JP5584336B2 - Preservative and aqueous composition containing the same - Google Patents

Description

The present invention relates to a preservative. In more detail, this invention relates to the preservative used suitably for aqueous composition. Furthermore, this invention relates to the aqueous composition to which the antiseptic effect was provided by containing this preservative.

It is desirable that an aqueous composition such as a pharmaceutical product is prevented from being spoiled due to microbial contamination during use. Therefore, antiseptics are blended in various aqueous compositions for the purpose of preventing the decay and improving the storage stability of the aqueous composition.

In particular, it is assumed that many ophthalmic aqueous compositions (ophthalmic agents) 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 in the air or in contact with the skin. There are eye drops that do not contain preservatives, but these are limited to eye drops that can be used once after opening (unit dose). For example, a unit dose type eye drop containing chlorpheniramine maleate is also known (Patent Documents 1 and 2).

Benzalkonium chloride and benzethonium chloride, 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, It has been pointed out that there are adverse effects such as deteriorating the contact lens itself by adsorbing it on the contact lens, and adverse effects on the eye due to wearing the contact lens adsorbed with the preservative. Therefore, it is usually prohibited to instill eye drops containing benzalkonium chloride or benzethonium chloride while wearing contact lenses.

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 ophthalmic solutions containing diphenhydramine hydrochloride or chlorpheniramine maleate (scheduled for repeated use multiple times), the products currently on the market are all preservatives for many reasons. It is blended. However, as mentioned above, there are concerns about the adverse effects of preservatives on the eyes, and the preservative efficacy of the aqueous composition tends to decrease when high-nutrient sugars, salts, vitamins, and amino acids are added to the aqueous composition. And
A preservative having a high preservative effect has been desired. Furthermore, in recent years, contact lens wearers, especially soft contact lens wearers who tend to absorb preservatives, are increasing, which may cause the above-mentioned inconveniences specific to contact lenses due to misuse that does not comply with compliance. Was a problem.

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

Knothe H, Beckmann I, Kiesel K, Oelschlager H., Arzneimittelforschung. 1980; 30 (4): 667-70.

An object of the present invention is to provide a novel preservative, particularly a preservative exhibiting an excellent antiseptic action when used in an aqueous composition such as an ophthalmic agent.

As a result of intensive studies to solve the above problems, the present inventors have combined boric acid and / or a salt of boric acid with at least one compound selected from diphenhydramine, chlorpheniramine or a salt thereof. It was found that the antiseptic action is synergistically enhanced. The present invention has been completed by further studies based on this finding.
That is, the present invention is the following invention:
Item 1. (A) at least one compound selected from diphenhydramine, chlorpheniramine or a salt thereof, and (B) a preservative comprising boric acid and / or a salt of boric acid,
Item 2. Item 2. The preservative according to Item 1, wherein the total amount of boric acid and / or a salt of boric acid is combined at 0.5 to 10,000 parts by weight with respect to 1 part by weight of the total amount of diphenhydramine or a salt thereof.
Item 3. Item 2. The preservative according to Item 1, wherein the total amount of boric acid and / or a salt of boric acid is combined at 0.5 to 10,000 parts by weight with respect to 1 part by weight of the total amount of diphenhydramine or a salt thereof.
Item 4. (A) an aqueous composition containing at least one compound selected from diphenhydramine, chlorpheniramine or a salt thereof, and (B) a preservative comprising boric acid and / or a salt of boric acid,
Item 5. Item 5. The aqueous composition according to Item 4, which is a multi-dose type,
Item 6. Item 6. The aqueous composition according to Item 4 or 5, which is a liquid agent or a semisolid agent,
Item 7. Item 7. The aqueous composition according to any one of Items 4 to 6, which is an ophthalmic agent used for an oxygen-permeable hard contact lens or soft contact lens,
Item 8. Furthermore, 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, antibacterial component, bactericidal component, saccharide, polysaccharide or the like Item 8. The derivative according to any one of Items 4 to 7, comprising at least one selected from the group consisting of a derivative, cellulose or a derivative thereof or a salt thereof, polyvinyl alcohol, polyvinylpyrrolidone, a local anesthetic component, a steroid component, and a glaucoma therapeutic agent. An aqueous composition,
Item 9. (A) at least one compound selected from diphenhydramine, chlorpheniramine or a salt thereof, and (B) a preservative comprising boric acid and / or a salt of boric acid,
Benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, sorbic acid or salts thereof, or alkylpolyaminoethylglycine A multi-dose type aqueous composition characterized by
Item 10. (A) At least one compound selected from diphenhydramine, chlorpheniramine or a salt thereof and (B) boric acid and / or a salt of boric acid are combined to provide an antiseptic effect to the aqueous composition. how to.

