JP5052028B2 - Ashitazanolast-containing composition - Google Patents

Description

  The present invention relates to a composition comprising acitazanolast and / or a salt thereof and an imidazoline-based decongestant. Furthermore, the present invention relates to a stable aqueous composition containing acitazanolast and / or a salt thereof and an imidazoline-based decongestant, which is prevented from being discolored by light exposure.

  It is known that type I allergic symptoms are caused by the release of chemical mediators such as histamine from mast cells and basophils upon contact with allergens. In order to prevent or ameliorate type I allergic symptoms, it is effective to suppress the release of histamine itself, and conventionally, drugs having an inhibitory action on histamine release have been developed and used for the purpose of an antiallergic effect. On the other hand, in recent years, the increase in allergic patients and the seriousness of allergic symptoms have become problems, and the development of pharmaceuticals exhibiting even better antiallergic action is desired.

  Acitazanolast has a histamine release inhibitory action, and is used as an antiallergic agent in eye drops (for example, see Patent Document 1). If the inhibitory action of acitazanolast on histamine release can be enhanced, the antiallergic action can be exhibited more effectively, and as a result, the above-mentioned demands of modern society can be met. However, there is no known method for enhancing the antiallergic action by enhancing the histamine release inhibitory action of acitazanolast.

In the course of studying various prescriptions of pharmaceutical compositions containing acetazanolast as a pharmacologically active ingredient, the present inventors, in an aqueous composition containing acitazanolast and an imidazoline-based decongestant, are exposed to light. It was confirmed that there was a drawback that the composition inevitably turned yellow. Conventionally, it is known that the combination of additives such as an antioxidant, a reducing agent, and a chelating agent may be effective as a means for suppressing discoloration of an aqueous composition. However, since the effectiveness of conventional discoloration suppressing means varies greatly depending on the cause of discoloration, the type of compounding component in the composition, the type of additive compounded to suppress discoloration, etc. It has been found that it is not universally applicable to discoloration suppression. Therefore, since discoloration suppression of the aqueous composition requires individual specific studies depending on the components of the aqueous composition, the discoloration of the aqueous composition containing acitazanolast and an imidazoline-based decongestant At present, it cannot be inferred from the prior art what measures are effective for the suppression.
Japanese Unexamined Patent Publication No. 01-29312

  Hitherto, not only the usefulness of an aqueous composition containing acitazanolast and an imidazoline-based decongestant but also an effective means for suppressing discoloration of the aqueous composition is not known at all.

  In view of this, the first object of the present invention is to provide a composition that uses acitazanolast and / or a salt thereof to more effectively express a histamine release inhibitory action. A second object of the present invention is to provide a stable aqueous composition that contains agitazanolast and / or a salt thereof and an imidazoline-based decongestant and is prevented from being discolored by light exposure. To do. Still another object of the present invention is to provide a method for suppressing discoloration of an aqueous composition containing acitazanolast and / or a salt thereof and an imidazoline-based decongestant due to light exposure.

  The inventors of the present invention have made extensive studies to solve the above-mentioned problems. As a result, (A) agitazanolast and / or a salt thereof and (B) an imidazoline-based decongestant are combined to provide excellent histamine release inhibition. It was found that the effect can be expressed. Further, an aqueous composition containing (A) agitazanolast and / or a salt thereof and (B) an imidazoline-based decongestant, (C) (c-1) thiosulfate, (c-2) sulfite (C-3) ethylenediaminetetraacetic acid or a salt thereof, (c-4) citric acid or a salt thereof, (c-5) vitamin E, (c-6) benzalkonium chloride, (c-7) sorbic acid or A salt thereof, (c-8) alkyldiaminoethylglycine or a salt thereof, (c-9) benzethonium chloride, (c-10) allantoin and (c-11) a polyoxyethylene sorbitan fatty acid ester. It has been found that by blending one kind, discoloration due to light exposure can be suppressed and excellent stability can be provided, and an aqueous composition having high medicinal or pharmaceutical utility can be provided. The present invention has been completed by making further improvements based on such findings.

