JP5649261B2 - High viscosity eye drops - Google Patents

Description

  The present invention relates to an eye drop having a high effect of suppressing the appearance or expansion of a dry spot.

  In eye tissue, dry eye, in other words, keratoconjunctival epithelial disorder caused by qualitative or quantitative abnormalities of tears tends to increase year by year. Specifically, a state in which tears are reduced may occur due to Sjogren's syndrome, dry keratoconjunctivitis, Steven Johnson syndrome, eyelid margin inflammation, allergic conjunctivitis, VDT work, indoor drying by air conditioning or the like.

  Tear is a mixture of secretions from the main, accessory, meibomian, Zeiss, and conjunctival tear glands that affect each other to form a three-layer tear film structure (the outermost layer is The oil layer and the intermediate layer form an aqueous layer, and the innermost layer forms a mucous mucin layer). The oil layer is composed of components secreted from the meibomian gland and the Zeiss gland, and spreads to the outermost surface of the tear film by blinking. The middle aqueous layer accounts for 98% of the three-layer tear film structure, and is composed of a mixture secreted from the main lacrimal gland, Wolfring gland, and the auxiliary lacrimal gland of the Krause gland. Proteins such as inorganic salts, secretory antibodies, and lactoferrin Contains carbohydrates, growth hormones, etc. The innermost layer, the mucus mucin layer, is mainly composed of mucus secreted from goblet cells in the conjunctiva. In addition to the mucin spreading evenly over the entire eye surface due to blinking, it plays a role in retaining tears on the eye surface and adsorbing to the glycocalyx on the corneal surface to make the corneal surface hydrophilic and easily wet. Plays.

  When the surface of the eye dries, the tear film partially breaks down and small holes called dry spots appear. The appearance of dry spots is presumed to be related to intrinsic factors such as tear film and tear volume, and extrinsic factors such as dryness and ultraviolet rays, but the details are still unclear. In particular, with dry eye eyes, the time until the appearance of a dry spot is short, and if the eye does not blink, the dry site will rapidly expand around the appearing dry spot. In addition, corneal epithelial damage is likely to occur in dry spots. For this reason, it is necessary to suppress the appearance of dry spots or to prevent further expansion of the appearing dry spots.

So far, as hyaluronic acid or a salt thereof as an active ingredient, collyrium composition having a protective effect of the tear film characterized by containing no preservative is known to have a protective effect of the tear film (Patent document 1), and a composition for eyewash which contains hydroxypropyl cellulose and sodium hyaluronate and preferably has a kinematic viscosity of 5 mm ² / s or less is known.

Japanese Patent No. 3455852

  Then, let it be a subject to provide the eye drop excellent in the effect which suppresses appearance or expansion of a dry spot.

  As a result of intensive studies for solving the problems, the present inventors contain at least one selected from A) acidic mucopolysaccharides and B) hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or polyvinyl alcohol. In addition, the present inventors have found that an eye drop having a viscosity at 20 ° C. of 15 mPa · s or more and 300 mPa · s or less exhibits an excellent effect of suppressing the appearance or expansion of a dry spot, and has completed the present invention.

The present inventor has been developed based on such knowledge.
That is, the present invention is eye drops listed in the following (1) to (9).
(1) A) acidic mucopolysaccharide, and B) at least one selected from hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose or a salt thereof, and a viscosity at 20 ° C. An ophthalmic solution having a viscosity of 15 mPa · s to 300 mPa · s,
(2) The eye drop according to (1), wherein the acidic mucopolysaccharide is at least one acidic mucopolysaccharide selected from chondroitin sulfate, chondroitin polysulfate, hyaluronic acid, heparin, heparan sulfate, or a salt thereof,
(3) The eye drop according to (1) or (2), wherein the acidic mucopolysaccharide is chondroitin sulfate or a salt thereof,
(4) Furthermore, it contains a nonionic surfactant selected from polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters or polyoxyethylene hydrogenated castor oil (5), menthol, The eye drop according to any one of (1) to (4), which contains at least one selected from borneol and camphor,
(6) The eye drop according to any one of (1) to (5), further containing at least one selected from a borate buffer, a phosphate buffer, a carbonate buffer, and a citrate buffer,
(7) Further, chlorpheniramine maleate, tetrahydrozoline hydrochloride, naphazoline hydrochloride, neostigmine methyl sulfate, epsilon aminocaproic acid, allantoin, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, cyanocobalamin, retinol palmitate, pyridoxine hydrochloride, pan From tenol, tocopherol acetate, aminoethyl sulfonic acid, potassium aspartate, magnesium and potassium aspartate, sodium sulfamethoxazole, glucose, propylene glycol, glycerin, potassium sorbate, flavin adenine dinucleotide, sodium edetate, polyethylene glycol The eye drop according to any one of (1) to (6), which contains at least one selected from the above;
(8) The eye drop according to any one of (1) to (7), wherein the viscosity at 20 ° C. is 15 mPa · s or more and 100 mPa · s or less,
(9) The eye drop according to any one of (1) to (8), which is for dry spot suppression.
In the present specification, unless otherwise specified,% means w / v%.

