Ophthalmic composition

Abstract

The present invention relates to an ophthalmic composition containing: (A) at least one substance selected from the group consisting of chondroitin sulfate having a weight-average molecular weight of 10,000-20,000 and salts thereof; and (B) at least one substance selected from the group consisting of water-soluble vitamins, amino acids, and salts thereof.

Description

Technical Field

[0001] This invention relates to ophthalmic compositions. Background Technology

[0002] Chondroitin sulfate or its salts are known to be acidic mucopolysaccharides used to prevent corneal dryness by utilizing physiological viscosity (e.g., Non-Patent Literature 1).

[0003] Existing technical documents Non-patent literature Non-Patent Literature 1: Chondroitin Sulfate Preparation for Ophthalmic Use: Chondron (Registered Trademark) Eye Drops 1% and Chondron (Registered Trademark) Eye Drops 3% - Instructions for Use (Revised November 2007) Summary of the Invention

[0004] The problem that the invention aims to solve The purpose of this invention is to provide a novel ophthalmic composition containing sodium chondroitin sulfate with a specific weight-average molecular weight (0.1 million to 20,000).

[0005] Methods for solving problems The inventors of this application have discovered that ophthalmic compositions containing sodium chondroitin sulfate with a weight-average molecular weight of 0.1 to 20,000, and water-soluble vitamins or amino acids can unexpectedly reduce the elastic modulus of soft contact lenses. In particular, ophthalmic compositions that are generally available as OTC pharmaceuticals can also be used when wearing implanted contact lenses. Ophthalmic compositions are useful for contact lenses and for substances beneficial to their use.

[0006] The present invention provides, for example, the following inventions. [1] An ophthalmic composition comprising: (A) at least one of chondroitin sulfate and its salts selected from the group consisting of chondroitin sulfate and its salts having a weight average molecular weight of 0.1 to 20,000; and (B) at least one of the group consisting of water-soluble vitamins, amino acids and their salts. [2] The ophthalmic composition as described in [1], wherein the content of component (A) is 0.001 to 1 w / v based on the total amount of the ophthalmic composition. [3] The ophthalmic compositions described in [1] or [2] do not contain nonionic surfactants. [4] The ophthalmic composition as described in any one of [1] to [3] is used for soft contact lenses.

[0011] Invention Effects According to the present invention, a novel ophthalmic composition containing sodium chondroitin sulfate with a weight-average molecular weight of 0.1 to 20,000 can be provided. Detailed Implementation

[0012] The following describes in detail the methods for implementing the present invention. However, the present invention is not limited to the following embodiments.

[0013] Unless otherwise specified, the unit "%" for content in this instruction manual refers to "w / v%", which has the same meaning as "g / 100mL".

[0014] [(A) Select at least one from the group consisting of chondroitin sulfate and its salts with a weight-average molecular weight of 0.1 to 20,000] The ophthalmic composition involved in this embodiment contains at least one of the group consisting of chondroitin sulfate and its salts with a weight average molecular weight of 0.1 to 20,000 (also referred to as "(A) component").

[0015] There are no special restrictions on chondroitin sulfate and its salts as long as they are substances permitted in medicine, pharmacology (pharmaceutical manufacturing) or physiology.

[0016] Examples of chondroitin sulfate salts include alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts include sodium salts and potassium salts. Examples of alkaline earth metal salts include magnesium salts and calcium salts.

[0017] Chondroitin sulfate and its salts are preferred, chondroitin sulfate and its alkali metal salts are more preferred, chondroitin sulfate and sodium chondroitin sulfate are more preferred, and sodium chondroitin sulfate is even more preferred.

[0018] Chondroitin sulfate and its salts can be natural or synthetic products. Generally, chondroitin sulfate and its salts derived from animals (preferably mammals, fish, mollusks, etc.; more preferably cattle, sharks, squid, rays, etc.), fungi such as wood ear mushrooms, and algae such as seaweed are suitable natural products. Chondroitin sulfate and its salts derived from sharks and / or rays are even more suitable. In addition, chondroitin sulfate and its salts produced by fermentation using microorganisms such as lactic acid bacteria, Escherichia coli, and yeast are also suitable.

