JP2019142855A - Eye drop - Google Patents

Abstract

To provide an eye drop having enhanced preservation efficacy.SOLUTION: An eye drop contains at least one selected from the group consisting of (A) alexidine and a salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to eye drops.

  Eye drops (especially multi-dose type eye drops) are supposed to be used over a period of time after the eye drop container is opened. Once the container is opened, air or contacted mucous membranes are used. There is a high possibility of causing microbial contamination of eye drops from skin and the like. For this reason, eye drops are required to have a storage effect of a certain level or more from the viewpoint of preventing the product from being spoiled due to microbial contamination or the like and achieving storage stability (for example, Patent Documents 1 and 2).

JP 2013-82751 A JP-A-10-109930

  An object of the present invention is to provide an eye drop with enhanced storage efficacy.

  The present inventors have found that the preservative efficacy of the eye drops can be enhanced by blending at least one selected from the group consisting of (A) alexidine and a salt thereof into the eye drops. The present invention is based on this novel finding.

The present invention provides the following inventions, for example.
[1]
(A) An eye drop containing at least one selected from the group consisting of alexidine and a salt thereof.
[2]
(B) The eye drop according to [1], further containing at least one selected from the group consisting of acidic saccharides and cellulose polymer compounds.
[3]
The eye drop according to [2], wherein the acidic saccharide is at least one selected from the group consisting of glycyrrhizic acid, hyaluronic acid, chondroitin sulfate, and salts thereof.
[4]
The eye drop according to [2] or [3], wherein the cellulosic polymer compound is at least one selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof.
[5]
The eye drop according to any one of [1] to [4], which has a pH of 5.5 to 8.0.
[6]
The eye drop according to any one of [1] to [5], which is used for eye drops while wearing a soft contact lens.
[7]
(A) The content of at least one selected from the group consisting of alexidine and a salt thereof is 0.000001 to 0.05 w / v% based on the total amount of eye drops [1] to [6] Ophthalmic solution according to any of the above.
[8]
A method for enhancing the preservative effect of the eye drop, comprising blending the eye drop with (A) at least one selected from the group consisting of alexidine and a salt thereof.
[9]
(A) An eye drop preservative containing at least one selected from the group consisting of alexidine and salts thereof.

  According to the present invention, it is possible to provide an eye drop with enhanced preservation efficacy.

  Hereinafter, embodiments for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

[1. Eye drops]
The eye drop according to the present embodiment contains at least one (also referred to as “component (A)”) selected from the group consisting of (A) alexidine and a salt thereof.

[Component (A)]
The component (A) alexidine and its salt are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Alexidine is a known compound also referred to as 1,1'-hexamethylene-bis- [5- (2-ethylhexyl) biguanide].

  Examples of alexidine salts include inorganic acid salts, organic acid salts, and sulfonate salts. Examples of the inorganic acid salt include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, phosphoric acid and nitric acid. Examples of the organic acid salt include salts with acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid and citric acid. Examples of the sulfonate include salts with methanesulfonic acid, isethionic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

  Specific examples of alexidine and salts thereof include, for example, alexidine and alexidine dihydrochloride. From the viewpoint of further enhancing the effects of the present invention, alexidine and its salt are preferably alexidine and an inorganic acid salt of alexidine, more preferably an inorganic acid salt of alexidine, more preferably a hydrochloride salt of alexidine, and alexidine dihydrochloride. Is particularly preferred.

  Commercially available alexidine and its salts can also be used. Alexidine and its salt may be used individually by 1 type, or may be used in combination of 2 or more type.

  From the viewpoint of further enhancing the effects of the present invention, the content of the component (A) in the eye drop according to the present embodiment is, for example, the total content of the component (A) is 0.00 on the basis of the total amount of the eye drop. It is preferably 000001 to 0.05 w / v%, more preferably 0.000005 to 0.005 w / v%, still more preferably 0.00001 to 0.0005 w / v%, and Even more preferably, it is 00005 to 0.0002 w / v%.

[(B) component]
The eye drop according to the present embodiment may further contain at least one selected from the group consisting of (B) an acidic saccharide and a cellulose polymer compound (also referred to as “component (B)”). Thereby, the effect by this invention can be heightened more. The acidic saccharide and cellulose-based polymer compound as component (B) are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  The acidic saccharide is not particularly limited as long as it is a compound having a sugar skeleton and an acidic group such as a carboxyl group or a sulfo group in the molecule. Specific examples of the acidic saccharide include, for example, glycyrrhizic acid and salts thereof; heparin, heparan sulfate, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, glycosaminoglycan and other mucopolysaccharides, and salts thereof. A compound having a sugar skeleton and an acidic group having a weight average molecular weight of 600 or more (preferably 700 or more, more preferably 800 or more) can also be used as the acidic saccharide. As the acidic saccharide, glycyrrhizic acid, hyaluronic acid, chondroitin sulfate and salts thereof are preferable from the viewpoint of further enhancing the effects of the present invention.

