JP2015057443A - Aqueous composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an aqueous composition excellent in formulation which has a significantly improved thermal stability of ketotifen and/or a salt thereof, while containing ketotifen and/or a salt thereof, and pranoprofen and/or a salt thereof.SOLUTION: In an aqueous composition, (A) ketotifen and/or a salt thereof, (B) pranoprofen and/or a salt thereof, and (C) dibutyl hydroxy toluene are combined with; and the pH is adjusted 6.5 or less.

Description

  The present invention relates to an aqueous composition comprising ketotifen and / or a salt thereof and pranoprofen and / or a salt thereof, wherein the thermal stability of ketotifen and / or a salt thereof is improved. Furthermore, the present invention relates to a method for improving the thermal stability of ketotifen and / or a salt thereof in an aqueous composition comprising ketotifen and / or a salt thereof and pranoprofen and / or a salt thereof.

  Ketotifen and / or its salts have pharmacological actions such as chemical mediator release inhibition and eosinophil activation inhibition in addition to antihistamine action. As antiallergic agents, eye drops, nasal drops, Widely used as an oral preparation.

  In addition, pranoprofen and / or a salt thereof is known as a propionic acid non-steroidal anti-inflammatory agent having an excellent anti-inflammatory action, analgesic action, and antipyretic action, and has high safety. And widely used as an oral preparation.

  And the aqueous composition which contains ketotifen fumarate and pranoprofen simultaneously is known until now (refer patent documents 1-4).

  For example, in Patent Document 1, after dissolving pranoprofen at a pH of 6.8 or more, ketotifen fumarate is added to the solution, and then the pH is adjusted to 5 or more and 6.5 or less, thereby causing precipitation or cloudiness. It is described that an ophthalmic solution containing pranoprofen and ketotifen fumarate that does not occur and can be stably maintained over time is obtained.

  Patent Document 2 discloses a composition containing pranoprofen or a salt thereof, and neostigmine methyl sulfate, which has a high effect of improving eye fatigue and has improved light stability. Patent Document 2 describes an ophthalmic solution that contains ketotifen fumarate and dibutylhydroxytoluene in addition to pranoprofen and neostigmine methylsulfate, and has a pH of 7.0.

  Patent Document 3 also discloses a composition containing pranoprofen or a salt thereof and glycyrrhizinate, which has a high effect of improving eye fatigue and has improved light stability. Patent Document 3 describes an ophthalmic solution containing ketotifen fumarate and dibutylhydroxytoluene having a pH of 7.0 in addition to pranoprofen and dipotassium glycyrrhizinate.

Patent Document 4 discloses an aqueous composition containing (A) pranoprofen or a salt thereof, (B) a zinc compound, and (C) citric acid or a salt thereof, in which decomposition by light is suppressed. Yes.
Patent Document 4 describes an ophthalmic solution that contains ketotifen fumarate and dibutylhydroxytoluene in addition to pranoprofen, zinc sulfate, and sodium citrate, and has a pH of 7.0.

On the other hand, there is also known a method for stabilizing pranoprofen (especially against light), characterized in that an aqueous pranoprofen solution is placed in the presence of an antioxidant such as dibutylhydroxytoluene ( (See Patent Document 5). However, although Patent Document 5 describes the stabilization of pranoprofen by the combined use of an antioxidant, it does not describe the relationship between the stabilization of pranoprofen and pH, and moreover, ketotifen fumarate. There is no teaching on a method for increasing the thermal stability of the material.

JP 2005-272462 A JP 2006-232822 A JP 2006-232823 A JP 2006-249076 A Japanese Patent Laid-Open No. 7-304670

