JP6150510B2 - Ophthalmic aqueous composition - Google Patents

Description

  The present invention relates to an aqueous ophthalmic composition. More specifically, the present invention relates to an aqueous ophthalmic composition having an action of suppressing the generation of precipitates and the white residue after dropping, further promoting the growth of corneal cells and enhancing the action of inhibiting histamine release.

  Zinc salts such as zinc sulfate and zinc lactate have an astringent action and an anti-inflammatory action, and are widely used in eye drops as an astringent and an anti-inflammatory agent. It is also known that the cytotoxicity of the detergent is suppressed by adding zinc or a zinc salt to the detergent for the ocular mucosa or nasal mucosa (Patent Document 1). Furthermore, it is also known that a detergent obtained by adding a zinc salt or a zinc salt and an antihistamine to a detergent for the ocular mucosa or nasal mucosa has an excellent antipruritic action on the ocular mucosa and nasal mucosa ( Patent Document 2).

  Chondroitin sulfate, aminoethyl sulfonic acid, aspartic acid, and their salts promote energy metabolism, promote metabolism and cell respiration, relieve eye fatigue, or supplement tear fluid components For this purpose, it has been conventionally used in ophthalmic compositions.

  However, in an ophthalmic aqueous composition containing zinc chloride, the effect of these components on the ophthalmic aqueous composition has not been clarified.

JP2003-146891 JP2003-146892

  As a result of various studies on an ophthalmic aqueous composition containing a zinc compound, the present inventors have confirmed that precipitates are generated in the ophthalmic aqueous composition containing zinc chloride as the zinc compound.

  Further, hyaluronic acid or a salt thereof is a component known to improve the retention of the composition in the mucosa in the composition applied to the mucous membrane applied to the ocular mucosa, the nasal mucosa, the oral mucosa and the like. In the ophthalmic aqueous composition containing hyaluronic acid or a salt thereof together with zinc chloride, it was confirmed that precipitates were more likely to occur.

  Generation | occurrence | production of the precipitate in the ophthalmic aqueous composition causes the fall of quality including safety | security, and the fall of commercial value, Therefore Controlling generation | occurrence | production of a precipitate is a very important subject.

  Therefore, the present invention provides an ophthalmic aqueous composition containing zinc chloride and, if necessary, containing hyaluronic acid or a salt thereof, wherein the generation of precipitates is suppressed. And a method of suppressing the generation of precipitates in the aqueous ophthalmic composition.

  Furthermore, another object of the present invention is to provide an ophthalmic aqueous composition having other improved effects.

  As a result of intensive research to solve the above-mentioned problems, the present inventors, as a result, contain zinc chloride and, if necessary, an aqueous ophthalmic composition containing hyaluronic acid or a salt thereof, chondroitin sulfate. , By adding at least one specific amino acid selected from the group consisting of aminoethylsulfonic acid, aspartic acid and salts thereof, the generation of precipitates can be suppressed and the white residue after dropping can be suppressed I found.

  Furthermore, an aqueous ophthalmic composition comprising zinc chloride and at least one selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof has an action of promoting the proliferation of corneal cells. Furthermore, it has also been found that it has an unexpected effect of significantly enhancing the inhibitory action of histamine release.

  The present invention has been completed as a result of further research based on these findings.

That is, this invention provides the ophthalmic aqueous composition of the aspect hung up below.
Item 1-1. An aqueous ophthalmic composition comprising (A) zinc chloride and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof.
Item 1-2. The aqueous ophthalmic composition according to Item 1-1, further comprising (C) at least one selected from the group consisting of hyaluronic acid and a salt thereof.
Item 1-3. The component (B) is at least one amino acid selected from the group consisting of sodium chondroitin sulfate, aminoethylsulfonic acid, aspartic acid, potassium aspartate, magnesium aspartate, and magnesium and potassium aspartate. The aqueous ophthalmic composition according to Item 1-1 or Item 1-2.
Item 1-4. The aqueous ophthalmic composition according to Item 1-2 or Item 1-3, wherein the component (C) is sodium hyaluronate.
Item 1-5. Item 5. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-4, which comprises 0.00001 to 0.05 w / v% of the component (A).
Item 1-6. Item 5. The ophthalmic aqueous composition according to any one of Items 1-1 to 1-5, wherein the total amount of the component (B) is 0.01 to 5 w / v%.
Item 1-7. (A) The aqueous ophthalmic composition according to any one of Items 1-1 to 1-6, wherein the total amount of the component (B) is 0.2 to 500,000 parts by weight with respect to 1 part by weight of zinc chloride.
Item 1-8. Item 8. The ophthalmic aqueous composition according to any one of Items 1-2 to 1-7, wherein the component (C) is contained in a total amount of 0.0001 to 1 w / v%.
Item 1-9. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-8, which has a pH of 6.5 or more.
Item 1-10. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-9, further comprising at least one selected from the group consisting of boric acid and salts thereof.
Item 1-11. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-10, wherein the viscosity at 25 ° C. is 0.01 to 1000 mPa · s.
Item 1-12. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-11, which is an eye drop, an artificial tear, an eye wash, or a contact lens mounting solution.

Moreover, this invention provides the method of suppressing generation | occurrence | production of the precipitate in the ophthalmic aqueous composition of the aspect hung up below.
Item 2-1. In the ophthalmic aqueous composition, (A) zinc chloride, and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof are characterized. And a method for suppressing the generation of precipitates in the aqueous ophthalmic composition.
Item 2-2. In the aqueous ophthalmic composition, (A) zinc chloride, (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof, and (C) hyaluronic acid and At least 1 type selected from the group which consists of the salt is mix | blended, The method to suppress generation | occurrence | production of the precipitate in this ophthalmic aqueous composition.
Item 2-3. The ophthalmic aqueous composition containing zinc chloride contains at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof, A method for suppressing generation of precipitates in an aqueous composition.
Item 2-4. In an aqueous ophthalmic composition containing (A) zinc chloride and (C) at least one selected from the group consisting of hyaluronic acid and salts thereof, (B) chondroitin sulfate, aspartic acid, amino A method for suppressing the occurrence of precipitates in the aqueous ophthalmic composition, comprising blending at least one amino acid selected from the group consisting of ethylsulfonic acid and salts thereof.

