 0.5 to 10% by mass, based on the total amount of the external pharmaceutical composition. It is preferably 1 to 5% by mass.

In the external pharmaceutical composition of the present invention, from the viewpoint of exerting the effect of the present invention more remarkably, the ratio of the polyvalent alcohol to the component (A) is, for example, relative to 1 part by mass of the total content of the component (A). The content of the polyhydric alcohol is preferably 0.01 to 30 parts by mass, more preferably 0.1 to 20 parts by mass, still more preferably 0.5 to 10 parts by mass, and particularly preferably 1 to 5 parts by mass. be.

The external pharmaceutical composition of the present invention may optionally contain a nonionic surfactant in addition to the components (A) to (D).

Examples of nonionic surfactants include sorbitan fatty acid esters, propylene glycol fatty acid esters, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyalkylene alkyl ethers, glycerin fatty acids, amines, and silicone-based surfactants. Examples thereof include activators, polyoxyethylene lauryl alcohol ether and the like. Examples of the sorbitan fatty acid esters include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, penta-2-ethylhexylate diglycerol sorbitan, tetra-2-ethylhexylate diglycerol sorbitan, and the like. Examples include sorbitan sesquioleic acid esters, examples of propylene glycol fatty acid esters include propylene glycol fatty acid esters such as propylene glycol monostearate, and examples of castor oil derivatives include polyoxyethylene hydrogenated castor oil. , Polyoxyethylene castor oil and the like, and examples of the polyoxyethylene sorbitan fatty acid esters include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20) and polyoxyethylene (20) sorbitan monostearate (polysorbate). 60), polyoxyethylene monooleate (20) sorbitan (polysorbate 80), polyoxyethylene (20) sorbitan isostearate, and the like, and examples of the polyoxyalkylene alkyl ether include polyoxyethylene monococonut oil fatty acid glyceryl. , Glycerin alkyl ether, alkyl glucoside, polyoxyethylene cetyl ether and the like. Examples of glycerin fatty acids include glyceryl monostearate and glycerin malic acid monostearate. Examples of amines include stearylamine and the like. Examples of the silicone-based surfactant include oleylamine and the like, and examples thereof include polyoxyethylene / methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone.

Preferred nonionic surfactants include sorbitan fatty acid esters, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, and glycerin fatty acids, with polyoxyethylene hydrogenated castor oil being more preferred.

The content of the nonionic surfactant is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, based on the total amount of the external pharmaceutical composition from the viewpoint of exerting the effect of the present invention more remarkably. be. The nonionic surfactant is preferably 10% by mass or less, more preferably 5% by mass or less, based on the total amount of the external pharmaceutical composition, from the viewpoint of exerting the effect of the present invention more remarkably. The content of the nonionic surfactant is preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, based on the total amount of the external pharmaceutical composition.

In the external pharmaceutical composition of the present invention, from the viewpoint of exerting the effect of the present invention more remarkably, the ratio of the nonionic surfactant to the component (A) is, for example, relative to 1 part by mass of the total content of the component (A). The content of the nonionic surfactant is preferably 0.01 to 10 parts by mass, more preferably 0.1 to 5 parts by mass.

(salt)
Examples of the "salt" referred to in the present specification include organic salts and inorganic salts. Examples of the organic salt include ammonium, diethanolamine, triethanolamine, ethylenediamine and the like, and examples of the inorganic salt include salts with sodium, potassium, calcium, magnesium and the like. Also, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, Salts with organic acids such as malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, silicic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid; And the like with salts with acidic amino acids such as. The "salt" may contain a solvate or a hydrate of the salt. In particular, the form of the salt of the component (A) is not limited, but from the viewpoint of availability, it is preferably a salt of an inorganic acid, and more preferably a hydrochloride, a nitrate or the like.

(Base, carrier, or other ingredient)
The external pharmaceutical composition of the present invention may contain a known base or carrier that can be used as a pharmaceutical product or a quasi-drug as long as the effects of the present invention are not impaired. In addition, the external pharmaceutical compositions of the present invention include, for example, anionic surfactants, amphoteric surfactants, oils, alcohols, higher fatty acids, preservatives, antioxidants, antioxidants, cooling agents, and various high-grade agents. Contains additives such as molecules, preservatives, chelating agents, pH regulators, stabilizers, solubilizers, suspending agents, isotonic agents, buffers, fragrances, colorants, pigments, or lubricants. can do. These additives may be used alone or in combination of two or more.

