TW201622700A - Water-based medicinal composition - Google Patents

Abstract

To provide a stable water-based medicinal composition comprising allantoin. Provided are a water-based medicinal composition, said composition comprising allantoin and hydrogen chloride, etc. The water-based medicinal composition according to the present invention, in which allantoin remains stable even at a high pH value, is useful in eye washes, etc.

Description

Aqueous pharmaceutical composition

The present invention relates to an aqueous pharmaceutical composition for allantoin stabilization.

Allantoin is a compound known to have potentiation of cell proliferation, repair and repair of wounds, inflammatory action of conjunctiva, and anti-allergic action, and is used in combination with pharmaceuticals or cosmetics. However, allantoin has a very low solubility in water and lacks stability at high temperatures. Further, since decomposition starts at around pH 5 and almost completely decomposes at pH 6, (for example, Non-Patent Document 1), there are a limited number of products that can be matched.

In particular, since eye wash is prescribed to pH 5.5 or higher in DRUG APPROVAL AND LICENSING PROCEDURES IN JAPAN, it is considered to be difficult to match allantoin.

[Previous Technical Literature] [Non-patent literature]

[Non-Patent Document 1] Japanese Journal of Pharmaceutical Sciences 113 (7) 515-524 (1993)

The enhancement of cell proliferative capacity of allantoin, the promotion and repair of wounds, the anti-inflammatory effect of conjunctiva, and the anti-allergic effect are used as an ophthalmic aqueous pharmaceutical composition and disinfection of the outer skin, which is led by eye drops or eye-washing agents. Various pharmaceutical compositions such as a dermatitis therapeutic drug, a dysentery drug, an oral bactericide, a nasal drop, and a nasal wash are also useful. Here, the present invention has been made in an effort to provide an aqueous pharmaceutical composition that is compatible with allantoin.

In order to solve the above problems, the inventors of the present invention have repeatedly conducted intensive studies, and as a result, it has been found that the stability of allantoin is remarkably improved by adding hydrogen chloride to an aqueous solution containing allantoin.

Further defined, the allantoin is particularly stable in the amount of hydrogen chloride added and pH, as well as other additives, and the present invention is completed.

That is, the present invention is that

[1] An aqueous pharmaceutical composition comprising allantoin and hydrogen chloride.

[2] The aqueous pharmaceutical composition according to [1], wherein the content of the hydrogen chloride is from 0.18 mg/100 mL to 2.19 mg/100 mL.

[3] The aqueous pharmaceutical composition according to [1] or [2], which further comprises pyridoxine hydrochloride.

[4] The aqueous pharmaceutical composition according to any one of [1] to [3] wherein the aqueous pharmaceutical composition has a pH of 5.5 to 6.3.

[5] The aqueous pharmaceutical composition according to any one of [1] to [4], wherein The aqueous pharmaceutical composition is an ophthalmic aqueous composition.

[6] The aqueous pharmaceutical composition according to [5], wherein the aqueous ophthalmic composition is an eye wash.

[7] A method for stabilizing allantoin in an aqueous pharmaceutical composition, comprising the step of adding hydrogen chloride to the aqueous pharmaceutical composition.

[8] The method according to [7], wherein the amount of the hydrogen chloride added is from 0.18 mg/100 mL to 2.19 mg/100 mL.

[9] The method of [7] or [8], which further comprises the step of adding pyridoxine hydrochloride to the aforementioned aqueous pharmaceutical composition.

[10] The method according to any one of [7] to [9] wherein the pH of the aqueous pharmaceutical composition is adjusted to 5.5 to 6.3.

[11] The method according to any one of [7] to [10] wherein the aqueous pharmaceutical composition is an ophthalmic aqueous composition.

[12] The method according to [11], wherein the aqueous ophthalmic composition is an eye wash.

According to the present invention, since allantoin is stably combined with an aqueous composition, an aqueous pharmaceutical composition having a cell proliferative strengthening action, a wound promoting and repairing action, an inflammatory effect of the conjunctiva, and an antiallergic action can be obtained. The aqueous pharmaceutical composition of the present invention is used as an ophthalmic aqueous composition, a skin disinfectant, a worm bite, an antipruritic, a dermatitis therapeutic, a dysentery, an oral bactericide, and a drip. Nasal agent, Nasal washes and the like are useful. Further, the aqueous pharmaceutical composition of the present invention is useful as an eye-washing agent because it is stable even at high pH allantoin.

