JP2012206977A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ophthalmic composition in which viscosity reduction due to light irradiation is suppressed while containing a carboxyvinyl polymer.SOLUTION: The ophthalmic composition contains the carboxyvinyl polymer and ε-aminocaproic acid or a pharmaceutically acceptable salt thereof, and has viscosity of 200-100,000 mPa s. Further, the composition preferably contains naphazoline or a pharmaceutically acceptable salt thereof. The composition is further, preferably contains boric acid. The composition is preferably an eye lotion filled in a transparent container.

Description

  The present invention relates to ophthalmic compositions.

In ophthalmic compositions such as eye drops and eyewashes, a polymer thickener is added to increase the viscosity in order to increase the residence time on the eyeball surface or to suppress evaporation of tears. It has been broken.
For example, Patent Document 1 describes a pharmaceutical preparation suitable for use in the eye, which includes a pharmaceutical acceptable carrier, a pharmaceutical component, and a component that reduces evaporation of the tear film. Yes. In addition, polyacrylic acid is described as a component that reduces evaporation of the tear film.
However, the viscosity of a carboxyvinyl polymer (hereinafter sometimes abbreviated as “CVP”), which is a polymer thickener, decreases when exposed to light for a long time. On the other hand, ophthalmic compositions such as eye drops, eyewashes, contact lens mounting solutions, and contact lens care compositions are preferably filled in highly transparent containers for quality control. For this reason, it is often exposed to light for a long time.

Special Table 2007-526292 (Claim 1, Paragraph 0077)

  It is an object of the present invention to provide an ophthalmic composition that contains CVP and in which a decrease in viscosity due to light irradiation is suppressed.

The present inventor repeated researches to solve the above problems, and obtained the following knowledge.
(i) An ophthalmic composition containing CVP and having a viscosity of 200 to 100,000 mPa · s is liable to decrease in viscosity by light irradiation, but by containing ε-aminocaproic acid in addition to CVP, the viscosity is decreased by light irradiation. Is effectively suppressed.
(ii) The ophthalmic composition containing CVP and having a viscosity of 200 to 100,000 mPa · s is liable to generate a precipitate called white residue after drying, but is dried by containing ε-aminocaproic acid in addition to CVP. The generation of subsequent precipitates is effectively suppressed.
(iii) The ophthalmic composition containing CVP and having a viscosity of 200 to 100,000 mPa · s contains ε-aminocaproic acid in addition to CVP, thereby effectively suppressing moisture transpiration.
(iv) An ophthalmic composition having CVP and ε-aminocaproic acid and having a viscosity of 200 to 100,000 mPa · s is filled with naphazoline in addition to CVP and ε-aminocaproic acid. Adhering to the container mouth of the container is extremely effectively suppressed.

The present invention has been completed based on these findings, and provides the following ophthalmic compositions.
Item 1. An ophthalmic composition comprising a carboxyvinyl polymer and ε-aminocaproic acid or a pharmaceutically acceptable salt thereof and having a viscosity of 200 to 100,000 mPa · s.
Item 2. Item 2. The ophthalmic composition according to item 1, wherein the content of the carboxyvinyl polymer is 0.001 to 10 w / v% in terms of dry weight with respect to the entire ophthalmic composition.
Item 3. Item 3. The ophthalmic composition according to Item 1 or 2, wherein the content of ε-aminocaproic acid or a pharmaceutically acceptable salt thereof is 0.1 to 10 w / v% with respect to the entire ophthalmic composition.
Item 4. Item 4. The item according to any one of Items 1 to 3, comprising 0.01 to 10,000 parts by weight of ε-aminocaproic acid or a pharmaceutically acceptable salt thereof with respect to 1 part by weight of the content converted to the dry weight of the carboxyvinyl polymer. Ophthalmic composition.
Item 5. Item 5. The ophthalmic composition according to any one of Items 1 to 4, further comprising naphazoline or a pharmaceutically acceptable salt thereof.
Item 6. Furthermore, the ophthalmic composition in any one of claim | item 1 -5 containing a boric acid.
Item 7. Item 7. The ophthalmic composition according to any one of Items 1 to 6, which is filled in a transparent container.
Item 8. Item 8. The ophthalmic composition according to any one of Items 1 to 7, which is an eye drop.
Item 9. An ophthalmic composition is prepared by blending an ophthalmic composition containing a carboxyvinyl polymer with ε-aminocaproic acid or a pharmaceutically acceptable salt thereof to prepare an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s. A method for suppressing a decrease in viscosity due to light irradiation.
Item 10. An ophthalmic composition is prepared by blending an ophthalmic composition containing a carboxyvinyl polymer with ε-aminocaproic acid or a pharmaceutically acceptable salt thereof to prepare an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s. A method for suppressing the generation of precipitates after drying.
Item 11. From an ophthalmic composition comprising preparing an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s by blending ε-aminocaproic acid or a pharmaceutically acceptable salt thereof with an ophthalmic composition containing a carboxyvinyl polymer. To suppress moisture transpiration.
Item 12. An ophthalmic composition having a viscosity of 200 to 100,000 mPa · s by blending naphazoline or a pharmaceutically acceptable salt thereof with an ophthalmic composition containing a carboxyvinyl polymer and ε-aminocaproic acid or a pharmaceutically acceptable salt thereof. A method for improving the liquid drainage performance in a container mouth of a container filled with the ophthalmic composition, which is prepared by a composition.

