JP2007023020A - Preparation for ocular mucosa application - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a safe preparation for mucosa application that exhibits antiseptic action and has low cytotoxicity in a preparation for ocular mucosa application. <P>SOLUTION: The eye drop or eye wash does not substantially contain benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate and comprises (A) one or more kinds selected from chlorpheniramine, diphenhydramine and their salts, (B) boric acid and/or borax in the ratio of ≥1.5(w/v)% based on the total of a composition and (C) one or more kinds selected from aminoethylsulfonic acid, aspartic acid and their salts and has pH 7.3-9.0. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to a preparation for ocular mucosa. More specifically, the present invention can prevent the spoilage of the ocular mucosa-applied product substantially without containing benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate, and has high cytotoxicity and high safety. The present invention relates to a preparation for application to the ocular mucosa.

Ophthalmic mucous membrane preparations such as eye drops and eye wash products are desired to prevent product decay due to microbial contamination during use. It is assumed that many ophthalmic mucosa preparations such as eye drops are used many times over a certain period after opening. Once the eye drops are opened, there is a high possibility that microbial contamination will be caused from the air or the contacted skin. Therefore, ophthalmic mucosa preparations are often formulated with benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate as an antiseptic agent for the purpose of preventing the decay and improving the storage stability of the ocular mucosa application preparation. . There are eye drops that do not contain preservatives, but after opening, they are limited to eye drops that can be used once (unit dose). For example, unit dose type eye drops containing chlorpheniramine maleate are also known (Patent Documents 1 and 2).

Benzalkonium chloride, benzethonium chloride, or chlorhexidine gluconate, which are widely used as preservatives, are known to be damaging to corneal cells and the like, and when eye drops containing these preservatives are instilled while wearing contact lenses. , Benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate is adsorbed on the contact lens to alter the contact lens itself, or wear a contact lens adsorbed with benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate Adverse effects on the eyes due to Therefore, it is usually prohibited to instill eye drops containing benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate while wearing contact lenses. Then, the ophthalmic composition for contact lenses which can maintain the outstanding preservative power by containing trometamol without mix | blending benzalkonium chloride is reported (patent document 3).

By the way, diphenhydramine hydrochloride and chlorpheniramine maleate are one of the highly safe components widely used as antihistamines, and antihistamine eye drops containing diphenhydramine hydrochloride and chlorpheniramine maleate are generally used. Many are marketed as pharmaceuticals. For multi-dose type eye drops containing diphenhydramine hydrochloride or chlorpheniramine maleate (scheduled for repeated use), benzalkonium chloride is the same as many eye drops for the above reasons. In many cases, benzethonium chloride or chlorhexidine gluconate is blended.

So far, it has been known that diphenhydramine or its salt itself has a slightly weak antiseptic action (Non-patent Document 1), but the antibacterial activity has not been sufficient. On the other hand, it is not known that chlorpheniramine or its salt itself has an antiseptic action.

Japanese Patent Laid-Open No. 2001-354592 JP 2002-249445 A JP 2002-316926 A Knothe H, Beckmann I, Kiesel K, Oelschlager H., Arzneimittelforschung. 1980; 30 (4): 667-70.

An object of the present invention is to provide a safe preparation for mucous membranes which is prevented from being spoiled and has no cytotoxicity.

The present inventor has found that an excellent antiseptic action is exhibited by using boric acid or / and borax together with diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof (Japanese Patent Application No. 2004-128661). ).
The inventor is also substantially free of benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate, and (A) one or more selected from chlorpheniramine, diphenhydramine and salts thereof, (B) Boric acid or / and borax in a total amount thereof is 1.5 (w / v)% or more based on the whole preparation, and (C) one type selected from aminoethylsulfonic acid, aspartic acid and salts thereof PH containing 7.3 or more is 7.3-9.
It was found that in the ocular mucosa-applied preparation of 0, cytotoxicity was reduced while exhibiting a remarkable antiseptic action.
That is, the present invention is the following invention:
(1) substantially free of benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate,
(A) One or more selected from chlorpheniramine, diphenhydramine and salts thereof,
(B) Boric acid or / and borax are 1.5 (w / v)% of the total formulation in these total amounts.
more than,
(C) an ophthalmic mucosa-applied preparation having a pH of 7.3 to 9.0, comprising one or more selected from aminoethylsulfonic acid, aspartic acid and salts thereof;
(2) The preparation for application to the ocular mucosa according to (1), which is an eye drop or an eye wash;
(3) The ocular mucosa-applied preparation according to claim 1 or 2, which is a multi-dose type eye drop or eye wash.
The term “preservation” as used in the present invention means preventing the growth of microorganisms and preventing spoilage. The “microorganism” includes bacteria, fungi and the like. In the present specification, unless otherwise specified, “%” means w / v% (g / 100 mL). In addition, the term “contact lens” is used in the sense of including all types of contact lenses such as hard, oxygen-permeable hard, and soft unless otherwise specified.

