JP2015193634A - aqueous composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an aqueous composition which contains pranoprofen and/or a salt thereof, and dibutylhydroxytoluene and/or butylhydroxyanisol, and in which stability to heat is improved, as well as which has excellent formulation properties.SOLUTION: An aqueous composition contains (A) pranoprofen and/or a salt thereof, and (B) dibutylhydroxytoluene and/or butylhydroxyanisol in combination with (C) a sulfa drug.

Description

  The present invention relates to an aqueous composition having improved thermal stability while containing pranoprofen and / or a salt thereof and dibutylhydroxytoluene and / or butylhydroxyanisole. The present invention further relates to a method for improving the thermal stability of an aqueous composition comprising pranoprofen and / or a salt thereof and dibutylhydroxytoluene and / or butylhydroxyanisole.

  Planoprofen and / or its salts are known as propionic non-steroidal anti-inflammatory agents that have excellent anti-inflammatory, analgesic and antipyretic effects and are highly safe. Widely used as an agent.

  Further, dibutylhydroxytoluene and / or butylhydroxyanisole is well known as an antioxidant and is widely used as an additive blended in foods and pharmaceuticals.

  A method for stabilizing pranoprofen (particularly stabilization against light), characterized in that an aqueous pranoprofen aqueous solution is coexisted with an antioxidant such as dibutylhydroxytoluene or butylhydroxyanisole. Is known (see Patent Document 1). However, Patent Document 1 does not describe the stability to heat when they coexist, and does not describe any further use of a sulfa drug.

  Sulfa drugs are known to have bacteriostatic action. For example, sulfa drugs are used as a therapeutic agent for inflammation caused by bacterial infections such as staphylococci and Escherichia coli. In order to exert bacteriostatic action against the bacteria to be used, it is widely used such as blended with eye drops.

  And so far, by combining a sulfa drug with an aqueous solution containing pranoprofen or a pharmacologically acceptable salt thereof, pranoprofen or a pharmacologically acceptable salt thereof in the aqueous solution There is known a method for stabilizing the above (Patent Document 2). However, Patent Document 2 does not describe the stability to heat when they coexist, and does not describe any further use of dibutylhydroxytoluene or butylhydroxyanisole.

Japanese Patent Laid-Open No. 7-304670 International Publication No. 01/088733 Pamphlet

The present inventor has been conducting various studies on an aqueous composition containing pranoprofen and / or a salt thereof and dibutylhydroxytoluene and / or butylhydroxyanisole. In this case, there is no problem in heat stability, but when the aqueous composition containing both components is stored under high temperature conditions, the thermal stability of the aqueous composition is significantly deteriorated, and the aqueous composition I got a completely new knowledge that things would turn yellow. Thus, when the thermal stability becomes insufficient and the yellowing of the aqueous composition occurs due to the destabilization of the blending components, not only the appearance is impaired, but the content of each blending component in the aqueous composition is reduced. Will be invited. Not only does the decrease in the content of pranoprofen blended as a medicinal component affect the decrease in the medicinal effect, but the decrease in the content of dibutylhydroxytoluene and / or butylhydroxyanisole blended as an additive is also a composition. By reducing the antioxidant ability of the product itself, the stability of other compounding ingredients will be adversely affected, and as a result, the intended effect may not be exhibited even if such an aqueous composition is used for treatment or the like. is there. Therefore, the thermal stability of the aqueous composition containing both components is improved while containing pranoprofen and / or a salt thereof and dibutylhydroxytoluene and / or butylhydroxyanisole, and the aqueous There is a need for the development of techniques to obtain compositions.

  As a result of intensive studies to solve the above problems, the inventor further blends a sulfa drug with an aqueous composition containing pranoprofen and / or a salt thereof and dibutylhydroxytoluene and / or butylhydroxyanisole. Thus, it has been found that the thermal stability deteriorated when pranoprofen and / or a salt thereof and dibutylhydroxytoluene and / or butylhydroxyanisole are combined can be remarkably improved. Further, as a result of further investigation, the present inventor further blended chlorpheniramine and / or a salt thereof with these aqueous compositions, or blended ethylenediamineacetic acid, a derivative thereof, and / or a salt thereof. As a result, it was found that the thermal stability is remarkably enhanced. The present invention has been completed by further studies based on this finding.

