JPWO2018066651A1 - Ophthalmic product and method for suppressing viscosity reduction - Google Patents

Abstract

(A) Water-soluble polymer compound, (B) One or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate , (C) one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent, and (D) one selected from the group consisting of (D-1) and (D-2) below (D-1) having an ophthalmic composition containing trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, and the like, a container filled with the ophthalmic composition, and an enclosure for packaging the container An ophthalmic product that uses means such as enclosing an oxygen absorber in the enclosure.

Description

  The present invention relates to an ophthalmic product in which a decrease in viscosity of a water-soluble polymer compound is suppressed.

  In an ophthalmic composition, a method is known in which a thickening agent such as a polymer compound is blended for improving effectiveness and maintaining a refreshing sensation to increase drug retention on the ocular surface. The improvement in retention of the active ingredient on the ocular surface is considered to be particularly beneficial for active ingredients that act on corneal epithelial cells on the ocular surface such as vitamin A. In order to maintain a refreshing feeling, a refreshing agent such as menthol is used. Furthermore, since a refreshing component such as vitamin A and menthol is a fat-soluble component, a surfactant is often blended at the same time in order to blend these components into an aqueous eye drop.

  A method of blending vegetable oil such as sesame oil (Patent Document 1: Japanese Patent Laid-Open No. 2005-206598) or a method of blending castor oil (Patent Document 2: Japanese Patent Laid-Open No. 2005) No. -206599), a method of adding mannitol or glycerin (Patent Document 3, JP-A-11-71478) is known. However, the decrease in viscosity of the ophthalmic composition blended with the polymer compound is caused by the influence of various blending components, and a surfactant used when blending fat-soluble components such as vitamin A and menthol was added. At that time, a decrease in viscosity is particularly likely to occur, and the above-described method was not sufficient in suppressing the decrease in viscosity.

  The viscosity of the ophthalmic composition greatly contributes to improving the effectiveness of the drug and the sustainability of the refreshing agent, and also greatly affects the feeling of use resulting from the viscosity. For example, a viscosity that is too high is sticky or sticky, after use. There is a possibility of causing blurring of the field of view. Maintaining the design viscosity of the formulation without changing it is very important in terms of effectiveness and usability in maintaining the quality of the ophthalmic composition. Such a high viscosity stabilization method. Was desired.

JP 2005-206598 A JP 2005-206599 A JP-A-11-71478

  The present inventors have found that an ophthalmic composition containing a polymer compound containing a fat-soluble component such as vitamin A and a surfactant is likely to cause a decrease in viscosity over time, and polyoxyethylene cured castor as a surfactant. It has been found that this is particularly remarkable when oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil or polyethylene glycol monostearate is used. Therefore, it aims at providing the technique which suppresses such a viscosity fall.

  As a result of intensive studies to achieve the above object, the present inventors have formulated specific components and used specific packaging means in an ophthalmic composition containing a polymer compound, a surfactant, and a fat-soluble component. Thus, it has been found that a high viscosity reduction suppressing effect is exhibited. In addition, the ophthalmic composition provided by the present invention exhibits a high retention during instillation and is excellent in a moist feeling sustaining effect.

Accordingly, the present invention provides the following.
[1]. (A) a water-soluble polymer compound,
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate,
(C) one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent, and (D) one or more selected from the group consisting of (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, Contains panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid That the ophthalmic composition, and the ophthalmic composition is filled container, an ophthalmic product which has a enclosure for packaging the containers,
(1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) A container having oxygen absorption capacity or (4) Enclosure having oxygen absorption capacity An ophthalmic product using the above means.
[2]. The ophthalmic product according to [1], wherein the component (D) is one or more from the (D-1) group and one or more from the (D-2) group.
[3]. The ophthalmic product according to [1] or [2], wherein the component (A) is at least one selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and salts thereof. .
[4]. (C) The ophthalmic product according to any one of [1] to [3], wherein the component is one or more selected from retinol palmitate, d-α-tocopherol acetate, dibutylhydroxytoluene, and menthol.
[5]. (A) a water-soluble polymer compound,
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate,
(C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorbent in the enclosure, (3) Container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any one or more means of an enclosure having a function, the ophthalmic composition includes:
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, One or more selected from the group consisting of panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid A method for suppressing a decrease in viscosity of the ophthalmic composition, which comprises blending.
[6]. (A) a water-soluble polymer compound,
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate,
(C) In an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent,
A container filled with the ophthalmic composition; and an enclosure for packaging the container; (1) injection of an inert gas into the enclosure; (2) bundling of an oxygen absorbent into the enclosure; While using any one or more means of (3) a container having oxygen absorption capacity or (4) an enclosure having oxygen absorption capacity,
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, One or more selected from the group consisting of panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid A method for suppressing a decrease in viscosity of the ophthalmic composition, which comprises blending.

