JP2002068974A - Antifungal medicine composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine composition suitable for fungal diseases, especially trichophytosis unguium. SOLUTION: This antifungal skin care medicine composition is characterized by comprising (1) terbinafine and/or its salt and (2) one or more compounds selected from vinylpyrrolidone-N,N'-dimethylaminoethyl methacrylate copolymer diethyl sulfate, N-methacryloyloxyethyl-N,N'-dimethylammonium-α,N- methylcarboxybetaine-alkyl methacrylate copolymer, urea, propylene glycol and sodium pyrrolidonecarboxylate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antifungal pharmaceutical composition, and more particularly to an antifungal pharmaceutical composition suitable for tinea unguium.

[0002]

BACKGROUND OF THE INVENTION Mycosis was a disease that was difficult to cure as long as the legend that "if a complete remedy for athlete's foot is developed, a Nobel Prize will be awarded". Mycosis is broadly divided into superficial mycosis and deep mycosis. Superficial mycosis includes 1) tinea pedis on the limbs and 2) tinea hirsutea on the body 3) tinea unguium occurring in the crotch, 4) tinea unguium occurring on the nail, and the like. Of these, mycosis occurring on the skin is being overcome by the development of novel antifungal agents such as butenafine and terbinafine, which have excellent effects, but no definitive means has been found for tinea unguium. It is known that long-term oral administration of terbinafine is effective for the treatment of tinea unguium, but the long-term oral administration is not likely to cause side effects, and a means of overcoming topical administration was required. . Until now, treatment by topical administration in tinea unguium has not been effective because its thick hard keratin layer has impeded drug penetration. As a topical topical preparation for tinea unguium, a topical topical preparation of amorolfin is known, but the efficacy of this topical topical amorolfine preparation for tinea unguium is not so high. Have been.

[0003] Terbinafine is known as an antifungal agent, and its production method is already known. Also, vinylpyrrolidone-N, N'-dimethylaminoethyl methacrylic acid copolymer diethyl sulfate, N-methacryloyloxyethyl-N, N'-dimethylammonium-α, N-methylcarboxybetaine / alkyl methacrylate copolymer Coalescence, urea, propylene glycol and sodium pyrrolidonecarboxylate are already widely known as film formers or humectants. However, it has not been known at all to produce an antifungal pharmaceutical composition by combining them, particularly to produce a pharmaceutical composition for tinea unguium.

[0004]

SUMMARY OF THE INVENTION The present invention has been made under such circumstances, and an object of the present invention is to provide a pharmaceutical composition suitable for antimycoses, especially tinea unguium.

[0005]

DISCLOSURE OF THE INVENTION In view of such circumstances, the present inventors have sought a pharmaceutical composition suitable for antimycotic disease and tinea unguium, and as a result of intensive research efforts, 1) terbinafine and / or Or its salt and 2) vinylpyrrolidone-N, N'-
Dimethylaminoethyl methacrylic acid copolymer diethyl sulfate, N-methacryloyloxyethyl-N, N'-dimethylammonium-α, N-methylcarboxybetaine / alkyl methacrylate copolymer, urea, propylene glycol and pyrrolidone carboxylic acid The inventor has found that a pharmaceutical composition having such characteristics can be obtained by incorporating one or more selected from sodium into a pharmaceutical composition, thereby completing the invention. That is, the present invention relates to the following technology. (1) 1) terbinafine and / or a salt thereof and 2) vinylpyrrolidone-N, N′-dimethylaminoethyl methacrylic acid copolymer diethyl sulfate, N-methacryloyloxyethyl-N, N′-dimethylammonium-α, N
One or more selected from methyl carboxybetaine-alkyl methacrylate copolymer, urea, propylene glycol and sodium pyrrolidone carboxylate
An antifungal pharmaceutical composition comprising at least one species. (2) The antifungal pharmaceutical composition according to (1), which is used for tinea unguium. (3) The antifungal pharmaceutical composition according to (1) or (2), which is an external preparation for skin. Hereinafter, the present invention will be described in more detail focusing on embodiments.

