JP6437148B2 - Composition for external use - Google Patents

Description

  The present invention relates to at least one selected from the group consisting of acyclovir, vidarabine, penciclovir, famciclovir, valacyclovir and salts thereof (hereinafter also simply referred to as “acyclovirs”), a nonionic surfactant, and tocopherol. , An isopropylmethylphenol, camphor, allantoin, cetylpyridinium, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable derivative thereof, and at least one selected from the group consisting of chlorobutanol About.

  Infection with herpes virus (herpes simplex) mainly causes cold sores, and other herpes stomatitis, herpes keratitis, herpes simplex encephalitis, genital herpes, neonatal herpes, herpes meningitis, herpes myelitis and the like. Of these, in cold sores, small blisters around the mouth occur on the face.

  On the other hand, acyclovir and penciclovir, which are known as antiviral agents, have been widely used as therapeutic agents for herpes, and their dosage forms are various, such as oral preparations, injection preparations, and external preparations depending on the affected site. (For example, patent document 1).

  For the treatment of cold sores, external preparations such as ointments are used. In particular, acyclovir is an ingredient that has long been used in the medical field as an ethical drug in the past. In recent years, this ingredient has been approved as an over-the-counter drug, and general consumers also obtain an acyclovir-containing ointment for the treatment of cold sores It became possible to do.

  Among acyclovirs, this acyclovir is particularly poorly soluble, so it can be combined with naphazoline hydrochloride or tetracaine hydrochloride to improve its solubility and improve permeability to the skin and mucous membranes. In addition, various studies have been made on formulation design, such as a method for stably dissolving or dispersing it in a formulation by combining it with a nonionic surfactant (Patent Documents 2 and 3).

  Patent Document 4 discloses an anti-inflammatory action associated with a disease while treating the viral disease with an external preparation for treating a viral skin disease in which acyclovir and vitamin E (tocopherol) and / or squalane are combined. It is described that it can be suppressed without the side effects that occur when a corticosteroid is used as an inflammatory agent.

JP 2000-507111 A JP 2004-196786 A JP 2001-354548 A JP 9-31001 A

  By the way, there are various conditions required for the content specification and stability of ingredients that are generally blended as active ingredients in pharmaceuticals and the like, for example, for vitamins that tend to change with time, 115 to 130% of the nominal content, menthol and In the case of methyl salicylate or the like, an initial blending of 90 to 120% is allowed, but for highly stable components, it may be required to narrow the content regulation according to the actual situation. In any case, in order for the usefulness of the blended components to be exhibited at the time of use, it is desirable to eliminate factors that reduce the content as much as possible and maintain the original content. Thus, maintaining the content stability of the active ingredient over a long period of time is very important from the viewpoint of ensuring the high effectiveness of the pharmaceutical.

  Basically, in the composition for external use, various additives are often used in order to obtain a desired dosage form with formulation. As described in Patent Document 3, a nonionic surfactant is often added.

  When the present inventor examined the formulation of an external preparation containing acyclovirs, when a nonionic surfactant was added, a phenomenon was observed in which the content of acyclovir in the external composition decreased.

  Accordingly, the present invention provides an acyclovir-containing external composition containing a nonionic surfactant, which suppresses a decrease in the stability of the acyclovir by the nonionic surfactant and has a higher active ingredient stability. The purpose is to provide.

  As a result of intensive studies to solve the above problems, the present inventors have found that acyclovir-containing external composition containing a nonionic surfactant, such as tocopherol, isopropylmethylphenol, camphor, allantoin, cetylpyridinium or chlorobutanol In order to complete the present invention, it has been found that by adding a specific component, a decrease in the stability of acyclovirs caused by a nonionic surfactant can be suppressed, and an external composition having a higher stability of the active ingredient can be obtained. It was.

That is, the gist of the present invention is as follows.
<1> (A) at least one selected from the group consisting of acyclovir, vidarabine, penciclovir, famciclovir, valacyclovir and salts thereof, (B) a nonionic surfactant, (C) tocopherol, isopropylmethyl A composition for external use containing at least one selected from the group consisting of phenol, camphor, allantoin, cetylpyridinium, pharmaceutically acceptable salts thereof, pharmaceutically acceptable derivatives thereof and chlorobutanol.