That is, the present invention is a composition listed below:
Item 1. (A) at least one selected from the group consisting of acitazanolast and a salt thereof, and
(B) A composition comprising an imidazoline-based decongestant.
Item 2. Item 2. The composition according to Item 1, wherein the component (B) is at least one selected from the group consisting of tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline, tramazoline, timazoline, methizolin, and salts thereof.
Item 3. Item 3. The composition according to Item 1 or 2, which is an aqueous composition.
Item 4. Item 4. The composition according to any one of Items 1 to 3, which is a topical mucosa application agent.
Item 5. (C) (c-1) thiosulfate, (c-2) sulfite, (c-3) ethylenediaminetetraacetic acid or salt thereof, (c-4) citric acid or salt thereof, (c-5) Vitamin E, (c-6) benzalkonium chloride, (c-7) sorbic acid or its salt, (c-8) alkyldiaminoethylglycine or its salt, (c-9) benzethonium chloride, (c-10) Item 5. The composition according to any one of Items 1 to 4, comprising at least one selected from the group consisting of allantoin and (c-11) polyoxyethylene sorbitan fatty acid ester.

Moreover, this invention is the discoloration suppression method hung up below.
Item 6. (C) (c-1) a thiosulfate salt in an aqueous composition containing (A) at least one selected from the group consisting of acitazanolast and a salt thereof, and (B) an imidazoline-based decongestant, (c-2) sulfite, (c-3) ethylenediaminetetraacetic acid or its salt, (c-4) citric acid or its salt, (c-5) vitamin E, (c-6) benzalkonium chloride, ( c-7) sorbic acid or salt thereof, (c-8) alkyldiaminoethylglycine or salt thereof, (c-9) benzethonium chloride, (c-10) allantoin, and (c-11) polyoxyethylene sorbitan fatty acid ester The method for inhibiting discoloration of the aqueous composition, wherein at least one selected from the group consisting of:

Hereinafter, the present invention will be described in detail. In addition, in this specification, an aqueous composition is a composition containing water. Examples of the aqueous composition include those containing 1% by weight or more, preferably 5% by weight or more, more preferably 20% by weight or more, and particularly preferably 50% by weight or more of water in the composition.
1. Composition The composition of the present invention comprises the following components (A) and (B).

The composition of the present invention contains at least one selected from the group consisting of acitazanolast and a salt thereof as component (A). Acitazanolast is a known compound represented by 3- (1H-tetrazol-5-yl) oxanilic acid (IUPAC name), 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 present invention, it is preferable to use acitazanolast monohydrate as the component (A).

  The blending ratio of the component (A) in the composition of the present invention is appropriately set according to the use and form of the composition.For example, if the composition of the present invention is an aqueous composition, it is usually As a blending ratio of the component (A) in the aqueous composition, the total amount of the component (A) is 0.001 to 2.0 w / v%, preferably 0.005 to 1.0 w / v%, more preferably 0.01 to 0.5 w / v%. Particularly preferably, 0.05 to 0.11 w / v% is exemplified.

  The composition of the present invention contains an imidazoline-based decongestant as the component (B). The decongestant is a drug that has an action of alleviating or eliminating hyperemia and is used as a vasoconstrictor. The imidazoline-based decongestant refers to a decongestant comprising a compound having an imidazoline skeleton. The component (B) used in the present invention is not particularly limited as long as it is a compound that acts as a decongestant and has an imidazoline skeleton, but preferably is a decongestant comprising a compound having a 2-imidazoline skeleton. Agents are exemplified. Specific examples of such a decongestant include tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline, tramazoline, timazoline, methizolin and salts thereof. Examples of the salt form of the compound include inorganic acid salts such as hydrochloride and nitrate. Further, the above compound and its salt may be in the form of a hydrate. Among these, tetrahydrozoline, naphazoline, and salts thereof are preferable from the viewpoint of developing a more excellent histamine release inhibitory action. Of these, tetrahydrozoline hydrochloride, naphazoline hydrochloride, and naphazoline nitrate are particularly preferable.

  In the composition of the present invention, the imidazoline-based decongestant may be used singly or in any combination of two or more.

  The blending ratio of the component (B) in the composition of the present invention varies depending on the type of the component (B), the blending ratio of the component (A), the use and form of the composition, etc. If the composition of the present invention is an aqueous composition, for example, the total amount of component (B) is 0.00005 to 2.0 w / v%, preferably 0.0001 to 1.0 w / v%, more preferably 0.0005 to 0.5 w / v%. Particularly preferably, 0.001 to 0.1 w / v% is exemplified.

  The composition of the present invention may be a composition substantially free of water, but is preferably an aqueous composition that can be easily applied to the skin or mucous membrane. On the other hand, in the case of an aqueous composition containing acitazanolast and an imidazoline-based decongestant, the composition tends to inevitably turn yellow when exposed to light. It is desirable to add a component that suppresses discoloration.

