JP2019123755A - Aqueous composition - Google Patents

Abstract

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; and the pH is adjusted to 6.5 or less.SELECTED DRAWING: None

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 of improving the thermal stability of ketotifen and / or its salt in an aqueous composition comprising ketotifen and / or its salt and pranoprofen and / or its salt.

  Ketotifen and / or a salt thereof has pharmacological actions such as inhibition of chemical mediator release and inhibition of activation of eosinophils in addition to antihistaminic action, and as anti-allergic agents, eye drops and nasal drops, It is widely used as an oral preparation.

  In addition, pranoprofen and / or a salt thereof is known as a non-steroidal anti-inflammatory drug of propionic acid type having an excellent anti-inflammatory action, analgesia action and antipyretic action, and because it is highly safe, eye drops And widely used as oral preparations.

  And until now, the aqueous composition which simultaneously contains ketotifen fumarate and pranoprofen is known (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 it is possible to obtain an eye drop containing a combination of pranoprofen and ketotifen fumarate which does not occur and can be stably held over time.

  Patent Document 2 discloses a composition containing pranoprofen or a salt thereof, and neostigmine methylsulfate having a high improvement effect on eye fatigue and an improved stability to light. And, in addition to pranoprofen and neostigmine methylsulfate, Patent Document 2 describes an eye drop containing ketotifen fumarate and dibutylhydroxytoluene, and having a pH of 7.0.

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

  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, which is inhibited from degradation by light. There is. And, in addition to pranoprofen, zinc sulfate and sodium citrate, Patent Document 4 describes an eye drop containing ketotifen fumarate and dibutylhydroxytoluene, and having a pH of 7.0.

  On the other hand, there is also known a method of stabilizing pranoprofen (particularly, against light) characterized by placing an aqueous solution of pranoprofen in coexistence with an antioxidant such as dibutyl hydroxytoluene (especially to light) Patent Document 5). However, Patent Document 5 describes stabilization of pranoprofen by the combined use of antioxidants, but does not describe the relationship between stabilization of pranoprofen and pH, and more preferably ketotifen fumarate There is no teaching about how to improve the thermal stability of

JP 2005-272462 A JP, 2006-232822, A Unexamined-Japanese-Patent No. 2006-223823 JP, 2006-249076, A JP-A-7-304670

  The present inventors have variously studied an aqueous composition containing ketotifen and / or a salt thereof and pranoprofen and / or a salt thereof. It has been found that the combination of prophen and / or a salt thereof causes the heat stability of ketotifen and / or a salt thereof to be insufficient, and the composition itself becomes yellowish, which is completely new. Thus, the thermal stability of ketotifen and / or the salt thereof is insufficient, and the yellowing caused by the destabilization of ketotifen and / or the salt thereof not only impairs the appearance but also ketotifen in the composition and The content of the salt thereof may be decreased, and even if such an aqueous composition is used for treatment etc., the intended effect may not be exhibited. Therefore, the thermal stability of ketotifen and / or a salt thereof is improved while containing ketotifen and / or a salt thereof, and pranoprofen and / or a salt thereof, to obtain a pharmaceutically excellent aqueous composition. Development of technology is needed.

  The present inventors have further incorporated dibutylhydroxytoluene into an aqueous composition containing ketotifen and / or a salt thereof, and pranoprofen and / or a salt thereof, as a result of intensive studies to solve the above problems. And by setting the pH of the composition to 6.5 or less, the thermal stability of ketotifen and / or its salt, which is destabilized by coexistence with pranoprofen and / or its salt, can be remarkably improved. I found it. The present invention has been completed by repeating studies based on such findings.