[Fig. 1] Fig. 1 shows an analysis result (residual ratio) of the amount of allantoin after the ophthalmic aqueous composition containing allantoin was prepared by changing the amount of hydrogen chloride, and the amount of allantoin was stored at 60 ° C for one week.

[Fig. 2] Fig. 2 shows an analysis result of the amount of allantoin after adding the various components commonly used in the ophthalmic aqueous composition and preparing the ophthalmic aqueous composition containing allantoin, and storing it at 60 ° C for one week ( Residual rate).

The aqueous pharmaceutical composition of the present invention contains allantoin and hydrogen chloride. The term "aqueous pharmaceutical composition" as used herein means an aqueous pharmaceutical composition, and the object to be applied is not particularly limited. As the aqueous pharmaceutical composition, for example, an aqueous ophthalmic composition, a skin disinfectant, a worm bite, an antipruritic, a dermatitis treatment, a dysentery, an oral bactericide, a nasal drop, and a wash can be mentioned. Nasal agents, etc., but are not limited to this.

Allantoin is a compound of CAS No. 97-59-6, and is known to have a cell proliferative potentiation, a wound-promoting and repairing action, an inflammatory effect of the conjunctiva, and an anti-allergic action. The amount of allantoin in the aqueous pharmaceutical composition of the present invention is such that as long as the allantoin is used for the purpose, and the allantoin is stable, there is no particular limitation, but for example, 0.006 w/v% (=g/100mL) or more, 0.01w/v% or more, 0.02w/v% or more, 0.025w/v% or more, 0.03w/v% or more, 0.3w/v% or less, 0.15 w/v% or less, 0.08 w/v% or less, and 0.06 w/v% or less.

The amount of hydrogen chloride in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as the allantoin can be stabilized, but for example, 0.09 mg/100 mL or more, 0.12 mg/100 mL or more, 0.15 mg/100 mL or more, 0.18 mg/100 mL or more may be 2.92 mg/100 mL or less, 2.56 mg/100 mL or less, 2.19 mg/100 mL or less, and 1.83 mg/100 mL or less. The ratio of hydrogen chloride to 1 part by weight of allantoin contained in the aqueous pharmaceutical composition of the present invention is, for example, 0.001 or more, 0.005 or more, 0.006 or more, 0.097 or less, 0.085 or less, 0.073 or less, and 0.061. The following is also possible. Further, it is preferably set to 0.001 to 0.097 parts by weight, more preferably 0.005 to 0.85 parts by weight, still more preferably 0.005 to 0.073 parts by weight, particularly preferably 0.005 to 0.061, and 0.006 to 0.061 parts by weight is optimal. It is appropriate.

The aqueous pharmaceutical composition of the present invention may further contain pyridoxine hydrochloride. The amount of pyridoxine hydrochloride is as long as the allantoin can be stabilized, that is, it is not particularly limited, and it can also be an ordinary amount of the aqueous pharmaceutical composition. The amount of pyridoxine hydrochloride is, for example, 0.001 w/v% or more, 0.002 w/v% (= g/100 mL) or more, 0.003 w/v% or more, 0.004 w/v% or more, 0.005 w/ The v% or more may be 0.1 w/v% or less, 0.09 w/v% or less, 0.08 w/v% or less, 0.07 w/v% or less, 0.06 w/v% or less, and 0.05 w/v% or less.

The aqueous pharmaceutical composition of the present invention, in order to stabilize the allantoin, Increasing the pH, for example, pH 5.5 or higher, pH 5.6 or higher, pH 5.7 or higher, pH 5.8 or higher, pH 6.3 or lower, pH 6.2 or lower, pH 6.1 or lower, pH 6.0 or lower. can.

The adjustment of the pH can be carried out by a well-known method. For example, it can also be adjusted to a desired pH by adding an appropriate amount of sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, triethanolamine or its ethanolamine.