In the eye drop of the present invention, the time until the appearance of a dry spot can be delayed. In addition, it is possible to suppress rapid expansion of the appearing dry spot. In other words, the ability to suppress the appearance or expansion of a dry spot means that the state in which the tear film covers the entire eye surface and protects the eye can be maintained stably for a long time. It maximizes the ocular surface protection effect of the tear film and brings about cell activation and cell healing effects, leading to the maintenance of normal eyes.
Furthermore, the eye drop of the present invention can alleviate the dry state by suppressing the appearance of dry spots on the eye surface of the user who exhibits dry eye symptoms, and thus can prevent corneal epithelial disorder. Application to contact lens wearers who are prone to cause dry eye symptoms is also useful.

Examples of the acidic mucopolysaccharide of the present invention include chondroitin sulfate, chondroitin polysulfate, hyaluronic acid, heparin, keratosulfuric acid, and salts thereof.
Among these, chondroitin sulfate, chondroitin polysulfate, at least one acidic mucopolysaccharide selected from hyaluronic acid, heparin, heparan sulfate, or a salt thereof is preferable. Examples of the salt include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with metals such as aluminum. Sodium salts and potassium salts are preferably used.

  Further, the molecular weight of the acidic mucopolysaccharide used in the present invention is not particularly limited, and for example, the acidic mucopolysaccharide can be used at an average molecular weight of about 10,000 to 10,000,000. The average molecular weight is preferably in the range of 300 to 8 million, more preferably in the range of 500,000 to 5 million, and particularly preferably in the range of 1 million to 3 million. The content of the acidic mucopolysaccharide in the eye drop varies depending on the molecular weight and type, and thus cannot be specified unconditionally. Usually, the concentration in the eye drop is 0.001 to 10%, preferably 0.005 to 5%. More preferably, it can be used at about 0.01 to 3%, particularly preferably about 0.1 to 0.5%.

  The present invention is characterized by containing at least one selected from hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose or a salt thereof. These are known compounds usually used for eye drops, and commercially available products can also be obtained.

  In the present invention, the content of these compounds in the ophthalmic solution is not limited because it varies depending on the type and molecular weight of the compound, but the total amount of these compounds is usually 0.001 to 25%, more preferably It is 0.01 to 10%, More preferably, it is 0.01 to 7%, Most preferably, it is about 0.05 to 7%. The content of each compound is preferably about 0.001 to 10%, more preferably about 0.01 to 10%, and particularly preferably about 0.05 to 5%. The content of hydroxypropylmethylcellulose is preferably about 0.001 to 10%, more preferably about 0.01 to 10%, and particularly preferably about 0.05 to 5%. The content of methylcellulose is preferably about 0.01 to 20%, more preferably about 0.1 to 15%. The content of polyvinyl pyrrolidone is preferably 0.001 to 20%, more preferably 0.01 to 10%, still more preferably about 0.05 to 5%, and the content of polyvinyl alcohol is 0.01 to 10%. More preferably, it is about 0.05 to 5%. The content of carboxymethyl cellulose or a salt thereof is preferably 0.001 to 10%, more preferably 0.005 to 5%, and particularly preferably about 0.01 to 3%.

  In the present invention, preferably, hydroxyethyl cellulose having a viscosity of 20% at 2 ° C. and a 2% aqueous solution of 100 mPa · s to 50000 mPa · s is used, more preferably 1000 mPa · s to 50000 mPa · s, and particularly preferably 1000 mPa · s. ˜30000 mPa · s of hydroxyethyl cellulose is used. Commercially available hydroxyethyl cellulose can be used, for example, HEC-CF-G (20 ° C., 2% aqueous solution viscosity is 300 mPa · s to 600 mPa · s) sold by Sumitomo Seika Co., Ltd., HEC -CF-V (viscosity of 2% aqueous solution at 20 ° C. is 5000 mPa · s to 10,000 mPa · s), HEC-CF-W (viscosity of 2% aqueous solution at 20 ° C. is 10,000 mPa · s to 16000 mPa · s), etc. can be used. .

