JP7534129B2 - Multi-ingredient eye drops - Google Patents

Description

The present invention relates to a multi-ingredient combination eye drop containing seven active ingredients that have an effect of alleviating ocular allergy symptoms.

It is estimated that there are approximately 20 million allergic conjunctivitis patients in Japan. Allergic conjunctivitis is accompanied by various symptoms such as itchy eyes, a gritty foreign body sensation, tears, eye discharge, and pain, and when symptoms are very severe, they can interfere with daily life such as work and school (Non-Patent Document 1).

Therefore, the use of eye drops containing multiple ingredients effective for each symptom (hereinafter referred to as multi-ingredient eye drops) can be expected to have a variety of effects by simply administering one eye drop, which greatly contributes to the convenience of users and improvement of their QOL. However, multi-ingredient eye drops may cause various problems such as discoloration of the eye drops, precipitation, and decomposition of the active ingredients due to interactions between the active ingredients or between the active ingredients and additives.

For example, it is known that in eye drops containing as active ingredients chondroitin sulfates having a corneal protective effect and glycyrrhizinates having an anti-inflammatory effect, when the pH becomes acidic, precipitates derived from the chondroitin sulfates and glycyrrhizinates are formed (Patent Document 1).

In addition, it has been reported that allantoin, which has anti-inflammatory and cell activation effects as an active ingredient, undergoes hydrolysis at pH 6 or higher (Non-Patent Documents 2 and 3). Therefore, it is necessary to make the pH of an eye drop containing allantoin acidic, but at the same time, if chondroitin sulfates or glycyrrhizinates are mixed, there is a risk of precipitation. Therefore, special ingenuity is required to develop an eye drop containing allantoin, chondroitin sulfates, and glycyrrhizinates.

In addition, pyridoxine hydrochloride has the effect of activating the metabolism of ocular tissue and improving eye fatigue, but since it is unstable in light, various techniques have been disclosed for the purpose of stabilization, such as adding oxymetazoline or a salt thereof to boric acid (Patent Document 2), blending a specific antioxidant (Patent Document 3), and blending berberine chloride (Patent Document 4).

Furthermore, it has been reported that eye drops containing chlorobutanol as an additive suffer from problems such as destabilization of the compounded ingredients and precipitation/precipitation due to a decrease in pH as a result of the chlorobutanol being decomposed over time by heat or light (Patent Document 5).

Thus, in developing a multi-ingredient eye drop, it is important to prevent changes in the efficacy and quality of each active ingredient. Various technologies are required to overcome this challenge, but the more active ingredients and additives are included in the eye drop, the more complex the physical and chemical interactions between the ingredients become, making the development extremely difficult.

In the OTC (over-the-counter) drug market, various multi-ingredient combination eye drops containing multiple active ingredients for the purpose of alleviating various symptoms of ocular allergies are commercially available, but among the combinations of active ingredients contained in these multi-ingredient combination eye drops, there is no multi-ingredient combination eye drop that contains the seven ingredients of naphazoline or its salt, allantoin, glycyrrhizic acid or its salt, chlorpheniramine maleate, pyridoxine hydrochloride, taurine, and chondroitin sulfate or its salt. Therefore, multi-ingredient combination eye drops containing these seven ingredients are considered to be useful as a new option for OTC eye drops, but it is necessary to develop a technology to suppress the occurrence of quality changes such as decomposition, discoloration, and precipitation of each ingredient during storage.

JP 2005-330271 A JP 2006-151969 A Japanese Patent Application Publication No. 8-104636 JP 2001-48780 A JP 2011-105706 A

Japan Ophthalmological Society, Public Interest Foundation. For the general public. Eye diseases. Allergic conjunctival diseases. January 22, 2019 http://www. nichigan. or. jp/public/disease/ketsumaku_allergy. jsp Shinya Yamamoto and 4 others, Pharmaceutical Journal, 1993, Vol. 113, No. 7, pp. 515-524 Ehime Institute of Environmental Science and Technology Annual Report 2004 No. 7, 2004

The present invention aims to provide a multi-component ophthalmic preparation containing seven active ingredients, namely naphazoline or a salt thereof, allantoin, glycyrrhizic acid or a salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, taurine, and chondroitin sulfate or a salt thereof, which is of good quality and in which discoloration, precipitation/deposition, decomposition of each active ingredient, etc. during storage are suppressed.

