JP2004149526A - Aqueous liquid composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an aqueous liquid composition in which an effective ingredient is stably maintained. <P>SOLUTION: This aqueous liquid composition contains 0.0003-0.006 wt.% chlorpheniramine salt and/or 0.0025-0.05 wt.% glycyrrhizinate, a POE-POP block copolymer or a POE sorbitan fatty acid ester and a chelating agent. <P>COPYRIGHT: (C)2004,JPO

Description

  The present invention relates to a method for increasing the stability of an active ingredient in an aqueous liquid composition containing a low concentration of chlorpheniramine salts and / or glycyrrhizinates as the active ingredient, and to a composition thus obtained.

Chlorpheniramine maleate and dipotassium glycyrrhizinate, which are generally used as chlorpheniramine salts and glycyrrhizinates, have antihistamine action and anti-inflammatory action, respectively, as ophthalmic compositions such as eye drops and eyewashes. First, it is widely used in medicines, quasi-drugs, and the like.
Usually, surfactants and fragrances are added to eye drops and eyewashes as additives in order to enhance the stability and solubility of the medicinal ingredients and to enhance the feeling of use (functionality). There is a problem of quality deterioration due to the decomposition of components and additives over time for some reason.

  For example, the above-mentioned chlorpheniramine maleate is relatively stable when it is formulated at the concentration usually used for eye drops (maximum concentration: 0.03%). Similarly, dipotassium glycyrrhizinate is stable at the concentration usually used in eye drops (maximum compounding concentration: 0.25%). However, in low-concentration compositions such as eyewashes (maximum concentration in eyewashes: chlorpheniramine maleate 0.003%, dipotassium glycyrrhizinate 0.025%), they are often used as solubilizing agents for eye drops and eyewashes It is known that these compounds are degraded with time in the presence of certain surfactants such as the above-mentioned ester nonionic surfactants and other components which are simultaneously incorporated into the preparation. Therefore, with respect to the aqueous liquid composition containing these drugs, depending on the compounding concentration of the medicinal component in the composition, even if it is slightly degraded, the effect on the quality cannot be ignored. It has been difficult to keep the composition stable for a long period of time with low pharmaceuticals.

  In the case of preparations containing relatively high concentrations of chlorpheniramine maleate or dipotassium glycyrrhizinate (such as certain eye drops), the effect of degradation is relatively small, but in the case of preparations containing these at low concentrations The effect on quality cannot be ignored even with slight decomposition. Therefore, in order to maintain the effect of the aqueous liquid composition containing these as a medicinal component, it is necessary to increase the stability of chlorpheniramine maleate or dipotassium glycyrrhizinate in the aqueous liquid. However, hitherto, no method has been reported for increasing the stability of these drugs.

  For example, a method in which the decomposition of a surfactant in an eye drop containing an ester-based nonionic surfactant and glycyrrhizinates is prevented by defining the compounding ratio of ε-aminocaproic acid to glycyrrhizates (Patent Document 1) The hydrolysis of a surfactant and the decomposition of a naphazoline salt in an eye drop containing an ester-based nonionic surfactant, glycyrrhizinates, naphazoline salts and tocopherols are determined by glycyrrhizic acid to an ester-based nonionic surfactant. A method of suppressing the salt by defining the compounding ratio and the pH of the salt (Patent Document 2), and a method of suppressing the decomposition of an ester-based nonionic surfactant by glycyrrhizic acid by using alkyl glycyrrhizinate (Patent Document 3) ) Is known, but in any literature chlorphenira maleate How to suppress / prevent degradation of emissions and dipotassium glycyrrhizinate is not disclosed.

  By the way, when the concentration of a medicinal ingredient is low, its decomposition becomes a more serious problem. For example, the amount of chlorpheniramine maleate or dipotassium glycyrrhizinate in eyewashes is only about 1/10 of that of eye drops. Has a major impact on maintaining quality over time. One of the causes of the decomposition of such medicinal ingredients is hydrogen peroxide generated from a surfactant.

  It is known that a surfactant is gradually decomposed to generate hydrogen peroxide when exposed to light or a temperature around room temperature (Non-Patent Documents 1 and 2). (J. Agri. Food. Chem. 1999. 7 4146-4149; J. Biochem. Biophys. Methods 29 1994 77-81). Decomposition of other components by the hydrogen peroxide generated in this way is a serious problem, especially in a formulation having a low component concentration, but the above-mentioned prior art does not solve such a problem. Also, no method has been provided for avoiding the effects of components other than the surfactant.