  <2> The external composition according to <1>, wherein the nonionic surfactant (B) is an ester-based nonionic surfactant.

  <3> The ester-based nonionic surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyglycerin fatty acid ester, The composition for external use as described in <2>.

  <4> The composition for external use according to any one of <1> to <3>, comprising 0.001 to 10% by weight of the component (A).

  <5> The external composition according to any one of <1> to <4>, wherein the nonionic surfactant (B) is contained in an amount of 0.01 to 5% by weight.

  <6> The composition for external use according to any one of <1> to <5>, which is used for treatment of viral diseases.

  <7> The composition for external use according to <6>, wherein the viral disease is cold sore.

  According to the present invention, in an acyclovir-containing external composition containing a nonionic surfactant, excellent acyclovir content stability can be achieved.

Hereinafter, the present invention will be described in detail.
[External composition]
The composition for external use of the present invention contains acyclovirs (A), a nonionic surfactant (B) and a specific component (C), and by using these in combination, the nonionic surfactant (B) Even in the presence of, it is possible to achieve excellent acyclovir content stability, thereby maintaining the effectiveness of acyclovir for a long time. Hereinafter, the acyclovirs (A), the nonionic surfactants (B) and (C), which are essential components of the composition for external use of the present invention, and other optional components will be described.

<(A) Acyclovirs>
Acyclovirs (A) are antiviral agents that have been widely used for the treatment of herpes and the like. In the composition for external use of the present invention, the content of acyclovir (A) is usually 0.001 to 10% by weight in 100% by weight of the composition for external use in view of the therapeutic effect of viral diseases (particularly herpes), preferably Is 0.1 to 6% by weight.

  The “acyclovir” in the present invention is at least one selected from the group consisting of acyclovir, vidarabine, pencyclovir, famciclovir, valacyclovir and salts thereof as described above. Examples of the salt include salts of mineral acids such as hydrochloric acid or phosphoric acid, salts of organic acids such as maleic acid or methanesulfonic acid, alkali metal salts such as sodium or potassium, and alkaline earth metal salts. As acyclovirs (A), when the composition for external use of the present invention is applied to cold sores, acyclovir, penciclovir and vidarabine are preferable from the viewpoint of usefulness.

<(B) Nonionic surfactant>
The nonionic surfactant (B) can be used as an emulsifier or a dispersant for improving the dispersibility of components in an external composition containing the acyclovir (A). In addition, since the nonionic surfactant (B) is nonionic and has no electric charge, it does not affect the characteristics of other components so much. Therefore, the acyclovir (A) is contained in the composition for external use. A preferred surfactant for dispersion.

  In the present invention, as the nonionic surfactant (B), nonionic surfactants usually used in pharmaceuticals, quasi drugs and cosmetics are not particularly limited and can be used alone or in combination of two or more. .

  Specific examples of the nonionic surfactant (B) include ester-based nonionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid ester and polyglycerin fatty acid ester; And ether-based nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene glycol, and polyoxyethylene polyoxypropylene alkyl ether.

  Specific examples of the nonionic surfactant (B) include POE (5) hydrogenated castor oil, POE (10) hydrogenated castor oil, POE (20) hydrogenated castor oil, POE (40) hydrogenated castor oil, POE ( 50) hydrogenated castor oil, POE (60) hydrogenated castor oil, POE (100) hydrogenated castor oil, polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80) ), Mono-coconut oil fatty acid polyoxyethylene (20) sorbitan, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan triisostearate, polyoxyethylene (20) sorbitan monoisostearate (20), polyoxyethylene ( 5) Behenyl ether, polyoxyethylene (10) Behenyl ether, polyoxyethylene (20) Behenyl ether, polyoxyethylene oleyl ether (oxyethylene is 3,5,7,10,15,20,50), polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene (POE) ( 1) Polyoxypropylene (hereinafter POP) (4) Cetyl ether, POE (1) POP (1) Cetyl ether, POE (10) POP (4) Cetyl ether, POE (20) POP (4) Cetyl ether, POE ( 20) POP (8) cetyl ether, POE (120) POP (40) glycol, POE (160) POP (30) glycol, POE (196) POP (67) glycol, POE (20) POP (20) glycol, POE (42) POP (67) glycol, POE (54) POP (39) glycol, polyglyceryl monolaurate, decagu monomyristate Examples include lysyl, polyglyceryl monostearate, polyglyceryl monoisostearate, polyglyceryl monooleate, polyglyceryl distearate, polyglyceryl diisostearate, and polyglyceryl condensed ricinoleate.

