JP7120018B2 - OPHTHALMIC PRODUCT AND METHOD FOR CONTROLLING VISCOSITY REDUCTION - Google Patents

Description

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

In ophthalmic compositions, a method is known in which thickening agents such as polymer compounds are blended in order to improve effectiveness and maintain a refreshing sensation, thereby increasing drug retention on the ocular surface. Improving retention of active ingredients on the ocular surface is considered particularly beneficial for active ingredients that act on corneal epithelial cells on the ocular surface, such as vitamin A. In addition, a cooling agent such as menthol is used to maintain a refreshing feeling. Furthermore, since cooling ingredients such as vitamin A and menthol are fat-soluble ingredients, surfactants are often added at the same time when these ingredients are added to aqueous eye drops.

In order to suppress the viscosity decrease of the cellulose polymer compound, a method of blending vegetable oil such as sesame oil (Patent Document 1: JP-A-2005-206598) and a method of blending castor oil (Patent Document 2: JP-A-2005) -206599), and a method of adding mannitol or glycerin (Patent Document 3, JP-A-11-71478). However, the decrease in viscosity of ophthalmic compositions containing polymer compounds is caused by the influence of various ingredients, and surfactants used when formulating fat-soluble ingredients such as vitamin A and menthol are added. In some cases, a decrease in viscosity is particularly likely to occur, and the above-described methods have not been sufficiently effective in suppressing a decrease in viscosity.

The viscosity of the ophthalmic composition greatly contributes to improving the effectiveness of the drug and the durability of the cooling agent, and also greatly affects the feeling of use caused by the viscosity. There is a possibility that it may cause a blurry feeling in the field of vision. Maintaining the design viscosity of the formulation without changing it as much as possible is very important in maintaining the quality of the ophthalmic composition, both in terms of effectiveness and in terms of feeling during use. was desired.

Japanese Patent Application Laid-Open No. 2005-206598 JP-A-2005-206599 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. It has been found to be particularly noticeable when oils, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil or polyethylene glycol monostearate are used. Accordingly, it is an object of the present invention to provide a technique for suppressing such a decrease in viscosity.

As a result of intensive studies to achieve the above object, the present inventors have found that an ophthalmic composition containing a polymer compound, a surfactant and a fat-soluble component contains specific components and uses specific packaging means. As a result, it was found that a high effect of suppressing a decrease in viscosity was exhibited. In addition, the ophthalmic composition provided by the present invention exhibits high staying power when instilled into the eye, and is excellent in sustaining moist feeling.

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 cooling agents, and (D) one or more selected from the group consisting of (D-1) and (D-2) below (D-1) trometamol, propylene glycol (D-2) ethylenediamine acetic acid derivative, ethylenediamine acetic acid derivative salt, tetrahydrozoline hydrochloride, epsilon aminocaproic acid, allantoin, glycyrrhizic acid, glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, an ophthalmic composition containing panthenol, chondroitin sulfate, chondroitin sulfate, sodium chloride, neostigmine methyl sulfate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, aspartic acid, aspartate, aminoethylsulfonic acid; An ophthalmic product comprising a container filled with an ophthalmic composition and an enclosure for packaging the container,
(1) Injecting an inert gas into the enclosure, (2) Packing an oxygen absorbent into the enclosure, (3) A container having oxygen absorption capacity, or (4) An enclosure having oxygen absorption capacity An ophthalmic product using the above means.
[2]. The ophthalmic product according to [1], wherein component (D) is at least one member from group (D-1) and at least one member from group (D-2).
[3]. The ophthalmic product according to [1] or [2], wherein component (A) is one or more selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, hyaluronic acid and salts thereof. .
[4]. The ophthalmic product according to any one of [1] to [3], wherein component (C) 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 ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent; a container filled with the ophthalmic composition; (1) Injecting an inert gas into the enclosure, (2) Enclosing an oxygen absorbent in the enclosure, (3) A container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any one or more means of an enclosure having the ability to:
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamine acetic acid derivative, ethylenediamine acetic 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, and aminoethylsulfonic acid A method for suppressing a decrease in the viscosity of the above ophthalmic composition, characterized in that the ophthalmic composition is blended.
[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) an ophthalmic composition containing one or more fat-soluble ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent,
The composition comprises a container filled with the ophthalmic composition and an envelope for packaging the container, wherein (1) inert gas is injected into the envelope, (2) an oxygen absorber is packed into the envelope, (3) a container having an oxygen absorbing capacity or (4) an envelope having an oxygen absorbing capacity;
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamine acetic acid derivative, ethylenediamine acetic 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, and aminoethylsulfonic acid A method for suppressing a decrease in the viscosity of the above ophthalmic composition, characterized in that the ophthalmic composition is blended.

