JP2007297331A - Aqueous composition including pantothenic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aqueous composition including at least one components of a group comprising pantothenic acids, derivatives of pantothenic acid and salts thereof, in a stable state. <P>SOLUTION: The aqueous composition is prepared by formulating (i) the pantothenic acids, derivatives of the pantothenic acid and/or the salts thereof, and (ii) acitazanolast and/or its salt. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an aqueous composition in which the stability of pantothenic acids is improved. Furthermore, the present invention relates to a method for stabilizing an aqueous composition containing pantothenic acids.

  Pantothenic acids such as pantothenic acid and panthenol, as main components of coenzymes, have an effect of assisting the metabolism of energy such as carbohydrates, proteins, and lipids, activating cells, activating metabolism, moisturizing, It is known to exhibit useful physiological activities such as enhancement of resistance. In anticipation of such useful physiological activity, pantothenic acids have been used by blending in preparations for applying to mucosa, external preparations for skin, cosmetics and the like. On the other hand, pantothenic acids have the disadvantage that they tend to be unstable in the presence of water. For this reason, when pantothenic acids are formulated in an aqueous composition, the desired action and effect may be reduced or lost with the degradation of pantothenic acids over time, and it may not be possible to guarantee a constant quality. . Therefore, when pantothenic acids are blended in an aqueous composition, it is considered important to formulate the pantothenic acids so that they are stably maintained.

On the other hand, acitazanolast has pharmacological effects such as antiallergy and intraocular pressure reduction against allergic conjunctivitis through the inhibitory action of histamine, platelet activating factor (PAF) and leukotriene B4 / D4 from mast cells. It has been found that it is useful as an active ingredient of preparations for mucosa including eye drops (see, for example, Patent Document 1). However, there has been no report on the combined use of acitazanolast and pantothenic acids in an aqueous composition, and how it affects the stabilization of pantothenic acids in an aqueous composition. Is not disclosed.
JP-A-1-29312

  An object of the present invention is to provide an aqueous composition containing at least one component selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof in a stable state. Furthermore, the present invention aims to provide a method for stabilizing an ingredient in an aqueous composition containing at least one ingredient selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof. And

  The present inventor has intensively studied to solve the above-mentioned problems. It has been found that (i) stability can be imparted to pantothenic acid, pantothenic acid derivatives, and / or their salts by preparing the composition. The present invention has been completed by making further improvements based on such findings.

That is, the present invention provides the following aqueous compositions:
Item 1. (i) containing at least one selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof, and (ii) at least one selected from the group consisting of acitazanolast and salts thereof An aqueous composition characterized by the above.
Item 2. Item 2. The aqueous composition according to Item 1, wherein the component (i) is at least one selected from the group consisting of pantothenic acid, a salt of pantothenic acid, and panthenol.
Item 3. Item 3. The aqueous composition according to Item 1 or 2, which is a topical mucosa application agent.

Furthermore, the present invention provides the stabilization methods listed below:
Item 4. (i) A method for stabilizing an aqueous composition comprising at least one selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof, wherein (ii) acitazanolast is added to the aqueous composition And at least one selected from the group consisting of salts thereof, and a stabilization method.

  Since the aqueous composition of the present invention contains pantothenic acid, pantothenic acid derivatives, and / or their salts in a stable state and has excellent stability, it effectively exhibits the pharmacological action of these components. it can. Furthermore, acitazanolast and / or a salt thereof contained in the aqueous composition of the present invention can not only contribute to the stabilization of the above components, but also exert their own pharmacological action. Therefore, the aqueous composition of the present invention has an antiallergic action and a decrease in intraocular pressure based on acitazanolast and / or a salt thereof, as well as physiological actions such as metabolism promotion based on pantothenic acid, pantothenic acid derivatives, and / or salts thereof. Since the action can be effectively exerted, it is useful as a pharmaceutical composition, particularly as a preparation for topical mucosa.

  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 of water, preferably 5% by weight or more, more preferably 20% by weight or more, and particularly preferably 50% by weight or more in the composition.

1. Aqueous Composition The aqueous composition of the present invention is represented by (i) at least one component selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof (hereinafter simply referred to as “component (i)”). In some cases).

  Pantothenic acid is a compound included in the vitamin B group and is also known as N- (2,4-dihydroxy-3,3-dimethylbutyryl) -β-alanine.