  According to the present invention, a high viscosity reduction inhibitory effect can be obtained in a composition containing a polymer compound, a surfactant and a fat-soluble component.

Hereinafter, the present invention will be described in detail.
[(A) component]
Examples of water-soluble polymer compounds include cellulose polymer compounds such as hydroxypropylmethylcellulose (hypromellose), methylcellulose, and hydroxyethylcellulose; polyvinyl polymer compounds such as polyvinylpyrrolidone (povidone) and polyvinyl alcohol; hyaluronic acid and salts thereof; carboxy A vinyl polymer etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. By blending such components, it is possible to impart viscosity to the composition, improve the retention of the blended active ingredients on the ocular surface, and prevent drying of the ocular surface by retaining on the ocular surface. it can. Of these, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, hyaluronic acid and salts thereof are preferable, and hydroxypropylmethylcellulose is more preferable.

  The water solubility of the water-soluble polymer compound is a polymer that can be dissolved in an aqueous solution, and its weight average molecular weight is preferably 5,000 to 5,000,000, more preferably 10,000 to 2,500,000. . In addition, the measurement of a weight average molecular weight can be calculated | required by the measurement by the liquid chromatography using a GPC column.

  The blending amount of the component (A) is preferably 0.01 to 10% (W / V% (mass / volume%, g / 100 mL or less)) in the composition, and more preferably 0.05 to 3%. Moreover, when mix | blending hydroxypropyl methylcellulose, 0.05 to 5% is preferable in a composition, 0.1 to 3% is more preferable, 0.1 to 0.5% is further more preferable. When mix | blending methylcellulose, 0.05 to 5% is preferable in a composition, 0.1 to 3% is more preferable, and 0.1 to 1% is further more preferable. When mix | blending hydroxyethyl cellulose, 0.05 to 5% is preferable in a composition, 0.1 to 3% is more preferable, 0.1 to 1% is further more preferable. When mix | blending polyvinylpyrrolidone, 0.01 to 10% is preferable in a composition, 0.05 to 5% is more preferable, and 0.05 to 3% is further more preferable. When mix | blending a carboxy vinyl polymer, 0.01 to 5% is preferable in a composition, 0.05 to 3% is more preferable, and 0.1 to 1% is further more preferable. When mix | blending hyaluronic acid and its salt, 0.01 to 3% is preferable in a composition, 0.01 to 1% is more preferable, and 0.02 to 1% is further more preferable. The effect of providing a viscosity can be obtained by setting the above. On the other hand, if the amount is too large, the viscosity becomes too high, the fluidity on the surface of the eye is poor, and problems such as blurring and stickiness may occur.

[Component (B)]
The component (B) is one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and polyethylene glycol monostearate.

  Several types of polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) are known depending on the average number of moles of ethylene oxide added to the hydrogenated castor oil. Specifically, polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, Examples include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, and polyoxyethylene hydrogenated castor oil 100. These polyoxyethylene hydrogenated castor oils can be used singly or in appropriate combination of two or more. From the viewpoint of safety, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

  As polyoxyethylene sorbitan fatty acid ester, monolauric acid POE (20) sorbitan (POE is polyoxyethylene, the numerical value is the average added mole number of ethylene oxide, the same applies hereinafter), monopalmitic acid POE (20) sorbitan (polysorbate 40), Examples include monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80), and the like. The above can be used in appropriate combination. Among these, monooleic acid POE (20) sorbitan (polysorbate 80) is preferable.

  As polyoxyethylene castor oil (POE castor oil), polyoxyethylene castor oil having an average addition mole number of ethylene oxide in the range of 3 to 60 mol is preferable. For example, polyoxyethylene castor oil 3 (the numerical value is that of ethylene oxide). Average number of moles added, the same applies hereinafter), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60 Is mentioned. More preferably, ethylene oxide addition mole number is 10-50, More preferably, it is 20-40. Polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil are different components.

