WO2015125921A1 - Medical aqueous composition having preservative effectiveness - Google Patents

Abstract

The present invention provides a medical aqueous composition which contains cysteine and malic acid and therefore has preservative effectiveness, and which is mildly irritative. The medical aqueous composition according to the present invention can additionally contain an additive that can be added to a medical aqueous composition, such as a buffering agent and a tonicity agent, and can optionally contain a medicinal agent.

Description

Pharmaceutical aqueous composition having storage efficacy

The present invention is a pharmaceutical product that has excellent preservative effect even when preservatives such as benzalkonium chloride and parabens are blended at a low concentration or not at all, and is hypoallergenic for diseases and troubled eyes. It relates to an aqueous composition.

In addition to the main drug, additives such as buffering agents, isotonic agents, preservatives, stabilizers, pH adjusters and the like are generally blended with eye drops. In the case of the monodose type, the eye drops are used up in a single administration, so that it is not necessary to add a preservative. In contrast, the multi-dose type is used in small amounts over a long period of time. Therefore, a multidose type eye drop that is frequently administered even after opening is often blended with a preservative from the viewpoint of preventing contamination due to contamination with microorganisms. Common preservatives used in eye drops include quaternary ammonium salts such as benzalkonium chloride, paraoxybenzoates, chlorobutanol, etc., of which the most frequently used Is benzalkonium chloride.

Benzalkonium chloride denatures the structure of the cell membrane by binding to phospholipids constituting the cell membrane of microorganisms and exerts a strong antibacterial effect. Benzalkonium chloride has not only an excellent antibacterial effect, but also has a feature that it is chemically stable and has a high solubility in water. Such a feature is also preserved in aqueous pharmaceutical compositions. This is the reason why those skilled in the art choose benzalkonium chloride as the agent.
However, benzalkonium chloride is known to act on cells other than microorganisms. That is, it is known that when benzalkonium chloride is added as a preservative in eye drops, it acts on corneal epithelial cells and induces corneal epithelial damage. Therefore, in order to reduce the influence of benzalkonium chloride on corneal epithelial cells, it has been frequently performed to reduce the concentration of benzalkonium chloride to be blended in the ophthalmic aqueous composition.

Recently, not only reducing the blending concentration of benzalkonium chloride, but preservatives replacing benzalkonium chloride have been actively studied. For example, currently in Japan, Sofzia (registered trademark) (buffering system containing zinc chloride and boric acid, Patent Document 1, Non-Patent Document 1), Polydronium chloride, Purite (registered trademark) (sodium chlorite) Eye drops formulated as a preservative to replace benzalkonium chloride are on the market.

In addition, as an alternative to benzalkonium chloride, there is an invention that has a preservative effect without combining a preservative in an ophthalmic composition by combining several additives that are not preservatives. Combinations are mentioned (Patent Document 2).

On the other hand, as an additive for a pharmaceutical composition, cysteine is L-cysteine (also known as 2-amino-3-mercaptopropionic acid) (Non-patent Document 2) or L-cysteine hydrochloride hydrate (Non-patent Document 3). In general, it is blended for uses such as a stabilizer of the active ingredient (also referred to as a stabilizer, hereinafter the same) and a solubilizer.

As an additive for a pharmaceutical composition, malic acid refers to DL-malic acid, and is generally formulated for use as an active ingredient stabilizer, buffering agent, flavoring agent, coating agent, etc. Patent Document 2).

However, even if the use is known as a general additive as described above, the combination of cysteine and malic acid shown in the present invention can be used to add a preservative to an aqueous pharmaceutical composition without adding a preservative. It is not known at all to have the same preservative effect as when blended, and there is no known aqueous pharmaceutical composition formulated in such a combination.

Special table 2010-504990 JP 2004-002364 A

The problem to be solved by the present invention is to replace preservatives, particularly benzalkonium chloride, which are currently blended in aqueous pharmaceutical compositions with additives that exhibit preservative effects without causing side effects peculiar to preservatives. And a pharmaceutical aqueous composition containing an additive or a combination of additives and additives that exhibit preservative effects without causing side effects peculiar to preservatives. It is to provide a composition, especially an ophthalmic aqueous composition.

The present invention relates to a method for blending cysteine and malic acid, which are additives, in order to obtain an aqueous pharmaceutical composition that is compatible with a storage efficacy test, a combination of additives having storage efficacy, and the aforementioned aqueous pharmaceutical composition Is to provide.