As a result of intensive research, the present inventors have found that stable eye drops in which changes such as precipitation and deposition of the eye drops and decomposition of the blended ingredients are significantly suppressed can be obtained by adding boric acid as an additive in a specific range to seven active ingredients, namely naphazoline or its salt, allantoin, glycyrrhizic acid or its salt, chlorpheniramine maleate, pyridoxine hydrochloride, taurine, and chondroitin sulfate or its salt, which have an effect of alleviating various symptoms of ocular allergy, adjusting the pH of the eye drops to a specific range, and further adding a specific amount of ethyl paraoxybenzoate and propyl paraoxybenzoate when used as a preservative, or adding a specific amount of polysorbate 80 when used as a preservative, and these eye drops also passed the preservative effectiveness test.

The present invention includes the following inventions.
(1) A multi-component eye drop containing, as active ingredients, naphazoline or a salt thereof, allantoin, glycyrrhizic acid or a salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, taurine, and chondroitin sulfate or a salt thereof.
(2) The multi-component eye drop according to (1), wherein the naphazoline or a salt thereof is naphazoline hydrochloride, the glycyrrhizinic acid or a salt thereof is dipotassium glycyrrhizinate, and the chondroitin sulfate or a salt thereof is sodium chondroitin sulfate.
(3) A multi-component eye drop preparation according to (1) or (2), containing 0.001 w/v% naphazoline hydrochloride, 0.3 w/v% allantoin, 0.25 w/v% dipotassium glycyrrhizinate, 0.03 w/v% chlorpheniramine maleate, 0.1 w/v% pyridoxine hydrochloride, 1.0 w/v% taurine and 0.5 w/v% sodium chondroitin sulfate.
(4) The multi-component ophthalmic solution according to any one of (1) to (3), further comprising boric acid as a stabilizer.
(5) The multi-component eye drop according to (4), containing 0.25 to 1.0 w/v % boric acid.
(6) The multi-component ophthalmic preparation according to any one of (1) to (5), further comprising a preservative.
(7) The multi-component ophthalmic preparation according to (6), wherein the preservative is two or more components selected from the group consisting of chlorobutanol, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and benzalkonium chloride.
(8) The multi-component ophthalmic preparation according to (6) or (7), wherein the preservative comprises three components, namely, chlorobutanol, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate.
(9) The multi-component eye drop preparation according to (8), containing 0.25 w/v % chlorobutanol, 0.013 w/v % ethyl parahydroxybenzoate, and 0.007 w/v % propyl parahydroxybenzoate.
(10) The multi-component ophthalmic preparation according to (6) or (7), wherein the preservative comprises two components, chlorobutanol and benzalkonium chloride.
(11) The multi-component eye drop preparation according to (10), containing 0.25 w/v % chlorobutanol and 0.01% benzalkonium chloride.
(12) The multi-component ophthalmic solution according to (10) or (11), further comprising polysorbate 80 as a solubilizing agent.
(13) The multi-component ophthalmic solution according to (12), containing 0.02 w/v % or less of polysorbate 80.
(14) The multi-component ophthalmic preparation according to any one of (1) to (13), having a pH in the range of 5.0 to 5.5.

According to the present invention, it is possible to provide a high-quality eye drop in which quality changes such as decomposition, discoloration, and precipitation of each component during storage of a multi-component eye drop containing seven components, i.e., naphazoline hydrochloride, allantoin, dipotassium glycyrrhizinate, chlorpheniramine maleate, pyridoxine hydrochloride, taurine, and sodium chondroitin sulfate, are suppressed.

In this specification, the phrase "the ingredients in the eye drop preparation are stabilized" means, for example, that the remaining rate of the ingredients in the eye drop preparation after storage at 40° C. for 6 months is 90% or more, and particularly preferably 95% or more.

In this specification, "the occurrence of precipitation/precipitate and discoloration in the eye drop are prevented" means, for example, that when the eye drop is observed after storage at 40°C for 6 months or at 50°C for 2 months in accordance with the Test for Insoluble Foreign Matter in Eye Drops in the Seventeenth Edition of the Japanese Pharmacopoeia, it is clear and contains no easily detectable insoluble foreign matter.

