JP2012184269A - Acitazanolast-containing composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide composition which contains an antihistaminic together with acitazanolast and/or its salt, which exhibits an excellent antiallergic action and gives a good use feeling with reduced irritation to the mucous membrane and the skin and uncomforts (stickiness, sense of foreign body and bad taste).SOLUTION: The composition is prepared by compounding (i) acitazanolast and/or its salt, (ii) an antihistaminic and (iii) menthol.

Description

  The present invention relates to a composition containing acitazanolast and / or a salt thereof and an antihistamine, which has no irritation and good usability.

  Acitazanolast has pharmacological actions such as anti-allergy and lowering of intraocular pressure, and is used in combination with eye drops (for example, see Patent Document 1). In the pharmaceutical field, in general, various pharmacological components are used in combination for the purpose of enhancing or imparting a pharmacological action. Even in a pharmaceutical composition containing acitazanolast, allergies can be achieved by adding an antihistamine. It has been found that it can have an effect of comprehensively suppressing the symptoms associated with.

  On the other hand, it has been found that Acitazanolast hardly feels irritation and discomfort even when applied to mucous membranes and skin. In addition, when antihistamines are applied to mucous membranes and skin, some irritation and discomfort may be felt within the allowable range for use. However, when acitazanolast and antihistamine are used in combination on mucous membranes and skin, the perceived irritation and discomfort (specifically, stickiness, foreign body feeling, unpleasant taste, etc.) are enhanced, and the feeling of use is extremely high. There is a problem of getting worse.

  Therefore, in order to use a pharmaceutical composition in which acitazanolast and an antihistamine are used in combination, it is indispensable to improve the feeling of use and to improve the sensation and discomfort that are inevitably generated.

Conventionally, various formulations for improving the feeling of use of the composition applied to mucous membranes and skin have been reported. For example, it is known that a feeling of use when applied to the skin or mucous membrane can be improved by blending a xanthine derivative such as caffeine or theophylline together with a compound that causes unpleasant irritation (for example, Patent Document 2) reference). However, it is not known what effect menthol or chlorobutanol exerts on the irritation and discomfort caused by the combined use of acitazanolast and an antihistamine.
Japanese Patent Laid-Open No. 9-30968 JP 2003-137781 A

  The present invention contains an antihistamine together with acitazanolast and / or a salt thereof, and can exhibit an excellent antiallergic action, and also causes irritation to mucous membranes and skin, stickiness, foreign body feeling, unpleasant taste, etc. An object of the present invention is to provide a composition that is reduced and has a good feeling in use.

The present inventor has conducted extensive research to solve the above-mentioned problems, and in the composition containing (i) acitazanolast and / or a salt thereof and (ii) an antihistamine, (iii) blending menthol. Thus, it was found that irritation and discomfort to the mucous membrane and skin can be suppressed, and a good feeling of use can be obtained. Furthermore, it has been found that a better feeling of use can be realized by setting the blending ratio of menthol to 0.0002 to 0.004% by weight, and that the feeling of use can be further improved by blending chlorobutanol with menthol. The present invention has been completed by further studies based on these findings.

That is, the present invention provides the following compositions:
Item 1. A composition comprising (i) acitazanolast and / or a salt thereof, (ii) an antihistamine, and (iii) menthol.
Item 2. Item 3. The composition according to Item 1, comprising the component (0.0002 to 0.004% by weight).
Item 3. Item 3. The composition according to Item 1 or 2, further comprising (iv) chlorobutanol.
Item 4. (ii) The composition according to any one of Items 1 to 3, wherein the antihistamine is at least one selected from the group consisting of diphenhydramine, chlorpheniramine, and salts thereof.
Item 5. Item 5. The composition according to any one of Items 1 to 4, which is a preparation for topical mucosa.
Item 6. Item 6. The composition according to any one of Items 1 to 5, which is an ophthalmic composition.