  Examples of the salt of glycyrrhizic acid include alkali metal salts, alkaline earth metal salts, and ammonium salts. Examples of the alkali metal salt include sodium salt and potassium salt. Examples of the alkaline earth metal salt include a magnesium salt and a calcium salt.

  As the glycyrrhizic acid and its salt, from the viewpoint of further enhancing the effect of the present invention, glycyrrhizic acid, an alkali metal salt of glycyrrhizic acid and an ammonium salt of glycyrrhizic acid are preferred, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate are more preferred, More preferred is dipotassium glycyrrhizinate.

  Examples of the salt of hyaluronic acid include alkali metal salts and alkaline earth metal salts. Examples of the alkali metal salt include sodium salt and potassium salt. Examples of the alkaline earth metal salt include a magnesium salt and a calcium salt.

  As the hyaluronic acid and its salt, hyaluronic acid and an alkali metal salt of hyaluronic acid are preferable, hyaluronic acid and sodium hyaluronate are more preferable, and sodium hyaluronate is still more preferable from the viewpoint of further enhancing the effects of the present invention.

  Examples of the chondroitin sulfate salt include alkali metal salts and alkaline earth metal salts. Examples of the alkali metal salt include sodium salt and potassium salt. Examples of the alkaline earth metal salt include a magnesium salt and a calcium salt.

  As a chondroitin sulfate and a salt thereof, chondroitin sulfate and an alkali metal salt of chondroitin sulfate are preferable, chondroitin sulfate and sodium chondroitin sulfate are more preferable, and sodium chondroitin sulfate is more preferable from the viewpoint of further enhancing the effect of the present invention.

  Commercially available acid saccharides can also be used. An acidic saccharide may be used individually by 1 type, or may be used in combination of 2 or more type.

  As the cellulose-based polymer compound, cellulose and a compound in which the hydroxyl group of cellulose is substituted with another functional group can be used. Examples of the functional group that substitutes the hydroxyl group of cellulose include a methoxy group, an ethoxy group, a hydroxymethoxy group, a hydroxyethoxy group, a hydroxypropoxy group, a carboxymethoxy group, and a carboxyethoxy group. Specific examples of the cellulose-based polymer compound include, for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose, and carboxy from the viewpoint of further enhancing the effects of the present invention. Examples include ethyl cellulose and salts thereof. As the cellulose polymer compound, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof are preferable, and hydroxyethylcellulose, hydroxypropylmethylcellulose and salts thereof are more preferable.

  A commercially available cellulose-based polymer compound can also be used. A cellulose polymer compound may be used individually by 1 type, or may be used in combination of 2 or more type.

  As the component (B), one type may be used alone, or two or more types may be used in combination.

  Content of (B) component in the eye drop which concerns on this embodiment is not specifically limited, According to the kind of (B) component, the kind and content of another compounding component, the use, formulation form, etc. of eye drop Is set. As a content of (B) component, from the viewpoint of further enhancing the effect of the present invention, for example, based on the total amount of eye drops, the total content of (B) component is 0.0001 to 12 w / v%. Preferably, it is 0.001-2.5 w / v%, more preferably 0.01-1.2 w / v%, still more preferably 0.1-1 w / v%. Is even more preferred.

  When the acidic saccharide is used as the component (B), the content of the acidic saccharide is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the acidic saccharide is 0 on the basis of the total amount of eye drops. It is preferably 0.0001 to 5 w / v%, more preferably 0.001 to 3 w / v%, still more preferably 0.01 to 2 w / v%, and 0.1 to 0.85 w. Even more preferred is / v%.

  (B) When using glycyrrhizic acid and its salt as a component, as content of glycyrrhizic acid and its salt, from the viewpoint of further enhancing the effect of the present invention, for example, based on the total amount of eye drops, glycyrrhizic acid and The total salt content is preferably 0.001 to 2 w / v%, more preferably 0.01 to 1 w / v%, and 0.05 to 0.5 w / v%. Is still more preferable, and it is still more preferable that it is 0.1-0.25 w / v%.

  In the case of using hyaluronic acid and a salt thereof as the component (B), the content of hyaluronic acid and the salt thereof is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, based on the total amount of eye drops, The total salt content is preferably 0.0001 to 1 w / v%, more preferably 0.001 to 0.5 w / v%, and 0.005 to 0.3 w / v%. More preferably, it is 0.01 to 0.1 w / v%.

