JP7104553B2 - Ophthalmic composition - Google Patents

Description

The present invention relates to an ophthalmic composition and a method for suppressing a decrease in viscosity of the ophthalmic composition.

Hyaluronic acid or a salt thereof is often used as a component of ophthalmic compositions, especially eye drops. Hyaluronic acid or a salt thereof binds to fibronectin in the epithelial cells of the eye to promote the adhesion and growth of epithelial cells and promote the healing of corneal wounds. In addition, it has a large number of water molecule retention functions in the molecule, which retains and stabilizes tears and prevents the eyes from drying out. Based on these effects, ophthalmic compositions containing hyaluronic acid or salts thereof can be used for endogenous keratoconjunctival epithelial disorders such as Sjogren's syndrome, Stevens-Johnson syndrome, dry eye, postoperative, drug-induced, trauma, contact lenses. It is used to treat extrinsic keratoconjunctival epithelial disorders caused by wearing.

Since hyaluronic acid or a salt thereof has a high viscosity, an ophthalmic composition containing hyaluronic acid or a salt thereof has a long contact time with the keratoconjunctival epithelium and can fully exert its pharmacological action. Therefore, in order to maintain the therapeutic effect, it is required that the viscosity of hyaluronic acid or a salt thereof does not decrease and is kept stable during the production, distribution, storage and the like of the ophthalmic composition.
However, hyaluronic acid or a salt thereof is easily decomposed by light in an aqueous solution to reduce the molecular weight, and thus the viscosity is likely to be lowered. Therefore, it is required to suppress a decrease in viscosity due to storage of an ophthalmic composition containing hyaluronic acid or a salt thereof.

A main object of the present invention is to provide an ophthalmic composition containing hyaluronic acid or a salt thereof, in which a decrease in viscosity in the presence of mucin due to storage is sufficiently suppressed.

The present inventor has repeated research to solve the above problems and obtained the following findings.
(i) An ophthalmic composition containing hyaluronic acid or a salt thereof has a remarkable decrease in viscosity due to storage, especially when the viscosity average molecular weight of hyaluronic acid or a salt thereof is 300,000 or more.
(ii) The degree of decrease in viscosity due to storage of an ophthalmic composition containing hyaluronic acid having an average molecular weight of 300,000 or more or a salt thereof differs between the case of measurement in the presence of mucin and the case of measurement in the absence of mucin. .. Since tears contain mucin, "in the presence of mucin" mimics the application of this ophthalmic composition to the eye.
(iii) When an ophthalmic composition containing hyaluronic acid having an average molecular weight of 300,000 or more or a salt thereof is stored, the decrease in viscosity measured in the presence of mutin is caused by adding a water-soluble polymer compound to the ophthalmic composition. It is suppressed by doing.

The present invention has been completed based on the above findings, and provides the following ophthalmic composition and a method for suppressing a decrease in viscosity of the ophthalmic composition.
Item 1. An ophthalmic composition containing (A) hyaluronic acid having an average molecular weight of 300,000 to 3.9 million and / or a salt thereof, and (B) a water-soluble polymer compound.
Item 2. Item 2. The ophthalmic composition according to Item 1, wherein the concentration of the component (A) is 0.001 to 10 w / v%.
Item 3. Item 1 or item (B), wherein the component (B) is at least one selected from the group consisting of chondroitin sulfate, hydroxypropylmethyl cellulose, ethyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, and salts thereof. 2. The ophthalmic composition according to 2.
Item 4. (B) The ophthalmic composition according to any one of Items 1 to 3, wherein the concentration of the component (B) is 0.001 to 10 w / v%.
Item 5. Item 4. The ophthalmic composition according to any one of Items 1 to 4, further comprising (C) an inorganic salt.
Item 6. The component (C) is sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium sulfate, zinc sulfate, chloride. Item 5. The ophthalmic composition according to Item 5, which is at least one selected from the group consisting of zinc and sodium tetraborate.
Item 7. (A) Viscosity By adding (B) a water-soluble polymer compound to an ophthalmic composition containing hyaluronic acid or a salt thereof having an average molecular weight of 300,000 to 3.9 million, the viscosity of the ophthalmic composition in the presence of mutin A method of suppressing the decrease due to storage of.

Tear fluid has a three-layer structure of an oil layer, an aqueous layer, and a mucin layer from the outside. The oil layer is a layer of oil secreted by the meibomian glands and prevents the tear fluid from evaporating. The water layer is a layer of fluid secreted from the lacrimal glands, contains various components such as proteins, prevents the cornea from drying out, and plays a role in nutritional supply to the cornea, infection prevention, wound healing, and the like. In addition, secretory mucin secreted from conjunctival goblet cells exists in the aqueous layer in a form of retaining water, and functions as a mucosal barrier by uniformly distributing tear fluid on the ocular surface. The mucin layer is a layer composed of membrane-bound mucin that exists in a state of being bound to the surface of the corneal epithelium. It acts as a barrier and improves the wettability of the epithelial surface to stably retain tear fluid on the surface of the eye. Play a role.

The ophthalmic composition containing hyaluronic acid or a salt thereof tends to decrease in viscosity due to storage, especially when the viscosity average molecular weight is 300,000 or more. In measuring the degree of viscosity reduction of this ophthalmic composition, the viscosity of the ophthalmic composition itself was measured after storage, and the viscosity of the ophthalmic composition in the presence of mutin was measured after storage. The degree varies greatly. Therefore, it is important to examine the effect of preservation on the viscosity of ophthalmic compositions in the presence of mucin, which mimics the case of application to the eye. In addition, when the ophthalmic composition is applied to the eye, it is mixed with the liquid layer of tears containing secretory mucin. Therefore, the effect of preservation on the viscosity of the ophthalmic composition in the coexistence of secretory mucin among mucins was investigated. It is important to.
The ophthalmic composition of the present invention contains hyaluronic acid or a salt thereof in the presence of mucin (particularly, secretory mucin) by containing a water-soluble polymer in addition to hyaluronic acid having a viscosity average molecular weight of 300,000 or more or a salt thereof. The decrease in the viscosity of mucin due to storage is effectively suppressed. Therefore, sufficient viscosity can be obtained on the ocular surface even after storage, and it can stay on the ocular surface for a sufficient time, and as a result, the medicinal effect of hyaluronic acid or a salt thereof or other components is sufficiently exhibited.

It is a graph which shows the suppression rate of the viscosity decrease in the presence of mucin of the ophthalmic composition containing sodium hyaluronate by blending a water-soluble polymer compound.