  The present inventors have conducted various studies on aqueous compositions containing ketotifen and / or a salt thereof and pranoprofen and / or a salt thereof. When prophene and / or its salt were combined and combined, ketotifen and / or its salt became insufficiently heat-stable and the composition itself was yellowed. Thus, when the thermal stability of ketotifen and / or its salt becomes insufficient and yellowing caused by destabilization of ketotifen and / or its salt occurs, not only the appearance is impaired, but also ketotifen and There is a possibility that the content of the salt thereof is lowered, and even if such an aqueous composition is used for treatment or the like, the desired effect cannot be exhibited. Accordingly, in order to obtain an aqueous composition excellent in formulation, the thermal stability of ketotifen and / or salt thereof is improved while containing ketotifen and / or salt thereof and pranoprofen and / or salt thereof. Development of technology is needed.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors further added dibutylhydroxytoluene to an aqueous composition containing ketotifen and / or a salt thereof and pranoprofen and / or a salt thereof. In addition, by making the pH of the composition 6.5 or less, the thermal stability of ketotifen and / or a salt thereof destabilized by coexistence with pranoprofen and / or a salt thereof can be remarkably improved. I found it. 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 ketotifen and its salt, (B) at least one selected from the group consisting of pranoprofen and its salt, and (C) dibutylhydroxytoluene. And an aqueous composition characterized by having a pH of 6.5 or lower.
Item 1-2. Item 11. The aqueous composition according to Item 1-1, which contains ketotifen fumarate as the component (A).
Item 1-3. Item 11. The aqueous composition according to Item 1-1 or 1-2, which contains pranoprofen 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) a surfactant.
Item 1-5. Item 5. The aqueous composition according to Item 1-4, which contains a nonionic surfactant as component (D).
Item 1-6. Item 6. The aqueous composition according to any one of Items 1-1 to 1-5, further comprising (E) a polyhydric alcohol.
Item 1-7. Item 7. The aqueous composition according to Item 1-6, which contains glycerin as a component.
Item 1-8. Item 8. The aqueous composition according to any one of Items 1-1 to 1-7, further comprising (F) a borate buffer. Item 1-9. Item 10. The aqueous composition according to Item 1-8, which contains boric acid and an alkali metal salt of boric acid as the component (F).
Item 1-10. Item 10. The aqueous composition according to Item 1-8 or 1-9, which contains boric acid and borax as a component.
Item 1-11. Item 11. The aqueous composition according to any one of Items 1-8 to 1-10, wherein the pH is adjusted to 6.5 or less with a borate buffer.
Item 1-12. Item 12. The aqueous composition according to any one of Items 1-1 to 1-11, which is an ophthalmic composition.
Item 1-13. Item 13. The aqueous composition according to any one of Items 1-1 to 1-12, which is an eye drop.

The present invention also provides a method for improving the heat stability of ketotifen and / or a salt thereof in an aqueous composition as described below.
Item 2-1. The aqueous composition comprises (C) dibutylhydroxy with at least one selected from the group consisting of (A) ketotifen and a salt thereof and (B) at least one selected from the group consisting of pranoprofen and a salt thereof. A method for improving the heat stability of ketotifen and / or a salt thereof in an aqueous composition, which comprises adding toluene and adjusting the pH of the aqueous composition to 6.5 or less.
Item 2-2. Item 3. The method for improving stability according to item 2-1, comprising ketotifen fumarate as the component (A).
Item 2-3. Item (B) The method for improving stability according to Item 2-1 or 2-2, comprising pranoprofen as the component.
Item 2-4. Item 4. The method for improving stability according to any one of Items 2-1 to 2-3, further comprising (D) a surfactant.
Item 2-5. Item 5. The method for improving stability according to Item 2-4, which comprises a nonionic surfactant as a component.
Item 2-6. Item 6. The method for improving stability according to any one of Items 2-1 to 2-5, further comprising (E) a polyhydric alcohol.
Item 2-7. Item 7. The method for improving stability according to Item 2-6, which comprises glycerin as a component.
Item 2-8. Item 8. The method for improving stability according to any one of Items 2-1 to 2-7, further comprising (F) a borate buffer.
Item 2-9. Item 9. The stability improving method according to Item 2-8, which contains boric acid and an alkali metal salt of boric acid as component (F).
Item 2-10. Item 10. The stability improving method according to Item 2-8 or 2-9, which contains boric acid and borax as the component (F).
Item 2-11. Item 11. The method for improving stability according to any one of Items 2-8 to 2-10, wherein the pH is adjusted to 6.5 or less using a borate buffer.
Item 2-12. Item 12. The method for improving stability according to any one of Items 2-1 to 2-11, wherein the aqueous composition is an ophthalmic composition.
Item 2-13. Item 13. The method for improving stability according to any one of Items 2-1 to 2-12, wherein the aqueous composition is an eye drop.