  In the case of using chondroitin sulfate and a salt thereof as the component (B), the content of chondroitin sulfate and the salt thereof is, for example, based on the total amount of eye drops, from the viewpoint of further enhancing the effect of the present invention. The total salt content is preferably 0.01 to 6 w / v%, more preferably 0.05 to 5 w / v%, and further preferably 0.1 to 4 w / v%. It is preferably 0.25 to 3 w / v%, more preferably 0.5 to 1 w / v%.

  In the case of using a cellulose-based polymer compound as the component (B), the content of the cellulose-based polymer compound is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, based on the total amount of eye drops, The total content of the molecular compounds is preferably 0.001 to 3 w / v%, more preferably 0.005 to 1 w / v%, and 0.01 to 0.6 w / v%. Is still more preferable, and it is still more preferable that it is 0.05-0.3 w / v%.

  In the eye drop according to the present embodiment, the content ratio of the component (B) to the component (A) is not particularly limited, the types of the components (A) and (B), the types and contents of other compounding components, and eye drops. It is appropriately set according to the use of the agent and the form of preparation. The content ratio of the component (B) to the component (A) is, for example, from the viewpoint of further enhancing the effect of the present invention, for example, to 1 part by mass of the total content of the component (A) contained in the eye drop according to the present embodiment. On the other hand, the total content of the component (B) is preferably 200 to 50000 parts by mass, more preferably 1000 to 24000 parts by mass, and still more preferably 2000 to 12000 parts by mass.

  When using acidic saccharides as the component (B), from the viewpoint of further enhancing the effect of the present invention, for example, with respect to 1 part by mass of the total content of the component (A) contained in the eye drop according to the present embodiment, The total content of acidic saccharides is preferably 100 to 40000 parts by mass, more preferably 200 to 20000 parts by mass, and still more preferably 1000 to 10,000 parts by mass.

  (B) When using glycyrrhizic acid and a salt thereof as the component, from the viewpoint of further enhancing the effects of the present invention, for example, the total content of the component (A) contained in the eye drop according to this embodiment is 1 part by mass. On the other hand, the total content of glycyrrhizic acid and salts thereof is preferably 500 to 10000 parts by mass, more preferably 1000 to 5000 parts by mass, and still more preferably 1500 to 2500 parts by mass.

  When using hyaluronic acid and its salt as the component (B), from the viewpoint of further enhancing the effects of the present invention, for example, the total content of the component (A) contained in the eye drop according to the present embodiment is 1 part by mass. On the other hand, the total content of hyaluronic acid and salts thereof is preferably 1 to 2000 parts by mass, more preferably 2.5 to 1500 parts by mass, and still more preferably 5 to 1250 parts by mass. .

  When using chondroitin sulfate and a salt thereof as the component (B), from the viewpoint of further enhancing the effects of the present invention, for example, the total content of the component (A) contained in the eye drop according to the present embodiment is 1 part by mass. On the other hand, the total content of chondroitin sulfate and salts thereof is preferably 300 to 60000 parts by mass, more preferably 500 to 50000 parts by mass, and still more preferably 1000 to 40000 parts by mass.

  In the case of using a cellulose-based polymer compound as the component (B), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of the component (A) contained in the eye drop according to the present embodiment is 1 part by mass. On the other hand, the total content of the cellulose-based polymer compound is preferably 200 to 5000 parts by mass, more preferably 500 to 4000 parts by mass, and still more preferably 1000 to 2500 parts by mass.

  The eye drops according to this embodiment may further contain amino acids. Thereby, the effect by this invention can be heightened more. The amino acids are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

  Examples of amino acids include amino acids and salts thereof, and amino acid derivatives and salts thereof. Specific examples of amino acids and salts thereof include, for example, monoamino monocarboxylic acids such as glycine, alanine, aminobutyric acid and aminovaleric acid, monoaminodicarboxylic acids such as aspartic acid and glutamic acid, diamino such as arginine and lysine. Examples thereof include monocarboxylic acids and salts thereof. Specific examples of amino acid derivatives and salts thereof include amino acid derivatives such as aminoethylsulfonic acid (taurine) and salts thereof. Amino acids may be any of D-form, L-form, and DL-form. As the amino acids, from the viewpoint of further enhancing the effects of the present invention, aspartic acid and salts thereof, and aminoethylsulfonic acid are preferable, and aminoethylsulfonic acid is more preferable.

  Commercially available amino acids can also be used. Amino acids may be used alone or in combination of two or more.

  The content of amino acids in the eye drop according to this embodiment is not particularly limited, and is appropriately set according to the type of amino acid, the type and content of other compounding components, the use of the eye drop, the formulation form, and the like. As the content of amino acids, from the viewpoint of further enhancing the effect of the present invention, for example, based on the total amount of eye drops, the total content of amino acids is preferably 0.01 to 5 w / v%, It is more preferably 0.05 to 3 w / v%, still more preferably 0.1 to 2 w / v%, and still more preferably 0.5 to 1 w / v%.