  When the composition of the present invention is an aqueous composition, it is desirable to contain the component (C) described below in addition to the components (A) and (B). In the present invention, the component (C) is (c-1) thiosulfate, (c-2) sulfite, (c-3) ethylenediaminetetraacetic acid or a salt thereof, and (c-4) citric acid or a salt thereof. (C-5) Vitamin E, (c-6) Benzalkonium chloride, (c-7) Sorbic acid or its salt, (c-8) Alkyldiaminoethylglycine or its salt, (c-9) Benzethonium chloride (C-10) allantoin and (c-11) polyoxyethylene sorbitan fatty acid ester. By blending these components (C), it becomes possible to suppress discoloration (yellowing) that inevitably occurs when the aqueous composition containing the components (A) and (B) is exposed to light.

  The specific compound used as the component (C) is not limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Specific examples of the thiosulfate used as the component (c-1) include sodium thiosulfate, potassium thiosulfate, and ammonium thiosulfate. As the thiosulfate, sodium thiosulfate is preferable. A thiosulfate may be used individually by 1 type, or may be used in combination of 2 or more types.

  Specific examples of the sulfite used as the component (c-2) include sodium sulfite, potassium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, sodium disulfite, and potassium disulfite. The sulfite used in the present invention may be in the form of a hydrate. The sulfite is preferably bisulfite, particularly preferably sodium bisulfite. A sulfite may be used individually by 1 type, or may be used in combination of 2 or more types arbitrarily.

  Specific examples of the salt of ethylenediaminetetraacetic acid used as the component (c-3) include disodium ethylenediaminetetraacetate (sodium edetate), tetrasodium ethylenediaminetetraacetate, barium ethylenediaminetetraacetate, calcium calcium ethylenediaminetetraacetate , Ethylenediaminetetraacetic acid cobalt ethylenediaminetetraacetic acid copper, ethylenediaminetetraacetic acid nitric acid, ethylenediaminetetraacetic acid dilithium, ethylenediaminetetraacetic acid dipotassium, ethylenediaminetetraacetic acid iron, ethylenediaminetetraacetic acid lanthanum, ethylenediaminetetraacetic acid magnesium, ethylenediaminetetraacetic acid manganese, ethylenediaminetetraacetic acid nickel , Ethylenediaminetetraacetic acid tripotassium, ethylenediaminetetraacetic acid trisodium, ethylenediaminetetraacetic acid zinc etc. It can be. Ethylenediaminetetraacetic acid or a salt thereof can also be used in the form of a hydrate. Specific examples of the hydrate form include disodium ethylenediaminetetraacetate dihydrate. The component (c-3) is preferably ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, or tetrasodium ethylenediaminetetraacetate. In the present invention, as the component (c-3), ethylenediaminetetraacetic acid or a salt thereof may be used alone, or two or more thereof may be used in combination.

  Examples of the salt of citric acid used as the component (c-4) include inorganic salts and organic salts. Specific examples include sodium citrate (trisodium citrate), disodium citrate, sodium dihydrogen citrate, calcium citrate, and triethyl citrate). The citric acid or salt thereof as the component (c-4) may be in any form of hydrate or anhydride. As the component (c-4), citric acid and sodium citrate are preferable. In the present invention, as the component (c-4), citric acid or a salt thereof may be used alone, or two or more thereof may be used in combination.

  Vitamin E used as the component (c-5) includes α-, β-, γ-, or δ-tocopherol; α-, β-, γ-, or δ-tocotrienol; derivatives thereof (for example, acetic acid Tocopherol, tocopherol nicotinate, tocopherol succinate); vitamin E linoleate and the like. The tocopherol and tocotrienol can be used regardless of whether they are d-form (natural vitamin E or the like) or dl-form. Of these, d-α-tocopherol acetate and dl-α-tocopherol acetate are preferable. In this invention, the said vitamin E may be used individually by 1 type, and may be used in combination of 2 or more type.

  Examples of the salt of sorbic acid used as the component (c-7) include ammonium salts, alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), and others. Inorganic salts such as metal salts (aluminum salts, etc.); organic salts such as methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt . Preferred examples of the component (c-7) include sorbic acid, potassium sorbate, and sodium sorbate.

  Examples of the salt of alkyldiaminoethylglycine used as the component (c-8) include hydrochloride.