Furthermore, the present invention provides a heat stability improving agent for ketotifen and / or a salt thereof listed below.
Item 3-1. (A) At least one selected from the group consisting of ketotifen and a salt thereof and (B) at least one selected from the group consisting of pranoprofen and a salt thereof are used in the case where they coexist in an aqueous composition. An agent for improving the heat stability of the component (A), which contains (C) dibutylhydroxytoluene, and the final pH of the aqueous composition is 6.
A thermal stability improver comprising an aqueous base adjusted to 5 or less.
Item 3-2. Item 3. The thermal stability improver according to Item 3-1, comprising ketotifen fumarate as the component (A).
Item 3-3. Item 3. The thermal stability improving agent according to item 3-1 or 3-2, which contains pranoprofen as a component.
Item 3-4. Item 4. The thermal stability improver according to any one of Items 3-1 to 3-3, wherein the aqueous base further contains (D) a surfactant.
Item 3-5. Item 5. The thermal stability improver according to Item 3-4, which contains a nonionic surfactant as a component.
Item 3-6. Item 6. The thermal stability improver according to any one of Items 3-1 to 3-5, wherein the aqueous base further contains (E) a polyhydric alcohol.
Item 3-7. Item (E) The thermal stability improver according to Item 3-6, which contains glycerin as a component.
Item 3-8. Item 8. The thermal stability improver according to any one of Items 3-1 to 3-7, wherein the aqueous base further contains (F) a borate buffer.
Item 3-9. Item 9. The thermal stability improver according to Item 3-8, which contains boric acid and an alkali metal salt of boric acid as the component (F).
Item 3-10. Item (F) The thermal stability improver according to Item 3-8 or 3-9, which contains boric acid and borax as a component.
Item 3-11. Item 3-8, adjusted with borate buffer so that the final pH is 6.5 or lower.
The thermal stability improving agent in any one of thru | or 3-10.
Item 3-12. The thermal stability improving agent according to any one of Items 3-1 to 3-11, wherein the aqueous composition is an ophthalmic composition.
Item 3-13. The thermal stability improving agent according to any one of Items 3-1 to 3-12, wherein the aqueous composition is an eye drop.

Still further, the present invention provides the uses listed below.
Item 4-1. (A) at least one selected from the group consisting of ketotifen and a salt thereof; and (B) at least one selected from the group consisting of pranoprofen and a salt thereof; An aqueous base containing (C) dibutylhydroxytoluene and adjusted so that the final pH of the aqueous composition is 6.5 or less for producing an aqueous composition having improved stability Use of.
Item 4-2. The use according to Item 4-1, comprising ketotifen fumarate as component (A).
Item 4-3. (B) Use of claim | item 4-1 or 4-2 containing pranoprofen as a component.
Item 4-4. Item 4. The use according to any one of Items 4-1 to 4-3, wherein the aqueous base further contains (D) a surfactant.
Item 4-5. Item 4. The use according to Item 4-4, which contains a nonionic surfactant as a component.
Item 4-6. The use according to any one of Items 4-1 to 4-5, wherein the aqueous base further contains (E) a polyhydric alcohol.
Item 4-7. (E) Use of claim | item 4-6 containing glycerol as a component.
Item 4-8. Item 8. The use according to any one of Items 4-1 to 4-7, wherein the aqueous base further contains (F) a borate buffer.
Item 4-9. Item 4. The use according to Item 4-8, which contains boric acid and an alkali metal salt of boric acid as the component (F).
Item 4-10. The use according to Item 4-8 or 4-9, which contains boric acid and borax as component (F).
Item 4-11. Item 11. The use according to any one of Items 4-8 to 4-10, wherein the aqueous base is adjusted with a borate buffer so that the final pH is 6.5 or lower.
Item 4-12. The use according to any one of Items 4-1 to 4-11, wherein the aqueous composition is an ophthalmic composition.
Item 4-13. The use according to any one of Items 4-1 to 4-12, wherein the aqueous composition is an eye drop.