Moreover, this invention provides the method of providing the effect | action which accelerates | stimulates the proliferation of a corneal cell to the ophthalmic aqueous composition of the aspect hung up below.
Item 3. In the ophthalmic aqueous composition, (A) zinc chloride, and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof are characterized. And a method of imparting an action of promoting proliferation of corneal cells to the aqueous ophthalmic composition.

Moreover, this invention provides the method of suppressing the white residue at the time of the ophthalmic aqueous composition dropping of the aspect hung up below.
Item 4. In the ophthalmic aqueous composition, (A) zinc chloride, and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof are characterized. A method for suppressing white residue when the aqueous ophthalmic composition is dropped.
Item 4-2. The ophthalmic aqueous composition containing zinc chloride contains at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof, A method for suppressing white residue when an aqueous composition is dropped.

Moreover, this invention provides the method of enhancing the histamine release inhibitory effect of the aqueous ophthalmic composition of the aspect hung up below.
Item 5-1. In the ophthalmic aqueous composition, (A) zinc chloride, and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof are characterized. And a method for enhancing the histamine release inhibitory action of the aqueous ophthalmic composition.
Item 5-2. In the aqueous ophthalmic composition, (A) zinc chloride, (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof, and ( C) A method for enhancing the histamine release inhibitory action of the aqueous ophthalmic composition, which comprises blending at least one selected from the group consisting of hyaluronic acid and salts thereof.

Furthermore, this invention also provides the method of providing the effect | action which suppresses an eye itch to the ophthalmic aqueous composition of the aspect hung up below.
Item 6-1. In the aqueous ophthalmic composition, (A) zinc chloride and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof are blended. The method of providing the effect | action which suppresses the itching of eyes to this ophthalmic aqueous composition by this.
Item 6-2. In the aqueous ophthalmic composition, (A) zinc chloride, (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof, and (C) hyaluronic acid and A method of imparting an action of suppressing eye itching to the aqueous ophthalmic composition by blending at least one selected from the group consisting of the salts.

  (1) In the ophthalmic aqueous composition of the present invention, the generation of precipitates is suppressed in the ophthalmic aqueous composition containing zinc chloride. Furthermore, the ophthalmic aqueous composition of the present invention contains at least one selected from the group consisting of hyaluronic acid and salts thereof in addition to zinc chloride, so that precipitates are more likely to occur. The generation of precipitates is suppressed. Therefore, the aqueous ophthalmic composition of the present invention has excellent performance possessed by zinc chloride and at least one superior performance selected from the group consisting of hyaluronic acid and salts thereof without deteriorating safety and quality. Can be stably exhibited over a long period of time.

  (2) The ophthalmic aqueous composition of the present invention has an action of promoting the proliferation of corneal cells, and a corneal repair effect can be expected.

  (3) The aqueous ophthalmic composition of the present invention has a high stability in which white residue at the time of dropping is suppressed. Thereby, excellent quality and safety can be maintained over a long period of time.

  (4) The aqueous ophthalmic composition of the present invention has an action of suppressing the release of histamine, and an antiallergic effect can be expected. Moreover, as a result of having the effect | action which suppresses histamine release, the antihistamine effect | action is strengthened and the effect | action which suppresses the itching of eyes is provided to this ophthalmic aqueous composition. For this purpose, the ophthalmic aqueous composition of the present invention is used as an eye drop, an eye wash, etc., and the eye itch is suppressed or treated by contacting the cornea and / or conjunctiva by a method such as eye drop or eye wash. Can do.

The image which shows the state at the time of 24 hours after dripping on a slide glass about each test liquid used in Test Example 4.

1. Ophthalmic aqueous composition The ophthalmic aqueous composition of the present invention comprises (A) zinc chloride, and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof. An aqueous ophthalmic composition containing

  In the present specification, the “aqueous composition” means a composition containing water, and the water content is, for example, 10 to 99.8 w / v%, preferably 55 to 97. 0.0 w / v%, more preferably 70 to 96.5 w / v%.

  In the ophthalmic aqueous composition of the present invention, the viscosity is not particularly limited. For example, a rotational viscometer (RE550 type) is used because it is an ophthalmic aqueous composition in which precipitates are easily generated in the aqueous ophthalmic composition. The viscosity at 25 ° C. measured with a viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × 24) is 0.01 to 1000 mPa · s, preferably 0.05 to 100 mPa · s, more preferably 0.1. ˜20 mPa · s.

  Hereinafter, the ophthalmic aqueous composition of the present invention will be specifically described.

(A) Zinc chloride The zinc chloride used in the present invention is not particularly limited as long as it can be used in an ophthalmic aqueous composition. For example, zinc chloride described in the 16th revision Japanese Pharmacopoeia, US Pharmacopoeia and European Pharmacopoeia can be mentioned.

  The content of zinc chloride in the aqueous ophthalmic composition of the present invention is not particularly limited, and can be determined according to the specific use, formulation form, usage method and the like of the aqueous ophthalmic composition. For example, based on the total amount of the ophthalmic aqueous composition of the present invention, the zinc chloride content is 0.00001 to 0.05 w / v%, preferably 0.00005 to 0.02 w / v%, more preferably 0.0001 to 0.01 w / v%. It is.

( B) At least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof:
Chondroitin sulfate, aminoethylsulfonic acid, aspartic acid, and salts thereof are all known compounds, and may be produced by a known method or may be obtained as a commercial product.

  Chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof may be used alone or in combination of two or more.

  The chondroitin sulfate used in the present invention is not particularly limited in its origin as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Etc.) and the like. The molecular weight of chondroitin sulfate used in the present invention is not particularly limited. For example, the viscosity average molecular weight is 10,000 to 100,000, preferably 50,000 to 70,000, and more preferably 10,000 to 50,000. It is. Here, the viscosity average molecular weight is determined according to the 16th revised Japanese Pharmacopoeia General Test Method Viscosity Measurement Method First Method: Intrinsic Viscosity η according to Capillary Viscometer Method (Measurement Condition: Solution 0.2 mol / L NaCl, Temperature 25.0 ± 0 ° C., Ubbelohde viscometer) and the obtained intrinsic viscosity η are calculated from the following formula I.