That is, the present invention provides an aqueous composition according to the following aspect.
Item 1-1. (A) at least one member selected from the group consisting of ketotifen and its salt, (B) at least one member selected from the group consisting of pranoprofen and its salt, and (C) dibutyl hydroxytoluene And pH is 6.5 or less, The aqueous composition characterized by the above-mentioned.
Item 1-2. The aqueous composition according to Item 1-1, comprising ketotifen fumarate as the component (A).
Item 1-3. The aqueous composition according to Item 1-1 or 1-2, which contains pranoprofen as the component (B).
Item 1-4. The aqueous composition according to any one of Items 1-1 to 1-3, further comprising (D) a surfactant.
Item 1-5. The aqueous composition according to Item 1-4, which contains a nonionic surfactant as the component (D).
Item 1-6. The aqueous composition according to any one of Items 1-1 to 1-5, further comprising (E) a polyhydric alcohol.
Item 1-7. The aqueous composition according to Item 1-6, which contains glycerin as the component (E).
Item 1-8. The aqueous composition according to any one of Items 1-1 to 1-7, further comprising (F) a borate buffer.
Item 1-9. 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. The aqueous composition according to Item 1-8 or 1-9, containing boric acid and borax as the component (F).
Item 1-11. The aqueous composition according to any one of Items 1-8 to 1-10, which has been adjusted to a pH of 6.5 or less with a borate buffer.
Item 1-12. The aqueous composition according to any one of Items 1-1 to 1-11, which is an ophthalmic composition.
Item 1-13. 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 its salt in an aqueous composition as listed below.
Item 2-1. An aqueous composition comprises (A) at least one member selected from the group consisting of ketotifen and its salt, and (B) dibutyl hydroxy, together with at least one member selected from the group consisting of pranoprofen and its salt. A method for improving the heat stability of ketotifen and / or a salt thereof in an aqueous composition, which comprises blending toluene and bringing the pH of the aqueous composition to 6.5 or less.
Item 2-2. The method for improving stability according to Item 2-1, comprising ketotifen fumarate as the component (A).
Item 2-3. The method for improving stability according to item 2-1 or 2-2, wherein pranoprofen is contained as the component (B).
Item 2-4. The method for improving stability according to any one of Items 2-1 to 2-3, further comprising (D) a surfactant.
Item 2-5. The method for improving stability according to item 2-4, wherein a nonionic surfactant is contained as the component (D).
Item 2-6. 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. The method of improving stability according to item 2-6, wherein glycerin is contained as the component (E).
Item 2-8. The method for improving stability according to any one of Items 2-1 to 2-7, further comprising (F) a boric acid buffer.
Item 2-9. The method for improving stability according to Item 2-8, wherein boric acid and an alkali metal salt of boric acid are contained as the component (F).
Item 2-10. Component (F) contains boric acid and borax
The method for improving stability according to Item 2-8 or 2-9.
Item 2-11. 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. 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. 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 thermal stability improver for ketotifen listed below and / or a salt thereof.
Item 3-1. (A) at least one member selected from the group consisting of ketotifen and its salt, and (B) at least one member selected from the group consisting of pranoprofen and its salt in the aqueous composition An agent for improving the thermal stability of the component (A), which comprises (C) dibutylhydroxytoluene, and the final pH of the aqueous composition is 6.5 or less A thermal stability improver comprising an aqueous base adjusted to
Item 3-2. The thermal stability improver according to Item 3-1, which comprises ketotifen fumarate as the component (A).
Item 3-3. The heat stability improver according to Item 3-1 or 3-2, which contains pranoprofen as the component (B).
Item 3-4. The thermal stability improver according to any one of Items 3-1 to 3-3, wherein the aqueous base further comprises (D) a surfactant.
Item 3-5. The thermal stability improving agent according to Item 3-4, which contains a nonionic surfactant as the component (D).
Item 3-6. 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. The heat stability improving agent according to Item 3-6, which contains glycerin as the component (E).
Item 3-8. The thermal stability improver according to any one of Items 3-1 to 3-7, wherein the aqueous base further comprises (F) a borate buffer.
Item 3-9. 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. The heat stability improver according to Item 3-8 or 3-9, which contains boric acid and borax as the component (F).
Item 3-11. The thermal stability improver according to any one of Items 3-8 to 3-10, which is adjusted to a final pH of 6.5 or less with a borate buffer.
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 improver according to any one of Items 3-1 to 3-12, wherein the aqueous composition is an eye drop.