The ocular mucosa-applied preparation of the present invention has an excellent antiseptic effect and suppresses the growth of microorganisms and prevents spoilage even though it does not substantially contain benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate. . Usually, when a cell activating component such as an amino acid is used in combination with an antiseptic, the antiseptic power tends to decrease, but the preparation for application to the ocular mucosa of the present invention maintains an excellent antiseptic effect and prevents the formulation from being spoiled. In addition, a safe preparation for mucosa that is free from cytotoxicity is provided. The preparation for application to the ocular mucosa of the present invention is particularly useful for soft contact lens wearers, dry eye patients, allergic eye diseases, patients after eye surgery, eyes of patients with corneal cell disorders, and the like.

In the preparation for application to the ocular mucosa of the present invention, an amount of benzalkonium chloride substantially exhibiting an antiseptic effect,
Contains no benzethonium chloride or chlorhexidine gluconate.
Further, the preparation for application to the ocular mucosa of the present invention does not exclude the preparation containing other preservatives, but the preparation for application to the ocular mucosa of the present invention imparts an excellent antiseptic action. It does not need to contain a preservative. However, some preservatives, such as ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, sorbic acid or salts thereof, or alkylpolyaminoethylglycine, are not suitable for formulation design. When such a preservative is contained, the content is preferably limited to a small amount, more preferably not contained substantially.

The preparation for application to the eye mucosa of the present invention comprises (A) one or more compounds selected from diphenhydramine, chlorpheniramine and salts thereof as essential components. These can be used alone (diphenhydramine hydrochloride, diphenhydramine lauryl sulfate and diphenhydramine hydrochloride combination, diphenhydramine and diphenhydramine hydrochloride combination, chlorpheniramine maleate, chlorpheniramine and chlorpheniramine maleate combination, etc.) They may be used, or two or more (such as a combination of diphenhydramine hydrochloride and chlorpheniramine maleate) may be used in any combination.

In the present invention, diphenhydramine is a known compound, and the salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable, but hydrochloride is particularly preferable. In the present invention, diphenhydramine or a salt thereof can be used in the form of a hydrate. Chlorpheniramine is a known compound, and the salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically acceptable, but maleate is particularly preferred. Chlorpheniramine or a salt thereof can also be used in the form of a hydrate.

In the preparation for application to the ocular mucosa of the present invention, the content in the preparation of one or more compounds selected from diphenhydramine, chlorpheniramine and salts thereof is not particularly limited. For example, chlorpheniramine or a salt thereof is
0.0001-0.1%, preferably 0.0006-0.05%, more preferably 0.0
The ratio which becomes 03 to 0.03% is mentioned. Diphenhydramine or a salt thereof is 0.00
01-0.1%, preferably 0.001-0.07%, more preferably 0.005-0.
A proportion of 05% is mentioned.

The preparation for ocular mucosa of the present invention comprises (B) boric acid and / or borax as an essential component. These may be used individually by 1 type and may be used in combination of 2 or more type. Boric acid and / or borax as a percentage of the ophthalmic mucosa applied formulation is the total of these 1.
It is characterized by containing 5% or more. Preferably it is 1.8% or more, more preferably 2.0%
% Or more. The upper limit is 5.0% or less, preferably 4.0% or less, more preferably 3.0% or less from the viewpoint of eye irritation.

In the preparation for application to the ocular mucosa of the present invention, for example, boric acid and / or borax may be mixed with diphenhydramine or a salt thereof in combination with boric acid and / or borax with respect to 1 part by weight of diphenhydramine or a salt thereof The total amount is preferably 0.5 to 10000 parts by weight, more preferably 1 to 5000 parts by weight, still more preferably 1 to 1000 parts by weight, and particularly preferably 2 to 600 parts by weight. For example, the mixing ratio of combining chlorpheniramine or its salt with boric acid and / or borax is preferably the total amount of boric acid and / or borax with respect to 1 part by weight of the total amount of chlorpheniramine or its salt. 0.5-10000
Parts by weight, more preferably 1 to 7000 parts by weight, still more preferably 2 to 5000 parts by weight,
Particularly preferred is 2 to 1000 parts by weight.