Furthermore, as a preferable embodiment of the composition of the present invention, specifically, the following composition is provided:
1-1. It comprises (i) acitazanolast and / or a salt thereof, (ii) an antihistamine, and (iii) menthol, and contains (iii) component in a proportion of 0.0002 to 0.004% by weight. And a composition.
1-2. The composition according to 1-1, further comprising (iv) chlorobutanol.
1-3. (Ii) The composition according to 1-1 or 1-2, wherein the antihistamine is at least one selected from the group consisting of diphenhydramine, chlorpheniramine, and salts thereof.
1-4. The composition according to any one of 1-1 to 1-3, which is a topical mucosa-applied preparation.
1-5. The composition according to any one of 1-1 to 1-4, which is an ophthalmic composition.
2-1. A composition comprising (i) acitazanolast and / or a salt thereof, (ii) an antihistamine, (iii) menthol, and (iv) chlorobutanol.
2-2. (Ii) The composition according to 2-1, wherein the antihistamine is at least one selected from the group consisting of diphenhydramine, chlorpheniramine, and salts thereof.
2-3. The composition according to 2-1 or 2-2, which is a preparation for topical mucosa.
2-4. The composition according to any one of 2-1 to 2-3, which is an ophthalmic composition.
3-1. An ophthalmic composition comprising (i) acitazanolast and / or a salt thereof, (ii) an antihistamine, and (iii) menthol (excluding a composition containing a xanthine derivative) .
3-2. The composition according to 3-1, further comprising (iv) chlorobutanol.
3-3. (Ii) The composition according to 3-1 or 3-2, wherein the antihistamine is at least one selected from the group consisting of diphenhydramine, chlorpheniramine, and salts thereof.
3-4. The composition according to any one of 3-1 to 3-3, which is a topical mucosa-applied preparation.

  Hereinafter, the present invention will be described in detail.

  The composition of the present invention contains acitazanolast and / or a salt thereof as component (i).

Acitazanolast is a 3- (1H-tetrazol-5-yl) oxanilic acid (IUPAC
Name), a known compound represented by the molecular formula C ₉ H ₇ N ₅ O ₃ . The compound is synthesized by a known method.

  The salt of acitazanolast is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include inorganic salts such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), and other metal salts (aluminum salts, etc.); Examples thereof include organic salts such as amine salts, triethylamine salts, diethylamine salts, and triethanolamine salts. These salts of acitazanolast may be used alone or in any combination of two or more.

Acitazanolast and a salt thereof used in the present invention may be in the form of a hydrate such as a half hydrate or a monohydrate.

  In the composition of the present invention, ititazanolast monohydrate is preferably used.

The blending ratio of the component (i) in the composition of the present invention is appropriately set according to the use and form of the composition. Usually, the blending ratio of the component (i) in the composition is 0.0001 to 2% by weight, preferably 0.0005 to 1% by weight, more preferably 0.001 to 0.5% by weight, and particularly preferably 0.005 to 0.11% by weight. % Is exemplified.

  The composition of the present invention contains an antihistamine as the component (ii).

  The antihistamine to be blended in the composition of the present invention is not particularly limited as long as it is pharmaceutically or pharmaceutically acceptable. Specific examples of antihistamines include ketotifen, bepotastine, chlorpheniramine, diphenhydramine, diphenylpyralin, iproheptin, emedastine, clemastine, azelastine, levocabastine, olopatadine, hydroxyzine, mequitazine, loratadine, fexofenadine, oxetiridine, cetirizine, cetirizine Epinastine, astemizole, ebastine, and salts of these compounds. The salt of the above compound is not particularly limited as long as it is pharmacologically or physiologically acceptable, and examples thereof include various salts such as organic acid salts, inorganic acid salts, and metal salts. Specific examples include chlorpheniramine maleate, diphenhydramine hydrochloride, diphenhydramine salicylate, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, diphenylpyralin hydrochloride, and the like. Among these antihistamines, diphenhydramine, chlorpheniramine, and salts thereof are preferable, and diphenhydramine hydrochloride and chlorpheniramine maleate are more preferable. In the present invention, these antihistamines may be used alone or in any combination of two or more.

Among the above components (i) and (ii), when (i) acitazanolast and / or a salt thereof and (ii) diphenhydramine, chlorpheniramine, and a salt thereof are used in combination, irritation and discomfort may occur. The manifestation tends to be particularly significant. In contrast, according to the present invention, (iii) described later.
Component (iv) to component (iv) can be used to improve the feeling of use for these combinations of components, so a composition containing component (i) and (ii) is put into practical use. It is particularly useful in doing so.