Hereinafter, the present invention will be described in detail.
(1) Ophthalmic composition
The ophthalmic composition of the present invention is a composition containing hyaluronic acid having a viscosity average molecular weight of 300,000 to 3.9 million and / or a salt thereof, and a water-soluble polymer compound.

Hyaluronic acid and its salt Hyaluronic acid is a polymer having a repeating unit of GlcUA-GlcNAc in which glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc) are bound.
The salt of hyaluronic acid may be any pharmaceutically or physiologically acceptable salt, for example, a salt with an organic base (methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, etc. Tripyridine salts, organic amine salts such as picolin salts), salts with inorganic bases (ammonium salts; alkali metal salts such as sodium salts and potassium salts, calcium salts, alkaline earth metal salts such as magnesium salts, zinc Salts, metal salts such as aluminum salts, etc.). Among these salts, salts with inorganic bases are preferable, alkali metal salts are more preferable, sodium salts and potassium salts are even more preferable, and sodium salts are particularly preferable.
When the ophthalmic composition in the present invention contains hyaluronate, it may be a mixture of hyaluronan, or as a result of separately blending hyaluronan and an organic or inorganic base, hyaluronan is contained in the composition. It may be salt.
Hyaluronic acid and / or a salt thereof can be used alone or in combination of two or more. For example, a plurality of types of hyaluronic acid and / or salts thereof having different average molecular weights can be used.

The viscosity average molecular weight of hyaluronic acid or a salt thereof is 300,000 or more, and 400,000 or more, 500,000 or more, 600,000 or more, 700,000 or more, 800,000 or more, 900,000 or more, 1 million or more, or 1.1 million or more. It can also be. The viscosity of hyaluronic acid or a salt thereof having such a viscosity average molecular weight is significantly reduced by storage in the presence of mucin.
The viscosity average molecular weight of hyaluronic acid or a salt thereof is 3.9 million or less, 3.5 million or less, 3 million or less, 2.5 million or less, 2.2 million or less, 2 million or less, 1.8 million or less, 1.6 million or less, 1.4 million or less, It can be 1.2 million or less, 1 million or less, 800,000 or less, or 700,000 or less. The viscosity of hyaluronic acid or a salt thereof having such a viscosity average molecular weight is significantly reduced by storage in the presence of mucin. The viscosity average molecular weight of hyaluronic acid or a salt thereof that can be actually obtained is about 3.9 million or less.
The viscosity average molecular weight of hyaluronic acid or a salt thereof is usually 300,000 to 3.9 million, preferably 400,000 to 3 million, more preferably 500,000 to 2.5 million, and even more preferably 500,000 to 2.2 million. Further, it can be 500,000 to 700,000, 500,000 to 1.6 million, 1.1 million to 1.6 million, 1.1 million to 2.2 million, or 1.8 million to 2.2 million.

In the present invention, for example, "hyaluronic acid having a viscosity average molecular weight of 300,000 to 3.9 million or a salt thereof" refers to hyaluronic acid or a salt thereof whose measured value of viscosity average molecular weight is in the range of 300,000 to 3.9 million.

The viscosity average molecular weight of hyaluronic acid or a salt thereof before blending into the ophthalmic composition is a value measured by the method for measuring the average molecular weight described in the item "Purified sodium hyaluronate" of the 17th revised Japanese Pharmacopoeia. The viscosity average molecular weight of hyaluronic acid or a salt thereof in the ophthalmic composition is a value measured by the method for measuring the average molecular weight described in the item "Purified sodium hyaluronate ophthalmic solution" of the 17th revised Japanese Pharmacopoeia.

Hyaluronic acid can be produced by a method of extracting from a comb or a fermentation method using a bacterium of the genus Streptococcus. In addition, natural hyaluronic acid or a salt thereof decomposed by an acid, an alkali, or an enzyme can also be used.
In addition, hyaluronic acid or a salt thereof can be purchased as a commercially available product. As commercial products, "Sodium hyaluronate" Biochemical "" (molecular weight average molecular weight 500,000 to 1.2 million) and "Sodium hyaluronate (HC) for cosmetics" (molecular weight average molecular weight 53) sold by Biochemical Industry Co., Ltd. 10,000 to 1.33 million), "Biohyaluronate sodium SZE" (viscosity average molecular weight 1.1 million to 1.6 million), "Biohyaluronate sodium HA9N" (viscosity average molecular weight 800,000 to 1.77 million), sold by Shiseido Co., Ltd. "Sodium biohyaluronate HA12N" (molecular weight average molecular weight 1.1 million to 1.6 million), "Sodium biohyaluronate HA20N" (molecular weight average molecular weight 1.9 million to 2.7 million), "Sodium biohyaluronate 1% aqueous solution (MP-PE) N" (Visibility average molecular weight 1.37 million to 1.53 million), "Biohyaluronate 1% aqueous solution (PE) N" (viscosity average molecular weight 1.37 million to 1.53 million), "Hyaluronic acid FCH" sold by Kikkoman Biochemifa Co., Ltd. -60 "(viscosity average molecular weight 500,000 to 700,000)," hyaluronic acid FCH-80 "(viscosity average molecular weight 600,000 to 1,000,000)," hyaluronic acid FCH-120 "(viscosity average molecular weight 1,000,000 to 1.4 million), "Hyaluronic acid FCH-150" (viscosity average molecular weight 1.4 million to 1.8 million), "hyaluronate FCH-151C" (viscosity average molecular weight 1.4 million to 1.8 million), "hyaluronic acid FCH-200" (viscosity average molecular weight 1.8 million to 2.2 million), "Hyaluronic acid FCH-201C" (molecular weight average molecular weight 1.8 million to 2.2 million), "Hyallonsan HA-QA" (molecular average molecular weight 600,000 to 1.2 million) sold by Cupy Co., Ltd., "Hyallonsan HA" -AM "(molecular average molecular weight of 600,000 to 1.2 million)," Hyaluronsan HA-Q "(average molecular weight of 530,000 to 1.13 million)," Hyaluronsan M5070 "(average molecular weight of 500,000 to 700,000)," Hyaluronsan HA- "LQ" (viscosity average molecular weight 850,000 to 1.6 million), "Hyallonsan HA-LQH" (viscosity average molecular weight 1.2 million to 2.2 million) and the like can be used.