  Polyethylene glycol monostearate (polyethylene glycol monostearate) is polyoxyl stearate 10 (polyethylene glycol monostearate (10), the value is the average number of moles of ethylene glycol added, the same applies hereinafter), polyoxyl stearate 40, stearin Acid polyoxyl 45, stearic acid polyoxyl 55, etc. are mentioned, and among them, stearic acid polyoxyl 40 is preferable.

  These surfactants may be used individually by 1 type, and may be used in combination of 2 or more types as appropriate. For example, polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester can be used in appropriate combination. In that case, it is particularly preferable to use a combination of polyoxyethylene hydrogenated castor oil 60 and monooleic acid POE (20) sorbitan (polysorbate 80).

  (B) As for the compounding quantity of a component, 0.01-7% is preferable in a composition as a total amount of (B) component, 0.05-5% is more preferable, 0.1-3% is further more preferable. By setting it to the above lower limit or more, the component (C) and the like can be blended more stably. By setting it to the upper limit or less, there is no fear of irritation due to the component (B).

[Component (C)]
It is 1 or more types of components chosen from vitamin A, vitamin E, dibutylhydroxytoluene, and a refreshing agent, This fat-soluble component can be used individually by 1 type or in combination of 2 or more types. Vitamin A has a corneal wound healing effect and the like, and in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters and the like can be mentioned. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate is preferred.

  When blending vitamin A, the blending amount is preferably 5,000 to 500,000 international units (IU) in 100 mL of the ophthalmic composition, more preferably 10,000 to 100,000 international units (IU), 30 More preferred is 7,000-75,000 international units (IU). A corneal wound healing effect due to vitamin A can be expected at a lower limit value or more, and vitamin A stability can be further obtained at an upper limit value or less.

  Examples of vitamin E include tocopherol acetate (dl-α-tocopherol acetate, d-α-tocopherol acetate (vitamin E)), tocopherol succinate, and derivatives thereof. Of these, d-α-tocopherol acetate is preferred.

  When blending vitamin E, the blending amount is preferably 0.005 to 0.5%, more preferably 0.01 to 0.1% in the ophthalmic composition. The effect and stability can be further improved within the above range.

  When blending dibutylhydroxytoluene, the blending amount is preferably 0.001 to 0.05%, more preferably 0.003 to 0.01% in the ophthalmic composition. The effect and stability can be further improved within the above range.

  As a refreshing agent, menthol, camphor, cool mint, geraniol, mint water, borneol, eucalyptus oil, fennel oil, rose oil, bergamot oil, peppermint oil, spearmint oil, linalool, anethole, eugenol, cineol, N-ethyl- p-menthane-carboxamide etc. are mentioned. These cooling agents can be used singly or in appropriate combination of two or more. Among them, menthol is preferable, and when combining two or more kinds, it is preferable to combine menthol and another cooling agent.

  When blending a refreshing agent, the blending amount is preferably 0.001 to 0.5%, and more preferably 0.005 to 0.3% in the ophthalmic composition. Within the above range, an effect and a good refreshing feeling upon instillation can be obtained.

[(D) component]
(D) It is 1 or more types chosen from the group which consists of following (D-1) and (D-2). (D) By mix | blending a component, the viscosity fall by using the said (A) and (B) component together can be suppressed.
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, Panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid

  Examples of the ethylenediamineacetic acid derivative or salt thereof include edetic acid (ethylenediaminetetraacetic acid), ethylenediaminediacetic acid, diethylenetriaminepentaacetic acid, N- (2-hydroxyethyl) ethylenediaminetriacetic acid, sodium edetate (ethylenediaminetetraacetic acid sodium), ethylenediamine Disodium tetraacetate), and hydrates thereof. Examples of glycyrrhizic acid or a salt thereof include glycyrrhizic acid, dipotassium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, and the like. Examples of chondroitin sulfate or a salt thereof include chondroitin sulfate, chondroitin polysulfate, sodium chondroitin sulfate, and the like. Aspartic acid or a salt thereof includes, for example, sodium L-aspartate, potassium L-aspartate, magnesium L-aspartate, calcium L-aspartate, magnesium L-aspartate and potassium (L-aspartate and L- And an equivalent mixture with potassium aspartate).