ADVANTAGE OF THE INVENTION According to this invention, the composition containing a high molecular compound, surfactant, and a fat-soluble component can acquire the high viscosity reduction inhibitory effect.

The present invention will be described in detail below.
[(A) component]
Examples of water-soluble polymer compounds include cellulosic polymer compounds such as hydroxypropyl methylcellulose (hypromellose), methylcellulose and hydroxyethyl cellulose; polyvinylpyrrolidone (povidone), polyvinyl alcohol and other such polyvinyl polymer compounds; A vinyl polymer etc. are mentioned and it can use individually by 1 type or in combination of 2 or more types as appropriate. By blending such components, viscosity is imparted to the composition, retention of the blended active ingredient on the ocular surface is improved, and the retention of the active ingredient on the ocular surface prevents drying of the ocular surface. can. Among them, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, hyaluronic acid and salts thereof are preferred, and hydroxypropylmethylcellulose is more preferred.

The water-soluble 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. . The weight average molecular weight can be determined by liquid chromatography using a GPC column.

The blending amount of component (A) is preferably 0.01 to 10% (W/V % (mass/volume %, g/100 mL and below)) in the composition, more preferably 0.05 to 3%. When hydroxypropylmethylcellulose is blended, it is preferably 0.05 to 5%, more preferably 0.1 to 3%, even more preferably 0.1 to 0.5% in the composition. When methylcellulose is blended, it is preferably 0.05 to 5%, more preferably 0.1 to 3%, even more preferably 0.1 to 1% in the composition. When blending hydroxyethyl cellulose, it is preferably 0.05 to 5%, more preferably 0.1 to 3%, even more preferably 0.1 to 1% in the composition. When polyvinylpyrrolidone is blended, it is preferably 0.01 to 10%, more preferably 0.05 to 5%, even more preferably 0.05 to 3% in the composition. When a carboxyvinyl polymer is blended, it is preferably 0.01 to 5%, more preferably 0.05 to 3%, even more preferably 0.1 to 1% in the composition. When hyaluronic acid or a salt thereof is added, it is preferably 0.01 to 3%, more preferably 0.01 to 1%, even more preferably 0.02 to 1% in the composition. By setting the content to be not less than the above, the effect of imparting viscosity can be obtained. On the other hand, when the amount is too large, the viscosity becomes too high, the fluidity on the eye surface is poor, and there is a risk of causing problems such as blurring and stickiness.

[(B) Component]
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.

As polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil), several types are known depending on the average number of moles of ethylene oxide added to hydrogenated castor oil. Specifically, polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average number of added moles of ethylene oxide, the same shall apply hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, Polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, polyoxyethylene hydrogenated castor oil 100 and the like. These polyoxyethylene hydrogenated castor oils can be used singly or in 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.

Examples of polyoxyethylene sorbitan fatty acid esters include POE (20) sorbitan monolaurate (POE is polyoxyethylene, the numerical value is the average number of moles of ethylene oxide added, the same shall apply hereinafter), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65), POE (20) sorbitan monooleate (polysorbate 80) and the like. The above can be used in combination as appropriate. Among them, POE (20) sorbitan monooleate (polysorbate 80) is preferred.

Polyoxyethylene castor oil (POE castor oil) is preferably polyoxyethylene castor oil having an average number of moles of ethylene oxide added in the range of 3 to 60 mol. average number of added moles, hereinafter the same), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60 are mentioned. The number of moles of ethylene oxide to be added is more preferably 10-50, more preferably 20-40. Polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil are different components.