  In the eyedrops according to this embodiment, the content ratio of amino acids to the component (A) is not particularly limited, and the types of (A) component and amino acids, the types and contents of other compounding components, the use of the eyedrops, and It is appropriately set according to the formulation form. As the content ratio of amino acids to the component (A), from the viewpoint of further enhancing the effect of the present invention, for example, with respect to 1 part by mass of the total content of the component (A) contained in the eye drop according to the present embodiment, The total content of amino acids is preferably 2000 to 40000 parts by mass, more preferably 5000 to 25000 parts by mass, and still more preferably 10,000 to 20000 parts by mass.

  The eye drop according to the present embodiment may further contain a buffer. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, and Tris buffer. As the buffering agent, a boric acid buffering agent (for example, a combination of boric acid and borax, etc.) is preferable from the viewpoint of further enhancing the effects of the present invention.

  The pH of the eye drop according to the present embodiment is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The pH of the eyedrops according to this embodiment may be, for example, 4.0 to 9.5, or 5.5 to 8.0 from the viewpoint of eye irritation and solubility of components to be blended. It is preferably 5.8 to 7.8, more preferably 6.0 to 7.5.

  The ophthalmic solution according to the present embodiment can be adjusted to an osmotic pressure ratio within a range that is acceptable for a living body, if necessary. An appropriate osmotic pressure ratio can be appropriately set according to the use, formulation form, method of use, etc. of the eye drop, but it can be set to, for example, 0.3 to 3.0 from the viewpoint of eye irritation, 0 It is preferably 4 to 2.5, more preferably 0.5 to 2.0, and still more preferably 0.8 to 1.5. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia. Measure with reference to (freezing point depression method). The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica gel). The solution is allowed to cool and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be used.

  The viscosity of the eye drop according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. The viscosity of the eye drop according to the present embodiment is, for example, a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° from the viewpoint of ease of eye drop and retention in the eye during application. The viscosity at 20 ° C. measured by 34 ′ × R24) is preferably 1 to 100 mPa · s, more preferably 1 to 60 mPa · s, and further preferably 1 to 30 mPa · s. Even more preferably, it is 7 mPa · s.

The eye drop 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 ingredients as long as the effects of the present invention are not impaired. Good. The said component is not specifically limited, For example, the active ingredient in the ophthalmic medicine described in the over-the-counter medicine manufacture sale approval standard 2012 version (supervised by General Society of Regulatory Science) can be illustrated. Specific examples of components used in ophthalmic drugs include the following components.
Antiallergic agents: for example, sodium cromoglycate, tranilast, pemirolast potassium and the like.
Antihistamine: for example, diphenhydramine hydrochloride, iproheptin, chlorpheniramine maleate, levocabastine hydrochloride, ketotifen fumarate, pemirolast potassium, olopatadine hydrochloride, etc.
Anti-inflammatory agents: for example, methyl salicylate, glycol salicylate, dipotassium glycyrrhizinate, allantoin, tranexamic acid, berberine, berberine chloride, berberine sulfate, lysozyme, lysozyme chloride, azulene sulfonic acid, sodium azulene sulfonate, indomethacin, pranoprofen, ibuprofen , Ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, zinc sulfate, epsilon-aminocaproic acid and the like.
Steroid agents: For example, fluticasone propionate, fluticasone furancarboxylate, mometasone furancarboxylate, beclomethasone propionate, flunisolide and the like.
Decongestant: for example, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride.
Eye muscle modulating agent: for example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate, etc.
Vitamins: for example, retinol acetate, retinol palmitate, tocopherol acetate, sodium flavin adenine dinucleotide, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate and the like.
Inorganic salts: For example, metal chlorides such as calcium chloride, magnesium chloride, sodium chloride and potassium chloride; ammonium chloride; metal sulfates such as calcium sulfate, magnesium sulfate, sodium sulfate, potassium sulfate and ammonium sulfate.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and salts thereof.