  The above can be used alone or in combination of two or more, among which (D-1) component: trometamol and propylene glycol are preferable, and (D-2) component is allantoin, panthenol, chloro. Phenylamine maleate and pyridoxine hydrochloride are preferred. Moreover, when combining 2 or more types, it is preferable that they are 1 or more types from a (D-1) group, and 1 or more types from a (D-2) group.

  (D) 0.001 to 10% is preferable in an ophthalmic composition, the compounding quantity of a component is 0.005 to 5% more preferable, and 0.01 to 3% is further more preferable. By setting it as this range, the viscosity fall by using together the viscosity reduction component by using together said (A) and (B) component can be suppressed more.

  The more preferable compounding quantity in the ophthalmic composition of each component is shown below. Trometamol is 0.01 to 10%, more preferably 0.1 to 5%. Propylene glycol is 0.01 to 10%, more preferably 0.1 to 5%. The ethylenediamineacetic acid derivative or a salt thereof is 0.001 to 2%, more preferably 0.01 to 1.5%. Tetrahydrozoline hydrochloride is 0.001-2%, more preferably 0.01-1%. Epsilon aminocaproic acid is 0.01 to 10%, more preferably 0.1 to 5%. Allantoin is 0.001 to 5%, more preferably 0.01 to 1%. Glycyrrhizic acid or a salt thereof is 0.001 to 5%, more preferably 0.01 to 1%. Chlorpheniramine maleate is 0.001-1%, more preferably 0.003-0.1%. Pyridoxine hydrochloride is 0.001-2%, more preferably 0.01-1%. Panthenol is 0.001-2%, more preferably 0.01-1%. Chondroitin sulfate or a salt thereof is 0.001 to 5%, more preferably 0.01 to 2%. Sodium chloride is 0.01 to 2%, more preferably 0.05 to 1%. Neostigmine methyl sulfate is 0.0001 to 1%, more preferably 0.0005 to 0.1%. Zinc sulfate is 0.001-2%, more preferably 0.025-1%. Flavin adenine dinucleotide sodium is 0.0001 to 1%, more preferably 0.005 to 0.1%. Cyanocobalamin is 0.001-1%, more preferably 0.002-0.1%. Aspartic acid or a salt thereof is 0.01 to 5%, more preferably 0.05 to 2%. Aminoethylsulfonic acid is 0.01 to 5%, more preferably 0.05 to 2%.

  In the ophthalmic composition of the present invention, various components used in the ophthalmic composition can be blended as necessary within a range not impairing the effects of the present invention. Preferred compounding ingredients include drugs, buffers, stabilizers, tonicity agents, antioxidants, preservatives and the like. These can be used individually by 1 type or in combination of 2 or more types, and can mix | blend suitable amount.

  Examples of the drug include a decongestant component other than the component (D), an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial component Or a bactericide component, saccharides, polysaccharides other than (A) component or derivatives thereof, polyhydric alcohol, local anesthetic components, steroid components, glaucoma treatment components, cataract treatment components, mydriasis components and the like. Specific examples are shown below.

  Decongestant: α-adrenergic agonist, for example, imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and their pharmaceutically or physiologically acceptable Salts (for example, inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, and methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate) and the like.

  Ocular muscle regulator component: cholinesterase inhibitor having an active center similar to acetylcholine, tropicamide, atropine sulfate and the like.

  Anti-inflammatory or astringent components: pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemetacin, ibuprofen, thiaprofenic acid, loxoprofen sodium, zinc thiaramide hydrochloride Examples thereof include salts (for example, zinc chloride and zinc lactate), lysozyme, lysozyme hydrochloride, methyl salicylate, sodium azulene sulfonate, berberine chloride, berberine sulfate and the like.

  Antihistamine component or antiallergic component: for example, ketotifen, acitazanolast, diphenhydramine, levocabastine, cromoglycic acid, tranilast, ibudilast, amlexanox, pemirolast and pharmaceutically or physiologically acceptable salts thereof (diphenhydramine hydrochloride, Ketotifen fumarate, sodium cromoglycate, etc.).