That is, the present invention
<1> An aqueous pharmaceutical composition comprising (A) cysteine and (B) malic acid.
<2> The aqueous pharmaceutical composition according to <1>, wherein (A) cysteine / (B) malic acid (concentration ratio) in the composition is 0.001 to 300.
<3> The aqueous pharmaceutical composition according to <1> or <2>, wherein the concentration of (A) cysteine is 0.001 to 3.0 (w / v%).
<4> (B) The aqueous pharmaceutical composition according to any one of <1> to <3>, wherein the malic acid concentration is 0.01 to 1.0 (w / v%).
<5> The aqueous pharmaceutical composition according to any one of <1> to <4>, wherein the pH is 3.0 to 9.0.
<6> The aqueous pharmaceutical composition according to any one of <1> to <5>, which does not contain a preservative.
<7> Further, the buffer is selected from the group consisting of boric acid, phosphoric acid, citric acid, ε-aminocaproic acid, acetic acid, tartaric acid, trometamol and pharmaceutically acceptable salts thereof or hydrates thereof. The aqueous pharmaceutical composition according to any one of <1> to <6>, comprising at least one kind.
<8> The aqueous pharmaceutical composition according to any one of <1> to <7>, which is in the form of an aqueous ophthalmic composition.
<9> A method of imparting storage efficacy to an aqueous pharmaceutical composition, comprising adding (A) cysteine and (B) malic acid to the aqueous pharmaceutical composition.
<10> A method for obtaining preservation efficacy by including (A) cysteine and (B) malic acid in an aqueous pharmaceutical composition.
<11> A preservative for an aqueous pharmaceutical composition comprising (A) cysteine and (B) malic acid.

The aqueous pharmaceutical composition of the present invention has a preservative effect even if it does not contain a preservative that causes factors such as corneal damage, particularly benzalkonium chloride, and therefore, for example, a drug is administered over a long period of time such as glaucoma or allergy. It hardly affects the cornea etc. of patients with the necessary symptoms.

It is the figure which showed the evaluation result of the cytotoxicity of this invention in a human corneal epithelial cell. (Test Example 5) It is the figure which showed the evaluation result of the corneal epithelial disorder of this invention in a white rabbit. (Test Example 6)

The aqueous pharmaceutical composition of the present invention can be used as an ophthalmic composition such as artificial tears, contact lens mounting liquids, and eye drops by taking advantage of its characteristics, and can also be used as injections, oral preparations, ear drops. It can also be used in the form of agents, nasal drops, coating agents and the like.
In the present specification, the preservative is added to a multi-dose type pharmaceutical product for the purpose of preventing microbial contamination, and has a sufficient bactericidal action against bacteria and fungi. It refers to those that show side effects by increasing permeability, causing membrane disruption and cytoplasmic degeneration, leading to inhibition of cell proliferation, decreased cell adhesion, and the development of hypersensitivity.

In addition to the side effects, the preservative causes a change in formulation with the main agent and other additives, or the preservative itself is not stable against heating and long-term storage. Specific examples of the preservative include parabens such as quaternary ammonium salts and paraoxybenzoic acid esters such as benzalkonium chloride and benzethonium chloride, and chlorobutanol.

In this specification, the preservative refers to a substance different from the preservative. The preservative in the present specification has a broad antibacterial spectrum against gram-negative bacteria, gram-positive bacteria, fungi, etc. without causing problems in side effects and pharmaceutical stability like the above-mentioned preservatives, and promotes the growth of microorganisms. It refers to those that can be blocked and are water-soluble and exhibit the storage stability of pharmaceuticals.
The preservative is less irritating at the time of administration, does not cause damage to the administered tissue, and does not cause an allergic reaction due to long-term use.

As used herein, a preservative refers to a combination of cysteine and malic acid.
Cysteine used in the present invention is L-cysteine and pharmaceutically acceptable salts. Examples of the pharmaceutically acceptable salt of L-cysteine include L-cysteine hydrochloride. The concentration of cysteine is usually 0.001 to 3.0 (w / v%), and is preferably 0.001 to 1.0 (w / v) because cysteine is completely dissolved and stable in an aqueous solution. v%), more preferably 0.001 to 0.3 (w / v%).

The malic acid used in the present invention is DL-malic acid. The concentration of malic acid is usually 0.01 to 1.0 (w / v%), preferably 0.05 to 1.0 (w / v%), more preferably 0.1 to 1.0 (w / v%). w / v%).