  In the present invention, preferably, methylcellulose having an average molecular weight of 50,000 to 500,000 is used. More preferably, methylcellulose having an average molecular weight of 100,000 to 500,000 and particularly preferably 200,000 to 500,000 is used. Commercially available methylcellulose can be used. For example, SM-15 (average molecular weight of about 70,000), SM-25 (average molecular weight of about 90,000) sold by Shin-Etsu Chemical Co., Ltd. as the Metrows SM series. ), SM-50 (average molecular weight of about 110,000), SM-100 (average molecular weight of about 120,000), SM-400 (average molecular weight of about 170,000), SM-1500 (average molecular weight of about 290,000), SM-4000 (Average molecular weight of about 360,000) can be used.

  In the present invention, it is preferable to use a known polyvinyl pyrrolidone having an average molecular weight of 10,000 to 150,000. More preferably, polyvinylpyrrolidone having an average molecular weight of 20,000 to 150,000 is used. Commercially available polyvinyl pyrrolidone can be used. For example, Kollidon 12PF (average molecular weight of about 20,000) and Kollidon 17PF (average molecular weight of about 90,000) sold by BASF Corporation as the Kollidon series. Kollidon 25 (average molecular weight of about 30,000), Kollidon 30 (average molecular weight of about 50,000), Kollidon 90 (average molecular weight of about 120,000) and the like can be used.

  In the present invention, it is preferable to use a known hydroxypropylmethylcellulose having an average molecular weight of 50,000 to 500,000. More preferred is hydroxypropylmethylcellulose having an average molecular weight of 100,000 to 500,000, particularly preferably 200,000 to 500,000. Commercially available hydroxypropylmethylcellulose can be used, for example, 60SH-15 (average molecular weight of about 70,000), 60SH-25 (average molecular weight of about 70,000 sold by Shin-Etsu Chemical Co., Ltd. as the Metrows SH series. 90,000), 60SH-50 (average molecular weight of about 100,000), 60SH-100 (average molecular weight of about 120,000), 60SH-400 (average molecular weight of about 170,000), 60SH-1500 (average molecular weight of about 200,000), 60SH- 4000 (average molecular weight of about 300,000), 60SH-10000 (average molecular weight of about 500,000), 65SH-50 (average molecular weight of about 100,000), 65SH-400 (average molecular weight of about 110,000), 65SH-1500 (average molecular weight of about 20 10,000), 65SH-4000 (average molecular weight of about 300,000), 60SH-15000 (average molecular weight of about 8) , 90SH-100 (average molecular weight of about 120,000), 90SH-400 (average molecular weight of about 110,000), 90SH-4000 (average molecular weight of about 300,000), 90SH-15000 (average molecular weight of about 800,000), etc. .

  In the present invention, it is preferable to use a known polyvinyl alcohol having an average molecular weight of 10,000 to 300,000. More preferably, polyvinyl alcohol having an average molecular weight of 30,000 to 200,000 is used. Commercially available polyvinyl alcohol can be used. For example, GOHSENOL EG05 (average molecular weight of about 30,000), GOHSENOL EG40 (average molecular weight of about 120,000) sold by Nippon Synthetic Chemical Co., Ltd. as Gohsenol series. ) Etc. can be used.