JP-A-5-139955 (paragraph number 0002-0004) Japanese Patent Application Laid-Open No. 5-271053 (paragraph number 0002-0004) JP-A-9-309835 (paragraph number 0003-004, 0008) J. Agri. Food. Chem. 1999.7 4146-4149 J. Biochem. Biophys. Methods 29 1994 77-81

  The present invention provides a long-term stable effect by suppressing the decomposition of these active ingredients in an aqueous liquid composition containing a low concentration of chlorpheniramine salts and / or glycyrrhizinates and a surfactant. An object of the present invention is to provide an aqueous liquid composition having high quality and high safety.

  The present inventors have proposed a surfactant which tends to generate hydrogen peroxide, and an aqueous liquid composition containing glycyrrhizinates and / or chlorpheniramine salts, glycyrrhizinates and chlorpheniramine salts. As a result of intensive studies to establish a method for improving the stability of the composition, it was found that the decomposition of the composition was suppressed by adding a certain amount of a chelating agent to the composition, and the present invention was completed.

That is, the present invention provides: (1) 0.0003 to 0.006% by weight of chlorpheniramine salts and / or 0.0025 to 0.05% by weight of glycyrrhizinates;
(2) polyoxyethylene-polyoxypropylene block copolymer or polyoxyethylene sorbitan fatty acid esters, and
(3) An aqueous liquid composition containing a chelating agent.
The present invention also relates to a method for stabilizing a solution comprising 0.0003 to 0.006% by weight of chlorpheniramine salts and / or 0.0025 to 0.05% by weight of glycyrrhizinate, comprising a polyoxyethylene-polyoxypropylene block copolymer or a polyoxyethylene block copolymer. It is an object of the present invention to provide a method characterized in that 0.002 to 20 parts by weight of a chelating agent is added to 1 part by weight of an ethylene sorbitan fatty acid ester.

  The aqueous liquid composition of the present invention contains 0.0003 to 0.006% by weight, preferably 0.0006 to 0.003% by weight of chlorpheniramine salts and 0.0025 to 0.05% by weight, preferably 0.005 to 0.025% by weight of glycyrrhizin as the active ingredient (main drug). The acid salts are contained simultaneously or alone. The above concentration range is a range in which these main drugs can exert an anti-inflammatory action and an anti-allergic action.

  Chlorpheniramine salts that can be used in the aqueous liquid composition of the present invention are not particularly limited as long as they are pharmacologically or physiologically acceptable, and include, for example, chlorpheniramine maleate.

  The glycyrrhizic acid salts that can be used in the aqueous liquid composition of the present invention are not particularly limited provided that they are pharmacologically or physiologically acceptable, and for example, dipotassium glycyrrhizinate, monoglycyrrhizic acid, etc. Ammonium.

The aqueous liquid composition of the present invention comprises, as a surfactant, at least polyoxyethylene (hereinafter, referred to as “POE”)-polyoxypropylene (hereinafter, referred to as “POP”) block copolymer (poloxamers) or POE sorbitan fatty acid Contains one or more selected from esters (polysorbates).
Examples of the POE-POP block copolymer include poloxamer 407, poloxamer 235, and poloxamer 188, and among them, poloxamer 407 is preferable.
Examples of the POE sorbitan fatty acid ester include POE (20) sorbitan monolaurate (polysorbate 20) and POE (20) sorbitan monooleate (polysorbate 80), with polysorbate 80 being preferred. (The numbers in parentheses indicate the number of moles added).
These surfactants may be blended alone or in combination of two or more.

  The concentration of the surfactant in the aqueous liquid composition of the present invention varies depending on the use and the type of the surfactant to be used, but is usually in the range of 0.01 to 1%, preferably 0.05 to 0.1%.

  The chelating agent used in the aqueous liquid composition of the present invention is not particularly limited as long as it is pharmacologically or physiologically acceptable. For example, ethylenediaminetetraacetic acid (hereinafter, “edetic acid” or “edetic acid” EDTA) or a salt thereof, citric acid or a salt thereof can be used. Among them, edetic acid or a salt thereof is preferable.