  In general, high-viscosity eye drops formulated with polymer thickeners lose their viscosity when exposed to light for a long time, and the effects of high-viscosity eye drops such as sustained efficacy and prevention of eye dryness are impaired. . And when CVP is used among polymer thickeners, this viscosity reduction appears strongly. Although the ophthalmic composition of the present invention is a high-viscosity eye drop formulated with CVP that tends to cause a decrease in viscosity as described above, the decrease in viscosity due to light irradiation is suppressed. The effect of high-viscosity eye drops such as drying prevention is maintained. In addition, since the influence of light irradiation is suppressed, the ophthalmic composition of the present invention can be filled in a highly transparent container that is easy to quality control, and the container does not necessarily need to be put in a light shielding bag. Easy to do.

In general, a highly viscous ophthalmic composition is likely to generate precipitates called white residue after drying. For example, in the case of eye drops, there is a possibility that precipitates may occur around the application site (for example, eyelids, eyelashes, under the eyes, etc.) at the time of use, and the feeling of use is bad and the appearance is uncomfortable. give. In addition, the components may be deposited near the container mouth to contaminate the container, or the deposited components may enter the eyes. In addition, when the component is deposited at the container mouth, the amount of liquid dropped may vary.
In this regard, since the ophthalmic composition of the present invention contains ε-aminocaproic acid even though it contains CVP with high viscosity, the generation of precipitates after drying is suppressed. The problem is avoided.

  Moreover, the ophthalmic composition of the present invention contains ε-aminocaproic acid in addition to CVP, thereby suppressing moisture evaporation. Thereby, it is excellent in eye-protecting action and can be suitably used as a preventive or therapeutic agent for dry eye.

In general, a high-viscosity ophthalmic composition is poor in liquid drainage at the container mouth when poured out from the container, and a large amount of liquid adheres and remains in the vicinity of the container mouth (for example, outside the nozzle) after the liquid is dropped. In the case of eye drops, since it is practically difficult to always instill at a fixed angle, the orientation of the container at the time of instillation varies depending on the user. In particular, when the container approaches sideways (the direction in which the container is parallel to the eye surface, that is, the direction in which the surface of the container mouth is perpendicular to the eye surface), the amount remaining on the container mouth increases.
When the ophthalmic composition of the present invention contains naphazoline or a pharmaceutically acceptable salt thereof, liquid drainage at the container mouth is extremely good, and therefore, precipitation of components attached near the container mouth is more effective. Is suppressed.

It is a figure which shows schematic structure of the single cylindrical rotational viscometer used for the viscosity measurement in the Example. It is drawing which shows the inhibitory effect of the deposit generation after drying by (epsilon) -aminocaproic acid. It is drawing which shows that naphazoline hydrochloride suppresses adhesion to the nozzle of an ophthalmic composition very effectively. It is drawing which shows the moisture evaporation suppression effect by (epsilon) -aminocaproic acid.

Hereinafter, the present invention will be described in detail.
The ophthalmic composition of the present invention contains CVP and ε-aminocaproic acid or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “salt”), and has a viscosity of 200 to 100,000 mPa · s. Is an ophthalmic composition.

CVP (carboxy vinyl polymer)
CVP is a hydrophilic polymer obtained by polymerizing acrylic acid as a main component, and may be either polyacrylic acid or polyacrylate.
Even when polyacrylic acid is used at the time of mixing each component, when the pH is adjusted, a part or all of the resulting composition may be a polyacrylate. Preferably, low viscosity polyacrylic acid is used when CVP and other components are mixed, and the viscosity of the composition may be increased by adjusting the pH and optionally using part or all of it as a polyacrylate. It is also preferable to use a polyacrylate from the time of mixing.
Polyacrylic acid salts include alkali metal salts such as polyacrylic acid sodium salt and potassium salt; polyacrylic acid monoethanolamine salt, diethanolamine salt, amine salt such as triethanolamine salt; polyacrylic acid ammonium salt Salt can be used. Of these, alkali metal salts are preferred.
Further, the polyacrylic acid or a salt thereof may be either a crosslinked type or a non-crosslinked type, but a crosslinked polymer is preferred because it has a high thickening effect and can easily exert the effects of the present invention.