In the eye drop according to the present embodiment, various additives are appropriately selected according to a conventional method according to the use and the formulation form within a range that does not impair the effects of the present invention, and one or more kinds are added. An appropriate amount may be contained in combination. Examples of such additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Carrier: An aqueous solvent such as water or hydrous ethanol.
Chelating agent: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA) and the like.
Stabilizer: For example, sodium formaldehyde sulfoxylate (Longalite), sodium bisulfite, sodium pyrosulfite, aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine and the like.
Base: for example, octyldodecanol, titanium oxide, potassium bromide, plastibase and the like.
pH adjuster: For example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine and the like.
Nonionic surfactant: For example, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, poloxamers and the like.
Anionic surfactant: For example, polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether sulfate, alkylbenzene sulfonate, alkyl sulfate, N-acyl taurine salt and the like.
Amphoteric surfactant: for example, lauryldimethylaminoacetic acid betaine.
Refreshing agents: menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymen, terpineol, pinene, camphene, isoborneol, fenchene, nerol, myrcene , Myrsenol, linalool acetate, lavandulol, eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil and the like.
Vinyl compounds: For example, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, etc.
Polyhydric alcohols: For example, aliphatic polyhydric alcohols such as glycerin, propylene glycol, ethylene glycol, diethylene glycol, and polyethylene glycol; sugar alcohols such as glucose, lactose, maltose, fructose, sorbitol, maltitol, mannitol, xylitol, and trehalose.
Preservatives other than component (A): for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, chlorhexidine and its salts (specifically, chlorhexidine hydrochloride, chlorhexidine acetate, chlorhexidine gluconate), sodium edetate, zinc chloride , Dibutylhydroxytoluene, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, chloride Benzalkonium, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), etc.), glow kill (trade name, manufactured by Rhodia), etc.
Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil and olive oil, animal oils such as squalane, mineral oils such as liquid paraffin and petrolatum.

  In addition, it is preferable that the eye drop which concerns on this embodiment does not contain eucalyptus oil. Moreover, the eye drop according to the present embodiment contains at least one selected from the group consisting of chlorhexidine and its salt (preferably chlorhexidine gluconate), benzalkonium chloride and polyhexanide hydrochloride from the viewpoint of eye irritation. Preferably not. Furthermore, the eye drop according to the present embodiment does not contain eucalyptus oil and at least one selected from the group consisting of chlorhexidine and its salt (preferably chlorhexidine gluconate), benzalkonium chloride and polyhexanide hydrochloride. Is preferred.

  When the eye drop according to the present embodiment contains water, the content of water is, for example, 80 w based on the total amount of eye drops from the viewpoint of more prominently achieving the effects of the present invention. / V% or more and less than 100 w / v%, more preferably 85 w / v% or more and 99.5 w / v% or less, and 90 w / v% or more and 99.2 w / v% or less. Further preferred.

  The water used in the eye drop according to the present embodiment may be any pharmaceutical, pharmacological (pharmaceutical) or physiologically acceptable. Examples of such water include distilled water, normal water, purified water, sterilized purified water, water for injection, and distilled water for injection. Their definitions are based on the 17th revised Japanese Pharmacopoeia.

  The eye drop according to the present embodiment can be prepared by adding and mixing the component (A) and other components as necessary to a desired concentration. For example, these components can be dissolved or dispersed in purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization or the like.

  The eye drop according to this embodiment can take various preparation forms depending on the purpose. Examples of the dosage form include solutions, gels, semi-solid agents (such as ointments) and the like. From the viewpoint of further enhancing the effect of the present invention, the preparation of the eye drop according to this embodiment is preferably a liquid.

  The eye drop according to the present embodiment includes an eye drop that can be applied while wearing a contact lens. The eye drop according to this embodiment is preferably used for eye drops while wearing a contact lens (preferably a soft contact lens) from the viewpoint of low cytotoxicity even at a concentration exhibiting sufficient storage efficacy.

  The eye drop according to this embodiment is provided by being accommodated in an arbitrary container. The container for storing the eye drops according to this embodiment is not particularly limited, and may be made of glass or plastic, for example. Preferably it is made of plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, a copolymer of monomers constituting these, and a mixture of these two or more. Preferred are polypropylene, polyethylene, and polyethylene terephthalate, and more preferred is polyethylene terephthalate. In addition, the container for storing the eye drop according to the present embodiment may be a transparent container that can visually recognize the inside of the container, or an opaque container that is difficult to visually recognize the inside of the container. A transparent container is preferable. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container.

  A nozzle may be attached to the container that stores the eye drop according to the present embodiment. The material of the nozzle is not particularly limited, and may be made of glass or plastic, for example. Preferably it is made of plastic. Examples of the plastic include polybutylene terephthalate, polyethylene, polypropylene, polyethylene naphthalate, a copolymer of monomers constituting these, and a mixture of two or more of these. As a material of the nozzle, polypropylene, polyethylene, polyethylene terephthalate, and polyethylene naphthalate are preferable, and polypropylene is more preferable from the viewpoint of further enhancing the effects of the present invention.

  The container for storing eye drops according to the present embodiment may be a multi-dose type in which a plurality of usage amounts are stored, or a unit dose type in which a single usage amount is stored. The multi-dose type is preferable because the effects of the present invention can be more remarkably exhibited.