In the composition of the present invention, the blending ratio of the component (ii) is appropriately set according to the type of the component (ii), the use and form of the composition, and the like. Usually, the mixing ratio of the component (ii) in the composition is 0.0001 to 0.5% by weight, preferably 0.0005 to 0.1% by weight, more preferably 0.001 in terms of the total amount of the components.
-0.05 wt% is exemplified.

In the composition of the present invention, the blending ratio of the component (ii) to the component (i) is not particularly limited, but for example, the component (ii) is added to 100 parts by weight of the component (i). The ratio is 0.1 to 10,000 parts by weight, preferably 0.45 to 2000 parts by weight, and more preferably 0.9 to 1000 parts by weight.

Furthermore, the composition of the present invention contains menthol as the component (iii). The menthol used in the present invention may be any of d-form, l-form and dl-form, but is preferably l-form. By containing menthol in combination with the above components (i) and (ii), a good feeling of use can be obtained without including other stimulus-reducing components such as xanthine derivatives. Here, the xanthine derivative is a compound represented by the following formula (1). Specific examples thereof include caffeine, theophylline, oxtriphyrin, diphylline, diisobutylaminobenzoyloxypropyltheophylline, theobromine, diprofylline, proxyphylline. And pentoxifylline.

[Wherein R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl] Group). ]

In the composition of the present invention, the blending ratio of the component (iii) is appropriately set according to the type of the component (iii), the use and form of the composition, and the like. Usually, the blending ratio of the component (iii) in the composition is 0.00015 to 0.5% by weight, preferably 0.0002 to 0.05% by weight, more preferably 0.0003 to 0.036.
Weight percent is exemplified.

  In particular, from the viewpoint of more effectively expressing the action of reducing irritation felt when applied to mucous membranes or skin and the action of improving discomfort, the blending ratio of the component (iii) in the composition is preferably 0.0002 to 0.004 wt. %, More preferably 0.0003 to 0.003% by weight.

  The component (iii) preferably satisfies the above blending ratio, and the blending ratio with respect to the above component (i) preferably satisfies the following range: The above (iii) ) Component is 0.04 to 400 parts by weight, preferably 0.18 to 60 parts by weight, more preferably 0.3 to 30 parts by weight.

  In the composition of the present invention, in addition to the above components (i) to (iii), further containing chlorobutanol as component (iv) further improves irritation and discomfort and further improves the feeling of use. Is planned.

The blending ratio of the component (iv) can be appropriately set according to the form and use of the composition, the blending ratio of the components (i) to (iii), and the like. In the composition, the proportion of the component is usually 0.005 to 0.4% by weight, preferably 0.01 to 0.26% by weight, more preferably 0.05 to 0.2% by weight.
Further, the component (iv) preferably satisfies the above-mentioned blending ratio, and further, the blending ratio with respect to the above-mentioned (i) component satisfies the following range: Component (iv) is usually 2 to 26000 parts by weight, preferably 45 to 4000 parts by weight, more preferably 50 to 400 parts by weight.

  Further, the composition of the present invention may contain a fragrance component such as borneol, geraniol, bergamot oil, eucalyptus oil, camphor, phenylethyl alcohol, cool mint oil, mint oil, mint water, fennel oil, and rose oil. Good. Of these fragrance components, any of d-form, l-form, and dl-form may be used for compounds having optical isomers. These perfume ingredients may be used alone or in any combination of two or more.

  Examples of the blending ratio of the fragrance component include 0.00001 to 0.5% by weight, preferably 0.00005 to 0.1% by weight, and more preferably 0.0001 to 0.05% by weight in the composition.

  The composition of the present invention may contain a combination of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients as long as the effects of the present invention are not hindered. The type of such components is not particularly limited, and examples thereof include a decongestant component, an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antiallergic component, vitamins, amino acids, an antibacterial component or a bactericidal agent. Examples include components, saccharides, polymer compounds or derivatives thereof, cellulose or derivatives thereof, local anesthetic components, steroid components, glaucoma treatment components, and cataract treatment components. Examples of the pharmacologically active component / physiologically active component suitable in the present invention include the following components.

  Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.

  Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.

  Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, Diclofenac sodium, bromfenac sodium, berberine chloride, berberine sulfate, etc.

  Antiallergic ingredients: for example, amlexanox, ibudilast, tazanolast, tranilast, isotipezil, dipheterol, triprolidine, tripelamine, tongylamine, mebhydroline, phenetazine, oxatomide, suplatast, sodium cromoglycate, pemirolast potassium and the like.

  Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, tocopherol nicotinate, succinic acid Tocopherol, tocopherol calcium succinate, ubiquinone derivatives, etc.

  Amino acids: for example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, glutamic acid, sodium glutamate, magnesium glutamate, epsilon-aminocaproic acid, glycine , Alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.

Antibacterial component or bactericidal component: for example, aminodeoxykanamycin sulfate, kanamycin sulfate, gentamicin sulfate, sisomycin sulfate, streptomycin sulfate, tobramycin, micronomycin sulfate, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, Sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomethazole sodium, sulfisomidine sodium, tetracycline hydrochloride, oxytetracycline hydrochloride, ofloxacin, Norfloxacin, Levofloxacin, Lomefloxacin hydrochloride, Sulbenicin sodium, Cefmenoxime hydrochloride, Benzylpenicillin potassium, Verbe sulfate , Berberine chloride, boric acid, sodium colistin metasulfonate, erythromycin, erythromycin lactobionate, kitasamycin, spiramycin, fradiomycin sulfate, polymyxin sulfate, dibekacin, amikacin, amikacin sulfate, acyclovir, iododeoxycytidine, idoxuridine , Cyclocytidine, cytosine arabinoside, trifluorothymidine, bromodeoxyuridine, polyvinyl alcohol iodine, iodine, amphotericin B, isoconazole, econazole, clotrimazole, nystatin, pimaricin, fluorocytosine, miconazole and the like.

  Saccharides: for example monosaccharides, disaccharides, specifically glucose, fructose, galactose, mannose, ribose, allose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, glucobiose, vicyanose, lutinose, Lactose, pullulan, lactulose, raffinose, maltitol, stachyose, cyclodextrin, xylitol, sorbitol, mannitol, etc.

  High molecular compound or derivative thereof: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac gum, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin Collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, sodium hyaluronate, chondroitin sulfate, ceramide, polyvinyl alcohol (complete or partial ken ), Polyvinylpyrrolidone, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, Okishiribo nucleic acids, and the like pharmaceutically acceptable salts.

  Cellulose or derivatives thereof: for example, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxyethyl cellulose, nitrocellulose and the like.

  Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride.

  Steroid component: for example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

Glaucoma treatment components: for example, isopropyl unoprostone, epinephrine, apraclonidine hydrochloride, carteolol hydrochloride, dipivefrin hydrochloride, dorzolamide hydrochloride, pilocarpine hydrochloride, bunazosin hydrochloride, bupranolol hydrochloride, betaxolol hydrochloride, benololol hydrochloride, carbachol, levobunolol hydrochloride, epinephrine hydrochloride , Distigmine bromide, nipradilol, timolol maleate, latanoprost and the like.

  Cataract treatment component: for example, glutathione, pirenoxine, sodium 5,12-dihydroazapentacene disulfonate and the like.

  The compounding amounts of various components are known in the fields of external use and mucosal preparations, and the compounding amounts of the above components in the composition are appropriately selected according to the dosage form of the composition, the type of active ingredient, and the like. For example, the blending ratio of the various components can be selected from the range of about 0.0001 to 30% by weight, preferably about 0.001 to 10% by weight, based on the entire composition.

  Further, in the composition of the present invention, various components and additives are appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired, and one or more are used in combination. And may be contained. As those components or additives, for example, carriers (aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of semi-solids and liquids, thickeners, sugars, sugar alcohols, surface activity And various additives such as agents, preservatives, bactericides or antibacterial agents, pH adjusters, isotonic agents, chelating agents, buffers, stabilizers, bases and the like.