The concentration of hyaluronic acid or a salt thereof in the ophthalmic composition is 0.001 w / v% or more, 0.005 w / v% or more, 0.01 w / v% or more, 0.02 w / / based on the total amount of the composition. v% or more, 0.03w / v% or more, 0.04w / v% or more, 0.05w / v% or more, 0.06w / v% or more, 0.07w / v% or more, 0.08w / v% As mentioned above, it can be 0.09 w / v% or more, or 0.1 w / v% or more. Within this range, the pharmacological activity can be sufficiently exerted. Further, within this range, the composition has a viscosity that allows contact with the eyeball for a sufficient time.
The concentration of hyaluronic acid or a salt thereof in the ophthalmic composition is 10 w / v% or less, 5 w / v% or less, 1 w / v% or less, 0.5 w / v% or less, based on the total amount of the composition. 0.45w / v% or less, 0.4w / v% or less, 0.35w / v% or less, 0.3w / v% or less, 0.25w / v% or less, 0.2w / v% or less, 0. 19w / v% or less, 0.18w / v% or less, 0.17w / v% or less, 0.16w / v% or less, 0.15w / v% or less, 0.14w / v% or less, 0.13w / It can be v% or less, 0.12 w / v% or less, 0.11 w / v% or less, or 0.1 w / v% or less. Within this range, the pharmacological activity can be sufficiently exhibited and the usability of the ophthalmic composition is not impaired.
The concentration of hyaluronic acid or a salt thereof in the ophthalmic composition can be usually 0.001 to 10 w / v%, preferably 0.005 to 5 w / v%, and 0, based on the total amount of the composition. 0.01 to 1 w / v% is more preferable, 0.03 to 0.5 w / v% is further preferable, 0.05 to 0.3 w / v% is further preferable, and 0.1 w / v% is most preferable.

The concentration of hyaluronic acid or a salt thereof in the ophthalmic composition is a value measured by the quantitative method described in the item of "Purified sodium hyaluronate ophthalmic solution" of the 17th revised Japanese Pharmacopoeia.

Water-soluble polymer compounds Examples of the water-soluble polymer compounds include polysaccharides containing sulfated amino sugars, cellulosic compounds, and vinyl polymers.
Examples of the polysaccharide containing sulfated amino sugar include chondroitin sulfate or a salt thereof, dermatan sulfate or a salt thereof, keratan sulfate or a salt thereof, heparan sulfate or a salt thereof, and heparin.
The salt of the polysaccharide containing the sulfated amino sugar may be any pharmaceutically or physiologically acceptable salt, for example, a salt with an organic base (methylamine salt, triethylamine salt, triethanolamine salt, morpholin). Salts, piperazine salts, pyrrolidine salts, tripyridine salts, organic amine salts such as picolin salts, etc.), salts with inorganic bases (ammonium salts; alkali metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, etc. Alkaline earth metal salts, zinc salts, metal salts such as aluminum salts, etc.). Among these salts, salts with inorganic bases are preferable, alkali metal salts are more preferable, sodium salts and potassium salts are even more preferable, and sodium salts are particularly preferable.

Examples of the cellulosic compound include hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose and the like.

Examples of vinyl-based polymers include polyvinyl alcohol (including completely or partially saponified products), polyvinylpyrrolidone, and carboxyvinyl polymers.

Other water-soluble polymer compounds include polyethylene glycol, dextran, alginic acid, guar gum, gum arabic, karaya gum, xanthan gum, agar, starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, gelatin, collagen, pectin, and elastin. , Macrogol, polyethyleneimine alginate (eg, sodium alginate), alginate ester (eg, propylene glycol alginate), tragant powder and the like. In addition to the above-exemplified examples, these components may be salts (for example, sodium salt, potassium salt, calcium salt, magnesium salt).

Among them, polysaccharides containing sulfated amino sugars or salts thereof, cellulosic compounds are preferable, and chondroitin sulfate or salts thereof (particularly sodium salts), hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylcellulose are more preferable. Polyvinyl alcohol (including completely or partially saponified products), polyvinylpyrrolidone, and carboxyvinyl polymers are also preferable.
The water-soluble polymer compound may be used alone or in combination of two or more.
Commercially available products can be used as the water-soluble polymer compound.

The concentration of the water-soluble polymer compound in the ophthalmic composition is 0.001 w / v% or more, 0.005 w / v% or more, 0.01 w / v% or more, 0.05 w / / of the total amount of the composition. v% or more, 0.06w / v% or more, 0.07w / v% or more, 0.08w / v% or more, 0.09w / v% or more, 0.1w / v% or more, 0.2w / v% As mentioned above, it can be 0.3 w / v% or more, or 0.4 w / v% or more. Within this range, the decrease in viscosity measured in the presence of mucin can be sufficiently suppressed by preserving the ophthalmic composition.
The concentration of the water-soluble polymer compound in the ophthalmic composition is 10 w / v% or less, 8 w / v% or less, 5 w / v% or less, 4 w / v% or less, 3 w / / of the total amount of the composition. It can be v% or less, 2w / v% or less, 1w / v% or less, 0.5w / v% or less, or 0.3w / v% or less. Within this range, the decrease in viscosity measured in the presence of mucin due to storage of the ophthalmic composition can be sufficiently suppressed, and the ophthalmic composition has an excellent usability.
The concentration of the water-soluble polymer compound in the ophthalmic composition can be usually 0.001 to 10 w / v%, preferably 0.01 to 5 w / v%, and 0, based on the total amount of the composition. .05 to 4 w / v% is more preferred, 0.1 to 3 w / v% is even more preferred, and 0.1 to 1 w / v% is even more preferred. Further, 0.01 to 0.5 w / v% and 0.05 to 0.3 w / v% are also preferably mentioned.

Decongestant The ophthalmic composition in the present invention can contain a decongestant (vasoconstrictor). Decongestants include phenylephrine or a salt thereof (eg, phenylephrine hydrochloride, epinephrine hydrogen tartrate), ephedrine or a salt thereof (eg, ephedrine hydrochloride), methylephedrine or a salt thereof (eg, methylephrine hydrochloride, particularly dl-methyl dl-methyl hydrochloride). Ephedrine), tetrahydrozoline or a salt thereof (eg, tetrahydrozoline hydrochloride), nafazoline or a salt thereof (eg, nafazoline hydrochloride, nafazoline nitrate), phenylephrine or a salt thereof (eg, phenylephrine hydrochloride), oxymetazoline or a salt thereof (eg, oxymetazoline). Metazoline) and the like.
The decongestant can be used alone or in combination of two or more.

Extraocular muscle regulator The ophthalmic composition in the present invention can include an extraocular muscle regulator. Eye muscle regulators include, but are not limited to, neostigmine or salts thereof (particularly neostigmine methylsulfate), physostigmine or salts thereof (eg, physostigmine salicylate, physostigmine sulfate), dystigmine or salts thereof (eg, distigmine bromide), Examples thereof include tropicamide, atropine or a salt thereof (particularly, atropine helenien sulfate), pilocarpine or a salt thereof (for example, pilocarpine hydrochloride).
The eye muscle regulator may be used alone or in combination of two or more.