[2. Method for enhancing the preservative effect of eye drops]
The ophthalmic solution according to the present embodiment contains (A) component, so that the storage efficacy is improved. Therefore, as one embodiment of the present invention, there is provided a method for enhancing the preservative efficacy of the eye drop, comprising blending the eye drop with at least one selected from the group consisting of (A) alexidine and a salt thereof. The

  Eye drops (especially multi-dose type eye drops) are supposed to be used over a period of time after the eye drop container is opened. Once the container is opened, air or contacted mucous membranes are used. There is a high possibility of causing microbial contamination of eye drops from skin and the like. Therefore, eye drops are required to have a certain level of preservation efficacy from the viewpoint of preservation stability by preventing product decay due to microbial contamination, etc. Is an extremely important issue.

  In the method, the type and content of the component (A), the type and content of the other components, the formulation form and use of the eye drop, etc. are described in [1. As described in [Eye drops].

[3. Method for stabilizing eye drops]
The ophthalmic solution according to the present embodiment contains the component (A), so that a decrease in viscosity is suppressed. Therefore, as one embodiment of the present invention, there is provided a method for stabilizing an eye drop, comprising blending the eye drop with at least one selected from the group consisting of (A) alexidine and a salt thereof. Moreover, as one embodiment of the present invention, there is provided a method for stabilizing the viscosity of the eye drop, which comprises blending the eye drop with at least one selected from the group consisting of (A) alexidine and a salt thereof. The

  In the method, the type and content of the component (A), the type and content of the other components, the formulation form and use of the eye drop, etc. are described in [1. As described in [Eye drops].

[4. Method for suppressing variation in dripping amount in eye drops]
The ophthalmic solution according to this embodiment contains the component (A), so that variation in the amount of dripping is suppressed. Therefore, as one embodiment of the present invention, there is provided a method for suppressing variation in the amount of dripping in an eye drop, which comprises adding at least one selected from the group consisting of (A) alexidine and a salt thereof to the eye drop. Provided.

  In the method, the type and content of the component (A), the type and content of the other components, the formulation form and use of the eye drop, etc. are described in [1. As described in [Eye drops].

[5. Preservative for eye drops]
(A) component has the effect of improving the preservative efficacy of eye drops. Therefore, as one embodiment of the present invention, there is provided an eye drop preservative containing at least one selected from the group consisting of (A) alexidine and a salt thereof.

  About the formulation form etc., such as the kind and content of (A) component in the preservative for eyedrops which concerns on this embodiment, the kind and content, etc. of other components, [1. As described in [Eye drops].

  Hereinafter, the present invention will be described more specifically based on examples and the like. However, the present invention is not limited to the following examples.

[Test Example 1: Preservative efficacy test (1)]
The eye drops shown in Table 1 below were prepared according to a conventional method. The unit of each component in Table 1 is w / v%. Next, each eye drop prepared was stored in a constant temperature bath at 60 ° C. for 3 weeks. Thereafter, the preservative efficacy test for each eye drop was conducted according to the 17th revised Japanese Pharmacopoeia by the following method.
First, Staphylococcus aureus (ATCC 6538) was inoculated on the surface of a soybean casein digest slope medium and cultured at 33 ° C. for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to prepare a bacterial suspension containing about 1 × 10 ⁷ CFU / mL viable bacteria. The number of viable bacteria in the suspension was measured by separately culturing. Next, 10 mL of each eye drop prepared was filled in a 50 mL CORNING conical tube (PET). Each of these eye drops was inoculated with Staphylococcus aureus bacterial solution (suspended in physiological saline) so that the viable cell count (final concentration) was about 10 ⁵ CFU / mL, and the sample was well stirred. The sample containing the bacteria was stored at 23 ° C. for 7 days under light shielding. Then, adjust the sample containing bacteria to an appropriate concentration for counting, inoculate on tryptosoya agar medium (SCD agar medium), incubate at 33 ° C for 3 days, and count the number of colonies observed. The number of viable bacteria was determined by The viable cell count immediately after inoculation was compared with the viable cell count in the sample after storage for 7 days, and the decrease in the bacterial count was calculated as Log Reduction. In addition, the culture | cultivation of the microbe for a count was implemented at 33 degreeC for 3 days. The results are shown in Table 1.

  In the eye drop containing dipotassium glycyrrhizinate, the decrease in the number of bacteria was small in the eye drop of Comparative Example 1-1 in which polyhexanide hydrochloride was blended, whereas in Example 1-1 in which alexidine dihydrochloride was blended. In the case of eye drops, the number of bacteria decreased significantly.