  Although the typical component used for the composition of this invention below is illustrated, it is not limited to these.

  Carrier: aqueous solvent such as water or water-containing ethanol.

  Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate and the like.

  Sugars: for example, glucose, cyclodextrin and the like.

  Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.

Surfactant: For example, polyoxyethylene (hereinafter abbreviated as POE) -polyoxypropylene (hereinafter abbreviated as POP) block copolymer (specifically, poloxamer 407, etc.), ethylenediamine POE-POP block copolymer adduct ( Specifically, non-ionic surfactants such as poloxamine), POE sorbitan monooleate, POE hydrogenated castor oil (specifically, POE (60) hydrogenated castor oil), polyoxyl stearate; alkyldiaminoethyl Glycine-type amphoteric surfactants such as glycine; alkyl quaternary ammonium salts (specifically, cationic surfactants such as benzalkonium chloride and benzethonium chloride. The numbers in parentheses indicate the number of moles added.

  Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glow Kill (manufactured by Rhodia) Name) etc.

  pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, boro Sand, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, ammonium acetate ,Such.

  Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.

  Chelating agent: for example, ascorbic acid, tetrasodium edetate, sodium edetate, citric acid and the like.

  Stabilizers: dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.

  Base: Octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, camellia oil, corn oil, rapeseed oil, cottonseed oil, paraffin, castor oil, plastibase, peanut oil, lanolin, petrolatum, propylene glycol, etc.

  The composition of the present invention is not particularly limited as to its dosage form, and widely includes dosage forms such as liquids, ointments, creams, gels, lotions, patches, sprays, aerosols and the like. Of these, liquids and ointments are preferred.

  The composition of the present invention can be produced according to a usual method by appropriately using an appropriate base or additive depending on the dosage form and the like.

  The composition of the present invention can provide not only the effect of suppressing the release of allergen-causing substances, but also the immediate effect on allergic symptoms such as itching that cannot be obtained with an antiallergic agent alone. In addition, since the irritation felt when applying both components of acitazanolast and antihistamine is reduced and the feeling of use is good, mucous membranes that easily feel irritation (corneal and conjunctival ocular mucosa, gums, tongue, lips, (Oral mucosa, nasal mucosa, pharyngeal mucosa, etc.). For example, it can be used as a pharmaceutical composition applied transmucosally or transdermally, a contact lens mounting solution, a contact lens preparation and the like. Examples of such compositions are eye drops (eye drops), eye washes (eye wash), eye ointments, nasal drops (nasal drops), nasal rinses, oropharyngeal drugs, mouthwashes, ear drops, hulls Ointment, skin cream, skin liquid, contact lens mounting liquid, contact lens liquid (cleaning liquid, preservative liquid, disinfecting liquid, multipurpose solution, etc.). In this specification, the contact lens includes all types of contact lenses such as hard contact lenses (including oxygen permeable hard contact lenses) and soft contact lenses. Among these, preferably, preparations for topical mucosa such as eye drops (eye drops), eye wash (eye drops) and nasal drops can be mentioned. Further, as another preferred example of the composition of the present invention, a composition used in the ophthalmic field, that is, an eye drop (eye drop), an eye wash (eye wash), an eye ointment, a contact lens mounting liquid, a contact An ophthalmic composition such as a lens preparation may be mentioned.

In particular, when the composition of the present invention is prepared as an ophthalmic composition, an embodiment of the ophthalmic composition includes a composition not containing a xanthine derivative.

  According to the composition of the present invention, in a composition in which acitazanolast and an antihistamine are used in combination, the effect of both these components is effectively exhibited, while the inevitable irritation and stickiness, foreign body, unpleasant taste This can improve the feeling of discomfort and improve the feeling of use. Therefore, the composition of the present invention is particularly a topical mucosa applied to mucous membranes (eg, ocular mucosa, gums, tongue, lips, oral mucosa, nasal mucosa, pharyngeal mucosa, etc.) that tend to feel irritation and discomfort. It is useful as an applicable formulation.