In the aqueous pharmaceutical composition of the present invention, other components which can be used for the aqueous pharmaceutical composition can be added as needed. The other components to be added are not particularly limited as long as the allantoin can be stabilized, and the obtained aqueous pharmaceutical composition can be used as an aqueous pharmaceutical composition, and examples thereof include anti-inflammatory components, astringent components, and antihistamine components. , anti-allergic ingredients, vitamins, amino acids, antibacterial ingredients, bactericidal ingredients, sugars, polysaccharides and their derivatives, cellulose and its derivatives, water-soluble polymers, local anesthetic ingredients, steroids.

Examples of the anti-inflammatory drug component or the astringent drug component include zinc sulfate, zinc lactate, ε-aminocaproic acid, indomethacin, lysozyme, silver nitrate, pranoprofen, dipotassium glycyrrhizinate, and diclofenac sodium. , bromfenac sodium, methyl salicylate, and the like.

Examples of the antihistamine component include chlorpheniramine fumarate, diphenylamine hydrochloride, diphenhydramine lauryl sulfate, diphenhydramine tannin, chlorpheniramine maleate, and HCl. Mintaidine, methyl disalicylate, carboxyethyl pamoate, phenylmethylheptazine hydrochloride, azelastine hydrochloride, octopaster, octatomidine, oxybenzoate Ketotifenyl fumarate, ezetimidate fumarate, lyophilized hydrochloride, pseudoephedrine hydrochloride, eplesine hydrochloride, hydrochloric acid Lottadine, ebastine, cetirizine hydrochloride, betaxetine besylate, levocetirizine hydrochloride, diphenylamine hydrochloride, chlorpheniramine maleate, and the like.

The vitamin may, for example, contain at least one vitamin selected from the group consisting of vitamin A, vitamin B (other than vitamin B12), vitamin C, vitamin D, vitamin E, and other vitamins. Examples of the vitamin A include retinal, retinol, retinoic acid, carotenes, dehydroretinal, lycopene, and pharmacologically acceptable salts thereof. As the vitamin B, for example, thiamine, thiamine disulfide, dicethiamine, thiocyanate, Cycothiamine, and Bisibuthiamine can be mentioned. , phenyl thiazide, propyl thiomethamine, phenylphosphine thiamine, furan thiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, folic acid, tetrahydrofolate, dihydrofolate , nicotinic acid, niacinamide, nicotinic alcohol, pantothenic acid, panthenol, biotin, choline, inositol and its pharmacologically acceptable salts. Examples of the vitamin C include ascorbic acid and derivatives thereof, erythorbic acid and derivatives thereof, and pharmacologically acceptable salts thereof. Examples of the vitamin D include ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrostanal sterol, and pharmacologically acceptable salts thereof. Examples of the vitamin E include tocopherol and its derivatives, ubiquinone and its derivatives, and pharmacologically acceptable salts thereof. Examples of other vitamins include carnitine, ferulic acid, γ-mysterol, orotic acid, rutin, eriocitrin, hesperidin, and pharmacologically acceptable salts thereof.

As the amino acid, for example, aminoethyl sulfonic acid (taurine), Glucuronic acid, creatinine, sodium glutamate, sodium chondroitin sulfate, aspartic acid, potassium aspartate, magnesium aspartate, and the like. These may be any of the d-type, l-type or dl type.

Examples of the antibacterial ingredient or the bactericidal ingredient include, for example, amine-deoxyacetic acid sulfate, oxytetracycline sulfate, gentamicin sulfate, sisosine sulfate, streptomycin sulfate, and tobramycin. , Xiaonomycin sulfate, alkyl polyaminoethylglycine, chloramphenicol, tetracycline hydrochloride, oxytetracycline hydrochloride, ofloxacin, norfloxacin, levofloxacin , lomefloxacin hydrochloride, benzylicillin sodium, cefmenoxime hydrochloride, benzyl penicillin potassium, colistin sodium sulfonate, erythromycin, erythromycin lactobionate, beryromycin, spiramycin, sulfuric acid Fradiomycin Sulfate, polymyxin sulfate, Dibekacin, Amilacin, amikacin sulfate, acyclovir, iodine deoxycytidine, iodine Glycosides, cyclocytidine, cytarabine, trifluorothymidine, bromodeoxyuridine, polyvinyl alcohol iodine, iodine, amphotericin B, isoconazole, econazole, clotrimazole, Mycotoxin, pimamycin, flucytosine, miconazole, and the like.