[0019] Chondroitin sulfate and its salts can also be commercially available substances. Chondroitin sulfate and its salts can be used alone or in combination of two or more. Furthermore, chondroitin sulfate and its salts can be used in combination with chondroitin sulfate and its salts with a weight-average molecular weight of 0.1 million to 20,000 as specified in this specification, and with chondroitin sulfate and its salts having a weight-average molecular weight outside the range specified in this specification. For example, sodium chondroitin sulfate with a weight-average molecular weight of 16,000 can be used in combination with sodium chondroitin sulfate with a weight-average molecular weight of 25,000. When using chondroitin sulfate and its salts with a weight-average molecular weight of 0.1 million to 20,000 as specified in this specification, and with chondroitin sulfate and its salts having a weight-average molecular weight outside the range specified in this specification, only chondroitin sulfate and its salts with a weight-average molecular weight of 0.1 million to 20,000 as a raw material is required.

[0020] In this specification, the "weight-average molecular weight" can be determined by gel permeation chromatography using a multi-angle light scattering detector (MALS detector) connected online to a differential refractive index detector (RI detector). Specifically, the following conditions are shown.

[0021] <Preparation of Standard Samples> The substance is obtained by adding 10 mL of 0.1 M sodium nitrate aqueous solution to 5 mg of chondroitin sulfate or its salt, and stirring slowly at room temperature until it is completely dissolved.

[0022] <Determination conditions for weight-average molecular weight> Apparatus: Gel permeation chromatography-multi-angle light scattering instrument Detector: Differential refractive index detector (Optilab rEX, manufactured by Wyatt Technology) Multi-angle light scattering detector (DAWN HELEOS, manufactured by Wyatt Technology) Columns: Shodex OHpak SB-806M HQ 2 ( 7.8mm x 30cm, Showa Denko (made in Japan) Solvent: 0.1M sodium nitrate aqueous solution Flow rate: 0.7 mL / min Column temperature: 23℃ Detector temperature: 23℃ Injection volume: 0.2 mL Data processing: Wyatt Technology's ASTRA data processing system. There are no particular restrictions on the weight-average molecular weight of chondroitin sulfate and its salts calculated by the above method, as long as they are in the range of 0.1 million to 20,000. Examples of lower limits for weight-average molecular weight include 0.1 million and above, 0.2 million and above, 0.5 million and above, 1.0 million and above, 1.1 million and above, 1.2 million and above, and 1.4 million and above. Examples of upper limits for weight-average molecular weight include below 20,000, below 1.95 million, below 1.9 million, below 1.8 million, below 1.7 million, below 1.5 million, below 1.4 million, and below 1.3 million. Examples of weight-average molecular weight ranges include 0.1 million to 20,000, 0.2 million to 1.95 million, 0.5 million to 1.9 million, 1.2 million to 1.8 million, and 1.4 million to 1.7 million. Additionally, a weight-average molecular weight range of 10,000 to 1.4 million is also possible.

[0023] The content of component (A) in the ophthalmic composition involved in this embodiment is not particularly limited, and can be appropriately set according to the type and content of other compounding components, the purpose of the ophthalmic composition, and the formulation. From the viewpoint of more significantly exerting the effects brought about by the present invention, based on the total amount of the ophthalmic composition, the content of component (A) is preferably, for example, 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. In addition, the content of component (A) can be 0.05 to 2 w / v%, 0.1 to 1 w / v%, 0.5 to 1 w / v, or 0.5 w / v% and 1 w / v.

[0024] [(B) Select at least one from the group consisting of water-soluble vitamins, amino acids and their salts] The ophthalmic composition described in this embodiment contains at least one selected from the group consisting of water-soluble vitamins, amino acids and their salts (also referred to as "(B) component"). There are no particular limitations on the water-soluble vitamins, amino acids or their salts, provided that they are pharmaceutically, pharmacologically (in pharmaceutical manufacturing) or physiologically permissible substances.

[0025] Examples of water-soluble vitamins include, for example, flavin adenine dinucleotide and its salts (such as sodium flavin adenine dinucleotide), cobalamin derivatives (such as cyanocobalamin and methylcobalamin), pantothenic acid and its salts (such as sodium pantothenate, potassium pantothenate, calcium pantothenate, and magnesium pantothenate), panthenol, pyridoxine or its salts (such as pyridoxine hydrochloride), pyridoxal and its salts (such as pyridoxal phosphate), and vitamin C, as well as ascorbic acid and its salts (such as sodium ascorbate). Among water-soluble vitamins, from the viewpoint of further enhancing the effects brought about by the present invention, B vitamins are preferred, panthenol, pyridoxine or its salts, flavin adenine dinucleotide or its salts, and cyanocobalamin are more preferred, and panthenol, pyridoxine or its salts are even more preferred.