  Examples of the polyoxyethylene sorbitan fatty acid ester used as the component (c-11) include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 120, and the like. Preferred examples of the component (c-11) include polysorbate 80.

  Among the components (C), preferably, (c-1), (c-2), (c-3), (c-5), (c-6), (c-7), (c- 8) and (c-11) components, more preferably (c-1), (c-2), (c-6), and (c-7) components. It is possible to effectively suppress discoloration due to light exposure.

  The blending ratio of the component (C) in the aqueous composition is appropriately set according to the type of the component (C), the blending ratio of the components (A) and (B), the use and form of the composition, etc. . Examples of the mixing ratio of the component (C) in the aqueous composition include a ratio in which the total amount of the component (C) is 0.0001 to 5.0 w / v%, preferably 0.0005 to 2.0 w / v%. More specifically, the total amount of the component (C) is further 0.001 to 1.0 w / v%, particularly preferably 0.003 to 0.85 w / v%.

Moreover, the following ranges are preferably exemplified as specific examples of the blending ratio of each component (C) in the aqueous composition:
In the case of the component (c-1) The total amount of the component (c-1) is 0.001 to 2.0 w / v%, preferably 0.01 to 1.0 w / v%, more preferably, based on the total amount of the aqueous composition. Is 0.05 to 0.5 w / v%, particularly preferably 0.1 to 0.2 w / v%.
In the case of the component (c-2) The total amount of the component (c-2) is 0.001 to 2.0 w / v%, preferably 0.01 to 1.0 w / v%, more preferably, based on the total amount of the aqueous composition. Is 0.05 to 0.5 w / v%, particularly preferably 0.1 to 0.4 w / v%.
In the case of the component (c-3) The total amount of the component (c-3) is 0.0001 to 2.0 w / v%, preferably 0.0005 to 1.0 w / v%, more preferably, based on the total amount of the aqueous composition. Is 0.001 to 0.5 w / v%, particularly preferably 0.003 to 0.2 w / v%.
In the case of the component (c-4) The total amount of the component (c-4) is 0.005 to 5.0 w / v%, preferably 0.01 to 2.0 w / v%, more preferably based on the total amount of the aqueous composition. Is 0.05 to 1.0 w / v%, particularly preferably 0.1 to 0.85 w / v%.
In the case of the component (c-5) The total amount of the component (c-5) is 0.0005 to 1.0 w / v%, preferably 0.001 to 0.5 w / v%, more preferably, based on the total amount of the aqueous composition. 0.005 to 0.1 w / v%, particularly preferably 0.01 to 0.05 w / v%. Is exemplified.
In the case of component (c-6) The total amount of component (c-6) is 0.0005 to 0.5 w / v%, preferably 0.001 to 0.1 w / v%, more preferably, based on the total amount of the aqueous composition Is 0.005 to 0.05 w / v%, particularly preferably 0.01 to 0.02 w / v%.
In the case of component (c-7) The total amount of component (c-7) is 0.005 to 2.0 w / v%, preferably 0.01 to 1.0 w / v%, more preferably, based on the total amount of the aqueous composition Is 0.05 to 0.5 w / v%, particularly preferably 0.1 to 0.2 w / v%.
In the case of the component (c-8) The total amount of the component (c-8) is 0.001 to 2.0 w / v%, preferably 0.005 to 1.0 w / v%, more preferably, based on the total amount of the aqueous composition. Is 0.01 to 0.5 w / v%, particularly preferably 0.05 to 0.1 w / v%.
In the case of the component (c-9) The total amount of the component (c-9) is 0.0001 to 0.5 w / v%, preferably 0.0005 to 0.1 w / v%, more preferably, based on the total amount of the aqueous composition Is 0.001 to 0.05 w / v%, particularly preferably 0.005 to 0.01 w / v%.
In the case of the component (c-10) The total amount of the component (c-10) is 0.005 to 2.0 w / v%, preferably 0.01 to 1.0 w / v%, more preferably, based on the total amount of the aqueous composition. Is 0.05 to 0.5 w / v%, particularly preferably 0.1 to 0.3 w / v%.
In the case of the component (c-11) The total amount of the component (c-11) is 0.005 to 2.0 w / v%, preferably 0.01 to 1.0 w / v%, more preferably, based on the total amount of the aqueous composition. Is 0.05 to 0.5 w / v%, particularly preferably 0.05 to 0.3 w / v%.