  The derivative of pantothenic acid is not particularly limited as long as it is pharmacologically (pharmaceutically) or physiologically acceptable. For example, panthenol, pantothenyl alcohol, pantothenyl ethyl ether, pantethein pantothenyl Examples include alcohol, acetyl pantothenyl ethyl ether, benzoyl pantothenyl ethyl ether, dicarboethoxy pantothenic acid ethyl ester, pantethein, pantethine, and phosphopantethein. These pantothenic acid derivatives may be used alone or in combination of two or more.

  The salt of pantothenic acid or pantothenic acid derivative is not particularly limited as long as it is pharmacologically (pharmaceutical) or physiologically acceptable, but as an example, an alkali metal such as sodium salt or potassium salt Salts: Examples include alkaline earth metal salts such as calcium salts and magnesium salts. These pantothenic acid or salt of pantothenic acid derivative may be used alone or in combination of two or more.

  In the present invention, as the component (i), only one of pantothenic acid, pantothenic acid derivatives, and salts thereof can be used alone, or two or more can be used in combination.

  The component (i) is preferably pantothenic acid, pantothenic acid salt and panthenol, more preferably pantothenic acid, calcium pantothenate, sodium pantothenate and panthenol, particularly preferably calcium pantothenate, sodium pantothenate and pantotenol. Tenor.

  The blending ratio of the component (i) in the aqueous composition of the present invention is appropriately set according to the use and form of the composition. Usually, the mixing ratio of the component (i) in the composition is 0.0005 to 2% by weight, preferably 0.001 to 1% by weight, and more preferably 0.005 to 0.2% by weight in terms of the total amount of the components.

  In addition to the above component (i), the aqueous composition of the present invention may be at least one selected from the group consisting of acitazanolast and a salt thereof (hereinafter simply referred to as “component (ii)”). ). By containing the component (ii), it becomes possible to impart stability to the component (i) in the aqueous composition.

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 used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include salts with organic bases (salts with organic amines such as methylamine, triethylamine, diethylamine, and triethanolamine); alkali metal salts (for example, sodium salts and potassium salts) An inorganic earth salt such as an alkaline earth metal salt (calcium salt, magnesium salt, etc.) and another metal salt (aluminum salt, etc.). These acitazanolasts and salts thereof 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 aqueous composition of the present invention, the component (ii) is preferably acitazanolast monohydrate.

  The blending ratio of the component (ii) in the aqueous composition of the present invention varies depending on the form and use of the aqueous composition, but as an example, the component (ii) is added to the total amount of the aqueous composition. 0.0005 to 2% by weight, preferably 0.001 to 1% by weight, and more preferably 0.005 to 0.11% by weight.

  Further, in the aqueous composition of the present invention, from the viewpoint of providing further excellent stability to the component (i), the component (ii) is 1 with respect to 100 parts by weight of the component (i). It is desirable to satisfy a ratio of ˜5000 parts by weight, preferably 10 to 2,000 parts by weight, more preferably 50 to 1000 parts by weight.

  In addition, the water contained in the aqueous composition of the present invention may be any pharmaceutical, 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.

  The aqueous composition of the present invention can further contain a buffer. The buffer that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer (boric acid, borax), phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, ε-aminocaproic acid, aspartic acid, aspartate, glutamic acid. Examples include salt. These buffering agents may be used alone or in any combination of two or more. Depending on the type of buffer used, it may promote instability of the component (i) in an aqueous solution, but the aqueous composition of the present invention effectively demonstrates the stabilization of the component (i). Therefore, even a buffer that has been conventionally unsuitable for combination with the component (i) can be blended in the aqueous composition of the present invention.

  When blending a buffering agent in the aqueous composition of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used and the expected effect, and cannot be defined uniformly, for example, In the aqueous composition, the ratio of the buffering agent is 0.01 to 3% by weight, preferably 0.1 to 2% by weight, more preferably 0.3 to 2% by weight.

  In addition, the aqueous composition of the present invention can be adjusted to a pH within a range acceptable for a living body. The appropriate pH varies depending on the application site, dosage form and the like of the aqueous composition, but is usually about 4 to 8.5, preferably 4.5 to 8, and more preferably about 4.5 to 7.5. Within such a pH range, the component (i) can be more effectively stabilized.

  If necessary, the aqueous composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable for a living body. 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 ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 0.9 w / v% sodium chloride aqueous solution based on the 14th revised Japanese pharmacopoeia. Method).

  In addition, adjustment of pH and osmotic pressure can be performed by a method known in the art using the buffer, a pH adjuster, an isotonic agent, salts, and the like described later.