Examples of the base or carrier include hydrocarbons, silicone oils, esters, and the like. Examples of the hydrocarbon include liquid paraffin, squalane, gelled hydrocarbon (plastibase and the like), ozokelite, α-olefin oligomer, light liquid paraffin and the like, and examples of the silicone oil include methyl polysiloxane and crosslinked methyl. Polysiloxane, highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, cross-linked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, cross-linked polyether-modified silicone, cross-linked alkyl polyether-modified silicone , Silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicon, phenyl-modified silicone, silicone resin, etc. Examples of the class include isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythlit tetra2-ethylhexanoate and the like.

The base or carrier may be used alone or in combination of two or more.

Examples of the anionic surfactant include laurate, palmitate, coconut glutamate, coconut oil methylalanine salt, acylmethyltaurine salt, polyoxyethylene lauryl sulfate and the like.
Examples of the amphoteric tenside agent include lauryl diaminoethyl glycine salt, coconut oil fatty acid betaine salt and the like.

Examples of the oil include natural animal and vegetable oils and fats, hydrocarbon oils, ester oils, silicone oils, higher alcohols, higher fatty acids, animal and plant and synthetic essential oils.

Natural animal and vegetable oils and fats include, for example, avocado oil, flaxseed oil, almond oil, olive oil, cacao oil, beef fat, millet oil, wheat germ oil, sesame oil, rice germ oil, rice bran oil, safflower oil, soybean oil, evening primrose oil. , Camellia oil, corn oil, rapeseed oil, horse fat, persic oil, palm oil, palm kernel oil, sunflower oil, sunflower oil, pork fat, grape oil, jojoba oil, macadamia nut oil, mink oil, cottonseed oil, mokuro, honeybee, Examples thereof include sardine oil, coconut oil, hardened coconut oil, peanut oil, lanolin, egg yolk oil, rose hip oil and the like.

As the hydrocarbon oil, paraffin-based hydrocarbons and olefin-based hydrocarbons are used, and examples thereof include squalane, squalane, selecin, paraffin, pristane, microcrystalline wax, liquid paraffin, and petrolatum.

As the ester oil, synthetic esters and esters of higher alcohols and higher fatty acids are used. For example, diisopropyl adipate, diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, isostear. Isostearyl Acidate, Trimethylol Propane Triisostearate, Cetyl 2-ethylhexanoate, Neopentyl Glycol Di-2-ethylhexanoate, Trimethylol Propane Tri-2-ethylhexanoate, Pentaerythritol Tetra-2-ethylhexanoate, Cetyl octanate, oleyl oleate, octyldodecyl oleate, decyl oleate, neopentyl glycol dicaprate, 2-ethylhexyl succinate, isocetyl stearate, butyl stearate, diisopropyl sebacate, diethyl sebacate, cetyl lactate, tetradecyl lactate , Isopropyl myristate, octyldodecyl myristate, cetyl myristate, myristyl myristate, octyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptyl undesyl palmitate, cholesteryl 12-hydroxystearate, Examples thereof include phytosteryl oleate, diisostearyl malate, paramethoxysilicate dermic acid ester, pentaerythlit tetralogate and the like.

Examples of the silicone oil include dimethylpolysiloxane, highly polymerized methylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, octamethylcyclotetrasiloxane, octamethylcyclopentasiloxane, decamethylcyclohexasiloxane, stearoxysilicone and the like. Examples thereof include higher alkoxy-modified silicones, alkyl-modified silicones, and higher fatty acid ester-modified silicones.

As the higher fatty acid, a saturated or unsaturated linear or branched fatty acid having 12 to 22 carbon atoms can be used, and for example, isostearic acid, oxystearic acid, oleic acid, stearic acid, palmitic acid, behenic acid, etc. Examples thereof include myristic acid, lauric acid, lanophosphate, linoleic acid and linolenic acid.

Preferable examples of preservatives include benzoic acid, acetic acid, phenol, iodotinki, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and the like.

Preferable examples of the antioxidant include sulfites, ascorbic acid and the like.