  As edetic acid or a salt thereof, a pharmacologically or physiologically acceptable salt can be used. Examples of pharmacologically or physiologically acceptable salts include, for example, disodium ethylenediaminetetraacetate (sodium edetate), tetrasodium ethylenediaminetetraacetate, barium ethylenediaminetetraacetate, calcium ethylenediaminetetraacetate, cobalt ethylenediaminetetraacetate, and copper ethylenediaminetetraacetate. Diammonium ethylenediaminetetraacetate, dilithium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, iron ethylenediaminetetraacetate, lanthanum ethylenediaminetetraacetate, magnesium ethylenediaminetetraacetate, manganese ethylenediaminetetraacetate, nickel ethylenediaminetetraacetate, tripotassium ethylenediaminetetraacetate, ethylenediaminetetraethylene Examples thereof include trisodium acetate and zinc ethylenediaminetetraacetate. Preferred are ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, tripotassium ethylenediaminetetraacetate, and trisodium ethylenediaminetetraacetate. Sodium is particularly preferred.

  As described above, the decomposition of chlorpheniramine maleate and dipotassium glycyrrhizinate is considered to be partially related to hydrogen peroxide generated from the surfactant. The mechanism of hydrogen peroxide generation is predicted to be due to the fact that trace metals contained in medicinal ingredients and other components act as catalysts, and oxidative decomposition of surfactants under the influence of light and heat . In the composition of the present invention, by adding an appropriate amount of a chelating agent, metal ions are chelated, and oxidative degradation of chlorpheniramine maleate and / or dipotassium glycyrrhizinate is suppressed. Therefore, it is necessary to add a chelating agent in an amount sufficient to chelate trace metals derived from components to be added to the aqueous liquid composition. However, if a large amount of a chelating agent is present, even essential metals contained in body fluids, for example, the eyes and tears, are chelated, which may cause a change in the composition of tears and the like. In particular, in the case of an eyewash in which the eyeball comes into contact with a few mL of liquid for a certain period of time in a single use, it is included because a large amount of components contained in the eyewash may be taken into the eye during use. The effect of chelating essential metals in the eyes and tears by the chelating agents cannot be ignored. Therefore, it is necessary to limit the concentration range of the chelating agent to a certain range.

  The concentration of the chelating agent in the aqueous liquid composition of the present invention is usually suitably in the range of 0.002 to 0.2%, preferably 0.005 to 0.02%, and more preferably 0.005 to 0.01%. However, it goes without saying that it is appropriately adjusted depending on the use of the composition. In addition, when the composition of the present invention is an ophthalmic composition, particularly when it is an eyewash, a chelating agent can be safely and effectively compounded within the above concentration range.

  The amount of the chelating agent used in the present invention is 0.002 to 20 parts by weight, preferably 0.005 to 2 parts by weight, more preferably 0.005 to 1 part by weight based on 1 part by weight of a surfactant (polysorbate or poloxamer). . This corresponds to 0.05 to 500 parts by weight, preferably 0.5 to 200 parts by weight, more preferably 1 to 200 parts by weight of the surfactant per part by weight of the chelating agent.

  The stabilization method of the present invention includes a step of blending a chelating agent with a solution containing (1) low-concentration chlorpheniramine salts and / or glycyrrhizic acids and (2) a surfactant, whereby the stability is improved. It can be said that this is a method for producing a composition. Here, the “composition” includes not only final products such as eye drops, but also intermediate products used as raw materials for drug products.

  Further, according to the stabilization method of the present invention, chlorpheniramine generated over time in a solution containing (1) low-concentration chlorpheniramine salts and / or glycyrrhizic acids and (2) a surfactant. The decomposition of salts and / or glycyrrhizic acids is suppressed, and the storage stability of the solution is improved. Therefore, the method can be said to be a method for stabilizing chlorpheniramine salts and / or glycyrrhizic acids. And, the chelating agent to be added in order to suppress the decomposition of chlorpheniramine salts and / or glycyrrhizic acids in connection with the present invention can be defined as a decomposition inhibitor of these components.