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

In Experiment 1, it is a figure which shows the result of having evaluated the thermal stability of the ketotifen fumarate in the test solutions 1, 2, and 4. FIG. In Experiment 2, it is a figure which shows the result of having evaluated the thermal stability of the ketotifen fumarate in the test liquid 5-7. In Experiment 3, it is a figure which shows the result of having evaluated the thermal stability of the ketotifen fumarate in the test liquid 8-10. In Experiment 4, it is a figure which shows the result of having evaluated the thermal stability of the ketotifen fumarate in the test liquid 11-16.

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

  Ketotifen is a compound also referred to as 4,9-dihydro-4- (1-methyl-4-piperidylidene) -10H-benzo [4,5] cyclohepta [1,2-b] thiophen-10-one. Ketotifen and its salts are known compounds as antiallergic agents, and may be synthesized by known methods or obtained as commercial products.

Among the components (A) used in the present invention, the salt of ketotifen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Organic acid salts [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate) Acid salt, 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, pyrrolidine, tripyridine , Salts with organic amines such as picoline), salts with inorganic bases [for example, ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc. Etc.]. Among these salts, an organic acid salt and / or an inorganic acid salt, preferably an organic acid salt, more preferably a polyvalent carboxylate, still more preferably a fumarate and / or maleate, particularly preferably Includes fumarate. These ketotifen salts may be used alone or in any combination of two or more.

In the aqueous composition of the present invention, as component (A), one kind of ketotifen and a salt thereof may be selected and used alone, or two or more kinds may be used in any combination. May be. The component (A) used in the present invention is preferably a salt of ketotifen, more preferably an organic acid salt and / or inorganic acid salt of ketotifen, more preferably an organic acid salt of ketotifen, and still more preferably a polyvalent carboxylic acid of ketotifen. Further preferred are ketotifen fumarate and / or maleate, particularly preferably ketotifen fumarate (ketotifen fumarate).

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, and the like. The total amount of the component (A) is 0.01 to 1 w / v%, preferably 0.03 to 0.5 w / v%, more preferably 0.03 to 0.1 w / v%, particularly Preferably, 0.05 to 0.1 w / v% is exemplified.

  In addition, 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 (B)).

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 (B) 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 (B), 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 (B) used in the present invention is preferably pranoprofen.

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, etc., for example, the total amount of the aqueous composition (B)
The total amount of the components is 0.01 to 1.5 w / v%, preferably 0.03 to 0.5 w / v%, more preferably 0.04 to 0.1 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) The total amount of component B) is 2 to 1000 parts by weight, preferably 10 to 400 parts by weight, more preferably 50 to 200 parts by weight, more preferably 50 to 150 parts by weight, particularly preferably 50 to 100 parts by weight. Illustrated.

Furthermore, the aqueous composition of the present invention contains dibutylhydroxytoluene (hereinafter sometimes simply referred to as the component (C)) in addition to the components (A) and (B). Dibutylhydroxytoluene is also called 2,6-bis (1,1-dimethylethyl) -4-methylphenol and is a known compound as an antioxidant.

In the aqueous composition of the present invention, the blending ratio of the component (C) is appropriately set according to the type of other blending components, etc., for example, the total amount of the aqueous composition, the (C) Ingredient 0.000
1 to 0.02 w / v%, preferably 0.0005 to 0.01 w / v%, more preferably 0.001 to 0.005 w / v%.

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) Component C) is 0.1 to 40 parts by weight, preferably 0.5 to 20 parts by weight, more preferably 1 to
A range of 15 parts by weight, more preferably 1 to 10 parts by weight, is exemplified.

  In addition, the aqueous composition of the present invention contains the components (A) to (C) and has a pH of 6.5 or less. By coexisting the above components (A) to (C) under specific pH conditions in this way, the destabilization of component (A) caused by component (B) with respect to heat is suppressed, and excellent stability is achieved. An aqueous composition can be provided.

  From the viewpoint of effectively providing the component (A) with thermal stability even in the presence of the component (B), the pH of the aqueous composition of the present invention is preferably 6.2 or less. Further, the lower limit value of the pH of the aqueous composition of the present invention is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, 4.0 or more , Preferably 5.0 or more, more preferably 5.5 or more, still more preferably 5.8 or more.

The pH can be adjusted by a known method in the technical field using a buffer, a pH adjusting agent, a tonicity agent, a salt and the like that are usually used in the technical field. Preferably, the pH is adjusted using a buffer and / or a pH adjusting agent that is usually used in the art.

