JP2022132391A - Aqueous ophthalmic composition and method for suppressing reduction in amount of compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an aqueous ophthalmic composition having high storage stability.

SOLUTION: Provided is an aqueous ophthalmic composition comprising xanthan gum and a pharmaceutical compound stable in an acidic range and having a pH of less than 5.5.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

TECHNICAL FIELD The present invention relates to an ophthalmic aqueous composition and a method for inhibiting a decrease in compound content.

Many pharmaceutical compounds are stable under acidic conditions, but easily decompose under neutral or alkaline conditions, making it difficult to store them in solution for long periods without the addition of buffers. do.

Examples include pantothenic acids and pantothenic acids such as panthenol. Pantothenic acids are a type of vitamin that functions as coenzyme A in the body, and have the effect of assisting the metabolism of energy such as carbohydrates, proteins, and lipids. It is known to exhibit useful physiological activities such as strength enhancement. In anticipation of such useful physiological activities, pantothenic acids are used by being blended in preparations for application to mucous membranes, preparations for external use on the skin, and the like. On the other hand, pantothenic acids have the disadvantage of low stability in aqueous solutions, and therefore attempts have been made to stabilize pantothenic acids. For example, an aqueous composition containing pantothenic acids and acitazanolast (Patent Document 1), an aqueous solution containing pyridoxine hydrochloride and pantothenic acids, 50% by weight or more of pyridoxine hydrochloride and 300% by weight of pantothenic acids % or less of boric acid (Patent Document 2), and an ophthalmic composition containing panthenol, boric acid, and a compound having 3 or more hydroxyl groups in one molecule (Patent Document 3). It is Moreover, Patent Documents 2 and 3 report that the presence of excess boric acid in an aqueous solution impairs the stability of pantothenic acids.

Allantoin, which is used as an anti-inflammatory agent, is known to decrease in content over time depending on the formulation of the formulation. Allantoin retains 98% of its initial content in pH 3.0 buffer even when stored at 50°C for 1 month, but is destabilized under neutral and alkaline conditions (non-patented Reference 1).

Xanthan gum is used as a thickening agent in the pharmaceutical, food or cosmetic fields. As ophthalmic compositions containing xanthan gum, for example, an ophthalmic composition containing xanthan gum and an amino acid (Patent Document 4) and an ophthalmic composition containing xanthan gum and glucose (Patent Document 5) are disclosed. Ophthalmic compositions have been reported to have therapeutic effects on corneal epithelial disorders. An eye drop containing xanthan gum and a terpenoid has also been reported (Patent Document 6). It is known that terpenoids are adsorbed to the plastic containers that are commonly used for eye drops, and their contents are reduced. However, it was not known until now that the xanthan gum aqueous solution has a buffering action in the acidic range and that this action can suppress the decrease in the content of a specific compound.

Japanese Patent Application Laid-Open No. 2007-297331 JP-A-5-17355 JP-A-2002-265357 WO2006/035969 WO2007/108541 WO2007/007894

Pharmaceutical Journal, 1993, 113(7) 515-523

An object of the present invention is to suppress the decrease in the content of compounds that tend to decrease in content due to reasons such as decomposition under neutral to alkaline conditions. Another object of the present invention is to provide an ophthalmic aqueous composition containing the compound and having high storage stability.

In view of the above problems, the inventors of the present invention have made intensive studies and surprisingly found that an aqueous solution of xanthan gum has a buffering effect in the acidic region. Then, the present inventors have found that by adding xanthan gum to an aqueous solution of a compound whose content tends to decrease under neutral to alkaline conditions, it is possible to suppress the decrease in content of the compound, leading to the present invention.