That is, this invention provides the aqueous composition of the following aspects.
Item 1-1. (A) at least one selected from the group consisting of pranoprofen and a salt thereof, (B) at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole, and (C) a sulfa drug An aqueous composition.
Item 1-2. Component (C) is selected from the group consisting of sulfamethoxazole, sulfisoxazole, sulfisomidine, salazosulfapyridine, sulfadimethoxine, sulfamonomethoxine, sulfadiazine, sulfamethizole, and salts thereof. Item 12. The aqueous composition according to Item 1-1, which comprises at least one selected from the group consisting of:
Item 1-3. Item 11. The aqueous composition according to Item 1-1 or 1-2, which contains dibutylhydroxytoluene as the component.
Item 1-4. Item 4. The aqueous composition according to any one of Items 1-1 to 1-3, further comprising (D) at least one selected from the group consisting of chlorpheniramine and a salt thereof.
Item 1-5. Item 5. The aqueous composition according to any one of Items 1-1 to 1-4, further comprising (E) at least one selected from the group consisting of ethylenediamineacetic acid, derivatives thereof, and salts thereof.
Item 1-6. Item 5. The aqueous composition according to any one of Items 1-1 to 1-5, further comprising (F) a buffer.
Item 1-7. Item (F) The aqueous composition according to Item 1-6, wherein the buffer is a borate buffer.
Item 1-8. The aqueous composition according to any one of Items 1-1 to 1-7, further comprising (G) a surfactant.
Item 1-9. Item 10. The aqueous composition according to Item 1-8, wherein the surfactant is a nonionic surfactant.
Item 1-10. Item 10. The aqueous composition according to any one of Items 1-1 to 1-9, which has a pH of 7.0 or more.
Item 1-11. Item 11. The aqueous composition according to any one of Items 1-1 to 1-10, which is an ophthalmic composition.
Item 1-12. Item 12. The aqueous composition according to any one of Items 1-1 to 1-11, which is an eye drop.

The present invention also provides a method for improving the heat stability of an aqueous composition containing pranoprofen and / or a salt thereof and dibutylhydroxytoluene and / or butylhydroxyanisole according to the following embodiment.
Item 2-1. The aqueous composition includes (A) at least one selected from the group consisting of pranoprofen and a salt thereof, and (B) at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole, and (C ) A method for improving the heat stability of an aqueous composition comprising the components (A) and (B), which comprises blending a sulfa agent.
Item 2-2. Component (C) is selected from the group consisting of sulfamethoxazole, sulfisoxazole, sulfisomidine, salazosulfapyridine, sulfadimethoxine, sulfamonomethoxine, sulfadiazine, sulfamethizole, and salts thereof. The method according to Item 2-1, comprising at least one selected from the group consisting of:
Item 2-3. Item (B) The method according to Item 2-1 or 2-2, which contains dibutylhydroxytoluene as a component.
Item 2-4. The method according to any one of Items 2-1 to 2-3, further comprising (D) at least one selected from the group consisting of chlorpheniramine and a salt thereof.
Item 2-5. The method according to any one of Items 2-1 to 2-4, further comprising (E) at least one selected from the group consisting of ethylenediamineacetic acid, derivatives thereof, and salts thereof.
Item 2-6. The method according to any one of Items 2-1 to 2-5, further comprising (F) a buffer.
Item 2-7. (F) The method according to Item 2-6, wherein the buffer is a borate buffer.
Item 2-8. The method according to any one of Items 2-1 to 2-7, further comprising (G) a surfactant.
Item 2-9. (G) The method according to Item 2-8, wherein the surfactant is a nonionic surfactant.
Item 2-10. Item 10. The method according to any one of Items 2-1 to 2-9, wherein the pH of the aqueous composition is 7.0 or more.
Item 2-11. Item 11. The method according to any one of Items 2-1 to 2-10, wherein the aqueous composition is an ophthalmic composition.
Item 2-12. Item 12. The method according to any one of Items 2-1 to 2-11, wherein the aqueous composition is an eye drop.

Furthermore, the present invention provides a thermal stability improver used for an aqueous composition containing pranoprofen and / or a salt thereof and dibutylhydroxytoluene and / or butylhydroxyanisole according to the following embodiment.
Item 3-1. (A) at least one selected from the group consisting of pranoprofen and a salt thereof and (B) at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole are allowed to coexist in the aqueous composition. An agent for improving the heat stability of the aqueous composition used in some cases, which comprises (C) a sulfa agent.
Item 3-2. Component (C) is selected from the group consisting of sulfamethoxazole, sulfisoxazole, sulfisomidine, salazosulfapyridine, sulfadimethoxine, sulfamonomethoxine, sulfadiazine, sulfamethizole, and salts thereof. Item 3. The thermal stability improver according to Item 3-1, comprising at least one selected from the group consisting of:
Item 3-3. Item 3. The thermal stability improver according to Item 3-1 or 3-2, which contains dibutylhydroxytoluene as a component.
Item 3-4. Item 4. The thermal stability improver according to any one of Items 3-1 to 3-3, further comprising (D) at least one selected from the group consisting of chlorpheniramine and a salt thereof.
Item 3-5. Item 5. The thermal stability improver according to any one of Items 3-1 to 3-4, further comprising (E) at least one selected from the group consisting of ethylenediamineacetic acid, derivatives thereof, and salts thereof.
Item 3-6. Item (F) The thermal stability improver according to any one of Items 3-1 to 3-5, further comprising a buffer.
Item 3-7. (F) The thermal stability improver according to Item 3-6, wherein the buffer is a borate buffer.
Item 3-8. The thermal stability improver according to any one of Items 3-1 to 3-7, further comprising (G) a surfactant. Item 3-9. (G) The thermal stability improver according to Item 3-8, wherein the surfactant is a nonionic surfactant.
Item 3-10. Item 10. The thermal stability improver according to any one of Items 3-1 to 3-9, wherein the pH of the aqueous composition is 7.0 or more.
Item 3-11. Item 11. The thermal stability improving agent according to any one of Items 3-1 to 3-10, wherein the aqueous composition is an ophthalmic composition.
Item 3-12. The thermal stability improver according to any one of Items 3-1 to 3-11, wherein the aqueous composition is an eye drop.