Examples of the antioxidant include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), sodium sulfite, erythorbic acid, L-cysteine hydrochloride, vitamin Cs, vitamin E and the like. Examples of vitamin Cs include ascorbicen-A, ascorbic acid stearate, ascorbic acid palmitate, dipalmitate L-ascorbic acid, ascorbic acid, sodium ascorbic acid, dehydroascorbic acid, sodium ascorbic acid ester, and ascorbic acid. Examples thereof include sodium acid phosphate salt and magnesium ascorbic acid ester. Examples of vitamin Es include dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and dl-α-tocopherol calcium succinate.

Examples of the refreshing agent include menthol (l-menthol, dl-menthol, etc.), camphor (d-camphor, dl-camphor, etc.), terpenoids such as borneol, terpenoid-containing essential oil (hakka oil), or a drug thereof. Examples include physically acceptable salts. It is also possible to use one kind or a combination of two or more kinds from these agents as appropriate.

Examples of various polymers include cellulose-based polymers, vinyl-based polymers, acrylic-based polymers, mucopolysaccharides, starch-based polymers, dextran, dextrin fatty acid esters, pectin, casein, and dimethyl distearyl ammonium hecterite. Acryloyldimethyltaurine ammonium / vinylpyrrolidone) copolymer, polyethylene glycol distearate, ethylene glycol triisostearate, polyoxyethylene triisostearate (20) methylglucoside, bentonite, hectrite, alginic acid and / or pharmaceutically acceptable salts thereof, Examples thereof include propylene glycol alginate, polyethylene glycol, and thickening polysaccharides.

Examples of the cellulosic polymer include sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like, and one or more of these can be used.

Examples of the vinyl polymer include polyvinylpyrrolidone, polyvinyl alcohol, polyvinylmethyl ether, and the like, and one or more of these can be used.

Examples of the acrylic polymer include acrylic acid / alkyl methacrylate copolymer, hydroxyethyl acrylate / acryloyldimethyltaurine salt copolymer (particularly hydroxyethyl acrylate / sodium acryloyldimethyltaurine copolymer), sodium acrylate / sodium. Acryloyldimethyltaurine copolymer, sodium acrylate / sodium acrylate / sodium methacrylate / alkyl methacrylate copolymer, steareth-10 allyl ether / acrylates copolymer, polyacrylic acid or pharmaceutically acceptable thereof Examples thereof include salts (carboxyvinyl polymers), acryloyldimethyltaurine ammonium copolymers, acrylate / polyoxyethylene glycol ether copolymers, polyacrylamides, and acrylamide / ammonium acrylate copolymers.

Examples of the thickening polysaccharide include carrageenan, xanthan gum, gum arabic, pectin, and mucopolysaccharide among those used as components of external preparations in the field of pharmaceuticals or quasi-drugs. Mucopolysaccharides include chondroitin sulfate (sodium salt, etc.), hyaluronic acid or its pharmaceutically acceptable salt (sodium salt, etc.), hyaluronic acid derivative or its pharmaceutically acceptable salt, heparin, heparinoid. Glycosaminoglycan and the like can be exemplified.

Examples of the starch-based polymer include hydroxypropyl starch phosphoric acid (for example, National Starch, manufactured by LLC, StructureXL), modified cornstarch, and cornstarch (corn starch).

Examples of the preservative include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoic acid. Examples thereof include benzyl, methyl paraoxybenzoate, and phenoxyethanol.

Examples of the chelating agent include EDTA / disodium salt, EDTA / calcium / disodium salt and the like.

Examples of the pH adjuster include inorganic acids (hydrochloride, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), and inorganic bases (potassium hydroxide, hydroxide). (Sodium, etc.), organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.) and the like.

Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene (BHT), butylatedhydroxyanisole (BHA) and the like.

Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, soybean lecithin, and glycerin monostearate.

Examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like.

Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates and citrates.

Examples of the colorant include inorganic pigments and natural pigments.
Examples of the lubricant include carnauba wax, hydrous silicon dioxide, sucrose fatty acid ester, silicone resin, magnesium stearate, setar, talc and the like.

The external pharmaceutical composition of the present invention may further contain other active ingredients as long as the effects of the present invention are not impaired. Specific examples of such components include, for example, anti-inflammatory agents, additional fungicides, additional antihistamines, antipruritic components, moisturizing components, blood circulation promoting components, astringent components, peptides or derivatives thereof, amino acids or derivatives thereof, cell activation. Examples include chemical components and vitamin preparations.