That is, the present invention has the following aspects.
[1]
An aqueous ophthalmic composition comprising xanthan gum and a pharmaceutical compound stable in the acidic region and having a pH of less than 5.5.
[2]
The composition according to [1], wherein the concentration of xanthan gum is 0.03 to 0.4 w/v%.
[3]
The composition according to [1] or [2], wherein the concentration of the pharmaceutical compound is 0.01 to 1.0 w/v%.
[4]
The composition according to any one of [1] to [3], wherein the pharmaceutical compound is panthenol or allantoin.
[5]
The composition according to any one of [1] to [4], wherein the pharmaceutical compound is panthenol.
[6]
The composition of [5], further comprising boric acid or a salt thereof.
[7]
The composition according to [5] or [6], wherein the panthenol concentration is 0.01 to 0.1 w/v%.
[8]
The composition according to any one of [1] to [4], wherein the pharmaceutical compound is allantoin.
[9]
The composition according to [8], wherein the concentration of allantoin is 0.03 to 0.3 w/v%.
[10]
A method for suppressing a decrease in the content of a compound stable in an acidic region, comprising adding xanthan gum to an aqueous solution of the compound.
[11]
The method of [10], wherein the compound is panthenol or allantoin.

According to the present invention, it is possible to suppress the decrease in the content of compounds that tend to decrease in content due to reasons such as decomposition in a neutral to alkaline environment. Also, an ophthalmic aqueous composition containing the compound and having high storage stability can be provided.

1 shows a titration curve for an aqueous solution of xanthan gum containing borax. Figure 2 shows a titration curve for xanthan gum aqueous solution without borax.

One aspect of the present invention relates to an aqueous ophthalmic composition comprising xanthan gum and a pharmaceutical compound stable in the acidic range and having a pH of less than 5.5. In the following, such compositions are also referred to as "compositions of the invention".

Xanthan gum is a gum made by fermenting starch such as corn with Xanthomonas campestris, and consists of repeating units of two molecules of glucose, two molecules of mannose and glucuronic acid.

The viscosity of xanthan gum used in the composition of the present invention is not particularly limited, but is usually 600 mPa·s or more, preferably 1200 mPa·s or more, more preferably 1400 to 2000 mPa·s, and still more preferably 1400 to 1700 mPa·s. . Examples of the xanthan gum include Echo Gum series such as Echo Gum T and Echo Gum F marketed by Sumitomo Dainippon Pharma Co., Ltd., San Ace series such as San Ace NXG-S marketed by San-Ei Gen FFI Co., Ltd. Ketorol series such as Ketorol CG and Ketorol CG-T, which are commercially available from Sansho Co., Ltd., are used, but Echogum T and Ketorol CG-T are preferred. The viscosity of xanthan gum can be measured, for example, using a Brookfield viscometer according to the method described in the item "viscosity" of "xanthan gum" in Pharmaceutical Excipients Standards 2013 (Yakuji Nippo Co., Ltd.).

As used herein, the term “pharmaceutical compound” is not particularly limited as long as it is a compound that acts on a living body and has some kind of pharmaceutical activity. vitamins (including provitamins), amino acids, etc.

As used herein, the term "pharmaceutical compound stable in the acidic range" means that the content of the compound decreases in the neutral or basic range of pH 5.5 or higher, while the stability is stable in the acidic range (less than pH 5.5). A group of pharmaceutical compounds with high More specifically, the term "pharmaceutical compound stable in the acidic region" means that an aqueous solution containing the compound with a pH of less than 5.5 and an aqueous solution containing the compound with a pH of 5.5 or higher are stored under the same storage conditions (temperature, humidity, A compound that loses less content in an aqueous solution with a pH of less than 5.5 compared to an aqueous solution with a pH of 5.5 or higher after storage for a period of time, etc. Further, in this specification, "the content is reduced" and "the content is reduced" means that the compound is decomposed, the compound is adsorbed to the container, or the compound is formed into a complex compound with another compound, etc. It includes reducing the content of the compound.

Pharmaceutical compounds that are stable in the acidic range include, but are not limited to, panthenol, a provitamin, and allantoin, an anti-inflammatory agent. In particular, when the pharmaceutical compound that is stable in the acidic range is panthenol, the decrease in the content of the pharmaceutical compound can be suppressed more remarkably when boric acid or a salt thereof is contained in the composition.