Still further, the present invention provides the use of the following embodiments.
Item 4-1. (A) at least one selected from the group consisting of pranoprofen and a salt thereof; and (B) at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole; (C) Use of a sulfa drug to produce an improved aqueous composition.
Item 4-2. Component (C) is selected from the group consisting of sulfamethoxazole, sulfisoxazole, sulfisomidine, salazosulfapyridine, sulfadimethoxine, sulfamonomethoxine, sulfadiazine, sulfamethizole, and salts thereof. The use according to Item 4-1, comprising at least one selected from the group consisting of:
Item 4-3. The use according to Item 4-1 or 4-2, which contains dibutylhydroxytoluene as the component (B).
Item 4-4. Item 4. The use according to any one of Items 4-1 to 4-3, wherein the component (C) is used in combination with at least one selected from the group consisting of (D) chlorpheniramine and a salt thereof.
Item 4-5. Item (4-1) is any one of Items 4-1 to 4-4, which is used in combination with at least one selected from the group consisting of (E) ethylenediamineacetic acid, derivatives thereof, and salts thereof together with component (C) use.
Item 4-6. The use according to any one of Items 4-1 to 4-5, wherein (F) a buffering agent is further used in combination.
Item 4-7. (F) The use according to Item 4-6, wherein the buffer is a borate buffer.
Item 4-8. The use according to any one of Items 4-1 to 4-7, wherein (G) a surfactant is further used in combination.
Item 4-9. (G) The use according to Item 4-8, wherein the surfactant is a nonionic surfactant.
Item 4-10. The use according to any one of Items 4-1 to 4-9, wherein the pH of the aqueous composition is 7.0 or more.
Item 4-11. The use according to any one of Items 4-1 to 4-10, wherein the aqueous composition is an ophthalmic composition.
Item 4-12. The use according to any one of Items 4-1 to 4-11, wherein the aqueous composition is an eye drop.

  ADVANTAGE OF THE INVENTION According to this invention, the aqueous | water-based composition excellent in the formulation which was improved in the stability with respect to heat | fever while containing dibutylhydroxytoluene and / or butylhydroxyanisole with pranoprofen and / or its salt is provided. be able to.

In the reference test example 1, it is a figure which shows the result of having evaluated the thermal stability of each test liquid (test liquid 1-3).

1. Aqueous Composition The aqueous composition of the present invention contains at least one selected from the group consisting of pranoprofen and a salt thereof (hereinafter sometimes simply referred to as component (A)).

Planoprofen is α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7.
-A known compound also called acetic acid, which may be synthesized by a known method or obtained as a commercial product.

Among the components (A) used in the present invention, the salt of pranoprofen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, a salt with an inorganic base [eg, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, etc.] or a salt with an organic base [eg, methylamine, triethylamine, diethylamine, triethanolamine, Salt with morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.]. These pranoprofen salts may be used alone or in any combination of two or more.

In the aqueous composition of the present invention, as component (A), pranoprofen and a salt thereof are selected from 1
Species may be selected and used alone, or two or more may be used in any combination. The component (A) used in the present invention is preferably pranoprofen.

In the aqueous composition of the present invention, the blending ratio of the component (A) is appropriately set according to the type of the component (A), the type of other blending components, etc., for example, the total amount of the aqueous composition (A)
The total amount of the components is 0.005 to 1.5 w / v%, preferably 0.01 to 0.5 w / v%, more preferably 0.02 to 0.2 w / v%.

Further, the aqueous composition of the present invention contains at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole (hereinafter sometimes simply referred to as component (B)). Dibutylhydroxytoluene (chemical name 2,6-di-tert-butyl-4-methylphenol; sometimes abbreviated as BHT) and butylhydroxyanisole (chemical names 2-tert-butyl-4-methoxyphenol and 3- tert-butyl-4-methoxyphenol (sometimes abbreviated as BHA) is a compound in which a t-butyl group is substituted on the benzene ring of hydroxytoluene or hydroxyanisole, and is known as an antioxidant. Dibutylhydroxytoluene and butylhydroxyanisole may be synthesized by a known method or may be obtained as a commercial product.

In the aqueous composition of the present invention, as component (B), any one of dibutylhydroxytoluene and butylhydroxyanisole may be used alone, or a combination thereof may be used. Among the components (B), dibutylhydroxytoluene shows a tendency to cause thermal destabilization more prominently in the presence of the component (A). Even an aqueous composition that becomes unstable can be provided with excellent thermal stability. In view of the effect of the present invention, the component (B) used in the present invention is preferably dibutylhydroxytoluene.

  In the aqueous composition of the present invention, the blending ratio of the component (B) is appropriately set according to the type of the component (B), the type of other blending components, and the like. The total amount of the component (B) is 0.0001 to 0.02 w / v%, preferably 0.0005 to 0.01 w / v%, more preferably 0.001 to 0.01 w / v%.

