JP2022088923A - Ophthalmic Composition and Method for Improving Preservation Efficacy of Ophthalmic Composition - Google Patents

Abstract

To provide an ophthalmic composition that contains (A) at least one selected from an anti-hyperemia agent and an anti-histamine agent and (B) glycyrrhizinic acid or a salt thereof and has a pH of 5.0-5.5, wherein the ophthalmic composition has reduced eye irritation.SOLUTION: An ophthalmic composition contains (A) at least one selected from an anti-hyperemia agent and an anti-histamine agent, (B) glycyrrhizinic acid or a salt thereof, and (C) hyaluronic acid or a salt thereof of 0.001-0.02 mass% and has a pH of 5.0-5.5.SELECTED DRAWING: None

Description

The present invention relates to an ophthalmic composition and a method for improving the preservation efficacy of the ophthalmic composition.

Glycyrrhizic acid or a salt thereof can form a complex with a coexisting drug, and can be expected to promote absorption of the coexisting drug. It is important to adjust the pH in order to form a complex with the coexisting drug. For example, there has been proposed a technique for improving the absorption of glycyrrhizic acid or a salt thereof from the mucous membrane by setting the concentration of glycyrrhizic acid to the critical micelle concentration or higher and adjusting the pH of the composition to 4 to 6. (Patent Document 1: JP-A-11-147825).

Japanese Unexamined Patent Publication No. 11-147825 Japanese Unexamined Patent Publication No. 2009-161456

In a composition containing a drug and glycyrrhizinic acid or a salt thereof, when a drug selected from (A) an antihyperemic drug and an antihistamine is blended and the pH is set to 5.5 or less, the feeling of use such as eye irritation deteriorates. Was found. As a technique for improving eye irritation, it is known to add l-menthol or the like to an ophthalmic composition (Patent Document 2: Japanese Patent Application Laid-Open No. 2009-161456), but it is merely a masking effect by a refreshing agent. However, the effect was insufficient. Based on the above, the present invention contains (A) one or more selected from antihyperemic agents and antihistamines, and (B) glycyrrhizinic acid or a salt thereof, and has a pH of 5.0 to 5.5 for ophthalmology. It is an object of the present invention to provide an ophthalmic composition in which eye irritation is alleviated.

As a result of diligent studies to achieve the above object, the present inventors contain (A) one or more selected from antihyperemic agents and antihistamines, and (B) glycyrrhizinic acid or a salt thereof, and have a pH of 5.0. It has been found that the above-mentioned problems can be solved by blending 0.001 to 0.02% by mass of (C) hyaluronic acid or a salt thereof in the ophthalmic composition of ~ 5.5, which led to the present invention. It is a thing.

Therefore, the present invention provides the following invention.
1. 1. (A) One or more selected from antihyperemic and antihistamines,
(B) Glycyrrhizic acid or a salt thereof, and (C) Hyaluronic acid or a salt thereof 0.001 to 0.02% by mass
An ophthalmic composition containing, and having a pH of 5.0 to 5.5.
2. 2. (A) The ophthalmic composition according to 1 in which the component is at least one selected from tetrahydrozoline hydrochloride and phenylephrine hydrochloride.
3. 3. 1 or 2 in which the content mass ratio represented by (C) / (A) is 0.01 to 2 and the content mass ratio represented by (C) / (B) is 0.004 to 0.4. The described ophthalmic composition.
4. The ophthalmic composition according to any one of 1 to 3, further comprising (D) one or more selected from amino acids and water-soluble vitamins.
5. The ophthalmic composition according to any one of 1 to 4, further comprising (E) a terpenoid.
6. The ophthalmic composition according to any one of 1 to 5, further comprising boric acid, tromethamole, and edetic acid or a salt thereof.
7. 6. The ophthalmic composition according to 6, wherein the content of the preservative is 0.001% by mass or less.
8. (A) One or more selected from antihyperemic and antihistamines,
(B) Glycyrrhizic acid or a salt thereof, and (C) Hyaluronic acid or a salt thereof 0.001 to 0.02% by mass
A method for improving the preservation efficacy of an ophthalmic composition, which comprises setting the pH of the ophthalmic composition to 5.0 to 5.5 in the ophthalmic composition containing the above.