CVP can use a commercial item. Commercially available products include Carbopol (trade name) (Lubrisol), Shintalen (trade name), Hibiswako (trade name) (Wako Pure Chemical Industries), Akpek (trade name) (Sumitomo Seika), Junron (product) Name) (Nippon Pure Chemicals) etc. can be used.
CVP can be used alone or in combination of two or more.

  The content of CVP is preferably about 0.001 to 10 w / v%, more preferably about 0.005 to 5 w / v%, more preferably about 0.000 in terms of dry weight with respect to the whole ophthalmic composition. 0.1 to 3 w / v% is more preferable, and about 0.05 to 0.5 w / v% is even more preferable. If it is the range of the said content, the thickening effect by CVP addition will fully be acquired. Moreover, if it is the range of the said content, a favorable usability | use_condition will be obtained and generation | occurrence | production of the deposit after the adhesion to a container mouth and drying will fully be suppressed.

ε-Aminocaproic acid or a salt thereof ε-aminocaproic acid is a kind of synthetic amino acid, and is generally a component that may be blended in an ophthalmic composition as an anti-inflammatory component or an astringent component.
In the present invention, ε-aminocaproic acid or a salt thereof is used. Examples of the salt include sodium salt and potassium salt. ε-aminocaproic acid or a salt thereof can be used alone or in combination of two or more. Preferably, ε-aminocaproic acid is used.

The content of ε-aminocaproic acid or a salt thereof is preferably about 0.1 to 10 w / v%, more preferably about 0.25 to 7.5 w / v% with respect to the total ophthalmic composition, and about 0 More preferably, it is 5 to 5.0 w / v%. If it is the range of the said content, it is safe with respect to eyes and the effect of this invention is fully show | played.
Further, the ratio of the content of ε-aminocaproic acid or a salt thereof to the content of CVP (value converted to dry weight) is about 1: 0.01 by weight ratio of CVP: ε-aminocaproic acid or a salt thereof. -10,000 is preferred, about 1: 0.1-1000 is more preferred, and about 1: 1-100 is even more preferred. If it is the range of the said content, the effect of this invention is fully show | played and it is safe with respect to eyes.

Naphazoline or a salt thereof Naphazoline or a salt thereof is generally a component that may be blended in an ophthalmic composition as a decongestant component or the like. The ophthalmic composition of the present invention preferably contains naphazoline or a salt thereof, which makes it very easy to drain from a container mouth (for example, a nozzle in the case of an eye drop container). Examples of the salt include hydrochloride and nitrate. Naphazoline or a salt thereof can be used alone or in combination of two or more. Preferably, naphazoline hydrochloride is used.

The content of naphazoline or a salt thereof is preferably about 0.0001 to 0.1 w / v%, more preferably about 0.0001 to 0.01 w / v%, and more preferably about 0.001 to 0.1% by weight with respect to the whole ophthalmic composition. Even more preferred is 0003-0.003 w / v%. If it is the range of the said content, the improvement effect of liquid cutting property will fully be acquired, and it is safe with respect to eyes.
In addition, the ratio of the content of naphazoline or a salt thereof to the content of CVP (value converted to dry weight) is preferably about 1: 0.00001 to 3 in terms of a weight ratio of CVP: naphazoline or a salt thereof, 1: 0.0001-1 is more preferred, and about 1: 0.0005-0.1 is even more preferred. If it is the range of the said content, it is safe with respect to eyes, and said effect by naphazoline or its salt is fully show | played.

Boric acid The ophthalmic composition of the present invention preferably contains boric acid, whereby a preservative effect by boric acid is obtained. As shown in the items of Examples described later, when an amino acid is added to a composition containing CVP and boric acid, the viscosity of the composition may be remarkably lowered. However, the composition of the present invention containing ε-aminocaproic acid even with the same amino acid. When boric acid is contained, no significant decrease in viscosity is observed, and conversely, the decrease in viscosity due to light irradiation is effectively suppressed.
The content of boric acid is preferably about 0.05 to 5 w / v%, more preferably about 0.1 to 5 w / v%, and about 0.2 to 3 w / v% with respect to the whole ophthalmic composition. Is even more preferred, with about 0.5 to 2.5 w / v% being particularly preferred. If it is the said range, antiseptic effect can fully be exhibited, and it is safe with respect to eyes. Moreover, if it is the said range, the crystal precipitation of a boric acid will be avoided.

Optional components In addition to the above components, the ophthalmic composition of the present invention may contain one or more active ingredients (pharmacologically active ingredients, physiologically active ingredients, etc.). The type of such component is not particularly limited, and examples thereof include a decongestant component, an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial agents. Examples thereof include a drug component or a bactericidal component, a saccharide, a polymer compound or a derivative thereof, cellulose or a derivative thereof, a local anesthetic component, a glaucoma treatment component, a cataract treatment component, and the like. Examples of the pharmacologically active component and physiologically active component suitable in the present invention include the following components.

  Decongestant: For example, α-adrenergic agonist, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate, and the like. These may be d-form, l-form or dl-form.

