Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• the present invention relates to an ophthalmic composition.
• Chondroitin sulfate or its salts are a type of acidic mucopolysaccharide, and are known to be used to prevent the cornea from drying out due to their physiological viscosity. (For example, Non-Patent Document 1).
• Chondroitin sulfate preparation for ophthalmic use Chondron (registered trademark) eye drops 1% Chondron (registered trademark) eye drops 3% Package insert (revised November 2007)
• the present invention aims to provide a novel ophthalmic composition containing sodium chondroitin sulfate having a specific weight-average molecular weight (1,000 to 20,000).
• an ophthalmic composition containing sodium chondroitin sulfate with a weight-average molecular weight of 1,000 to 20,000 and a water-soluble vitamin or amino acid can reduce the elastic modulus of soft contact lenses.
• ophthalmic compositions that are OTC drugs generally can be used while contact lenses are being worn. Ophthalmic compositions that have advantages in contact lenses and their wear are useful.
• An ophthalmic composition comprising: (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof having a weight-average molecular weight of 1,000 to 20,000; and (B) at least one selected from the group consisting of water-soluble vitamins, amino acids, and salts thereof.
• A at least one selected from the group consisting of chondroitin sulfate and salts thereof having a weight-average molecular weight of 1,000 to 20,000
• B at least one selected from the group consisting of water-soluble vitamins, amino acids, and salts thereof.
• the present invention provides a novel ophthalmic composition containing sodium chondroitin sulfate with a weight-average molecular weight of 1,000 to 20,000.
• the unit of content "%” means “w/v %” and is synonymous with “g/100 mL.”
• the ophthalmic composition of this embodiment contains at least one type selected from the group consisting of chondroitin sulfate and its salts having a weight-average molecular weight of 1,000 to 20,000 (also referred to simply as "component (A)").
• Chondroitin sulfate and its salts are not particularly limited, so long as they are medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable.
• Examples of salts of chondroitin sulfate include alkali metal salts and alkaline earth metal salts.
• Examples of alkali metal salts include sodium salt and potassium salt.
• Examples of alkaline earth metal salts include magnesium salt and calcium salt.
• chondroitin sulfate and its salts As chondroitin sulfate and its salts, chondroitin sulfate and alkali metal salts of chondroitin sulfate are preferred, chondroitin sulfate and sodium chondroitin sulfate are more preferred, and sodium chondroitin sulfate is even more preferred.
• Chondroitin sulfate and its salts may be natural or synthetic, but generally, chondroitin sulfate and its salts derived from natural animals (preferably mammals, fish, mollusks, etc.; more preferably cows, sharks, squid, rays, etc.), chondroitin sulfate and its salts derived from mushrooms such as wood ear mushrooms, and chondroitin sulfate and its salts derived from algae such as seaweed are preferably used, with chondroitin sulfate and its salts derived from sharks and/or rays being more preferably used. Also, chondroitin sulfate and its salts produced by fermentation using microorganisms such as lactic acid bacteria, E. coli, and yeast are preferably used.
• Chondroitin sulfate and its salts can be commercially available. Chondroitin sulfate and its salts can be used alone or in combination of two or more. In addition, chondroitin sulfate and its salts having a weight-average molecular weight of 1,000 to 20,000 as specified in this specification can be used in combination with chondroitin sulfate and its salts having a weight-average molecular weight outside the range specified in this specification. For example, sodium chondroitin sulfate having a weight-average molecular weight of 16,000 can be used in combination with sodium chondroitin sulfate having a weight-average molecular weight of 25,000.
• chondroitin sulfate and its salts having a weight-average molecular weight of 1,000 to 20,000 as specified in this specification are used in combination with chondroitin sulfate and its salts having a weight-average molecular weight outside the range specified in this specification, it is sufficient to contain chondroitin sulfate and its salts having a weight-average molecular weight of 1,000 to 20,000 as a raw material.
• the "weight average molecular weight” can be determined by using gel permeation chromatography in which a multi-angle light scattering detector (MALS detector) and a differential refractive index detector (RI detector) are connected online. Specifically, the following conditions are presented. ⁇ Standard sample preparation> 10 mL of 0.1 M aqueous sodium nitrate solution was added to 5 mg of chondroitin sulfate or a salt thereof, and the mixture was gently stirred at room temperature until completely dissolved.