  The aqueous composition of the present invention preferably further contains 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 hydrogenated castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE alkyl ethers such as POE (9) lauryl ether; POE (20 ) POE-POP alkyl ethers such as POP (4) cetyl ether; POE alkyl phenyl ethers such as POE (10) nonyl phenyl 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 surfactants, from the viewpoint of further improving the thermal stability of the component (A) destabilized by the component (B), preferably a nonionic surfactant; more preferably POE sorbitan Fatty acid esters, POE hydrogenated castor oil, POE-POP block copolymers;
Particularly preferred are polysorbate 80, polyoxyethylene hydrogenated castor oil 60, POE-POP block copolymer; particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60; most preferably polysorbate 80.

  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 preferably further contains a polyhydric alcohol. The polyhydric alcohol used in the present invention is not particularly limited as long as it is a compound having two or more hydroxyl groups and is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of the polyhydric alcohol include glycerin, 1,3-butylene glycol, ethylene glycol, polyethylene glycol, propylene glycol, sucrose, glucose, lactose, sorbitol, xylitol, mannitol, maltitol, polydextrose, and dextrin. be able to. In the aqueous composition of the present invention, these polyhydric alcohols may be used alone or in combination of two or more.

Among the above polyhydric alcohols, propylene glycol and / or glycerin are preferable, and most preferable from the viewpoint of further improving the thermal stability of the component (A) destabilized by the component (B). Is glycerin.

  When the polyhydric alcohol is blended with the aqueous composition of the present invention, the blending ratio of the polyhydric alcohol depends on the type of the polyhydric alcohol, the type and amount of other blending components, the use of the aqueous composition, etc. Can be set as appropriate. As an example of the blending ratio of the polyhydric alcohol, the total amount of the polyhydric alcohol is 0.05 to 3.5 w / v%, preferably 0.1 to 3 w / v%, based on the total amount of the aqueous composition. Preferably, 0.5 to 2.5 w / v% is exemplified.

  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 bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate and the like. Of these isotonic agents, potassium chloride, calcium chloride, sodium chloride and magnesium chloride are preferred. 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 aqueous composition of the present invention preferably further contains 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. Examples of the boric acid buffer include borates such as boric acid, alkali metal borate, and alkaline earth metal borate. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphate, and alkaline earth metal phosphate. Examples of the carbonate buffer include carbonates such as carbonic acid, alkali metal carbonate, and alkaline earth metal carbonate. 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.). 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, the use of the aqueous composition, etc. However, for example, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.1 to 5 w / v%, more preferably, with respect to the total amount of the aqueous composition. Is 0.2-2 w / v%,
Particularly preferably, the ratio is 0.2 to 1 w / v%.

Among the above-mentioned buffering agents, boric acid buffering agent is particularly suitable, and as a suitable specific example of boric acid buffering agent, a combination of boric acid and its salt; preferably boric acid and an alkali metal salt of boric acid and / or A combination of an alkaline earth metal salt; more preferably a combination of boric acid and an alkali metal salt of boric acid; particularly preferably a combination of boric acid and borax. By using the borate buffer in such a combination mode, not only a buffering effect can be imparted, but also the pH of the aqueous composition can be adjusted, and as a result, combined with the component (B). In this case, the thermal stability of the component (A) can be further improved. An example of a method for adjusting the pH using a boric acid buffer is a method in which each component is dissolved in an aqueous solvent, and then the amount of boric acid salt added is adjusted to the target pH.

Also, the destabilization of component (A) with respect to heat usually caused by component (B) is 0.2 to 2 w / v% (particularly 0.2 to 1 w) of boric acid buffer in the aqueous composition. / v%), a tendency to become prominent when contained, but according to the present invention, while containing such a borate buffer, the (B) component brings about the heat of the (A) component. It becomes possible to provide an aqueous composition excellent in stability by remarkably suppressing destabilization. In view of the effects of the present invention, as a suitable blending ratio of the boric acid buffer in the aqueous composition of the present invention, the boric acid buffer is 0.2 to 2 w / w in total with respect to the total amount of the aqueous composition. v%, preferably 0.2-1 w / v%.