In this specification, the phrase "the eye drop conforms to the preservative effectiveness test" means that the eye drop is judged to have preservative effectiveness in the preservative effectiveness test method of the Japanese Pharmacopoeia, 17th Edition.

In the present invention, the multi-ingredient ophthalmic solution contains seven active ingredients, namely naphazoline or a salt thereof, allantoin, glycyrrhizic acid or a salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, taurine, and chondroitin sulfate or a salt thereof.

In the present invention, naphazoline or a salt thereof refers to naphazoline, naphazoline hydrochloride, and naphazoline nitrate, which are active ingredients having a vasoconstrictive effect, and are used in the present invention for the purpose of suppressing bloodshot eyes. Among these, naphazoline hydrochloride is particularly preferred, and its blending amount is preferably 0.001 w/v%.

In the present invention, allantoin has the effect of suppressing conjunctival inflammation and allergic symptoms, and its blending amount is preferably 0.3 w/v %.

In the present invention, glycyrrhizinic acid or a salt thereof refers to glycyrrhizinic acid, dipotassium glycyrrhizinate, and monoammonium glycyrrhizinate, and has the effect of suppressing inflammation and allergic symptoms. In the present invention, dipotassium glycyrrhizinate is preferred, and the blending amount thereof is preferably 0.25 w/v%.

In the present invention, chlorpheniramine maleate has antiallergic and decongestant effects, and its amount is preferably 0.03 w/v %.

In the present invention, pyridoxine hydrochloride has the effect of activating the metabolism of ocular tissue and relieving eye fatigue, and its amount is preferably 0.1 w/v %.

In the present invention, taurine refers to aminoethylsulfonic acid, which has the effect of increasing the metabolism of ocular tissue and promoting the repair of ocular tissue, and its blending amount is preferably 1.0 w/v %.

In the present invention, chondroitin sulfate or its salt refers to chondroitin sulfate and sodium chondroitin sulfate, and has the effect of repairing corneal damage and retaining moisture to keep tears on the cornea and protect the cornea from external stimuli. In the present invention, sodium chondroitin sulfate is preferred, and its blending amount is preferably 0.5 w/v%.

The eye drop of the present invention may contain additives that are commonly used in eye drops, provided that the effects of the present invention are not impaired. The additives may be one or more in any proportion. Examples of additives include thickeners, sugars, antioxidants, preservatives, solubilizing agents, pH regulators, isotonicity agents, refreshing agents, buffers, stabilizers, etc.

Examples of "thickeners" include carboxyvinyl polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, alginic acid, polyvinyl alcohol, polyvinylpyrrolidone, macrogol, and the like.

"Sugars" include glucose, cyclodextrin, xylitol, sorbitol, mannitol, and the like.

The "antioxidants" include dibutylhydroxytoluene, butylhydroxyanisole, hydroquinone, propyl gallate, sodium hydrogen sulfite, and the like.

Examples of the "preservative" include alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine gluconate hydrochloride, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, etc. In the eye drops of the present invention, in order to achieve effective preservative efficacy and to improve storage stability, it is preferable to use three components, chlorobutanol, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate, in combination, or two components, chlorobutanol and benzalkonium chloride, in combination. When the three components of chlorobutanol, ethyl parahydroxybenzoate and propyl parahydroxybenzoate are used in combination, their contents are preferably 0.25 w/v%, 0.013 w/v% and 0.007 w/v%, respectively, and when the two components of chlorobutanol and benzalkonium chloride are used in combination, their contents are preferably 0.25 w/v% and 0.01%, respectively.

Examples of the "solubilizing agent" include polysorbates, polyoxyethylene polyoxypropylene block copolymers, poloxamine, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil derivatives, alkyldiaminoethylglycine, alkyl quaternary ammonium salts, polyethylene glycol, epsilon aminocaproic acid, and propylene glycol. In the eye drops of the present invention, it is preferable to use polysorbate 80. The content of polysorbate 80 is preferably 0.02 w/v% or less.

Examples of the "pH adjuster" include hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, boric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate (sodium hydrogen phosphate), sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, borax, triethanolamine, monoethanolamine, etc. The type of the "pH adjuster" in the eye drop of the present invention is not particularly limited, but in order to maintain good storage stability of the active ingredient, it is preferable to adjust the pH of the eye drop to a range of 5.0 to 5.5.