  Ocular muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate and the like.

  Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, diclofenac sodium, bromfena Sodium chloride, berberine chloride, berberine sulfate, etc.

  Antihistamine component or antiallergic agent component: for example, agitazanolast, diphenhydramine or its hydrochloride, chlorpheniramine maleate, ketotifen fumarate, levocabastine or its hydrochloride, etc., amlexanox, ibudilast, tazanolast, tranilast, oxatomide, Suplatast or its tosylate, such as sodium cromoglycate, potassium pemirolast, etc.

  Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, pantothenic acid, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, tocopherol nicotinate, succinic acid Tocopherol, tocopherol calcium succinate, ubiquinone derivatives, etc.

  Amino acids: for example, aminoethyl sulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate mixture, glutamic acid, sodium glutamate, magnesium glutamate, glycine, alanine, arginine, Lysine, γ-aminobutyric acid, γ-aminovaleric acid, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.

  Antibacterial component or bactericidal component: for example, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxa Zole monoethanolamine, sodium sulfisomezole, sodium sulfisomidine, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, acyclovir and the like.

  Sugars: For example, monosaccharides, disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like.

  High molecular compound or derivative thereof: for example, alginic acid, sodium alginate, dextrin, dextran, pectin, hyaluronic acid, chondroitin sulfate, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol and pharmaceutically acceptable salts thereof Such.

  Cellulose or derivatives thereof: for example, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxyethyl cellulose, nitrocellulose and the like.

  Local anesthetic components: for example, chlorobutanol, procaine hydrochloride, lidocaine hydrochloride, etc.

  The blending ratio of various components is known in the field of ophthalmic compositions, and the blending ratio of the pharmacologically active component or the physiologically active component in the ophthalmic composition of the present invention is determined depending on the type of the component or the dosage form of the ophthalmic composition. It can be set appropriately according to the above. The blending ratio of the pharmacologically active ingredient or the physiologically active ingredient can be selected, for example, from the range of about 0.0001 to 30 w / v%, preferably about 0.001 to 10 w / v% based on the total amount of the composition.

  In addition, in the ophthalmic composition of the present invention, various components and additives are appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired. More than one species can be used in combination. As those components or additives, for example, carriers (aqueous solvents, aqueous or oily bases, etc.), surfactants, preservatives, bactericides, or antibacterial agents that are commonly used in the preparation of semi-solid agents and liquids And various additives such as pH adjusters, tonicity agents, chelating agents, buffering agents, and stabilizers.

  Although the typical component used for the ophthalmic composition of this invention is illustrated below, it is not limited to these.

  Carrier: An aqueous solvent such as water or hydrous ethanol.

  Surfactant: For example, polyoxyethylene (hereinafter abbreviated as POE) -polyoxypropylene (hereinafter abbreviated as POP) block copolymer (specifically, poloxamer 407, etc.), ethylenediamine POE-POP block copolymer adduct ( Specifically, such as poloxamine), POE sorbitan fatty acid ester (specifically, polysorbate 80), POE hydrogenated castor oil (specifically, POE (60) hydrogenated castor oil), non-oxygen such as polyoxyl stearate Ionic surfactants; glycine type amphoteric surfactants such as alkyldiaminoethylglycine; cationic surfactants of alkyl quaternary ammonium salts (specifically, benzalkonium chloride, benzethonium chloride, etc.). The numbers in parentheses indicate the number of added moles.

  Perfume or refreshing agent: For example, terpenes (specifically, anethole, eugenol, camphor, geraniol, cineol, borneol, menthol, limonene, ryuuno, etc. These may be any of d-form, l-form or dl-form. ), Essential oils (such as fennel oil, cool mint oil, cinnamon oil, spearmint oil, mint water, mint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil).

  Preservatives, bactericides or antibacterials: for example, polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide or its hydrochloride) , Glow Kill (trade name, manufactured by Rhodia).

  pH adjuster: For example, hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid and the like.

  Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.

  Chelating agent: for example, ascorbic acid, tetrasodium edetate, sodium edetate, citric acid and the like.

  Buffer: citrate buffer, acetate buffer, carbonate buffer, borate buffer, phosphate buffer, etc. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, boric acid, borax, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid Such as potassium dihydrogen.

  Stabilizers: dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.