Examples of the sugars include monosaccharides and disaccharides, and specific examples thereof include glucose, trehalose, lactose, and fructose.

Examples of the polysaccharide and its derivative include sodium hyaluronate and sodium chondroitin sulfate.

Examples of the cellulose and its derivatives or salts thereof include sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, and the like. .

Examples of the water-soluble polymer include, in addition to the above, polyvinyl alcohol (all or part of the saponified product), polyvinylpyrrolidone, dextrin, and polyethylene glycol. ,

As the local anesthetic component, for example, lidocaine, oxybuprocaine, bupivacaine, procaine, ethyl urethane, mepucaine, and salts thereof can be mentioned.

Examples of the steroid component include hydrocortisone, corticosterone, and salts thereof.

When the aqueous pharmaceutical composition of the present specification is an ophthalmic aqueous composition, other components which can be used for the ophthalmic aqueous composition may be further added to the above components. The other components to be added are not particularly limited as long as the allantoin can be stabilized, and the obtained aqueous composition can be used as an ophthalmic aqueous composition, for example, a decongestant component, an eye-regulating component, and a glaucoma therapeutic component. And cataract treatment ingredients.

In addition, the "ophthalmic aqueous composition" as used in the present specification means an aqueous composition which is applied to an eye, an object directly attached to the eye, or an extracted eye tissue. Specific examples of the aqueous composition of ophthalmology include eye drops, eye wash, artificial tears, eye ointment, contact lens wear solution, and contact lens care agent (including detergent, preservation solution, rinse solution, The disinfectant or the like, the preservative for the extracted eye tissue, the intraocular injection, and the like, but are not limited thereto.

As a decongestant component, for example, an α-adrenergic agent can be mentioned, and specific examples thereof include adrenaline, epinephrine hydrochloride, ephedrine hydrochloride, hydroxyxazoline hydrochloride, tetrahydrozoline nitrate, and naphthyl hydrochloride. Porphyrin, naphtholine nitrate, salt Acid phenylephrine, methyl ephedrine hydrochloride, hydrogen epinephrine tartrate, and the like. These may be any of the d-type, l-type or dl type.

As the component of the ocular muscle regulating drug, for example, a cholinesterase inhibitor having an active center similar to acetylcholine may be mentioned, and specifically, a quaternary ammonium compound such as methyl sulfate neostigmine and They are pharmacologically acceptable salts and the like.

As a therapeutic component of glaucoma, for example, Levobunolol, Timolol, and salts thereof may be mentioned.

As a cataract treatment component, for example, pirenoxine or the like can be mentioned.

In the aqueous pharmaceutical composition of the present invention, the content ratio of these components is appropriately determined depending on the use and the type of the component to be contained. For example, the aqueous composition for ophthalmology may be 0.0001 to 50 w/v%, 0.0001 to 25 w/v%, or 0.001 to 10 w/v%, etc., relative to the entire composition.

Further, the aqueous pharmaceutical composition of the present invention may further contain additives commonly used in the field as long as it does not impair the effects of the respective pharmaceutical effects. Examples of such a component include preservatives, bactericides or antibacterial agents, thickeners, solubilizers or solubilizers, pH adjusters, isotonic agents, perfumes, cooling agents, chelating agents, and buffers. , stabilizers, bases, etc.

Examples of the preservative, bactericide, or antibacterial agent include alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, and dehydrated acetic acid. Sodium, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, hydroxyquinoline sulfate, phenylethyl alcohol, benzyl alcohol, biguanide Object, acrinol, rivanol, etc.

As the thickener, for example, sodium carboxymethylcellulose, dextran, polyethylene glycol, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose can be mentioned. , methyl cellulose, polyvinyl alcohol (all or part of the saponified product), polyvinylpyrrolidone, polyethylene glycol, sodium chondroitin sulfate and the like.