  Among these, from the viewpoint of formulation stability, an ester-based nonionic surfactant is preferable as the nonionic surfactant (B). Among them, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene Glycerin fatty acid ester is more preferable.

  Specific examples of these polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyglycerin fatty acid ester include POE (40) hydrogenated castor oil, POE (60) hydrogenated castor oil, polyoxyethylene monostearate (20 ) Sorbitan, polyoxyethylene monooleate (20) sorbitan, monococonut oil fatty acid polyoxyethylene (20) sorbitan, polyoxyethylene monopalmitate (20) sorbitan, polyoxyethylene (20) sorbitan triisostearate and monoisostearic acid Polyoxyethylene (20) sorbitan, polyglyceryl monolaurate, decaglyceryl monomyristate, polyglyceryl monostearate, polyglyceryl monoisostearate, polyglyceryl monooleate, distearic acid Polyglyceryl, polyglyceryl diisostearate, and condensed ricinoleic acid polyglyceryl the like.

  In the composition for external use of the present invention, the content of the nonionic surfactant (B) is based on the dispersion effect of the acyclovir (A) and the stability of the preparation with respect to the entire composition for external use (100% by weight). The amount is usually 0.01 to 5% by weight, preferably 0.05 to 5% by weight.

  Further, in the external composition of the present invention, the HLB value of the nonionic surfactant (B) is usually 3 or more and 20 or less, preferably 8 from the viewpoint of the dispersion effect of the acyclovir (A) and the preparation stability. Although it is desirable that it is 19.5 or less, it is not necessarily limited by the HLB value.

  In this specification, the HLB value is calculated by the Kawakami equation (see below) using the hydrophilic group molecular weight (Mw) and the lipophilic group molecular weight (MO) of the nonionic surfactant molecule. .

<(C) component>
In addition to the acyclovirs (A) and the nonionic surfactant (B) described above, the composition for external use of the present invention includes tocopherol, isopropylmethylphenol, camphor, allantoin, cetylpyridinium, and pharmaceutically acceptable products thereof. Or at least one selected from the group consisting of pharmaceutically acceptable derivatives and chlorobutanol.

  Tocopherol is a component that has been conventionally blended in anticipation of inflammation or antioxidation as described in Patent Document 4, and isopropylmethylphenol is a component that has been blended conventionally as a bactericidal agent, Camphor is an ingredient that has been conventionally blended as a preservative and a fragrance, etc. Allantoin is a ingredient that has been blended in the treatment of rough skin as a skin protecting ingredient for over-the-counter drugs, and cetylpyridinium (especially cetylpyridinium chloride) It is a component conventionally blended as a bactericidal agent, and chlorobutanol is a component conventionally blended as a preservative.

  When the present inventor adds these specific components to an external composition containing acyclovirs (A) and a nonionic surfactant (B), the stability of the acyclovirs (A) increases (nonionic The decrease in the stability of the acyclovirs (A) due to the surfactant (B) is suppressed), and the content of the acyclovirs (A) in the composition for external use is close to the initial value even after a long period of time. Found to be maintained.

  The tocopherol, its pharmaceutically acceptable salt and its pharmaceutically acceptable derivative (hereinafter collectively referred to as “tocopherol etc.”. The same applies to the following isopropylmethylphenol, camphor, allantoin and cetylpyridinium. As for tocopherol, any of natural products and synthetic products can be used. Specifically, d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol can be used. Is mentioned.