The preparation for ocular mucosa of the present invention comprises (C) one or more compounds selected from aminoethylsulfonic acid, aspartic acid and salts thereof as essential components. The salt of aspartic acid is not particularly limited as long as it is pharmaceutically acceptable.
Potassium aspartate, magnesium aspartate, magnesium aspartate
A potassium mixture is preferred.

In the preparation for application to the ocular mucosa of the present invention, the content in the preparation of one or more compounds selected from aminoethylsulfonic acid, aspartic acid and salts thereof is not particularly limited. As the total amount of the compound is usually about 0.03 to 5.0%,
More preferably, it is contained at 0.03 to 3.0%, and further preferably 0.1 to 2.0%.

The ophthalmic mucosa-applied preparation of the present invention has a pH of 7.3 to 9.0. More preferably, it is 7.3-8.0. Within such a range, it is possible to provide a safe preparation that imparts an excellent antiseptic action to the ocular mucosa-applied preparation and has low cytotoxicity. The pH can be adjusted using a buffer, a pH adjuster or the like.

The ocular mucosa-applied preparation of the present invention is not particularly limited. An example of an ophthalmic mucosa-applied preparation is eye drops (
Agent) (including eye drops (agent) that can be used while wearing contact lenses), eye wash (agent) (including eye wash (agent) that can be used while wearing contact lenses), eye ointment, contact lens mounting solution, etc. Can be mentioned. Among these, eye drops (agent) and eye wash (agent) are preferable. The preparation for application to the ocular mucosa of the present invention is also excellent in that it can be used as an ocular mucosa application preparation for use in all contact lenses including hard contact lenses and soft contact lenses. In addition, since the ophthalmic mucosa preparation of the present invention has an excellent antiseptic action, the multi-dose type ocular mucosa application preparation, that is, the ocular mucosa application preparation used several times or more after the product is once opened. It is preferably used, and the preparation for application to the ocular mucosa can be stably stored for several days or weeks.

The form of the preparation for ocular mucosa of the present invention is not particularly limited, and examples thereof include liquids, gels, ointments and the like. In particular, an aqueous liquid preparation is a preparation form in which microorganisms are easy to propagate. However, in the preparation for application to the ocular mucosa of the present invention, the aqueous liquid preparation has a high antiseptic effect and prevents spoilage.

Since diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof, which is an essential component of the ophthalmic mucosa preparation of the present invention, itself acts as an antihistamine component, the ophthalmic mucosa application preparation of the present invention exhibits an antihistaminic action. Can do. Furthermore, other medicinal ingredients can be contained. For example, a decongestant component, an eye regulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, sulfa drugs, saccharides, polysaccharides or salts thereof, cellulose derivatives or Examples thereof include salts thereof, water-soluble polymers other than those described above, local anesthetic components, steroid components, and glaucoma therapeutic agents. Examples of suitable components in the present invention include the following components.

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

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

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

Antihistamine component or antiallergic agent component: for example, acitazanolast, amlexanox, ibudilast, tranilast, levocabastine hydrochloride, sodium cromoglycate, ketotifen fumarate, pemirolast potassium and the like.

Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride,
Flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid,
Tocopherol acetate etc.

Amino acids: For example, glutamic acid, creatinine, sodium glutamate and the like. These may be d-form, l-form or dl-form.

Sulfa drugs: For example, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium and the like.

  Sugars: for example, monosaccharides, disaccharides, specifically glucose, trehalose and the like.

Polysaccharides or salts thereof: for example, sodium hyaluronate, sodium chondroitin sulfate, etc.

Cellulose derivatives or salts thereof: For example, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose and the like.

Water-soluble polymers other than those described above: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, dextran and the like.

Local anesthetic ingredients: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothokine hydrochloride, lidocaine hydrochloride, chloro Butanol and so on.

Steroid component: for example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

Glaucoma treatment components: for example, isopropyl unoprostone, epinephrine, apraclonidine hydrochloride, carteolol hydrochloride, dipivefrin hydrochloride, dorzolamide hydrochloride, pilocarpine hydrochloride, bunazosin hydrochloride, bupranolol hydrochloride, betaxolol hydrochloride, befnolol hydrochloride, carbachol, levobunolol hydrochloride, epinephrine hydrochloride , Distigmine bromide, nipradilol, timolol maleate, latanoprost and the like.