According to the present invention, in an ophthalmic composition containing (A) one or more selected from antihyperemic agents and antihistamines and (B) glycyrrhizinic acid or a salt thereof and having a pH of 5.0 to 5.5. , It is possible to provide an ophthalmic composition in which eye irritation is alleviated.

Hereinafter, the present invention will be described in detail.
[(A) component]
The component (A) of the present invention is one or more selected from antihyperemic agents and antihistamines, and can be used alone or in combination of two or more. Antihyperemic agents include tetrahydrozoline, naphazoline, phenylephrine and their pharmacologically acceptable salts. Examples of the antihistamine include chlorpheniramine maleate, diphenhydramine hydrochloride and the like. Of these, tetrahydrozoline hydrochloride and phenylephrine hydrochloride are preferable.

The content of the component (A) is preferably 0.0001 w / v% (mass / volume%, g / 100 mL, the same applies hereinafter) or more in the ophthalmic composition from the viewpoint of the drug effect of the component, and the point of suppressing eye irritation. Therefore, it is preferably 1 w / v% or less. 0.001 to 0.3 w / v% is more preferable, 0.01 to 0.2 w / v% is further preferable, and 0.03 to 0.1 w / v% is particularly preferable. In the case of an antihyperemic drug, 0.0001 to 0.5 w / v% is preferable, 0.001 to 0.3 w / v% is more preferable, 0.01 to 0.2 w / v% is further preferable, and 0. 05-0.1% w / v% is particularly preferable. In the case of an antihistamine, 0.001 to 1 w / v% is preferable, 0.01 to 0.1 w / v% is more preferable, and 0.03 to 0.05 w / v% is further preferable.

[(B) component]
The component (B) is glycyrrhizic acid or a salt thereof, and can be used alone or in combination of two or more, and is expected to promote the transfer and absorption of the drug component to the cornea. Examples of the salt include pharmacologically acceptable salts. Examples of the component (B) include glycyrrhizinate itself, disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, monoammonium glycyrrhizinate, and the like, and dipotassium glycyrrhizinate is preferable.

The content of the component (B) is preferably 0.01 w / v% or more in the ophthalmic composition from the viewpoint of migration of the drug component to the cornea and promotion of absorption, and 0.5 w / v from the viewpoint of suppressing eye irritation. % Or less is preferable, 0.03 to 0.4 w / v% is more preferable, and 0.05 to 0.3 w / v% is further preferable.

[(C) component]
The hyaluronic acid of the present invention or a salt thereof is not particularly limited, and any hyaluronic acid commonly used for mucosal application preparations in an ophthalmic region or the like can be used. An ophthalmic composition containing (A) one or more selected from an antihyperemic drug and an antihistamine, and (B) dipotassium glycyrrhizinate, having a pH of 5.0 to 5.5, depending on the composition of the component (C). In, eye irritation can be remarkably alleviated.

Examples of hyaluronic acid or salts thereof include hyaluronic acid, derivatives thereof, and pharmaceutically physiologically acceptable salts thereof. As these, those obtained by a method of extracting from a comb, a fermentation method using a microorganism, or the like can be used, and the origin and production method are not particularly limited. Hyaluronic acid or a salt thereof may be used alone or in combination of two or more. Specific examples of the component (C) include hyaluronic acid, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate and the like. Of these, sodium hyaluronate is preferable. Commercially available products can be used as the component (A), for example, purified sodium hyaluronate (manufactured by Seikagaku Corporation, Shiseido Co., Ltd., Kewpie Co., Ltd., Kikkoman Biochemifa Co., Ltd., Iwaki Pharmaceutical Co., Ltd., Blue Medibiotechnology). (Manufactured by the company) and the like.

The viscosity average molecular weight of the component (C) is preferably 50 to 5,000,000, more preferably 50 to 4,000,000, still more preferably 50 to 2,500,000, and preferably 50 to 2,000,000. It is particularly preferable, and most preferably 500,000 to 1,490,000. (C) The viscosity average molecular weight of the component is measured by the method for measuring the viscosity average molecular weight described in "Purified sodium hyaluronate" described in each article of the 17th revised Japanese Pharmacopoeia. The viscosity average molecular weight of hyaluronic acid or a salt thereof in the eye drops is measured by the method for measuring the viscosity average molecular weight described in "Purified Sodium Hyaluronic Acid Ophthalmic Solution" of the 17th revised Japanese Pharmacopoeia. It should be noted that a plurality of types of hyaluronic acid and / or salts having different viscosity average molecular weights can be used.