Polyethylene glycol monostearate (polyethylene glycol monostearate ester) includes polyoxyl 10 stearate (polyethylene glycol (10) monostearate, the numerical value is the average number of added moles of ethylene glycol, the same shall apply hereinafter), polyoxyl 40 stearate, stearin Polyoxyl 45 stearate, polyoxyl 55 stearate, etc. are mentioned, and among them, polyoxyl 40 stearate is preferable.

These surfactants may be used singly or in combination of two or more. For example, a suitable combination of polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester can be used. In that case, it is particularly preferable to use a combination of polyoxyethylene hydrogenated castor oil 60 and POE (20) sorbitan monooleate (polysorbate 80).

The blending amount of component (B) is preferably 0.01 to 7%, more preferably 0.05 to 5%, and even more preferably 0.1 to 3% as the total amount of component (B) in the composition. By making it more than the said minimum, (C)component etc. can be mix|blended more stably. By making it below the upper limit, there is no risk of stimulating feeling due to the component (B).

[(C) component]
It is one or more components selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent, and these fat-soluble components can be used singly or in combination of two or more. 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 and vitamin A derivatives such as vitamin A fatty acid esters can be used. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Among them, retinol palmitate is preferred.

When vitamin A is blended, the blending amount is preferably 5,000 to 500,000 international units (IU), more preferably 10,000 to 100,000 international units (IU) in 100 mL of the ophthalmic composition, and 30 ,000 to 75,000 International Units (IU) are more preferred. A corneal wound healing effect by vitamin A can be expected at the lower limit or more, and the stability of vitamin A can be further obtained at the upper limit or less.

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

When vitamin E is added, its content is preferably 0.005 to 0.5%, more preferably 0.01 to 0.1%, in the ophthalmic composition. Within the above range, more effect and stability can be achieved.

When dibutylhydroxytoluene is added, its content is preferably 0.001 to 0.05%, more preferably 0.003 to 0.01%, in the ophthalmic composition. Within the above range, more effect and stability can be achieved.

Cooling agents include 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- and p-menthane-carboxamide. These cooling agents can be used singly or in combination of two or more. Among them, menthol is preferred, and when two or more are combined, it is preferred to combine menthol with other cooling agents.

When a cooling agent is blended, its blending amount is preferably 0.001 to 0.5%, more preferably 0.005 to 0.3%, in the ophthalmic composition. Within the above range, it is possible to obtain an effect and a good cooling sensation at the time of instillation.

[(D) Component]
(D) One or more selected from the group consisting of (D-1) and (D-2) below. By blending the component (D), it is possible to suppress the decrease in viscosity due to the combined use of the components (A) and (B).
(D-1) trometamol, propylene glycol (D-2) ethylenediamine acetic acid derivative, ethylenediamine acetic 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 ethylenediamineacetic acid derivatives or salts thereof include edetic acid (ethylenediaminetetraacetic acid), ethylenediaminediacetic acid, diethylenetriaminepentaacetic acid, N-(2-hydroxyethyl)ethylenediaminetriacetic acid, sodium edetate (ethylenediaminetetraacetic acid sodium), ethylenediamine. disodium tetraacetate), hydrates thereof, and the like. Examples of glycyrrhizic acid or salts thereof include glycyrrhizic acid, dipotassium glycyrrhizinate, disodium glycyrrhizinate, and diammonium glycyrrhizinate. Examples of chondroitin sulfate or salts thereof include chondroitin sulfate, chondroitin polysulfate, chondroitin sulfate sodium, and the like. Examples of aspartic acid or salts thereof include sodium L-aspartate, potassium L-aspartate, magnesium L-aspartate, calcium L-aspartate, magnesium and potassium L-aspartate (magnesium L-aspartate and L- an equivalent mixture with potassium aspartate) and the like.

The above can be used alone or in combination of two or more. Among them, component (D-1): trometamol and propylene glycol are preferred, and component (D-2) includes allantoin, panthenol and chlorine. Pheniramine maleate, pyridoxine hydrochloride are preferred. Further, when two or more kinds are combined, it is preferable that one or more kinds are selected from the (D-1) group and one or more kinds are selected from the (D-2) group.