  Moreover, in this invention, carboxymethylcellulose sodium is preferable among well-known carboxymethylcellulose or its salt. Further, carboxymethyl cellulose or a salt thereof is preferably used at a sodium carboxymethyl cellulose temperature of 25 ° C. and a 2% aqueous solution having a viscosity of 20 mPa · s to 8000 mPa · s, more preferably 20 mPa · s to 6000 mPa · s, particularly preferably. A sodium carboxymethyl cellulose of 20 mPa · s to 3000 mPa · s is used. The degree of etherification of sodium carboxymethylcellulose can usually be in the range of 0.1 to 3.0, but is preferably 0.6 to 1.0, more preferably 0 for the mucosa-applied composition of the present invention. .6 to 0.9, particularly preferably 0.7 to 0.9. Such carboxymethyl cellulose sodium can be commercially available, for example, Serogen (registered trademark) series PR-S (25 ° C., 2% aqueous solution having a viscosity of 20 mPa · s) sold by Daiichi Kogyo Seiyaku Co., Ltd. 40 mPa · s, degree of etherification 0.70 to 0.85), P-715A (25 ° C., 2% aqueous solution viscosity 80 mPa · s to 140 mPa · s, degree of etherification 0.60 to 0.70), F-SC (25 ° C., 2% The viscosity of the aqueous solution is 300 mPa · s to 400 mPa · s, the degree of etherification 0.70 to 0.85), AG-GUM (25 ° C., the viscosity of the 2% aqueous solution is 900 mPa · s to 1500 mPa · s, the degree of etherification 0.70 to 0.85), etc. CMC Daicel series sold by Daicel Chemical Industries, Ltd., Sunrose F series sold by Nippon Paper Chemicals Co., Ltd. Available.

  The eye drop of the present invention exhibits an excellent dry spot improving effect by adjusting the viscosity and adjusting the viscosity at 20 ° C. to 15 mPa · s to 300 mPa · s. More preferably, it is 20-200 mPa * s, More preferably, it is 30-150 mPa * s, Most preferably, it is 30-100 mPa * s.

  A known method can be used as the viscosity measuring method. For example, a method using a conical one-plate rotary viscometer (general test method, 45. Viscosity measuring method, second method described in the 14th revised Japanese pharmacy method) It can be measured according to the rotational viscometer method, the method described in the section “(3) Cone-Plate type rotational viscometer”. In measuring viscosity, commercially available viscometers such as E-type viscometers (manufactured by TOKIMEC, sold by Toki Sangyo (Japan)), Synchronic PC type (Brookfield, USA), Ferranti Shirley (Feranti, UK), Rot Bisco R (Haake, Germany), IGK Hischer Rheometer (Ishida Giken, Japan), Shimadzu Rheometer R (Shimadzu, Japan), Weissenberg Greogoniometer (Sangamo, UK), Mechanical Spectro Meters (rheometrics, rice), etc. can be used. Then, by appropriately selecting these commercially available viscometers and rotors, by appropriately adjusting the petroleum-based hydrocarbon oil (Newtonian fluid) defined by JIS Z8809 for each test sample measurement as a calibration standard solution, The viscosity at 20 ° C. can be measured.

When the eye drop of the present invention contains at least one selected from menthol, camphor or borneol, the dry spot improving effect is further enhanced. These compounds may be either d-form or l-form. In the eye drop of the present invention, the total content of these compounds is usually 0.0005 to 3%, preferably 0.001 to 1%, particularly preferably about 0.001 to 0.5%.
The eye drop of the present invention is suitable for containing various components (including pharmacologically active components and physiologically active components) in combination. Decongestant component, ophthalmic modulator component, anti-inflammatory component or astringent component, antihistamine component or antiallergic component, vitamins, amino acids, antibacterial component, bactericidal component, saccharide, etc. Can be illustrated. Specifically, the following components can be exemplified.

Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.
Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.
Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diclofenac sodium, bromfena Sodium chloride, berberine chloride, berberine sulfate, etc.
Antihistamine component or antiallergic agent component: for example, acitazanolast, amlexanox, ibudilast, tranilast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, pemirolast potassium, chlorpheniramine maleate, and the like.
Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate and the like.
Amino acids: for example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, potassium aspartate, magnesium aspartate, magnesium / aspartate mixture, sodium glutamate and the like. These may be d-form, l-form or dl-form.
Antibacterial or bactericidal component: for example, alkylpolyaminoethylglycine, berberine sulfate, berberine chloride, boric acid, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium and the like.
Sugars: for example, monosaccharides, disaccharides, specifically glucose, trehalose and the like.
Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride, etc.
Steroid component: for example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

  In addition, the eye drop of the present invention contains various components and additives as appropriate according to conventional methods and forms within a range not impairing the effects of the invention, and contains one or more in combination. You may let them. As those components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of semi-solids and liquids, thickeners, sugars, surfactants, Various additives such as preservatives, bactericides or antibacterial agents, pH regulators, tonicity agents, fragrances or refreshing agents, and buffering agents can be mentioned.