• MALS detector multi-angle light scattering detector
• RI detector differential refractive index detector
• Apparatus Gel permeation chromatography - multi-angle light scattering meter Detector: Differential refractive index detector (Optilab rEX, manufactured by Wyatt Technology) Multi-angle light scattering detector (DAWN HELEOS, manufactured by Wyatt Technology) Column: Shodex OHpak SB-806M HQ x 2 ( ⁇ 7.8 mm x 30 cm, Showa Denko) Solvent: 0.1 M aqueous sodium nitrate solution Flow rate: 0.7 mL/min Column temperature: 23°C Detector temperature: 23°C Injection volume: 0.2 mL Data processing: Wyatt Technology data processing system (ASTRA)
• ASTRA Wyatt Technology data processing system
• the weight-average molecular weight of chondroitin sulfate and its salts calculated by the above method is not particularly limited as long as it is in the range of 1,000 to 20,000.
• Examples of lower limits of the weight-average molecular weight include 1,000 or more, 2,000 or more, 5,000 or more, 10,000 or more, 11,000 or more, 12,000 or more, and 14,000 or more.
• Examples of upper limits of the weight-average molecular weight include 20,000 or less, 19,500 or less, 19,000 or less, 18,000 or less, 17,000 or less, 15,000 or less, 14,000 or less, and 13,000 or less.
• ranges of the weight-average molecular weight include 1,000 to 20,000, 2,000 to 19,500, 5,000 to 19,000, 12,000 to 18,000, and 14,000 to 17,000.
• the weight-average molecular weight may also be in the range of 10,000 to 14,000.
• the content of component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type and content of other blended components, the purpose of the ophthalmic composition, the formulation form, etc. From the viewpoint of more prominently exhibiting the effects of the present invention, the content of component (A) is, for example, preferably 0.001 to 1 w/v%, more preferably 0.005 to 0.75 w/v%, and even more preferably 0.01 to 0.5 w/v%, based on the total amount of the ophthalmic composition. In addition, the content of component (A) may be 0.05 to 2 w/v%, 0.1 to 1 w/v%, 0.5 to 1 w/v%, or may be 0.5 w/v% or 1 w/v%.
• the ophthalmic composition according to the present embodiment contains at least one selected from the group consisting of water-soluble vitamins, amino acids, and salts thereof (also referred to simply as "component (B)").
• the water-soluble vitamins, amino acids, or salts thereof are not particularly limited as long as they are medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable.
• water-soluble vitamins examples include vitamin B such as flavin adenine dinucleotide and its salts (such as sodium flavin adenine dinucleotide), cobalamins (such as cyanocobalamin and methylcobalamin), pantothenic acid and its salts (such as sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), panthenol, pyridoxine or its salts (such as pyridoxine hydrochloride), pyridoxal and its salts (such as pyridoxal phosphate), and vitamin C such as ascorbic acid and its salts (such as sodium ascorbate).
• vitamin B such as flavin adenine dinucleotide and its salts (such as sodium flavin adenine dinucleotide), cobalamins (such as cyanocobalamin and methylcobalamin), pantothenic acid and its salts (such as sodium pantothenate, potassium pan
• vitamin B is preferred, panthenol, pyridoxine or its salts, flavin adenine dinucleotide or its salts, and cyanocobalamin are more preferred, and panthenol and pyridoxine or its salts are even more preferred.
• water-soluble vitamins can also be used.
• the water-soluble vitamins can be used alone or in combination of two or more types.
• amino acids examples include aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, glycine, alanine, ⁇ -aminobutyric acid, ⁇ -aminovaleric acid, trimethylglycine, ⁇ -aminocaproic acid, aminoethylsulfonic acid (taurine), etc.
• amino acid salts include salts with inorganic acids (e.g., salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), salts with organic acids (e.g., salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid, etc.), salts with inorganic bases (e.g., alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, ammonium salts), and salts with organic bases (e.g., salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, etc.).
• amino acids and salts thereof can also be used.
• the amino acids and salts thereof may be any of L-, D-, and DL-isomers.