The concentration of xanthan gum in the composition of the present invention is not particularly limited as long as it can stabilize the pharmaceutical compound, preferably 0.005 to 1 w/v%, more preferably 0.01 to 0.6 w/v%. Yes, more preferably 0.03 to 0.4 w/v%, particularly preferably 0.15 to 0.3 w/v%. In the present specification, "w/v%" is synonymous with the number of grams of a component per 100 mL of the ophthalmic aqueous composition (g/100 mL).

The concentration of the "pharmaceutical compound stable in the acidic region" in the composition of the present invention is not particularly limited, but is preferably 0.01 to 1.0 w/v%, more preferably 0.01 to 0.3 w/v. v %, more preferably 0.01 to 0.1 w/v %.

When the "pharmaceutical compound stable in the acidic region" in the composition of the present invention is panthenol, the concentration of panthenol is preferably 0.01 to 1.0 w/v%, more preferably 0.01 to 0.5 w/v %, more preferably 0.01 to 0.1 w/v %.

When the "pharmaceutical compound stable in the acidic region" in the composition of the present invention is allantoin, the concentration of allantoin is preferably 0.01 to 1.0 w/v%, more preferably 0.03 to 0.3 w/v%. v%.

The pH of the composition of the present invention is less than 5.5, and from the viewpoint of the stability of the pharmaceutical compound in the composition, it is preferably 5.4 or less, 5.3 or less, 5.2 or less, 5.1 or less, or 5.0 or less. The lower limit of the pH of the composition of the present invention is not particularly limited, but from the viewpoint of the stability of the pharmaceutical compound in the composition, the pH is preferably 3.0 or higher, 3.5 or higher, 4.0 or higher, 4.1 or higher. , 4.2 or greater, 4.3 or greater, 4.4 or greater, or 4.5 or greater. From the viewpoint of the stability of the pharmaceutical compound in the composition, the pH range of the composition of the present invention is preferably less than 5.5, more preferably less than 3.0, and more preferably less than 5.5. , the lower limit is 4.5 or more, more preferably the upper limit is 5.4 or less, and the lower limit is 4.5 or more. A slight decrease in the content of the "pharmaceutical compound stable in the acidic range" may occur in the composition of the present invention, and the pH of the composition of the present invention may fluctuate accordingly.

The composition of the present invention may contain pharmacological ingredients in addition to the above-mentioned pharmaceutical compound stable in the acidic region, depending on the use of the composition. The pharmacological components to be used are not particularly limited, but examples include vasoconstrictors, anticholinesterase agents, anti-inflammatory agents, therapeutic agents for corneal epithelial disorders, antiphlogistic analgesics, chemotherapy agents, antibacterial agents, antiviral agents, and hormonal agents. , vitamin drugs, amino acids, anticataract drugs, antiangiogenic drugs, immunosuppressive drugs, protease inhibitors, aldose reductase inhibitors, antihistamines, antiallergic drugs, anxiety drugs, antipsychotic drugs, antibiotics, antitumor drugs, Antihyperlipidemic drugs, antitussives/expectorants, muscle relaxants, antiepileptic drugs, antiulcer drugs, antidepressants, cardiotonic drugs, antiarrhythmic drugs, vasodilators, hypertensive diuretics, antidiabetic drugs, antituberculous drugs , anesthetic antagonists, drugs for skin diseases, drugs for dental and oral health, drugs for diagnostics, drugs for public health, and the like.