  In addition, it is desirable that the component (C) satisfies the above-described blending ratio, and that the blending ratio with the component (A) satisfies the following range: (A) 100 parts by weight of the component (C) The component is usually 0.005 to 500,000 parts by weight, preferably 0.05 to 40,000 parts by weight, more preferably 0.2 to 10,000 parts by weight, and particularly preferably 2.5 to 2000 parts by weight.

  In the present invention, the water used in the aqueous composition may be any one that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like can be used. These definitions are based on the 14th revised Japanese Pharmacopoeia.

  Moreover, when making the composition of this invention an aqueous composition, this aqueous composition may contain a solubilizing agent as needed. Examples of such a solubilizer include organic amines such as trometamol, monoethanolamine, diethanolamine, and triethanolamine; surfactants such as polyvinylpyrrolidone and polysorbate; and polyhydric alcohols such as propylene glycol. Among these, the organic amine is a suitable solubilizing agent for dissolving the component (A) to prepare a preparation. These solubilizing agents may be used alone or in any combination of two or more.

  When a solubilizing agent is blended, the blending ratio of the solubilizing agent in the aqueous composition is usually 0.0005 to 5 w / v%, preferably 0.005 to 3 w / v% in the case of an aqueous composition, Preferably, the ratio is 0.05 to 1.03 w / v%.

  When the composition of the present invention is an aqueous composition, the aqueous composition may further contain a buffer. The buffering agent that can be incorporated into the aqueous composition is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid, aspartate, glutamate and the like. These buffering agents may be used alone or in any combination of two or more. Among the above buffering agents, boric acid buffering agents and phosphate buffering agents are suitable. Specific examples of the boric acid buffer include boric acid and salts thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). In particular, boric acid and borax are suitable.

  When a buffering agent is blended in an aqueous composition, the blending ratio of the buffering agent varies depending on the type of buffering agent used and the expected effect and cannot be uniformly defined. In the product, the buffering agent is 0.01 to 3 w / v%, preferably 0.1 to 2 w / v%, more preferably 0.3 to 2 w / v%, particularly preferably 0.5 to 2 w / v%. The ratio which becomes is illustrated.

  In addition, the aqueous composition can be adjusted to a pH within a range acceptable to the living body. The appropriate pH varies depending on the application site, dosage form and the like of the aqueous composition, but is usually 3.5 to 9, preferably 4 to 8, and more preferably about 4.5 to 7. The pH and osmotic pressure can be adjusted by a method known in the art using the buffer, the pH adjuster, tonicity agent, salts, etc. described later.

  The aqueous composition can be further adjusted to an osmotic pressure ratio within a range acceptable for a living body, if necessary. The appropriate osmotic pressure ratio varies depending on the application site, dosage form and the like, but is usually about 0.4 to 2, preferably about 0.5 to 1.8, and more preferably about 0.6 to 1.6. The osmotic pressure can be adjusted by adding an inorganic salt, a polyhydric alcohol, a sugar alcohol, a saccharide or the like.

  The osmotic pressure ratio of the aqueous composition is the ratio of the osmotic pressure of the sample to the osmotic pressure of the 0.9 w / v% sodium chloride aqueous solution based on the 14th revised Japanese Pharmacopoeia. Measure using the method (freezing point depression method). The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500 to 650 ° C for 40 to 50 minutes and then allowed to cool in a desiccator (silica gel). Dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

  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 component is not particularly limited, and examples thereof include an eye regulator component, an anti-inflammatory component or an astringent component, an antihistamine component or 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, water-soluble polymers other than those described above, local anesthetic components, steroid components, glaucoma treatment components, and cataract treatment components. Examples of suitable components in the present invention include the following components.

  Decongestant: α-adrenergic agonists such as β-phenylethylamine derivatives (epinephrine, ephedrine, phenylephrine, methylephedrine, etc.) and pharmaceutically or physiologically acceptable salts thereof (eg epinephrine hydrochloride, ephedrine hydrochloride) Inorganic acid salts such as phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, and organic acid salts such as epinephrine hydrogen tartrate). 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.

  Antihistamine component or antiallergic agent component: for example, amlexanox, ibudilast, tazanolast, tranilast, isothipentyl, dipheterol, diphenylpyraline, triprolidine, tripelenamine, tondilamine, mebhydroline, phenetazine, oxatomide, mequitazine, terfenadine, espinastine, azoestine, astemistatin Cetirizine, loratadine, fexofenadine, suplatast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, pemirolast potassium, chlorpheniramine maleate, emedastine fumarate Clemastine, azelastine hydrochloride, iproheptin hydrochloride, olopatadine hydrochloride, etc.