Viscosity The viscosity of the ophthalmic composition of the present invention is about 200 mPa · s or more, preferably about 300 mPa · s or more, more preferably about 400 mPa · s or more, and even more preferably about 500 mPa · s or more. The upper limit of the viscosity is usually about 100,000 mPa · s, preferably about 10,000 mPa · s or less, more preferably about 3,000 mPa · s or less. An ophthalmic composition having the above viscosity can be obtained by appropriately selecting the type and amount of CVP used, or the type and amount of other components that may be optionally used in combination.
The ophthalmic composition of the present invention has a practically sufficient viscosity within the above range and can effectively exhibit the effect of suppressing the decrease in viscosity due to light irradiation. In addition, in the above range, good usability can be obtained, and adhesion to the container mouth and generation of precipitates after drying can be sufficiently suppressed.
In the present invention, the viscosity is the general test method, viscosity measurement method, second method rotational viscometer method, “(2) single cylindrical rotational viscometer (Brookfield type viscosity) described in the 15th revision Japanese Pharmacopoeia. Is a value measured at 25 ° C. using a B-type rotational viscometer (RB-80L; Toki Sangyo Co., Ltd.) according to the method described in the section “ Select according to the instruction manual of the machine. Specifically, it is a value measured by the method described in the item of Example.

In addition , the dosage form of the ophthalmic composition of the present invention is not particularly limited, and examples thereof include liquid forms, suspensions, and emulsions. In these cases, the water content is usually about 85% by weight or more, preferably about 90% by weight or more. A liquid agent is preferable.
The pH of the ophthalmic composition of the present invention may be about 3 to 10, preferably about 4 to 9, more preferably about 5 to 8.5, and particularly preferably about 5.5 to 8.
The material of the container for storing the ophthalmic composition of the present invention is not particularly limited. For example, the container is made of plastic such as polyethylene terephthalate, polyethylene naphthalate, polyarylate, polycarbonate, polyethylene, polypropylene, or glass. A transparent container is mentioned. Since the ophthalmic composition of the present invention is suppressed in viscosity reduction due to light irradiation, such a transparent container (a container having such a degree of transparency that it does not interfere with the observation of foreign matter, and at least partly (For example, it is sufficient that the container has a transparency with a surface area of about 80% or more of the side surface of the container). In particular, a container containing polyethylene terephthalate, polyethylene naphthalate, or polyarylate is preferable, and among them, a container containing polyethylene terephthalate and polyethylene naphthalate is more preferable. The ophthalmic composition of the present invention may be filled in a light-shielded container. The light shielding may be performed, for example, by adding a colorant to the transparent container material described above, or may be shielded by covering the container with a shrink film, an outer box, or the like. In addition, the capacity of the container is preferably about 0.5 to 20 mL, more preferably about 3 to 18 mL, and even more preferably about 5 to 15 mL in order to make it easier to exert the effect of improving liquid breakage by adjusting the extrusion.
Further, when the ophthalmic composition of the present invention is an eye drop, the structure and constituent materials of the nozzle provided in the container for storing the eye drop are not particularly limited. The structure of the nozzle may be a structure that is generally employed as a nozzle of an eye drop container, and the constituent material of the nozzle is exemplified by the same material as that of the plastic container, for example. . From the viewpoint of making the ophthalmic composition of the present invention run out more satisfactorily, a nozzle containing polyethylene or polypropylene as a constituent material is suitable. Examples of the polyethylene include high-density polyethylene and low-density polyethylene.

Production Method The ophthalmic composition of the present invention can be prepared by a conventional method. For example, after each component is dispersed in a carrier such as water, it may be prepared by homogenizing, dissolving or emulsifying using a homogenizer and adjusting the pH with a pH adjuster. In addition, as a method for sterilizing the preparation, methods such as autoclave sterilization and filter sterilization are selected.

Applications / Methods of Use As the ophthalmic composition of the present invention, specifically, eye drops (including eye drops and eye drops), eye wash (including eye drops and eye wash), eye ointments, contact lens mounting liquids And contact lens care agents (cleaning solution, preserving solution, disinfecting solution, multi-purpose solution, etc.). The eye drops and eye wash include eye drops and eye wash that can be used while wearing a contact lens. In the present specification, the contact lens includes all types of contact lenses such as hard contact lenses (including oxygen permeable hard contact lenses) and soft contact lenses.
The dosage varies depending on the use of the composition, and may be used at a dosage generally employed for each use.
In the case of pharmaceuticals such as eye drops and eyewashes, inspection of foreign substances in the container in the manufacturing process is essential, and particularly high quality assurance is required because it is desirable to have less change in viscosity. The ophthalmic composition of the present invention can withstand such quality assurance because viscosity reduction is suppressed.
In particular, in the case of eye drops and eye wash, since the precipitate at the container mouth may fall and adversely affect the eyes, the ophthalmic composition of the present invention in which the precipitation at the container mouth is suppressed is an eye drop. And can be suitably used as an eyewash.
In addition, the ophthalmic composition of the invention of the present application can be suitably used as an eye drop particularly because moisture transpiration is suppressed, and in particular, as an eye drop for preventing or treating dry eye and other dry eye symptoms. It can be used suitably.