  Vitamins: Examples include ascorbic acid, thiamine, niacin, vitamin D, vitamin K, and the like.

  Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, serine, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, γ-amino Examples include butyric acid and glutamic acid.

  Antibacterial component or bactericidal component: sulfonamides (for example, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.) ), Etc.), acrinol, alkylpolyaminoethylglycine, new quinolone (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), β-lactam antibacterial (sulbenicillin, cefmenoxime, etc.), aminoglycoside Antibacterial drugs (kanamycin, gentamicin, tobramycin, sisomycin, dibekacin, bekanamycin, micronomycin, etc.), tetracycline antibacterial drugs (oxytetracycline etc.), macrolide antibacterial drugs ( Risuromaishin etc.), chloramphenicol antibacterials (chloramphenicol), polypeptide antibacterials (colistin, etc.) and the like. In addition, antiviral drugs (idoxuridine, acyclovir, adenine arabinoside, ganciclovir, foscarnet, valacyclovir, trifluorothymidine, cidofovir, carbocyclic oxetanocin G, etc.), antifungal drugs (pimaricin, fluconazole, itraconazole, And miconazole, flucytosine, amphotericin B, etc.).

  Examples of the saccharide include lactulose, raffinose, pullulan, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, mannitol, sorbitol and the like.

  Polysaccharides or derivatives thereof: gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac gum, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, Examples include pectin, starch, polygalacturonic acid (alginic acid), chitin and derivatives thereof, chitosan and derivatives thereof, and elastin.

  Polyhydric alcohols: glycerin, butylene glycol, polyethylene glycol and the like.

  Local anesthetic ingredients: chlorobutanol, lidocaine, oxybuprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilucaine, mepivacaine, bupivacaine, cocaine and their salts (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) .

  Steroid component: Hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, parameterzone, betamethasone and salts thereof can be mentioned.

  Glaucoma treatment ingredients: distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, isopropylunoprostone, dipivefrine hydrochloride, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide, metazolamide Etc.

  Cataract treatment components: pirenoxine, glutathione, salivary gland hormone, thiopronin, Dihydro azapentacene disulfonate and salts thereof (for example, Sodium 5, 12-dihydro azapentene disulfonate) and the like.

  Mydriatic component: cyclopentrate hydrochloride, tropicamide and the like.

  When a drug is compounded, an effective appropriate amount of each drug can be selected as the compounding amount, but 0.0001 in the ophthalmic composition from the viewpoint of eye irritation, composition stability, and the like. It is preferable to be in the range of ˜5%, and it is preferable to be in the range of 0.001 to 5%.

  Examples of the buffer include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, acetic acid, sodium acetate, glacial acetic acid, sodium carbonate. Sodium bicarbonate and sodium sulfite are preferably used. When a buffering agent is blended, the blending amount is preferably in the range of 0.003 to 4% in the composition.

  Examples of the stabilizer include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and the like. When a stabilizer is blended, the blending amount is preferably in the range of 0.003 to 2% in the composition.

  Examples of the isotonic agent include potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium carbonate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen sulfite and the like. When an isotonizing agent is blended, the blending amount is preferably in the range of 0.001 to 3% in the composition.

  Examples of the antioxidant include butylhydroxyanisole (BHA), hydroquinone, propyl gallate, sodium hydrogen sulfite and the like. When the antioxidant is blended, the blending amount is preferably in the range of 0.001 to 1% in the composition.

  Examples of preservatives include parabens such as benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, chlorobutanol, paraoxybenzoate, polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, Examples include polyhexamethylene biguanide. When mix | blending antiseptic | preservative, it is preferable that the compounding quantity is the range of 0.0001-0.5% in a composition, and it is more preferable that it is the range of 0.001-0.5%. Furthermore, when prescribing vitamin A having a corneal wound healing effect or the like as the component (C), in order to further reduce irritation to the cornea and to make a safer composition, these preservatives are not added. Most preferred.

  The ophthalmic composition of the present invention can be produced by a known production method with the balance being water. For example, each of the above components can be obtained by dissolving in sterilized purified water, water such as ion exchange water, or a mixed solvent with water. Preferably, after dissolving a fat-soluble component such as the component (C) in the surfactant of the component (B), the solution is charged into a high-temperature (70 to 95 ° C.) aqueous solution in which other aqueous components are dissolved, and then the pH is adjusted. Furthermore, it can be obtained by adjusting the osmotic pressure and the like appropriately with a pH adjusting agent and an isotonizing agent as required.