Commercially available products can be used as the component (C), for example, "sodium hyaluronate" biochemical "" (viscosity average molecular weight 500,000 to 1.2 million) and "cosmetic sodium hyaluronate (HC)" manufactured by Biochemical Industry Co., Ltd. ) ”(Molecular weight average molecular weight 530,000 to 1.33 million),“ Sodium biohyaluronate SZE ”(Molecular weight average molecular weight 1.1 million to 1.6 million) manufactured by Shiseido Co., Ltd.,“ Sodium biohyaluronate HA9N ”(Molecular weight average molecular weight 800,000 to 177) 10,000), "Biohyaluronate sodium HA12N" (molecular weight average molecular weight 1.1 million to 1.6 million), "Sodium biohyaluronate HA20N" (molecular weight average molecular weight 1.9 million to 2.7 million), "Biohyallate sodium 1% aqueous solution (MP-) "PE) N" (molecular weight average molecular weight 1.37 million to 1.53 million), "1% aqueous sodium biohyaluronate (PE) N" (molecular weight average molecular weight 1.37 million to 1.57 million), "Hyaluronic acid FCH-" manufactured by Kikkoman Biochemifa. "60" (viscosity average molecular weight 500,000 to 700,000), "hyaluronic acid FCH-80" (viscosity average molecular weight 600,000 to 1,000,000), "hyaluronate FCH-120" (viscosity average molecular weight 1,000,000 to 1.4 million), " "Hyaluronic acid FCH-150" (viscosity average molecular weight 1.4 million to 1.8 million), "hyaluronic acid FCH-151C" (viscosity average molecular weight 1.4 million to 1.8 million), "hyaluronic acid FCH-200" (viscosity average molecular weight 1.8 million to 220 million) 10,000), "Hyaluronate FCH-201C" (viscosity average molecular weight 1.8 million to 2.2 million), "Hyaluronic acid FCH-80LE" (viscosity average molecular weight 600,000 to 1.2 million), "Hyaluronic acid GS-100" (viscosity average molecular weight) 500,000 to 1.49 million), Cupy's "Hyallonsan HA-QA" (molecular average molecular weight of 600,000 to 1.2 million), "Hyallonsan HA-AM" (average molecular weight of 600,000 to 1.2 million), "Hyallonsan HA-Q" (Visibility average molecular weight 530,000 to 1.13 million), "Hyaluronsan M5070" (viscosity average molecular weight 500,000 to 700,000), "Hyaluronsan HA-LQ" (viscosity average molecular weight 850,000 to 1.6 million), "Hyaluronsan HA-LQH" (Vibration average molecular weight 1.2 million to 2.2 million), "Hyallonsan HA-AML" (viscosity average molecular weight 500,000 to 1.2 million) "Hyallonsan HA-SHL" (viscosity average molecular weight 1.6 million to 2.4 million), manufactured by Iwaki Pharmaceutical Co., Ltd. "Hyaluronic acid IW90" (molecular weight average molecular weight 800,000 to 1.17 million), "Hyaluronic acid IW120" (flat viscosity) An average molecular weight of 1.1 million to 1.6 million), "hyaluronic acid IW200" (viscosity average molecular weight of 1.9 million to 2.7 million), and the like can be mentioned.

The content of the component (C) is 0.001 to 0.02 w / v%, preferably 0.002 to 0.02 w / v%, preferably 0.005 in the ophthalmic composition from the viewpoint of the irritation suppressing effect. -0.02 w / v% is more preferable. If the content of the component (C) is too small, the irritation suppressing effect is insufficient, and if it is too large, the retention of the ophthalmic composition becomes high, and eye irritation due to the component (A) or the like is likely to occur.