Other Embodiments of the Invention The present invention includes the following methods (a) to (d).
(a) An ophthalmic composition comprising an ophthalmic composition containing CVP and an ε-aminocaproic acid or a pharmaceutically acceptable salt thereof to prepare an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s. To suppress a decrease in viscosity due to light irradiation.
(b) An ophthalmic composition prepared by blending an ophthalmic composition containing CVP with ε-aminocaproic acid or a pharmaceutically acceptable salt thereof to prepare an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s. To suppress the generation of precipitates after drying.
(c) An ophthalmic composition prepared by blending ε-aminocaproic acid or a pharmaceutically acceptable salt thereof with an ophthalmic composition containing CVP to prepare an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s. To suppress moisture transpiration from water.
(d) An ophthalmic composition having a viscosity of 200 to 100,000 mPa · s by blending naphazoline or a pharmaceutically acceptable salt thereof with an ophthalmic composition containing CVP and ε-aminocaproic acid or a pharmaceutically acceptable salt thereof. A method for improving the liquid drainage performance at the container mouth of a container filled with the ophthalmic composition.
In each of the above methods, the type, content, optional component, composition form, viscosity, pH, application / use method of each component are the same as those of the ophthalmic composition described above.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.
(1) Light stability test 1
Using each test solution having the composition described in Table 1 below, the viscosity before and after light irradiation was measured, and the stability to light was evaluated.

The specific test method is as follows.
First, CVP (crosslinked type, trade name: AQUPEC HV-505E, manufactured by Sumitomo Seika Co., Ltd.) dried at 105 ° C. for 3 hours was stirred and dissolved in water so as to be a 2 w / v% solution. Then, after diluting this solution so that the CVP concentration becomes 0.15 w / v%, boric acid, borax, and if necessary, ε-aminocaproic acid are added to each concentration, and the viscosity is further increased to 50. Sodium chloride was added so as to be about ˜1500 mPa · s (25 ° C.), and the mixture was sufficiently stirred until the solution became uniform. Thereafter, an appropriate amount of hydrochloric acid or sodium hydroxide solution was added to adjust the pH to 7 to 8, and water was added to make up the volume. Moreover, also about the formulation which mix | blended hydroxypropyl methylcellulose (brand name: SH65-4000, the Shin-Etsu Chemical Co., Ltd. product; also called a hypromellose), it is about 1000-1500 mPa * s (25 degreeC) similarly to CVP. Prepared.

30 ml of these ophthalmic compositions were filled in a 30 ml capacity glass container. The container filled with these compositions was irradiated with light at an irradiance of 350 W / m ² for 4 hours using a sun tester (SUNTEST XLS +; Toyo Seiki Seisakusho). This corresponds to 5000 kJ / m ² .
After the completion of irradiation, the sample not irradiated with light (unirradiated sample) and the sample irradiated with light (irradiated sample) were stored at 25 ° C. overnight. Immediately thereafter, the viscosity at 25 ° C. was measured under the conditions described below. Furthermore, the viscosity after light irradiation was expressed as a relative viscosity when the viscosity of the unirradiated sample was taken as 100.

Relative viscosity = [viscosity of irradiated sample (25 ° C.) / Viscosity of unirradiated sample (25 ° C.)] × 100

<Viscosity measurement conditions>
The viscosity of each sample used in the test is described in "General Test Method, Viscosity Measurement Method, Second Method Viscometer Method" described in the 15th revision Japanese Pharmacopoeia. Measured according to the test method described in the section “Shape Rotational Viscometer (Brookfield Viscometer)”. A B-type rotational viscometer (RB-80L; Toki Sangyo Co., Ltd.) was used as the viscometer.
The measurement conditions for the viscosity are as follows.
Measurement temperature 25 ℃
Measured value Rotational speed and rotor No. with viscosity after 1 minute as measured value
・ Viscosity less than 100 mPa · s: Rotation speed 60rpm, Rotor No.M2
・ Viscosity of 100 mPa · s or more and less than 2500 mPa · s: 12 rpm, rotor No. M2
・ Viscosity 2500mPa · s or more and less than 10000mPa · s: Rotating speed 12rpm, Rotor No.M3

A single cylindrical rotational viscometer is a viscometer that measures torque when a cylinder in a liquid is rotated at a constant angular velocity. The outline of the apparatus is shown in FIG. By establishing experimentally K _B in advance using a viscometer calibration standard solution, to calculate the viscosity of the liquid η by the following equation.
η = K _B × T / ω
η: Viscosity of liquid (mPa · s)
K _B : Equipment constant (rad / cm ³ )
ω: Angular velocity (rad / s)
T: Torque acting on the cylindrical surface (10 ^-7 N · m)

The results are also shown in Table 1 above.
As is apparent from Table 1, the CVP preparation having a high viscosity of about 1000 mPa · s did not contain ε-aminocaproic acid (Comparative Example 1), and the viscosity was significantly reduced by light irradiation. On the other hand, in the preparations (Examples 1 and 2) in which ε-aminocaproic acid was further added to such a high-viscosity CVP preparation, the decrease in viscosity due to light irradiation was effectively suppressed.
In addition, in the CVP preparation (Comparative Example 4) having a low viscosity of about 50 mPa · s, the problem of viscosity reduction due to light irradiation was not recognized in the first place.
In addition, when a general-purpose thickening agent, hydroxypropylmethylcellulose, is used instead of CVP as a thickening agent, even if it is a high-viscosity preparation having a viscosity of about 1000 mPa · s, a significant decrease in viscosity after light irradiation. Was not observed (Comparative Example 3), and even when ε-aminocaproic acid was added, a phenomenon in which the decrease in viscosity after light irradiation was highly suppressed was not observed (Comparative Example 2).