[η] = 5.8 × 10 ⁻⁴ M ^0.74 (Formula I)
(M is the viscosity average molecular weight.)
The salt of chondroitin sulfate used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, the salt of chondroitin sulfate is a salt with an organic base (for example, a salt with an organic amine such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), an inorganic base and Various salts such as ammonium salts (for example, salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), metals such as aluminum, etc.). Among these salts, a salt of chondroitin sulfate with an inorganic base is preferable, an alkali metal salt is more preferable, and sodium chondroitin sulfate is more preferable. These chondroitin sulfate salts may be used singly or in combination of two or more.

  The aminoethylsulfonic acid used in the present invention is a compound also called taurine.

  The salt of aminoethylsulfonic acid used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of the salt of aminoethylsulfonic acid include those having the same form as the salt that can be taken by the chondroitin sulfate. These salts of aminoethylsulfonic acid may be used alone or in combination of two or more.

  Aspartic acid used in the present invention is an acidic amino acid also called 2-aminobutanedioic acid. Aspartic acid may be any of L, D, and DL, but is preferably L.

  The salt of aspartic acid used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of aspartic acid salts include those having the same form as the salts that can be taken by the chondroitin sulfate. Among these salts, preferably, a salt of aspartic acid with an inorganic base, more preferably an alkali metal salt and an alkaline earth metal salt, still more preferably potassium aspartate, magnesium aspartate, and magnesium potassium aspartate, particularly Preferably, it is potassium aspartate. These aspartic acid salts may be used alone or in combination of two or more.

  Among chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof used in the present invention, in particular, chondroitin sulfate sodium, aminoethylsulfonic acid, aspartic acid, potassium aspartate, magnesium aspartate and magnesium potassium aspartate At least one selected from the group consisting of

  In the aqueous ophthalmic composition of the present invention, the content of at least one amino acid selected from the group consisting of (B) chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof is not particularly limited. It can be determined according to the use, formulation form, method of use and the like of the ophthalmic aqueous composition. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of component (B) is 0.01 to 5 w / v%, preferably 0.05 to 4 w / v%, more preferably 0.1 to 3 w / v. %.

  In addition, regarding the content ratio of at least one amino acid selected from the group consisting of (B) chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof to (A) zinc chloride in the ophthalmic aqueous composition, Although not limited, the total amount of component (B) is, for example, 0.2 to 500000 parts by weight, preferably 3 to 100000 parts per 1 part by weight of (A) zinc chloride contained in the ophthalmic aqueous composition. Parts by weight, more preferably 10 to 30000 parts by weight, particularly preferably 30 to 10,000 parts by weight.

An aqueous ophthalmic composition comprising at least one selected from the group consisting of hyaluronic acid and salts thereof. Further, in the present invention, at least selected from the group consisting of (C) hyaluronic acid and salts thereof together with (A) zinc chloride. Even in the ophthalmic aqueous composition in which a precipitate containing one kind is more likely to be generated, (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof is blended. Accordingly, it is possible to suppress the generation of precipitates caused by the combined use of the component (A) and the component (C).

  Hyaluronic acid is a polymer composed of a basic structure (repeat unit) of GlcUA-GlcNAc in which glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc) are combined.

  Hyaluronic acid and a salt thereof used in the present invention are known compounds, and may be produced by a known method, or may be obtained as a commercial product. Hyaluronic acid and its salt may be used alone or in combination of two or more.

  The hyaluronic acid used in the present invention may be a natural product or a synthetic product. The molecular weight of the hyaluronic acid used in the present invention is not particularly limited, but is usually a weight average molecular weight of from 10,000 to 5,000,000, preferably from 10,000 to 4,000,000, more preferably from 10,000 to 3,000,000, More preferably, it is 100,000 to 2.5 million, and particularly preferably 500,000 to 2,000,000.

  The salt of hyaluronic acid used in the present invention is not particularly limited as long as it is in the form of a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable salt. Specifically, alkali metal salts such as sodium salt and potassium salt are exemplified, and sodium hyaluronate is preferable. The hyaluronic acid salt used in the present invention may be used singly or in combination of two or more.

  When blending at least one selected from the group consisting of (C) hyaluronic acid and salts thereof into the ophthalmic aqueous composition of the present invention, the content of the hyaluronic acid used, the aqueous ophthalmic composition It can be determined according to the use of the product, the formulation form, the method of use and the like. For example, based on the total amount of the ophthalmic aqueous composition of the present invention, the total content of component (C) is 0.0001 to 1 w / v%, preferably 0.0005 to 0.3 w / v%, more preferably 0.001 to 0.1 w. / V%.

  Moreover, the content ratio of at least one component selected from the group consisting of (C) hyaluronic acid and its salt with respect to (A) zinc chloride in the ophthalmic aqueous composition of the present invention is not particularly limited, The total amount of component (C) is, for example, 0.002 to 100,000 parts by weight, preferably 0.02 to 5000 parts by weight, based on 1 part by weight of (A) zinc chloride contained in the ophthalmic aqueous composition. Preferably it is 0.1-1000 weight part.

  In addition, from the group consisting of (B) chondroitin sulfate, aminoethyl sulfonic acid, aspartic acid and salts thereof for at least one selected from the group consisting of (C) hyaluronic acid and salts thereof in the ophthalmic aqueous composition of the present invention. Although the content ratio of the selected at least one amino acid is not particularly limited, the total amount of the component (B) is 1 part by weight of the total amount of the component (C) contained in the aqueous ophthalmic composition. For example, 0.01 to 50000 parts by weight, preferably 0.2 to 10000 parts by weight, and more preferably 1 to 3000 parts by weight.

Surfactant The aqueous ophthalmic composition of the present invention can contain a surfactant. A surfactant is effective as a solubilizing agent for improving the solubility of various pharmacologically active ingredients, physiologically active ingredients, additives and the like described later depending on the purpose of use of the ophthalmic composition. is there.