Anti-inflammatory agents include, for example, steroidal anti-inflammatory agents such as prednisolone valerate, dexamethacin acetate, hydrocortisone acetate, or pharmaceutically acceptable salts thereof, allantin, diisopropylic acid glycyrrhetin adipate, glycyrrhizinic acid, glycyrrhetin. Stearyl acid, aldioxa, ufenamate, bufexamac, ibprofenpiconol, indomethacin, diclofenac, pyroxicum, epsilon-aminocaproic acid, velverine, lysoteam, sodium azulene sulfonate, dimethylisopropylazulene, bromeline, therapeptase, semi-alkali proteinase, or their pharmacology Examples thereof include non-steroidal anti-inflammatory agents such as salts that are generally acceptable. Among these agents, non-steroidal anti-inflammatory agents are preferable from the viewpoint of exerting the effects of the present invention more remarkably, and salts of glycyrrhizic acid, glycyrrhetinic acid, glycyrrhetinic acid, and glycyrrhizic acid (for example, dipotassium glycyrrhizinate, glycyrrhizin). Monoammonium acid), allantin is more preferable. It is also possible to use one kind or a combination of two or more kinds from these agents as appropriate.

Additional disinfectants include, for example, decalinium chloride, decalinium acetate, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, chlorobutanol, timol. , Sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, acrinol, hinokithiol, resorcin, benzoic acid Examples thereof include berberine, salicylic acid, and biganide compounds. It is also possible to use one kind or a combination of two or more kinds from these agents as appropriate.

Additional antihistamines include, for example, diphenhydramine, diphenylpyraline, diphenylimidazole, salts thereof and the like.

Examples of the antipruritic component include crotamiton and the like.

Moisturizing ingredients include, for example, hyaluronic acid or a pharmaceutically acceptable salt thereof (sodium salt, etc.), a hyaluronic acid derivative or a pharmaceutically acceptable salt thereof, saccharides such as trehalose, xylitol, oligosaccharide; heparin. Similar substances, high molecular weight compounds such as collagen, elastin, keratin, chitin, chitosan; amino acids such as glycine, aspartic acid, arginine; natural moisturizing factors such as sodium lactate, sodium pyrrolidone carboxylate; ceramide, cholesterol, phospholipids Lipids such as: chamomile extract, hamamelis extract, cha extract, plant extract such as perilla extract and the like.

Examples of blood circulation promoters include acetylcholine, caffeine, capsaicin, cantalis tincture, gamma oryzanol, shokyo tincture, zingeron, cepharantin, sembly extract, tannin acid, tocopherol tincture, tolazoline, tocopherol nicotinate, nicotinic acid benzyl ester, and the like. Examples include nicotinic acid amide.

Examples of the astringent component include zinc sulfate, chlorohydroxyaluminum, aluminum chloride, zinc sulfonate and tannic acid.

Examples of the peptide or its derivative include keratin-degrading peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, and elastin. Degrading Peptide, Conchiolin Degrading Peptide, Hydrolyzed Conchiolin, Silk Proteolytic Peptide, Hydrolyzed Silk, Lauroyl Hydrolyzed Silk Sodium, Soy Proteolytic Peptide, Hydrolyzed Soy Protein, Wheat Protein, Wheat Proteolytic Peptide, Hydrolyzed Wheat Protein, Casein Degrading peptides, acylated peptides (palmitoyl oligopeptides, palmitoyl pentapeptides, palmitoyl tetrapeptides, etc.) and the like can be mentioned.

Examples of amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, and cystine. , Methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosin, creatine and the like.

Examples of the cell activating component include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid, vitamins such as retinol, thiamine, riboflavin, pyridoxin hydrochloride and pantothenic acids, and α-hydroxy acids such as glycolic acid and lactic acid. Examples thereof include tannin, flavonoid, saponin, and photosensitizer No. 301.