In the ophthalmic composition of the present invention, the content mass ratio of the component (A) to the component (C) represented by (C) / (A) is preferably 0.01 to 2, preferably 0.1 to 2. 0 is more preferable, and 0.2 to 2.0 is even more preferable. The mass ratio of the component (B) to the component (C) represented by (C) / (B) is preferably 0.004 to 0.4, more preferably 0.02 to 0.2. 0.04 to 0.2 is more preferable. By setting the (C) / (A) ratio and the (C) / (B) ratio within the above ranges, the effect of alleviating eye irritation becomes higher. Although the above ratio is a w / v% ratio, it is the same value as the mass ratio.

[(D) component]
From the viewpoint of suppressing irritation, the ophthalmic composition of the present invention is preferably further blended with one or more selected from (D) amino acids and water-soluble vitamins. The component (D) can be used alone or in combination of two or more. Examples of the amino acid include potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid and the like. Examples of the water-soluble vitamin include pyridoxine hydrochloride, panthenol, calcium pantothenate, and sodium pantothenate. Of these, aminoethyl sulfonic acid and pyridoxine hydrochloride are preferable.

The content of the component (D) is preferably 0.005 to 3 w / v%, more preferably 0.01 to 2 w / v%, and 0.05 to 1 w / v% in the ophthalmic composition from the viewpoint of the irritation suppressing effect. v% is more preferred.

[(E) component]
From the viewpoint of suppressing irritation, it is preferable to further add (E) a terpenoid to the ophthalmic composition of the present invention. The component (E) can be used alone or in combination of two or more. The terpenoid in the present invention has a structure having an isoprene unit as a constituent unit, and examples thereof include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. In addition, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes depending on the number of carbon atoms. Specific examples thereof include monoterpenes such as menthol, menthol, camphor, borneol, ryuno, geraniol, cineole, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Above all, it is preferable to use a monoterpene. These terpenoids can be used in any of d-form, l-form or dl-form. Among them, menthol, menthol, camphor, borneol, geraniol, cineol and linalool are preferable, and menthol, camphor, borneol, geraniol, cineol and linalool are more preferable. More preferably, geraniol and menthol. In the present invention, an essential oil containing the above compound may be used as the terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, sardine oil, rose oil, peppermint oil, peppermint oil, sparemint oil, and essential oils of the Futabagaki family, rosmarin oil, lavender oil and the like.

The content of the component (E) when blended is preferably 0.0001 to 0.1 w / v%, more preferably 0.0005 to 0.05 w / v%, and 0.001 to 0 in the ophthalmic composition. .03w / v% is more preferable.

From the viewpoint of improving the preservation effect, it is preferable to further add boric acid, tromethamole, and edetonic acid or a salt thereof to the ophthalmic composition of the present invention. Examples of the edetate include sodium edetate, sodium edetate hydrate and the like. Since the antiseptic effect can be obtained by blending these, the content of the preservative in the ophthalmic composition is 0.01 w / v% or less, preferably 0.005 w / v% or less, more preferably 0. It can be 001 w / v% or less, more preferably 0.0001 w / v% or less.

Examples of the preservative include benzalconium chloride, benzethonium chloride, thimerosal, phenylethyl alcohol, alkylpolyaminoethylglycine, alkyldiaminoethylglycine and / or a salt thereof (for example, alkyldiaminoethylglycine hydrochloride), chlorhexidine gluconic acid, paraoshiki. Methyl benzoate, ethyl paraoxybenzoate, ethylpropyl paraoxybenzoate, sodium benzoate, sorbic acid, boric acid, borosand, sodium sulfite, potassium sulfite, dry sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite , Sodium hydrogen sulfite, sulfites such as potassium hydrogen sulfite, chlorobutanol, oxyquinoline sulfate, benzyl alcohol, polyhexamethylene biguanide, polydronium chloride and the like.

In addition, the present inventors have an ophthalmic composition containing (A) one or more selected from antihyperemic agents and antihistamines and (B) glycyrrhizinic acid or a salt thereof, and having a pH of 5.0 to 5.5. As described above, when boric acid, tromethamole, edetonic acid or a salt thereof are blended and the content of the preservative in the ophthalmic composition is 0.001% by mass or less, the eye irritation is alleviated. It has been found that the effect can be obtained more prominently. In this case, it is important that the pH is 5.0 to 5.5 in order to obtain the preservation effect.