And furthermore, the present invention provides the use listed below.
Item 4-1. (A) at least one member selected from the group consisting of ketotifen and its salt, and (B) at least one member selected from the group consisting of pranoprofen and its salt, to the heat of the component (A) An aqueous base containing (C) dibutyl hydroxytoluene and adjusted so that the final pH of the aqueous composition is 6.5 or less, for producing an aqueous composition with improved stability. Use of.
Item 4-2. The use according to item 4-1, which comprises ketotifen fumarate as the component (A).
Item 4-3. The use according to Item 4-1 or 4-2, which comprises pranoprofen as the component (B).
Item 4-4. The use according to any one of paragraphs 4-1 to 4-3, wherein the aqueous base further comprises (D) a surfactant.
Item 4-5. The use according to item 4-4, comprising a nonionic surfactant as the component (D).
Item 4-6. The use according to any one of paragraphs 4-1 to 4-5, wherein the aqueous base further contains (E) a polyhydric alcohol.
Item 4-7. The use according to item 4-6, which comprises glycerin as the component (E).
Item 4-8. The use according to any one of paragraphs 4-1 to 4-7, wherein the aqueous base further comprises (F) a borate buffer.
Item 4-9. 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 comprises boric acid and borax as the component (F).
Item 4-11. 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 less.
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.

  According to the present invention, a pharmaceutical composition having an excellent aqueous composition in which the heat stability of ketotifen and / or its salt is improved while containing pranoprofen and / or its salt together with ketotifen and / or its salt. Can provide the goods.

In Experiment 1, it is a figure which shows the result of having evaluated the thermal stability of fumaric acid ketotifen in test liquids 1, 2, and 4. In Experiment 2, it is a figure which shows the result of having evaluated the thermal stability of fumaric acid ketotifen in the test liquid 5-7. In Experiment 3, it is a figure which shows the result of having evaluated the thermal stability of fumaric acid ketotifen in the test liquid 8-10. In Experiment 4, it is a figure which shows the result of having evaluated the thermal stability of fumaric acid ketotifen in 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-piperidinyl) -10H-benzo [4,5] cyclohepta [1,2-b] thiophen-10-one. Ketotifen and salts thereof are compounds known as anti-allergic agents, and may be synthesized by known methods and may be obtained as commercial products.

Among the above-mentioned component (A) used in the present invention, the ketotifen salt is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Organic acid salts (eg, monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polyvalent carboxylates (fumarates, maleates, Acid salts, malonic acid salts etc.), oxycarboxylic acid salts (lactate, tartrate, citrate etc.), organic sulfonates (methane sulfonate, toluene sulfonate, tosylate etc.) etc., inorganic Acid salts (eg, hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine Salts with organic amines such as picoline), salts with inorganic bases [eg ammonium salts; salts with metals such as alkali metals (sodium, potassium etc.), alkaline earth metals (calcium, magnesium etc.), aluminum etc. Etc.]. Among these salts, preferably organic and / or inorganic acid salts, more preferably organic acid salts, even more preferably polyvalent carboxylic acid salts, still more preferably fumarate and / or maleate salts, particularly preferably Are fumaric acid salts. These salts of ketotifen may be used alone or in any combination of two or more.

  In the aqueous composition of the present invention, as the component (A), one of ketotifen and a salt thereof may be selected and used alone, or two or more of them may be used in optional combination. You may As component (A) to be used in the present invention, preferably a salt of ketotifen, more preferably an organic and / or inorganic acid salt of ketotifen, more preferably an organic acid salt of ketotifen, still more preferably a polycarboxylic acid of ketotifen Mention may be made of acid salts, even more preferably fumaric and / or maleate salts of ketotifen, and particularly preferably fumaric acid salt of ketotifen (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, etc. For example, the composition of the aqueous composition 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%, relative to the total amount 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, may be simply referred to as component (B)).

  Pranoprofen is a known compound also referred to as α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid, and may be synthesized by a known method and obtained as a commercial product. It can also be done.