In the aqueous composition of the present invention, the ratio of the component (B) to the component (A) is not particularly limited, but as an example, the above (A) per 100 parts by weight of the total amount of the component (A) Examples include a range in which the total amount of component B) is 0.2 to 100 parts by weight, preferably 1 to 50 parts by weight, more preferably 1 to 20 parts by weight, and particularly preferably 2 to 20 parts by weight.

Furthermore, the aqueous composition of the present invention contains a sulfa agent (hereinafter sometimes simply referred to as the component (C)) in addition to the components (A) and (B). By containing the sulfa agent as described above, the aqueous composition containing the components (A) and (B) can be provided with heat stability.

  A sulfa drug is a drug that has a sulfanilamide moiety and is known to have a bacteriostatic action. The sulfa drug may be synthesized by a known method or obtained as a commercial product.

The sulfa drug used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples include sazol, sulfisoxazole, sulfisomidine, salazosulfapyridine, sulfadimethoxine, sulfamonomethoxine, sulfadiazine, sulfamethizole, and salts thereof. The sulfa drugs may be solvates (for example, hydrates).

  When the sulfa drug is in the form of a salt, the salt is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and specifically, an organic acid salt [ For example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.) ), Oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (eg, hydrochloride) , Sulfates, nitrates, hydrobromides, phosphates, etc.) and salts with organic bases (eg methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.) Salts with amines, etc.), salts with inorganic bases [for example, ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.] It is done. Among these salts, preferably a salt with an inorganic base and / or a salt with an organic base, more preferably a salt with an inorganic base, still more preferably an alkali metal salt, particularly preferably a sodium salt. These salts may be used alone or in any combination of two or more.

In the aqueous composition of the present invention, as the component (C), one type of sulfa drug may be used alone, or two or more types may be used in any combination. Among the components (C), sulfamethoxy is preferably used from the viewpoint of further remarkably improving the thermal stability when the component (A) and the component (B) coexist in the aqueous composition. Examples include sazol, sulfisoxazole, sulfisomidine, and salts thereof, more preferably sulfamethoxazole and salts thereof.

In the aqueous composition of the present invention, the blending ratio of the component (C) is appropriately set according to the type of the component (C), the type of other blending components, and the like. The total amount of the component (C) is 0.01 to 20 w / v%, preferably 0.1 to 10 w / v%, more preferably 1.0 to 8.0 w / v.
% Is exemplified.

In the aqueous composition of the present invention, the ratio of the component (C) to the component (A) is not particularly limited, but as an example, the above (A) per 100 parts by weight of the total amount of the component (A) Examples include a range in which the total amount of component C) is 1 to 100000 parts by weight, preferably 50 to 80000 parts by weight, and more preferably 100 to 50000 parts by weight.

Further, in the aqueous composition of the present invention, the ratio of the component (C) to the component (B) is not particularly limited, but as an example, per 100 parts by weight of the total amount of the component (B), Examples include a range in which the total amount of the component (C) is 100 to 100000 parts by weight, preferably 1000 to 800,000 parts by weight, and more preferably 10,000 to 500000 parts by weight.

In addition to the components (A) to (C), the aqueous composition of the present invention is at least one selected from the group consisting of chlorpheniramine and a salt thereof (hereinafter, simply referred to as component (D)). In some cases). Thus, by containing (D) component, the thermal stability of the aqueous composition of this invention can be improved further notably.

  Chlorpheniramine and salts thereof are known compounds as antihistamines, and may be synthesized by a known method or obtained as a commercial product.

Among the components (D) used in the present invention, the salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate; and various salts such as metal salts. Among these salts, organic acid salts are preferable, and maleates are more preferable. These chlorpheniramine salts may be used alone or in any combination of two or more.

Further, chlorpheniramine and / or a salt thereof used as component (D) may be in the form of a hydrate, and may be any of d-form, l-form, and dl-form.

As the component (D), one kind of chlorpheniramine and a salt thereof may be selected and used alone, or two or more kinds may be used in any combination. From the viewpoint of further improving the thermal stability of the aqueous composition of the present invention, the component (D) is preferably a salt of chlorpheniramine, more preferably an organic acid salt of chlorpheniramine, particularly preferably chlorpheniramine. Maleate (chlorpheniramine maleate).

In the aqueous composition of the present invention, the blending ratio of the component (D) is appropriately set according to the type of the component (D), the type of other blending components, and the like. The total amount of the component (D) is 0.005 w / v% or more, more preferably 0.01 to 0.1 w / v%, particularly preferably 0.01 to 0.06 w / v%. Is done.

When blending the component (D) in the aqueous composition of the present invention, the ratio of the component (D) to the component (A) is not particularly limited, but as an example, the component (A) Total amount of 1
A range in which the total amount of the component (D) is 1 to 500 parts by weight, preferably 10 to 300 parts by weight, and more preferably 20 to 200 parts by weight per 00 parts by weight.

When blending the component (D) in the aqueous composition of the present invention, the ratio of the component (D) to the component (B) is not particularly limited, but as an example, the component (B) Total amount of 1
A range in which the total amount of the component (D) is 10 to 10,000 parts by weight, preferably 50 to 8000 parts by weight, and more preferably 100 to 5000 parts by weight per 00 parts by weight.