Examples of the solubilizing agent or the solubilizing agent include a glycine type amphoteric surfactant such as an alkyldiaminoethylglycine, a sulfonic acid such as an alkyl ether carboxylate or a tetradecenesulfonate. Alkyl sulfate such as salt, sodium lauryl sulfate, N-mercapto taurate such as N-cocoylmethyltaurate, POE alkyl ether phosphate such as POE (10) sodium lauryl ether phosphate An anion such as a N-mercaptoamino acid salt such as a salt or a sodium lauryl methyl propylamine, a POE alkyl ether sulfate such as POE (3) sodium lauryl ether sulfate, or an α-olefin sulfonate Surfactant and the like. Specifically, there are polyoxyethylene hardened castor oil 60, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) deionized Sorbitol tristearate, polyoxyethylene (20) sorbitan oleate, polyoxyethylene stearate 40, sucrose stearate, decaglyceryl monostearate, lauryl glucoside, Polyethylene glycol 4000. In addition, the numbers in parentheses represent the number of moles added.

Examples of the pH adjuster include aminoethyl sulfonic acid, ε-aminohexanoic acid, acetic acid, sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, triethanolamine, and ethanolamine.

As the isotonic agent, for example, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, calcium acetate, acetic acid Sodium, sodium hydrogencarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, and the like.

Examples of the flavoring agent or the cooling agent include terpenes (specifically, anethole, eugenol, camphor, geraniol, eucalyptol, decyl alcohol, menthol, limonene, borneol, etc.) Etc. can be any type of d-type, l-type or dl type). Essential oils (specifically, fennel oil, cool peppermint oil, cinnamon oil, spearmint leaves, mint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.).

Examples of the chelating agent include ascorbic acid, tetrasodium ethylenediaminetetraacetate, sodium edetate, citric acid, and the like.

The buffering agent may, for example, be citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium hydrogencarbonate, sodium carbonate, boric acid or borax.

Examples of the stabilizer include cyclodextrin, dibutylhydroxytoluene, tromethamine, tocopherol, sodium metabisulfite, monoethanolamine, and aluminum monostearate.

As a base, for example, octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, tea tree oil, corn oil, rapeseed oil, paraffin wax, castor oil, resin matrix, and peanut oil may be mentioned. , lanolin, petroleum jelly, etc.

The aqueous pharmaceutical composition of the present invention is adjusted to an osmotic pressure within a range acceptable to the living body as needed. The osmotic pressure ratio to physiological saline can also be 0.3 to 4.0, 0.5 to 2.0, 0.5 to 1.4, and the like. For the adjustment of the osmotic pressure ratio, in addition to the use of the aforementioned pH adjuster, a buffer or isotonic solution can be suitably used. Pressing agents, salts, etc. are carried out.

The aqueous pharmaceutical composition of the present invention can be produced by a well-known method. For example, eye drops, eye washes, and the like, the components are first mixed, and then further subjected to filter sterilization treatment as needed, and finally prepared by filling into a container.

The present invention also provides a method for stabilizing allantoin in an aqueous pharmaceutical composition. The method for stabilizing allantoin in the aqueous pharmaceutical composition of the present invention comprises the step of adding hydrogen chloride to the aqueous pharmaceutical composition.

The terminology used in the method for stabilizing allantoin in the aqueous pharmaceutical composition of the present invention, which is also used in the above aqueous pharmaceutical composition of the present invention, unless otherwise specified, is synonymous with the aqueous pharmaceutical composition. .

The amount of hydrogen chloride added is not particularly limited as long as the allantoin can be stabilized, and may be equivalent to the aqueous pharmaceutical composition of the present invention.

The method for stabilizing allantoin in the aqueous pharmaceutical composition of the present invention may further comprise the step of adding pyridoxine hydrochloride to the aqueous pharmaceutical composition. The order in which allantoin, hydrogen chloride, pyridoxine hydrochloride, and other ingredients are added to the aqueous pharmaceutical composition is not particularly limited.