Specific examples of these pharmacological components include dipotassium glycyrrhizinate, epsilon aminocaproic acid, bromfenac, ketorolac tromethamine, nepafenac, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate, and lysozyme hydrochloride. Anti-inflammatory agents such as chlorpheniramine maleate, diphenhydramine hydrochloride and other antihistamines; cromoglycate sodium, ketotifen fumarate, acitazanolast, amlexanox, pemirolast potassium, tranilast, ibudilast and other antiallergic agents; norfloxacin, Antibacterial agents such as ofloxacin, lomefloxacin, levofloxacin, gentamicin, gatifloxacin; vitamins such as ascorbic acid, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, tocopherol acetate, retinol acetate, retinol palmitate; aspartic acid , taurine, sodium chondroitin sulfate; anticholinesterase agents such as neostigmine methyl sulfate; vasoconstrictors such as naphazoline, tetrahydrozoline, epinephrine, ephedrine, phenylephrine, dl-methylephedrine; Therapeutic agents; sulfadiazine, sulfisoxazole, sulfisomidine, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxazole, sulfaethidol, sulfamethidine, sulfaphenazole, sulfaguanidine, phthalylsulfathiazole, and sulfa drugs such as succinylsulfathiazole. The compounds exemplified here may be in the form of salts as long as they are pharmaceutically acceptable.

Various additives such as buffers, tonicity agents, preservatives, solubilizers, stabilizers, chelating agents, thickeners, and pH adjusters can be appropriately added to the composition of the present invention. .

Examples of buffering agents include boric acid or salts thereof (borax etc.), citric acid or salts thereof (sodium citrate etc.), tartaric acid or salts thereof (sodium tartrate etc.), gluconic acid or salts thereof (sodium gluconate etc.). ), acetic acid or salts thereof (sodium acetate, etc.), phosphoric acid or salts thereof (sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.), various amino acids such as glutamic acid and epsilonaminocaproic acid, and Tris buffers. These are used singly or in combination of two or more.

In the composition of the present invention, when boric acid or a salt thereof is used as a buffering agent, its concentration is not particularly limited, but preferably 0.01 to 3.0 w/v%, more preferably 0.03 to 2 0.5 w/v %, more preferably 0.1 to 1.8 w/v %, and particularly preferably 0.3 to 1.5 w/v %.

When the "pharmaceutical compound stable in the acidic region" in the composition of the present invention is panthenol, and boric acid or a salt thereof is contained in the composition, boric acid or a salt thereof is relative to panthenol. It is preferably included in the composition in excess of 300% by weight.

Examples of tonicity agents include sorbitol, glucose, mannitol, glycerin, propylene glycol, sodium chloride, potassium chloride and the like. These are used singly or in combination of two or more.

Examples of preservatives include paraoxybenzoic acid esters, benzalkonium chloride, benzethonium chloride, benzyl alcohol, sorbic acid or its salts, chlorhexidine or its salts, sodium dehydroacetate, cetylpyridinium chloride, alkyldiaminoethylglycine hydrochloride, chloro butanol and the like. These are used singly or in combination of two or more.

Examples of solubilizing agents include nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters (polysorbate 80, etc.), polyoxyethylene hydrogenated castor oil, polyoxyethylene monostearate (polyoxyl 40 stearate, etc.), and polyethylene. Glycols (Macrogol 4000, etc.), water-soluble polymers such as polyvinylpyrrolidone, propylene glycol, cyclodextrins, and the like. These are used singly or in combination of two or more.

Stabilizers include, for example, sodium edetate, sodium thiosulfate, ascorbic acid, cyclodextrins, condensed phosphoric acid or its salts, sulfites, citric acid or its salts, dibutylhydroxytoluene and the like. These are used singly or in combination of two or more.

Chelating agents include, for example, sodium edetate, sodium citrate, condensed phosphoric acid or salts thereof (condensed sodium phosphate, etc.). These are used singly or in combination of two or more.

Examples of thickeners other than xanthan gum include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and hyaluronic acid. These are used alone or in combination of two or more together with xanthan gum.

Examples of pH adjusters include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, boric acid or salts thereof (borax), hydrochloric acid, citric acid or salts thereof (sodium citrate, sodium dihydrogen citrate etc.), phosphoric acid or its salts (sodium dihydrogen phosphate, potassium dihydrogen phosphate etc.), acetic acid or its salts (sodium acetate, ammonium acetate etc.), tartaric acid or its salts (sodium tartrate etc.) and the like. These are used singly or in combination of two or more.