Furthermore, the aqueous composition of the present invention comprises at least one selected from the group consisting of ethylenediamineacetic acid, derivatives thereof, and salts thereof (hereinafter simply referred to as (E)) in addition to the components (A) to (C). (It may be expressed as a component). Thus, the thermal stability of the aqueous composition of the present invention can be further remarkably improved by containing the component (E).

Ethylenediamineacetic acid is a compound in which 1 to 4 carboxymethyl groups are bonded to the two amino groups of ethylenediamine. The ethylenediamineacetic acid used as the component (E) in the present invention is pharmaceutical, pharmacological, As long as it is physically (pharmaceutical) or physiologically acceptable. Specific examples of ethylenediamineacetic acid used in the present invention include ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), and the like. Examples of the ethylenediamineacetic acid derivative include N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA) and diethylenetriaminepentaacetic acid (DTPA). Among these ethylenediamineacetic acids and derivatives thereof, ethylenediaminetetraacetic acid is preferable. These ethylenediamineacetic acids and / or their derivatives may be used alone or in any combination of two or more.

The salt of ethylenediamineacetic acid and / or its derivative used as the component (E) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, organic acid salts [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate) Succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)] , Inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, Salts with organic amines such as loridine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), metals such as aluminum Etc.] and the like. Among these salts, preferred are salts with inorganic bases, more preferred are alkali metal salts, still more preferred are sodium salts and potassium salts, and particularly preferred are sodium salts. These salts may be used alone or in any combination of two or more.

The ethylenediamineacetic acid, its derivative and / or salt used as the component (E) may be in the form of a hydrate.

In the aqueous composition of the present invention, as the component (E), one kind may be selected from ethylenediamineacetic acid, derivatives thereof, and salts thereof and used alone, or two or more kinds may be used. May be used in any combination. From the viewpoint of further improving the thermal stability of the aqueous composition of the present invention, the component (E) used in the present invention is preferably ethylenediaminetetraacetic acid and / or a salt thereof, more preferably ethylenediaminetetraacetic acid and / or The sodium salt thereof, more preferably, disodium ethylenediaminetetraacetate and / or disodium ethylenediaminetetraacetate dihydrate can be mentioned.

In the aqueous composition of the present invention, the blending ratio of the component (E) is appropriately set according to the type of the component (E), the type of other blending components, and the like. The total amount of the component (E) is 0.001 w / v% or more, preferably 0.001 to 1 w / v%, more preferably 0.001 to 0.5 w / v%, still more preferably 0. 0.001 to 0.3 w / v%, particularly preferably 0.001 to 0.1 w / v%.

When blending the component (E) in the aqueous composition of the present invention, the ratio of the component (E) to the component (A) is not particularly limited, but as an example, the component (A) Total amount of 1
A range in which the total amount of the component (E) is 0.2 to 2000 parts by weight, preferably 0.5 to 1000 parts by weight, and more preferably 1 to 500 parts by weight per 00 parts by weight.

When the component (E) is added to the aqueous composition of the present invention, the ratio of the component (E) to the component (B) is not particularly limited, but as an example, the component (B) Total amount of 1
A range in which the total amount of the component (E) is 0.1 to 10,000 parts by weight, preferably 1 to 8000 parts by weight, and more preferably 10 to 5000 parts by weight per 00 parts by weight.

In the aqueous composition of the present invention, any one of the above components (D) and (E) may be used in combination with the components (A) to (C), but the above (D) and (E) By using both of the components in combination with the components (A) to (C), higher thermal stability can be obtained. In the aqueous composition of the present invention, the ratio of both components when blending both the component (D) and the component (E) is not particularly limited, but as an example, the total amount of the component (D) is 100. Examples are a range in which the total amount of the component (E) is 1 to 3000 parts by weight, more preferably 1 to 1000 parts by weight per part by weight.

  The aqueous composition of the present invention may further contain a surfactant. The surfactant that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is a nonionic surfactant. Any of an amphoteric surfactant, an anionic surfactant, and a cationic surfactant may be used.

Specific examples of the nonionic surfactant that can be blended in the aqueous composition of the present invention include POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), mono Stearic acid POE (20) sorbitan (polysorbate 60)
, POE sorbitan fatty acid esters such as POE (20) sorbitan tristearate (polysorbate 65), POE (20) sorbitan (polysorbate 80) monooleic acid; Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer POE / POP block copolymers such as 124; POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (50) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 50), POE (60) hydrogenated castor POE hydrogenated castor oil such as oil (polyoxyethylene hydrogenated castor oil 60), POE (80) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 80); POE alkyl ethers such as POE (9) lauryl ether; POE ( 20) POE-POP alkyl ethers such as POP (4) cetyl ether; POE alkylphenyl ethers such as POE (10) nonylphenyl ether . In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added. Specific examples of the amphoteric surfactant that can be incorporated into the aqueous composition of the present invention include alkyldiaminoethylglycine. Specific examples of the cationic surfactant that can be blended in the aqueous composition of the present invention include benzalkonium chloride and benzethonium chloride. Examples of the anionic surfactant that can be blended in the aqueous composition of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, aliphatic α-sulfomethyl ester, Examples include α-olefin sulfonic acid. In the aqueous composition of the present invention, these surfactants may be used alone or in combination of two or more.