  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, 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, befnolol 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 in preparations for external use, mucous membranes and the like are known in the art, and the compounding amounts of the above components in the composition of the present invention are appropriately determined according to the dosage form of the composition, the type of active ingredient, etc. Selected. For example, when the composition of the present invention is an aqueous composition, it can be selected from a range of about 0.0001 to 30 w / v%, preferably about 0.001 to 10 w / v% with respect to the entire aqueous 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 solvent, aqueous or oily base, etc.) generally used for the preparation of solid agents, semisolid agents, liquid agents, thickeners, sugars, sugar alcohols , Surfactants, preservatives, bactericides or antibacterial agents, pH adjusters, tonicity agents, fragrances or cooling agents, chelating agents, buffering agents, stabilizers, solubilizers, and the like. it can.

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

  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.

  A fragrance or a refreshing agent: for example, camphor, geraniol, borneol, menthol, leopard, fennel oil, cinnamon oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These may be d-form, l-form or dl-form.

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

  Buffers: potassium aspartate, magnesium aspartate, aminoethylsulfonic acid, epsilon-aminocaproic acid, citrate buffer, acetate buffer, carbonate buffer, borate buffer, phosphate buffer and the like. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, boric acid, borax, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid Such as potassium dihydrogen.

  Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.

  Solubilizer, 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.

  When making the composition of this invention aqueous composition, it can take a various form according to the use. For example, a liquid agent, a semi-solid agent (ointment etc.) etc. are mentioned as a form of an aqueous composition. A liquid agent is preferable.

  Specific examples of liquid preparations include eye drops [however, eye drops include eye drops that can be applied while wearing contact lenses], artificial tears, eye wash [however, eye drops can be washed while wearing contact lenses. Contact lens composition, contact lens mounting fluid, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative), etc. ], Nasal drops, nasal rinses, oropharyngeal drugs, gargles (harvesting agents), ear drops and the like. Moreover, an eye ointment is illustrated as a specific example of a semisolid agent.

  The contact lens composition can be applied to all contact lenses including hard contact lenses and soft contact lenses. Moreover, since the said composition for contact lenses is comprised from the component which is hard to adsorb | suck with respect to especially an oxygen-permeable hard contact lens or a soft contact lens, it is used more suitably with respect to these contact lenses.

  The composition of the present invention contains the component (A) and the component (B), exhibits an enhanced antiallergic effect, and further has a useful pharmacology including a decongestion effect, an intraocular pressure reduction effect and the like. Since it can also exert its action, it is particularly useful as a topical mucosa application agent (for example, eye drops, eye wash, eye ointment, nasal drop, nasal wash, etc.) used by topical application to the mucous membrane. Of these, eye drops, eye washes, and nasal drops are preferable, and eye drops are more preferable.

  The composition of this invention can be manufactured by a well-known method.

  The composition of the present invention is stored and used in a container or package according to its form or use. For example, if it is an aqueous composition, it is stored and used in various containers made of glass or plastic. In particular, the aqueous composition containing the above components (A) to (C) has the advantage of being stable without being discolored even when exposed to light, so that it can be used as a container for containing the aqueous composition. A transparent container in which the inside of the container can be visually recognized from the outside is suitable.

  Examples of the plastic container resin that can contain the aqueous composition include olefin resins (polyethylene, polypropylene, etc.), polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, and hard vinyl chloride resins. And styrene resins (polystyrene, acrylonitrile-styrene copolymer (AS resin), etc.), cellulose acetates and the like. Preferred resins are polyethylene, polypropylene, polyester resins, and polycarbonate resins, and particularly preferred resins are polyester resins.

As the polyester resin, a resin composed of a dicarboxylic acid component (such as an aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid, or naphthalenedicarboxylic acid) and a diol component can be used. Specifically, aromatic polyester resins such as polyalkylene terephthalate [poly C _2-4 alkylene terephthalate such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)], polyalkylene naphthalate [polyethylene naphthalate ( PEN), poly C _2-4 alkylene naphthalate such as polybutylene naphthalate, etc.], polycycloalkylene terephthalate [poly (1,4-cyclohexylene dimethylene terephthalate) (PCT) etc.], polyarylates (bisphenols ( Homopolyesters such as bisphenol-A) and phthalic acids (resins composed of phthalic acid and terephthalic acid). The polyester resin also includes a copolyester containing the homopolyester unit as a main component (for example, 50% by weight or more), a copolymer of the homopolyester (such as a copolymer of PET and PCT), and the like. . Of these, olefin resins (such as polyethylene), aromatic polyester resins (polyethylene terephthalate, polyethylene naphthalate, polyarylate, etc.) and polycarbonate resins are preferred. The polycarbonate-based resin is, for example, an aromatic polycarbonate based on bisphenols (such as bisphenol-A).