  Specific examples of pharmaceutically acceptable derivatives of tocopherol include tocopherol acetate, tocopherol nicotinate, tocopherol succinate, tocopherol linolenic acid, tocopherol calcium succinate and the like.

  As the tocopherol described above, tocopherol acetate is preferable from the viewpoint of the stabilizing effect of the acyclovir (A).

  In the present invention, the isopropylmethylphenol derivative includes thymol (an isomeric structure of isopropylmethylphenol).

  As the isopropylmethylphenol described above, isopropylmethylphenol and thymol are preferable from the viewpoint of the stabilizing effect of the acyclovir (A).

  As the camphor, either natural products or synthetic products can be used, and any of d-form, l-form or dl-form may be used. Moreover, when using camphor, the essential oil containing camphor can also be used. Examples of such an essential oil include camphor oil.

  As the camphor described above, dl-camphor, d-camphor and camphor oil are preferable from the viewpoint of the stabilizing effect of the acyclovirs (A).

  Specific examples of the pharmaceutically acceptable derivatives of allantoin include allantoinchlorohydroxyaluminum and allantoindihydroxyaluminum.

  As the allantoin described above, allantoin, allantoinchlorohydroxyaluminum and allantoindihydroxyaluminum are preferable from the viewpoint of the stabilizing effect of the acyclovirs (A).

  Specific examples of the pharmaceutically acceptable salt of cetylpyridinium include cetylpyridinium bromide and cetylpyridinium chloride.

  As the cetylpyridinium described above, cetylpyridinium chloride is preferable from the viewpoint of the stabilizing effect of the acyclovir (A).

  The content of the component (C) described above in the composition for external use of the present invention is as follows. For example, “content of tocopherol” refers to the total content of tocopherol, its pharmaceutically acceptable salts and derivatives. The same applies to the following isopropylmethylphenol, camphor, allantoin, and cetylpyridinium.

  In the external composition of the present invention, the tocopherol content is usually 0.01 to 10% by weight, preferably 0.01 to 5% by weight, based on the total weight (100% by weight) of the external composition. . If it is less than 0.01% by weight, a sufficient acyclovir (A) stabilizing effect may not be obtained, and if it exceeds 10% by weight, problems such as irritation may occur.

  In the external composition of the present invention, the content of isopropylmethylphenol is usually 0.01 to 5% by weight, preferably 0.01 to 1% by weight, based on the total weight (100% by weight) of the external composition. It is. If it is this range, sufficient acyclovir (A) stabilization effect will be acquired.

  In the external composition of the present invention, the camphor content is usually 0.001 to 10% by weight, preferably 0.01 to 5% by weight, based on the total weight (100% by weight) of the external composition. . If it is less than 0.001% by weight, a sufficient acyclovir (A) stabilizing effect may not be obtained, and if it exceeds 10% by weight, problems such as irritation may occur.

  In the composition for external use of the present invention, the content of allantoin is usually 0.0001 to 5% by weight, preferably 0.01 to 3% by weight, based on the total weight (100% by weight) of the composition for external use. . If it is less than 0.0001% by weight, a sufficient acyclovir (A) stabilizing effect may not be obtained.

  In the external composition of the present invention, the content of cetylpyridinium is usually 0.001 to 3.0% by weight, preferably 0.01 to 1.% by weight based on the total weight (100% by weight) of the external composition. 0% by weight. If it is less than 0.001% by weight, a sufficient acyclovir (A) stabilizing effect may not be obtained, and if it exceeds 0.5% by weight, the formulation may be affected.

  In the external composition of the present invention, the content of chlorobutanol is usually 0.01 to 1% by weight, preferably 0.01 to 0.5% by weight, based on the total weight (100% by weight) of the external composition. %, More preferably 0.05 to 0.5% by weight. If it is this range, antiseptic sterilization power will be obtained with sufficient acyclovir (A) stabilization effect.