The aqueous composition of the present invention may further contain a pH adjusting agent. The pH adjusting 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 pH adjusters include, for example, hydrochloric acid, aminoethylsulfonic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, propionic acid. Oxalic acid, gluconic acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone and the like. Of these pH adjusters, hydrochloric acid and sodium hydroxide are preferred. These pH adjusters may be used alone or in any combination of two or more.

  If necessary, the aqueous composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable for a living body. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, and the like, but is usually 0.7 to 5.0, more preferably 0.9 to 3.0, and particularly preferably 1.0 to 2.0. It is done. The osmotic pressure can be adjusted by a known method in the technical field using an inorganic salt, a polyhydric alcohol, or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 0.9w / v% sodium chloride aqueous solution based on the 15th revised Japanese Pharmacopoeia. The osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia (freezing point depression method) Measure with reference to. The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500-650 ° C for 40-50 minutes, and then allowed to cool in a desiccator (silica gel). Dissolve in water to prepare 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 a combination of various pharmacologically active components and physiologically active components in addition to the above components as long as the effects of the present invention are not hindered. The kind of such components is not particularly limited, and examples thereof include antihistamines, decongestants, bactericides, amino acids, anti-inflammatory agents, and astringents.

  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). The kind of such components is not particularly limited, and examples thereof include carriers, thickeners, preservatives, bactericides or antibacterial agents, chelating agents, fragrances, and cooling agents.

  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.

In the aqueous composition of the present invention, a desired amount of the component (A), the component (B), and the component (C), and other compounding components as necessary, are added so as to have a desired concentration, and the pH is adjusted. It is prepared by adjusting to meet the range.

  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. 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, an effect of improving stability under high temperature conditions 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 in which visual recognition inside a container is difficult may be sufficient. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container. According to the present invention, an aqueous composition containing ketotifen and / or a salt thereof and pranoprofen and / or a salt thereof is stable even when exposed to heat and hardly causes yellowing of the aqueous composition. Since the concern of a change in appearance properties is dispelled, it can be provided in a transparent container. In view of such a viewpoint, a transparent container can be mentioned as a suitable example of a container for housing the aqueous composition of the present invention.

The aqueous composition of the present invention can also exhibit an antiallergic action based on the component (A), and is therefore useful as a preventive or alleviating agent for allergic symptoms. Furthermore, since the aqueous composition of the present invention can also exhibit an anti-inflammatory action or the like based on the component (B), it is effective for the treatment or prevention of inflammatory diseases, and can also be used as a treatment or prevention agent for inflammatory diseases. Useful. Here, as an example of a target inflammatory disease, an inflammatory eye disease (for example, blepharitis, conjunctivitis, keratitis, scleritis, superior scleritis, anterior uveitis, postoperative inflammation, etc.) Can be mentioned.

2. Method for Improving Stability of Ketotifen and / or its Salt to Heat As described above, the heat destabilization of the component (A) caused by the coexistence with the component (B) in the aqueous composition is the above (C). It can suppress by mix | blending a component and making pH of this aqueous composition 6.5 or less.

Accordingly, the present invention, from yet another aspect, comprises selecting the aqueous composition from at least one selected from the group consisting of (A) ketotifen and a salt thereof, and (B) a group consisting of pranoprofen and a salt thereof. The heat of ketotifen and / or a salt thereof in an aqueous composition, characterized in that (C) dibutylhydroxytoluene is blended with at least one of the above and the pH of the aqueous composition is 6.5 or lower Also provided is a method of improving the stability against.

  In the method, the types and blending ratios of the 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 in “1. Aqueous composition”.

3. Agent for improving stability to heat of ketotifen and / or salt thereof and use thereof As described above, an aqueous composition containing the component (C) and having a pH of 6.5 or less,
The heat destabilization of the component (A) caused by coexistence with the component (B) can be suppressed.