The blending amount of these components in the preparation for application to the ocular mucosa is appropriately selected according to the kind of the preparation, the kind of the active ingredient, etc., for example, 0.0001 to 30%, preferably 0.00
It can be selected from a range of about 1 to 10%.

In addition, in the ophthalmic mucosa-applied preparation of the present invention, various components and additives are appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired. May be contained in combination. What is necessary is just to set suitably about the mixture ratio of this component or additive based on the range normally employ | adopted in this industry. As the component or additive, for example, a carrier (water, aqueous solvent, aqueous or oily base, etc.) generally used for the preparation of semi-solid agents and liquid agents, thickeners, pH adjusters, isotonicity Various additives, such as an agent, a fragrance | flavor or a refreshing agent, a chelating agent, and a buffering agent, can be mentioned. Below, although the typical component used for the ocular mucosa application formulation to which the preservative of this invention is applied is illustrated, it is not limited to these.

In the preparation for application to the ocular mucosa of the present invention, as described above, the preservative is preferably limited to a small amount, and more preferably substantially free of preservatives. In the ophthalmic mucosa preparation of the present invention, a polyoxyethylene (hereinafter abbreviated as POE) -polyoxypropylene (hereinafter abbreviated as POP) block copolymer (specifically, from the viewpoint of emphasizing reduction in cytotoxicity) Poloxamer
407), ethylenediamine POE-POP block copolymer adduct (specifically,
Poloxamine), POE sorbitan monooleate (specifically, polysorbate 80)
The content of nonionic surfactants such as POE hydrogenated castor oil (specifically, POE (60) hydrogenated castor oil) and polyoxyl stearate is desirably limited to a small amount. It is preferable that the agent is not substantially contained.

Aqueous carrier: for example, water, methanol, hydrous methanol, ethanol, hydrous ethanol and the like.

Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid or salts thereof, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, sodium carboxymethylcellulose, dextran, glycerin and the like.

pH adjusting agent: for example, hydrochloric acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, triethanolamine, monoethanolamine and the like.

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

Perfume or refreshing agent: for example, camphor, geraniol, borneol, menthol, leopard, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These are d-form, l-form or dl
Any body.

Chelating agents: for example, ascorbic acid, edetate tetrasodium, edetate sodium,
Citric acid and so on.

Buffer: citrate buffer, acetate buffer, carbonate buffer, phosphate buffer, etc. In particular,
Citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like.

Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glycerin, propylene glycol, cyclodextrin, dextran, etc.

Solubilizer, base: octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, camellia oil, corn oil, rapeseed oil, paraffin, castor oil, plastibase, peanut oil, lanolin, petrolatum, glycerin, propylene Glycol, cyclodextrin, macrogol, etc.

Hereinafter, the present invention will be described in detail based on examples, test examples, and the like, but the present invention is not limited thereto.

Test Example 1 Preservative Efficacy Test According to the formulation described in Table 1, each component was dissolved in purified water to make a total volume of 100 mL as a test solution (
Examples and Comparative Examples) were prepared, sterilized by filtration, and filled into polyethylene terephthalate eye drop containers to produce eye drops. The antiseptic effects of these test solutions after filter sterilization were evaluated according to the 14th revised Japanese Pharmacopoeia Reference Information Preservation Efficacy Test Method. Specifically, a bacterial solution was prepared using gram-negative bacteria ( Escherichia coli ). The bacteria solution was inoculated into the test solution so as to be 10 ⁵ ~10 ⁶ CFU / mL, and stored at 23 ° C.. The test solution 14 days after inoculation was sampled, the number of bacteria in the test solution was measured by the membrane filter method, and the survival rate was determined according to the following formula. Further, the antiseptic effect of the test solution was evaluated from the measured number of bacteria in the test solution based on the following evaluation criteria. The results are shown in Table 1.

<Expression>
Survival rate (%) = (number of bacteria after 14 days / initial number of bacteria) × 100
<Evaluation criteria>
○: Survival rate after 14 days is 0.1% or less ×: Survival rate after 14 days is more than 0.1%