Among the above surfactants, from the viewpoint of further improving the thermal stability of the aqueous composition of the present invention, preferably nonionic surfactants, more preferably POE sorbitan fatty acid esters, POE hydrogenated castor oils, And POE / POP block copolymers, more preferably POE hydrogenated castor oil, particularly preferably polyoxyethylene hydrogenated castor oil 60.

  When a surfactant is blended in the aqueous composition of the present invention, the blending ratio of the surfactant depends on the type of the surfactant, the type and amount of other blended components, the use of the aqueous composition, etc. Can be set as appropriate. As an example of the blending ratio of the surfactant, the total amount of the surfactant is 0.001 to 1.0 w / v%, preferably 0.005 to 0.5 w / v% based on the total amount of the aqueous composition. More preferably, 0.01 to 0.3 w / v% is exemplified.

The aqueous composition of the present invention may further contain a buffer. The buffer that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid, aspartate and the like. These buffering agents may be used in combination. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer, and citrate buffer, and more preferred are borate buffer and phosphate buffer, and particularly preferred buffer. Is a borate buffer. Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid, etc.) Calcium acetate, sodium dihydrogen citrate, disodium citrate, etc.); with acetate buffer Examples thereof include acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). Among these buffering agents, boric acid buffering agents are preferably used in the aqueous composition of the present invention because they are expected to exhibit the effects of the present invention more reliably. These buffering agents may be used alone or in any combination of two or more.

When a buffering agent is blended in the aqueous composition of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used, the type and amount of other blending components, and is defined uniformly. However, for example, the total amount of the buffer is 0.01 to 10 w / v% with respect to the total amount of the aqueous composition.
The ratio is preferably 0.1 to 5 w / v%, more preferably 0.4 to 2 w / v%.

  The aqueous composition of the present invention may further contain an isotonic agent. The isotonic agent that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such isotonic agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, acetic acid Examples include potassium, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like. These isotonic agents may be used alone or in any combination of two or more.

  When blending an isotonic agent in the aqueous composition of the present invention, the blending ratio of the tonicity agent varies depending on the type of tonicity agent used and cannot be uniformly defined. For example, the ratio by which the tonicity agent is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 2 w / v% in total is exemplified.

  The pH of the aqueous composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. The aqueous composition containing the components (A) and (B) tends to deteriorate the thermal stability and cause severe yellowing, particularly when the pH is higher than a specific pH. According to the present invention, even in an aqueous composition in which thermal stability is deteriorated and yellowing is likely to be severe, it is possible to effectively provide thermal stability and maintain the original quality. In view of the effects of the present invention, as a suitable example of the pH of the aqueous composition of the present invention, the pH is 7.0 or more, preferably 7.0 to 9.0, and more preferably 7.5 to 9.0. A particularly preferable range is 8.0 to 9.0.

In addition, the osmotic pressure of the aqueous composition of the present invention is not particularly limited as long as it is within a range acceptable for a living body. An example of the osmotic pressure ratio of the aqueous composition of the present invention is preferably in the range of 0.7 to 5.0, more preferably 0.9 to 3.0, and particularly preferably 1.0 to 2.0. . The osmotic pressure can be adjusted by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, saccharides and the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 15th revised Japanese Pharmacopoeia. Measure with reference to the descent method. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then released in a desiccator (silica gel). Cool and accurately measure 0.900 g and dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

The aqueous composition of the present invention may contain an appropriate amount of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include an active ingredient in an ophthalmic drug described in an over-the-counter drug manufacturing (import) approval standard 2000 version (supervised by the Pharmaceutical Affairs Research Committee). Specifically, the following components are listed as components used in ophthalmic drugs.
Antihistamines: for example, iproheptin, diphenhydramine hydrochloride, ketotifen fumarate, etc.
Decongestant: for example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
Fungicide: For example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanide hydrochloride, and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid and the like.
Anti-inflammatory agent: for example, dipotassium glycyrrhizinate, allantoin, azulene, sodium azulenesulfonate, guaiazulene, ε-aminocaproic acid, berberine chloride, berberine sulfate, lysozyme chloride, licorice and the like.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Other: For example, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate and the like.

In addition, in the aqueous composition of the present invention, various additives are appropriately selected according to conventional methods and used in combination with one or more, as long as the effects of the invention are not impaired. Thus, an appropriate amount may be contained. Examples of these additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate, sodium hyaluronate and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glowyl (manufactured by Rhodia) Name) etc.
pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, boro Sand, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, ammonium acetate etc.
Stabilizers: for example, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.
Perfume or refreshing agent: for example, menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuno and the like. These may be either d-form, l-form or dl-form, and are formulated as essential oils (mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.) May be.

  In the present specification, the aqueous composition means a composition containing water, and usually contains 1% by weight or more, preferably 5% by weight or more, more preferably 20% by weight or more of water in the composition. Preferably, it means 50% by weight or more. The water contained in the aqueous composition of the present invention only needs to be pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like can be used. These definitions are based on the 1st 5th Japanese Pharmacopoeia.