Anti-inflammatory agents The ophthalmic compositions of the present invention can include anti-inflammatory agents. Anti-inflammatory agents include epsilon-aminocaproic acid, planoprofen, allantin, velverine or salts thereof (eg, velverine chloride, velverin sulfate), azulene sulfonic acid or salts thereof (eg, sodium azulene sulfonate, azulene). Potassium sulfonate, calcium azulene sulfonate, magnesium azulene sulfonate), glycyrrhizinic acid or salts thereof (eg dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), zinc salts (eg zinc sulfate, zinc lactate), lysozyme or salts thereof (For example, lysoteam chloride), indomethacin, silver salt (for example, silver nitrate), diclofenacic acid or a salt thereof (for example, diclofenac sodium), bromufenacic acid or a salt thereof (for example, bromufenac sodium) and the like.
The anti-inflammatory agent may be used alone or in combination of two or more.

Antihistamines The ophthalmic compositions of the present invention can include antihistamines. Examples of the antihistamine include diphenhydramine or a salt thereof (for example, diphenhydramine hydrochloride), chlorpheniramine or a salt thereof (for example, chlorpheniramine maleate, chlorpheniramine fumarate), ketotifen or a salt thereof (for example, ketotifen fumarate), olopatadine. Alternatively, a salt thereof (for example, olopatadine hydrochloride) and the like can be mentioned.
The antihistamine can be used alone or in combination of two or more.

Vitamins The ophthalmic composition in the present invention can include vitamins. Vitamins include flavin adenin dinucleotide or a salt thereof (eg, flavin adenin dinucleotide sodium), cobalamine or a salt thereof (eg, cyanocobalamin, methylcobalamin, hydroxocobalamine, adenosyl cobalamine), retinol or a salt thereof (eg acetic acid). Retinol, retinol palmitate), pyridoxine or a salt thereof (eg, pyridoxine hydrochloride), pantenol, pantothenic acid or a salt thereof (eg, sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol or a salt thereof (For example, tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or a salt thereof (for example, pyridoxal phosphate), ascorbic acid or a salt thereof (for example, sodium ascorbate, calcium ascorbate) and the like.
One type of vitamins can be used alone, or two or more types can be used in combination.

Amino Acids The ophthalmic composition in the present invention may contain amino acids other than chondroitin sulfate or a salt thereof. Amino acids other than chondroitin sulfate or a salt thereof include L-aspartic acid or a salt thereof (for example, potassium L-aspartate, sodium L-aspartate, magnesium L-aspartate, calcium L-aspartate, L-aspartic acid). Magnesium-potassium (equal mixture of magnesium L-aspartate and potassium L-aspartate), aminoethylsulfonic acid (taurine), glutamic acid or salts thereof (eg, sodium glutamate, magnesium glutamate), creatinine, glycine, alanine , Arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid and the like.
Aminoethyl sulfonic acid is a compound similar to an amino acid synthesized from a sulfur-containing amino acid, and is included in amino acids in the field of ophthalmic compositions, particularly in the field of ophthalmic compositions as over-the-counter drugs. In addition, sodium chondroitin sulfate is also included in amino acids in the field of ophthalmic compositions, particularly in the field of ophthalmic compositions as over-the-counter drugs.
Amino acids other than chondroitin sulfate or a salt thereof may be used alone or in combination of two or more.

Antibacterial component The ophthalmic composition in the present invention may contain an antibacterial component. Examples of the antibacterial component include sulfamethoxazole or a salt thereof (for example, sodium sulfamethoxazole, potassium sulfamethoxazole, calcium sulfamethoxazole, magnesium sulfamethoxazole), and sulfamethoxazole. , Sulfa-based antibacterial agents such as sulfamethoxazole or salts thereof (eg, sodium sulfamethoxazole, potassium sulfamethoxazole, calcium sulfamethoxazole, magnesium sulfamethoxazole), alkylpolyaminoethylglycine, chloramphenicol, Examples include offloxacin, norfloxacin, levofloxacin, romefloxacin hydrochloride, and acyclovir.
The antibacterial component may be used alone or in combination of two or more.

Anti-allergic agents The ophthalmic compositions of the present invention can include anti-allergic agents. Examples of the antiallergic agent include cromoglycic acid or a salt thereof (for example, sodium cromoglycate, potassium cromoglycate, calcium cromoglycate, magnesium cromoglycate), acitazanolast, anlexanox, ibudilast, tranilast, pemirolast potassium and the like.
The anti-allergic drug may be used alone or in combination of two or more.

Antioxidants The ophthalmic compositions of the present invention can contain antioxidants.
Fat-soluble antioxidants include butyl group-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguayaletic acid (NDGA); ascorbic acid palmitate, ascorbic acid stearate, ascorbin. Ascorbic acid esters such as aminopropyl acid phosphate, tocopherol ascorbate, triphosphate ascorbate, palmitate ascorbate; tocopherols such as α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol; acetic acid Tocopherol derivatives such as tocopherols, tocopherols nicotinate, tocopherols succinate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinoline- 2 on; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins and curcumin; retinol, retinol esters (retinol acetate, retinol propionate, retinol butyrate, retinol octylate, retinol lauric acid, stearic acid Retinol, retinol myristate, retinol oleate, retinol linolenate, retinol linoleate, retinol palmitate, etc.), retinal, retinal esters (retinal acetate, retinal propionate, retinal palmitate, etc.), retinonic acid, retinoic acid esters Methyl acid acid, ethyl retinoate, retinol retinoate, tocopherol retinoate, etc.), retinol dehydro, retinal dehydro, dehydro retinoate, provitamin A (α-carotene, β-carotene, γ-carotene, δ-carotene, Ricopine, zeaxanthin, β-cryptoxanthin, ekinenone, etc.), vitamin A such as vitamin A; CoQ10 and the like.
In addition, as a water-soluble antioxidant, ascorbic acid, an ascorbic acid derivative (ascorbic acid-2-sodium sulfate, sodium ascorbate, magnesium ascorbic acid-2-phosphate, sodium ascorbic acid-2-phosphate, etc.) , Sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid or a salt thereof (sodium edetate, disodium edetate, tetrasodium edetate) and the like.
One type of antioxidant may be used alone, or two or more types may be used in combination.