As used herein, "aqueous ophthalmic composition" refers to aqueous compositions for topical administration to the eye (e.g., eye drops, artificial tears, eye washes, eye ointments), contact lens wetting solutions, and contact lens care products. It refers to an aqueous composition containing agents (eg, contact lens disinfectant, contact lens preservative, contact lens cleanser, contact lens cleansing preservative). Preferably, the ophthalmic aqueous composition is an eye drop.

When the composition of the present invention is an aqueous composition for topical administration to the eye, the subject of administration is not particularly limited, but mammals are preferred, and primates (humans, monkeys, etc.) and rodents are more preferred. (mice, rats, guinea pigs, etc.), cats, dogs, rabbits, sheep, pigs, cows, horses, donkeys, goats or ferrets, particularly preferably humans.

When the composition of the present invention is an aqueous composition for topical administration to the eye, the timing of administration of the composition is not limited, and it is appropriately administered to the subject based on the clinically used dose. can do.

One aspect of the present invention relates to a method for suppressing a decrease in content of a compound stable in an acidic range, comprising adding xanthan gum to an aqueous solution of the compound. The compound stable in the acidic range is not particularly limited, but is preferably a pharmaceutical compound stable in the acidic range, more preferably panthenol and allantoin.

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the scope of the present invention is not limited by the examples.

[Test Example 1] Xanthan gum suppresses decrease in content of panthenol in solution Test solutions shown in Table 1 (Example 1, Comparative Examples 1 and 2) were prepared as follows. A borax aqueous solution was prepared by dissolving borax (manufactured by Kosakai Pharmaceutical Co., Ltd.) in water at room temperature. A solution A was prepared by adding boric acid (manufactured by BORAX) to the borax aqueous solution. In addition, xanthan gum (manufactured by MP Biomedicals) with a viscosity of 1460 mPa s is added to the borax aqueous solution, dissolved at a high temperature and then cooled, and boric acid (manufactured by BORAX) is added to the xanthan gum-containing aqueous solution ( Solution B) was prepared. Also, hydroxypropyl methylcellulose (HPMC) (manufactured by Shin-Etsu Chemical Co., Ltd.) is added to an aqueous solution of borax, dissolved at a high temperature, cooled, and then boric acid (manufactured by BORAX) is added to An HPMC-containing aqueous solution (solution C) was prepared. Panthenol (manufactured by DSM Nutrition Japan) was added to solution A, solution B and C, respectively. After that, the pH was adjusted to 5.0 using an appropriate amount of pH adjuster (1 mol/L hydrochloric acid). Thereafter, purified water was added so as to obtain the predetermined concentration shown in Table 1, and each test solution of Comparative Example 2 (panthenol), Example 1 (panthenol + xanthan gum) and Comparative Example 1 (panthenol + HPMC) got

After each test liquid was stored at 4° C. and 60° C. for 4 weeks, the panthenol content of each was measured using HPLC. The ratio of the panthenol content in the product stored at 60°C to the panthenol content in the product stored at 4°C for each test solution was defined as the residual ratio. Table 1 shows the results.

When xanthan gum was not added (Comparative Example 2), the pH of the test solution increased over time, and the residual panthenol rate decreased significantly (54.8% after 4 weeks at 60°C). On the other hand, when xanthan gum was added (Example 1), the increase in pH over time in the test solution was suppressed. This indicates that xanthan gum has a buffering action below pH 5.5, which is below the buffering capacity of boric acid. Moreover, in Example 1, the residual rate of panthenol was extremely high (81.5% after 4 weeks at 60°C). In Comparative Example 1, in which HPMC, which is known as a thickening agent like xanthan gum, was used instead of xanthan gum, the pH of the test solution increased over time, and the residual rate of panthenol decreased significantly (after 4 weeks at 60°C). at 54.8%). This indicates that the effect shown in Example 1 is unique to xanthan gum.