  Examples of the pH regulator include hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like. The pH (20 ° C.) of the ophthalmic composition of the present invention is preferably 3.5 to 8.0, more preferably 4.5 to 7.7, and still more preferably 5.5 to 7.5. If the pH is too low or too high, the feeling of irritation can be strong. The pH is measured at 20 ° C. using a pH osmometer (HSMO-1, Toa DKK). As the pH adjuster, sodium hydroxide, potassium hydroxide, hydrochloric acid and the like are preferable.

[Ophthalmic composition]
The ophthalmic composition of the present invention is preferably a liquid, and the viscosity at 20 ° C. is preferably 1 to 400 mPa · s, more preferably 1 to 100 mPa · s, further preferably 1 to 60 mPa · s, and 1 to 30 mPa · s. Particularly preferred. The viscosity is measured using a B-type viscometer.

  The ophthalmic composition of the present invention can be used as a preparation for use in contact lens care in addition to pharmaceuticals and quasi drugs applied to the eye. For example, eye drops (including eye drops for general use, artificial tears, eye drops that can be instilled while wearing contact lenses, etc.), eye wash (eye wash to be used for naked eyes, eye wash that can be washed while wearing contact lenses, Contact lens removal solution, contact lens removal solution, contact lens care solution (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens) Can be used as preservatives for isolated corneas for transplantation, eye ointments and the like. Among these, eye drops, eye washes, and contact lens mounting liquids are suitable preparation forms of the ophthalmic composition of the present invention, and eye drops are particularly preferable. In addition, in this specification, when it only describes with a contact lens, all contact lenses including a hard contact lens and a soft contact lens are included.

[Ophthalmic products]
The present invention is an ophthalmic product comprising an ophthalmic composition, a container filled with the ophthalmic composition, and an enclosure for packaging the container, wherein the oxygen concentration in the ophthalmic composition is reduced. Using the means stored in a wet state, it is possible to further suppress the decrease in viscosity due to the combined use of the above components (A) and (B). Means include (1) injecting inert gas into the enclosure, (2) bundling of oxygen absorbent into the enclosure, (3) container having oxygen absorption capacity, or (4) enclosure having oxygen absorption capacity. Etc. By such means, a decrease in viscosity due to the combined use of the above components (A) and (B) can be further suppressed. The enclosure is preferably capable of sealing the container.

The container is preferably a plastic container, and materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials can be used. Polyethylene terephthalate is particularly preferable. The oxygen permeability coefficient of the container is preferably 10 cc / m ² · 24 hr · atm or more. The amount of the ophthalmic composition in the product can be appropriately selected according to the product and its method of use. For example, in the case of eye drops, 2 to 20 mL is preferable, and 5 to 20 mL is more preferable. Further, the capacity of the container is preferably appropriately selected according to the amount of the ophthalmic composition to be filled, and is preferably 100 to 150% with respect to the amount of the ophthalmic composition to be filled. For example, in the case of eye drops, 2 to 30 mL is preferable. The eye drop is not particularly limited, and may be a multi-dose eye drop or a disposable eye drop.

Examples of the envelope include polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, polyvinyl alcohol / polyamide film deposited with aluminum, and polyvinylidene chloride. Examples thereof include composites such as films and laminate films, and multilayer films. Oxygen permeability coefficient of the ^{enclosure, 10cc / m 2 · 24hr ·} atm or less ^{(i.e., 0~10cc / m 2 · 24hr ·} atm) oxygen-permeable enclosure is preferred.

(1) Inert gas injection into enclosure The inert gas includes nitrogen, helium, neon, argon, and the like. Of these, nitrogen gas is preferred. The concentration of the inert gas is preferably 50% by volume or more, more preferably 80% by volume or more, and still more preferably 90% by volume or more in the space volume formed between the enclosure and the plastic container. An upper limit is not specifically limited, It is 100 volume% or less. In order to achieve such a concentration, the space formed between the enclosure and the plastic container may be replaced with an inert gas.