  Here, the surfactant can be appropriately selected from known surfactants that are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, depending on the components to be dissolved. Either an ionic surfactant or an ionic (amphoteric, negative, positive) surfactant may be used. Surfactant used by this invention may be used individually by 1 type, and may be used in combination of 2 or more type.

  Specific examples of the nonionic surfactant include monouraric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60). POE sorbitan fatty acid esters such as POE (20) sorbitan tristearate (polysorbate 65), POE (20) sorbitan monooleate (polysorbate 80); POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE hydrogenated castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (3) castor oil (polyoxyethylene castor oil 3), POE (10) castor oil (polyoxyethylene castor oil) 10), POE (3 POE castor oil such as castor oil (polyoxyethylene castor oil 35), POE (70) castor oil (polyoxyethylene castor oil 70); POE alkyl ether such as POE (9) lauryl ether; POE (20) POP ( 4) POE-POP alkyl ethers such as cetyl ether; polyoxyethylene / polyoxypropylene block copolymers such as POE (196) POP (67) glycol (poloxamer 407, Pluronic F127), POE (200) POP (70) glycol; Examples thereof include polyethylene glycol monostearate such as polyoxyl stearate 10 and polyoxyl 40 stearate. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.

  Specific examples of amphoteric surfactants include alkyldiaminoethylglycine and salts thereof (for example, hydrochloride and the like).

  Specific examples of the anionic surfactant include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, α-sulfo fatty acid ester salt, α-olefin sulfonic acid and the like.

  Specific examples of the cationic surfactant include benzalkonium chloride and benzethonium chloride.

When the aqueous ophthalmic composition of the present invention contains a surfactant, the content of the surfactant is not particularly limited, the type of surfactant used, the type and amount of other components, ophthalmic aqueous It can set suitably according to the use of a composition, a usage method, etc. For example, based on the total amount of the ophthalmic aqueous composition, the total amount of the surfactant is 0.0001 to 5 w / v%, preferably 0.001 to 2 w / v%, more preferably 0.005 to 0.5 w / v. %
Other ingredients :
The aqueous ophthalmic composition of the present invention contains (A) zinc chloride, and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof. However, within the range that does not impair the effects of the present invention, various pharmacologically active ingredients and physiologically active ingredients can be appropriately selected and contained according to conventional methods according to their uses and preparation forms. Examples of these pharmacologically active components and physiologically active components include active ingredients in various pharmaceuticals described in the generic drug manufacture (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee).

  Specific examples of the pharmacologically active component or physiologically active component include the following components.

  Antihistamine or antiallergic agent: for example, ketotifen fumarate, iproheptin, chlorpheniramine maleate, diphenhydramine hydrochloride, sodium cromoglycate, tranilast, pemirolast potassium and the like.

  Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.

  Bactericides: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, etc.

  Vitamins: For example, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, panthenol, calcium pantothenate, tocopherol acetate and the like.

  Anti-inflammatory agent: for example, dipotassium glycyrrhizinate, azulene sulfonic acid, allantoin, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme and the like.

  Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.

  Other: For example, neostigmine methyl sulfate, sulfamethoxazole, sulfamethoxazole sodium, pranoprofen and the like.

  In the ophthalmic aqueous composition of the present invention, the content of the pharmacologically active ingredient and the physiologically active ingredient described above is appropriately determined depending on the specific use of the ophthalmic aqueous composition, formulation form, method of use, type of active substance, and the like. It can be selected, and can be appropriately selected from a range known in the technical field according to the type and use of the component to be used.

  Further, the aqueous ophthalmic composition of the present invention further contains various additives according to conventional methods according to the use and formulation form, as long as the effects of the present invention are not impaired. can do. Examples of these additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.

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

  Terpenoids: menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, derivatives thereof, etc., and these compounds are d-form, l-form and Any of the dl forms may be used. Further, essential oils such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, mint oil, fennel oil, cinnamon oil, rose oil, camphor oil and the like may be used.

  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, glowul (trade name, manufactured by Rhodia), biguanide compound (specifically, polyhexamethylene biguanide) And so on.

  Isotonizing agents: disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, thiosulfuric acid Sodium, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol, etc.

  pH regulators: for example, hydrochloric acid, boric acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, borax, triethanolamine, 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 and the like.

  Stabilizers: For example, dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, aluminum monostearate, glyceryl monostearate and the like.

  Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like.

  In the ophthalmic aqueous composition of the present invention, the content of the additive described above is appropriately selected from a known range in the technical field depending on the specific use, formulation form, usage method, and the like of the ophthalmic aqueous composition. You can choose.

PH of aqueous ophthalmic composition
The pH (25 ° C.) of the ophthalmic aqueous composition of the present invention varies depending on the intended use, usage form, and the like, but is preferably pH 6.5 or more from the viewpoint that precipitates are likely to be generated. 9.5, preferably 6.5-9, particularly preferably 7-8. In the present specification, the pH value is a value measured at 25 ° C.

  In the ophthalmic aqueous composition of the present invention, the pH can be adjusted using the aforementioned pH adjusting agent, buffering agent and the like.

  Here, as a buffering agent, it can select and use from the well-known buffering agent accept | permitted pharmacologically, pharmacologically (pharmaceutically) or physiologically according to the target pH value. Examples of such buffering agents include borate buffer, phosphate buffer, acetate buffer, Tris buffer, epsilon-aminocaproic acid, and the like. Preferred buffering agents are borate buffering agents and phosphate buffering agents, and particularly preferred buffering agents are boric acid buffering agents. Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); acetic acid buffer, acetic acid Or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); Tris (hydroxymethyl) aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.) and the like are exemplified as a Tris buffer. . These buffering agents may be used alone or in any combination of two or more.

  The aqueous ophthalmic composition of the present invention preferably contains at least one selected from the group consisting of boric acid and salts thereof as a buffering agent from the viewpoint that the effects of the invention can be remarkably obtained. It is preferable that the composition does not contain citric acid and salts thereof.

  Examples of the salt of boric acid include borates such as alkali metal borate and alkaline earth metal borate. Further, a borate hydrate may be used as the borate. Examples of specific components include boric acid (orthoboric acid), sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax and the like. Boric acid and its salt can be used alone or in combination of two or more. As a suitable specific example of combining boric acid and its salt, a combination of boric acid and an alkali metal salt of boric acid, more preferably a combination of boric acid and borax is exemplified.