[0026] As water-soluble vitamins, commercially available substances can also be used. Water-soluble vitamins can be used alone or in combination of two or more.

[0027] Examples of amino acids include, for example, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, glycine, alanine, γ-aminobutyric acid, γ-aminovaleric acid, trimethylglycine, ε-aminohexanoic acid, and aminoethylsulfonic acid (taurine). Examples of 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, ethanesulfonic acid, p-toluenesulfonic acid, etc.), salts with inorganic bases (e.g., alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, and ammonium salts), and salts with organic bases (e.g., salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, etc.). Commercially available substances can also be used for amino acids and their salts. The amino acid and its salt can be any of the L-form, D-form, and DL-form. From the viewpoint of further enhancing the effects brought about by the present invention, aspartic acid or its salt, ε-aminohexanoic acid, and aminoethylsulfonic acid are preferred, with aminoethylsulfonic acid being more preferred.

[0028] The content of component (B) in the ophthalmic composition according to this embodiment is not particularly limited, and can be appropriately set according to the type of component (B), the type and content of other compounding components, the formulation, etc. As for the content of component (B), from the viewpoint of more significantly exerting the effects brought about by the present invention, for example, based on the total amount of the ophthalmic composition according to this embodiment, the total content of component (B) is 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. Alternatively, the total content of component (B) can be 0.005 to 1 w / v% or 0.01 to 0.1 w / v.

[0029] The content ratio of component (B) relative to component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and can be appropriately set according to the types of components (A) and (B), the types and contents of other compounding components, the purpose of the ophthalmic composition, and the formulation. From the viewpoint of further improving the effects brought about by the present invention, the total content of component (B) relative to component (A) 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, relative to 1 part by mass of component (A) in the ophthalmic composition according to this embodiment. Furthermore, the total content of component (B) relative to 1 part by mass of component (A) can 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.

[0030] (B) In the case where the component is a water-soluble vitamin, from the viewpoint of more significantly exerting the effects brought about by the present invention, for example, based on the total amount of the ophthalmic composition according to this embodiment, the total content of water-soluble vitamins 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. Furthermore, in the case where (B) the component is a water-soluble vitamin, the total content of water-soluble vitamins can be 0.01 to 0.1 w / v.

[0031] When component (B) is a water-soluble vitamin, from the viewpoint of further improving the effects brought about by the present invention, the total content of water-soluble vitamins relative to component (A) is 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, relative to 1 part by mass of component (A) contained in the ophthalmic composition according to this embodiment. Furthermore, when component (B) is a water-soluble vitamin, the total content of water-soluble vitamins relative to 1 part by mass of component (A) can 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.

[0032] (B) In the case of amino acids and their salts, from the viewpoint of more significantly exerting the effects brought about by the present invention, for example, based on the total amount of the ophthalmic composition according to this embodiment, the total content of amino acids and their salts 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. Furthermore, in the case of (B) in the case of amino acids and their salts, the total content of amino acids and their salts can be 0.1 to 2 w / v% or 0.2 to 1 w / v. Further, in the case of (B) in the case of aminoethylsulfonic acid, the content of aminoethylsulfonic acid is preferably 0.1 to 1 w / v.

[0033] When component (B) is an amino acid or its salt, from the viewpoint of further improving the effects brought about by the present invention, the total content of amino acids and their salts relative to component (A) 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, relative to 1 part by mass of the total content of component (A) in the ophthalmic composition according to this embodiment. Furthermore, when component (B) is an amino acid or its salt, the total content of amino acids and their salts relative to 1 part by mass of the total content of component (A) can 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.

[0034] [Buffer] The ophthalmic composition according to this embodiment preferably also contains a buffer. By including a buffer in the ophthalmic composition, the effects of the present invention are more significantly achieved. There are no particular limitations on the buffer as long as it is a pharmaceutically, pharmacologically (in pharmaceutical manufacturing), or physiologically permissible substance. Examples of buffers include, for instance, buffers derived from inorganic acids, i.e., inorganic buffers, and buffers derived from organic acids or organic bases, i.e., organic buffers.