[Test Example 2] Effect of changing the viscosity of xanthan gum Same as the test solution of Example 1, except that xanthan gum with a viscosity of 1,600 to 1,700 mPa s (Echo Gum T, manufactured by Sumitomo Dainippon Pharma Co., Ltd.) is used. to prepare the test solution of Example 2. After each test liquid was stored at 4° C. and 60° C. for 4 weeks, the panthenol content of each was measured using HPLC. The ratio of the panthenol content in the product stored at 60°C to the panthenol content in the product stored at 4°C for each test solution was defined as the residual ratio. Table 2 shows the results.

Even when the viscosity of xanthan gum was changed, the decrease in the panthenol content was successfully suppressed.

[Test Example 3] Effect of Change in pH and Concentration of Components of Test Solution Test solutions shown in Table 3 below were prepared according to the test solution preparation method of Test Example 1. As xanthan gum, xanthan gum with a viscosity of 1,600 to 1,700 mPa·s (Echo Gum T, manufactured by Dainippon Sumitomo Pharma Co., Ltd.) was used. After each test liquid was stored at 4° C. and 60° C. for 4 weeks, the panthenol content of each was measured using HPLC. The ratio of the panthenol content in the product stored at 60°C to the panthenol content in the product stored at 4°C for each test solution was defined as the residual ratio. Table 3 shows the results.

When the pH immediately after preparation of the test solution was 5.4 or less and xanthan gum was added, the decrease in panthenol content was suppressed compared to when xanthan gum was not added and when HPMC was added. (Examples 3-6, Comparative Examples 5-12). When the pH is 5.5 or higher, the effect of suppressing the decrease in panthenol content is reduced, and when the pH is 6.0 and xanthan gum is added, the panthenol content is reduced to the same extent as when xanthan gum is not added and when HPMC is added. content decreased (Comparative Examples 13 to 18). Even when the concentrations of xanthan gum and panthenol in the test solution were changed, suppression of panthenol content reduction was confirmed (Examples 7 to 11).

[Test Example 4] Suppression of reduction in content of panthenol in solution by xanthan gum Test solutions shown in Table 4 below were prepared according to the method for preparing test solutions in Test Example 1. As xanthan gum, xanthan gum with a viscosity of 1,600 to 1,700 mPa·s (Echo Gum T, manufactured by Dainippon Sumitomo Pharma Co., Ltd.) was used. In addition, concentrated glycerin manufactured by Sakamoto Yakuhin Kogyo Co., Ltd., D-mannitol manufactured by Bussan Food Science Co., Ltd., and glucose manufactured by Sanei Sugar Chemical Co., Ltd. were used. After each test liquid was stored at 4° C. and 60° C. for 4 weeks, the panthenol content of each was measured using HPLC. The ratio of the panthenol content in the product stored at 60°C to the panthenol content in the product stored at 4°C for each test solution was defined as the residual ratio. Table 4 shows the results.

When xanthan gum was added (Example 12), compared with the case where polyhydric alcohols such as glycerin (Comparative Example 28), mannitol (Comparative Example 29) and glucose (Comparative Example 30) were added instead of xanthan gum, bread The residual rate of tenors was high. From these results, it was found that xanthan gum is more effective than other polyhydric alcohols in suppressing the decrease in panthenol content.

[Test Example 5] Suppression of decrease in content of allantoin in solution by xanthan gum Echo Gum T, manufactured by Dainippon Sumitomo Pharma Co., Ltd.) was added, dissolved at a high temperature, and then cooled to obtain a xanthan gum solution (solution E). An HPMC solution (solution F) was obtained by adding HPMC to the solution A, dissolving it at a high temperature, and then cooling it. Allantoin (manufactured by Permachem Asia Co., Ltd.) was added to solution D, solution E and F, respectively. After that, the pH was adjusted to 5.0 using an appropriate amount of pH adjuster (1 mol/L hydrochloric acid). Thereafter, purified water was added so as to obtain the predetermined concentration shown in Table 5 to obtain test solutions of Comparative Example 32 (allantoin), Example 13 (allantoin + xanthan gum) and Comparative Example 31 (allantoin + HPMC). .