The method for stabilizing allantoin in the aqueous pharmaceutical composition of the present invention may include a step of adjusting the pH of the aqueous pharmaceutical composition to 5.5 to 6.3. As long as the pH of the finally obtained aqueous pharmaceutical composition is adjusted to 5.5 to 6.3, the pH adjustment can be performed at any stage.

All of the patent documents and non-patent documents cited in the specification are hereby incorporated by reference.

[Examples]

Hereinafter, the present invention will be specifically described on the basis of the examples, but the present invention is not limited thereto. The present invention can be modified into various forms without departing from the spirit and scope of the invention, and the modifications are also included in the scope of the invention.

[Experimental Example 1]

The ophthalmic aqueous composition is formulated according to the amount of collocation described below. The pH was adjusted with sodium hydroxide to sterilize pure water to a total amount of 100 mL. Hydrogen chloride was used in a concentration of 1 N hydrochloric acid and formulated into the table.

The allantoin analysis values of the collocation examples 1 to 6 after storage at 60 ° C for one week are shown in Fig. 1 . Allantoin was analyzed by a usual method using a high performance liquid chromatography instrument manufactured by Shimadzu Corporation. It was confirmed that once an appropriate amount of hydrogen chloride was added, the decomposition of allantoin was remarkably reduced.

[Experimental Example 2]

The aqueous ophthalmic composition was prepared by substituting sodium chloride for sodium chloride in the same manner as in Experimental Example 1, and the amount of allantoin was analyzed after storage at 60 ° C for one week. The analysis of the composition of each collocation example and the amount of allantoin is shown in the following table.

As shown in the table, allantoin could not be stabilized even if sodium chloride was added. From this, it can be seen that the stabilization effect of allantoin is not derived from chloride ions but from hydrogen chloride.

[Experimental Example 3]

When the pH was changed, the ophthalmic aqueous composition was prepared in the same manner as in Experimental Example 1, and after storage at 60 ° C for one week, the amount of allantoin was analyzed. The analysis of the composition of each collocation example and the amount of allantoin is shown in the following table.

It was confirmed that allantoin was stable even at pH 6.0.

[Experimental Example 4]

The ophthalmic aqueous composition was prepared in the same manner as in Experimental Example 1, and the amount of allantoin was analyzed after storage at 60 ° C for one week. The analysis of the composition of each collocation example and the amount of allantoin is shown in the following table.

The analysis results of the amount of allantoin in the collocations 16 to 18 are shown in Fig. 2 together with the results of the collocation example 4. It was confirmed that the stability of allantoin was remarkably improved when pyridoxine hydrochloride was added.

[Formulation Example]

In the same manner as in Experimental Example 1, the ophthalmic pharmaceutical composition having the composition shown in Table 5 was prepared.

Claims (12)

An aqueous pharmaceutical composition comprising allantoin and hydrogen chloride. The aqueous pharmaceutical composition according to claim 1, wherein the content of the hydrogen chloride is from 0.18 mg/100 mL to 2.19 mg/100 mL. The aqueous pharmaceutical composition according to claim 1 or 2, which further comprises pyridoxine hydrochloride. The aqueous pharmaceutical composition according to any one of claims 1 to 3, wherein the aqueous pharmaceutical composition has a pH of 5.5 to 6.3. The aqueous pharmaceutical composition according to any one of claims 1 to 4, wherein the aqueous pharmaceutical composition is an ophthalmic aqueous composition. The aqueous pharmaceutical composition according to claim 5, wherein the aqueous ophthalmic composition is an eye wash. A method for stabilizing allantoin in an aqueous pharmaceutical composition, comprising the step of adding hydrogen chloride to the aqueous pharmaceutical composition. The method of claim 7, wherein the amount of the hydrogen chloride added is 0.18 mg/100 mL to 2.19 mg/100 mL. The method of claim 7 or 8, which further comprises the step of adding pyridoxine hydrochloride to the aforementioned aqueous pharmaceutical composition. The method of any one of claims 7 to 9, which comprises adjusting the pH of the aqueous pharmaceutical composition to 5.5 to 6.3. The method according to any one of claims 7 to 10, wherein the aqueous pharmaceutical composition is an ophthalmic aqueous composition. The method of claim 11, wherein the aforementioned ophthalmic water use group The object is an eye wash.