  The aqueous liquid composition of the present invention can contain various components other than chlorpheniramine maleate and / or dipotassium glycyrrhizinate in combination as long as the object of the present invention is not adversely affected. Components that can be combined include, for example, decongestant components, other anti-inflammatory drug components, other antihistamine drug components, astringent drug components, bactericide components, antitumor drug components, hormones, proteins or peptides, vitamins , Amino acids and the like can be used. Examples of the components that can be added to the composition of the present invention include the following components.

  Decongestant: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof.

  Ocular muscle modulator component: Cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methyl sulfate and salts thereof.

Anti-inflammatory drug components: celecoxib, rofecoxib, indomethacin, diclofenac, pranoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine, azulene sulfonic acid, lysozyme, methyl salicylate, allantoin and pharmacology Salts (eg, berberine chloride, berberine sulfate, sodium diclofenac, sodium azulene sulfonate, lysozyme chloride) and the like.
Astringent components: zinc and their salts (eg, zinc sulfate, zinc lactate) and the like.

  Antihistamine components: for example, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglycate, amlexanox, mequitadine, loratadine, loratadine, fexofenadine irase, inexitine, fexofenadine irazetin , Pemirolast, and pharmacologically acceptable salts (eg, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, sodium cromoglicate, etc.).

  Fungicide components: for example, sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.); Acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, etc.), alkylpolyaminoethyl Glycine, new quinolones (lomefloxacin, levofloxacin, ciprofloxacin hydrochloride, ofloxacin, norfloxacin, etc.) and the like.

  Vitamin B: Vitamin B such as, for example, vitamin A (for example, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmaceutically acceptable salts thereof (for example, retinol acetate, retinol palmitate, etc.)) (E.g., thiamine, thiamine disulfide, dicetiamine, octiamine, sicotiamine, bisibutiamine, bisbenthamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, Cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolate, dihydrofolate, nicotinic acid, nicotinamide, nicotinic alcohol, pantothenic acid, bread Knol, biotin, choline, inositol and their pharmacologically acceptable salts (eg, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, phosphoric acid Vitamin Cs (ascorbic acid and its derivatives, erythorbic acid and its derivatives and its pharmacologically acceptable), such as pyridoxal, calcium pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, and sodium pantothenate). Vitamins (eg, ergocalciferol, cholecalciferol, hydroxycholecalciferol) such as salts (eg, sodium ascorbate, sodium erythorbate, etc.) Vitamin E (for example, tocopherol and its derivatives, ubiquinone derivatives and its pharmacologically acceptable salts (tocopherol acetate, And other vitamins (e.g., carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, hesperidin and its pharmacologically acceptable). Salts (such as carnitine chloride).

  Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxy Lysine, glycylglycine, aminoethylsulfonic acid (taurine) and pharmacologically acceptable salts thereof (eg, potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.);

  Saccharides: monosaccharides (eg, glucose, etc.), disaccharides (eg, trehalose, lactose, fructose, etc.), oligosaccharides (eg, lactulose, raffinose, pullulan, etc.), cellulose or derivatives thereof (eg, methylcellulose, ethylcellulose, hydroxyethylcellulose) , Hydroxypropylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose, etc.), high molecular weight saccharides (eg, chondroitin sulfate, hyaluronic acid) and pharmaceutically acceptable salts thereof (eg, chondroitin sulfate, sodium hyaluronate, etc.) ), Sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.), antipruritic components (crotamiton, itctamole, moctamole, thymol acid, etc.), etc.

Other components: polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone and the like.
The content of these components can be selected according to the type of the preparation, the type of the active ingredient, and the like. For example, the content is in the range of about 0.0001 to 30%, preferably about 0.001 to 10% based on the whole preparation. You can choose.

More specifically, in the preferred aqueous topical composition for use in the present invention, the content of each component is, for example, as follows.
Ocular muscle modulator component: for example, 0.0001 to 0.5%, preferably 0.0002 to 0.1%.
Anti-inflammatory component or astringent component: for example, 0.001 to 10%, preferably 0.002 to 3%.
Antihistamine component: for example, 0.0001 to 10%, preferably 0.001 to 5%.
Fungicide component: for example, 0.001 to 10%, preferably 0.01 to 5%
Vitamins: for example, 0.0001 to 1%, preferably 0.001 to 0.3%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.