Although the typical component used for the eye drop of this invention is illustrated below, it is not limited to these.
Thickener: for example, alginic acid or a salt thereof, propylene glycol alginate, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, cyclodextrin, glycerin, hydroxypropyl cellulose, polyethylene glycol, carboxyvinyl polymer, dextran and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like.
Surfactant: For example, glycine-type amphoteric surfactant such as alkyldiaminoethylglycine; alkyl quaternary ammonium salt (specifically, cationic surfactant such as benzalkonium chloride, benzethonium chloride, etc.) The number indicates the number of moles added.
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glow Kill (manufactured by Rhodia) Name) etc.
pH adjuster: For example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, borax, triethanolamine, monoethanolamine and the like.
Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.
Perfume or refreshing agent: for example, menthol, camphor, borneol, geraniol, agate, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These may be d-form, l-form or dl-form.
Buffer: aminoethyl sulfonic acid, epsilon-aminocaproic acid, citrate buffer, acetate buffer, carbonate buffer, borate buffer, phosphate buffer, etc. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate Such.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.
Solubilizer, base: octyldodecanol, titanium oxide, potassium bromide, paraffin, castor oil, plastibase, lanolin, petrolatum, etc.

  The eye drop of the present invention is used by adjusting to an osmotic pressure within a range acceptable for a living body, if necessary. The osmotic pressure is about 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.4.

  The eye drop of the present invention is used by adjusting to an osmotic pressure within a range applicable to a living body, if necessary. The pH is usually 4.0 to 10.0, preferably 5.0.0 to 9.0, particularly preferably 6.0 to 8.0. The pH can be adjusted using a buffer, the pH adjuster, or the like.

  Here, examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer and citrate buffer. Particularly preferred buffering agents are borate buffers or phosphate buffers. Examples of the boric acid buffer include borates such as boric acid, alkali metal borates, and alkaline earth metal borates, and combinations of boric acid and borates. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, and combinations of phosphoric acid and phosphates. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, etc.). When a borate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the eye drop of the present invention is, for example, about 0.0001 to 10.0%.

  The eye drop of the present invention can be produced by a known method. Semi-solid and liquid preparations can be prepared by mixing the base and each component. Furthermore, if necessary, a filtration sterilization treatment process, a container filling process, and the like can be added.

  Hereinafter, the present invention will be described in detail based on test examples and examples, but the present invention is not limited to these examples.

Viscosity measurement method Viscosity measurement method is a method using a cone-and-plate rotational viscometer (general test method, 45. Viscosity measurement method, second method rotational viscometer method described in the 14th revision Japanese Pharmacopoeia, 3) The method described in the section “Cone-plate rotational viscometer” was followed. The viscosity of each comparative example and each example in this test is a TVE-20L type viscometer cone plate type (manufactured by TOKIMEC, Toki Sangyo (Japan)), which is a type of E-type viscometer. Measurement was performed under the following measurement conditions.

Measurement condition:
Standard cone rotor (corresponding to cone 1 in Fig. 1) (α = 1 ° 34 ', radius (R) = 2.4cm) attached to TVE-20L viscometer cone plate type full scale torque 67.37 × 10 ^-6 Rotate by motor through Nm spring. During measurement, the viscometer is installed so that the rotation axis is perpendicular to the horizontal plane.
1 ml of the test sample is placed on a predetermined position of the cone rotor (a plate, which corresponds to the flat disk 2 in FIG. 1), and is left until the temperature reaches 20.0 ° C. Next, the apparatus is rotated at a rotational speed corresponding to the viscosity of the test sample, and after 3 minutes, the displayed viscosity is read. In order to obtain highly accurate measurement results, before measurement of the test sample, petroleum-based hydrocarbon oil (Newtonian fluid) specified by JIS Z 8809 is used as the calibration standard solution, and the measured value is the viscosity of the standard solution. Adjust to match. The same result can be obtained by using a commercially available model other than the TVE-20L viscometer cone plate type, selecting a cone rotor in the same manner as described above, and performing calibration appropriately.
Rotor used: Standard rotor (1 ° 34 ', R = 24mm)
Rotation speed: 50rpm
Sample volume: 1ml
Measurement temperature: 20 ° C
Time: Viscosity after 3 minutes was taken as a measured value.