<Other ingredients>
The composition for external use of the present invention contains the acyclovirs (A), nonionic surfactants (B) and (C) components described above, and in addition, according to various purposes, a moisturizing component, a polyhydric alcohol, Other ingredients such as anti-inflammatory agents, astringent ingredients, vitamins, peptides or derivatives thereof, amino acids or derivatives thereof, antibacterial ingredients, keratin softening ingredients, cell activation ingredients, anti-aging ingredients, blood circulation promoting ingredients, etc. You may include in the range which does not impair an effect. In addition, these other components may be used individually by 1 type, or may be used in combination of 2 or more type. Moreover, what corresponds to the following several components shall be added as a component of arbitrary efficacy among them.

  Examples of the moisturizing component include diglycerin trehalose; high molecular compounds such as sodium hyaluronate, heparin-like substance, sodium chondroitin sulfate, collagen, elastin, keratin, chitin, chitosan; amino acids such as glycine, aspartic acid, arginine; Natural moisturizing factors such as sodium, urea and sodium pyrrolidone carboxylate; lipids such as ceramide, cholesterol and phospholipid; plant extract extracts such as chamomile extract, hamamelis extract, tea extract and perilla extract.

  The polyhydric alcohol is preferably one having 2 to 10 carbon atoms, such as glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, 1 , 3-butylene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol, decanediol, neopentyl glycol and the like.

  Among these, glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol Glycerin, diglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, diethylene glycol, isoprene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, and hexanediol are more preferable.

  Examples of the anti-inflammatory agent include glycyrrhetinic acid, glycyrrhizic acid derivatives, azulene, components derived from plants (eg, Comfrey), zinc oxide, aminocaproic acid, and hydrocortisone.

  Examples of the astringent component include zinc oxide, zinc sulfate, aluminum chloride, zinc sulfocolate and tannic acid.

  Examples of the vitamins include vitamin B2 such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5′-phosphate, riboflavin tetranicotinate; nicotinic acid, nicotine Nicotinic acids such as benzyl acid, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, nicotinamide; ascorbigen-A, ascorbic acid stearate, ascorbyl palmitate, Vitamin Cs such as L-ascorbyl dipalmitate; Vitamin Ds such as methyl hesperidin, ergocalciferol, cholecalciferol; phylloquinone, farnoquinone Γ-oryzanol, dibenzoyl thiamine, dibenzoyl thiamine hydrochloride; thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, Vitamin B1 such as thiamine triphosphate, thiamine monophosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate monophosphate; pyridoxine hydrochloride , Vitamin B6 such as pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride; vitamin B12 such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin Folates such as folic acid and pteroylglutamic acid; pantothenic acids such as pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-panthecin, D-panthetin, coenzyme A, pantothenyl ethyl ether; biotin and biocytin Biotins such as ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, vitamin C which is an ascorbic acid derivative such as magnesium ascorbate phosphate; carnitine, ferulic acid, α-lipoic acid, Examples include vitamin-like agents such as orotic acid.

  Examples of the peptide or derivatives thereof include keratin-degrading peptide, hydrolyzed keratin, collagen, collagen derived from fish, 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 Degradation Peptides, acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.) and the like can be mentioned.

  Examples of the 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, cystine, Examples include methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatine and the like.

  Examples of the antibacterial component include chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and derivatives thereof, popidone iodine, potassium iodide, iodine, triclocarban, triclosan, photosensitizer 101, photosensitizer No. 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiaminoglycine hydrochloride, pyroctoolamine, miconazole and the like.

  Examples of the keratin flexible component include lactic acid, salicylic acid, salicylic acid glycolic acid, gluconic acid, citric acid, malic acid, fruit acid, phytic acid, urea, sulfur and the like.

  Examples of the cell activation component include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride and pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid; tannins , Flavonoids, saponins, photosensitive element 301 and the like.

  Examples of the anti-aging component include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivative, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone.