The ratio of (A) cysteine concentration and (B) malic acid concentration used in the present invention is expressed as (A) / (B). (A) / (B) is not particularly limited as long as the effect of the present invention can be obtained, but is usually 0.001 to 300, and cysteine and malic acid are completely dissolved in an aqueous solution. In order to achieve this, it is preferably 0.001 to 20, more preferably 0.001 to 3.

The buffer used in the present invention is not particularly limited as long as the effects of the present invention are obtained, but boric acid, phosphoric acid, citric acid, ε-aminocaproic acid, acetic acid, tartaric acid, trometamol, and pharmaceutically acceptable salts thereof. Or at least one selected from the group consisting of hydrates thereof.

The pH of the aqueous pharmaceutical composition in the present invention (measured with a glass electrode at 25 ° C.) is usually 3.0 to 9.0, preferably 5.0 to 8.0, more preferably 5.5 to 8. .0.

In order to adjust the pH of the aqueous pharmaceutical composition of the present invention, various pH adjusting agents that are usually added can be used. Examples of the acids include ascorbic acid, hydrochloric acid, glucuronic acid, gluconic acid, acetic acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, sulfuric acid, citric acid, malic acid, tartaric acid and the like. Examples of the base include borax, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide and the like. Examples of other pH adjusters include amino acids such as glycine, histidine, and epsilon aminocaproic acid.

In preparing the aqueous pharmaceutical composition of the present invention, pharmaceutically acceptable isotonic agents, solubilizers, thickeners, stabilizers, etc., if necessary, do not impair the effects of the present invention. It can be added to the aqueous pharmaceutical composition of the present invention within a range.
Examples of the isotonic agent include sugars such as glucose, sugar alcohols such as mannitol, sorbitol, and xylitol, propylene glycol, glycerin, sodium chloride, potassium chloride and the like. Sodium chloride and propylene glycol are preferred.
Examples of the solubilizer include polysorbate (for example, polysorbate 80), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyl stearate (for example, polyoxyl 40 stearate), tyloxapol, polyethylene glycol and the like. You may use these solubilization individually or in combination of 2 or more types.
Other additives include water-soluble polymers (eg, viscous agents such as methylcellulose and povidone K25), ethylenediaminetetraacetic acid and their pharmaceutically acceptable salts, tocopherol and its derivatives, taurine, epsilon aminocaproic acid, sulfite. Stabilizers such as sodium can be mentioned.

The osmotic pressure ratio of the aqueous pharmaceutical composition of the present invention is not particularly limited as long as the effects of the present invention are obtained, but is usually 0.5 to 2.0, preferably 0.7 to 1.6, more preferably Is 0.8 to 1.3, most preferably 0.9 to 1.2.

The aqueous pharmaceutical composition of the present invention includes a dry eye therapeutic agent, a corneal injury healing agent, a glaucoma therapeutic agent, an anti-inflammatory agent, an allergy therapeutic agent, a mydriatic agent, an ophthalmic surface anesthetic agent, a cataract therapeutic agent or an antibacterial agent A variety of drugs can be indicated. For example, diquafosol sodium, rebamipide, purified sodium hyaluronate, sodium chondroitin sulfate, isopropyl unoprostone, latanoprost, tafluprost, travoprost, bimatoprost, nipradilol, carteolol hydrochloride, timolol maleate, levobunolol hydrochloride, brimonidine Tartrate, apraclonidine hydrochloride, dorzolamide hydrochloride, brinzolamide, pilocarpine hydrochloride, diclofenac sodium, pranoprofen, nepafenac, bromfenac sodium hydrate, indomethacin, fluorometholone, dexamethasone metasulfobenzoate sodium, betamethasone phosphorus Acid ester sodium, olopatadine hydrochloride, acitazanolast hydrate, cromoglycate sodium , Tranilast, ketotifen fumarate, levocabastine hydrochloride, epinastine hydrochloride, phenylephrine hydrochloride, tropicamide, oxybuprocaine hydrochloride, lidocaine hydrochloride, pirenoxine, gentamicin sulfate, tobramycin, doxycycline, chloramphenicol, erythromycin, Azithromycin, colistin methanesulfonate sodium, vancomycin hydrochloride, norfloxacin, ofloxacin, tosufloxacin tosylate hydrate, levofloxacin hydrate, gatifloxacin hydrate, moxifloxacin hydrochloride, amphotericin B, fluconazole, triamcinolone acetonide Flavin adenine dinucleotide sodium, pyridoxine hydrochloride and the like.