(2) Enclosure of oxygen absorber in the enclosure Specifically, AGELESS (registered trademark) manufactured by Mitsubishi Gas Chemical Co., Ltd. (FX, SP, SS, SPE, ZP, Z-PT, Z-PKC, GLS, GL-M, Z-20PK), Pharmakeep, Tokiwa Sangyo Co., Ltd., Vitalon Co., Ltd., Hiroyo Sansores Co., Ltd., Powder Tech Co., Ltd. Wonderkeep Co., Ltd. A manufactured sanso cut or the like can be used.

(3) Container having oxygen absorbing ability Specifically, an oxyblock manufactured by Toyo Seikan Co., Ltd., an oxyvanish manufactured by Mitsubishi Gas Chemical Co., Ltd., or the like can be used.

(4) Enclosed body having oxygen absorbing ability Specifically, Oxycatch (registered trademark) ICA manufactured by Kyodo Printing Co., Ltd., Cryovac (registered trademark) OS film manufactured by Shield Air Co., Ltd., manufactured by Star Plastic Industry Histar O2, Noge Omega manufactured by Mitsubishi Gas Chemical Co., Ltd., Oxydec manufactured by Toyo Seikan Co., Ltd., and the like can be used.

  The above means can be combined as appropriate, (2) and (4) are preferred, and (1) + (2) and (1) + (4) are more preferred.

The present invention provides (A) a water-soluble polymer compound,
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate,
(C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorbent in the enclosure, (3) Container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any one or more means of an enclosure having a function, the ophthalmic composition includes:
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, One or more selected from the group consisting of panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid Provided is a method for suppressing a decrease in the viscosity of an ophthalmic composition, which is characterized by being formulated. Suitable ones, amounts, etc. are the same as above.

The present invention provides (A) a water-soluble polymer compound,
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate,
(C) In an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent,
A container filled with the ophthalmic composition; and an enclosure for packaging the container; (1) injection of an inert gas into the enclosure; (2) bundling of an oxygen absorbent into the enclosure; While using any one or more means of (3) a container having oxygen absorption capacity or (4) an enclosure having oxygen absorption capacity,
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, One or more selected from the group consisting of panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid A method for suppressing a decrease in the viscosity of the ophthalmic composition is provided. Suitable ones, amounts, etc. are the same as above.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In addition, W / V% of a composition is g / 100mL.

[Examples and Comparative Examples]
The ophthalmic composition having the composition shown in the following table is shown in the following table by dissolving the fat-soluble component in the component (B) and then injecting it into a high-temperature (70 to 95 ° C.) aqueous solution in which other aqueous solution components are dissolved. A compositional ophthalmic composition was prepared. After the obtained ophthalmic composition (15 mL) was filled in a polyethylene terephthalate eye drop container (16 mL), an oxygen absorbent (AGELESS: Z-20PK manufactured by Mitsubishi Gas Chemical Co., Ltd.) was included in the film packaging ( Enclosed body). Moreover, about the comparative example 4 and Examples 4-1 to 4-4, and the comparative example 6 and Examples 6-1 to 6-3, the film (Ageless Omak: Mitsubishi Gas Chemical Co., Ltd.) which has oxygen absorption ability The product was made into a package (enclosure). The oxygen permeability coefficient of the enclosure is 10 cc / m ² · 24 hr · atm or less. The viscosity before storage was measured with a B-type viscometer (digital viscometer DV2T, manufactured by Eiko Seiki Co., Ltd.) and stored for 2 months in an environment of 50 ° C. and 75% RH. After storage, the eye drops were returned to room temperature (20 ° C.) and measured in the same manner as before storage. Based on the following formula, the viscosity retention rate (%) of each example was determined from the obtained viscosity, and the viscosity retention rate enhancement effect (%) was calculated as follows.
Viscosity maintenance ratio (%) = viscosity after storage / viscosity before storage × 100
Viscosity retention rate enhancement effect (%) = [viscosity retention rate of each example (%) / viscosity retention rate of comparative example corresponding to each example (%)-1] × 100
In addition, the comparative example corresponding to each Example means the comparative example which does not contain (D) component.

  The decrease in viscosity of the ophthalmic composition due to the combination of the components (A) and (B) can be suppressed by the addition of the component (D), and the retention effect on the ocular surface such as active ingredients and cooling agents can be maintained.