  Examples of the blood circulation promoting component include plants (for example, ginseng, ashitaba, arnica, ginkgo, fennel, enmelio, dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake, ginger, hawthorn, prunus , Cucumber, assembly, thyme, clove, chimpi, capsicum, touki, tonin, spruce, carrot, garlic, butcher bloom, grapes, buttons, maronier, melissa, yuzu, yakuinin, ryokucha, rosemary, rosehip, chimpi, touki, Spruce, peach, apricot, walnut, corn) components; acetylcholine, ictamol, cantalis tincture, gamma oryzanol, cephalanthin, tolazoline, glucosyl hesperi Such as emissions, and the like.

<Method for producing composition for external use>
The method for producing the composition for external use of the present invention is not particularly limited. In addition to the essential components acyclovirs (A), nonionic surfactants (B) and (C), the usual composition for external use is produced. Various components (the above-mentioned other components, bases or carriers described later, additives, etc.) necessary for the preparation can be appropriately selected and blended, and can be produced by a conventional method.

<Use of composition for external use>
Since the composition for external use of the present invention contains acyclovirs (A) as described above, it can be used for the treatment of viral diseases, and can be particularly suitably used for the treatment of cold sores.

<Formulation>
The composition for external use of the present invention comprises the essential components and the other components described above, such as a base or carrier usually used in pharmaceuticals, quasi drugs, or cosmetics, and additives described later as necessary. In addition, it can be mixed according to a conventional method to obtain an external composition in the form of a pharmaceutical, quasi-drug, or cosmetic preparation.

  Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, petrolatum, gelled hydrocarbon (such as plastic base), ozokerite, α-olefin oligomer, and light liquid paraffin; methyl polysiloxane, highly polymerized methyl polysiloxane, cyclic Silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin Silicone oils such as modified branched silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; oils and fats such as coconut oil, olive oil, rice bran oil, and shea butter; jojoba Waxes such as cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, cholesterol and the like; ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. Cellulose derivatives of: polyvinyl pyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; diisopropyl adipate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, tetranoate 2-Ethylhexanoic acid pentaeryth Esters such as lit; polysaccharides such as dextrin and maltodextrin; vinyl polymers such as carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer; lower alcohols such as ethanol and isopropanol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, Ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, etc. Glycol Ether; and water. When the composition for external use of the present invention contains a polyhydric alcohol, the polyhydric alcohol may also serve as a base or a carrier.

  When the composition for external use of the present invention contains a base or carrier other than water, the base or carrier is preferably a higher alcohol, hydrocarbon, fat, ester, silicone oil, wax, and higher alcohol, ester oil. Silicone oil is more preferable. Among these components, cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, glyceryl tri-2-ethylhexanoate, dimethicone, cyclomethicone, polyether-modified silicone, and polyglycerin-modified silicone are more preferable.

  The bases or carriers described above can be used singly or in combination of two or more, and the amount used thereof is appropriately selected from a range known to those skilled in the art.

<Form>
The form of the external composition of the pharmaceutical preparation is not particularly limited, and examples thereof include ointments, solutions, suspensions, emulsifiers (emulsions and creams), gels, liniments, lotions, and poultices. These preparations can be manufactured according to the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.

  The form of the composition for external use of a quasi-drug or cosmetic preparation is not particularly limited, and examples thereof include lotion, emulsion, cream, ointment, hand cream, body lotion, body cream, lip balm and the like. These preparations can be manufactured according to a conventional method.

<Additives>
In the composition for external use of the present invention, known additives that are added to pharmaceuticals, quasi drugs, or cosmetics, for example, surfactants (nonionic surfactants) are added to the extent that the effects of the present invention are not impaired. Except), stabilizers, antioxidants, colorants, pearl luster imparting agents, dispersants, chelating agents, pH adjusters, preservatives, thickeners, irritation reducing agents and the like can be added. These additives can be used alone or in combination of two or more. Moreover, what corresponds to the following several components shall be added as a component of arbitrary functions among them.

  Examples of the surfactant include amines such as stearylamine and oleylamine; silicones such as polyoxyethylene / methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone. And surface active agents.

  Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.

  Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid, L-cysteine hydrochloride, and the like.

  Examples of the colorant include inorganic pigments and natural pigments.

  Examples of the pearl luster imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate.