The amount of component (D) is preferably 0.001 to 10%, more preferably 0.005 to 5%, and even more preferably 0.01 to 3% in the ophthalmic composition. Within this range, it is possible to further suppress the decrease in viscosity due to the combined use of the components (A) and (B) that reduce the viscosity.

Preferred amounts of each component in the ophthalmic composition are shown below. Trometamol is 0.01-10%, more preferably 0.1-5%. Propylene glycol is 0.01-10%, more preferably 0.1-5%. The ethylenediamine acetic acid derivative or its salt is 0.001 to 2%, more preferably 0.01 to 1.5%. Tetrahydrozoline hydrochloride is 0.001 to 2%, more preferably 0.01 to 1%. Epsilon aminocaproic acid is 0.01-10%, more preferably 0.1-5%. Allantoin is 0.001-5%, more preferably 0.01-1%. Glycyrrhizic acid or its salt 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 its salt is 0.001 to 5%, more preferably 0.01 to 2%. Sodium chloride is 0.01-2%, more preferably 0.05-1%. Neostigmine methyl sulfate is 0.0001-1%, more preferably 0.0005-0.1%. Zinc sulfate is 0.001-2%, more preferably 0.025-1%. Flavin adenine dinucleotide sodium is 0.0001-1%, more preferably 0.005-0.1%. Cyanocobalamin is 0.001-1%, more preferably 0.002-0.1%. Aspartic acid or its salt is 0.01 to 5%, more preferably 0.05 to 2%. Aminoethylsulfonic acid is 0.01-5%, more preferably 0.05-2%.

The ophthalmic composition of the present invention may optionally contain various components used in the ophthalmic composition as long as the effects of the present invention are not impaired. Preferred ingredients include drugs, buffers, stabilizers, tonicity agents, antioxidants, preservatives and the like. These can be used singly or in combination of two or more, and can be blended in an appropriate amount.

Drugs include, for example, decongestant components other than component (D), ocular muscle modulator components, anti-inflammatory drug components or astringent drug components, antihistamine drug components or anti-allergic drug components, vitamins, amino acids, antibacterial drug components Alternatively, bactericidal components, saccharides, polysaccharides other than component (A) or derivatives thereof, polyhydric alcohols, local anesthetic components, steroid components, glaucoma therapeutic components, cataract therapeutic components, mydriatic components and the like. Specific examples are shown below.

Decongestant components: α-adrenergic agonists such as 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, methylephedrine hydrochloride; organic acid salts such as epinephrine bitartrate) and the like.

Ingredients for ocular muscle modulators: cholinesterase inhibitors, tropicamide, atropine sulfate, etc., which have active centers similar to those of acetylcholine.

Anti-inflammatory or astringent ingredients: pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemethacin, ibuprofen, tiaprofenic acid, loxoprofen sodium, tiaramide hydrochloride, zinc. Salts (eg, zinc chloride, zinc lactate, etc.), lysozyme, lysozyme hydrochloride, methyl salicylate, sodium azulene sulfonate, berberine chloride, berberine sulfate and the like.

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

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 butyric acid, glutamic acid and the like.

Antibacterial agent or bactericidal agent: sulfonamides (e.g., sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.) ), etc.), acrinol, alkylpolyaminoethylglycine, new quinolones (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), β-lactam antimicrobials (sulbenicillin, cefmenoxime, etc.), aminoglycosides Antibacterial agents (kanamycin, gentamicin, tobramycin, sisomycin, dibekacin, bekanamycin, micronomycin, etc.), tetracycline antibacterial agents (oxytetracycline, etc.), macrolide antibacterial agents (erythromycin, etc.), chloramphenicol antibacterial agents ( chloramphenicol, etc.), polypeptide antibacterial agents (colistin, etc.), etc. In addition, antiviral drugs (idoxuridine, acyclovir, adenine arabinoside, ganciclovir, foscarnet, valacyclovir, trifluorothymidine, cidofovir, carbocyclic oxetanosine G, etc.), antifungal drugs (pimaricin, fluconazole, itraconazole, miconazole, flucytosine, amphotericin B, etc.) and the like.

Sugars 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 butter, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid (alginic acid), chitin and its derivatives, chitosan and its derivatives, elastin and the like.