The aqueous composition of the present invention is prepared by adding a desired amount of the above-mentioned components (A), (B), and (C), and if necessary, other compounding components to a desired concentration. The

  The aqueous composition of the present invention can take various preparation forms depending on the purpose. For example, the form of the aqueous composition of the present invention includes a liquid agent, a semisolid agent (ointment etc.) and the like. A liquid agent is preferable.

  In addition, the aqueous composition of the present invention can be used as a pharmaceutical preparation, a quasi-drug, and the like. For example, an ophthalmic composition, a nasal composition, an oral composition, an ear composition, a composition for subcutaneous administration. It can be used in various applications such as products and skin external compositions. Here, ophthalmic compositions include eye drops, artificial tears, eyewashes, eye ointments, contact lens mounting liquids, contact lens care agents (contact lens disinfectants, contact lens preservatives, contact lens cleaners). , Contact lens cleaning preservatives, etc.). In addition, nasal compositions include nasal drops, nasal washings, and the like. Oral compositions include internal medicines (eg, liquids, syrups, extracts, etc.), oropharyngeal drugs, mouthwashes, and the like. The eardrop composition includes eardrops. The composition for subcutaneous administration includes injections and the like.

  Among the above uses, ophthalmic compositions are often much lower in concentration of compounding components than compositions for other uses such as oral compositions, and even a slight decrease in content is a major problem. It can be. In particular, among ophthalmic compositions, eye drops are greatly affected by a decrease in content because the amount of one-time use is extremely small. In addition, eye drops and contact lens care products are often stored at room temperature such as a wash basin, while eye drops are often carried around. Since it may be placed under a high temperature by being placed in a basket or being carried outdoors, it is very susceptible to the difference in temperature. Furthermore, it can be said that the eye drop is a preparation form that is easily affected by a temperature change from the outside because it is generally individually packaged in a small amount. According to the aqueous composition of the present invention, the effect of improving the thermal stability can be effectively exhibited even for an ophthalmic composition (particularly an eye drop) that is easily affected by temperature changes. In view of the effects of the present invention, a preferred example of the aqueous composition of the present invention is an ophthalmic composition, and a particularly preferred example is an eye drop.

  The aqueous composition of the present invention is provided by being contained in an arbitrary container. The container for storing the aqueous composition of the present invention is not particularly limited, and may be made of, for example, glass or plastic. Moreover, the transparent container which can visually recognize the inside of a container may be sufficient as the container which accommodates the aqueous composition of this invention, and the opaque container where it is difficult to visually recognize the inside of a container may be sufficient as it. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container.

Since the aqueous composition of the present invention can exhibit an anti-inflammatory action and the like based on the component (A), it is effective for the treatment or prevention of inflammatory diseases and is also useful as an ameliorating agent for inflammatory diseases. Here, as an example of the target inflammatory disease, inflammatory eye disease (for example, blepharitis, conjunctivitis, keratitis, scleritis, superior scleritis, anterior uveitis, postoperative inflammation, lacrimal adenitis Lacrimal cystitis, lacrimal canalitis, etc.). Therefore, the aqueous composition of the present invention is used for alleviating various symptoms (for example, eye foreign body sensation, sullen eyes, redness, itchy eyes, blurred eyes, etc.) resulting from these inflammatory diseases. Can be. Moreover, since the aqueous composition of the present invention can exert a bacteriostatic action based on the above component (C), it is also useful as an agent for improving symptoms caused by bacterial infection such as stylus and conjunctivitis.

2. As stability improved method described above to heat, from being destabilized discolor (yellow) when the aqueous composition containing the above components (A) and (B) is exposed to heat, the ( It can suppress by mix | blending a C) component.

Accordingly, the present invention, from yet another aspect, comprises an aqueous composition comprising (A) at least one selected from the group consisting of pranoprofen and a salt thereof, and (B) dibutylhydroxytoluene and butylhydroxyanisole. Also provided is a method for improving the heat stability of an aqueous composition comprising the components (A) and (B), which comprises blending (C) a sulfa drug with at least one selected from the group .

  In the method, the types and blending ratios of components (A) to (C) to be used, the types and blending ratios of other components, the pH of the aqueous composition, the formulation form and use of the aqueous composition, The same as in “1. Aqueous composition”.

3. Agent for improving stability to heat and use thereof As mentioned above, the component (C) is used when the aqueous composition containing the components (A) and (B) is exposed to heat. It is possible to suppress destabilization and discoloration (yellowing).

Accordingly, the present invention is further selected from the group consisting of (A) at least one selected from the group consisting of pranoprofen and a salt thereof, and (B) dibutylhydroxytoluene and butylhydroxyanisole from another viewpoint. An agent for improving the heat stability of the aqueous composition, which is used in the case where at least one kind is allowed to coexist in the aqueous composition, comprising (C) a sulfa agent, Provide a stability improver. Furthermore, the present invention provides (A)
It includes at least one selected from the group consisting of pranoprofen and a salt thereof and (B) at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole, and has improved heat stability. (C) for producing an aqueous composition
Also provided is the use of sulfa drugs.

  In these inventions, the types and blending ratios of components (A) to (C) to be used, the types and blending ratios of other components, the pH of the aqueous composition, the formulation form and use of the aqueous composition, etc. The same as “1. Aqueous composition”.

EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Reference test example 1: thermal stability evaluation (1)
Test solutions (Test Solution 1-3) shown in Table 1 below were prepared, and the stability of the aqueous composition to heat was evaluated.

  According to Table 1, each test solution was prepared. In addition, it confirmed visually that all each test liquid immediately after preparation was colorless and transparent. Thereafter, each test solution was filled in a 10 ml-capacity headspace vial, sealed in 10 ml, and stored at 70 ° C. for 1 week under shading. One week later, the absorbance at 405 nm (A405) was measured for each test solution as an index of yellowing. As a blank group, the absorbance of purified water A405 was also measured. By calculating a value obtained by subtracting the absorbance of A405 of the blank group from the absorbance of A405 of each test solution, the degree of yellowing was examined for each test solution.

  The results are shown in FIG. As is clear from FIG. 1, when pranoprofen is blended alone (test solution 1) or dibutylhydroxytoluene is blended alone (test solution 2), there is no problem with respect to heat stability. Yellowing of the aqueous composition was not observed. On the other hand, unexpectedly, when test solution 3 containing a combination of pranoprofen and dibutylhydroxytoluene was stored under high temperature conditions, significant yellowing occurred and there was a problem in formulation. Became clear for the first time. In general, when pranoprofen is decomposed, it is more often cloudy than yellowing. Therefore, the yellowing observed during the combined use of pranoprofen and dibutylhydroxytoluene is dibutylhydroxytoluene. It is presumed that the part of the decomposition contributed greatly.

Test Example 1: Thermal stability evaluation (2)
Test solutions (Comparative Example 1 and Example 1-3) shown in Table 2 below were prepared, and the stability of the aqueous composition to heat was evaluated.

  According to Table 2, each test solution was prepared. In addition, it confirmed visually that all each test liquid immediately after preparation was colorless and transparent. Thereafter, each test solution was filled in a 10 ml-capacity headspace vial, sealed in 10 ml, and stored at 70 ° C. for 1 week under shading. One week later, the absorbance at 405 nm (A405) was measured for each test solution as an index of yellowing. As a blank group, the absorbance of purified water A405 was also measured. The value of A405 after blank correction was calculated for each test solution by subtracting the absorbance of A405 of the blank group from the absorbance of A405 of each test solution. Using the value of A405 obtained after blank correction, the yellowing suppression rate (%) was calculated by the following formula I.

  The results are shown in the bottom column of Table 2. As is clear from Table 2, the aqueous composition of Example 1 in which sulfa drug was further blended in addition to pranoprofen and dibutylhydroxytoluene showed a high yellowing suppression rate and markedly caused yellowing under high temperature conditions. It became clear that it could be suppressed. Further, from the results of Examples 2 and 3, in addition to the sulfa agent, chlorpheniramine maleate or disodium ethylenediaminetetraacetate dihydrate is further combined and blended to obtain remarkably high thermal stability. It became clear.

Test Example 2: Thermal stability evaluation (3)
For the test solutions shown in Table 3 below (Comparative Example 2 and Example 4-6), except that the heat treatment conditions were changed from 70 ° C. for 1 week to 60 ° C. for 30 days, 50 ° C. for 90 days, or 40 ° C. for 180 days, The stability to heat was evaluated in the same manner as in Test Example 1.

  Using the value of A405 after blank correction obtained for each test solution, the yellowing suppression rate (%) for Comparative Example 2 was calculated in the same manner as in Formula I shown in Test Example 1 above. The results are also shown in Table 3. As is clear from Table 3, as in Test Example 1, in addition to pranoprofen and dibutylhydroxytoluene, it was confirmed that the thermal stability at 40 to 60 ° C. can be enhanced by further adding a sulfa agent. . It was also recognized that thermal stability was further improved by further blending disodium ethylenediaminetetraacetate dihydrate, and by further blending with chlorpheniramine maleate.

Test Example 5: Thermal stability evaluation (4)
The test solutions shown in Table 4 below (Comparative Example 3 and Examples 7-9) were evaluated for heat stability in the same manner as in Test Example 1 above.

  Using the value of A405 after blank correction obtained for each test solution, the yellowing inhibition rate (%) for Comparative Example 3 was calculated in the same manner as in Formula I shown in Test Example 1 above. The results are shown in the bottom column of Table 4. As is clear from Table 4, it was confirmed that the thermal stability can be improved by further adding a sulfa agent in addition to pranoprofen and dibutylhydroxytoluene as in the previous test examples. It was also recognized that thermal stability was further enhanced by further combining and blending ethylenediaminetetraacetic acid disodium dihydrate and chlorpheniramine maleate.

Formulation Example Eye drops (Examples 10-29) are prepared according to the formulation described in Table 5.

Claims (3)

  (A) at least one selected from the group consisting of pranoprofen and a salt thereof, (B) at least one selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole, and (C) a sulfa drug An aqueous composition characterized in that:   The aqueous composition according to claim 1, wherein the total amount of component (C) is 1 to 100,000 parts by weight per 100 parts by weight of component (A).   The aqueous composition according to claim 1 or 2, wherein the total amount of component (C) is 100 to 1,000,000 parts by weight per 100 parts by weight of component (B).

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