2. Discoloration suppression method as described above, (A) acitazanolast and at least one selected from the group consisting of a salt thereof, and (B) to the aqueous composition containing the imidazoline-based decongestants, the (C) By blending the components, discoloration (yellowing) inevitably caused by exposure to light can be suppressed, and the aqueous composition can be stably maintained. Therefore, the present invention, from another point of view, the (A) component and the (B) component, characterized in that the (C) component is blended with the aqueous composition containing the (A) component and the (B) component. A method for suppressing discoloration of a water-containing composition is provided. In the discoloration suppressing method, the types and concentrations of the component (A), component (B), component (C), and other compounding components used, the form of the aqueous composition, etc. are described in “1. Composition It is the same as the case of “.

According to the present invention, the following excellent effects are achieved:
1) By containing (A) agitazanolast and / or a salt thereof and (B) an imidazoline-based decongestant in combination, the histamine release inhibitory action is enhanced and a more excellent antiallergic action can be exhibited. Therefore, the composition of the present invention is useful as an antiallergic preparation.
2) Since the discoloration (yellowing) due to light exposure inevitably generated in the aqueous composition containing the components (A) and (B) can be suppressed by blending the component (C), (A) to ( The aqueous composition containing the component (C) can maintain a clear appearance even when stored and used for a long period of time, and is excellent in stability.

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. The “PIPES buffer” used in the following Test Examples 1 and 2 is 25 mM PIPES (Piperazine-1,4-bis (2-ethanesulfonic acid)), 118 mM NaCl, 7.5 mM KCl, 5.6 mM glucose, 0 An aqueous solution (pH 7.2) containing ₄ mM MgCl ₂ , 3 mM CaCl ₂ and 0.1% BSA (Bovine Serum Albumin).

Test Example 1 Confirmation Test of Histamine Release Inhibitory Action-1
Various compositions were prepared according to the formulation described in Table 1 (Example 1, Comparative Example 1-2, control). The following tests were conducted using these compositions, and the histamine release inhibitory action of each composition was evaluated.

<Test method>
Rat basophil leukemia cell line RBL-2H3 was suspended in DME (Dulbecco's Modified Eagle's Medium) medium supplemented with 10% FBS to a concentration of 2.3 × 10 ⁵ cells / ml. Each well of the plate was seeded. After incubating at 37 ° C. under 5% CO ₂ overnight to allow the cells to adhere to the bottom of the well, 100 μL of each composition shown in Table 1 was added to the well, and 37 ° C. under 5% CO _2. Incubated for 1 hour. Next, 100 μL of 10 μM calcium ionophore (A23187, Cat.C7522 manufactured by SIGMA; diluted with PIPES buffer) was added to each well and incubated at 37 ° C. for 30 minutes. Thereafter, the supernatant of each well was collected, and the histamine concentration of the obtained supernatant was quantified by ELISA. From the quantified histamine concentration, the histamine release inhibition rate (%) was calculated according to the following formula.

<Result>
The obtained results are shown in FIG. The combination of acitazanolast and tetrahydrozoline hydrochloride (Example 1) far outweighs the additive action of acitazanolast alone (Comparative Example 1) and tetrahydrozoline hydrochloride alone (Comparative Example 2). An excellent histamine release inhibitory action was observed.

Test Example 2 Confirmation Test 2 for Inhibiting Histamine Release-2
Various compositions were prepared according to the formulation described in Table 2 (Example 2-3, Comparative Example 3-5, control). Using these compositions, the histamine release inhibitory action was evaluated in the same manner as in Test Example 1.

  The obtained results are shown in FIG. In the case where acitazanolato and naphazoline hydrochloride were combined (Examples 2 and 3), an excellent inhibitory effect on histamine release was observed, and the inhibition rate of histamine release was observed in the case of acitazanolast alone (Comparative Example 3) and that of naphazoline hydrochloride alone. The additive effect of the cases (Comparative Examples 4 and 5) was far greater.