• aspartic acid or a salt thereof ⁇ -aminocaproic acid, and aminoethylsulfonic acid are preferred, and aminoethylsulfonic acid is more preferred.
• the content of component (B) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of component (B), the type and content of other blended components, the formulation form, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of component (B) is, for example, preferably 0.0001 to 5 w/v%, more preferably 0.0005 to 4 w/v%, and even more preferably 0.001 to 3 w/v%, based on the total amount of the ophthalmic composition according to this embodiment.
• the total content of component (B) may also be 0.005 to 1 w/v%, or 0.01 to 0.1 w/v%.
• the content ratio of the (B) component to the (A) component in the ophthalmic composition according to this embodiment is not particularly limited, and is appropriately set depending on the types of the (A) and (B) components, the types and contents of other blended components, the use and formulation form of the ophthalmic composition, etc.
• the content ratio of the (B) component to the (A) component is preferably 0.0001 to 5000 parts by mass, more preferably 0.0005 to 4000 parts by mass, and even more preferably 0.001 to 3000 parts by mass, per part by mass of the total content of the (A) component contained in the ophthalmic composition according to this embodiment.
• the total content of the (B) component may be 0.001 to 20 parts by mass, 0.01 to 5 parts by mass, 0.01 to 1 part by mass, or 0.02 to 2 parts by mass per part by mass of the total content of the (A) component.
• component (B) is a water-soluble vitamin
• the total content of the water-soluble vitamin is preferably 0.0001 to 0.5 w/v%, more preferably 0.0005 to 0.3 w/v%, and even more preferably 0.001 to 0.2 w/v%.
• the total content of the water-soluble vitamin may be 0.01 to 0.1 w/v%.
• the content ratio of the water-soluble vitamin to the (A) component is, from the viewpoint of further enhancing the effect of the present invention, for example, preferably 0.0001 to 500 parts by mass, more preferably 0.0005 to 300 parts by mass, and even more preferably 0.001 to 200 parts by mass, per part by mass of the total content of the (A) component contained in the ophthalmic composition according to this embodiment.
• the total content of the water-soluble vitamin to 1 part by mass of the total content of the (A) component may be 0.001 to 20 parts by mass, 0.01 to 5 parts by mass, 0.01 to 1 part by mass, or 0.02 to 2 parts by mass.
• the total content of the amino acid and its salt is preferably 0.0001 to 5 w/v%, more preferably 0.001 to 4 w/v%, and even more preferably 0.05 to 3 w/v%.
• the total content of the amino acid and its salt may be 0.1 to 2 w/v%, or 0.2 to 1 w/v%.
• the content of aminoethylsulfonic acid is preferably 0.1 to 1 w/v%.
• the content ratio of the amino acid and its salt relative to the (A) component is, from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the amino acid and its salt relative to 1 part by mass of the total content of the (A) component contained in the ophthalmic composition according to this embodiment is preferably 0.0001 to 5000 parts by mass, more preferably 0.001 to 4000 parts by mass, and even more preferably 0.05 to 3000 parts by mass.
• the total content of the amino acid and its salt relative to 1 part by mass of the total content of the (A) component may be 0.001 to 20 parts by mass, 0.01 to 5 parts by mass, 0.01 to 1 part by mass, or 0.02 to 2 parts by mass.
• the ophthalmic composition according to the present embodiment preferably further contains a buffering agent.
• a buffering agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.
• the buffering agent include inorganic buffering agents derived from inorganic acids, and organic buffering agents derived from organic acids or organic bases.
• inorganic buffers include borate buffers, phosphate buffers, carbonate buffers, etc.
• borate buffers include boric acid or its salts (alkali metal borates, alkaline earth metal borates, etc.).
• phosphate buffers include phosphoric acid or its salts (alkali metal phosphates, alkaline earth metal phosphates, etc.).
• carbonate buffers include carbonic acid or its salts (alkali metal carbonates, alkaline earth metal carbonates, etc.).
• hydrates of borates, phosphates, or carbonates may be used as borate buffers, phosphate buffers, or carbonate buffers.
• borate buffers include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers include phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers include carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.).