Local anesthetic or pain-relieving agent The ophthalmic composition in the present invention can contain a local anesthetic or pain-relieving agent. Examples of local anesthetics or soothing agents include chlorobutanol, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperokine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, and hydrochloric acid. Examples include hexotiocaine and lidocaine hydrochloride.
The local anesthetic or pain-relieving agent may be used alone or in combination of two or more.

The ophthalmic composition in the present invention may also contain any pharmacological or physiologically active ingredient.

Among the components of the ophthalmic composition in the present invention, the component in which the d-form, l-form, or dl-form is present can be any of d-form, l-form, or dl-form. Further, as the component having a hydrate, a hydrate can also be used.

Preparation The properties of the ophthalmic composition in the present invention are not particularly limited, and may be, for example, liquid or fluid properties. In addition, those that have become liquid or fluid due to preparation at the time of use are also included.

Further, the ophthalmic composition may be an aqueous composition (mainly containing an aqueous or hydrophilic composition as a base or carrier), and an oily composition (mainly an oily or hydrophobic composition as a base or carrier). However, it is preferably an aqueous composition in order to stably dissolve hyaluronic acid and / or a salt thereof.
The water content in the case of the aqueous composition is preferably 50 w / v% or more, more preferably 75 w / v% or more, and even more preferably 90 w / v% or more, based on the total amount of the preparation. Further, it may be 95 w / v% or more, or 98 w / v% or more. Further, the base or carrier may consist only of water.

The dosage form of the ophthalmic composition in the present invention is not particularly limited, and for example, an eye drop (also referred to as an eye drop or an eye drop. The eye drop includes an eye drop that can be instilled while wearing a contact lens, and is artificial. Includes tear fluid), eye drops, contact lens wearing fluid, and the like. Eye drops and eyewashes include those used when wearing contact lenses. Among them, eye drops or contact lens wearing liquids are preferable, and eye drops are more preferable.

In the present invention, the "contact lens" includes a hard contact lens (including an O2 lens), a soft contact lens (both ionic and non-ionic, and a silicone hydrogel contact lens and a non-silicone hydrogel contact lens. Includes both).

The ophthalmic composition in the present invention contains a component containing hyaluronic acid having a viscosity average molecular weight of 300,000 to 3.9 million and / or a salt thereof and a water-soluble polymer compound, as a pharmaceutically acceptable base or carrier, if necessary. It can be prepared by conventional methods by mixing with pharmaceutically acceptable additives and other active ingredients of the ophthalmic composition.

Bases or carriers Examples of bases or carriers include water; polar solvents such as ethanol; oily bases and the like. The base or carrier may be used alone or in combination of two or more.

In the ophthalmic composition of the present invention, those used as additives for the ophthalmic composition can be blended within a range that does not impair the effects of the present invention. Examples of additives include refreshing agents, inorganic salts, thickening agents, preservatives, surfactants, buffers, pH regulators, tonicity agents, stabilizers, oils, sugars, polyhydric alcohols and the like. can.
As the additive, one type can be used alone, or two or more types can be used in combination. In addition, for each additive, one type can be used alone, or two or more types can be used in combination.
Specific examples of additives are illustrated below.

Cooling Agent Examples of the refreshing agent include menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and terpenoids such as Ryunou. These may be d-form, l-form, or dl-form. Also included are essential oils such as peppermint oil, cool mint oil, sparemint oil, peppermint oil, uikyo oil, kehi oil, bergamot oil, eucalyptus oil and rose oil.

Inorganic salts Inorganic salts include chloride salts such as sodium chloride, potassium chloride, zinc chloride, calcium chloride, magnesium chloride; sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), potassium hydrogen carbonate, potassium carbonate, etc. Carbonates; phosphates such as sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate; magnesium sulfate, zinc sulfate Sulfates such as; sodium hydrogen sulfite, sulfites such as sodium sulfite; thiosulfates such as sodium thiosulfate; borates such as sodium tetraborate, potassium tetraborate; such as potassium acetate, sodium acetate Acetate and the like.
Among them, chloride salts, carbonates, phosphates and borates are preferable, chloride salts are more preferable, and sodium chloride is even more preferable.

The concentration of the inorganic salt in the ophthalmic composition is preferably 0.00001 w / v% or more, more preferably 0.0001 w / v% or more, and even more preferably 0.001 w / v% or more. Further, 3 w / v% or less is preferable, 2 w / v% or less is more preferable, and 1.5 w / v% or less is even more preferable. Within this range, the osmotic pressure of the ophthalmic composition becomes appropriate, and the decrease in viscosity of the ophthalmic composition is suppressed.
The concentration of the inorganic salts in the ophthalmic composition is preferably 0.00001 to 3 w / v%, more preferably 0.0001 to 2 w / v%, and even more preferably 0.001 to 1.5 w / v%.

Thickening agent The ophthalmic composition of the present invention may contain a thickening agent other than the water-soluble polymer compound as long as the effects of the present invention are not impaired. Examples of such a thickening agent include α-cyclodextrin, dextrin, glucose, sorbitol, liquid paraffin, glycerin and the like.

Preservatives Examples of preservatives include alkylpolyaminoethylglycine, boric acid, alkyldiaminoethylglycine and / or salts thereof (eg, alkyldiaminoethylglycine hydrochloride), benzoic acid and / or salts thereof (eg, sodium benzoate, benzoic acid). Potassium), ethanol, quaternary ammonium salts (eg, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride), chlorhexidine and / or salts thereof (eg, chlorhexidine gluconate), chlorobutanol, sorbic acid and / or salts thereof. (For example, potassium sorbate), sodium dehydroacetate, paraoxybenzoic acid ester (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, Examples thereof include bigamides such as polyhexamethylene biguanide, glokill (trade name, Rhodia), and polydronium chloride.

Surfactants Of the surfactants, nonionic surfactants are preferred.
Non-ionic surfactants include POE monolaurate (20) sorbitan (polysorbate 20), POE monopalmitate (20) sorbitan (polysorbate 40), POE monostearate (20) sorbitan (polysorbate 60), and POE tristearate. (20) POE sorbitan fatty acid esters such as sorbitan (polysolvate 65) and monooleic acid POE (20) sorbitan (polysolvate 80); POP block copolymers; POE cured castor oil 40, POE cured castor oil 50, POE cured castor oil 60, POE cured castor oil 80, etc. POE cured castor oil; POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, POE castor oil 50, etc. Oil; polyethylene glycol monostearate (2EO), polyethylene glycol monostearate (4EO), polyethylene glycol monostearate (9EO), polyethylene glycol monostearate (10EO), Polyethylene glycol monostearate (23EO), polyethylene glycol monostearate (25EO), polyethylene glycol monostearate (32EO), polyethylene glycol monostearate (40EO, polyoxyl stearate) 40), polyethylene glycol monostearate (45EO), polyethylene glycol monostearate (55EO), polyethylene glycol monostearate (75EO), polyethylene glycol monostearate (140EO) Polyethylene glycol monostearate such as; POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE (10) POE such as nonylphenyl ether Alkylphenyl ethers and the like can be mentioned. In the above-exemplified compounds, POE indicates polyoxyethylene, POP indicates polyoxypropylene, and the numbers in parentheses indicate the number of added moles.