[Other ingredients]
The composition of the present invention may contain an appropriate amount of other components to be blended in the ophthalmic composition as long as the effects of the present invention are not impaired. Examples of other components include nonionic surfactants, sugars, buffers, tonicity agents, stabilizers, polyhydric alcohols, oily components, thickening agents, drugs and the like. These components may be blended alone or in combination of two or more. The content of the components shown below is a preferable range when blended, and is an amount in the composition.

The nonionic surfactant is not particularly limited, and the nonionic surfactant used in the ophthalmic composition may be used alone or in combination of two or more as appropriate. Specific examples thereof include polyoxyethylene castor oil, polyoxyethylene cured castor oil, and nonionic surfactants other than the above.

Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types with different average moles of ethylene oxide are known. .. The average number of moles of ethylene oxide added to the polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles is exemplified. Specifically, polyoxyethylene castor oil 3 (EO average number of moles added 3), polyoxyethylene castor oil 10 (EO average number of moles added 10), polyoxyethylene castor oil 20 (EO average number of moles added 20), poly Oxyethylene castor oil 35 (EO average number of moles added 35), polyoxyethylene castor oil 40 (EO average number of moles added 40), polyoxyethylene castor oil 50 (EO average number of moles added 50), polyoxyethylene castor oil 60 (EO average number of added moles 60) and the like. These polyoxyethylene castor oils can be used alone or in combination of two or more. From the viewpoint of reducing the irritation feeling at the time of instillation, it is preferable to use polyoxyethylene castor oil 35.

Polyoxyethylene cured castor oil (POE cured castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types with different average number of moles of ethylene oxide are known. ing. The average number of moles of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is not particularly limited, but 5 to 100 mol is exemplified. Specifically, polyoxyethylene cured castor oil 5 (EO average number of added moles 5), polyoxyethylene cured castor oil 10 (EO average number of added moles 10), polyoxyethylene cured castor oil 20 (EO average number of added moles 20). ), Polyoxyethylene cured castor oil 30 (EO average number of added moles 30), Polyoxyethylene cured castor oil 40 (EO average number of added moles 40), Polyoxyethylene cured castor oil 50 (EO average number of added moles 50), Polyoxyethylene cured castor oil 60 (EO average number of added moles 60), polyoxyethylene cured castor oil 80 (EO average number of added moles 80), polyoxyethylene cured castor oil 100 (EO average number of added moles 100), etc. Will be. These polyoxyethylene cured castor oils can be used alone or in combination of two or more. From the viewpoint of reducing the irritation feeling at the time of instillation, it is preferable to use polyoxyethylene cured castor oil 40 and polyoxyethylene cured castor oil 60.

Examples of non-ionic surfactants other than the above include polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) represented by polysorbate 80 (polyoxyethylene (20) sorbitan oleic acid ester), and polyoxyethylene represented by porox summer. Examples thereof include polyoxypropylene glycol (POEPOP glycol), polyethylene glycol monostearate (10), polyethylene glycol monostearate typified by polyethylene glycol monostearate (40), and the like.

When a nonionic surfactant is blended, the content thereof is not particularly limited as long as it satisfies the above ratio, but is preferably 0.0001 to 10 w / v% in the composition, preferably 0.0001 to 5 w / v%. More preferred.
When polyoxyethylene castor oil is blended, 0.003 to 10 w / v% is preferable, 0.003 to 5 w / v% is more preferable, and 0.03 to 1 w / v% is further preferable in the composition.
When the polyoxyethylene hydrogenated castor oil is blended, 0.003 to 10 w / v% is preferable, 0.003 to 5 w / v% is more preferable, and 0.03 to 1 w / v% is further preferable in the composition.
When a nonionic surfactant other than the above is blended, 0.0003 to 1 w / v% is preferable, 0.0003 to 0.5 w / v% is more preferable, and 0.003 to 0.1 w / v% is more preferable in the composition. v% is more preferred.

Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be D-form, L-form or DL-form. When a saccharide is blended, the content thereof is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v in the ophthalmic composition. % Is more preferable.