• organic buffers include citrate buffers, acetate buffers, lactate buffers, succinate buffers, tris buffers, AMPD buffers, etc.
• citrate buffers include citric acid or its salts (alkali metal citrate, alkaline earth metal citrate, etc.).
• acetate buffers include acetic acid or its salts (alkali metal acetate, alkaline earth metal acetate, etc.).
• lactate buffers include lactic acid or its salts (alkali metal lactate, alkaline earth metal lactate, etc.).
• succinate buffers include succinic acid or its salts (alkali metal succinate, etc.).
• citrate buffers examples include citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.);
• the acetate buffer includes acetic acid or a salt thereof (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.);
• the lactate buffer includes lactic acid or a salt thereof (sodium lactate, potassium lactate, calcium lactate, etc.);
• succinate buffer includes succinic acid or a salt thereof (monosodium succinate, disodium succinate, etc.).
• An example of a tris buffer is trometamol or a salt thereof (trometamol hydrochloride, etc.).
• An example of an AMPD buffer is 2-amino-2-methyl-1,3-propanediol or a salt thereof.
• boric acid buffering agents e.g., a combination of boric acid and borax
• boric acid and its salts are more preferred, and a combination of boric acid and borax is even more preferred.
• buffers may be used. One type of buffer may be used alone, or two or more types may be used in combination.
• the content of the buffering agent in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of buffering agent, the type and content of other blended ingredients, the intended use of the ophthalmic composition, the formulation form, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of the buffering agent is, for example, preferably 0.01 to 4 w/v%, more preferably 0.05 to 3 w/v%, and even more preferably 0.1 to 2 w/v%, based on the total amount of the ophthalmic composition.
• the content ratio of the buffering agent relative to component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of component (A) and buffering agent, the type and content of other blended components, the intended use of the ophthalmic composition, the formulation form, etc.
• the content ratio of the buffering agent relative to component (A) is preferably 0.01 to 4000 parts by mass, more preferably 0.05 to 3000 parts by mass, and even more preferably 0.1 to 2000 parts by mass, of the total content of the buffering agent relative to 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment.
• the pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a medicamentously, pharmacologically (pharmaceutical), or physiologically acceptable range.
• the pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, even more preferably 4.5 to 8.5, even more preferably 5.0 to 8.5, and particularly preferably 5.0 to 8.0.
• the ophthalmic composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary.
• the appropriate osmotic pressure ratio can be set appropriately depending on the application, formulation form, method of use, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and even more preferably 0.8 to 2.0.
• the osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w/v% sodium chloride aqueous solution) based on the 17th Revised Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia.
• the standard solution for measuring osmolality ratios (0.9 w/v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, allowing it to cool in a desiccator (silica gel), and then accurately weighing out 0.900 g of it and dissolving it in purified water to make exactly 100 mL, or a commercially available standard solution for measuring osmolality ratios (0.9 w/v% sodium chloride aqueous solution) can be used.
• the viscosity of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range that is medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable.
• the viscosity of the ophthalmic composition according to this embodiment as measured at 20°C using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24), is preferably 1 to 10,000 mPa ⁇ s, more preferably 1 to 8,000 mPa ⁇ s, even more preferably 1 to 1,000 mPa ⁇ s, even more preferably 1 to 100 mPa ⁇ s, particularly preferably 1 to 20 mPa ⁇ s, and most preferably 1.5 to 10 mPa ⁇ s.
• the ophthalmic composition according to the present embodiment may contain an appropriate amount of a combination of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients, as long as the effects of the present invention are not impaired.
• the ingredients are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs listed in the 2017 edition of the General Drug Manufacturing and Sales Approval Standards (supervised by the Japan Society of Regulatory Science). Specific examples of ingredients used in ophthalmic drugs include the following ingredients.
• Antiallergic agents for example, sodium cromoglycate, tranilast, pemirolast potassium, ashitazanolast, amlexanox, ibudilast, etc.
• Antihistamines for example, chlorpheniramine or a salt thereof (e.g., chlorpheniramine maleate), diphenhydramine or a salt thereof (e.g., diphenhydramine hydrochloride), iproheptine or a salt thereof (e.g., iproheptine hydrochloride), levocabastine or a salt thereof (e.g., levocabastine hydrochloride), ketotifen or a salt thereof (e.g., ketotifen fumarate), pemirolast potassium, olopatadine or a salt thereof (e.g., olopatadine hydrochloride), etc.