The aqueous pharmaceutical composition of the present invention preferably contains no preservative. If the concentration is as low as about 0.001 to 0.003 w / v%, the side effects caused by the preservatives can be significantly reduced, and may be included.
Since the aqueous pharmaceutical composition of the present invention exhibits a preservative effect without containing a preservative, it can be used as a multi-dose type or a mono-dose type. For the same reason, the container for storing the aqueous pharmaceutical composition of the present invention is not particularly limited.

Hereinafter, an aqueous pharmaceutical composition of the present invention was prepared and a storage efficacy test was conducted.

<Test Example 1>
According to Table 1, L-cysteine (product name: L-cysteine, manufacturer name: Kanto Chemical Co., Ltd.), malic acid (product name: DL-malic acid, manufacturer name: Kanto Chemical Co., Ltd.) and other components Added to 80 mL of purified water and dissolved. After adjusting the pH of this liquid appropriately, purified water was added to make up the volume to make 100 mL of a colorless and clear solution. Thereafter, those sterilized by filtration with a membrane filter were designated as Examples 1 to 8 and Comparative Examples 1 and 2.

For Examples 1 to 8 and Comparative Examples 1 and 2, the storage efficacy was confirmed by a storage efficacy test.
The test procedure for the preservation efficacy test was based on the 16th revised Japanese Pharmacopoeia Manual, reference information, and the preservation efficacy test method. Three kinds of bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus) and two kinds of fungi (Candida albicans, Aspergillus brasiliensis) were each cultured under an appropriate condition. These cultured cells were collected aseptically, and a suspension containing about 10 ⁸ cells / mL viable bacteria or spores was used as each inoculum. Prepare Examples 1 to 8 and Comparative Examples 1 and 2, aseptically inject each inoculum, and mix evenly so that the number of viable bacteria is 10 ⁵ to 10 ⁶ per mL of each drug solution. Inoculated and mixed. The number of bacteria was measured by smearing method on the 7th and 14th day after inoculation with the bacterial solution.
Judgment criteria for the preservative efficacy test were made by integrating the judgment criteria of the Japanese Pharmacopoeia and the US Pharmacopoeia. That is, in the case of bacteria, if the number of bacteria was 10% or less of the number of inoculated bacteria on the 7th day and the number of bacteria was 0.1% or less of the number of inoculated bacteria on the 14th day, it was determined as “conforming”. . In the case of fungi, it was determined as “Compliant” when the number was the same as or less than the number of inoculated bacteria on both day 7 and day 14.
When any one of the three types of bacteria and two types of fungi exceeded the above number of bacteria, it was determined as “non-conforming”.
When the determinations on the 7th and 14th days for bacteria and fungi were both “conformity”, the comprehensive determination was “adapted”, and otherwise, the determination was “not compatible”.
Table 1 shows the test results and overall judgment.

Comparative Example 1 is a composition containing cysteine but not malic acid. Comparative Example 1 met the 7th day in the storage efficacy test, but failed on the 14th day. From the determination on the 7th day, it was shown that the boric acid formulation of Comparative Example 1 had a storage effect, albeit slightly.
Comparative Example 2 contains cysteine but does not contain malic acid, and is further added with EDTA (sodium edetate hydrate), which is used as a stabilizer.
However, even in Comparative Example 2 to which EDTA was added, in the storage efficacy test, it matched on the 7th day, but it showed non-conformity on the 14th day.
From the above, it was found that, in the formulation containing cysteine as in Comparative Examples 1 and 2, but not containing malic acid, it was necessary to add a preservative or the like in order to have sufficient storage efficacy.

In addition, it was found that Examples 1 to 8, which are the compositions of the present invention, have a preservative effect without adding a preservative such as benzalkonium chloride.

From the results of Test Example 1, it was revealed that the present invention exerts a storage effect by a combination of cysteine and malic acid. Further, it has been clarified that the effects of the present invention can be obtained with the composition of the present invention regardless of the type of general buffer selected in pharmaceuticals.

<Test Example 2>
According to Table 2, arbitrary components were added to 80 mL of purified water and dissolved. After adjusting this solution to a predetermined pH, purified water was added to make up the volume to make 100 mL of a colorless and clear solution. Subsequently, Examples 9 to 21 were prepared by filtration sterilization with a membrane filter.