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. Moreover, unless otherwise indicated in this specification,% shall mean w / v% (g / 100 mL). Further, the term “contact lens” is used in the meaning of including all types of contact lenses such as hard, oxygen-permeable hard, and soft unless otherwise specified. The aqueous composition means that the composition contains water at least 5 w / v% or more, preferably 20 w / v% or more, more preferably 50 w / v% or more.

The preservative of the present invention comprises (A) at least one compound selected from diphenhydramine, chlorpheniramine or a salt thereof and (B) boric acid and / or a salt of boric acid as active ingredients. It is highly safe, can exhibit excellent antiseptic action, and is useful as an alternative to preservatives used in conventional ophthalmic agents.
In addition, an aqueous composition containing such a preservative is highly safe and effectively suppresses the growth of microorganisms and prevents spoilage. In particular, the ophthalmic agent containing the preservative of the present invention is
It is useful for ophthalmic agents used for oxygen permeable hard contact lenses or soft contact lenses without preservatives adsorbing to contact lenses.

The preservative of the present invention comprises (A) at least one compound selected from diphenhydramine, chlorpheniramine or a salt thereof as an essential component. These can be used alone (diphenhydramine hydrochloride, diphenhydramine lauryl sulfate and diphenhydramine hydrochloride, diphenhydramine and diphenhydramine hydrochloride, chlorpheniramine maleate, chlorpheniramine and chlorpheniramine maleate, 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. For example, an organic acid salt [for example, monocarboxylate (acetate, Fluoroacetate, butyrate, palmitate, stearate, etc., polyvalent carboxylate (fumarate, maleate, etc.), oxycarboxylate (lactate, tartrate, citrate, succinate, etc.) Salt, malonate, etc.), organic sulfonate (lauryl sulfate, methanesulfonate, toluenesulfonate, tosylate, etc.)
Etc.], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.),
Salts with organic bases (eg, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg, ammonium salts; alkali metals ( Sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.]. Of these, hydrochloride is preferred. In the preservative of the present invention, diphenhydramine or a salt thereof can be used in the form of a hydrate.

In the present invention, chlorpheniramine is a known compound, and a chlorpheniramine salt is not particularly limited as long as it is pharmaceutically acceptable. For example, an organic acid salt [for example, a monocarboxylate ( Acetate, trifluoroacetate, butyrate, palmitate, stearate, etc., polyvalent carboxylate (fumarate, maleate, etc.), oxycarboxylate (lactate, tartrate, citric acid) Salt, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.), inorganic acid salt (eg hydrochloride, sulfate, nitrate, odor) Hydrides, phosphates, etc.), salts with organic bases (
For example, methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, salts with organic amines such as tripyridine, picoline, etc.), salts with inorganic bases [for example, ammonium salts; alkali metals (sodium, potassium, etc.), Examples include alkaline earth metals (calcium, magnesium, etc., salts with metals such as aluminum, etc.). Of these, maleates are preferred. In the preservative of the present invention, chlorpheniramine or a salt thereof can be used in the form of a hydrate.

The preservative of the present invention contains (B) boric acid and / or a salt of boric acid as an essential component. These may be used alone or in any combination of two or more.

The salt of boric acid is not limited as long as it is pharmaceutically acceptable. Examples of the boric acid salt include sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. Of these, borax is preferred.

In the preservative of the present invention, the combination ratio when the antiseptic effect is enhanced by combining boric acid and / or a salt of boric acid with diphenhydramine or a salt thereof is 1 part by weight of the total amount of diphenhydramine or a salt thereof. The total amount of acid and / or boric acid salt is preferably 0.
5-10,000 parts by weight, more preferably 1-5000 parts by weight, still more preferably 1-1
000 parts by weight, particularly preferably 2 to 600 parts by weight.

The compounding ratio when the antiseptic effect is enhanced by combining boric acid and / or a salt of boric acid with chlorpheniramine or a salt thereof is as follows: boric acid and / or salt with respect to 1 part by weight of the total amount of chlorpheniramine or a salt thereof. Alternatively, the total amount of boric acid salt is preferably 0.5 to 10000 parts by weight, more preferably 1 to 7000 parts by weight, still more preferably 2 to 5000 parts by weight, and particularly preferably 2 to 1000 parts by weight. When it is lower than such a ratio, even if boric acid and / or a salt of boric acid is blended, it tends to be difficult to obtain a sufficient enhancement of storage efficacy.