Other amphoteric surfactants such as glycine-type amphoteric surfactants (eg, alkyldiaminoethylglycine, alkylpolyaminoethylglycine) and betaine-type amphoteric surfactants (eg, lauryldimethylaminoacetate betaine, imidazolinium betaine). Activator; Cationic surfactants such as alkyl quaternary ammonium salts (eg, benzalkonium chloride, benzethonium chloride) can also be used.

Buffering Agent The ophthalmic composition of the present invention can contain a buffering agent.
Examples of the buffer include borate buffer, phosphate buffer, carbon dioxide buffer, citric acid buffer, acetate buffer, epsilon-aminocaproic acid buffer, aspartic acid buffer and the like. Examples of the components of the boric acid buffer include boric acid and borate (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borate sand, etc.). The borate may be a hydrate. The components of the phosphate buffer include phosphoric acid, phosphate (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, (Calcium dihydrogen phosphate, etc.) and the like. The phosphate may be a hydrate. Examples of the components of the carbon dioxide buffer include carbonic acid and carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, magnesium carbonate, etc.). Examples of the component of the citric acid buffer include citric acid and citrate (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.). Examples of the components of the acetate buffer include acetic acid and acetic acid salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Examples of the components of the aspartic acid buffer include aspartic acid and salts of aspartic acid (sodium aspartate, magnesium aspartate, potassium aspartate, etc.).
Among them, a boric acid buffer, a phosphoric acid buffer, and a citric acid buffer are preferable, and a boric acid buffer is more preferable, in that the effect of the present invention is further improved.

pH adjuster pH adjusters include hydrochloric acid, sulfuric acid, polyphosphate, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide. , Calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine and the like.

Isotonic agent Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, propylene glycol and the like. Some isotonic agents are compounded as inorganic salts.

Stabilizer Stabilizers include tromethamole, sodium formaldehyde sulfoxylate (longalit), monoethanolamine, aluminum monostearate, glycerin monostearate and the like.

Oils Examples of oils include animal oils such as squalane, liquid paraffin, mineral oils such as petrolatum, castor oil, and vegetable oils such as sesame oil.

Sugars Examples of saccharides include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like. Some sugars are compounded as a thickening agent.

Polyhydric alcohol Examples of the polyhydric alcohol include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, and sorbitol. Some polyhydric alcohols are formulated as thickeners.

Viscosity The viscosity of the ophthalmic composition of the present invention is preferably 1.1 mPa · s or more, more preferably 2 mPa · s or more, and even more preferably 3 mPa · s or more. Further, 100 mPa · s or less is preferable, 50 mPa · s or less is more preferable, and 20 mPa · s or less is even more preferable. Within this range, the contact time with the eyeball or the contact lens becomes sufficiently long, and the effect of the ophthalmic composition can be exhibited.

The viscosity of the ophthalmic composition of the present invention is determined by the "single cylindrical rotational viscometer" of the "second method rotational viscometer method" in the "viscosity measurement method" of the general test method described in the 17th revised Japanese Pharmacy. (Brookfield type viscometer) ”is a value measured at 25 ° C. using a B type rotational viscometer (RB-80L; Toki Sangyo Co., Ltd.) by the method described in the item. Select the conditions such as the rotor and rotation speed to be used according to the instruction manual of this machine. The viscosity of the ophthalmic composition of the present invention is specifically a value measured by the method described in the item of Examples.

pH
The pH of the ophthalmic composition of the present invention is preferably 3 or more, more preferably 4 or more, even more preferably 5 or more, and even more preferably 5.5 or more. It can also be 6 or more. Further, 10 or less is preferable, 9 or less is more preferable, 8.5 or less is even more preferable, and 8 or less is even more preferable. Within the above range, irritation to the eyes can be suppressed and the above effects of the present invention can be obtained.

Osmotic pressure The osmotic pressure ratio of the ophthalmic composition of the present invention is preferably 0.4 or more, more preferably 0.6 or more, and even more preferably 0.85 or more. Further, 5 or less is preferable, 3 or less is more preferable, 2 or less is even more preferable, and 1.55 or less is even more preferable. Within the above range, irritation to the eyes can be suppressed and the above effects of the present invention can be obtained. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point drop method) described in the 17th revised Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (standard reagent of the Japanese Pharmacopoeia) at 500 to 650 ° C. for 40 to 50 minutes and then in a desiccator (silica). Allow to cool, weigh accurately 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).

Applications When the ophthalmic composition of the present invention is used as an eye drop or eye wash, eye fatigue, conjunctival congestion, eye inflammation (snow eyes, etc.) due to ultraviolet rays or other rays, eyelid inflammation (eyelid dripping), hard contact lenses or It can be used to prevent, improve, or treat discomfort when wearing soft contact lenses, itchy eyes, and blurred vision (such as when there are many eyelids). It can also be used to prevent eye diseases (when dust or sweat gets into the eyes after swimming) and to assist tears (drying the eyes). It can also be used to clean the eyes.

Method of use When the ophthalmic composition in the present invention is an eye drop or an eyewash, its usage varies depending on the target symptom, but for example, once or more, twice or more, three times or more, four times or more a day, It can be 5 times or more, or 6 times or more. Further, it can be 9 times or less, 8 times or less, 7 times or less, 6 times or less, 5 times or less, or 4 times or less per day.

The use may be started at the same time as or after the onset of symptoms, but the use may be started 1 day or more before the onset of symptoms, particularly 3 days or more, especially 7 days or more. In addition, the use can be started 10 days or more before the onset of symptoms. In addition, the use may be started within 30 days before the onset of symptoms, particularly within 20 days, particularly within 14 days. By using it before the symptoms appear, the symptoms can be effectively prevented.