[Test Example 2: Preservative efficacy test (2)]
The eye drops shown in Table 2 below were prepared according to a conventional method. The unit of each component in Table 2 is w / v%. Next, each eye drop prepared was stored in a constant temperature bath at 60 ° C. for 3 weeks. For each stored eye drop, a preservative efficacy test was performed in the same manner as in Test Example 1. The results are shown in Table 2.

In the ophthalmic solution containing sodium chondroitin sulfate, the ophthalmic solution of Example 2-1 formulated with alexidine dihydrochloride compared to the amount of decrease in the number of bacteria in the ophthalmic solution of Comparative Example 2-1 formulated with polyhexanide hydrochloride The number of bacteria decreased to a level below the detection limit (Log Reduction:> 4.1), and the amount of bacteria decreased significantly.
Moreover, in each eye drop containing sodium hyaluronate or hydroxyethyl cellulose, the number of bacteria is less than the detection limit (Log Reduction:> 4) in each of the eye drops of Examples 2-2 and 2-3 in which alexidine dihydrochloride is blended. 1).

[Test Example 3: Preservative efficacy test (3)]
Eye drops shown in Table 3 below were prepared according to a conventional method. The unit of each component in Table 3 is w / v%. Next, each eye drop prepared was stored in a constant temperature bath at 60 ° C. for 3 weeks. For each ophthalmic solution stored, a storage efficacy test was performed in the same manner as in Test Example 1 except that the sample containing the bacteria was stored for 14 days at 23 ° C. in the dark. The results are shown in Table 3.

  In the ophthalmic solution containing sodium chondroitin sulfate and dipotassium glycyrrhizinate, the eye drop of Comparative Example 3-1 in which polyhexanide hydrochloride was blended had a small decrease in the number of bacteria, whereas the example in which alexidine dihydrochloride was blended In the case of the eye drop of 3-1, the number of bacteria was remarkably reduced.

[Test Example 4: Cytotoxicity test using rabbit corneal epithelial cell line (SIRC)]
A 96-well culture plate (Corning) was seeded with a rabbit corneal epithelial cell line (SIRC) at a density of 2.5 × 10 ⁴ cells per well, and was cultured for 1 day under conditions of 37 ° C., 90% humidity and 5% CO _2. Cultured. Next, 10% (v / v) fetal bovine serum (first chemical) was added to Medium 199 (GIBCO) to prepare a cell culture medium. Subsequently, alexidine dihydrochloride was dissolved in the prepared cell culture medium, and the concentrations of the components were adjusted to the concentrations shown in Table 4 below (concentrations showing preservation efficacy). 0.1 mL of the obtained solution was added to each well and cultured for 24 hours. Medium 199 was added to the control. After culturing, the supernatant was removed, and Medium 199 containing 10% (v / v) live cell detection reagent (Cell Counting Kit-8; Dojin Chemical) was supplemented with 10% (v / v) fetal calf serum (primary chemical). v) The cell culture medium prepared by addition was added and incubated for 1 hour at 37 ° C., 90% humidity and 5% CO ₂ . Thereafter, the absorbance (450 nm) of the dye that developed color in response to living cells was measured with a spectrophotometer (VersaMax). The relative cell viability was calculated using Equation 1 below. The results are shown in Table 4.
(Expression 1) Relative cell viability (%) = {(Absorbance in well added component solution−Absorbance of mixed solution of medium and living cell detection reagent) / (Absorbance in control well−Medium and living cell detection reagent) Absorbance of the mixed solution)} × 100

  The relative cell viability was significantly higher in the solution to which alexidine dihydrochloride was added. That is, it was confirmed that the cytotoxicity of alexidine dihydrochloride was low even at a concentration showing sufficient storage efficacy.

[Test Example 5: Viscosity stability test]
The eye drops shown in Table 5 below were prepared according to a conventional method. The unit of each component in Table 5 is w / v%. Next, the viscosity of each eye drop prepared was measured by the following method. Furthermore, 10 mL of each eye drop was filled into a transparent glass bottle, sealed, and stored in a thermostatic bath at 60 ° C. for 3 weeks, and then the viscosity of each eye drop was measured again by the following method.
Standard cone rotor (α = 1 ° 34 ', radius (R) = attached to TVE-20L type viscometer cone plate type (manufactured by Tokimec, Toki Sangyo (Japan)), which is a kind of E type viscometer 24 mm) was rotated by a motor through a spring with a full-scale torque of 6.737 × 10 ⁻⁵ Nm. During the measurement, the viscometer was installed so that the rotation axis was perpendicular to the horizontal plane. 1 mL of each eye drop was placed on a predetermined position (plate) of the cone rotor and allowed to stand until the temperature reached 20.0 ° C. Next, the apparatus was rotated at a rotation speed corresponding to the viscosity of each eye drop, and the displayed viscosity was read. In order to obtain highly accurate measurement results, before measurement of the viscosity of each eye drop, petroleum-based hydrocarbon oil (Newtonian fluid) defined by JIS Z 8809 was used as a calibration standard solution, and the measured value was The viscosity was adjusted to match the viscosity of the standard solution. The same results can be obtained by using a commercially available viscometer other than the TVE-20L viscometer cone plate type, selecting and implementing a cone rotor in the same manner as described above, and appropriately calibrating.
From the viscosity before and after storage at 60 ° C., the viscosity reduction rate was calculated based on the following formula 2. The results are shown in Table 5.
(Formula 2) Viscosity reduction rate (%) = 100− (viscosity after storage for 3 weeks at 60 ° C./viscosity before storage at 60 ° C.) × 100