The preservative of this invention is mix | blended with an aqueous composition as a preservative for aqueous compositions, Thereby, this aqueous composition can be provided with antiseptic action.

The type of the aqueous composition to which the preservative of the present invention is applied is not particularly limited. Examples of the aqueous composition include various internal preparations (particularly internal liquids); injections; skin external preparations such as ointments for skins, creams for skins, liquids for skins; otolaryngological agents such as nasal drops; and 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 ointments, contact lenses Ophthalmic agents such as a mounting solution and a contact lens agent (cleaning solution, preserving solution, disinfecting solution, multipurpose solution, etc.) can be mentioned. Among these, preferably an ophthalmic agent or an otolaryngological agent,
More preferred are eye drops (agents), eye wash (agent) and nasal drops.

Since the preservative of the present invention prevents the adverse effects of conventional preservatives (benzalkonium chloride and benzethonium chloride) on contact lenses, it is used for ophthalmics used in all contact lenses including hard contact lenses and soft contact lenses. It can be applied to agents. In particular, the aqueous composition to which the preservative of the present invention is applied is preferably an ophthalmic agent used for an oxygen-permeable hard contact lens or soft contact lens. Conventional antiseptics (benzalkonium chloride and benzethonium chloride) are easily adsorbed to hard or soft contact lenses that are permeable to oxygen, and have adverse effects on these contact lenses. Is also excellent in that adsorption to these contact lenses is suppressed.

The form of the aqueous composition to which the preservative of the present invention is applied is not particularly limited, and examples thereof include solutions, semi-solid agents [ointments (hard ointments, ointments, etc.), creams, etc.], jelly-like agents, etc. Can be mentioned. Among these, the liquid agent and semi-solid agent which are preparation forms in which microorganisms are easy to propagate are suitable aqueous compositions for application of the preservative of the present invention.

About the compounding ratio with respect to the aqueous composition of the preservative of the present invention, the kind of the active ingredient of the preservative,
It can be appropriately adjusted according to the type and form of the aqueous composition.

As an example of the blending ratio of the preservative of the present invention, diphenhydramine or a salt thereof in the aqueous composition is usually 0.0001 to 0.1%, preferably 0.001 to 0.07%, more preferably 0.00. The ratio which becomes 005-0.05% is mentioned. Within the above range, when a preservative comprising chlorpheniramine or a salt thereof and boric acid and / or a salt of boric acid is used, the antiseptic action can be enhanced more synergistically. When the blending amount of diphenhydramine or a salt thereof deviates significantly from this concentration range, eye irritation occurs and it tends to be difficult to be used as an ophthalmic composition.

As an example of the blending ratio of the preservative of the present invention, chlorpheniramine or a salt thereof is usually 0.0001 to 0.1%, preferably 0.0006 to 0.05%, more preferably in the aqueous composition. The ratio which becomes 0.003-0.03% is mentioned. Within the above range, when a preservative comprising chlorpheniramine or a salt thereof and boric acid and / or a salt of boric acid is used, the antiseptic action can be enhanced more synergistically.

As an example of the blending ratio of the preservative of the present invention, the content of boric acid and / or a salt of boric acid in the aqueous composition is 0.01 to 10% by weight, preferably 0.05 to 5% by weight. Furthermore, the ratio which becomes 0.1 to 3 weight% more preferably is mentioned. If the content of boric acid and / or salt of boric acid is significantly higher than this concentration range, eye irritation occurs, and if it is significantly lower, sufficient effects in the present invention tend not to be achieved.

The aqueous composition to which the preservative of the present invention is applied has a pH within a range acceptable to the living body,
Although it does not restrict | limit especially as long as the effect of this preservative is not impaired, Usually 4.5-9.
0, preferably 5 to 8.5, more preferably about 5 to 8.0. Within such a range, an excellent antiseptic action can be imparted to the aqueous composition. Adjustment of pH can be performed using a buffer, a pH adjuster, etc.

In addition, the aqueous composition to which the preservative of the present invention is applied does not exclude those in which a conventionally known preservative is blended, but an excellent antiseptic action is imparted by the preservative of the present invention. Other known preservatives may not be contained. However, some of the conventionally known preservatives include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, sorbic acid or its salts or alkyls. Since some preservatives such as polyaminoethylglycine have disadvantages in formulation as well as safety, when these known preservatives are contained, it is preferable to limit the content to a small amount. More preferably, it is not substantially contained.