The aqueous liquid composition of the present invention is optionally formulated as a variety of components and additives used in pharmaceuticals, quasi-drugs, etc., as long as the effects of the present invention are not impaired. It is possible to Specific examples are described below, but the present invention is not limited to these examples.
Saccharides: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol and the like, and pharmacological properties thereof And the like.

  Thickeners: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac oil, 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, hyaluronic acid, chondroitin sulfate, ceramide, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy Propylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, cellulose, nitro Lurose, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, carboxyvinyl polymer, etc., and their pharmacological properties And the like.

  Surfactants: POE-hardened castor oil such as POE (60) hardened castor oil, POE alkyl ethers such as POE (9) lauryl ether, POE-POP alkyl ether such as POE (20) POP (4) cetyl ether , Nonionic surfactants such as POE alkylphenyl ethers such as POE (10) nonylphenyl ether, glycine type such as alkyldiaminoethylglycine, betaine acetate type such as betaine lauryldimethylaminoacetate, and amphoteric type such as imidazoline Surfactants, POE (10) POE alkyl ether phosphoric acid such as sodium lauryl ether phosphate and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylate, sodium N-cocoyl methyl taurine and the like N-acyl taurine salt, tetradesensel Sulfonates such as sodium phonate; alkyl sulfates such as sodium lauryl sulfate; POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate; anionic surfactants such as α-olefin sulfonate; Can be POE is an abbreviation for polyoxyethylene, and POP is an abbreviation for polyoxypropylene. The numbers in parentheses indicate the number of moles added.

  Antiseptic, antibacterial, and bactericidal agents: For example, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, acrylol, methylrosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide , Chlorhexidine, polyhexamethylene biguanide, alkyl polyaminoethyl glycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, sulfur, zirconium phosphate silver, zinc, zinc oxide, etc., silver zinc aluminosilicate , Mercurochrome, thimerosal, povidone-iodine, dehydroacetic acid, chlorxylenol, cresol, chlorophen, phenol, resorcinol Orthophenylphenol, isopropylmethylphenol, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, sorbic acid, triclocarban sorbate, halocarban Thiabendazole, polymyxin B, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, quaternary ammonium polymer (polydronium chloride (poly Quarterium-1), Glokill (trade name, manufactured by Rhodia), Unisense CP (trade name, poly (diallyldimethylammonium chloride), manufactured by SENKA), WSCP (trade name, poly [oxyethylene Dimethyliminio) ethylene- (dimethyliminio) ethlenechloride], about 60% by weight, manufactured by Bachman Laboratories, Inc.), biguanide compound (Cosmosil CQ (trade name, polyhexamethylene biguanide hydrochloride about 20% by weight) And pharmacologically acceptable salts thereof.

  pH adjusters: for example, hydrochloric acid, sulfuric acid, lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon aminocaproic acid, glutamic acid, aminoethyl Sulfonic acid, phosphoric acid, polyphosphoric acid, boric acid, gluconolactone, ammonium acetate, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, monoethanolamine, triethanolamine, Examples include diisopropanolamine, triisopropanolamine, lysine, borax, and the like, and pharmacologically acceptable salts thereof.

  Isotonicity agents: Examples include polyhydric alcohols such as glycerin and propylene glycol, and sugars such as glucose, mannitol and sorbitol.

  Chelating agents: for example, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid and the like, and pharmacologically acceptable thereof And the like.

  Water-soluble polymer substances: for example, gelatin, polyacrylic acid and salts thereof, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, methylvinylether / maleic anhydride copolymer, alginic acid Sodium, polyethylene oxide, gum arabic, xanthan gum, tragacanth gum and the like.

Polyhydric alcohols: for example, glycerin, sorbitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, ethylene glycol and the like.
Crosslinking agent: For example, polyhydric metal compounds such as aluminum hydroxide, aluminum hydroxide magnesium, aluminum glycinate, dihydroxyaluminum aminoacetate, synthetic leather hydrotalcite and the like can be mentioned.
Swelling agent: For example, kaolin, bentonite, titanium oxide, silicic anhydride and the like can be mentioned.

Inorganic salts: for example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulfate, sodium acetate and the like. Can be
Further, if necessary, a fragrance or a cooling agent (eg, menthol, camphor, borneol, geraniol, eucalyptus oil, bergamot oil, fennel oil, peppermint oil, cauliflower oil, rose oil, peppermint oil, etc.), a local anesthetic (eg, , Lidocaine, lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.).