Examples of the buffering agent include citric acid, sodium citrate, borosand, phosphoric acid, sodium hydrogenphosphate, sodium dihydrogen phosphate, glacial acetic acid, sodium hydrogencarbonate and the like. When a buffer is added, the content thereof is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 2 w / v%, and 0.001 to 1 w / v% in the ophthalmic composition. Is even more preferable.

Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like. Can be mentioned. The osmotic pressure ratio of the composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20. The osmotic pressure is measured at 25 ° C. using an automatic osmometer (A2O, Advanced Instruments).

Examples of the stabilizer include cyclodextrin, sulfites, dibutylhydroxytoluene and the like. When a stabilizer is blended, the content thereof is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v in the composition. % Is more preferable.

Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like. When the polyhydric alcohol is blended, the content of the polyhydric alcohol is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and 0.001 to 0. 1 w / v% is more preferable.

The oily components include soybean oil, olive oil, corn oil, palm oil, almond oil, medium-chain fatty acid triglyceride, liquid paraffin, vitamin E such as acetic acid-d-α-tocopherol, vitamin A such as retinol palmitate, and white vaseline. , Purified lanolin, cholesterol, mixed tocopherol and the like. The content thereof is preferably 0.001 to 1.0 w / v%, more preferably 0.001 to 0.5 w / v%, and most preferably 0.001 to 0.25 w / v%.

Examples of the drug (pharmaceutically active ingredient) include anti-inflammatory and astringent agents (eg, neostigmine methyl sulfate, epsilon-aminocaproic acid, allantin, velverin chloride hydrate, velverin sulfate hydrate, sodium azulene sulfonate, sulfuric acid). Zinc, zinc lactate, lysoteam hydrochloride, etc.), fat-soluble vitamins (vitamin A, vitamin E), sulfa agents, etc. may be mentioned. When a drug is blended, the content of the drug can be selected from an effective appropriate amount of each drug, but is preferably 0.001 to 5.0 w / v% in the composition, preferably 0.001 to 1 w / v%. Is more preferable, and 0.001 to 0.1 w / v% is even more preferable.

Specific examples of the vitamin A include retinol palmitate (retinyl palmitate ester) and retinyl acetate.
Specific examples of vitamin E include tocopherol acetate, tocopherol succinate, tocopherol nicotinate and the like.
The content of vitamins is preferably 0.001 to 1 w / v%, more preferably 0.003 to 0.5 w / v%, and even more preferably 0.005 to 0.1 w / v%.
When the vitamins are vitamin A, the content of vitamin A is preferably 1000 units / 100 mL or more, more preferably 3000 units / 100 mL or more, further preferably 5000 to 100,000 units / 100 mL, and 10,000 to 8.0. 10,000 units / 100 mL is particularly preferable, and 50,000 to 65,000 units / 100 mL is most preferable. In addition, 1 unit in the content of vitamin A means 1 unit of vitamin A described in the 17th revised Japanese Pharmacopoeia Vitamin A quantification method.

[Production method]
The method for producing the ophthalmic composition is not particularly limited, and is obtained, for example, by mixing the above components (A) to (C) and, if necessary, any component, adjusting the pH, and then adjusting the total volume with water. be able to. The mixing method of each liquid may be a general method, and is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., but the rotation speed is not particularly limited and should be set to such that it does not foam violently. Is preferable.

[Ophthalmic composition]
The ophthalmic composition of the present invention is preferably an "aqueous ophthalmic composition". In the present invention, the "aqueous ophthalmic composition" refers to an ophthalmic composition in which the medium is water. The water content is preferably 90.0 to 99.5 w / v%, more preferably 95.0 to 99.0 w / v% in the composition.

The pH of the ophthalmic composition of the present invention at 25 ° C. is 5.0 to 5.5 in terms of migration of the drug component to the cornea, promotion of absorption, and storage efficacy, and 5.1 to 5 5.5 is more preferable, and 5.3 to 5.5 is even more preferable. In the present invention, the pH is a value measured at 25 ° C. with a pH meter, for example, HM-25R, DKK-TOA CORPORATION. Preferred pH adjusters include inorganic acids or inorganic alkaline agents. Specifically, examples of the inorganic acid include (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like.