Further, since the preservative of the present invention has an excellent antiseptic action, it is suitably used for a multi-dose type aqueous composition, that is, an aqueous composition used several times or more after the product is once opened. The aqueous composition can be stably stored for several days or weeks. Among such multi-dose type aqueous compositions, eye drops, eye wash,
Examples include nasal drops.

The preservative of the present invention can be applied to an aqueous composition containing various medicinal ingredients. In addition, since diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof, which is an active ingredient of the preservative of the present invention, itself acts as an antihistamine component, an aqueous composition containing the preservative of the present invention is Even if it does not contain other medicinal ingredients, it can exert medicinal effects (antihistamine action).

Examples of the medicinal ingredients blended in the aqueous composition to which the preservative of the present invention is applied include, for example, a decongestant ingredient, an eye regulator ingredient, an anti-inflammatory ingredient or an astringent ingredient, an antihistamine ingredient or an antiallergic ingredient. , Vitamins, amino acids, antibacterial components, bactericidal components, saccharides, polysaccharides or derivatives thereof, cellulose or derivatives thereof or salts thereof, water-soluble polymers other than those mentioned above, local anesthetic components, steroid components, glaucoma treatment Examples include drugs. 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, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, potassium aspartate, magnesium aspartate, magnesium / aspartate mixture, sodium glutamate, sodium chondroitin sulfate and the like.
These may be d-form, l-form or dl-form.

Antimicrobial component or bactericidal component: for example, aminodeoxykanamycin sulfate, kanamycin sulfate, gentamicin sulfate, sisomycin sulfate, streptomycin sulfate, tobramycin, micronomycin sulfate, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, Sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomethazole sodium, sulfisomidine sodium, tetracycline hydrochloride, oxytetracycline hydrochloride, ofloxacin, Norfloxacin, Levofloxacin, Lomefloxacin hydrochloride, Sulbenicin sodium, Cefmenoxime hydrochloride, Benzylpenicillin potassium, Bell sulfate Verin, berberine chloride, boric acid, colistin sodium metasulfonate, erythromycin, erythromycin lactobionate, kitasamycin, spiramycin, fradiomycin sulfate, polymyxin sulfate, dibekacin, amikacin, amikacin sulfate, acyclovir, iododeoxycytidine, idoxuridine , Cyclocytidine, cytosine arabinoside, trifluorothymidine, bromodeoxyuridine, polyvinyl alcohol iodine, iodine, amphotericin B, isoconazole, econazole, clotrimazole, nystatin, pimaricin, fluorocytosine, miconazole and the like.

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

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

Cellulose or a derivative thereof or a salt 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, and the like.

Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine 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, benololol hydrochloride, carbachol, levobunolol hydrochloride, epinephrine hydrochloride , Distigmine bromide, nipradilol, timolol maleate, latanoprost and the like.

Cataract treatment components: for example, glutathione, pirenoxine, sodium 5,12-dihydroazapentacene disulfonate and the like.

The amount of these components in the aqueous composition is appropriately selected according to the type of preparation, the type of active ingredient, etc., and the amounts of various components in internal use, skin use, mucosal preparation, etc. are known in the art. It is. For example, 0.0001 to 30%, preferably 0.001
It can be selected from a range of about -10%.

The amount of these components in the aqueous composition is appropriately adjusted according to the type of the composition, the type of medicinal component, and the like.

Further, in the aqueous composition to which the preservative of the present invention is applied, various components and additives are appropriately selected according to conventional methods depending on the use and form as long as the effects of the invention are not impaired. , One or more 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 or liquids, thickeners, sugars, surfactants, antiseptics Various additives such as agents, bactericides or antibacterial agents, pH adjusting agents, tonicity agents, fragrances or refreshing agents, chelating agents, buffering agents and the like can be mentioned. Below, although the typical component used for the aqueous composition to which the preservative of this invention is applied is illustrated, it is not limited to these.

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

Thickener: For example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (
Complete or partially saponified product), polyvinylpyrrolidone, macrogol, sodium carboxymethylcellulose, dextran and the like.

  Sugars: for example, glucose, trehalose, etc.

Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like.
These may be d-form, l-form or dl-form.