  Examples 5-1 and 5-2 containing alexidine compared to the eye drops of Comparative Examples 5-1 and 5-2 that do not contain alexidine dihydrochloride in eye drops formulated with sodium hyaluronate or hydroxyethyl cellulose In the case of this eye drop, the viscosity reduction rate was small.

[Test Example 6: Evaluation of variation in dripping amount (1)]
Eye drops shown in Table 6 below were prepared by a conventional method. The unit of each component in Table 6 is w / v%. Next, 10 mL of each prepared eye drop was filled into a 10 mL polyethylene terephthalate eye drop container, and a polyethylene nozzle was attached to the container.
As the polyethylene nozzle, a nozzle suitable for dropping 30 to 50 μL was used. The ophthalmic solution in a container was dropped with the nozzle drop opening facing substantially vertically downward, and the drop weight was measured for each drop. From the average dripping amount (AVG: mg) and the standard deviation (SD: mg) obtained by repeating this operation 20 times, variation in dripping amount (variation coefficient CV:%) was calculated by the following equation 3. Using each obtained variation coefficient, the variation suppression rate of the dripping amount of the example with respect to the comparative example was calculated based on the following formula 4. The results are shown in Table 6.
(Expression 3) Variation in dropping amount (variation coefficient CV:%) = (SD / AVG) × 100
(Equation 4) Variation variation rate of dripping amount (%)
= {(Variation coefficient of comparative example−variation coefficient of example) / variation coefficient of comparative example} × 100

  Example 6 in which alexidine dihydrochloride was blended in eye drops formulated with aminoethyl sulfonic acid or dipotassium glycyrrhizinate, compared to eye drops in Comparative Examples 6-1 and 6-2 that did not contain alexidine dihydrochloride In the eye drops of -1 and 6-2, variation in the dripping amount was suppressed.

[Test Example 7: Variation evaluation of dripping amount (2)]
The eye drops shown in Table 7 below were prepared by a conventional method. The unit of each component in Table 7 is w / v%. Next, with respect to each of the prepared eye drops, the variation suppression rate of the dripping amount of the example with respect to the comparative example was calculated in the same manner as in Test Example 6. The results are shown in Table 7.

  Example 7- in which alexidine dihydrochloride was blended in eye drops formulated with sodium hyaluronate, hydroxyethyl cellulose or hydroxypropyl methyl cellulose, compared with eye drops in Comparative Examples 7-1 to 7-3 formulated with polyhexanide hydrochloride In the eye drops of 1 to 7-3, variation in the dripping amount was suppressed.

[Formulation example]
Eye drops were prepared according to the formulation described in Table 8 (Formulation Examples 1 to 12). The units in Table 8 are all (w / v%) except those described in the table.

Claims (9)

  (A) An eye drop containing at least one selected from the group consisting of alexidine and a salt thereof.   (B) The ophthalmic solution according to claim 1, further comprising at least one selected from the group consisting of acidic saccharides and cellulose polymer compounds.   The eye drop according to claim 2, wherein the acidic saccharide is at least one selected from the group consisting of glycyrrhizic acid, hyaluronic acid, chondroitin sulfate and salts thereof.   The eye drop according to claim 2 or 3, wherein the cellulosic polymer compound is at least one selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof.   The ophthalmic solution according to any one of claims 1 to 4, wherein the pH is 5.5 to 8.0.   The eye drop according to any one of claims 1 to 5, which is used for eye drops during wearing of a soft contact lens.   (A) The content of at least one selected from the group consisting of alexidine and a salt thereof is 0.000001 to 0.05 w / v% based on the total amount of eye drops, The eye drop according to claim 1.   A method for enhancing the preservative efficacy of the eye drop, comprising blending the eye drop with at least one selected from the group consisting of (A) alexidine and a salt thereof.   (A) An eye drop preservative containing at least one selected from the group consisting of alexidine and salts thereof.