Examples of "isotonicity agents" include sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate (sodium hydrogen phosphate), sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, boric acid, glycerin, propylene glycol and the like.

Examples of the "cooling agent" include d-camphor, dl-camphor, geraniol, d-borneol, l-menthol, ryuzu, fennel oil, peppermint water, peppermint oil, bergamot oil, eucalyptus oil, etc. In the present invention, peppermint oil and l-menthol are preferred.

Examples of the "buffer" include citrate buffer, acetate buffer, carbonate buffer, borate buffer, phosphate buffer, tartrate buffer, amino acid and the like.

Examples of the "stabilizer" include epsilon aminocaproic acid, dibutylhydroxytoluene, trometamol, tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, tetrasodium edetate, sodium edetate, boric acid, etc. In the eye drop of the present invention, it is preferable to use boric acid. The content of boric acid is preferably 0.25 to 1.0 w/v%, particularly preferably 0.35 to 0.7 w/v%.

The eye drops of the present invention can be instilled in the eye in an amount of, for example, 1 to 3 drops at a time, 2 to 6 times a day, but are not limited thereto, and can be used in any desired dosage and administration.

The efficacy and effects of the eye drops of the present invention include, for example, relief of bloodshot eyes, itchy eyes, blurred vision due to eye discharge, watery eyes, and a gritty foreign body sensation.

The eye drop of the present invention can be produced by a method known in the art for producing eye drops. For example, it can be produced by dissolving the active ingredient and additives in distilled water or purified water, adjusting the osmotic pressure and pH to a predetermined level, and filling the solution into a container. In some cases, a sterilization process can be included in the production process.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

1 mg of naphazoline hydrochloride, 300 mg of allantoin, 250 mg of dipotassium glycyrrhizinate, 30 mg of chlorpheniramine maleate, 100 mg of pyridoxine hydrochloride, 1000 mg of taurine, 500 mg of sodium chondroitin sulfate, 500 mg of epsilon-aminocaproic acid, 340 mg of boric acid, 610 mg of sodium hydrogen phosphate hydrate, 10 mg of sodium edetate hydrate, 3 mg of peppermint oil, 40 mg of l-menthol, 250 mg of chlorobutanol, 13 mg of ethyl parahydroxybenzoate, and 7 mg of propyl parahydroxybenzoate were dissolved in purified water to prepare a solution with a total volume of 100 mL.

1 mg of naphazoline hydrochloride, 300 mg of allantoin, 250 mg of dipotassium glycyrrhizinate, 30 mg of chlorpheniramine maleate, 100 mg of pyridoxine hydrochloride, 1000 mg of taurine, 500 mg of sodium chondroitin sulfate, 500 mg of epsilon aminocaproic acid, 550 mg of boric acid, 90 mg of sodium hydrogen phosphate hydrate, 10 mg of sodium edetate hydrate, 3 mg of peppermint oil, 40 mg of 1-menthol, 250 mg of chlorobutanol, 13 mg of ethyl parahydroxybenzoate, 7 mg of propyl parahydroxybenzoate, and 500 mg of propylene glycol were dissolved in purified water to prepare a solution with a total volume of 100 mL.

1 mg of naphazoline hydrochloride, 300 mg of allantoin, 250 mg of dipotassium glycyrrhizinate, 30 mg of chlorpheniramine maleate, 100 mg of pyridoxine hydrochloride, 1000 mg of taurine, 500 mg of sodium chondroitin sulfate, 500 mg of epsilon-aminocaproic acid, 700 mg of boric acid, 10 mg of sodium edetate hydrate, 3 mg of peppermint oil, 40 mg of 1-menthol, 250 mg of chlorobutanol, and 10 mg of benzalkonium chloride were dissolved in purified water to prepare a solution with a total volume of 100 mL.