  Among the above-mentioned 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, salts with inorganic bases [eg, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts etc.] and salts with organic bases [eg, methylamine, triethylamine, diethylamine, triethanolamine, And salts thereof with morpholine, piperazine, pyrrolidine, tripyridine, picoline and the like] and the like. These salts of pranoprofen may be used alone or in any combination of two or more.

  In the aqueous composition of the present invention, as the component (B), one of pranoprofen and a salt thereof may be selected and used alone, or two or more of them may be optionally combined. You may use it. As the (B) component to be used in the present invention, pranoprofen is preferably mentioned.

  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 types of other components, etc. For example, the total amount of the aqueous composition The total amount of the component (B) 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%. It is illustrated.

  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, per 100 parts by weight of the total of the component (A), The total amount of the 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. It is illustrated.

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

  In the aqueous composition of the present invention, the blending ratio of the above component (C) is appropriately set according to the type of other blending components, etc., for example, relative to the total amount of the aqueous composition, the (C) The components are exemplified by 0.0001 to 0.02 w / v%, preferably 0.0005 to 0.01 w / v%, and 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, per 100 parts by weight of the total of the component (A), A range in which component C) is 0.1 to 40 parts by weight, preferably 0.5 to 20 parts by weight, more preferably 1 to 15 parts by weight, and still more preferably 1 to 10 parts by weight is exemplified.

  Moreover, the aqueous composition of this invention contains the said (A)-(C) component, and pH satisfy | fills 6.5 or less. Thus, the coexistence of the components (A) to (C) under specific pH conditions suppresses the destabilization of the component (A) brought about by the component (B) to a high degree of stability. It is possible to provide an aqueous composition.

  The aqueous composition of the present invention preferably has a pH of 6.2 or less from the viewpoint of effectively providing the component (A) with thermal stability even in the presence of the component (B). 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 pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range, for example, 4.0 or more Preferably, it is 5.0 or more, more preferably 5.5 or more, and further preferably 5.8 or more.

  Adjustment of pH can be performed by methods known in the art using buffers, pH adjusters, tonicity agents, salts and the like usually used in the art. Preferably, pH adjustment is performed using a buffer and / or a pH adjustor commonly 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 nonionic surfactants, It may be any of amphoteric surfactants, anionic surfactants and cationic surfactants.

  Specific examples of the nonionic surfactant that can be incorporated into the aqueous composition of the present invention include monolaurate POE (20) sorbitan (polysorbate 20), monopalmitate POE (20) sorbitan (polysorbate 40), mono POE sorbitan fatty acid esters such as stearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); poloxamer 407, poloxamer 235 And POE / POP block copolymers such as poloxamer 188, poloxamer 403, poloxamer 237, poloxamer 124; POE hydrogenated castor oils such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (9) lauryl POE alkyl ethers such as ether; POE (20) POP (4) POE-POP alkyl ethers such as cetyl ether; POE (10 And POE alkylphenyl ethers such as nonylphenyl ether and the like. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of added moles. Moreover, as an amphoteric surfactant which can be mix | blended with the aqueous composition of this invention, an alkyl diamino ethyl glycine etc. are specifically illustrated. Specific examples of the cationic surfactant that can be added to the aqueous composition of the present invention include benzalkonium chloride and benzethonium chloride. Specific examples of the anionic surfactant that can be added to the aqueous composition of the present invention include alkyl benzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, aliphatic α-sulfomethyl ester, An alpha-olefin sulfonic acid etc. are illustrated. 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 component (A) destabilized by the component (B), preferably a nonionic surfactant; more preferably POE sorbitan Fatty acid esters, POE hydrogenated castor oils, POE-POP block copolymers; particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60, POE-POP block copolymers; particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60; most preferably polysorbate 80 is used.

  When a surfactant is blended into 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 blending components, the use of the aqueous composition, etc. Can be set appropriately. 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% with respect to 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 pharmacologically, pharmacologically (pharmaceutically) or physiologically acceptable. Glycerin, 1,3-butylene glycol, ethylene glycol, polyethylene glycol, propylene glycol, sucrose, glucose, lactose, sorbitol, xylitol, mannitol, maltitol, polydextrose, dextrin, etc. are exemplified as specific examples of polyhydric alcohol. 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, from the viewpoint of further improving the thermal stability of the component (A) destabilized by the component (B), preferred are propylene glycol and / or glycerin, and most preferable. Is glycerin.