• chlorpheniramine or a salt thereof e.g., chlorpheniramine maleate
• diphenhydramine or a salt thereof e.g., diphenhydramine hydrochloride
• iproheptine or a salt thereof e.g., iproheptine hydrochloride
• Anti-inflammatory agents for example, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, glycyrrhizinic acid or a salt thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), etc.
• methyl salicylate for example, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lys
• Steroids for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc.
• Decongestants for example, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and the like.
• Ocular muscle regulating drugs for example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically, neostigmine methylsulfate, tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride, etc.
• Fat-soluble vitamins for example, retinol acetate, retinol palmitate, tocopherol acetate, etc.
• Others For example, sulfamethoxazole, sulfisoxazole, sulfisomidine and their salts.
• additives may be appropriately selected according to the intended use and formulation form, and one or more of them may be used in combination in an appropriate amount, as long as the effect of the present invention is not impaired.
• additives include various additives listed in the Pharmaceutical Additives Encyclopedia 2016 (edited by the Japan Pharmaceutical Additives Association).
• Representative components include the following additives.
• Carrier For example, an aqueous solvent such as water or aqueous ethanol.
• Chelating agents for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like.
• Bases For example, octyldodecanol, titanium oxide, potassium bromide, plastibase, etc.
• pH adjusters for example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, etc.
• Thickeners for example, cellulose-based polymer compounds such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose; polyvinyl-based polymer compounds such as polyvinylpyrrolidone and polyvinyl alcohol; carboxyvinyl polymers; guar gum; hydroxypropyl guar gum; gum arabic; karaya gum; xanthan gum; agar; alginic acid and its salts (sodium salt, etc.); heparin-like substances, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and its salts (sodium salt, etc.); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; monosaccharides such as glucose, etc.
• Stabilizers for example, edetic acid, edetate salts (disodium edetate, calcium disodium edetate, trisodium edetate, tetrasodium edetate), sodium formaldehyde sulfoxylate (Rongalit), aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, sodium hydrogensulfite, sodium pyrosulfite, etc.
• edetic acid for example, edetic acid, edetate salts (disodium edetate, calcium disodium edetate, trisodium edetate, tetrasodium edetate), sodium formaldehyde sulfoxylate (Rongalit), aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, sodium
• Preservatives for example, alkyl polyaminoethyl glycine quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, polydonium chloride, zinc chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), alexidine, etc.), Gloquil (trade name, manufactured by Rhodia), etc.
• alkyl polyaminoethyl glycine quaternary ammonium salts e.g., benz
• Isotonicity agents for example, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, sodium hydrogen sulfite, sodium sulfite, etc.
• Sugar alcohols for example, xylitol, sorbitol, mannitol, glycerin, etc. These may be in the d-, l- or dl-form.
• the ophthalmic composition according to this embodiment preferably does not contain POE sorbitan monolaurate, more preferably does not contain POE sorbitan monolaurate and polyoxyethylene hydrogenated castor oil, and even more preferably does not contain a nonionic surfactant, since this allows the effect of the present invention to be more significantly exhibited.
• nonionic surfactants include POE sorbitan fatty acid esters such as POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65), and POE (20) sorbitan monooleate (polysorbate 80); poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 403, POE POP glycols such as Poloxamer 237 and Poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, and POE hydrogenated castor oil 80; POE castor oils such as POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil
• the ophthalmic composition according to this embodiment preferably does not contain a terpenoid, since this allows the effects of the present invention to be more pronounced.
• terpenoids include menthol, camphor, borneol, and geraniol.
• the water content is, for example, preferably 80 w/v% or more and less than 100 w/v%, more preferably 85 w/v% or more and 99.5 w/v% or less, and even more preferably 90 w/v% or more and 99.2 w/v% or less, based on the total amount of the ophthalmic composition.
• the water used in the ophthalmic composition according to this embodiment may be any water that is medicamentally, pharmacologically (pharmaceutical) or physiologically acceptable.
• examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. These definitions are based on the 17th Edition of the Japanese Pharmacopoeia.
• the ophthalmic composition according to this embodiment can be prepared by adding and mixing the desired amounts of component (A), component (B), and other components as necessary to obtain the desired concentrations.
• it can be prepared by dissolving or dispersing those components in purified water, adjusting the pH and osmotic pressure to the desired levels, and sterilizing the composition by filtration sterilization or the like.
• the ophthalmic composition according to this embodiment can be in various formulation forms depending on the purpose.
• the formulation forms include liquids, gels, semi-solids (ointments, etc.), etc.
• the ophthalmic composition according to this embodiment can be used, for example, as eye drops (also called eye drops or eye drops.
• Eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, eyewash (also called eyewash or eyewash.
• Eyewash includes eyewash that can be applied while wearing contact lenses), and contact lens compositions [contact lens wearing solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaner, contact lens cleaning and preservative), contact lens packaging solution, etc.].
• contact lenses includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).
• the ophthalmic composition according to this embodiment is preferably an eye drop (including eye drops that can be applied while wearing contact lenses) because it can more significantly exert the effects of the present invention.
• the method of use and dosage are not particularly limited as long as they are effective and have few side effects, but for adults (15 years of age or older) and children aged 7 years or older, examples of methods include applying 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops at a time, 2 to 4 times a day, or 5 to 6 times a day.
• the ophthalmic composition according to the present embodiment is provided in any container.
• the container for storing the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example.
• Plastic is preferable. Examples of plastic include polyethylene terephthalate (PET), polyarylate (PAR), polyethylene naphthalate (PEN), polycarbonate (PC), polyethylene (PE), polypropylene (PP), polyimide (PI), cyclic olefin copolymer (COC), copolymers of monomers constituting these, and mixtures of two or more of these.
• PET polyethylene terephthalate
• PAR polyarylate
• PEN polyethylene naphthalate
• PC polycarbonate
• PE polyethylene
• PE polypropylene
• PI polyimide
• COC cyclic olefin copolymer
• the container for storing the ophthalmic composition according to the present embodiment may be a transparent container that allows the inside of the container to be seen, or may be an opaque container that makes it difficult to see the inside of the container.
• a transparent container is preferable.
• transparent container includes both colorless transparent containers and colored transparent containers.
• a nozzle may be attached to the container that holds the ophthalmic composition according to this embodiment.
• the material of the nozzle is not particularly limited, and may be made of glass or plastic, for example.
• Plastic is preferable. Examples of plastic include polybutylene terephthalate (PBT), polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), copolymers of monomers constituting these, and mixtures of two or more of these.
• the nozzle material is preferably polypropylene (PP), polyethylene (PE), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), or polyethylene naphthalate (PEN), and more preferably polyethylene (PE).
• PP polypropylene
• PE polyethylene
• PET polyethylene terephthalate
• PBT polybutylene terephthalate
• PEN polyethylene naphthalate
• the container that holds the ophthalmic composition according to this embodiment may be a multi-dose type that holds an amount for multiple uses, or a unit-dose type that holds an amount for a single use.
• the ophthalmic composition according to this embodiment is preferably filled in a container with an internal volume of 4 to 30 mL, more preferably filled in a container with an internal volume of 5 to 20 mL, even more preferably filled in a container with an internal volume of 10 to 18 mL, and even more preferably filled in a container with an internal volume of 15 to 18 mL. It may also be filled in a container with an internal volume of 0.1 to 3 mL, or may be filled in a container with an internal volume of 0.2 to 1 mL.
• the ophthalmic composition according to this embodiment contains sodium chondroitin sulfate having a weight-average molecular weight of 1,000 to 20,000 and has the effect of significantly reducing the elastic modulus of soft contact lenses, and is therefore preferably an ophthalmic composition for soft contact lenses.
• the soft contact lens becomes soft, and this makes it possible to more effectively reduce the discomfort caused by the roughness, stiffness, and poor wearing comfort when wearing and/or placing the soft contact lens.