As the vitamin preparation, any of vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, and other vitamins can be used. Examples of B vitamins include vitamin B1, vitamin B2, vitamin B6, vitamin B12, nicotinic acid, pantothenic acid, folic acid, biotin and the like. Examples of vitamin B1s include dibenzoylthiamine, dibenzoylthiamine hydrochloride thiamine hydrochloride, thiaminecetyl hydrochloride, thiaminethiocyanate, thiaminelauryl hydrochloride, thiamine nitrate, thiaminemonophosphate, thiaminelysine salt, and thiaminetrilin. Acid salt, thiamine monophosphate ester phosphate, thiamine monophosphate ester, thiamine diphosphate ester, thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate monophosphate and the like; as vitamin B2, for example, Riboflavin, flavin mononucleotide, flavin adenin dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinic acid, etc .; Examples of nicotinic acids include nicotinic acid, nicotinic acid amide, etc. Dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, etc .; Examples of vitamin B6s include pyridoxin hydrochloride, pyridoxin acetate, etc. Pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, etc .; Examples of vitamin B12 include cyanocobalamine, hydroxocobalamine, deoxyadenosylcobalamine, etc.; Pantothenic acids include, for example, pantothenic acid, calcium pantothenate, pantothenyl alcohol. (D-pantenol), D-pantesin, D-pantetin, coenzyme A, pantothenyl ethyl ether and the like can be mentioned.
Examples of vitamin Cs include ascorbicen-A, ascorbic acid stearate, ascorbic acid palmitate, dipalmitate L-ascorbic acid, ascorbic acid, sodium ascorbic acid, dehydroascorbic acid, sodium ascorbic acid ester, and ascorbic acid. Examples thereof include sodium acid phosphate salt and magnesium ascorbic acid ester.
Examples of vitamin Ds include methyl hesperidin, ergocalciferol, choleciferol and the like.
Examples of vitamin Es include dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and dl-α-tocopherol calcium succinate.
Examples of vitamin Ks include phylloquinone and farnoquinone. These pharmacologically acceptable salts and other vitamin-like acting factors are also mentioned as vitamins.

The external pharmaceutical composition according to the present invention preferably does not contain salicylic acid from the viewpoint that the effects of the present invention can be remarkably exhibited. Above all, an embodiment containing 1% by mass or more of salicylic acid is more preferable.

(PH)
The pH of the external pharmaceutical composition of the present invention is appropriately set and is not limited as long as it is within a physiologically or pharmaceutically acceptable range, but from the viewpoint of safety, it can be, for example, pH 2-9, preferably pH 2-9. , About 3-8, more preferably about 5-7.

(hardness)
The hardness of the external pharmaceutical composition of the present invention is preferably 10 to 200 g, more preferably 20 to 150 g, still more preferably 50 to 110 g, based on the total amount of the external pharmaceutical composition, from the viewpoint of ease of handling of the preparation. Is. The hardness in the present specification is the result obtained when measured using a FUDOH RHEO METER, a 30 mm disk type adapter at a table speed of 2 cm / min and a measurement time of 30 seconds.

(Dosage form)
The external pharmaceutical composition of the present invention is provided in any form that can be widely used as a pharmaceutical product, a quasi drug, or the like. Preferably, it is provided as a preparation that can be used as an external preparation for skin. The external pharmaceutical composition of the present invention is not particularly limited as long as it is in a known form, but from the viewpoint of exerting the effect of the present invention more remarkably, for example, a cream, a liquid, a suspension, an emulsion, a gel, or a lotion. It is preferably provided in the form of an external pharmaceutical composition such as an agent, an aerosol agent, a mist agent, or a spray agent, and more preferably a gel agent, a cream agent, a liquid agent, or an aerosol agent.

A pharmaceutical product can be produced by mixing each component in accordance with or in accordance with the 17th revised Japanese Pharmacopoeia General Regulations.

(Use)
The external pharmaceutical composition of the present invention is preferably used for treating athlete's foot, worm, candidiasis, etc., without limitation. The external pharmaceutical composition of the present invention can also be used on the feet, nails, whole body skin, hair, and around the nails. From the viewpoint of exerting the effect of the present invention more remarkably, it can be particularly preferably applied to athlete's foot in places such as between the toes, the sole and the edge of the foot, the base of the toe, the sole and the heel.

Athlete's foot is a skin condition caused by Trichophyton. Itching, small bumps, peeling, dryness, swelling, hardening, powder blowing, roughening, etc. Ringworm is particularly likely to form in the thick areas of the keratin where the keratin component keratin is present, and symptoms may appear especially on the skin and nails.

Ringworm is a skin condition caused by Trichophyton. There is a small red ring on the skin that gradually spreads. Itchy and similar to athlete's foot, but worms tend to form on thin skin.