Test Example 3 Discoloration Suppression Effect Confirmation Test-1
According to the formulation described in Table 3, an aqueous composition containing acitazanolast and tetrahydrozoline was prepared (control, Examples 4-14). Using these aqueous compositions, the following tests were conducted and their light stability was evaluated.

  10 mL of each aqueous composition was filled into a transparent glass ampoule tube (capacity 10 mL), and these were used as test samples (n = 2). For this test sample, a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Kagaku Co., Ltd.) was used, and a light of 5000 lx was used at a room temperature of 25 ° C. using a D65 lamp as a light source. Irradiation was continued for 120 hours, and the test solution was exposed to light with an integrated dose of 600,000 lx · hr. For the test sample before and after light irradiation, the absorbance at a wavelength of 420 nm (denoted as A420 in the following formula) is measured as an index of discoloration (coloration to yellow), and the discoloration inhibition rate (%) is calculated according to the following formula. did. For reference, the concentrations of acitazanolast and tetrahydrozoline in each test sample were measured before and after light irradiation.

  The obtained results are also shown in Table 3. From this result, it was confirmed that the composition of Example 4-14 had a high rate of color change inhibition and was stable to light as compared with the control. Further, in this test, when the appearance of the aqueous composition was visually confirmed after the test was completed, discoloration was clearly recognized in the control aqueous composition, whereas in the aqueous composition of Example 4-14, discoloration was observed. Was suppressed.

  In addition, it was confirmed that the content of acitazanolast and tetrahydrozoline was constant before and after light irradiation, regardless of whether the aqueous composition was discolored. It was also confirmed that degradation was not a direct cause.

Test Example 4 Discoloration Suppression Effect Confirmation Test-2
According to the formulation described in Table 4, an aqueous composition containing acitazanolast and naphazoline or oxymetazoline was prepared (control, Examples 15-16). These aqueous compositions were evaluated for light stability. The light stability was evaluated in the same manner as in Test Example 3 except that the light irradiation condition was continuous irradiation with 5000 lx light for 72 hours (integrated irradiation amount: 360,000 lx · hr). .

  The results obtained are shown in Table 4. From these results, it was confirmed that the aqueous compositions of Examples 15-16 had a higher discoloration suppression rate than the control and were stable to light. Moreover, when the external appearance of each aqueous composition was visually confirmed after the test was completed, discoloration was clearly recognized in the control aqueous composition, whereas discoloration was suppressed in the aqueous composition of Examples 15-16. It was.

Reference test example 1
An aqueous composition was prepared according to the formulation described in Table 5 (Reference Example 1-4). Using these aqueous compositions, the light stability was evaluated in the same manner as in Test Example 3 or 4. As a result, almost no discoloration was observed in any of the aqueous compositions of Reference Example 1-4. From the above results, the discoloration of the control aqueous composition shown in Tables 3 and 4 above occurs when acetazanolast and an imidazoline-based decongestant are used in combination, and the agitazanolast or imidazoline-based decongestant is used alone. It has been confirmed that it does not occur when used.

Examples 17-37
Eye drops (Examples 17-37) with various formulations shown in Tables 6 and 7 were prepared.

Examples 38-41
Eyewashes (Example 38) with prescriptions shown in Table 8, eye drops that can be instilled while wearing contact lenses (Example 39), contact lens mounting solutions (Example 40), and contact lens disinfectants (Example 41) Was prepared.

In Test Example 1, it is a figure which shows the result of having measured the histamine release inhibition rate (%) about the aqueous composition of Example 1 and Comparative Example 1-2. In Experiment 2, it is a figure which shows the result of having measured the histamine release suppression rate (%) about the aqueous composition of Example 2-3 and Comparative Example 3-5.

Claims (5)

(A) at least one selected from the group consisting of acitazanolast and a salt thereof, and
(B) An antiallergic composition comprising at least one selected from the group consisting of tetrahydrozoline, naphazoline and salts thereof. An aqueous composition, an antiallergic composition according to claim 1. The antiallergic composition according to claim 1 or 2 , which is a topical mucosa application agent. The antiallergic composition according to any one of claims 1 to 3 , comprising component (A) in a proportion of 0.001 to 2.0 w / v% and component (B) in a proportion of 0.00005 to 2.0 w / v%. A histamine release inhibitory action potentiator of acitazanolast or a salt thereof, comprising at least one selected from the group consisting of tetrahydrozoline, naphazoline and a salt thereof .

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