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

Local anesthetic ingredients: chlorobutanol, lidocaine, oxybuprocaine, zipcaine, procaine, ethyl aminobenzoate, meprilcaine, mepivacaine, bupivacaine, cocaine and salts thereof (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.), etc. .

Steroid components: hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, paramethasone, betamethasone, salts thereof, and the like.

Glaucoma therapeutic ingredients: distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, isopropyl unoprostone, dipivefrin hydrochloride, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide, methazolamide etc.

Cataract treatment ingredients: pirenoxine, glutathione, salivary gland hormones, thiopronin, dihydro azapentacene disulfonate and salts thereof (eg, Sodium 5,12-dihydro azapentacene disulfonate, etc.) and the like.

Mydriatic component: cyclopentolate hydrochloride, tropicamide and the like.

When a drug is compounded, the compounding amount can be selected to be an effective and appropriate amount of each drug. It is preferably in the range of -5%, preferably in the range of 0.001-5%.

Examples of buffering agents 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 blending a buffering agent, the blending amount is preferably in the range of 0.003 to 4% in the composition.

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

Examples of isotonizing agents 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 a tonicity agent is blended, its blending amount is preferably in the range of 0.001 to 3% in the composition.

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

Examples of antiseptics include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, chlorobutanol, parabens such as paraoxybenzoic acid esters, polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, and polyhexamethylene biguanide. When a preservative is blended, its blending amount is preferably in the range of 0.0001 to 0.5%, more preferably in the range of 0.001 to 0.5%. Furthermore, when vitamin A, which has a corneal wound healing effect, etc., is blended as the component (C), these preservatives are not blended in order to further reduce irritation to the cornea and to make the composition safer. is most preferred.

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

Examples of pH adjusters 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, still more preferably 5.5 to 7.5. If the pH is too low or too high, the feeling of stimulation may become strong. The pH is measured at 20° C. using a pH osmometer (HSMO-1, Toa DKK Co., Ltd.). Sodium hydroxide, potassium hydroxide, hydrochloric acid and the like are preferable as the pH adjuster.

[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, still more preferably 1 to 60 mPa·s, further preferably 1 to 30 mPa·s. Especially preferred. The viscosity is measured using a Brookfield viscometer.

The ophthalmic composition of the present invention can be used as pharmaceuticals and quasi-drugs applied to eyes, as well as preparations for contact lens care. For example, eye drops (general eye drops, artificial tears, eye drops that can be instilled while wearing contact lenses, etc.), eye washes (eye wash used for the naked eye, eye wash that can be washed while wearing contact lenses, eyewash, etc. used after removing contact lenses), contact lens fitting solution, contact lens removal solution, contact lens care agents (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens (including preservatives for cleaning and preservatives), preservatives for excised corneas for transplantation, eye ointments, and the like. Among these, eye drops, eye washes and contact lens wetting solutions are suitable formulation forms of the ophthalmic composition of the present invention, and eye drops are particularly preferred. In addition, in this specification, when simply describing 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. By using a means for storing the composition in a stable state, it is possible to further suppress the decrease in viscosity due to the combined use of the components (A) and (B). Means include (1) injecting an inert gas into the enclosure, (2) enclosing an oxygen absorbent in the enclosure, (3) a container having oxygen absorption capacity, or (4) an enclosure having oxygen absorption capacity. etc. By such means, it is possible to further suppress the decrease in viscosity due to the combined use of the components (A) and (B). In addition, it is preferable that the enclosure can seal the container.

As the container, a plastic container is preferable, and a container made of a material such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials can be used. Polyethylene terephthalate is particularly preferred. 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 usage. For example, in the case of eye drops, the amount is preferably 2-20 mL, more preferably 5-20 mL. Also, the volume of the container is preferably selected appropriately according to the amount of the ophthalmic composition to be filled, preferably 100 to 150% of the amount of the ophthalmic composition to be filled. For eye drops, for example, 2 to 30 mL is preferred. The eye drops are not particularly limited, and may be multi-dose eye drops or disposable eye drops.