  When the aqueous ophthalmic composition of the present invention contains a buffering agent, the content of the buffering agent is not particularly limited, and the type of buffering agent used, the type and amount of other components, the ophthalmic aqueous composition It can be set as appropriate according to the purpose and usage. For example, based on the total amount of the ophthalmic aqueous composition, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.1 to 5 w / v%, more preferably 0.5 to 3 w / v%. .

2. Preparation Method and Use of Ophthalmic Aqueous Composition The ophthalmic aqueous composition of the present invention is selected from the group consisting of (A) zinc chloride and (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof. Any ophthalmic aqueous composition containing at least one amino acid can be prepared according to methods known to those skilled in the art. For example, each component can be dissolved in an appropriate amount of purified water, adjusted to a predetermined pH value, and then the remaining purified water is added to adjust the volume. Moreover, it can also be filtered and sterilized as needed, and can be filled with a container. The aqueous ophthalmic composition of the present invention can be used as a pharmaceutical preparation, quasi-drug, and the like, and includes eye drops [however, eye drops include eye drops that can be applied while wearing contact lenses], artificial tears [ However, artificial tears include artificial tears that can be instilled while wearing contact lenses], eyewashes [however, eyewashes include eyewashes that can be washed while wearing contact lenses], contact lens compositions [Contact lens mounting liquid, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative) and the like]. Preferred examples of the ophthalmic aqueous composition of the present invention include eye drops, artificial tears, eye washes, and contact lens mounting liquids, and particularly preferred examples include eye drops and artificial tears. In addition, when using as a composition for contact lenses, it is applicable to all contact lenses including a hard contact lens and a soft contact lens.

  The ophthalmic aqueous composition of the present invention can be provided by being contained in an arbitrary container. The container for storing the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is made of a material that can be used for a general container in the field, for example, a glass material and a plastic material ( For example, polyethylene terephthalate resin, polypropylene resin, polyethylene resin, polyethylene naphthalate resin) can be appropriately selected and used depending on the purpose and application. In addition, the container containing the ophthalmic aqueous composition of the present invention may be a transparent container that allows the inside of the container to be visually recognized, or may be an opaque container that is difficult to visually recognize the inside of the container. A transparent container is particularly preferred because it is easy to confirm the amount of the aqueous ophthalmic composition solution and to check for foreign matters in the production process. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container. Furthermore, the aqueous ophthalmic composition of the present invention is not only a single-use type packaging form, but also a multi-dose aqueous ophthalmic composition that is packaged in a form to be administered multiple times and continuously used by the user. It is also useful as a product.

3. Method for suppressing generation of precipitate in aqueous ophthalmic composition As described above, in the aqueous ophthalmic composition, (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof together with (A) zinc chloride By blending at least one amino acid selected from the group consisting of: (A) Oxidation generated in the aqueous ophthalmic composition containing zinc chloride can be suppressed.

  Accordingly, the present invention provides an aqueous ophthalmic composition comprising (A) zinc chloride and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof. The present invention provides a method for suppressing the generation of precipitates in the aqueous ophthalmic composition by blending.

  Further, the present invention provides (A) an aqueous ophthalmic composition containing zinc chloride with (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof. The present invention also provides a method for suppressing generation of precipitates in the aqueous ophthalmic composition by blending.

  Furthermore, in the present invention, an ophthalmic aqueous composition in which precipitates are more easily generated by containing at least one selected from the group consisting of (A) zinc chloride and (C) hyaluronic acid and salts thereof. (B) Precipitation caused by the combined use of the component (A) and the component (C) by blending at least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof Generation of an object can be suppressed.

  Accordingly, the present invention provides at least one amino acid selected from the group consisting of (A) zinc chloride, (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof in the aqueous ophthalmic composition, and (C) Provided is a method for suppressing the generation of precipitates in the aqueous ophthalmic composition, which comprises blending at least one selected from the group consisting of hyaluronic acid and salts thereof.

  Further, the present invention provides (A) zinc chloride, and (C) an aqueous ophthalmic composition containing at least one selected from the group consisting of hyaluronic acid and salts thereof, and (B) chondroitin sulfate, aspartic acid, The present invention also provides a method for suppressing the generation of precipitates in the aqueous ophthalmic composition, which comprises blending at least one amino acid selected from the group consisting of aminoethylsulfonic acid and salts thereof.

  In each of the above methods, at least one amino acid selected from the group consisting of (A) zinc chloride, (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof in the aqueous ophthalmic composition, and necessary Accordingly, the order of addition thereof is not particularly limited as long as at least one selected from the group consisting of (C) hyaluronic acid and a salt thereof coexists. In addition, for the components (A) to (C), the type and content of each component, the type and content of the other components, the formulation form of the composition, etc. are the aqueous ophthalmic composition of the present invention. It is the same.

  In addition, in this specification, it can be determined by the method as described in the below-mentioned Example (Test Example 1) whether the generation | occurrence | production of the precipitate in the ophthalmic aqueous composition is suppressed.

4). Method for imparting action of promoting corneal cell proliferation As described above, the ophthalmic aqueous composition comprises (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof together with (A) zinc chloride. By blending at least one amino acid selected from the group, the ophthalmic aqueous composition can be imparted with an action of promoting the proliferation of corneal cells.

  Accordingly, the present invention provides an aqueous ophthalmic composition comprising (A) zinc chloride and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof. The present invention provides a method for imparting an action of promoting the proliferation of corneal cells to the ophthalmic aqueous composition by blending.

  In the above-described method, at least one amino acid selected from the group consisting of (A) zinc chloride and (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof coexists in the aqueous ophthalmic composition. If it is, those addition orders will not be specifically limited. In addition, for the component (A) and the component (B), the type and content of each component, the type and content of other components, the formulation form of the composition, etc. are the ophthalmic aqueous composition of the present invention. It is the same as a thing.

  In addition, in this specification, it can be determined by the method as described in the below-mentioned Example (Test Example 3) whether the proliferation of a corneal cell is promoted with the ophthalmic aqueous composition.