After each test liquid was stored at 4° C. and 60° C. for 2 weeks, the allantoin content of each was measured using HPLC. The ratio of the allantoin content of each test solution stored at 60°C to the allantoin content of the product stored at 4°C was defined as the residual ratio. Table 5 shows the results.

When xanthan gum was added, the increase in pH over time in the test solution was suppressed (Example 13). This indicates that xanthan gum has a buffering effect. In addition, the residual rate of allantoin was higher than when xanthan gum was not added (Comparative Example 32) and when HPMC was added instead of xanthan gum (Comparative Example 31).

[Test Example 6] Titration curve of xanthan gum solution containing borax with hydrochloric acid Borax (manufactured by Kosakai Pharmaceutical Co., Ltd.) was dissolved in water at room temperature to prepare an aqueous solution of borax (solution G). Xanthan gum having a viscosity of 1,600 to 1,700 mPa s (Echo Gum T, manufactured by Sumitomo Dainippon Pharma Co., Ltd.) was added to solution A, dissolved at a high temperature, and then cooled to obtain a xanthan gum solution (solution H). did. After that, the pH of solutions G and H was adjusted to 7.5 using an appropriate amount of pH adjuster (1 mol/L hydrochloric acid). After that, purified water was added so as to obtain the predetermined concentration shown in Table 6, and test solutions of Reference Examples 1 and 2 were prepared. The pH change was measured when 1 mol/L hydrochloric acid was added to 1,000 mL of the obtained test solution. The results are shown in FIG. Xanthan gum exhibited a buffering effect at pH 6.0 or lower. The buffering effect of xanthan gum was significant below pH 5.5.

[Test Example 7] Titration curve of xanthan gum solution containing no borax with hydrochloric acid Solution I was prepared by adjusting the pH to 9.2 using 1N aqueous sodium hydroxide solution. Xanthan gum with a viscosity of 1,600 to 1,700 mPa s (Echo Gum T, manufactured by Sumitomo Dainippon Pharma Co., Ltd.) was added to solution I, dissolved at a high temperature, and then cooled to obtain a xanthan gum solution (solution J). did. After that, the pH of solutions I and J was adjusted to 8.0 using an appropriate amount of a pH adjuster (1N sodium hydroxide aqueous solution). After that, purified water was added so as to obtain the predetermined concentration shown in Table 7, and test solutions of Reference Examples 3 and 4 were prepared. A change in pH was measured when 0.5 mol/L hydrochloric acid was added to 500 mL of the obtained test solution. The results are shown in FIG. Xanthan gum exhibited a buffering effect at pH 8.0 or lower.

Formulation Examples Ophthalmic solutions having the formulations shown in Table 8 below were prepared by a conventional method.

According to the present invention, it is possible to suppress the decrease in the content of compounds that tend to decrease in content due to decomposition under neutral to alkaline conditions. This makes it possible to provide an ophthalmic aqueous composition with high storage stability.

Claims (10)

An aqueous ophthalmic composition comprising a pharmaceutical compound stable in the acidic region and xanthan gum, wherein said pharmaceutical compound is panthenol or allantoin and has a pH of 5.3 or less. The ophthalmic aqueous composition according to claim 1, which has a pH of 5.2 or less. The composition according to claim 1 or 2, wherein the concentration of xanthan gum is 0.03-0.4 w/v%. The composition according to any one of claims 1 to 3, wherein the concentration of said pharmaceutical compound is 0.01-1.0 w/v%. A composition according to any one of claims 1 to 4, wherein said pharmaceutical compound is panthenol. 6. The composition of Claim 5 , further comprising boric acid or a salt thereof. A composition according to claim 5 or 6, wherein the concentration of panthenol is 0.01-0.1 w/v%. A composition according to any one of claims 1 to 4, wherein said pharmaceutical compound is allantoin. The composition according to claim 8, wherein the concentration of allantoin is 0.03-0.3 w/v%. A method for suppressing an increase in pH of an aqueous solution over time, comprising adding xanthan gum to the aqueous solution.

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