Surfactant: For example, polyoxyethylene (hereinafter abbreviated as POE) -polyoxypropylene (hereinafter abbreviated as POP) block copolymer (specifically, poloxamer 407, etc.)
, POE-POP block copolymer adduct of ethylenediamine (specifically, poloxamine), POE sorbitan monooleate (specifically, polysorbate 80),
Nonionic surfactants such as POE hydrogenated castor oil (specifically POE (60) hydrogenated castor oil), polyoxyl stearate; glycine-type amphoteric surfactants such as alkyldiaminoethylglycine; alkyl quaternary ammonium salts ( Specifically, cationic surfactants such as benzalkonium chloride, benzethonium chloride, etc. The numbers in parentheses indicate the number of moles added.

Preservatives, bactericides or antibacterials: for example, alkylpolyaminoethylglycine, sodium benzoate, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate,
Sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, poly Hexamethylene biguanide, etc.), Glow Kill (Rhodia brand name), etc.

pH adjuster: For example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, borax, 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: aminoethyl sulfonic acid, epsilon-aminocaproic acid, citrate buffer,
Acetate buffer, carbonate buffer, borate buffer, phosphate buffer, etc. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate Such.

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 of Diphenhydramine Hydrochloride According to the formulation shown in Table 1, each component was dissolved in purified water to make a total volume of 100 mL.
Examples and Comparative Examples) were prepared and sterilized by filtration. These test solutions were evaluated for antiseptic action according to the 14th revised Japanese Pharmacopoeia Reference Information Preservation Efficacy Test Method. In particular,
Each bacterial solution was prepared using gram-negative bacteria ( Escherichia coli ). Each bacterial solution
The test solution was inoculated to 10 ⁵ to 10 ⁶ CFU / mL and stored at 23 ° C. The test solution 7 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.
<Formula>
Survival rate (%) = (number of bacteria after 7 days / initial number of bacteria) × 100
<Criteria>
○: Survival rate after 7 days is 0.1% or less ×: Survival rate after 7 days is more than 0.1%

From the obtained results, the antiseptic action was synergistically enhanced against gram-negative bacteria ( Escherichia coli ) by combining diphenhydramine hydrochloride with boric acid and / or a salt of boric acid. Although not shown in the data, other species (bacteria: Pseudomonas aerugin
14th revised Japanese Pharmacopoeia reference information for osa, Staphylococcus aureus, fungi: Candida albicans, Aspergillus niger) As a result of conducting a preservation efficacy test according to the preservation efficacy test method and making a determination in accordance with the standards of preparations of the Japanese Pharmacopoeia preservation efficacy category IA, a conforming result is obtained in any of the examples. In addition, 15ml each of the test solution immediately after preparation (does not ingest the bacterial solution) into a polyethylene terephthalate container,
When the same storage efficacy test was conducted after storage for 6 months under the condition of 40 ° C. and 75%, the antiseptic effect was maintained almost stably.

Test Example 2 Preservative Efficacy Test of Chlorpheniramine Maleate According to the formulation shown in Table 2, 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 and sterilized by filtration. These test solutions were evaluated for antiseptic action according to the 14th revised Japanese Pharmacopoeia Reference Information Preservation Efficacy Test Method. In particular,
Each bacterial solution was prepared using gram-negative bacteria ( Escherichia coli ). Each bacterial solution
The test solution was inoculated to 10 ⁵ to 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.
<Formula>
Survival rate (%) = (number of bacteria after 14 days / initial number of bacteria) × 100
<Criteria>
○: Survival rate after 14 days is 0.1% or less ×: Survival rate after 14 days is more than 0.1%

From the obtained results, the combination of chlorpheniramine maleate and boric acid and / or a salt of boric acid synergistically enhanced the antiseptic action against gram-negative bacteria ( Escherichia coli ). Although not shown in the data, other species (bacteria: Pseudomonas aer
uginosa, Staphylococcus aureus, fungi: Candida albicans, Aspergillus niger) "14th revised Japanese Pharmacopoeia Reference Information Preservative Efficacy Test Method 15. Preservative Efficacy Test Method"
As a result of carrying out a storage efficacy test at, and making a determination according to the formulation standards of the “Japanese Pharmacopoeia Storage Efficacy Test Category IA”, a suitable result was obtained in any of the examples. In addition, when the test solution immediately after preparation (does not ingest the bacterial solution) was filled into polyethylene terephthalate containers 15 mL each, and the same storage efficacy test was conducted after storage for 6 months under the condition of 40 ° C. and 75%.
The antiseptic effect was maintained almost stably.

Examples 10-29
Eye drops or eye washes having the formulations shown in Tables 3 to 6 below were prepared by a conventional method.