Accordingly, the present invention, from yet another point of view, is at least one selected from the group consisting of (A) ketotifen and its salt, and (B) at least one selected from the group consisting of pranoprofen and its salt. Is an agent for improving the heat stability of the component (A), which is used in the case where it is coexisted in an aqueous composition, and contains (C) dibutylhydroxytoluene and the final component of the aqueous composition And a heat stability improver characterized by comprising an aqueous base adjusted to have a pH of 6.5 or less. Furthermore, the present invention includes (A) at least one selected from the group consisting of ketotifen and a salt thereof, and (B) at least one selected from the group consisting of pranoprofen and a salt thereof, A) In order to produce an aqueous composition having improved heat stability of component, (C) dibutylhydroxytoluene is contained and the final pH of the aqueous composition is 6.5 or less. Also provided is the use of a conditioned aqueous base.

In these inventions, the aqueous base containing the component (C) and adjusted so that the final pH of the aqueous composition is 6.5 or less comprises the component (A) and the component (B). Used as a base for. That is, the aqueous base means a composition in which the components (A) and (B) are not blended in the aqueous composition described in the column of “1. Aqueous composition” above. Any component that is not the component (B) (for example, various pharmacologically active components, physiologically active components, additives, etc.) may be included. In addition, “adjusted so that the final pH of the aqueous composition is 6.5 or less” means that the aqueous base contains (A) component, (B) component, and any optional It means that the aqueous composition obtained by blending the components is designed to have a pH of 6.5 or lower.

  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.

Test Example 1: Thermal stability evaluation (1)
Test solutions (test solutions 1-4) shown in Table 1 below were prepared, and the stability of ketotifen fumarate to heat was evaluated. It is known that ketotifen fumarate is yellowed when it becomes unstable, and in this test example, the thermal stability of ketotifen fumarate was evaluated by examining the degree of yellowing of the test solution. Specific experimental methods and results are shown below.

  First, each test solution (test solution 1-4) shown in Table 1 was prepared. Each test solution was prepared as a solution of three types of pH (specifically, a solution of pH 6.2, pH 7.0, and pH 7.5) by appropriately adjusting the blending amount of borax. 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 glass vial with a capacity of 10 ml, sealed in 8 ml, and stored at 70 ° C. for 1 week under light shielding. One week later, the absorbance at 405 nm (A405) was measured for each test solution. As a blank group, the absorbance value of purified water A405 was also measured. By calculating a value obtained by subtracting the absorbance value of A405 of the blank group from the absorbance value 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, in Test Solution 1 containing ketotifen fumarate but not containing pranoprofen, yellowing was not confirmed at pH 6.2, but when pH was 7.0 or higher. It was confirmed that significant yellowing occurred. And in test liquid 2 containing pranoprofen together with ketotifen fumarate, a remarkable yellowing of a level that is clearly visible at any pH was confirmed, and it is clear that the degree of this yellowing is a problem in formulation. Met. Further, even when dibutylhydroxytoluene was further blended, it was found that when the pH was 7.0 or higher, the inhibitory effect on yellowing was hardly observed or conversely deteriorated (test solution 4). Moreover, although not shown in FIG. 1, in test solution 3 containing pranoprofen but not containing ketotifen fumarate, no yellowing was observed at any pH.

  On the other hand, surprisingly, in the test solution 4 in which dibutylhydroxytoluene was added in addition to ketotifen fumarate and pranoprofen and the pH was further adjusted to 6.2, the absorbance value of A405 in the test solution was significantly reduced. However, yellowing was not recognized at all visually. Therefore, according to the present invention, it is possible to obtain an aqueous composition that is very stable to heat and excellent in terms of formulation while coexisting ketotifen and / or a salt thereof and pranoprofen and / or a salt thereof. It became clear.

Test Example 2: Thermal stability evaluation (2)
According to the following Table 2, each test solution was prepared, and the heat stability of ketotifen fumarate was evaluated. Specific experimental methods and results are shown below.