Dry Spot Inhibitory Effect Test Each example and test example used in the test were prepared according to the formulation shown in Table 1, and the pH was adjusted to 7.0. About the adjusted Example and Comparative Example, the time until the appearance of the dry spot was measured. Specifically, 1 minute after applying the examples or comparative examples, the corneal surface was stained with fluorescein and visually observed with a slit lamp microscope, and the time (seconds) until the appearance of a dry spot was measured. The average time was calculated for 10 subjects. As a control, it was also measured when the eyelid was opened without instillation. The results are shown in Table 1.

  As a result of the test, eyedrops containing sodium chondroitin sulfate or sodium hyaluronate and hydroxyethyl cellulose or / and hydroxypropyl methylcellulose and having a viscosity at 20 ° C. of 15 mPa · s or more significantly delay the time until the appearance of the dry spot. doing. Moreover, when the comparative example 1 was instilled, the appearing dry spot expanded rapidly after the appearance, but in the instillation of the example of the present invention, the expansion speed of the appeared dry spot was slow and the expansion was suppressed. In the embodiment of the present invention, the appearance of dry spots is suppressed, and the expansion speed of the appeared dry spots is slow, and the dry spot suppression effect is high. It is useful as an eye drop for dry spot suppression.

Dry spot suppression effect test About the test subject with a dry eye tendency, the eye drop of Example 2 and the commercially available eye drops A and B were instilled, and the time until a dry spot appearance was measured. Eyedrop A contains 0.5 g / 100 ml of chondroitin sulfate sodium and hydroxypropylmethylcellulose and has a viscosity at 20 ° C. of 12 mPa · s, and eye drop B contains 0.05% sodium chondroitin sulfate and has a viscosity at 20 ° C. 2 mPa · s.
The test was conducted on 15 subjects (30 eyes) over the age of 20 who had a dry eye tendency that could not keep their eyes open for more than 30 seconds without blinking. In the test, 1 minute after instillation of Example 2, eye drops A or B, the surface of the cornea was stained with fluorescein, visually observed with a slit lamp microscope, and the time (seconds) until the appearance of a dry spot was measured. The average time of subjects was calculated. As a control, it was also measured when the eyelid was opened without instillation. Each application of eye drops was tested at intervals of 30 minutes or more. The results are shown in Table 2.

  As a result of a test by a subject having a dry eye tendency, in Example 2, the time until the appearance of the dry spot was significantly delayed, and the expansion speed of the appeared dry spot was slowed to suppress the expansion. In the examples of the present invention, the appearance of dry spots was suppressed even for subjects with a dry eye tendency, and the expansion rate of the appeared dry spots was slow, indicating that the dry spot suppression effect was high. . It is useful as an eye drop for dry spot suppression.

Claims (9)

A) chondroitin sulfate saury other at least one acidic mucopolysaccharide is selected from its salts, and B) hydroxyethyl cell row scan, or hydroxypropylmethylcellulose row scan some have the at least one or more selected from a salt thereof An eye drop having a viscosity at 20 ° C. of 30 mPa · s or more and 300 mPa · s or less (excluding an eye drop containing insulin) . The eye drop according to claim 1, wherein the content of the component A) is 0.001 to 10 W / V%, and the total amount of the component B) is 0.001 to 25 W / V%. The eye drop according to claim 1 or 2, wherein the component A) has an average molecular weight of 0.1 to 10 million. 4. A nonionic surfactant selected from polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, or polyoxyethylene hydrogenated castor oils. Eye drops. The ophthalmic solution according to any one of claims 1 to 4, further comprising at least one selected from menthol, borneol, and camphor. The eye drop according to any one of claims 1 to 5, further comprising at least one selected from a borate buffer, a phosphate buffer, a carbonate buffer, and a citrate buffer. In addition, chlorpheniramine maleate, tetrahydrozoline hydrochloride, naphazoline hydrochloride, neostigmine methyl sulfate, epsilon aminocaproic acid, allantoin, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, cyanocobalamin, retinol palmitate, pyridoxine hydrochloride, panthenol, acetic acid Selected from tocopherol, aminoethylsulfonic acid, potassium aspartate, magnesium and potassium aspartate, sodium sulfamethoxazole, glucose, propylene glycol, glycerin, potassium sorbate, flavin adenine dinucleotide, sodium edetate, polyethylene glycol The eye drop according to any one of claims 1 to 6, comprising at least one kind. The eye drop according to any one of claims 1 to 7, which has a viscosity at 20 ° C of 30 mPa · s to 100 mPa · s. The eye drop according to any one of claims 1 to 8, which is used for dry spot suppression.