For Examples 9 to 21, a storage efficacy test was conducted in the same manner as in Test Example 1.
The test results are shown in Table 2.

When Examples 9 to 21, which are the compositions of the present invention, were subjected to a storage efficacy test, they all met.

In the combination of cysteine and malic acid, good results were obtained even if the amount of either additive was very small.
The composition of the present invention was optimal over a wide pH range from basic to acidic.

<Test Example 3>
According to Table 3, each component was added to 80 mL of purified water and dissolved. After adjusting the pH of this liquid appropriately, purified water was added to make up the volume to make 100 mL of a colorless and clear solution. Then, Examples 22 to 26 were obtained by sterilizing by filtration with a membrane filter.

For Examples 22 to 26, the storage efficacy test was conducted in the same manner as in Test Example 1.
The test results are shown in Table 3.

When Examples 22 to 26, which are the compositions of the present invention, were subjected to a storage efficacy test, they all met.

As described above, the present invention can also be effective when a solubilizer such as polysorbate 80 or polyoxyl 40 stearate, a stabilizer such as EDTA, or a thickener such as methylcellulose or povidone is further added. Indicated.

Thus, it is possible to add a solubilizer to the present invention even when a poorly soluble active ingredient is selected as a drug to be included in the composition of the present invention. It can be dispersed evenly, suggesting that it can have excellent storage stability.
In addition, the addition of a thickening agent to the present invention means that in the composition of the present invention, the increase in the retention at the administration site increases the sustainability and migration of the active ingredient, and the bioactivity of the active ingredient. This suggests that it is possible to improve availability.
From the above, it was found that the composition of the present invention can be provided as a highly versatile base.

<Test Example 4>
According to Table 4, each component was added to 80 mL of purified water and dissolved, and then any amount of purified sodium hyaluronate, travoprost, timolol maleate, diclofenac sodium, acitazanolast hydrate or moxifloxacin hydrochloride Salt was added to dissolve. After adjusting the pH of this liquid appropriately, purified water was added to make up the volume to make 100 mL of a colorless and clear solution. Then, Examples 27-32 were those sterilized by filtration with a membrane filter.

For Examples 27 to 32, the storage efficacy test was conducted in the same manner as in Test Example 1.
The test results are shown in Table 4.

When Examples 27 to 32, which are the compositions of the present invention, were subjected to a storage efficacy test, they all met.

As a result of Test Example 4, the composition of the present invention did not show a phenomenon that the storage efficacy was lowered due to the change in the composition in an aqueous solution even when a drug selected as an active ingredient of a pharmaceutical was added.
It has been found that the present invention can be widely used as pharmaceutical preparations.

<Test Example 5>
Examples 33 and 34 were prepared according to Table 5. As Comparative Examples 3 and 4, 0.002% and 0.005% benzalkonium chloride aqueous solutions were selected, respectively.

For Examples 33 and 34 and Comparative Examples 3 and 4, cytotoxicity in human corneal epithelial cells was confirmed.

Human corneal epithelial cells (product name: Human Corneal Epithelial Cell (HCE-T), RIKEN BioResource Center) were used as test materials. In addition, a total of five drug solutions were used: Examples 33 and 34, Comparative Examples 3 and 4, and phosphate buffered saline (PBS) as a negative control.
Human corneal epithelium suspended in SHEM modified medium (DMEM / F-12 (1: 1) + 1% PS + 10 ng / mL EGF + 5 μg / mL insulin + 0.5% DMSO containing 5% FBS) in each well of a 96-well plate Cells were seeded at 2.0 × 10 ⁴ cells and cultured for 24 hours in a CO ₂ incubator. After culturing, 5 drug solutions were added to each 50 μL so that each drug solution had a total of 6 wells. In each chemical solution, the contact time is 1, 2, 5 or 10 minutes. After contact, the wells are washed with PBS, and each well has a reagent for measuring the cell number (Product name: Cell counting kit-8, Dojin Chemical Research Co., Ltd.). 10 μL each) was added. After a color reaction in a CO ₂ incubator for 2 hours, the absorbance at 450 nm was measured using a microplate reader (device name: Infinite M200 PRO, manufactured by TECAN). At each contact time, the cell viability (%) was calculated from the absorbances of Examples 33 and 34 and Comparative Examples 3 and 4 with the absorbance of the negative control as 100.
The test results are shown in FIG.