When the ophthalmic composition in the present invention is an eye drop, an eye drop containing each component at the above concentration may be instilled in an amount of, for example, 1 to 3 drops, preferably 1 to 2 drops at a time. It can be one drop. The volume of one drop of eye drops is usually about 5 to 100 μl, preferably about 10 to 80 μl, more preferably about 20 to 60 μl, and even more preferably about 30 to 50 μl.
When the ophthalmic composition in the present invention is an eyewash, the eyewash containing each component at the above concentration may be used, for example, 1 to 30 mL at a time, preferably 1 to 20 mL, and more preferably 4 Eyewash may be performed using ~ 6 mL.

When the ophthalmic composition in the present invention is a contact lens wearing solution, when the contact lens is put on and taken off, for example, 1 to 3 drops, preferably 1 to 2 drops, are applied to one side of the contact lens and / Alternatively, the contact lens may be dropped on both sides and wet, and then worn, preferably after both sides of the contact lens are wet.

Container The ophthalmic composition of the present invention is usually contained or filled in an ophthalmic container. The material of the container is not particularly limited, and examples thereof include a plastic container, a metal container, and a glass container. Specifically, for example, polyolefin, acrylic acid resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethylpentene, fluororesin, polyvinyl chloride, polyamide, ABS resin, AS resin, polyacetal, modification. Examples thereof include polyphenylene ether, polyarylate, polysulfone, polyimide, plastics such as cellulose acetate, metals such as aluminum, and glass. The container may be made of one kind of material or may be made of two or more kinds of materials. In the case of plastic, it may be a mixture or a copolymer.
Of these, plastic containers are preferable, and polyolefin containers and terephthalic acid ester containers are more preferable.
In a container having a spout or nozzle, the entire portion including the spout or nozzle may be molded with the above material, or only the main body portion other than the spout or nozzle may be molded with the above material.

Polyethylene includes polyethylene (including high-density polyethylene, low-density polyethylene, ultra-low-density polyethylene, linear low-density polyethylene, ultra-high-molecular-weight polyethylene, etc.), polypropylene (isotactic polypropylene, syndiotactic polypropylene, tactic polypropylene). Etc.), and polyethylene / propylene copolymers and the like.
Examples of the acrylic acid resin include acrylic acid esters such as methyl acrylate, methacrylic acid esters such as methyl methacrylate, cyclohexyl methacrylate and t-butylcyclohexyl methacrylate.
Examples of the terephthalic acid ester include polyethylene terephthalate, polytrimethylene terephthalate, and polybutylene terephthalate.
Examples of the 2,6-naphthalenedicarboxylic acid ester include polyethylene naphthalate and polybutylene naphthalate.
Fluororesin includes fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, vinyl fluoride, perfluoroalkoxyfluororesin, ethylene tetrafluoride / propylene hexafluoride copolymer, ethylene / tetra. Examples thereof include a fluoroethylene copolymer and an ethylene / chlorotrifluoroethylene copolymer.
Examples of the polyamide include nylon and the like.
Examples of polyacetals include those consisting of only oxymethylene units and those containing some oxyethylene units.
Examples of the modified polyphenylene ether include polystyrene-modified polyphenylene ether.
Examples of polyarylate include amorphous polyarylate.
Examples of the polyimide include an aromatic polyimide obtained by polymerizing pyromellitic acid dianhydride and 4,4'-diaminodiphenyl ether.
Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

Further, the container of the ophthalmic composition may be a multi-unit type container or a single-use unit dose type container.

(2) Method for suppressing decrease in viscosity of ophthalmic composition In the present invention, mucin (preferably secreted) of this ophthalmic composition is contained by adding a water-soluble polymer compound to the ophthalmic composition containing hyaluronic acid and / or a salt thereof. Includes a method of suppressing a decrease in viscosity in the presence of (type mucin). It is included in the scope of the present invention as long as the decrease in viscosity of the ophthalmic composition when mixed with mucin, which is measured by the method described in Examples, due to preservation is suppressed even a little.
The ophthalmic composition, the components contained therein, the viscosity measuring method, and the like are as described for the ophthalmic composition of the present invention.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
Test Example 1 (decrease in viscosity of hyaluronic acid or its salt in the presence of mucin due to preservation)
The ophthalmic compositions of Reference Examples 1 to 4 having the compositions shown in Table 1 were prepared according to a conventional method. Each ophthalmic composition was stored at 60 ° C. for 3 weeks, and the viscosity of the ophthalmic composition before and after storage and the viscosity when mucin was mixed were measured.
Mucin is a mixture of glycoproteins in which various sugar chains composed of N-acetylglucosamine, galactose, fucose, sialic acid and the like are bound to core proteins. As described above, mucin includes secretory mucin produced by epithelial cells and the like, and membrane-bound mucin having a hydrophobic transmembrane site and existing in a state of being bound to the cell membrane. Since the layer of tear fluid contains membrane-bound mucin, the ophthalmic composition applied to the eye is mixed with membrane-bound mucin. Therefore, here, mucin derived from pig stomach, which is one of the secretory mucins, was used.

The test was conducted in Physical Research, 491-495, Vol. 7, No. 5, 1990 was performed by the method described.
Specifically, the viscosity of each ophthalmic composition before and after storage at 60 ° C. for 3 weeks was measured. In addition, mucin derived from pig stomach (M1778-10G, SIGMA) was dissolved in water to prepare a 4 w / v% mucin solution, and then stored at 60 ° C. for 3 weeks before and after storage with 2 mL of each ophthalmic composition. The viscosity of the mixture with 6 mL of 4 w / v% mucin solution was measured.

<Viscosity measurement conditions>
The viscosity of the ophthalmic composition used in the test is the "single cylindrical rotational viscosity" of the "second method rotational viscometer method" in the "viscosity measurement method" of the general test method described in the 17th revised Japanese Pharmacy. Measured using a B-type rotational viscometer (RB-80L; Toki Sangyo Co., Ltd.) as a viscometer by the method described in the item of "meter (Brookfield type viscometer)".

The viscosity measurement conditions are as follows.
Measurement temperature: 20 ° C
Measured value: Average value of 3 measurements Rotation speed:
When the viscosity is less than 6 mPa · s: Rotation speed 100 rpm
When the viscosity is 6 mPa · s or more and less than 12 mPa · s: Rotation speed 50 rpm
When the viscosity is 12 mPa · s or more and less than 30 mPa · s: Rotation speed 20 rpm
When the viscosity is 30 mPa · s or more and less than 60 mPa · s: Rotation speed 10 rpm
When the viscosity is 60 mPa · s or more and less than 120 mPa · s: Rotation speed 5 rpm
When the viscosity is 120 mPa · s or more and less than 240 mPa · s: Rotation speed 2.5 rpm
When the viscosity is 240 mPa · s or more and less than 600 mPa · s: Rotation speed 1.0 rpm
Rotor No. : Rotor No. with all the above viscosities. 01

A single cylindrical rotational viscometer is a viscometer that measures the torque when a cylinder in a liquid is rotated at a constant angular velocity. The viscosity η of the liquid is calculated by the following formula by experimentally determining the device constant _KB using the viscometer calibration standard solution in advance.
η = KB × _T / ω
η: Liquid viscosity (mPa · s)
_KB : Device constant (rad / cm ³ )
ω: Angular velocity (rad / s)
T: Torque acting on the cylindrical surface ( ^10-7 Nm)

Based on the following formula, the rate of decrease in viscosity of the ophthalmic composition due to storage was determined.