[0035] Examples of inorganic buffers include borate buffers, phosphate buffers, and carbonate buffers. Examples of borate buffers include boric acid or its salts (alkali metal borate salts, alkaline earth metal borate salts, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphate salts, alkaline earth metal phosphate salts, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonate salts, alkaline earth metal carbonate salts, etc.). Additionally, hydrates of borates, phosphates, or carbonates can be used as borate buffers, phosphate buffers, or carbonate buffers. For more specific examples, examples of boric acid buffers include boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); examples of phosphate buffers include phosphate or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, etc.); examples of carbonate buffers include carbonate or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.).

[0036] Examples of organic buffers include citric acid buffers, acetate buffers, lactic acid buffers, succinic acid buffers, Tris buffers, and AMPD buffers. Examples of citric acid buffers include citric acid or its salts (alkali metal citrate salts, alkaline earth metal citrate salts, etc.). Examples of acetate buffers include acetic acid or its salts (alkali metal acetate salts, alkaline earth metal acetate salts, etc.). Examples of lactic acid buffers include lactic acid or its salts (alkali metal lactate salts, alkaline earth metal lactate salts, etc.). Examples of succinic acid buffers include succinic acid or its salts (alkali metal succinic acid salts, etc.). Furthermore, hydrates of citrate, acetate, lactate, or succinate can be used as citric acid buffers, acetate buffers, lactate buffers, or succinic acid buffers. For more specific examples, examples of citric acid buffers include citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); examples of acetic acid buffers include acetic acid or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.); examples of lactic acid buffers include lactic acid or its salts (sodium lactate, potassium lactate, calcium lactate, etc.); examples of succinic acid buffers include succinic acid or its salts (monosodium succinate, disodium succinate, etc.); examples of Tris buffers include, for example, tromethamine or its salts (tromethamine hydrochloride, etc.); and examples of AMPD buffers include, for example, 2-amino-2-methyl-1,3-propanediol or its salts.

[0037] As a buffer, boric acid buffers (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.

[0038] Buffers can be commercially available substances. Buffers can be used alone or in combination of two or more.

[0039] The content of the buffer in the ophthalmic composition involved in this embodiment is not particularly limited, and can be appropriately set according to the type of buffer, the type and content of other compounding ingredients, the purpose of the ophthalmic composition, and the formulation. As for the content of the buffer, from the viewpoint of more significantly exerting the effects brought about by the present invention, for example, based on the total amount of the ophthalmic composition, the total content of the buffer is 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.

[0040] The content ratio of the buffer relative to component (A) in the ophthalmic composition according to this embodiment is not particularly limited, and can be appropriately set according to the type of component (A) and buffer, the type and content of other compounding components, the purpose of the ophthalmic composition, and the formulation. As for the content ratio of the buffer relative to component (A), from the viewpoint of further improving the effects brought about by the present invention, for example, the total content of the buffer is preferably 0.01 to 4000 parts by mass relative to 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to this embodiment, more preferably 0.05 to 3000 parts by mass, and even more preferably 0.1 to 2000 parts by mass.

[0041] The pH of the ophthalmic composition involved in this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical), or physiologically permissible range. For example, the pH of the ophthalmic composition involved in this embodiment can be 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, further preferably 4.5 to 8.5, even more preferably 5.0 to 8.5, and particularly preferably 5.0 to 8.0.

[0042] The ophthalmic composition described in this embodiment can be adjusted to an osmotic pressure ratio within a range permissible by the organism as needed. An appropriate osmotic pressure ratio can be set according to the intended use, formulation, and method of application of the ophthalmic composition. For example, it can be set to 0.4–5.0, preferably 0.6–3.0, more preferably 0.8–2.2, and even more preferably 0.8–2.0. The osmotic pressure ratio is based on the 17th revision of the Japanese Pharmacopoeia and is defined as 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). The osmotic pressure is determined with reference to the osmotic pressure determination method (freezing point depression method) described in the Japanese Pharmacopoeia. It should be noted that, regarding the standard solution (0.9 w / v% sodium chloride aqueous solution) for osmotic pressure ratio determination, sodium chloride (Japanese Pharmacopoeia standard reagent) can be dried at 500-650°C for 40-50 minutes, then cooled in a desiccator (silica gel). Accurately weigh 0.900 g of the sodium chloride and dissolve it in purified water to prepare 100 mL. Alternatively, commercially available standard solution (0.9 w / v% sodium chloride aqueous solution) for osmotic pressure ratio determination can be used.