  ADVANTAGE OF THE INVENTION According to this invention, since the active ingredient is stably maintained in the aqueous liquid composition even at a low concentration, the quality control of the preparation is easy. Therefore, the present invention can be applied to a wide range of fields such as pharmaceuticals, quasi-drugs, cosmetics, and foods. The composition of the present invention is preferably an ophthalmic composition, and more preferably an eye drop (also referred to as an eye drop) (including an eye drop that can be used even while wearing a contact lens (CL)), an eye wash (eye wash) (Also referred to as medicines) (including eyewashes that can be used even while wearing CL), and CL agents. In particular, it is preferably an eyewash or a CL agent. Here, the “CL agent” includes not only a composition for preserving, cleaning and disinfecting contact lenses, but also a contact lens mounting solution. The composition of the present invention is adjusted to a pH and / or osmotic pressure within a range acceptable for a living body, if necessary. Acceptable pH is usually pH 5.0 to 9.0, preferably 5.5 to 8.5, particularly preferably 6.5 to 7.5. The osmotic pressure is 100 to 1200 mOsm, preferably 100 to 600, particularly preferably about 150 to 400, and the osmotic pressure ratio to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.6. Adjustment of pH and osmotic pressure can be performed by a method known in the art using the above-mentioned pH adjuster, isotonic agent, salts and the like.

  The aqueous liquid composition of the present invention can be produced by a known method. For example, using distilled or purified water, and additives with 0.0003-0.006% by weight of chlorpheniramine salts and / or 0.0025-0.05% by weight of glycyrrhizinate, any polysorbate and / or poloxamer, and a chelating agent. It can be manufactured by mixing in the above concentration range, adjusting to a predetermined osmotic pressure and pH, filtering and sterilizing in an aseptic environment, and aseptically filling a container which has been washed and sterilized.

  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Examples 1 to 13
An aqueous liquid composition (eyewash) (Examples 1 to 13) was prepared according to the formulations described in the following tables. Similarly, Comparative Examples 1 to 10 were prepared and subjected to a severe test at 70 ° C.
The severe test was performed according to the following method.
Each formulation of the example and the comparative example was prepared, sealed in a brown glass ampule tube, and stored in an oven at 70 ° C. for a certain period (7 days, 1 month (30 days)).
For a sample after a predetermined time, chlorpheniramine maleate and dipotassium glycyrrhizinate (measurement was glycyrrhizic acid) in the formulation were measured by the HPLC method under the following conditions, and the residual ratio was obtained according to the following formula.

HPLC conditions 1. Chlorpheniramine maleate Detector: UV absorption spectrophotometer Column: ODS column Column temperature: Constant temperature around 40 ° C Mobile phase: SDS-phosphate buffer / acetonitrile mixed solution Glycyrrhizic acid Detector: UV absorption spectrophotometer Column: ODS column Column temperature: Constant temperature around 40 ° C Mobile phase: acetic acid / acetonitrile mixture

（１）マレイン酸クロルフェニラミン含有洗眼剤（実施例１）

(1) Chlorpheniramine maleate-containing eyewash (Example 1)

比較例１と比較例２から、界面活性剤が存在するとマレイン酸クロルフェニラミンが分解されることが分かる。これに対してエデト酸ナトリウムが添加された実施例１では、分解が抑制され、マレイン酸クロルフェニラミンが安定に存在している。

From Comparative Examples 1 and 2, it can be seen that chlorpheniramine maleate is degraded when a surfactant is present. On the other hand, in Example 1 to which sodium edetate was added, decomposition was suppressed, and chlorpheniramine maleate was stably present.

上記（１）の場合と同様に、界面活性剤存在下でのグリチルリチン酸二カリウムの分解（比較例３〜５）と、エデト酸ナトリウムによる安定化（実施例２、３）が示されている。 (2) Eyewash containing dipotassium glycyrrhizinate (Examples 2 and 3)

As in the case of the above (1), decomposition of dipotassium glycyrrhizinate in the presence of a surfactant (Comparative Examples 3 to 5) and stabilization by sodium edetate (Examples 2 and 3) are shown. .