(2) Light stability test 2
Using each test solution having the composition described in Table 2 below, the viscosity before and after light irradiation was measured, and the stability to light was evaluated.
The experimental method was a light irradiation treatment at an irradiance of 765 W / m ² for 1 hour and a half instead of a light irradiation treatment at an irradiance of 350 W / m ² for 4 hours (equivalent to 5000 kJ / m ² ). The same procedure as in the photostability test 1 was conducted except that the filling amount was changed from 30 ml to 100 ml. Light irradiation for one hour and a half at this irradiance 765 W / ^{m 2} corresponds to 4000kJ / ^{m 2.}
The results are also shown in Table 2 above. As is clear from Table 2, even in the case of a CVP high-viscosity preparation having an initial viscosity of about 400 mPa · s, a decrease in viscosity due to light irradiation was significantly suppressed by combining ε-aminocaproic acid.

(3) Evaluation of white residue Using a test solution having the composition shown in Table 3 below, the degree of precipitate generation (white residue) after drying was evaluated.

The specific test method is as follows.
First, each test solution was prepared by the method described in the item of the light stability test 1, and the viscosity was measured. Next, 50 μL of each test solution was dropped on a slide glass, and left to stand in an incubator at 25 ° C. for 2 hours to be dried. Two hours later, the state of each test solution was visually observed and photographed.
The photograph after drying for 2 hours of each test solution is shown in FIG. As is clear from FIG. 2, in Comparative Examples 6 and 7 containing CVP but not ε-aminocaproic acid, a large amount of white precipitate was produced after drying. On the other hand, in Examples 4 and 5 containing CVP and ε-aminocaproic acid, the generation of white precipitates was almost completely suppressed.
Further, in Comparative Example 9 containing hydroxypropylmethylcellulose as a thickener but not containing ε-aminocaproic acid, the generation of white precipitates was slightly less than in Comparative Examples 6 and 7. Further, in Comparative Example 8 in which ε-aminocaproic acid was combined with hydroxypropylmethylcellulose, the generation of white precipitates was not completely eliminated, and the effect of suppressing the generation of white precipitates by ε-aminocaproic acid was weak.

(4) Nozzle adhesion test Using a test solution having the composition shown in Table 4 below, the amount of the test solution adhering to the nozzle and remaining when it was dropped from the nozzle was measured. Performance was evaluated.

The specific test method is as follows.
First, each test solution was prepared by the method described in the item of the light stability test 1, and the viscosity was measured. Next, 13 mL of each test solution was filled in a polyethylene terephthalate (PET) eye drop container, and a polyethylene (PE) nozzle was attached. Next, filter paper was attached to the glass container, and the weight was measured. Next, the test liquid was dropped with the nozzle angle being substantially horizontal, and then the liquid adhering to the outside of the nozzle was sucked into the filter paper. This operation was repeated 20 drops for each test solution, and the change in the weight of the filter paper was measured to evaluate the amount of the adhered liquid (total weight) outside the nozzle.
The results are shown in FIG. As is clear from FIG. 3, although it was in a practically acceptable range even in the case of a high viscosity test solution such as Example 6 containing CVP and ε-aminocaproic acid, an example in which naphazoline hydrochloride was further blended In the test solution No. 7, the amount of the liquid attached to the nozzle was approximately halved.

(5) Moisture transpiration test 1
About the test liquid which has a composition shown in following Table 5, the amount of moisture transpiration was evaluated.

The specific test method is as follows.
First, each test solution was prepared by the method described in the item of the light stability test 1, and the viscosity was measured. Next, 5.0 g of each test solution was weighed into a 60 mm petri dish (made of polystyrene) (sample weight before moisture evaporation) and incubated at 50 ° C. for 90 minutes. The weight after 90 minutes was measured. From the measured value of the sample weight before and after moisture transpiration, the moisture transpiration rate (%) was calculated according to the following formula.

Moisture transpiration rate (%) = [(sample weight before moisture transpiration−sample weight after moisture transpiration) /
Sample weight before moisture transpiration] × 100

The results are shown in FIG. As is clear from FIG. 4, the moisture transpiration rate was suppressed depending on the dose of ε-aminocaproic acid by blending ε-aminocaproic acid with the high-viscosity preparation containing CVP. Thereby, it was demonstrated that the composition of the present invention is an excellent preparation capable of retaining (holding) moisture on the eyeball surface for a long period of time.
On the other hand, even when ε-aminocaproic acid was added to a preparation containing a general-purpose thickener, hydroxypropylmethylcellulose, no water transpiration suppression effect was observed.