The viscosity of the ophthalmic composition at 25 ° C. is preferably 1 to 2 mPa · s, more preferably 1 to 1.5 mPa · s, still more preferably 1 to 1.1 mPa · s. The usability is good in this range. If the viscosity is too high, the retention will be high and eye irritation will easily occur. In the present invention, the viscosity is a value measured at 20 ° C. with a B-type viscometer, for example, BROOKFIELD DV2T, manufactured by Eiko Seiki Co., Ltd.

Preferred viscosity modifiers include water-soluble polymer compounds and the like. For example, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, dextran, alginic acid, sodium alginate, xanthan gum and the like can be mentioned. When a viscosity modifier is blended, it can be blended within a range that does not cause eye irritation due to the high retention of the ophthalmic composition and that does not impair the usability such as stickiness and blurring. The content of the case is preferably 0.001 to 1.0 w / v%, more preferably 0.001 to 0.5 w / v%, and further preferably 0.001 to 0.1 w / v% in the ophthalmic composition. preferable.

The dosage form of the ophthalmic composition of the present invention is not particularly limited, and is suitable as, for example, an eye drop (including an eye drop that can be instilled while wearing a contact lens), an eye wash, a contact lens wearing solution, a contact lens removing solution, and the like. Can be used for.
The contact lens is not particularly limited, such as a hard contact lens (including O ₂ hard contact lens), a soft contact lens (including both ionic and non-ionic), a silicone hydrogel contact lens, and a color contact lens. When no preservative is added, it is particularly suitable for soft contact lenses and silicone hydrogel contact lenses.

[Containers, packaging]
The obtained ophthalmic composition may be filled in a resin container, sealed with a package, and an inert gas such as nitrogen may be sealed in the space formed between the container and the package. After filling the resin container with the ophthalmic composition, it may be sealed with a package together with an oxygen scavenger.

As the container, a plastic container is preferable, and a material such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride resin, or a composite of these materials can be used. Especially polyethylene terephthalate is preferable. The amount of the ophthalmic composition in the product can be appropriately selected depending on the product and the method of use thereof. For example, in the case of eye drops, 2 to 20 mL is preferable, and 5 to 20 mL is more preferable. The container for the ophthalmic composition is not particularly limited, but may be a multi-dose type (multi-unit type) container or a single-use unit-dose type container. A multi-dose type (multi-unit type) container is preferable.

The obtained ophthalmic composition may be filled in a resin container, then sealed with a package, and an inert gas in the space formed between the container and the package may be sealed. The object may be filled in a resin container and sealed with a deoxidizing agent by a package.

As the inner plug and cap, a cap made of a material used for a container of a known ophthalmic product can be used. As the material of the inner plug, polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8 is preferable. As the material of the cap, polyethylene and polypropylene are preferable.

[Preservation efficacy method]
The present invention relates to (A) one or more selected from antihyperemic agents and antihistamines.
(B) Glycyrrhizic acid or a salt thereof, and (C) Hyaluronic acid or a salt thereof 0.001 to 0.02% by mass
Provided is a method for preserving an ophthalmic composition, which comprises setting the pH of the ophthalmic composition to 5.0 to 5.5 in the ophthalmic composition containing the above. Suitable components, amounts and the like are the same as above.

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. Unless otherwise specified, "%" of the composition is w / v% (mass / volume%, g / 100 mL), and the ratio is the w / v% ratio, which is the same as the mass ratio.

[Examples, comparative examples]
Each component of the composition shown in the table below was mixed to prepare an ophthalmic composition (eye drops). The obtained ophthalmic composition was evaluated as follows. The results are also shown in the table.

[Eye irritation]
The ophthalmic composition (eye drops) was filled in an eye drop container (made of polyethylene terephthalate) having a capacity of about 16 mL. One drop of the ophthalmic composition (eye drops) was instilled into each of the five subjects, and the stimulating sensation (feeling of squeezing) in 3 minutes immediately after the instillation was evaluated based on the following scores. From the average score of the obtained scores, the following evaluation criteria are shown.