10 mg of naphazoline hydrochloride, 3000 mg of allantoin, 2500 mg of dipotassium glycyrrhizinate, 300 mg of chlorpheniramine maleate, 1000 mg of pyridoxine hydrochloride, 10,000 mg of taurine, 5000 mg of sodium chondroitin sulfate, 2000 mg of epsilon aminocaproic acid, 7000 mg of boric acid, 1500 mg of sodium hydrogen phosphate hydrate, 100 mg of sodium edetate hydrate, 30 mg of peppermint oil, 400 mg of l-menthol, 2500 mg of chlorobutanol, 100 mg of benzalkonium chloride, and 200 mg of polysorbate 80 were dissolved in purified water to prepare a solution with a total volume of 1000 mL.

10 mg of naphazoline hydrochloride, 3000 mg of allantoin, 2500 mg of dipotassium glycyrrhizinate, 300 mg of chlorpheniramine maleate, 1000 mg of pyridoxine hydrochloride, 10,000 mg of taurine, 5000 mg of sodium chondroitin sulfate, 2000 mg of epsilon aminocaproic acid, 7000 mg of boric acid, 1600 mg of sodium hydrogen phosphate hydrate, 100 mg of sodium edetate hydrate, 30 mg of peppermint oil, 400 mg of l-menthol, 2500 mg of chlorobutanol, 130 mg of ethyl parahydroxybenzoate, 70 mg of propyl parahydroxybenzoate, and 5000 mg of propylene glycol were dissolved in purified water to prepare a solution with a total volume of 1000 mL.

The same ingredients, amounts and preparation method were used as in Example 5, but the amount was 1.5 times that of Example 5.

The same ingredients, amounts and preparation method were used as in Example 4, but the amount was 1.5 times that of Example 4.

(Comparative Example 1)
1 mg of naphazoline hydrochloride, 300 mg of allantoin, 250 mg of dipotassium glycyrrhizinate, 30 mg of chlorpheniramine maleate, 100 mg of pyridoxine hydrochloride, 1000 mg of taurine, 500 mg of sodium chondroitin sulfate, 500 mg of epsilon-aminocaproic acid, 600 mg of sodium hydrogen phosphate hydrate, 10 mg of sodium edetate hydrate, 3 mg of peppermint oil, 40 mg of 1-menthol, 250 mg of chlorobutanol, 13 mg of ethyl parahydroxybenzoate, 7 mg of propyl parahydroxybenzoate, and 500 mg of propylene glycol were dissolved in purified water to prepare a solution with a total volume of 100 mL.

(Comparative Example 2)
1 mg of naphazoline hydrochloride, 300 mg of allantoin, 250 mg of dipotassium glycyrrhizinate, 30 mg of chlorpheniramine maleate, 100 mg of pyridoxine hydrochloride, 1000 mg of taurine, 500 mg of sodium chondroitin sulfate, 500 mg of epsilon-aminocaproic acid, 60 mg of boric acid, 230 mg of sodium hydrogen phosphate hydrate, 10 mg of sodium edetate hydrate, 3 mg of peppermint oil, 40 mg of 1-menthol, 250 mg of chlorobutanol, 13 mg of ethyl parahydroxybenzoate, 7 mg of propyl parahydroxybenzoate, and 500 mg of propylene glycol were dissolved in purified water to prepare a solution with a total volume of 100 mL.

(Comparative Example 3)
1 mg of naphazoline hydrochloride, 300 mg of allantoin, 250 mg of dipotassium glycyrrhizinate, 30 mg of chlorpheniramine maleate, 100 mg of pyridoxine hydrochloride, 1000 mg of taurine, 500 mg of sodium chondroitin sulfate, 500 mg of epsilon aminocaproic acid, 690 mg of boric acid, 50 mg of sodium hydrogen phosphate hydrate, 10 mg of sodium edetate hydrate, 3 mg of peppermint oil, 40 mg of l-menthol, 250 mg of chlorobutanol, 10 mg of benzalkonium chloride, and 80 mg of polysorbate 80 were dissolved in purified water to prepare a solution with a total volume of 100 mL.

(Comparative Example 4)
10 mg of naphazoline hydrochloride, 3000 mg of allantoin, 2500 mg of dipotassium glycyrrhizinate, 300 mg of chlorpheniramine maleate, 1000 mg of pyridoxine hydrochloride, 10,000 mg of taurine, 5000 mg of sodium chondroitin sulfate, 2000 mg of epsilon aminocaproic acid, 7000 mg of boric acid, 6200 mg of sodium hydrogen phosphate hydrate, 100 mg of sodium edetate hydrate, 30 mg of peppermint oil, 400 mg of l-menthol, 2500 mg of chlorobutanol, 130 mg of ethyl parahydroxybenzoate, 70 mg of propyl parahydroxybenzoate, and 5000 mg of propylene glycol were dissolved in purified water to prepare a solution with a total volume of 1000 mL.