  First, each test solution (Test Solution 5-7) shown in Table 2 was prepared. Each test solution was prepared as a solution having two pHs (specifically, pH 6.5 and 7.0) by appropriately adjusting the amount of borax. Moreover, also about each test solution of this test example, it confirmed visually that all the test solutions immediately after preparation were colorless and transparent. Thereafter, each test solution was filled in a glass vial with a capacity of 10 ml, sealed in 8 ml, and stored at 70 ° C. for 1 week under light shielding. One week later, the absorbance at 405 nm (A405) was measured for each test solution. As a blank group, the absorbance value of purified water A405 was also measured. By calculating a value obtained by subtracting the absorbance value of A405 of the blank group from the absorbance value 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. 2, in the same manner as in Test Example 1 above, in Test Solution 5 containing ketotifen fumarate but not pranoprofen, significant yellowing occurred when the pH was 7.0. And in the test solution 6 containing pranoprofen together with ketotifen fumarate, a remarkable yellowing of a level that was obvious visually was confirmed at any pH. Moreover, in the test liquid 7 which further mix | blended dibutylhydroxytoluene, when pH 7.0, the inhibitory effect with respect to yellowing was not recognized at all. On the other hand, in addition to ketotifen fumarate and pranoprofen, dibutylhydroxytoluene was added and the pH of the test solution 7 was 6.5. Could not be recognized at all.

Test Example 3: Thermal stability evaluation (3)
Each test solution described in Table 3 below was prepared so as to have two kinds of pH (specifically, pH 6.2 and 7.0) by appropriately adjusting the blending amount of borax. Next, for each test solution, the stability of ketotifen fumarate to heat was evaluated in the same manner as in Test Example 2 except that the filling amount into the glass headspace vial was changed from 8 ml to 5 ml.

The result is shown in FIG. As apparent from FIG. 3, even when the blending amount of ketotifen fumarate was 0.0345 w / v%, the same tendency as in Test Example 1-2 was observed.
That is, in the case of pH 7.0, even when dibutylhydroxytoluene was further contained together with ketotifen fumarate and pranoprofen, no yellowing inhibitory effect was observed. It was confirmed that yellowing caused by coexistence of ketotifen acid and pranoprofen can be suppressed by further combining dibutylhydroxytoluene.

Test Example 4: Thermal stability evaluation (4)
Each test solution described in Table 4 below is prepared by adjusting the blending amount of borax as appropriate so as to obtain a predetermined pH, and the same method as in Test Example 2 using a glass headspace vial In each test solution, the stability of ketotifen fumarate to heat was evaluated.

  The result is shown in FIG. From this result, in the same manner as in Test Example 1-3, even when dibutylhydroxytoluene is further added together with ketotifen fumarate and pranoprofen at pH 7.0, significant yellowing may occur. It was confirmed (test solution 13). On the other hand, even when ketotifen fumarate and pranoprofen were allowed to coexist, it was found that when dibutylhydroxytoluene was added and the pH was adjusted to 6.5 or less, a remarkable yellowing suppression effect was obtained. (Test solutions 11, 12). In addition, when polysorbate 80 is used as a nonionic surfactant (test solution 12) under the condition that ketotifen fumarate and pranoprofen further contain dibutylhydroxytoluene and have a pH of 6.5, polyoxyethylene cured castor When oil 60 was used (test solution 14), a remarkable yellowing suppression effect was observed in both cases.

  In addition, when polyketol (glycerin or propylene glycol) is contained under the condition that ketotifen fumarate and pranoprofen further contain dibutylhydroxytoluene and have a pH of 6.5 (test solutions 12 and 16), Compared with the case where no alcohol was contained (test solution 15), the yellowing suppression effect was increased. In particular, when glycerin was included as the polyhydric alcohol (test solution 12), the yellowing suppression effect was significantly improved.

(General consideration)
From the above results, by adding dibutylhydroxytoluene and adjusting the pH of the aqueous composition to 6.5 or less, the destabilization of ketotifen fumarate caused by pranoprofen can be significantly suppressed, It was clarified that an aqueous composition excellent in formulation that does not cause yellowing even under conditions can be obtained. Moreover, in order to obtain the heat stability improvement effect of ketotifen fumarate which is remarkably higher, it was also recognized that it is beneficial to combine glycerin as a polyhydric alcohol.

Formulation Example An eye drop (Example 1-12) is prepared according to the formulation described in Table 5.

Claims (1)

(A) at least one selected from the group consisting of ketotifen and its salt, (B) at least one selected from the group consisting of pranoprofen and its salt, and (C) dibutylhydroxytoluene. (A) The content of at least one selected from the group consisting of ketotifen and a salt thereof is 0.01 to 1 w / v% based on the total amount of the aqueous composition, and the pH is 6.5 or less An aqueous composition characterized by the above.

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