Examples of the enclosure include polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, polyvinyl alcohol-based/polyamide-based film deposited with aluminum, and polyvinylidene chloride coated. Examples thereof include films, laminated films, composites thereof, multilayer films, and the like. An oxygen-impermeable enclosure having an oxygen permeability coefficient of 10 cc/m ² ·24 hr·atm or less (that is, 0 to 10 cc/m ² ·24 hr·atm) is preferable.

(1) Injection of Inert Gas into the Enclosure Nitrogen, helium, neon, argon and the like can be used as the inert gas. Among them, 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. The upper limit is not particularly limited, and is 100% by volume or less. In order to obtain such a concentration, the space formed between the enclosure and the plastic container should be replaced with an inert gas.

(2) Packing an oxygen absorber in the enclosure GLS, GL-M, Z-20PK Ya), Pharmakeep, Vitalon manufactured by Tokiwa Sangyo Co., Ltd., Sunsoles manufactured by Hakuyo Co., Ltd., Wonderkeep manufactured by Powdertech Co., Ltd., Iris Fine Products Co., Ltd. Sanso Cut manufactured by Sanso Cut, etc. can be used.

(3) Container having Oxygen Absorbing Capacity Specifically, Oxyblock manufactured by Toyo Seikan Co., Ltd., Oxyvanish manufactured by Mitsubishi Gas Chemical Co., Ltd., and the like can be used.

(4) Enclosure having oxygen absorption capacity 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 Co., Ltd. Hyster O2 manufactured by Mitsubishi Gas Chemical Co., Ltd., Ageless Omac 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, with (2) and (4) being preferred, and (1)+(2) and (1)+(4) being 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 ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent; a container filled with the ophthalmic composition; (1) Injecting an inert gas into the enclosure, (2) Enclosing an oxygen absorbent in the enclosure, (3) A container having oxygen absorption capacity, or (4) Oxygen absorption In an ophthalmic product using any one or more means of an enclosure having the ability to:
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamine acetic acid derivative, ethylenediamine acetic 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, and aminoethylsulfonic acid Provided is a method for suppressing a decrease in viscosity of an ophthalmic composition, characterized by blending. Preferred substances, 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) an ophthalmic composition containing one or more fat-soluble ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and a cooling agent,
The composition comprises a container filled with the ophthalmic composition and an envelope for packaging the container, wherein (1) inert gas is injected into the envelope, (2) an oxygen absorber is packed into the envelope, (3) a container having an oxygen absorbing capacity or (4) an envelope having an oxygen absorbing capacity;
(D) (D-1) and (D-2) below
(D-1) trometamol, propylene glycol (D-2) ethylenediamine acetic acid derivative, ethylenediamine acetic 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, and aminoethylsulfonic acid Provided is a method for suppressing a decrease in viscosity of the ophthalmic composition, characterized by blending. Preferred substances, amounts, etc. are the same as above.

EXAMPLES Hereinafter, the present invention will be specifically described by showing examples and comparative examples, but the present invention is not limited to the following examples. The W/V% of the composition is g/100 mL.

[Examples, Comparative Examples]
An ophthalmic composition having the composition shown in the table below is prepared by dissolving a fat-soluble component in component (B), and then adding it to a high-temperature (70 to 95°C) aqueous solution in which other aqueous solution components are dissolved. An ophthalmic composition of the composition was prepared. After filling the obtained ophthalmic composition (15 mL) into a polyethylene terephthalate eye drop container (16 mL), a film packaging ( enclosure) was applied. In addition, for Comparative Example 4 and Examples 4-1 to 4-4, and Comparative Example 6 and Examples 6-1 to 6-3, a film having oxygen absorption capacity (Ageless Omac: Mitsubishi Gas Chemical Company, Inc. (manufactured) was used to wrap (envelope). 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 under 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 obtained viscosity, the viscosity retention rate (%) of each example was determined based on the following formula, and the viscosity retention rate enhancement effect (%) was calculated as follows.
Viscosity retention rate (%) = Viscosity after storage/Viscosity before storage x 100
Viscosity retention rate enhancement effect (%) = [viscosity retention rate (%) of each example/viscosity retention rate (%) of comparative example corresponding to each example - 1] x 100
In addition, the comparative example corresponding to each Example means the comparative example which does not contain (D) component.