  Examples of the dispersant include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinyl pyrrolidone, methyl vinyl ether / maleic anhydride crosslinked copolymer, and organic acid.

  Examples of the chelating agent include EDTA · disodium salt and EDTA · calcium disodium salt.

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

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

  Examples of the thickener include cellulose-based thickeners such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, guar gum, pectin, pullulan, gelatin, locust bean Gum, carrageenan, agar, xanthan gum, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, sodium chondroitin sulfate, hyaluronic acid, hyaluronic acid Sodium, (hydroxyethyl acrylate / Acryloyl dimethyl taurine Na) copolymer, and the like (ammonium acryloyldimethyltaurate / vinylpyrrolidone) copolymer.

  Examples of the irritation reducing agent include licorice extract, sodium alginate, gum arabic, polyvinylpyrrolidone, licorice extract, sodium alginate and the like.

<How to use>
The composition for external use of the present invention is useful for the treatment of viral diseases, particularly cold sores as described above. The method of use varies depending on the age of the target of use, but may be the following method, for example.

  That is, an appropriate amount (for example, about 0.05 to 5 g) may be applied to the affected part (skin) several times a day (for example, about 1 to 5 times, preferably 3 to 5 times). Moreover, what is necessary is just to apply | coat a composition so that the daily usage-amount of acyclovir (A) may be about 2.5-250 mg, for example, Preferably it is 2.5-50 mg. The application period may be, for example, 1 to 15 days, preferably 2 to 10 days.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited at all by these.

[Test 1: Stability test]
<Manufacture of test preparations>
(Cream)
The water-soluble component and the oil-soluble component described in Tables 1 and 2 below were mixed and dissolved at 70 to 80 ° C., respectively. Next, the oil phase was gradually added to the aqueous phase with stirring with a homomixer and mixed well. Subsequently, the mixed solution was stirred and mixed so that the acyclovir was sufficiently dispersed. Each test preparation was obtained by cooling with stirring to room temperature.

(Liquid)
Each component described in Tables 3 to 5 below was mixed and dissolved at 70 to 80 ° C. and cooled to room temperature while stirring to obtain each test preparation.

<Test method>
The test preparations of Examples and Comparative Examples in Tables 1 to 5 below were filled in screw bottles, respectively, and stored for 1 week in a thermostatic bath at 60 ° C. After each test preparation after storage was sufficiently returned to room temperature in a 25 ° C. constant temperature bath, the content of acyclovir was quantified by HPLC under the following measurement conditions, and the product immediately after production of each test preparation was used as a standard (100%). As a relative value, the residual ratio of acyclovir was determined. The results are shown in Tables 1-5.

(Quantitative conditions)
Detector: Ultraviolet absorptiometer (measurement wavelength: 254nm)
Column: ODS2 (4.6mm * 15cm).
Column temperature: Constant temperature around 30 ° C Mobile phase solution: Add 1.25 g of phosphoric acid to 25 mL of dilute acetic acid, add water to 900 mL, and add sodium hydroxide.
Adjust the pH to 2.5 with a lithium reagent, and add water to make 1000 mL. This liquid 950
The solution obtained by adding 50 mL of methanol to mL is used as the mobile phase solution.

  The accelerated test condition of storing at 60 ° C. for one week corresponds to the storage condition at room temperature (25 ° C.) for one year. Moreover, in the following Tables 1-5, "remaining amount" is the quantity which makes the quantity of the whole formulation 100 weight%.

<Test results>
Since the test preparations of Comparative Examples 2 and 4 did not contain a nonionic surfactant, a decrease in the content of acyclovir was not observed under storage conditions at 60 ° C. for 1 week, but contained a nonionic surfactant. In Comparative Examples 1, 3, and 5, the content of acyclovir was reduced by about 5-6% under the same storage conditions as before the start of the stability test. At such a rate of content reduction, the content stability of the active ingredient may not be maintained over a long period of time.