(6) Moisture transpiration test 2
About the test liquid which has a composition shown in following Table 6, the moisture transpiration | evaporation amount was evaluated using the moisture meter.
The specific test method is as follows.
First, each test solution was prepared by the method described in the item of the light stability test 1, and the viscosity was measured. Subsequently, the moisture transpiration rate of each test solution was measured using a heat drying moisture meter MS-70 (manufactured by A & D Co., Ltd.). The test was performed according to the instruction manual attached to the moisture meter. Specifically, before starting the test, it was operated with UF water at 34 ° C for 3 hours to stabilize the numerical value of the machine, and then the moisture transpiration rate after 60 minutes at 34 ° C using 300 mg of each test solution. (%) Was measured. The moisture transpiration rate (%) was calculated by calculation software (RsFig Ver.2.41M) attached to the moisture meter.

  The results are also shown in Table 6 above. The smaller the value of the moisture transpiration rate (%) in Table 6, the lower the moisture transpiration. As is clear from Table 6, also in the case of the CVP preparation having an initial viscosity of about 200 mPa · s, moisture transpiration was suppressed by combining ε-aminocaproic acid. On the other hand, in the case of a low-viscosity CVP preparation having an initial viscosity of about 60 to 70 mPa · s, an effect of suppressing moisture transpiration by using ε-aminocaproic acid in combination was not recognized.

(7) Effect of amino acid type on viscosity Test solutions of Comparative Examples 16 and 17 having the compositions shown in Table 7 below were prepared. The test solution of Comparative Example 16 contains CVP and boric acid. Further, the test solution of Comparative Example 17 further contains L-arginine, which is an amino acid. The amounts of hydrochloric acid and sodium hydroxide are substantially the same in Comparative Example 16 and Comparative Example 17.

Both test solutions of Comparative Examples 16 and 17 were water bathed at 25 ° C. for 1 hour to stabilize the temperature, and then the viscosity of each test solution was measured by the method described in the item of the light stability test 1.
The results are also shown in Table 7 above. As is apparent from Table 7, the viscosity of the CVP formulation of Comparative Example 16 containing no L-arginine is 773 mPa · s, whereas the viscosity of the CVP formulation of Comparative Example 17 containing L-arginine is 17.7 mPa · s. s.
In many cases, boric acid is blended in an ophthalmic composition for the purpose of, for example, enhancing a buffering action or preserving efficacy. However, when L-arginine, which is another amino acid instead of ε-aminocaproic acid, is added to the high-viscosity CVP preparation containing boric acid, not only the viscosity decrease is suppressed, but the viscosity is remarkably decreased. .

Formulation Examples Formulation examples of the ophthalmic composition of the present invention are shown in Table 8 below. The unit of the content of each component is g / 100 mL.

  The ophthalmic composition of the present invention can be stored for a long period of time even when filled in a general-purpose transparent container because the viscosity reduction due to light exposure is effectively suppressed.

Claims (9)

  An ophthalmic composition comprising a carboxyvinyl polymer and ε-aminocaproic acid or a pharmaceutically acceptable salt thereof and having a viscosity of 200 to 100,000 mPa · s.   The ophthalmic composition according to claim 1, further comprising naphazoline or a pharmaceutically acceptable salt thereof.   The ophthalmic composition according to claim 1, further comprising boric acid.   The ophthalmic composition according to any one of claims 1 to 3, which is filled in a transparent container.   The ophthalmic composition according to any one of claims 1 to 4, which is an eye drop.   An ophthalmic composition is prepared by blending an ophthalmic composition containing a carboxyvinyl polymer with ε-aminocaproic acid or a pharmaceutically acceptable salt thereof to prepare an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s. A method for suppressing a decrease in viscosity due to light irradiation.   An ophthalmic composition is prepared by blending an ophthalmic composition containing a carboxyvinyl polymer with ε-aminocaproic acid or a pharmaceutically acceptable salt thereof to prepare an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s. A method for suppressing the generation of precipitates after drying.   From an ophthalmic composition comprising preparing an ophthalmic composition having a viscosity of 200 to 100,000 mPa · s by blending ε-aminocaproic acid or a pharmaceutically acceptable salt thereof with an ophthalmic composition containing a carboxyvinyl polymer. To suppress moisture transpiration.   An ophthalmic composition having a viscosity of 200 to 100,000 mPa · s by blending naphazoline or a pharmaceutically acceptable salt thereof with an ophthalmic composition containing a carboxyvinyl polymer and ε-aminocaproic acid or a pharmaceutically acceptable salt thereof. A method for improving the liquid drainage performance in a container mouth of a container filled with the ophthalmic composition, which is prepared by a composition.