Hereinafter, the present invention will be described in detail based on test examples, examples, and the like, but the present invention is not limited thereto.
Test example 1
Eye drops (Example 1-2 and Comparative Example 1-3) having the compositions shown in Table 1 were prepared, and the degree of discomfort was evaluated using a visual analog scale (VAS) using these eye drops. In particular,
The above-mentioned eye drops are instilled on four panelists, and a line of 10 cm is drawn for each of the four items “feeling of irritation”, “feeling of stickiness”, “feeling of a foreign object” and “unpleasant taste” felt at the time of instillation. The subjective symptom survey sheet is 0 cm when you do not feel it, 5 cm when you feel it, and 10 cm when you feel strong, and check the level of the symptoms felt by the panelists. The thickness (cm) was measured and used as the discomfort score. The degree of discomfort was evaluated by calculating the average score of four panelists for each evaluation item. Moreover, the test was carried out using an eye drop of the same formulation as in Comparative Example 1 except that it did not contain acitazanolast monohydrate, and the average value was subtracted from each score. Furthermore, the total discomfort score of each item was used as the total discomfort index, and the overall discomfort level at the time of instillation was calculated and compared.

The obtained results are also shown in Table 1. From this result, even with diphenhydramine, discomfort was felt slightly when instilled, and the degree of discomfort increased dramatically when combined with acitazanolast (see Comparative Example 1-3). On the other hand, in the composition containing menthol together with diphenhydramine and acitazanolast, an improvement effect was observed in all items of irritation, stickiness, foreign body sensation, and unpleasant taste. In particular, when the blending ratio of menthol is 0.004% by weight or less, it was revealed that an excellent stimulus reduction effect was recognized and an improved usability was obtained. Furthermore, it was confirmed that the feeling of use is improved by blending chlorobutanol with menthol.

Test example 2
An eye drop (Example 3-4 and Comparative Example 4-6) having the composition shown in Table 2 was prepared, and evaluation of “feeling of irritation” felt at the time of eye drop by using a visual analog scale (VAS) with these eye drops. A test was conducted. This test was conducted by two panelists in the same manner as in Test Example 1 above. The feeling of irritation was evaluated by calculating the average score of two panelists. In addition, as a blank, the eye drop similar to the comparative example 4 was used except not including agitazanolast.

  The obtained results are shown in Table 2. Even when chlorpheniramine maleate was used as an antihistamine, as in the case of diphenhydramine hydrochloride, irritation at the time of use was remarkably increased in the presence of acitazanolast (see Comparative Example 4-6). On the other hand, it was confirmed that the irritation feeling at the time of instillation was significantly improved by blending l-menthol or blending l-menthol and chlorobutanol (see Example 3-4).

Example 5-23
According to conventional methods, eye drops, eyewashes, contact lens mounting liquids (referred to as CL mounting liquids in the table) and contact lens disinfectants (in the table, CL disinfecting agents) of the formulations shown in Tables 3 and 4 below. (Noted) was prepared.

Example 24 Ophthalmic Ointment Acitazanolast Monohydrate 100mg
Chlorpheniramine maleate 30mg
l-Menthol 0.3mg
Propylene glycol 500mg
Methyl paraoxybenzoate 300mg
Polyoxyethylene hydrogenated castor oil 2g
3g glyceryl monostearate
Liquid paraffin 10g
White petrolatum
100g total
An eye ointment (sterile preparation) having the above formulation was prepared by a known method.

Example 25 Ophthalmic ointment Acitazanolast monohydrate 100 mg
Diphenhydramine hydrochloride 50mg
l-Menthol 10mg
Chlorobutanol 200mg
Propylene glycol 500mg
Methyl paraoxybenzoate 300mg
Polyoxyethylene hydrogenated castor oil 2g
3.5g glyceryl monostearate
Liquid paraffin 10g
White petrolatum
100g total
An eye ointment (sterile preparation) having the above formulation was prepared by a known method.

Claims (4)

A composition comprising (i) acitazanolast and / or a salt thereof, (ii) an antihistamine, and (iii) menthol.   (iii) The composition of Claim 1 which contains a component in the ratio of 0.0002 to 0.004 weight%.   The composition according to claim 1 or 2, further comprising (iv) chlorobutanol.   The composition according to any one of claims 1 to 3, which is a preparation for topical mucosa.