(Comparative Example 5)
10 mg of naphazoline hydrochloride, 3000 mg of allantoin, 2500 mg of dipotassium glycyrrhizinate, 300 mg of chlorpheniramine maleate, 1000 mg of pyridoxine hydrochloride, 10000 mg of taurine, 5000 mg of sodium chondroitin sulfate, 2000 mg of epsilon aminocaproic acid, 7000 mg of boric acid, 3000 mg of sodium hydrogen phosphate hydrate, 100 mg of sodium edetate hydrate, 30 mg of peppermint oil, 400 mg of l-menthol, 2500 mg of chlorobutanol, 100 mg of benzalkonium chloride, and 200 mg of polysorbate 80 were dissolved in purified water to prepare a solution with a total volume of 1000 mL.

(Comparative Example 6)
10 mg of naphazoline hydrochloride, 3000 mg of allantoin, 2500 mg of dipotassium glycyrrhizinate, 300 mg of chlorpheniramine maleate, 1000 mg of pyridoxine hydrochloride, 10000 mg of taurine, 5000 mg of sodium chondroitin sulfate, 2000 mg of epsilon aminocaproic acid, 7000 mg of boric acid, 6200 mg of sodium hydrogen phosphate hydrate, 100 mg of sodium edetate hydrate, 30 mg of peppermint oil, 400 mg of l-menthol, 2500 mg of chlorobutanol, 100 mg of benzalkonium chloride, and 200 mg of polysorbate 80 were dissolved in purified water to prepare a solution with a total volume of 1000 mL.

The formulations of the examples and comparative examples are shown below.

[Test Example 1] Effect of boric acid on the stability of multi-component ophthalmic solutions Multi-component ophthalmic solutions containing seven types of active ingredients were prepared by varying the amount of boric acid added as a stabilizer, pH, and osmotic pressure in Examples 1, 2, 5, Comparative Example 1, Comparative Example 2, and Comparative Example 4. Each was stored at 50°C for two months, and the changes in the properties of the medicinal solution were evaluated. The results are shown below.

In Comparative Example 1, in which boric acid was not added to the multi-component ophthalmic solution, and Comparative Example 2, in which boric acid was added at 0.06 w/v%, the medicinal solution turned brown after storage at 50° C. for two months. On the other hand, in Example 1, in which boric acid was added at 0.34 w/v%, Example 2, in which boric acid was added at 0.55 w/v%, and Example 5 and Comparative Example 4, in which boric acid was added at 0.7 w/v%, respectively, there was no change in properties even after storage at 50° C. for two months, and the effect was not affected by differences in pH and osmotic pressure when the ophthalmic solution was prepared. From this, it was found that when boric acid, a stabilizer, was added at 0.34 w/v% or more, the change in properties of the medicinal solution could be suppressed.

[Test Example 2] Effect of the amount of polysorbate 80 (solubilizing agent) added on the stability of multi-component ophthalmic solutions containing chlorobutanol and benzalkonium chloride Multi-component ophthalmic solutions containing seven kinds of active ingredients were prepared by adding 0.25 w/v% chlorobutanol and 0.01 w/v% benzalkonium chloride as preservatives, and further adding no polysorbate 80 as a solubilizing agent, Example 3, in which 0.02 w/v% polysorbate 80 was added, and Example 4, in which 0.08 w/v% polysorbate 80 was added, and Comparative Example 3, in which 0.08 w/v% polysorbate 80 was added, at 50°C for two months, and the changes in the properties of the medicinal solutions were evaluated. The results are shown below.