• a method for imparting an effect of reducing the elastic modulus of soft contact lenses to an ophthalmic composition which comprises blending (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof having a weight-average molecular weight of 1,000 to 20,000 with (B) at least one selected from the group consisting of water-soluble vitamins, amino acids, and salts thereof.
• the rate at which the elastic modulus of the soft contact lens is reduced (hereinafter also referred to as the "reduction rate of elastic modulus”) is not particularly limited, but it is preferable that the reduction rate of the elastic modulus of the soft contact lens is 10 to 50%.
• the reduction rate of the elastic modulus of the soft contact lens in this embodiment is calculated by the following formula.
• the "elastic modulus of the soft contact lens” means a value measured using a MCR302 rheometer manufactured by Anton Paar and a parallel plate PP12/P12.
• Elastic modulus decrease rate (%) elastic modulus of comparative composition (Pa) ⁇ elastic modulus of the agent according to the present embodiment (Pa)/elastic modulus of comparative composition (Pa) ⁇ 100
• the comparative composition is a composition having the same composition as the ophthalmic composition of this embodiment except that it does not contain (B) at least one selected from the group consisting of water-soluble vitamins, amino acids and their salts.
• test solution The test solutions shown in Table 1 were prepared according to standard methods. The units of each component in Table 1 are g/100 mL.
• the sodium chondroitin sulfate used in the following test examples is as follows. Sodium chondroitin sulfate, weight average molecular weight: approx. 16,000; Maruha Nichiro Corporation; non-regulated sodium chondroitin sulfate
• Test Example 1 Evaluation of change in elastic modulus Physiological saline (Otsuka Pharmaceutical Factory) was dispensed in 4 mL portions into a 12-well plate (BD Falcon, No. 35-3043), and a contact lens (Precision One: Alcon) was immersed in each well and allowed to stand at room temperature for 4 hours or more.
• a contact lens Precision One: Alcon
• 4 mL portions of each of the test solutions prepared above and listed in Table 1 were dispensed, and the contact lenses, which had been lightly wiped to remove moisture with lint-free paper, were immersed in each well and allowed to stand at 34°C for 24 hours.
• 0.5 mL of physiological saline solution was dropped onto the cap plate, and the convex surface of a contact lens that had been wiped dry was placed on top of it (the convex surface of the lens was placed facing the cap plate), and 0.5 mL of physiological saline solution was dropped onto the contact lens.
• the parallel plate was lowered to approach the cap plate, and the position was set so that the contact lens was sandwiched with a distance of 0.1 mm between the two plates, and the measurement of shear stress (Pa) was started.
• the measurement intervals were 5 equal points for strain amounts of 0.01-0.1% and 5 equal points for strain amounts of 0.1-1%.
• the elastic modulus (Pa) was calculated using [Formula 1], which is 0.0325%, the second measurement interval for strain amounts of 0.01-0.1%, and 1% of the measurement interval for strain amounts of 0.1-1%. The measurement was performed three times, and the average value was taken as the average elastic modulus (Pa).
• Examples 1 to 3 which contain sodium chondroitin sulfate with a weight-average molecular weight of 16,000 and a water-soluble vitamin or amino acid, the reduction in the elastic modulus of the soft contact lens was 16.6 to 31.9% compared to Reference Example 1, which does not contain a water-soluble vitamin or amino acid, demonstrating that in an ophthalmic composition containing sodium chondroitin sulfate with a weight-average molecular weight of 1 to 20,000, the water-soluble vitamin or amino acid has the effect of softening hardened soft contact lenses.
• Formulation Examples 1 to 16 are prepared according to the formulations shown in Tables 2 and 3 below.
• Formulation Examples 1 to 16 were filled into polyethylene terephthalate containers and fitted with nozzles made of low-density polyethylene, which were designated as Formulation Examples 1 to 16.
• Formulation Examples 17 to 32 were filled into polyethylene terephthalate containers and fitted with nozzles made of polybutylene terephthalate on the entire wall surface that may come into contact with the content liquid when the cap is attached (during storage).
• Formulation Examples 33 to 48 were filled into polyethylene terephthalate containers and fitted with nozzles made of polyethylene terephthalate on part of the wall surface that may come into contact with the content liquid.
• the units are w/v % unless otherwise specified.

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