[0043] The viscosity of the ophthalmic composition involved in this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical), or physiologically permissible range. For example, the viscosity of the ophthalmic composition involved in this embodiment, measured using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1°34'×R24) at 20°C, 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.

[0044] Regarding the ophthalmic composition involved in this embodiment, in addition to the above-described components, it is also possible to combine components selected from various pharmacologically and physiologically active ingredients, provided that the effects of the present invention are not impaired. There are no particular limitations on these components; for example, active ingredients in ophthalmic medications listed in the 2017 edition of the General Pharmaceutical Manufacturing and Sales Approval Standards (supervised by the General Incorporated Organization Law and Scientific Society) can be cited. Specifically, as components used in ophthalmic medications, examples include the following.

[0045] Antihistamines: such as sodium cromoglycate, tranilast, pyrimilast potassium, azastarst, ammoniazanol, isobetastarst, etc.

[0046] Antihistamines: such as chlorpheniramine or its salts (e.g., chlorpheniramine maleate), diphenhydramine or its salts (e.g., diphenhydramine hydrochloride), isoproheptadine or its salts (e.g., isoproheptadine hydrochloride), levocabastine or its salts (e.g., levocabastine hydrochloride), ketotifen or its salts (e.g., ketotifen fumarate), pirimethasone potassium, olopatadine or its salts (e.g., olopatadine hydrochloride), etc.

[0047] Anti-inflammatory agents: such as methyl salicylate, ethylene salicylate, allantoin, tranexamic acid, lysozyme, chlorinated lysozyme, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, biphenylacetic acid, benzalkonium chloride, piroxicam, butyl hydrochloride, butyl flufenamic acid, ε-aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, glycyrrhizic acid or its salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate), etc.

[0048] Steroid agents: such as fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisulfanilamide, etc.

[0049] Decongestants: such as tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, adrenaline, adrenaline hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.

[0050] Ocular muscle modulatory agents: For example, cholinesterase inhibitors with an active center similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride, etc.

[0051] Fat-soluble vitamins: such as retinyl acetate, retinyl palmitate, tocopheryl acetate, etc.

[0052] Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and their salts.

[0053] In the ophthalmic composition involved in this embodiment, various additives can be appropriately selected according to their use and formulation form using conventional methods, as long as they do not impair the effects of the present invention. Furthermore, one or more additives can be used together in appropriate amounts. Examples of such additives include those described in the Pharmaceutical Additives Encyclopedia 2016 (compiled by the Japan Pharmaceutical Additives Association). The following additives are representative examples.

[0054] Carrier: For example, water, aqueous solvents such as water and aqueous ethanol.

[0055] Chelating agents: such as ethylenediamine diacetic acid (EDDA), ethylenediamine triacetic acid, ethylenediamine tetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediamine triacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc.

[0056] Base agents: for example, octyldodecyl alcohol, titanium dioxide, potassium bromide, Plastibase, etc.

[0057] pH adjusters: such as hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, etc.

[0058] Thickeners include: cellulose-based polymers such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose; polyethylene-based polymers such as polyvinylpyrrolidone and polyvinyl alcohol; carboxyvinyl polymers; guar gum; hydroxypropyl guar gum; gum arabic; ebony gum; xanthan gum; agar; alginic acid and its salts (sodium salts, etc.); heparin analogs, heparin, heparin sulfate, heparan sulfate, heparin-like substances, hyaluronic acid and its salts (sodium salts, etc.) and other mucopolysaccharides; starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; glucose and other monosaccharides, etc.

[0059] Stabilizers: such as edema, edema salts (disodium edema, calcium disodium edema, trisodium edema, tetrasodium edema), sodium formaldehyde sulfoxylate (sodium formaldehyde sulfoxylate), aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine, butylated hydroxytoluene, sodium bisulfite, sodium metabisulfite, etc.

[0060] Preservatives: For example, alkyl polyaminoethyl glycine quaternary ammonium salts (e.g., benzalkonium chloride, benzyl chloride, etc.), chlorhexidine gluconate, polidocanol, zinc chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methylparaben, ethylparaben, propylparaben, butylparaben, hydroxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide hydrochloride, alexidine, etc.), Glokill (a trade name manufactured by Rhodia), etc.