Rate of decrease due to preservation of viscosity (%)
= [1- (Viscosity after storage / Viscosity before storage)] x 100

The results are also shown in Table 1.

As shown in Table 1, when any sodium hyaluronate was used, the viscosity measured in the presence of mucin and the viscosity measured in the absence of mucin decreased due to storage. However, in both the viscosity in the presence of mutin and in the absence of mutin, the viscosity average molecular weight is 500,000 as compared with the ophthalmic composition of Reference Example 4 using sodium hyaluronate having a viscosity average molecular weight of 50,000 to 110,000. The ophthalmic compositions of Reference Examples 1, 2 and 3 using ~ 700,000, 1.1 million to 1.6 million, and 1.8 million to 2.2 million sodium hyaluronate, respectively, had a significantly large rate of decrease in viscosity due to storage. Therefore, it can be seen that the viscosity of hyaluronic acid or a salt thereof having a viscosity average molecular weight of 300,000 to 3.9 million is significantly reduced by storage.
Further, the viscosity reduction rate was different between the case where the viscosity was measured in the presence of mucin and the case where the viscosity was measured in the absence of mucin (that is, when the viscosity of the ophthalmic composition itself was measured). It can be seen that it is necessary to measure the viscosity in the presence of mucin in order to grasp the viscosity when the ophthalmic composition is applied to the eye.

Test Example 2 (Effect of blending water-soluble polymer)
Whether or not the water-soluble polymer compound suppresses the decrease in viscosity due to storage in the presence of mucin for each sodium hyaluronate having a viscosity average molecular weight of 500,000 to 700,000, 1.1 million to 1.6 million, and 1.8 million to 2.2 million. Was tested.
Ophthalmic compositions having the compositions shown in Table 2 were prepared according to a conventional method and stored at 60 ° C. for 3 weeks. The viscosity of each ophthalmic composition before and after storage was measured in the same manner as in Test Example 1 in the presence of mucin, and the rate of decrease in viscosity due to storage in the presence of mucin was determined.
Furthermore, the suppression rate of the decrease in viscosity in the presence of mucin due to the addition of the water-soluble polymer compound was determined by the following formula. The results are shown in Table 2 and FIG.

Suppression rate of decrease in viscosity due to storage by water-soluble polymer compound (%)
= [1- (Viscosity reduction rate when water-soluble polymer compound is added / Viscosity reduction rate when water-soluble polymer compound is not added)] × 100

As shown in Table 2 and FIG. 1, by adding sodium chondroitin sulfate or hydroxypropyl methylcellulose to each sodium hyaluronate having a viscosity average molecular weight of 500,000 to 700,000, 1.1 million to 1.6 million, and 1.8 million to 2.2 million. , The decrease in viscosity due to preservation in the presence of mucin was suppressed.
The suppression rate of the decrease in viscosity by the water-soluble polymer compound in the presence of mutin is about 11% or more in the composition containing sodium hyaluronate having a viscosity average molecular weight of 500,000 to 700,000, and the viscosity average molecular weight is 1.1 million to 1.6 million. The composition containing sodium hyaluronate was about 13% or more, and the composition containing sodium hyaluronate having a viscosity average molecular weight of 1.8 million to 2.2 million was about 10% or more.
In particular, in Example 2 in which 0.5 w / v% of sodium chondroitin sulfate was added to a composition containing sodium hyaluronate having a viscosity average molecular weight of 1.1 million to 1.6 million, the viscosity in the presence of mutin was completely reduced even when stored. However, the decrease in viscosity was completely suppressed by sodium chondroitin sulfate. Further, in Example 3 in which 3.0 w / v% of sodium chondroitin sulfate was added to a composition containing sodium hyaluronate having a viscosity average molecular weight of 1.1 million to 1.6 million, the decrease in viscosity due to preservation in the presence of mutin was significantly suppressed. The suppression rate of the decrease in viscosity with sodium chondroitin sulfate in the coexistence of mutin was 40% or more.
From the above results, by adding a water-soluble polymer compound to sodium hyaluronate having a viscosity average molecular weight of 300,000 to 3.9 million, the decrease in viscosity of sodium hyaluronate due to preservation in the presence of mutin is effectively suppressed. You can see that.

Examples of the pharmaceutical composition of the ophthalmic composition of the present invention are shown in Tables 3 to 30. The component concentrations in Tables 3 to 30 are "w / v%".

Even if the ophthalmic composition of the present invention is stored, the viscosity when applied to the eye does not easily decrease, and the contact time with the eye is sufficient, so that the medicinal effect of hyaluronic acid or a salt thereof or other components is sufficient. It will be demonstrated. That is, the deterioration of the medicinal effect due to manufacturing, distribution, and storage is suppressed, and the commercial value is high.

Claims (6)

(A) Hyaluronic acid and / or a salt thereof having a viscosity average molecular weight of 500,000 to 2.2 million is 0.03 to 0.35 w / v% based on the total amount of eye drops, and (B) chondroitin sulfate and / or its salt. Eye drops containing salt. The eye drop according to claim 1, further comprising (C) an inorganic salt. The component (C) is sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium sulfate, zinc sulfate, chloride. The eye drops according to claim 2, which is at least one selected from the group consisting of zinc and sodium tetraborate. The eye drop according to any one of claims 1 to 3, wherein the composition containing zinc chloride is excluded. The eye drop according to any one of claims 1 to 4, which has a viscosity of 1.1 mPa · s to 50 mPa · s. (A) Hyaluronic acid having a viscosity average molecular weight of 500,000 to 2.2 million or a salt thereof is contained in an eye drop containing 0.03 to 0.35 w / v% with respect to the total amount of the eye drop, and (B) chondroitin sulfuric acid and / Or a method of suppressing a decrease in the viscosity of an eye drop due to preservation in the presence of mutin by containing a salt thereof.

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