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS (1) Vinylpyrrolidone-N, N'-dimethylaminoethyl methacrylic acid copolymer diethyl sulfate, an essential component of the pharmaceutical composition of the present invention, N-
One or more selected from methacryloyloxyethyl-N, N'-dimethylammonium-α, N-methylcarboxybetaine / alkyl methacrylate copolymer, urea, propylene glycol and sodium pyrrolidonecarboxylate The pharmaceutical composition comprises vinylpyrrolidone-N, N'-
Dimethylaminoethyl methacrylic acid copolymer diethyl sulfate, N-methacryloyloxyethyl-N, N'-dimethylammonium-α, N-methylcarboxybetaine / alkyl methacrylate copolymer, urea, propylene glycol and pyrrolidone carboxylic acid It is characterized by containing one or more kinds selected from sodium. Of these, vinylpyrrolidone-N, N'-
Dimethylaminoethyl methacrylic acid copolymer diethyl sulfate and N-methacryloyloxyethyl-N, N'-
Dimethylammonium-α, N-methylcarboxybetaine / methacrylic acid alkyl ester copolymer is already known as a film-forming agent in skin external preparations such as cosmetics, and is usually used as a pack cosmetic or nail enamel. Used as a film-forming agent. All of these are commercially available in cosmetic grade, and these commercially available products can also be used. Also, urea, propylene glycol and sodium pyrrolidonecarboxylate are used as humectants in skin external preparations such as cosmetics. There are also commercially available products for these, and such commercially available products can be used. Of these components, preferred are vinylpyrrolidone-N,
N′-dimethylaminoethyl methacrylic acid copolymer diethyl sulfate, N-methacryloyloxyethyl-N,
N′-dimethylammonium-α, N-methylcarboxybetaine / alkyl methacrylate copolymer, and it is preferable to use one or both of them. In addition to these, it is a more preferable form to further contain one or more selected from urea, propylene glycol and sodium pyrrolidonecarboxylate. In the pharmaceutical composition of the present invention, these components have an action of assisting the penetration of terbinafine or a salt thereof shown below, which is an antifungal agent, into nails. The preferred content of these components is based on the total amount of the external preparation for skin.
The total amount is preferably 0.5 to 30% by weight, more preferably 1 to 20% by weight. If the amount is too small, the drug may not be able to penetrate into living tissue such as nails, and if the amount is too large, the effect may reach a plateau or the drug penetration may be inhibited. It is.

(2) Terbinafine which is an essential component of the pharmaceutical composition of the present invention and / or a salt thereof The pharmaceutical composition of the present invention comprises the above-mentioned vinylpyrrolidone-N,
N′-dimethylaminoethyl methacrylic acid copolymer diethyl sulfate, N-methacryloyloxyethyl-N,
N′-dimethylammonium-α, N-methylcarboxybetaine / alkyl methacrylate copolymer,
In addition to one or more selected from urea, propylene glycol and sodium pyrrolidonecarboxylate, terbinafine and / or a salt thereof as an active ingredient having an antifungal effect is contained. Terbinafine has already been used as an antifungal agent and its production method is already known. That is, it can be obtained by condensing the corresponding N-methylaminonaphthalene with 1-chloro-6,6-dimethylheptene-4-yne in the presence of an alkali. As a salt thereof, any salt can be applied without particular limitation as long as it forms a salt with a substituted amino group bonded to a naphthalene ring, for example, mineral salts such as hydrochloride, nitrate and sulfate, and citric acid Organic salts such as salts, oxalates and succinates can be preferably exemplified, and hydrochloride is particularly preferred. These may contain only one kind, or may contain two or more kinds in combination. The preferred content of these terbinafine and / or salts thereof in the pharmaceutical composition of the present invention is 0.1 to 10% by weight, more preferably 0.5 to 10% by weight, based on the total amount of the pharmaceutical composition.
~ 7% by weight.

(3) Pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is characterized by containing the above essential components. The administration route of the pharmaceutical composition of the present invention is not particularly limited. However, from the viewpoint of its effect, it is preferable to administer the composition locally, that is, to use it as a skin external preparation including nails. Particularly preferred in such applications are nails that exhibit an unparalleled effect, but because of their excellent permeability in the skin,
Application to the skin also belongs to the technical scope of the present invention. The pharmaceutical composition of the present invention may contain optional components usually used in pharmaceutical compositions in addition to the above essential components. Such optional components include, for example, squalane,
Hydrocarbons such as petrolatum and microcrystalline wax, jojoba oil, carnauba wax, esters such as octyldodecyl oleate, triglycerides such as olive oil, tallow, coconut oil, stearic acid, oleic acid,
Fatty acids such as ritinoleic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, and octyl dodecanol; anionic surfactants such as sulfosuccinates and sodium polyoxyethylene alkyl sulfate; amphoteric interfaces such as lauryl dimethylamine oxide and alkyl betaine salts Surfactants, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts thereof, polyoxyethylene alkyl ethers, nonionic surfactants such as polyoxyethylene fatty acid esters, Polyhydric alcohols such as polyethylene glycol, glycerin, and 1,3-butanediol, acrylic resins not essential components, hydroxypropylcellulose, hydroxypropylmethyl Le cellulose, ethyl cellulose,
Cellulose-based film forming agents such as methylcellulose, triacetin, diethyl phthalate, glyceryl caprylate,
Plasticizers such as triethyl citrate, diethyl adipate, diisopropyl adipate, propylene carbonate, ethylene carbonate, thickening and gelling agents, antioxidants, ultraviolet absorbers,
Preferred examples include a coloring agent, a preservative, and a powder. The pharmaceutical composition of the present invention can be produced by treating these essential components and optional components according to a conventional method.