[0061] Isotonic agents: such as potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerol, propylene glycol, sodium bisulfite, sodium sulfite, etc.

[0062] Sugar alcohols: such as xylitol, sorbitol, mannitol, glycerol, etc. They can be any of the d-form, l-form, or dl-form.

[0063] From the perspective of maximizing the effects brought about by the present invention, the ophthalmic composition involved in 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 nonionic surfactants. Examples of nonionic surfactants include, for example: POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65), POE (20) sorbitan monooleate (polysorbate 80), and other POE sorbitan fatty acid esters; poloxamer 407, poloxamer 235, etc. POE·POP diols such as Loxam 188, Poloxamer 403, 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; and POE castor oils 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, and POE castor oil 2. 5. POE castor oil 30, POE castor oil 35, POE castor oil 50, etc.; POE castor oil; POE monostearate (2E.O.), POE monostearate (4E.O.), POE monostearate (9E.O.), POE monostearate (10E.O.), POE monostearate (23E.O.), POE monostearate (25E.O.), POE monostearate (32E.O.), POE monostearate (40E.O.), etc. E.O. (poly(alkyl) stearate 40), polyethylene monostearate (45E.O.), polyethylene monostearate (55E.O.), polyethylene monostearate (75E.O.), polyethylene monostearate (140E.O.), etc.; POE (9) lauryl ether, etc.; POE-POP alkyl ethers such as POE (20) POP (4) hexadecyl ether, etc.; POE (10) nonylphenyl ether, etc., etc. It should be noted that in the compounds in the above examples, POE represents polyethylene oxide, POP represents polypropylene oxide, and the numbers in parentheses represent the number of moles added.

[0064] From the viewpoint of maximizing the effects brought about by the present invention, the ophthalmic composition according to this embodiment preferably does not contain terpenes. Examples of terpenes include menthol, camphene, borneol, and geraniol.

[0065] When the ophthalmic composition according to this embodiment contains water, from the viewpoint of more significantly exerting the effects brought about by the present invention, the water content is 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.

[0066] The water used in the ophthalmic composition according to this embodiment can be pharmaceutically, pharmacologically (in pharmaceutical manufacturing), or physiologically permissible. Examples of such water include distilled water, everyday water, purified water, sterile purified water, water for injection, and distilled water for injection. Their definitions are based on the 17th revision of the Japanese Pharmacopoeia.

[0067] 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 needed at the desired concentration. For example, these components can be dissolved or dispersed in purified water, adjusted to a specified pH and osmotic pressure, and sterilized by filtration sterilization, etc.

[0068] The ophthalmic composition described in this embodiment can be used in various formulations depending on the purpose. Examples of formulations include liquids, gels, and semi-solids (ointments, etc.).

[0069] The ophthalmic compositions described in this embodiment can be used, for example, as eye drops (also known as eye solutions or eye medications; eye drops include those that can be instilled while wearing contact lenses), artificial tears, eye washes (also known as eye washes or eye medications; eye washes include those that can be used to wash the eyes while wearing contact lenses), and contact lens compositions [contact lens lubricants, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens cleaning and preservatives), contact lens packaging solutions, etc.]. It should be noted that "contact lenses" include rigid contact lenses and soft contact lenses (including both ionic and non-ionic lenses, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0070] From the viewpoint of being able to more significantly exert the effects brought about by the present invention, the ophthalmic composition according to this embodiment is preferably an eye drop (including an eye drop that can be instilled while wearing contact lenses). When the ophthalmic composition according to this embodiment is an eye drop, there are no particular limitations on its usage and dosage, as long as it is effective and has few side effects. For example, in the case of adults (15 years and older) and children 7 years and older, the following method can be used: instilling 2 to 4 or 5 to 6 times a day, and using 1 to 3 drops, 1 to 2 drops or 2 to 3 drops each time.