  The aqueous composition of the present invention may contain a combination of various pharmacologically active components and physiologically active components in addition to the above components 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 a decongestant component, an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial agents. Examples of the drug component or bactericidal component, sugars, 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: 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.

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

  Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, ε-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, azestatin 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, pyridoxal phosphate, cyanocobalamin, ascorbic acid, tocopherol acetate, tocopherol nicotinate, tocopherol succinate, 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, ε-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 oil, quince seed, dummar gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, sodium alginate, 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 partially saponified products), polyvinylpyrrolidone, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethylene N'imin, ribonucleic acid, deoxyribonucleic acid, 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, etc.

  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 the various components in various applications are known in the art, and the compounding amounts of the components in the aqueous composition are appropriately selected according to the dosage form of the aqueous composition, the type of the active ingredient, and the like. . For example, 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 aqueous composition of the present invention, various components and additives are appropriately selected according to a conventional method according to the use and form as long as the effects of the invention are not impaired. You may contain together. 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, surfactants And various additives such as agents, preservatives, bactericides or antibacterial agents, pH adjusters, tonicity agents, fragrances or refreshing agents, chelating agents, buffering agents, stabilizers, bases and the like.

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

  Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, sodium alginate, polyvinyl alcohol (completely or partially saponified), 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 antibacterials: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid Methyl, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glow Kill (trade name, manufactured by Rhodia) Such.

  pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, ε-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydrogen carbonate, sodium carbonate, boron 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.

  Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum 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 and the like.

  Solubilizer or solubilizer: ethanol, glycerin, hydrochloric acid, sodium hydroxide, trometamol, macrogol 4000, monoethanolamine and the like.

  The dosage form of the aqueous composition of the present invention is arbitrary, and various forms can be taken depending on its use. For example, it may be liquid or semi-solid such as ointment. Preferably it is liquid.

  Specific examples of the formulation of the aqueous composition of the present invention include eye drops [however, eye drops include eye drops that can be instilled while wearing contact lenses], artificial tears, eye wash [however, eye wash Ophthalmic compositions such as eyewashes that can be washed while wearing contact lenses], ophthalmic ointments, etc .; contact lens compositions [contact lens mounting fluids, contact lens care compositions (contact lens disinfectants, Contact lens preservatives, contact lens cleaning agents, contact lens cleaning preservatives, etc.]]; nasal compositions such as nasal drops and nasal washings; ear drops; other skin external preparations and the like. Since the aqueous composition of the present invention can exhibit various useful effects based on the above component (i) and an antiallergic effect and an intraocular pressure lowering effect based on the above component (ii), it can be applied locally to the mucosa. It is particularly useful as a preparation (eg eye drops, eye wash, eye ointment, nasal drop, nasal wash, etc.). Of these, eye drops, eye washes, and nasal drops are preferable, and eye drops are more preferable.

  The contact lens composition can be applied to all contact lenses including hard contact lenses and soft contact lenses, and is particularly composed of components that are difficult to adsorb to oxygen permeable hard contact lenses or soft contact lenses. Therefore, the composition for contact lenses is more suitably used for these contact lenses.

  The aqueous composition of the present invention can be produced by a known method.

  Although it does not restrict | limit especially as a container filled with the aqueous composition of this invention, From a viewpoint of improving the stability with respect to the light of a formulation, it is preferable to fill with the following plastic container.

  The plastic container is not particularly limited as long as it can be used as a container for an aqueous composition, but preferably has a low moisture permeability, and more preferably does not easily adsorb each component. Specific examples of the plastic container include a container made of hard plastic. Specific examples of constituent materials for rigid plastic containers include olefin resins, polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, rigid vinyl chloride resins, styrene resins, and cellulose. Acetate resin etc. can be illustrated.

  Examples of the olefin resin include polymers such as polyethylene (PE) and polypropylene (PP).

  Examples of the polyester-based resin include a resin composed of a dicarboxylic acid component (such as an aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid, and naphthalenedicarboxylic acid) and a diol component. Specifically, aromatic polyester resins, for example, polyalkylene terephthalates such as poly C2-4 alkylene terephthalates such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT); polyethylene naphthalate (PEN) and polybutylene naphthalate Such as poly C2-4 alkylene naphthalate, polyalkylene naphthalate such as poly (1,4-cyclohexylenedimethylene terephthalate) (PCT), bisphenols (such as bisphenol-A) and phthalic acids ( And homopolyesters such as polyarylate such as resin composed of phthalic acid and terephthalic acid. The polyester resin 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.

  Examples of the polycarbonate-based resin include aromatic polycarbonates based on bisphenols such as bisphenol-A.