Candidiasis is caused by Candida, and symptoms include rough skin on the surface of the hands, peeling of the skin between the fingers, and discoloration of the base of the nails to white.

The external pharmaceutical composition of the present invention can be used for the treatment of such symptoms caused by Trichophyton, tinea versicolor, candidiasis, interdigital erosion, intertrigo and the like.

The method of using the external pharmaceutical composition of the present invention varies depending on the condition of the skin, nails, etc., age, gender, etc., but for example, the following method may be used. That is, an appropriate amount (for example, about 0.5 to 2 g) may be applied several times a day (for example, about 1 to 5 times, preferably 1 to 3 times, more preferably once). Further, the composition may be applied so that the daily usage amount of terbinafine or a pharmaceutically acceptable salt thereof is, for example, about 5 to 20 mg. The application method is performed according to the dosage form, preferably coating. The application period is preferably, for example, about 30 days or more.

(container)
The container filled with the external pharmaceutical composition of the present invention is not particularly limited. It may be used as a container for external medicines, quasi-drugs, and cosmetics. As such a container material, for example, a part or all, preferably all of the contact surface with the pharmaceutical composition is made of a polyolefin resin, an acrylic acid resin, a polyester, a polycarbonate, a fluororesin, a polyvinyl chloride, a polyamide, an ABS resin, etc. Examples thereof include containers made of at least one material selected from the group consisting of AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, aluminum, and glass.

From the viewpoint of ease of handling of the preparation, the material of the container filled with the external pharmaceutical composition of the present invention is polyethylene (PE) (high density polyethylene (HDPE), low density polyethylene (LDPE), ultra low density polyethylene, straight chain. Low-density polyethylene (LLDPE), ultra-high molecular weight polyethylene, etc.), Polyethylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), and ethylene-propylene copolymer, polymethylpentene, Polyethylene resins such as polybutene-1,1,2-polybutadiene, polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate are preferred, with polyethylene or polypropylene being more preferred.

The shape of the container is not limited, but is preferably a tube, a spray can, a mist spray bottle, a dropping container, and a squeezing container.

(Production method)
The external pharmaceutical composition of the present invention can be produced by a known method. If necessary, a sterilization step and a filtration step can be included.

[Stability improver]
The present invention improves stability for an external pharmaceutical composition containing (A) at least one selected from the group consisting of terbinafine and a pharmaceutically acceptable salt thereof, and (B) a local anesthetic. An external pharmaceutical composition comprising (C) one or more selected from the group consisting of chlorpheniramine and a pharmaceutically acceptable salt thereof and (D) isopropylmethylphenol. Regarding stability improvers for. That is, the components (C) and (D) are used to improve the stabilization of the components (A) and (B). The concentrations of the components (C) and (D) for such a stability improver are the same as the concentrations of the components (A) and (B) in the above-mentioned external pharmaceutical composition of the present invention. It is possible to adopt the same conditions as the pH, hardness, formulation conditions, etc. when coexisting with.

[How to improve stability]
The present invention is a method for improving the stability of an external pharmaceutical composition containing (A) at least one selected from the group consisting of terbinafine and a pharmaceutically acceptable salt thereof, and (B) a local anesthetic. For an external pharmaceutical composition, wherein one or more selected from the group consisting of (C) chlorpheniramine and a pharmaceutically acceptable salt thereof and (D) isopropylmethylphenol coexist. On how to improve the stability of. In such a method, the same conditions as the concentration, pH, hardness, formulation conditions, etc. of each component in the above-mentioned external pharmaceutical composition of the present invention can be adopted.

Next, the present invention will be specifically described with reference to Examples, but the present invention is not limited to the following Examples. The absorbance at 450 nm to 480 nm is in the range usually used for detecting yellow to orange tint. In addition, the numerical values shown in the following table are all w / w% except for the parts not particularly indicated.

[Test Example 1. Thermal stability test]
The external pharmaceutical compositions shown in Table 1 below were prepared by a conventional method.
25 mL of each of these external pharmaceutical compositions was filled in a glass screw vial having a capacity of 30 mL, and after closing, the mixture was stored in an incubator at 60 ° C. for 7 days under shading.