[0071] The ophthalmic composition according to this embodiment is provided in any container. There are no particular limitations on the container for containing the ophthalmic composition according to this embodiment; for example, it can be made of glass or plastic. Plastic is preferred. Examples of plastics include polyethylene terephthalate (PET), polyarylate (PAR), polyethylene naphthalate (PEN), polycarbonate (PC), polyethylene (PE), polypropylene (PP), polyimide (PI), cyclic olefin copolymers (COC) and copolymers of their monomers, as well as substances composed of two or more of these. Polyethylene terephthalate (PET) is preferred. Furthermore, the container for containing the ophthalmic composition according to this embodiment can be a transparent container that allows observation of the interior, or an opaque container that makes observation of the interior difficult. A transparent container is preferred. Here, "transparent container" includes both colorless transparent containers and colored transparent containers.

[0072] The nozzle can also be mounted on the container holding the ophthalmic composition according to this embodiment. There are no particular limitations on the material of the nozzle; for example, it can be made of glass or plastic. Plastic is preferred. Examples of plastics include polybutylene terephthalate (PBT), polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), copolymers of their monomers, and mixtures of two or more thereof. From the viewpoint of further improving the effects of the present invention, polypropylene (PP), polyethylene (PE), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), and polyethylene naphthalate (PEN) are preferred as the nozzle material, and polyethylene (PE) is more preferred.

[0073] The container for containing the ophthalmic composition according to this embodiment can be a multi-dose type containing multiple uses or a single-dose type containing a single use.

[0074] The ophthalmic composition according to this embodiment is preferably filled into a container with an internal volume of 4 to 30 mL, more preferably into a container with an internal volume of 5 to 20 mL, even more preferably into a container with an internal volume of 10 to 18 mL, and even more preferably into a container with an internal volume of 15 to 18 mL. Alternatively, it can be filled into a container with an internal volume of 0.1 to 3 mL, or into a container with an internal volume of 0.2 to 1 mL.

[0075] Regarding the ophthalmic composition involved in this embodiment, as shown in the examples described later, since it contains sodium chondroitin sulfate with a weight-average molecular weight of 0.1 to 20,000 and has the effect of significantly reducing the elastic modulus of soft contact lenses, it is preferably an ophthalmic composition for soft contact lenses. If the elastic modulus of soft contact lenses is reduced, the soft contact lenses become softer, thereby more effectively reducing the foreign body sensation, stiffness, and discomfort caused by poor usability during wearing and / or insertion of soft contact lenses. In addition, as an embodiment of the present invention, a method for imparting the effect of reducing the elastic modulus of soft contact lenses to an ophthalmic composition is provided, the method comprising: adding (B) at least one of the group consisting of (A) chondroitin sulfate and its salts selected from the group consisting of 0.1 to 20,000 weight-average molecular weight.

[0076] In the above embodiments, the percentage reduction in the elastic modulus of the soft contact lens (hereinafter also referred to as the "reduction rate of elastic modulus") is not particularly limited, but preferably the reduction rate of the elastic modulus of the soft contact lens is 10% to 50%. Here, the reduction rate of the elastic modulus of the soft contact lens in this embodiment is calculated by the following formula. It should be noted that, in this specification, the "elastic modulus of the soft contact lens" refers to the value measured using an MCR302 rheometer manufactured by AntonPaar and using parallel plates PP12 / P12.

[0077] [Formula] Reduction rate of elastic modulus (%) = Elastic modulus of the comparison composition (Pa) - Elastic modulus of the formulation involved in this embodiment (Pa) / Elastic modulus of the comparison composition (Pa) × 100 Here, the comparative composition refers to a composition that has the same composition as the ophthalmic composition involved in this embodiment, except that it does not contain at least one of the group consisting of (B) water-soluble vitamins, amino acids and their salts.

[0078] Example The present invention will now be described in detail based on experimental examples, but the present invention is not limited thereto.

[0079] [Preparation of the test solution] The test solutions shown in Table 1 were prepared according to standard methods. It should be noted that the units for each component in Table 1 are g / 100 mL. Additionally, the sodium chondroitin sulfate used in the following test examples is described below.

[0080] Sodium chondroitin sulfate Weight-average molecular weight approximately 16,000: MARUHA NICHIRO Co., Ltd.: Chondroitin Sulfate Sodium (Japanese Pharmacopoeia Non-Pharmaceutical Standard) [Experimental Example 1: Evaluation of Changes in Elastic Modulus] 4 mL of physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) was dispensed into each well of a 12-well plate (BD Falcon, No. 35-3043). One contact lens (PRECISION 1: manufactured by ALCON) was placed in each well and incubated at room temperature for at least 4 hours. 4 mL of each of the test solutions listed in Table 1, prepared as described above, was dispensed into another 12-well plate (BD Falcon, No. 35-3043). One contact lens, gently wiped dry with lint-free paper, was placed in each well and incubated at 34°C for 24 hours.