5. Method for suppressing white residue at the time of dropping ophthalmic aqueous composition As described above, (A) zinc chloride, (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof in the aqueous ophthalmic composition By blending at least one amino acid selected from the group consisting of: (A) A white residue at the time of dropping produced in an aqueous ophthalmic composition containing zinc chloride can be suppressed. Thereby, the white residue at the time of dropping the aqueous ophthalmic composition can be suppressed, the stability can be improved, and a composition excellent in quality and safety can be provided over a long period of time.

  Accordingly, the present invention provides an aqueous ophthalmic composition comprising (A) zinc chloride and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof. The present invention provides a method for suppressing white residue when the aqueous ophthalmic composition is dropped by blending.

  Further, the present invention provides (A) an aqueous ophthalmic composition containing zinc chloride with (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof. The present invention also provides a method for suppressing white residue when the aqueous ophthalmic composition is dropped by blending.

  In the above-described method, at least one amino acid selected from the group consisting of (A) zinc chloride and (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof coexists in the aqueous ophthalmic composition. If it is, those addition orders will not be specifically limited. In addition, for the component (A) and the component (B), the type and content of each component, the type and content of other components, the formulation form of the composition, etc. are the ophthalmic aqueous composition of the present invention. It is the same as a thing.

  In addition, in this specification, it can be determined by the method as described in the below-mentioned Example (Test Example 4) whether the white residue at the time of dripping the ophthalmic aqueous composition is suppressed.

6). Method for enhancing histamine release inhibiting action and method for imparting eye itching inhibiting action Further, as described above, in the aqueous ophthalmic composition, together with (A) zinc chloride, (B) chondroitin sulfate, aspartic acid, aminoethyl By adding at least one amino acid selected from the group consisting of sulfonic acid and salts thereof, the histamine release inhibitory action of the aqueous ophthalmic composition can be enhanced.

  Accordingly, the present invention provides an aqueous ophthalmic composition comprising (A) zinc chloride and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof. The present invention provides a method for enhancing the histamine release inhibitory action of the aqueous ophthalmic composition by blending.

  Furthermore, in the present invention, the aqueous ophthalmic composition contains (A) zinc chloride and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof. , (C) By adding at least one selected from the group consisting of hyaluronic acid and salts thereof, the histamine release inhibitory action of the aqueous ophthalmic composition can be further enhanced.

  Accordingly, the present invention provides at least one amino acid selected from the group consisting of (A) zinc chloride, (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof in the aqueous ophthalmic composition, and (C) The present invention also provides a method for enhancing the histamine release inhibitory action of the ophthalmic aqueous composition by blending at least one selected from the group consisting of hyaluronic acid and salts thereof.

  Further, the aqueous ophthalmic composition of the present invention has an action of suppressing histamine release, and as a result, has an enhanced antihistaminic action. The ophthalmic aqueous composition is imparted with an action of suppressing eye itching. ing.

  Therefore, the present invention is further selected from the group consisting of (A) zinc chloride and (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof in the ophthalmic aqueous composition from another viewpoint. The present invention provides a method for imparting an action of suppressing eye itching to the ophthalmic aqueous composition by blending at least one amino acid.

  Further, the present invention provides an aqueous ophthalmic composition comprising (A) zinc chloride, (B) chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and at least one amino acid selected from the group thereof, and (C) The present invention also provides a method for imparting an action of suppressing eye itching to the ophthalmic aqueous composition by blending at least one selected from the group consisting of hyaluronic acid and salts thereof.

  In each of the above methods, in the aqueous ophthalmic composition, (A) zinc chloride, and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid, and salts thereof, and As long as at least 1 type selected from the group which consists of (C) hyaluronic acid and its salt coexists as needed, those addition orders are not specifically limited. In addition, for the components (A) to (C), the type and content of each component, the type and content of the other components, the formulation form of the composition, etc. are the aqueous ophthalmic composition of the present invention. It is the same.

  In addition, in this specification, it can be determined by the method as described in the below-mentioned Example (Test Example 5) whether the histamine release inhibitory action in the ophthalmic aqueous composition is enhanced.

  Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like.

Test Example 1 (Test 1 for precipitates and turbidity)
Ophthalmic aqueous compositions of Examples 1 to 3 and Comparative Examples 1 to 3 shown in Table 1 below were prepared. Specifically, 80 mL of purified water was added to and dissolved in each component except for borax shown in Table 1, and then borax was added to adjust to each pH. Thereafter, purified water was added to make up a total volume of 100 mL. In this test, zinc chloride, aminoethylsulfonic acid, potassium L-aspartate, and zinc sulfate were used as the raw materials (reagents). Sodium chondroitin sulfate conforms to the standard of the pharmaceutical additive standard 2003.

  Each ophthalmic aqueous composition prepared by the above-described method is filled into 30 mL glass screw vials in an amount of 30 mL, and stored in an incubator immediately after preparation or at 70 ° C. for 24 hours, and then precipitated in each ophthalmic aqueous composition. The occurrence of the product was evaluated by visual observation or turbidity measurement.

In addition, the evaluation criteria of the visual deposit generation were determined according to the following.
<Evaluation criteria for precipitate generation>
There is precipitation: +++
There is some precipitation: ++
There is a slight precipitation: +
Clear without any precipitation:-
For turbidity measurement, purified water was used as a blank, and a turbidimeter 2100AN (manufactured by HACK) was used. The turbidity suppression rates of Examples 1 to 3 were calculated by the following formula (1), and the turbidity suppression rates of Comparative Example 3 were calculated by the following formula (2). The results are listed in Table 1.

Turbidity suppression rate (%) =
(1- (Turbidity of Examples 1 to 3) / (Turbidity of Comparative Example 1)) x100 Formula (1)
Turbidity suppression rate (%) =
(1- (Turbidity of Comparative Example 3) / (Turbidity of Comparative Example 2)) × 100 Formula (2)

  In the ophthalmic aqueous composition containing only zinc chloride, generation of precipitates was observed both immediately after preparation and after storage at 70 ° C. (Comparative Example 1). On the other hand, in the ophthalmic aqueous composition containing sodium chondroitin sulfate, aminoethylsulfonic acid or potassium L-aspartate together with zinc chloride, the turbidity is remarkably reduced and almost all precipitates are observed. None (Examples 1-3).