[Prescription example]
The ophthalmic product filled with the ophthalmic composition having the composition shown in the following table in the container described in the present invention and packaged in the packaging form described in the present invention is suppressed in viscosity reduction over time, and maintains its effectiveness and refreshing feeling It can be used as an eye drop having excellent properties and a long-lasting moist feeling. In particular, Formulation Examples 3, 5, and 10-12 are suitable as eye drops for contacts that can be instilled even when a soft contact lens is worn.

The raw materials used in the above examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Hydroxypropyl methylcellulose: Metroles 60SH-4000, JP, Shin-Etsu Chemical Co., Ltd., weight average molecular weight of about 300,000 (g / mol)
Methylcellulose: Metroles SM-4000, JP, Shin-Etsu Chemical Co., Ltd., weight average molecular weight of about 360,000 (g / mol)
Hydroxyethyl cellulose: HEC-CF-V, supplementary regulations, Sumitomo Seika Co., Ltd., weight average molecular weight of about 1 million (g / mol)
Polyvinylpyrrolidone: Kollidon 90F, JP, BASF Corporation, weight average molecular weight 1 million (g / mol)
Carboxyvinyl polymer: Carbopol (registered trademark) 971PNF, supplementary regulations, Lubrizol Corporation Sodium hyaluronate: Biohyaluronate sodium, Shiseido Co., Ltd.
・ Polyoxyethylene hydrogenated castor oil 60: HCO60, supplementary regulations, Nippon Surfactant Co., Ltd.
Monooleic acid POE (20) sorbitan (polysorbate 80): Rheodor TW-0120V, Kao Corporation
・ Polyoxyethylene castor oil 35: NIKKOL CO-35, Nikko Chemicals Corporation
・ Polyoxyl stearate 40: NIKKOL MYS-40MV, Nikko Chemicals Co., Ltd.
-Retinol palmitate: Retinol palmitate, JP, DSM Nutrition Japan Co., Ltd.
-D-α-tocopherol acetate: RIKEN E Acetate α, Extraordinary Code, RIKEN Vitamin Co., Ltd.
・ Dibutylhydroxytoluene: Dibutylhydroxytoluene, supplementary regulations, Wako Pure Chemical Industries, Ltd.
As the component (D) and other optional components, various raw materials conforming to official standards (Japanese Pharmacopoeia, Japanese Pharmacopoeia Pharmaceutical Standards, Pharmaceutical Additive Standards, etc.) standards were used.

Claims (6)

(A) a water-soluble polymer compound,
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate,
(C) one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent, and (D) one or more selected from the group consisting of (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, Contains panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid That the ophthalmic composition, and the ophthalmic composition is filled container, an ophthalmic product which has a enclosure for packaging the containers,
(1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorber into the enclosure, (3) A container having oxygen absorption capacity or (4) Enclosure having oxygen absorption capacity An ophthalmic product using the above means.   The ophthalmic product according to claim 1, wherein the component (D) is one or more from the group (D-1) and one or more from the (D-2) group.   The ophthalmic product according to claim 1 or 2, wherein the component (A) is one or more selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and salts thereof.   The ophthalmic product according to any one of claims 1 to 3, wherein the component (C) is one or more selected from retinol palmitate, d-α-tocopherol acetate, dibutylhydroxytoluene and menthol. (A) a water-soluble polymer compound,
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate,
(C) an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent, a container filled with the ophthalmic composition, and the container (1) Inert gas injection into the enclosure, (2) Enclosure of oxygen absorbent in the enclosure, (3) Container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any one or more means of an enclosure having a function, the ophthalmic composition includes:
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, One or more selected from the group consisting of panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid A method for suppressing a decrease in viscosity of the ophthalmic composition, which comprises blending. (A) a water-soluble polymer compound,
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate,
(C) In an ophthalmic composition containing one or more fat-soluble components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a refreshing agent,
A container filled with the ophthalmic composition; and an enclosure for packaging the container; (1) injection of an inert gas into the enclosure; (2) bundling of an oxygen absorbent into the enclosure; While using any one or more means of (3) a container having oxygen absorption capacity or (4) an enclosure having oxygen absorption capacity,
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamineacetic acid derivative, ethylenediamineacetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, One or more selected from the group consisting of panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid A method for suppressing a decrease in viscosity of the ophthalmic composition, which comprises blending.