The stability of the multi-component ophthalmic solution containing chlorobutanol and benzalkonium chloride as preservatives after storage for 2 months at 50°C differed depending on the amount of polysorbate 80 used as a solubilizing agent. Comparative Example 3, which contained 0.08 w/v% polysorbate 80, became cloudy, but no change was observed in Example 4, which contained 0.02 w/v% polysorbate 80, and Example 3, which did not contain polysorbate 80. From this, it was found that when chlorobutanol and benzalkonium chloride are added as preservatives to the multi-component ophthalmic solution, the change in the properties of the medicinal solution can be suppressed by setting the amount of polysorbate 80, a solubilizing agent, to 0.02 w/v% or less.

[Test Example 3] Effect of preservatives and pH on the stability of multi-component ophthalmic solutions Multi-component ophthalmic solutions containing seven kinds of active ingredients were prepared using chlorobutanol as a preservative, and ethyl parahydroxybenzoate, propyl parahydroxybenzoate, or benzalkonium chloride in Examples 4, 5, Comparative Examples 4, 5, and 6, and were stored at 40° C. and 50° C., respectively, and the changes in pH, osmotic pressure, and content of active ingredients were evaluated. The results are shown below.

The multi-component eye drops containing seven active ingredients, each adjusted to pH 5.9 or higher, were stored at 40° C. for six months, resulting in a decrease in the allantoin content. Furthermore, in the multi-component eye drops of Comparative Example 4 and Comparative Example 6, in which the pH of the multi-component eye drops was adjusted to 6.5 or higher, it was confirmed that the allantoin content was significantly decreased, and the naphazoline hydrochloride content was also decreased, and the pH was also decreased by about 1, by storing at 40° C. for six months. On the other hand, in the multi-component eye drops of Examples 4 and 5, in which the pH of the multi-component eye drops was adjusted to about 5.4, there was almost no decrease in the active ingredient content or any change in pH or osmotic pressure, and the eye drops were stable even after storing at 40° C. for six months.

[Test Example 4] Preservative Effectiveness Test of Multi-Component Ophthalmic Preparations The multi-component ophthalmic preparations of Examples 6 and 7 were subjected to a test based on the preservative effectiveness test method of the 17th Edition of the Japanese Pharmacopoeia.

As shown in Table 6, the preservative effectiveness of the multi-component ophthalmic solutions of Examples 6 and 7 according to the present invention was confirmed.

The present invention provides a multi-ingredient combination eye drop containing seven active ingredients and having excellent storage stability, which makes it possible to relieve various symptoms of ocular allergy with a single administration, thereby contributing to the convenience and improvement of the QOL of users.

Claims (6)

A multi-component eye drop comprising naphazoline or a salt thereof, allantoin, glycyrrhizic acid or a salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, taurine, and chondroitin sulfate or a salt thereof , as well as 0.34 to 1.0 w/v % boric acid, 0.02 w/v % or less polysorbate 80, and a preservative , the preservative consisting of two components, chlorobutanol and benzalkonium chloride, and having a pH in the range of 5.0 to 5.5 . 2. The multi-component ophthalmic solution according to claim 1 , comprising 0.25 w/v % chlorobutanol and 0.01 w/v % benzalkonium chloride. A multi-component eye drop comprising naphazoline or a salt thereof, allantoin, glycyrrhizic acid or a salt thereof, chlorpheniramine maleate, pyridoxine hydrochloride, taurine, and chondroitin sulfate or a salt thereof, as well as 0.34 to 1.0 w/v % boric acid and a preservative, the preservative consisting of three components, chlorobutanol, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate, and having a pH in the range of 5.0 to 5.5. 4. The multi-component ophthalmic solution according to claim 3 , comprising 0.25 w/v % chlorobutanol, 0.013 w/v % ethyl parahydroxybenzoate, and 0.007 w/v % propyl parahydroxybenzoate. 5. The multi-component ophthalmic preparation according to claim 1, wherein the naphazoline or a salt thereof is naphazoline hydrochloride, the glycyrrhizinic acid or a salt thereof is dipotassium glycyrrhizinate, and the chondroitin sulfate or a salt thereof is sodium chondroitin sulfate. 6. The multi-component eye drop according to claim 5, comprising 0.001 w/v% naphazoline hydrochloride, 0.3 w/v% allantoin, 0.25 w/v% dipotassium glycyrrhizinate, 0.03 w/v% chlorpheniramine maleate, 0.1 w /v% pyridoxine hydrochloride, 1.0 w/v% taurine and 0.5 w/v% sodium chondroitin sulfate.