上記（１）の場合と同様に、界面活性剤存在下でのマレイン酸クロルフェニラミン、グリチルリチン酸二カリウムの分解（比較例６〜９）と、エデト酸ナトリウムによる安定化（実施例４、５）が示されている。 (3) Eyewash containing chlorpheniramine maleate and dipotassium glycyrrhizinate (Examples 4 to 13)

As in the case of the above (1), decomposition of chlorpheniramine maleate and dipotassium glycyrrhizinate in the presence of a surfactant (Comparative Examples 6 to 9) and stabilization with sodium edetate (Examples 4 and 5) )It is shown.

  From the results of the severe test described in the above table, it is clear that chlorpheniramine maleate and / or dipotassium glycyrrhizinate are stably maintained in the composition of the present invention.

Further, aqueous liquid compositions (eyewash) described in the following Examples 14 to 16 were prepared.
Example 14 Eyewash Component Ingredient Content Chlorpheniramine Maleate 0.003 g
Dipotassium glycyrrhizinate 0.025 g
Aminoethylsulfonic acid 0.100 g
1.7 g boric acid
Borax 0.005 g
1-menthol 0.010 g
Benzalkonium chloride 0.005 g
Poloxamer 407 0.05 g
Sodium edetate 0.1 g
1N hydrochloric acid qs 1N sodium hydroxide qs Sterilized purified water qs
Total volume 100 mL
These components were mixed and treated as usual to prepare an eyewash.

Example 15 Eyewash Component Ingredient Amount Chlorpheniramine Maleate 0.003 g
Dipotassium glycyrrhizinate 0.025 g
Epsilon aminocaproic acid 0.200 g
1.7 g boric acid
Borax 0.015 g
1-menthol 0.006 g
D-Camphor 0.003 g
Benzalkonium chloride 0.0025 g
Polysorbate 80 0.05 g
Sodium edetate 0.005 g
1N hydrochloric acid qs 1N sodium hydroxide qs Sterilized purified water qs
Total volume 100 mL
These components were mixed and treated as usual to prepare an eyewash.

Example 16 Eyewash Component Ingredient Content Anhydrous Caffeine 0.05 g
Naphazoline hydrochloride 0.0001 g
Chlorpheniramine maleate 0.003 g
Dipotassium glycyrrhizinate 0.025 g
Pyridoxine hydrochloride 0.010 g
0.005 g tocopherol hydrochloride
0.100 g of potassium L-aspartate
Aminoethylsulfonic acid 0.100 g
Chondroitin sulfate 0.050 g
Boric acid 1.700 g
Borax 0.100 g
Polysorbate 80 0.05 g
Potassium sorbate 0.1 g
Sodium edetate 0.0001 g
1N hydrochloric acid qs 1N sodium hydroxide qs Sterilized purified water qs
Total volume 100 mL
These components were mixed and treated as usual to prepare an eyewash.

  In the aqueous liquid composition of the present invention containing a low concentration of chlorpheniramine salts and / or glycyrrhizinates together with a surfactant, since these components are maintained without being substantially decomposed, the quality is stable. A safe and effective composition can be provided.

Claims (6)

(1) 0.0003-0.006% by weight of chlorpheniramine salts and / or 0.0025-0.05% by weight of glycyrrhizinates,
(2) polyoxyethylene-polyoxypropylene block copolymer or polyoxyethylene sorbitan fatty acid esters, and
(3) An aqueous liquid composition comprising a chelating agent.   The aqueous solution according to claim 1, wherein the chelating agent is blended in a ratio of 0.002 to 20 parts by weight with respect to 1 part by weight of the polyoxyethylene-polyoxypropylene block copolymer or the polyoxyethylene sorbitan fatty acid ester. Liquid composition.   The aqueous liquid composition according to claim 1, which is an eyewash.   The aqueous liquid composition according to any one of claims 1 to 3, wherein the chelating agent is edetic acid or a salt thereof.   A method for stabilizing a solution containing 0.0003 to 0.006% by weight of chlorpheniramine salts and / or 0.0025 to 0.05% by weight of glycyrrhizinate, comprising a polyoxyethylene-polyoxypropylene block copolymer or a polyoxyethylene sorbitan fatty acid ester. A method comprising mixing 0.002 to 20 parts by weight of a chelating agent with respect to 1 part by weight.   The method according to claim 5, wherein the chelating agent is edetic acid or a salt thereof.