  When a polyhydric alcohol is blended into 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 appropriately. As an example of the blending ratio of polyhydric alcohol, the total amount of polyhydric alcohol is 0.05 to 3.5 w / v%, preferably 0.1 to 3 w / v% with respect to 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 isotonicity agent. The tonicity agent which can be added to 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 tonicity agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, sodium chloride, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, acetic acid Potassium, sodium acetate, sodium hydrogencarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate and the like can be mentioned. Among these tonicity agents, potassium chloride, calcium chloride, sodium chloride and magnesium chloride are preferred. These tonicity agents may be used alone or in any combination of two or more.

  When an isotonizing agent is blended in the aqueous composition of the present invention, the blending ratio of the isotonizing agent varies depending on the type of tonicity agent used, etc., and can not be defined uniformly. For example, a ratio in 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, aspartate, aspartate and the like. These buffers may be used in combination. Preferred buffers are borate buffer, phosphate buffer, carbonate buffer, and citrate buffer. The boric acid buffer includes boric acid, boric acid alkali metal salts, boric acid alkaline earth metal salts and the like. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkaline metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates such as carbonates, alkali metal carbonates and alkaline earth metal carbonates. As a citrate buffer, citric acid, an alkali metal citrate, an alkaline earth metal citrate and the like can be mentioned. Alternatively, a borate or phosphate hydrate may be used as a borate buffer or a phosphate buffer. More specifically, boric acid or its salt (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a borate buffer; phosphoric acid or its as a phosphate buffer Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate etc.); carbonated buffer, carbonated Or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid) as a citric acid buffer Acid calcium, sodium dihydrogen citrate, disodium citrate etc.); And 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.) and the like. These buffers may be used alone or in any combination of two or more.

  When a buffer is added to the aqueous composition of the present invention, the mixing ratio of the buffer depends on the type of buffer used, the type and amount of other components, the application of the aqueous composition, etc. Although it can not be specified uniformly, for example, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.1 to 5 w / v%, more preferably to the total amount of the aqueous composition. Is a ratio of 0.2 to 2 w / v%, particularly preferably 0.2 to 1 w / v%.

  Among the above-mentioned buffers, a borate buffer is particularly preferable, and as a preferable specific example of the borate buffer, a combination of boric acid and a salt thereof; preferably boric acid and an alkali metal salt of boric acid and / or boric acid A combination of alkaline earth metal salts; 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 buffering but also pH of the aqueous composition can be adjusted, and as a result, it is combined with the component (B). It is possible to further improve the thermal stability of the component (A) in the case. One example of the method of adjusting the pH using a borate buffer is a method of adjusting each amount of the boric acid salt to adjust to a desired pH after dissolving each component in an aqueous solvent.

  In general, the heat destabilization of the component (A) brought about by the component (B) is 0.2 to 2 w / v% (especially 0.2 to 1 w) in total of the boric acid buffer in the aqueous composition. / v%) tends to be noticeable when it is contained, but according to the present invention, it is against the heat of the component (A) brought about by the component (B) while containing the borate buffer in such a blending ratio It becomes possible to significantly suppress the destabilization and to provide an aqueous composition excellent in stability. In view of the effects of the present invention, the total content of the boric acid buffer is 0.2 to 2 w / total based on the total weight of the aqueous composition as a suitable blending ratio of the boric acid buffer in the aqueous composition of the present invention. v%, preferably 0.2 to 1 w / v% can be mentioned.

  The aqueous composition of the present invention may further contain a pH adjuster. The pH adjuster 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. As specific examples of such pH adjusters, for example, hydrochloric acid, aminoethylsulfonic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diethanolamine amine, sulfuric acid, propionic acid And oxalic acid, gluconic acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone and the like. Among 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.