In Comparative Examples 3 and 4, cell viability decreased with increasing contact time. Further, even when the contact time was the same, Comparative Example 4 having a higher concentration of the preservative showed lower cell viability than Comparative Example 3.
On the other hand, in Examples 33 and 34 of the present invention, the cell viability was higher than in Comparative Examples 3 and 4, and the cell viability was not significantly reduced with the increase in contact time.

From the results of Test Example 5, Examples 33 and 34 of the present invention to which a general preservative was not added are more cytotoxic than Comparative Examples 3 and 4 which are aqueous solutions containing a general preservative. Was found to be low.
From the above, it was shown that the composition of the present invention has a preservative effect without adding a preservative, and thus is a highly safe aqueous pharmaceutical composition with reduced side effects.

<Test Example 6>
Example 35 was prepared according to Table 6. As Comparative Example 5, a 0.01% benzalkonium chloride aqueous solution was selected.

For Example 35 and Comparative Example 5, corneal epithelial disorder in white rabbits was confirmed.

Male Japanese white rabbits were used as test animals. A total of two chemical solutions of Example 35 and Comparative Example 5 were used.
Example 35 and Comparative Example 5 were instilled into 4 eyes of each test animal at 50 μL, 3 times a day, 4 hours apart for 15 days. After instillation for 15 days, the corneas of the test animals were stained with fluorescein, and excess fluorescein was washed away with physiological saline. The stained spots of the cornea were observed, and photographs were taken in the dark state (under blue light irradiation).
A photograph is shown in FIG.

In Comparative Example 5, stained spots were observed in 2 out of 4 eyes, and corneal epithelial disorder was observed.
On the other hand, in Example 35 of the present invention, no staining spots were observed in all four eyes, and no corneal epithelial disorder was observed.

From the results of Test Example 6, in the condition in which corneal epithelial disorder was observed in Comparative Example 5 containing a general preservative, Example 35 which did not contain a general preservative showed no corneal epithelial disorder. Thus, it was speculated that Example 35 had a lower risk of developing corneal epithelial disorder during clinical use than Comparative Example 5.
From the above, it was shown that the composition of the present invention has a preservative effect without adding a preservative, and thus is a highly safe aqueous pharmaceutical composition with reduced side effects.

By combining cysteine and malic acid in combination, it is possible to prepare an aqueous medicinal composition having a preservative effect without adding a preservative such as benzalkonium chloride or parabens. The aqueous pharmaceutical composition provided by the present invention can reduce corneal damage caused by preservatives by adapting it to a liquid preparation such as an eye wash or eye drops.

Claims (11)

1. An aqueous pharmaceutical composition comprising (A) cysteine and (B) malic acid.
2. The aqueous pharmaceutical composition according to claim 1, wherein (A) cysteine / (B) malic acid (concentration ratio) in the composition is (A) cysteine / (B) malic acid = 0.001 to 300.
3. (A) The aqueous pharmaceutical composition according to claim 1 or 2, wherein the concentration of cysteine is 0.001 to 3.0 (w / v%).
4. The aqueous pharmaceutical composition according to any one of claims 1 to 3, wherein the concentration of (B) malic acid is 0.01 to 1.0 (w / v%).
5. The aqueous pharmaceutical composition according to any one of claims 1 to 4, having a pH of 3.0 to 9.0.
6. The aqueous pharmaceutical composition according to any one of claims 1 to 5, which contains no preservative.
7. Furthermore, as the buffer, at least one selected from the group consisting of boric acid, phosphoric acid, citric acid, ε-aminocaproic acid, acetic acid, tartaric acid, trometamol, and pharmaceutically acceptable salts or hydrates thereof. The aqueous pharmaceutical composition according to any one of claims 1 to 6, comprising
8. The aqueous pharmaceutical composition according to any one of claims 1 to 7, which is in the form of an aqueous ophthalmic composition.
9. (A) A method for imparting storage efficacy to an aqueous pharmaceutical composition, comprising adding cysteine and (B) malic acid to the aqueous pharmaceutical composition.
10. A method for obtaining preservation effect by including (A) cysteine and (B) malic acid in an aqueous pharmaceutical composition.
11. A preservative for an aqueous pharmaceutical composition, comprising (A) cysteine and (B) malic acid.

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