  On the other hand, the content of acyclovir in the test preparations of Examples 1 to 23 by further containing any of tocopherol acetate, dl-camphor, chlorobutanol, isopropylmethylphenol, allantoin, and cetylpyridinium chloride under the same storage conditions The decrease was suppressed. Therefore, in these test preparations, the stability of the active ingredient acyclovir is improved, and the drug efficacy is expected to be maintained for a longer period.

[Test 2: Stability test]
<Manufacture of test preparations>
(Cream)
The water-soluble component and the oil-soluble component described in Tables 6 and 7 below were mixed and dissolved at 70 to 80 ° C., respectively. Next, the oil phase was gradually added to the aqueous phase with stirring with a homomixer and mixed well. Subsequently, the mixed solution was stirred and mixed so that the acyclovir was sufficiently dispersed. Each test preparation was obtained by cooling with stirring to room temperature.

<Test method>
The test preparations of Examples and Comparative Examples shown in Tables 6 and 7 below were each filled in a screw bottle and stored in a thermostatic bath at 60 ° C. for 2 weeks. After each test preparation after storage is sufficiently returned to room temperature in a 25 ° C. constant temperature bath, the content of acyclovir is quantified by HPLC under the same measurement conditions as in Test 1, and the product immediately after production of each test preparation is used as a standard (100% The residual ratio of acyclovir was determined as a relative value. The results are shown in Tables 6 and 7.

  The accelerated test condition of storing at 60 ° C. for 2 weeks corresponds to the storage condition at room temperature (25 ° C.) for 2 years. In Tables 6 and 7 below, the “remaining amount” is an amount that makes the total amount of the preparation 100% by weight.

<Test results>
Since the test preparations of Comparative Examples 6 and 10 did not contain a nonionic surfactant, a decrease in the content of acyclovir was not observed under storage conditions at 60 ° C. for 2 weeks, but contained a nonionic surfactant. In the test preparations of Comparative Examples 7, 8, 9 and 11, it was found that the content of acyclovir decreased under the same storage conditions. However, by further including any of tocopherol acetate, chlorobutanol, isopropylmethylphenol, and allantoin, the decrease in the content of acyclovir was suppressed in the test preparations of Examples 24-31 under the same storage conditions. In addition, from the results of each example, it was found that the same effect was observed even when the type of nonionic surfactant or the polymerization degree of the polymer was changed.

[Formulation example]
The formulation example of the composition for external use of this invention is shown below. In Tables 8 to 11 below, the “remaining amount” is an amount that makes the total amount of the preparation 100 g.

Claims (9)

(A) at least one selected from the group consisting of acyclovir, vidarabine, penciclovir, famciclovir, valacyclovir and salts thereof;
(B) a nonionic surfactant;
(C) containing tocopherol acetate,
Formula (I)

Wherein R ¹ and R ² are the same or different and each represents a lower alkyl group or a lower alkyl group substituted with one or more substituents selected from substituent group α. Nitroimidazole compounds, pharmacologically acceptable salts thereof, esters thereof or other derivatives thereof,
External composition (excluding external compositions containing hydrocarbon propellant at a concentration of 3% to 25% by weight of the total composition).
[Substituent group α] Halogen atom, hydroxyl group, amino group, aryl group, heteroaryl group, cycloalkyl group and lower alkoxy group. Furthermore, isopropyl methyl phenol, camphor, allantoin, cetylpyridinium, external composition of claim 1 containing at least one selected from the group consisting of pharmaceutically acceptable Shio及 beauty chlorobutanol.   The composition for external use according to claim 1 or 2, wherein the nonionic surfactant (B) is an ester nonionic surfactant.   The ester-based nonionic surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyglycerin fatty acid ester. The external composition in any one of -3.   The external composition according to any one of claims 1 to 4, comprising 0.001 to 10% by weight of the component (A).   The composition for external use according to any one of claims 1 to 5, comprising 0.01 to 5% by weight of the nonionic surfactant (B).   The composition for external use according to any one of claims 1 to 6, comprising 0.01 to 1% by weight of the tocopherol acetate (C).   The composition for external use in any one of Claims 1-7 used for treatment of a viral disease.   The composition for external use according to claim 8, wherein the viral disease is cold sore.