The viscosity reduction of the ophthalmic composition due to the combination of components (A) and (B) can be suppressed by the addition of component (D), and the retention effect of the active ingredient, cooling agent, etc. on the ocular surface can be maintained.

[Prescription example]
An ophthalmic composition having the composition shown in the table below is filled in the container according to the present invention and packaged in the packaging form according to the present invention. It can be used as an eye drop with excellent moisturizing effect and long-lasting moist feeling. In particular, Formulation Examples 3, 5, and 10 to 12 are suitable as contact eye drops that can be applied even when wearing soft contact lenses.

The raw materials used in the above examples are shown below. In addition, unless otherwise specified, the amount of each component in the table is the amount in terms of pure content.
・ Hydroxypropyl methylcellulose: Metolose 60SH-4000, Japanese Pharmacopoeia, Shin-Etsu Chemical Co., Ltd., weight average molecular weight of about 300,000 (g / mol)
・Methylcellulose: Metolose SM-4000, Japanese Post Office, Shin-Etsu Chemical Co., Ltd., weight average molecular weight of about 360,000 (g / mol)
・Hydroxyethyl cellulose: HEC-CF-V, Pharmaceutical Additives, Sumitomo Seika Co., Ltd., weight average molecular weight of about 1 million (g / mol)
· Polyvinylpyrrolidone: Kollidon 90F, Japanese Pharmacopoeia, BASF Corporation, weight average molecular weight 1,000,000 (g / mol)
Carboxyvinyl polymer: Carbopol (registered trademark) 971PNF, Pharmaceutical Addendum, Lubrizol Co., sodium hyaluronate: biosodium hyaluronate, Shiseido Co., Ltd.
・Polyoxyethylene hydrogenated castor oil 60: HCO60, Pharmaceutical Additives, Nippon Surfactant Kogyo Co., Ltd.
・POE (20) sorbitan monooleate (polysorbate 80): Rheodol TW-0120V, Kao Corporation
・Polyoxyethylene castor oil 35: NIKKOL CO-35, Nikko Chemicals Co., Ltd.
・ Polyoxyl 40 stearate: NIKKOL MYS-40MV, Nikko Chemicals Co., Ltd.
・ Retinol palmitate: Retinol palmitate, Japanese Pharmacopoeia, DSM Nutrition Japan Co., Ltd.
・D-α-Tocopherol Acetate: Riken E Acetate α, External Regulations, Riken Vitamin Co., Ltd.
・Dibutylhydroxytoluene: Dibutylhydroxytoluene, Pharmaceutical Additives, Wako Pure Chemical Industries, Ltd.
For component (D) and other optional components, various raw materials conforming to compendial standards (Japanese Pharmacopoeia, Japanese Pharmaceutical Standards, Pharmaceutical Excipient Standards, etc.) were used.

Claims (2)

(A) one or more selected from hyaluronic acid and salts thereof ;
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate, and
(C) an ophthalmic composition containing one or more fat-soluble ingredients selected from vitamin A, vitamin E, dibutylhydroxytoluene and menthol , a container filled with the ophthalmic composition, and packaging the container and an enclosure;
(1) Injecting an inert gas into the enclosure, (2) Packing an oxygen absorbent into the enclosure, (3) A container having oxygen absorption capacity, or (4) An enclosure having oxygen absorption capacity In the ophthalmic product using the above means, the ophthalmic composition comprises:
(D) A method for suppressing a decrease in viscosity of the ophthalmic composition, which comprises blending one or more selected from epsilon aminocaproic acid and panthenol . (A) one or more selected from hyaluronic acid and salts thereof ;
(B) one or more surfactants selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and polyethylene glycol monostearate, and (C) vitamin A and vitamins In an ophthalmic composition containing one or more fat-soluble ingredients selected from E, dibutylhydroxytoluene and menthol ,
The composition comprises a container filled with the ophthalmic composition and an envelope for packaging the container, wherein (1) inert gas is injected into the envelope, (2) an oxygen absorber is packed into the envelope, (3) a container having an oxygen absorbing capacity or (4) an envelope having an oxygen absorbing capacity;
(D) A method for suppressing a decrease in viscosity of the ophthalmic composition, which comprises blending one or more selected from epsilon aminocaproic acid and panthenol .