[0009]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.

<Examples 1 to 5> Pharmaceutical compositions of the present invention were prepared according to the following formulations. That is, the ingredients were stirred and solubilized at room temperature to obtain the pharmaceutical composition of the present invention. These samples were tested for nail penetration of terbinafine hydrochloride using pig nails. That is, the pig nails are 20 μm
And a Teflon O-ring was adhered to the front side with a silicone rubber adhesive, 5 μl of the pharmaceutical composition of Example 1 was applied, and dried at 37 ° C. for 30 minutes. The glass filter was placed in a vial, and the pig nail with the O-ring was gently placed on the glass filter. 1 ml of PBS was added to the glass filter and wetted. This was capped and stored at 37 ° C. for 1 week. After storage, the drug was recovered from the filter and PBS with methanol, quantified by high performance liquid chromatography, and the nail permeability of the drug was calculated. Comparative Example 1 using hydroxypropyl methylcellulose phthalate as an additive component and Comparative Example 2 using shellac
Was also considered. Table 1 shows the results. This indicates that the pharmaceutical composition of the present invention has excellent nail penetration. Additives * 5 parts by weight Water 4 parts by weight Diisopropyl adipate 5 parts by weight Terbinafine hydrochloride 5 parts by weight Ethanol 81 parts by weight

[0011]

[Table 1]

Example 6 A pharmaceutical composition of the present invention was prepared according to the following formulation. That is, the ingredients were stirred and solubilized at room temperature to obtain the pharmaceutical composition of the present invention. This had a more excellent drug penetration promoting effect than the additive alone. Vinylpyrrolidone-N, N'-dimethylaminoethyl methacrylic acid copolymer diethyl sulfate 5 parts by weight Sodium pyrrolidonecarboxylate 1 part by weight Water 3 parts by weight Propylene glycol 5 parts by weight Urea 1 part by weight Terbinafine hydrochloride 5 parts by weight Ethanol 80 parts by weight Department

Example 7 A pharmaceutical composition of the present invention was prepared according to the following formulation. That is, the ingredients were stirred and solubilized at room temperature to obtain the pharmaceutical composition of the present invention. This had a more excellent drug penetration promoting effect than the additive alone. N-methacryloyloxyethyl-N, N'-dimethylammonium-α, N-methylcarboxybetaine / alkyl methacrylate copolymer 5 parts by weight Sodium pyrrolidonecarboxylate 1 part by weight Water 3 parts by weight Propylene glycol 5 parts by weight Urea 1 Parts by weight terbinafine hydrochloride 5 parts by weight ethanol 80 parts by weight

[0014]

According to the present invention, it is possible to provide a pharmaceutical composition suitable for antifungal diseases, especially for tinea unguium.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61P 31/10 A61P 31/10 (72) Inventor Yasuyuki Kawakatsu 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture F-term in Totsuka Laboratory Co., Ltd. (reference) 4C076 AA07 BB31 CC31 CC41 DD38N DD54N DD58N EE11N FF34 4C206 AA01 AA02 FA07 MA83 NA10 NA11 ZA89 ZB35

Claims (3)

[Claims] 1) Terbinafine and / or a salt thereof and 2) vinylpyrrolidone-N, N'-dimethylaminoethyl methacrylic acid copolymer diethyl sulfate, N-methacryloyloxyethyl-N, N'-dimethylammonium- An antifungal pharmaceutical composition comprising α, N-methylcarboxybetaine / alkyl methacrylate copolymer, urea, propylene glycol and one or more selected from sodium pyrrolidonecarboxylate. . 2. The antifungal pharmaceutical composition according to claim 1, which is for tinea unguium. 3. The antifungal pharmaceutical composition according to claim 1, which is an external preparation for skin.