[0081] An MCR302 rheometer (Anton Paar) was used, set to: parallel plates PP12 / P12 (12mm diameter, meshed; 1×0.5, part number: 23935), cover plate P-PTD200 / 80-77 / SS / P2 (meshed, part number: 7894), measurement temperature 20℃, frequency 1Hz, and measurement time "no time setting" mode. Shear stress (Pa) was measured relative to a corresponding variable of 0.01–1%. Specifically, 0.5 mL of physiological saline was added to the cover plate, and the convex side of a contact lens (with the convex side of the lens facing the cover plate) was placed on it. 0.5 mL of physiological saline was then added to the contact lens. The parallel plates were lowered close to the cover plate, and the contact lens was positioned with a distance of 0.1 mm between the two plates. The shear stress (Pa) measurement began. Regarding the measurement intervals, measurements were taken equally at 5 points for the dependent variable ranging from 0.01% to 0.1%, and equally at 5 points for the dependent variable ranging from 0.1% to 1%. The elastic modulus (Pa) was calculated by using the second point (0.0325%) of the measurement interval for the dependent variable ranging from 0.01% to 0.1% and 1% of the measurement interval for the dependent variable ranging from 0.1% to 1% [Equation 1]. The measurements were performed three times, and the average value was taken as the average elastic modulus (Pa).

[0082] [Equation 1] Elastic modulus (Pa) = Shear stress / Strain = (Shear stress of 1% strain) - (Shear stress of 0.0325% strain) / (1 - 0.0325) Using the average elastic modulus (Pa) in Examples 1 to 3, the rate of decrease in elastic modulus (%) relative to the corresponding reference example is calculated according to [Equation 2].

[0083] [Equation 2] The rate of decrease in elastic modulus relative to the corresponding reference example (%) = Average elastic modulus of the corresponding reference example (Pa) - Average elastic modulus of the embodiment (Pa) / Average elastic modulus of the corresponding reference example (Pa) × 100 The reference example corresponding to Examples 1 to 3 is Reference Example 1.

[0084] [Table 1] Examples 1-3, containing sodium chondroitin sulfate with a weight-average molecular weight of 16,000 and water-soluble vitamins or amino acids, showed a decrease in the elastic modulus of soft contact lenses of 16.6-31.9% compared to Reference Example 1, which did not contain water-soluble vitamins or amino acids. This demonstrates that in ophthalmic compositions containing sodium chondroitin sulfate with a weight-average molecular weight of 1,000-20,000, water-soluble vitamins or amino acids have the effect of softening hardened soft contact lenses.

[0085] [Formulation Example] Formulation Examples 1-16 were prepared using the formulations described in Tables 2 and 3 below. Formulation Examples 1-16 were filled into containers made of polyethylene terephthalate and nozzles made of low-density polyethylene were installed, thereby producing Formulation Examples 1-16. Formulation Examples 1-16 were filled into containers made of polyethylene terephthalate and nozzles were installed, wherein the entire wall surface of the nozzle that may come into contact with the contents when the lid is installed (during storage) is made of polyethylene terephthalate, thereby producing Formulation Examples 17-32. Formulation Examples 1-16 were filled into containers made of polyethylene terephthalate and nozzles were installed, wherein a portion of the wall surface that may come into contact with the contents is made of polyethylene terephthalate, thereby producing Formulation Examples 33-48.

[0086] It should be noted that, unless otherwise specified, all units in the table are w / v.

[0087] [Table 2] [Table 3]

Claims

1. An ophthalmic composition comprising: (A) at least one of chondroitin sulfate and its salts selected from the group consisting of chondroitin sulfate and its salts having a weight average molecular weight of 0.1 to 20,000; and (B) at least one of the group consisting of water-soluble vitamins, amino acids and their salts.

2. The ophthalmic composition of claim 1, wherein, (A) The content of the ingredient is 0.001 to 1 w / v based on the total amount of the ophthalmic composition.

3. The ophthalmic composition of claim 1, wherein it does not contain a nonionic surfactant.

4. The ophthalmic composition of claim 1, for use in soft contact lenses.

Images