  The aqueous composition of the present invention can be further adjusted, if necessary, to an osmotic pressure ratio within the range acceptable to the living body. Although the appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., it is usually 0.7 to 5.0, more preferably 0.9 to 3.0, particularly preferably 1.0 to 2.0. Be Adjustment of the osmotic pressure can be performed using inorganic salts, polyhydric alcohols and the like by methods known in the art. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 0.9 w / v% sodium chloride aqueous solution based on the 15th Amended Japanese Pharmacopoeia, and the osmotic pressure is the osmotic pressure measurement method described in Japanese Pharmacopoeia (Freezing Point Drop Method) Measure according to Sodium chloride (Japanese Pharmacopoeia Standard Reagent) is dried at 500 to 650 ° C for 40 to 50 minutes, and then it is allowed to cool in a desiccator (silica gel), and its 0.900 g is accurately measured and purified. Dissolve in water, prepare exactly as 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).

  The aqueous composition of the present invention may contain various pharmacologically active ingredients and physiologically active ingredients in combination in addition to the above components, as long as the effects of the present invention are not impaired. The kind in particular of such a component is not restrict | limited, For example, an antihistamine agent, a decongestant, a disinfectant, amino acids, an antiinflammatory agent, an astringent agent etc. can be illustrated.

  In addition, various additives may be appropriately selected according to a conventional method according to the application and the form, as long as the effects of the invention are not impaired in the aqueous composition of the present invention, and one or more of them may be used in combination. It may be contained in an appropriate amount. As those additives, for example, various additives described in Pharmaceutical Additives Dictionary 2007 (edited by Japan Pharmaceutical Additives Association) can be exemplified. The type of such components is not particularly limited, and examples thereof include carriers, thickeners, preservatives, disinfectants or antibacterial agents, chelating agents, flavors or refreshing agents, and the like.

  In the present specification, an aqueous composition means a composition containing water, and usually 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 one containing 50% by weight or more. The water contained in the aqueous composition of the present invention may be pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, distilled water, normal water, purified water, sterile purified water, water for injection, distilled water for injection, etc. can be used. These definitions are based on the first revision of the Japanese Pharmacopoeia.

  The aqueous composition of the present invention is prepared by adding desired amounts of the above components (A), (B) and (C), and optionally, other compounding components, to a desired concentration, and the above pH It is prepared by adjusting to satisfy the range.

  The aqueous composition of the present invention can take various formulation forms depending on the purpose. For example, examples of the form of the aqueous composition of the present invention include solutions, semisolids (ointments etc.) and the like. Preferably it is a liquid agent.

  In addition, the aqueous composition of the present invention can be used as a preparation for pharmaceuticals and quasi-drugs, for example, ophthalmic composition, nasal composition, oral composition, eardrop composition, composition for subcutaneous administration It can be used in various applications such as products and compositions for external use on the skin. Here, the ophthalmic composition includes eye drops, artificial tears, eye wash, eye ointment, contact lens attachment solution, agent for contact lens care (contact lens disinfectant, preservative for contact lens, detergent for contact lens) , A cleaning preservative for contact lenses, etc. are included. In addition, nasal compositions include nasal drops, nasal washes and the like. The composition for oral use includes internal medicine (eg, solution, syrup, extract, etc.), oropharyngeal agent, gargle and the like. Ear drops compositions include ear drops. The composition for subcutaneous administration includes injections and the like.

  Among the above applications, the ophthalmic composition often has a very low concentration of the compounding component compared to the composition for other applications such as the oral composition, and even a slight content reduction is a major problem It could be. Among the ophthalmic compositions, particularly, the amount of the single use of eye drops is extremely small, and the effect of the reduction in the content is large. In addition, eye drops and contact lens care products are often stored at room temperature, such as a washstand, while eye drops are often carried around, so it is on the dashboard of the car during the day They are very susceptible to temperature differences because they may be placed under high temperatures such as being placed in a cage or being carried outdoors as they may be stored outdoors. Furthermore, the eye drop can be said to be a formulation form that is susceptible to external temperature changes, also in that it is generally packaged individually in small quantities. According to the aqueous composition of the present invention, it is possible to effectively exhibit the effect of improving the stability under high temperature conditions also for an ophthalmic composition (especially, eye drops) susceptible to temperature change. In view of the effects of the present invention, an ophthalmic composition can be mentioned as a suitable example of the aqueous composition of the present invention, and an eye drop can be mentioned as a particularly suitable example.