  On the other hand, for the ophthalmic aqueous composition containing only zinc sulfate, the occurrence of precipitates was not observed immediately after the preparation, but after being stored in a thermostat at 70 ° C. for 24 hours, precipitation was slightly recognized. It was. In addition, regarding the ophthalmic aqueous composition containing aminoethylsulfonic acid together with zinc sulfate, generation of precipitates was not observed immediately after preparation, but after storage in a thermostat at 70 ° C. for 24 hours, Generation | occurrence | production of the deposit was recognized (Comparative Examples 2 and 3). Therefore, in the ophthalmic aqueous composition containing aminoethylsulfonic acid together with zinc sulfate, the turbidity slightly decreased when stored at 70 ° C. when compared with the aqueous ophthalmic composition containing only zinc sulfate. It was only.

  Therefore, the ophthalmic aqueous composition contains at least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof together with zinc chloride, thereby suppressing the occurrence of precipitates. It was revealed that an aqueous ophthalmic composition having excellent stability can be obtained. Furthermore, it has been clarified that this effect is a specific effect when zinc chloride is used as the zinc compound.

Test Example 2 (Test 2 on precipitates and turbidity)
Ophthalmic aqueous compositions of Examples 4 to 6 and Comparative Examples 4 to 5 shown in Table 2 below were prepared. Specifically, 80 mL of purified water was added to each component except borax shown in Table 2 and dissolved, and then borax was added to adjust the pH. Thereafter, purified water was added to make up a total volume of 100 mL. In this test, zinc chloride, aminoethylsulfonic acid and potassium L-aspartate were used as raw materials (reagents). Sodium hyaluronate conforms to the standard of purified sodium hyaluronate of the 16th revision Japanese Pharmacopoeia, and sodium chondroitin sulfate conforms to the standard of pharmaceutical additive standard 2003.

  Each ophthalmic aqueous composition prepared by the method described above is filled in 7 mL each in a 10 mL glass screw vial and stored in a thermostat at 70 ° C. for 1 week, and then precipitates are generated in each ophthalmic aqueous composition. Was evaluated by turbidity measurement.

  For the turbidity measurement, purified water was used as a blank and a turbidimeter 2100AN (manufactured by HACK) was used.

  Precipitation was observed in the aqueous ophthalmic composition containing only zinc chloride (Comparative Example 4), and further, precipitation increased in the aqueous ophthalmic composition containing sodium hyaluronate together with zinc chloride, resulting in an increase in turbidity. (Comparative Example 5).

  On the other hand, in the ophthalmic aqueous composition containing sodium chondroitin sulfate, aminoethylsulfonic acid or potassium L-aspartate together with zinc chloride and sodium hyaluronate, the turbidity was remarkably reduced and almost precipitation was observed. (Examples 4 to 6).

  Accordingly, an aqueous ophthalmic composition containing zinc chloride and at least one selected from the group consisting of hyaluronic acid and salts thereof is selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof. It has been clarified that the inclusion of at least one kind of amino acid prevents the formation of precipitates and provides an aqueous ophthalmic composition having excellent stability.

Test Example 3 (Cornea Cell Growth Promotion Test)
Rabbit corneal cell line SIRC cells (ATCC number: CCL-60) seeded in a 96-well plate at 3.0 x 10 ³ cells / well were cultured for 24 hours at 37 ° C under 5% CO ₂ , and the supernatant was removed. 90 μl of growth medium (10% fetal bovine serum-containing DMEM medium (GIBCO)) was added. Furthermore, 10 μL of each test solution prepared at the concentrations shown in Table 3 was added to each well, cultured for 24 hours under conditions of 37 ° C. and 5% CO ₂ , and then a living cell number detection reagent WST-8 (manufactured by Dojindo Laboratories). ) Was added. Absorbance as an index of the number of living cells was measured (450 nm), and the cell viability was calculated. In this test, zinc chloride and zinc sulfate (reagents) were used as raw materials. Sodium chondroitin sulfate conforms to the standard of the pharmaceutical additive standard 2003. The results are shown in Table 3 below as an average value ± standard deviation.

  In the test solution containing zinc chloride, zinc sulfate or sodium chondroitin sulfate alone, the survival rate of SIRC cells was hardly affected as compared with the test solution to which these were not added (Comparative Example 6) (Comparative Example). 7-9). On the other hand, in the test solution containing sodium chondroitin sulfate together with zinc chloride, the number of cells increased and cell proliferation was remarkably promoted (Example 7). On the other hand, in the test solution containing chondroitin sulfate together with zinc sulfate, the number of cells was rather lowered and no cell proliferation action was observed (Comparative Example 10).

  Accordingly, the proliferation of corneal cells is promoted by containing zinc chloride and at least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof in the aqueous ophthalmic composition. It became clear that

Test example 4 (white residue suppression test)
Ophthalmic aqueous compositions of Comparative Example 11 and Example 8 shown in Table 4 below were prepared. Specifically, 80 mL of purified water was added to zinc chloride, potassium L-aspartate, boric acid and borax, dissolved, and then adjusted to pH 7.5 by adding hydrochloric acid or sodium hydroxide, and then purified water. Was added to make a total volume of 100 mL to prepare a test solution. In this test, zinc chloride and potassium L-aspartate were used as the raw materials (reagents) manufactured by Wako Pure Chemical.

30 μL of each prepared test solution was dropped on a slide glass and allowed to stand at 33 ° C. for 24 hours. The state of each test solution on the slide glass after 24 hours was observed, and the degree of the remaining white amount was evaluated according to the following evaluation criteria. The results are shown in Table 4 below. FIG. 1 shows an image taken with a digital camera.
<Evaluation criteria for remaining amount of white>
The white balance is intense: +++
There is white rest: ++
There is a slight white balance: +
No white residue is seen: −

  As is clear from Table 4 and FIG. 1, in the ophthalmic aqueous composition containing only zinc chloride, it was observed that a white solid remained after dropping on the slide glass (Comparative Example 11). On the other hand, no white residue was observed in the aqueous ophthalmic composition containing potassium L-aspartate together with zinc chloride (Example 8).