Neutral red assay method using rabbit corneal epithelial cells The test was performed according to the neutral red assay method using rabbit corneal epithelial cells in Kornepack kit (Kurabo Co., Ltd.). A suspension of rabbit corneal epithelial cells was seeded at 2500 cells / well in a well of a 96-well microplate at 100 μl, and cultured for 3 days in a CO ₂ incubator (37.0 ° C., 5% CO ₂ , humidified).
Culture medium (serum-free medium for tissue culture RCGM) was added to the cultured corneal epithelial cells.
100 μl of 2 medium) is added, and 100 μl of test medium diluted 10 times with the RCGM2 medium is added to the test wells with the formulation shown in Table 1, and the CO ₂ incubator (37.0 ° C., 2 days) is added.
5% CO _2, and incubated in a humidified). Neutral red solution (150 μg / ml) was added to each well in an amount of 100 μl, and further incubated for 2 hours, so that neutral red was incorporated into lysosomes of living cells. Next, the supernatant was discarded, the cells were fixed with 200 μl of a 1% formalin solution containing 1% calcium chloride for 1 minute, and neutral red that had not been incorporated was washed. Subsequently, the supernatant was discarded, and neutral red incorporated into living cells was extracted by adding 100 μl of a 50% ethanol solution containing 1% acetic acid. Further, the absorbance at 540 nm was measured using a microplate reader. Corneal epithelial cell survival rate (%) = (540 nm absorbance of test drug solution / 540 nm control)
The corneal epithelial cell viability (%) of each well was calculated as (absorbance of) × 100. Corneal epithelial cell survival rate of each comparative example and example when the corneal epithelial cell survival rate (%) of comparative example 1 is set to 1 (
%) Is shown in Table 1.

As a result of the test, the Example of the present invention has a sufficient antiseptic effect equivalent to Comparative Example 1 containing benzalkonium chloride, and corneal epithelial cell survival compared to Comparative Example 1 containing benzalkonium chloride. The rate increased approximately 20 times. In Comparative Example 3 containing boric acid and borax, the preservative effect was reduced by containing potassium aspartate and aminoethylsulfonic acid, and the Japanese Pharmacopoeia Preservative Efficacy Test Category IA formulation could not be satisfied. In Examples of the present invention, potassium aspartate, aminoethyl were prepared by adding chlorpheniramine maleate or diphenhydramine hydrochloride to boric acid and / or borax and adjusting pH to 7.3-9.0. Although it contains sulfonic acid, it has been confirmed that it has a sufficient antiseptic effect. Furthermore, the same preservative effect was stably maintained when the same preservative effect test was conducted after storing the ophthalmic solution adjusted for each example (each filled with 15 mL) under the condition of 40 ° C. and 75% for 6 months. .

In addition, although not shown in the data, for each example, other bacterial species (bacteria: Pseudomona
s aeruginosa, Staphylococcus aureus, fungi: Candida albicans, Aspergillus nig
As for er), a preservation efficacy test was conducted according to the 14th revised Japanese Pharmacopoeia Reference Information Preservation Efficacy Test Method. As a result, results conforming to the criteria of the Japanese Pharmacopoeia Preservation Efficacy Category IA formulation were obtained.

Example 6
Boric acid 1.3g
Borax 0.5g
0.03 g chlorpheniramine maleate
L-aspartate potassium 0.2g
Aminoethylsulfonic acid 1.0g
Pyridoxine hydrochloride 0.05g
Hydrochloric acid appropriate amount sodium hydroxide appropriate amount purified water appropriate amount
Each of the above components is weighed and dissolved in an appropriate amount of purified water to adjust the pH to 7.5. The total amount is adjusted to 100 ml with purified water, and then sterilized by filtration in an aseptic environment, filled in a container and an eye drop. Got.

Example 7
Boric acid 1.8g
Borax 0.35g
Chlorpheniramine maleate 0.003g
L-potassium potassium aspartate 0.05g
Aminoethylsulfonic acid 0.1g
0.01 g of pyridoxine hydrochloride
Hydrochloric acid appropriate amount sodium hydroxide appropriate amount purified water appropriate amount
Each of the above components is weighed and dissolved in an appropriate amount of purified water to adjust the pH to 7.3, and the total amount is adjusted to 100 ml with purified water. Then, the solution is sterilized by filtration in an aseptic environment, filled in a container, and an eye wash. Got.

Claims (3)

Substantially free of benzalkonium chloride, benzethonium chloride or chlorhexidine gluconate,
(A) One or more selected from chlorpheniramine, diphenhydramine and salts thereof,
(B) Boric acid and / or borax are 1.5 (w / v)% of the total formulation in these total amounts.
more than,
(C) An ophthalmic mucosa-applied preparation having a pH of 7.3 to 9.0 containing one or more selected from aminoethylsulfonic acid, aspartic acid and salts thereof.   The ocular mucosa-applied preparation according to claim 1, which is an eye drop or an eye wash.   The ophthalmic mucosa-applied preparation according to claim 1 or 2, which is a multi-dose type eye drop or eye wash.