Claims (18)

(A) 0.0001 to 0.1 w / v% of at least one compound selected from diphenhydramine, chlorpheniramine, and salts thereof;
(B) at least one compound selected from boric acid and salts thereof;
(C) Tetrahydrozoline hydrochloride, naphazoline hydrochloride, neostigmine methyl sulfate, epsilon-aminocaproic acid, berberine sulfate, allantoin, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, sodium flavin adenine dinucleotide, cyanocobalamin, pyridoxine hydrochloride, panthenol, At least four compounds selected from the group consisting of retinol palmitate, tocopherol acetate, potassium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and sodium hyaluronate; containing, aqueous ophthalmic composition (however, further Torometamo Except Le, tranilast or a pharmaceutically acceptable salt, aqueous ophthalmic composition containing either).   The aqueous ophthalmic composition according to claim 1, which is housed in a multi-dose container. (A) The aqueous composition of Claim 1 or 2 whose content of the at least 1 sort (s) of compound selected from diphenhydramine and its salt as a component is 0.005-0.05 w / v % . (A) The aqueous composition of Claim 1 or 2 whose content of the at least 1 sort (s) of compound selected from the chlorpheniramine and its salt as a component is 0.003-0.03 w / v%. (B) The aqueous composition in any one of Claims 1-4 which contains a boric acid and borax as a component. As component (C), tetrahydrozoline hydrochloride, naphazoline hydrochloride, neostigmine methyl sulfate, epsilon-aminocaproic acid, berberine sulfate, allantoin, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, At least six selected from the group consisting of panthenol, retinol palmitate, tocopherol acetate, potassium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and sodium hyaluronate The aqueous group according to any one of claims 1 to 5 , comprising Adult. In addition, alkylpolyaminoethylglycine, sodium benzoate, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxy The aqueous composition according to any one of claims 1 to 6 , comprising at least one selected from the group consisting of butyl benzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, polyhexamethylene biguanide and glowkill. . The aqueous composition according to any one of claims 1 to 7 , which is an eye drop or an eye wash. The aqueous composition according to claim 8, which is an eye drop or an eye wash that can be used during contact lens wearing. (C) The aqueous composition in any one of Claims 1-9 whose content of a component is 0.001-10 w / v%. The aqueous composition according to any one of claims 1 to 10, further comprising at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60 and polysorbate 80. The aqueous composition according to claim 11, wherein the content of at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 is 0.05 w / v% or more. Furthermore, it contains at least one selected from the group consisting of 1-menthol, d-camphor, menthone, cool mint, peppermint oil, peppermint oil, d-borneol, geraniol, eucalyptus oil, bergamot oil and sodium edetate. The aqueous composition according to any one of claims 1 to 12. (A) 0.0001 to 0.1 w / v% of at least one compound selected from diphenhydramine, chlorpheniramine, and salts thereof;
(B) at least one compound selected from boric acid and salts thereof;
(C) Tetrahydrozoline hydrochloride, naphazoline hydrochloride, neostigmine methyl sulfate, epsilon-aminocaproic acid, berberine sulfate, allantoin, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, sodium flavin adenine dinucleotide, cyanocobalamin, pyridoxine hydrochloride, panthenol, At least four compounds selected from the group consisting of retinol palmitate, tocopherol acetate, potassium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and sodium hyaluronate; Preservative effect of an aqueous ophthalmic composition characterized by containing Method of enhancing (but further excluding trometamol, tranilast or a pharmaceutically acceptable salt, if it is aqueous ophthalmic composition containing either). The method for enhancing the preservative effect of the aqueous ophthalmic composition according to claim 14, wherein the aqueous ophthalmic composition is contained in a multi-dose container. In addition to the aqueous ophthalmic composition, alkylpolyaminoethylglycine, sodium benzoate, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl paraoxybenzoate The ophthalmologic according to claim 14 or 15, which contains at least one selected from the group consisting of propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, polyhexamethylene biguanide, and glowkill. A method for enhancing the antiseptic effect of an aqueous composition. The ophthalmic aqueous composition according to any one of claims 14 to 16, wherein the ophthalmic aqueous composition further contains at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60 and polysorbate 80. A method to enhance the antiseptic effect. The aqueous ophthalmic composition is further selected from the group consisting of l-menthol, d-camphor, menthone, cool mint, peppermint oil, peppermint oil, d-borneol, geraniol, eucalyptus oil, bergamot oil and sodium edetate. The method for enhancing the antiseptic effect of the aqueous ophthalmic composition according to any one of claims 14 to 17, comprising at least one kind.