<Score>
0: No stimulus (no squeaky feeling)
1: Almost no irritation 2: Slight irritation 3: Feel irritation
<Evaluation criteria>
⊚: Average score 0 or more and less than 1 〇: Average score 1 or more and less than 2 ×: Average score 2 or more and less than 3

[Preservation effect]
The 17th revision of the Japanese Pharmacopoeia ・ The preservation efficacy test was conducted in accordance with the reference information preservation efficacy test method. Escherichia coli (ATCC8739) was used as the test strain, and bacteria were added so that the number of each sample was 105 per ¹ mL of each sample, and the strain was allowed to stand at 25 ° C. After 7 days and 14 days, 1 mL of each sample was cultured on an agar medium for 5 days, and the viable cell count was measured.
The residual rate (%) with respect to the initial number of bacteria ⁽ 105 cells / mL) was calculated. The operation was performed aseptically.
Those that meet the criteria are considered conforming, and those that do not meet are considered nonconforming.
Judgment criteria (residual rate to the number of inoculated bacteria: 7 days later: 10% or less and 14 days later: 0.1% or less

[Prescription example]
An ophthalmic composition (eye drops) was obtained in the same manner as in the above Examples. Eye irritation was suppressed as in the examples.

The raw materials used in the above example are shown below. Unless otherwise specified, the amount of each component in the table is a net conversion amount.
Tetrahydrozoline hydrochloride: Tetrahydrozoline hydrochloride, Phenirefrin hydrochloride manufactured by Okami Chemical Industry Co., Ltd .: Phenilefurin hydrochloride (crystal), Chlorpheniramine maleate manufactured by Iwaki Pharmaceutical Co., Ltd .: Chlorpheniramine maleate (chlorpheniramine maleate), manufactured by Kongo Chemical Co., Ltd. Dipotassium glycyrrhizinate: Dipotassium glycyrrhizinate, Sodium hyaluronate manufactured by Maruzen Pharmaceutical Co., Ltd .: FCH-80 hyaluronate, Vibrate average molecular weight: 500 to 1.49 million, Hypromerose manufactured by Kikkoman Biochemifa: METROSE Hypromerose 60SH- 4000, Shin-Etsu Chemical Industry Co., Ltd. Biohyaluronate (SZE), Shiseido Co., Ltd. Aminoethyl Sulfonic Acid: Taurine, Iwaki Pharmaceutical Co., Ltd. Pyridoxin Hydrochloride: Pyridoxin Hydrochloride Pyridoxin Hydrochloride, BASF Japan Co., Ltd. Pantenol: Pantenol, DSM Nutrition Boric acid manufactured by Japan: Boric acid, Trometamol manufactured by Kanto Chemical Co., Ltd .: 2-Amino-2-hydroxymethyl-1,3-propanediol, Sodium edetate manufactured by Kanto Chemical Co., Ltd .: Clewat N, l-menthol manufactured by Nagase Chemtex Co., Ltd. : L-Mentor (light brain), manufactured by Suzuki Light Carriage Co., Ltd.

Claims (8)

(A) One or more selected from antihyperemic and antihistamines,
(B) Glycyrrhizic acid or a salt thereof, and (C) Hyaluronic acid or a salt thereof 0.001 to 0.02% by mass
An ophthalmic composition containing, and having a pH of 5.0 to 5.5. (A) The ophthalmic composition according to claim 1, wherein the component is at least one selected from tetrahydrozoline hydrochloride and phenylephrine hydrochloride. Claim 1 in which the content mass ratio represented by (C) / (A) is 0.01 to 2, and the content mass ratio represented by (C) / (B) is 0.004 to 0.4. Or the ophthalmic composition according to 2. The ophthalmic composition according to any one of claims 1 to 3, further comprising (D) one or more selected from amino acids and water-soluble vitamins. The ophthalmic composition according to any one of claims 1 to 4, further comprising (E) a terpenoid. The ophthalmic composition according to any one of claims 1 to 5, further comprising boric acid, tromethamole, and edetic acid or a salt thereof. The ophthalmic composition according to claim 6, wherein the content of the preservative is 0.001% by mass or less. (A) One or more selected from antihyperemic and antihistamines,
(B) Glycyrrhizic acid or a salt thereof, and (C) Hyaluronic acid or a salt thereof 0.001 to 0.02% by mass
A method for improving the preservation efficacy of an ophthalmic composition, which comprises setting the pH of the ophthalmic composition to 5.0 to 5.5 in the ophthalmic composition containing the above.