For each composition before and after storage, put 150 μL into a 96-well plate (Tissue Culture Plate (manufactured by FALCON)) and measure the absorbance at 450 nm using a plate reader (SH-9000 Lab type microplate reader (manufactured by Corona Electric)). It was measured. Using the measured absorbance, the discoloration suppression rate of each composition with respect to Comparative Example 1 was calculated by the following formula 1.
The results are also shown in Table 1.

[Formula 1] Discoloration suppression rate (%) = {(absorbance after storage of Comparative Example 1-absorbance before storage of Comparative Example 1)-(absorbance after storage of the target sample-absorbance before storage of the target sample) / (Asorbance after storage of Comparative Example 1-Asorbance before storage of Comparative Example 1)} × 100

It was confirmed that in the composition of the example, yellowing was suppressed and the thermal stability was remarkably increased as compared with the composition of the comparative example.

[Test Example 2. Test on light stability]
The external pharmaceutical compositions shown in Table 2 below were prepared by a conventional method.
Fill a 30 mL glass screw vial with 25 mL each of the external pharmaceutical composition, and use a stability test device (“(LT-120D3CJ)”, manufactured by (Nagano Science)) using a D65 lamp as a light source at room temperature. The composition was continuously irradiated with light of 4500 lux for 72 hours, and the composition was exposed to light having an integrated irradiation amount of 324,000 lux · hr.

For each composition before and after storage, 150 μL each was placed in a 96-well plate (Tissue Culture Plate (manufactured by FALCON)), and the absorbance at 480 nm was measured using a plate reader (SH-9000 Lab type microplate reader (manufactured by Corona Electric)). It was measured. Using the measured absorbance, the discoloration suppression rate of each composition with respect to Comparative Example 1 was calculated by the following formula 2.
The results are also shown in Table 2.

[Formula 2] Discoloration suppression rate (%) = {(absorbance after irradiation of Comparative Example 1-absorbance before irradiation of Comparative Example 1)-(absorbance after irradiation of target sample-absorbance before irradiation of target sample) / (Asorbance after irradiation of Comparative Example 1-Asorbance before irradiation of Comparative Example 1)} × 100

It was confirmed that in the composition of the example, yellowing was suppressed and the photostability was significantly increased as compared with the composition of the comparative example.

Hereinafter, an example of a pharmaceutical formulation of the present invention will be shown. The pharmaceutical compositions were prepared by a conventional method according to the formulations shown in Tables 3 to 5, and the pharmaceutical compositions Examples 1 to 18 were filled in a polypropylene container and the pharmaceutical examples 19 to 36 were filled in an aluminum laminated tube. These preparations are the preparations effectively used for the skin symptoms caused by Trichophyton. For Examples 37-52, a solution having the composition shown in Table 5 was prepared, and the solution was appropriately filled with gas together with gas as a drug solution into a container for an aerosol preparation to prepare an aerosol preparation.

Claims (6)

A group consisting of (A) at least one selected from the group consisting of terbinafine and a pharmaceutically acceptable salt thereof, (B) a local anesthetic, (C) a group consisting of chlorpheniramine and a pharmaceutically acceptable salt thereof. An external pharmaceutical composition containing (D) isopropylmethylphenol, which is one or more selected from the above. The external pharmaceutical composition according to claim 1, further comprising (E) water. One or two local anesthetics selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and their pharmaceutically acceptable salts, and ethyl aminobenzoate. The external pharmaceutical composition according to claim 1 or 2, which is more than a species. The external pharmaceutical composition according to any one of claims 1 to 3, which is a liquid agent, a gel agent, a cream agent, or an aerosol agent. A stability improver for an external pharmaceutical composition containing (A) at least one selected from the group consisting of terbinafine and a pharmaceutically acceptable salt thereof, and (B) a local anesthetic. , (C) One or more selected from the group consisting of chlorpheniramine and a pharmaceutically acceptable salt thereof, and (D) Stability for an external pharmaceutical composition. Improver. A method for improving the stability of an external pharmaceutical composition containing (A) at least one selected from the group consisting of terbinafine and a pharmaceutically acceptable salt thereof, and (B) a local anesthetic. Improves the stability of an external pharmaceutical composition, characterized in that one or more selected from the group consisting of (C) chlorpheniramine and a pharmaceutically acceptable salt thereof and (D) isopropylmethylphenol coexist. How to make it.