  Examples of the styrene resin include polystyrene, acrylonitrile-styrene copolymer (AS resin), and the like.

  The plastic container used in the present invention is made of a polymer alloy (polymer blend, etc.) as a constituent material unless there is any actual harm in cost performance, strength, light transmission, gas or water vapor barrier properties (moisture permeability), etc. May be. Preferred polymer alloys include a polymer blend of a plurality of synthetic resins (eg, a polymer blend of PET and PEN).

  The resin is preferably a resin having good squeeze properties and durability against repeated pressing, and a transparent or translucent resin, and is colored yellow, orange, brown or the like as necessary. May be. Then, by incorporating a component that can inhibit light transmission (such as an ultraviolet absorber or an infrared absorber) into the resin, or by applying a coating agent containing the above component to the resin surface, the effect of the present invention is achieved. The stability may be further improved by working.

  The shape of the plastic container is not particularly limited, and can be appropriately set according to the dosage form and application of the aqueous composition.

2. Method for Stabilizing Aqueous Composition As described above , in the aqueous composition containing (i) at least one selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof, Destabilization can be suppressed by adding (ii) acitazanolast and / or a salt thereof to the aqueous composition. Accordingly, the present invention further provides the following method for stabilizing an aqueous composition: (i) an aqueous composition containing at least one selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof. (Ii) Agitazanolast and / or a salt thereof is added to the product, and the method for stabilizing the aqueous composition.

  In the stabilization method, the components (i) and (ii) to be used, the respective blending ratios in these aqueous compositions, optional additional components that can be blended in the aqueous composition, the form of the aqueous composition, etc. 1. As described in the column “Aqueous composition”.

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
In accordance with the formulation described in Table 1, panthenol-containing aqueous solutions (Examples 1-3 and Comparative Examples 1-3) were prepared. Each panthenol-containing aqueous solution was filtered, filled into a glass ampoule (capacity 10 mL) at 8 mL, and stored at 60 ° C. for a predetermined period in a dark place. Before and after storage, the panthenol concentration in the panthenol-containing aqueous solution was measured by HPLC, and the panthenol residual rate was calculated according to the following formula.

  The obtained results are shown in Table 1. It was observed that panthenol was decomposed in a panthenol-containing aqueous solution (Comparative Example 1-3) that did not contain acitazanolast. On the other hand, in the panthenol-containing aqueous solution (Example 1-3) containing acitazanolast, it was confirmed that the decomposition of panthenol was suppressed and that panthenol was stably held. In particular, from the results of Examples 2 and 3, the panthenol degradation inhibitory effect of acitazanolast was recognized even in the presence of a borate buffer or an ε-aminocaproic acid buffer.

  Separately, a panthenol-containing aqueous solution having the same composition as in Example 1 and Comparative Example 1 except that the pH was changed to 6 was prepared and tested in the same manner as described above. Similar to the results, the inhibitory effect on pantenol degradation by acitazanolast was confirmed.

Test example 2
A pantothenic acid-containing aqueous solution (Example 4 and Comparative Example 4) was prepared according to the formulation described in Table 2. Using each pantothenic acid-containing aqueous solution, the storage stability of pantothenic acid was evaluated in the same manner as in Test Example 1 above.

  The obtained results are shown in Table 2. Also from this result, pantothenic acid was notably decomposed in the pantothenic acid-containing aqueous solution not containing acitazanolast (Comparative Example 4). However, in the aqueous solution containing acitazanolast, the decomposition of pantothenic acid was suppressed. It was confirmed (Example 4).

Example 5-24
In the formulations shown in Tables 3 and 4 below, eye drops (Example 5-21; eye drops of Examples 9 and 21 can be used while wearing contact lenses), eye wash (Example 22). ), Contact lens mounting liquid (Example 23), and contact lens disinfectant (Example 24).

Claims (4)

(i) at least one selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof; and
(ii) An aqueous composition comprising at least one selected from the group consisting of acitazanolast and a salt thereof.   The aqueous composition according to claim 1, wherein the component (i) is at least one selected from the group consisting of pantothenic acid, a salt of pantothenic acid, and panthenol.   The aqueous composition according to claim 1 or 2, which is a topical mucosa application agent.   (i) A method for stabilizing an aqueous composition comprising at least one selected from the group consisting of pantothenic acid, pantothenic acid derivatives, and salts thereof, wherein (ii) acitazanolast is added to the aqueous composition And at least one selected from the group consisting of salts thereof, and a stabilization method.