  Therefore, when the ophthalmic aqueous composition contains zinc chloride and at least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid, and salts thereof, white residue at the time of dropping is reduced. It was revealed that an ophthalmic aqueous composition which is completely suppressed and excellent in quality can be obtained.

Test Example 5 (Histamine release inhibition test)
96-well rat basophil cell line (RBL-2H3) suspended in DMEM medium (Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen) at a density of 1.4 × 10 ⁵ cells / cm ² The cells were seeded on a microtiter plate (Corning) and cultured at 37 ° C. under 5% CO ₂ for 24 hours. Thereafter, the culture supernatant was removed by aspiration, and a PIPES buffer solution (pH 7.2, composition: 0.1 w / v% bovine serum albumin (manufactured by Sigma) in which the test substance was dissolved so as to have the concentrations shown in Tables 5 and 6; CaCl ₂ · 2H ₂ O 3.0 mM, MgCl ₂ · 6H ₂ O 0.40 mM, KCl 7.38 mM, NaCl 118.93 mM, D (+)-Glucose 5.60 mM, 25 mM PIPES (Piperazine-1,4-bis (2-ethanesulfonic acid ), 0.1 ml per well, and incubated for 1.5 hours at 37 ° C. under 5% CO _{2. The} culture supernatant was then aspirated and removed in PIPES buffer containing the test substance. Furthermore, 0.2 ml of PIPES buffer solution to which A23187 (reagent: Sigma) was added so as to be 10 μM was added per well, and further incubated at 37 ° C. under 5% CO _{2 for} 30 minutes.

  The supernatant of each well was collected, and the histamine concentration was quantified using an ELISA kit (Oxford Biochemical Research). Using the histamine concentration of each test solution obtained, the histamine release inhibition rate (%) was calculated according to the following formula (3). The results are shown in Tables 5 and 6.

Histamine release inhibition rate (%) =
(Histamine concentration of Comparative Example 12−Histamine concentration of each test solution) / (Histamine concentration of Comparative Example 12) × 100 Formula (3)
In this test, zinc chloride and aminoethylsulfonic acid (reagents) were used as raw materials. Sodium chondroitin sulfate conforms to the standard of the pharmaceutical additive standard 2003, and sodium hyaluronate conforms to the standard of purified sodium hyaluronate of the 16th revision Japanese Pharmacopoeia.

  The histamine concentration in the test solution containing sodium chondroitin sulfate or aminoethylsulfonic acid alone is increased compared to the histamine concentration in the test solution containing only zinc chloride (Comparative Example 12), and the histamine release inhibition rate is On the contrary, histamine release was promoted (Comparative Examples 13 and 14). On the other hand, the histamine concentration in the test solution containing only chondroitin sulfate or aminoethylsulfonic acid together with zinc chloride is reduced compared to the histamine concentration in the test solution containing only zinc chloride (Comparative Example 12). It was revealed that histamine release was remarkably suppressed (Examples 9 and 10).

  In addition, the histamine concentration in the test solution containing sodium chondroitin sulfate or aminoethylsulfonic acid together with hyaluronic acid is increased or slightly decreased compared to the histamine concentration in the test solution containing only zinc chloride (Comparative Example 12). However, the histamine release inhibition rate declined and promoted histamine release, or the release inhibition was hardly enhanced (Comparative Examples 15 and 16). On the other hand, the histamine concentration in the test solution containing hyaluronic acid and sodium chondroitin sulfate or aminoethylsulfonic acid together with zinc chloride is decreased compared to the histamine concentration in the test solution containing only zinc chloride (Comparative Example 12). It was revealed that the inhibition of histamine release was remarkably enhanced (Examples 11 and 12).

  In addition, the histamine concentration in the test solution (Examples 11 and 12) containing sodium hyaluronate and sodium chondroitin sulfate or aminoethylsulfonic acid together with zinc chloride was determined by adding sodium chondroitin sulfate or aminoethylsulfonic acid together with zinc chloride. Even when compared with the histamine concentration in the test solutions contained alone (Examples 9 and 10), it was revealed that the inhibition of histamine release was further significantly enhanced.

  Therefore, when the aqueous ophthalmic composition contains zinc chloride and at least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof, histamine release is significantly suppressed. It became clear that it was strengthened.

  Furthermore, it has been clarified that the inhibition of histamine release is further enhanced by containing at least one selected from the group consisting of hyaluronic acid and salts thereof.

Formulation Examples Artificial tears (formulation examples 1 to 5) and eye drops (formulation examples 6 to 16) are prepared according to conventional methods with the formulations described in Tables 7 to 9.

Claims (8)

An aqueous ophthalmic composition comprising (A) zinc chloride, and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aminoethylsulfonic acid, aspartic acid and salts thereof , and further boric acid And an ophthalmic aqueous composition comprising at least one selected from the group consisting of salts thereof .   The aqueous ophthalmic composition according to claim 1, further comprising (C) at least one selected from the group consisting of hyaluronic acid and salts thereof.   The component (B) is at least one amino acid selected from the group consisting of sodium chondroitin sulfate, aminoethylsulfonic acid, aspartic acid, potassium aspartate, magnesium aspartate and magnesium potassium aspartate. An aqueous ophthalmic composition as described in 1. above.   The aqueous ophthalmic composition according to claim 2 or 3, wherein the component (C) is sodium hyaluronate.   The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the total amount of the component (B) is 0.2 to 500000 parts by weight with respect to 1 part by weight of the component (A).   The aqueous ophthalmic composition according to any one of claims 1 to 5, which has a pH of 6.5 or more. The ophthalmic aqueous composition according to any one of claims 1 to 6, wherein the total content of the component (B) is 0.01 to 5 w / v%. In the aqueous ophthalmic composition, (A) zinc chloride and (B) at least one amino acid selected from the group consisting of chondroitin sulfate, aspartic acid, aminoethylsulfonic acid and salts thereof are further blended , and boric acid And at least one selected from the group consisting of the salts thereof, a method for suppressing the generation of precipitates in the aqueous ophthalmic composition.

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