  The aqueous composition of the present invention is provided in any container. The container for containing the aqueous composition of the present invention is not particularly limited. For example, it may be made of glass or plastic. Moreover, the container which accommodates the aqueous composition of this invention may be a transparent container which can visually recognize the inside of a container, and may be an opaque container where visual recognition of the inside of the container is difficult. Here, "a transparent container" includes both a colorless transparent container and a colored transparent container. According to the present invention, although it is an aqueous composition comprising ketotifen and / or a salt thereof and pranoprofen and / or a salt thereof, it is stable even when exposed to heat, and yellowing of the aqueous composition does not easily occur. Since the concern of the change in appearance properties is eliminated, it is possible to store and provide in a transparent container. In view of this point, a transparent container can be mentioned as a suitable example of the container which accommodates the aqueous composition of the present invention.

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

2. Method for Improving the Heat Stability of Ketotifen and / or Its Salt As described above, the heat destabilization of the above component (A) caused by the coexistence with the above component (B) in the aqueous composition is the above (C). It can be controlled by blending the components and adjusting the pH of the aqueous composition to 6.5 or less.

  Therefore, the present invention provides, from still another aspect, an aqueous composition selected from the group consisting of (A) at least one selected from the group consisting of ketotifen and its salt, and (B) pranoprofen and its salt. Heat of ketotifen and / or a salt thereof in an aqueous composition, characterized in that (C) dibutyl hydroxytoluene is blended together with at least one selected and the pH of the aqueous composition is set to 6.5 or less It also provides a way to improve the stability against

  In the method, the types and blending ratios of the components (A) to (C), the types and blending ratios of the components to be blended, the pH of the aqueous composition, the formulation form and use of the aqueous composition, etc. The same as the above-mentioned "1. aqueous composition".

3. An agent for improving the thermal stability of ketotifen and / or a salt thereof and its use , and as described above, an aqueous composition containing the above-mentioned component (C) and having a pH of 6.5 or less is It is possible to suppress the heat destabilization of the component (A) caused by the coexistence with the component B).

  Therefore, in still another aspect, the present invention provides (A) at least one member selected from the group consisting of ketotifen and its salt, and (B) at least one member selected from the group consisting of pranoprofen and its salt. And an agent for improving the heat stability of the component (A), which is used when an aqueous composition is made to coexist, which comprises (C) dibutylhydroxytoluene, and the final of the aqueous composition. The present invention provides a thermal stability improver comprising an aqueous base adjusted to have a basic pH of 6.5 or less. Furthermore, the present invention comprises (A) at least one selected from the group consisting of ketotifen and its salt, and (B) at least one selected from the group consisting of pranoprofen and its salt ( (C) In order to produce an aqueous composition in which the thermal stability of the component A is improved, the composition contains (C) dibutylhydroxytoluene and the final pH of the aqueous composition is 6.5 or less It also provides 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 combines the components (A) and (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 above “1. Aqueous composition” column, and the component (A) is also used. The component (B) may not contain any component (for example, various pharmacologically active components, physiologically active components, additives, etc.). In addition, “the final pH of the aqueous composition was adjusted to be 6.5 or less” means that the above aqueous base contains the (A) component, the (B) component, and the optional one. It means that the pH of the aqueous composition obtained by blending the components is designed to be 6.5 or less.

  In these inventions, the types and blending proportions of the components (A) to (C) used, the types and blending proportions of the other components to be blended, the pH of the aqueous composition, the formulation form and use of the aqueous composition, etc. It is the same as that of said "1. aqueous composition".

  Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited by these examples.

Test Example 1: Thermal Stability Evaluation (1)
The test solutions (Test solutions 1-4) shown in Table 1 below were prepared to evaluate the stability to heat of ketotifen fumarate. It is known that ketotifen fumarate causes yellowing of the preparation when it becomes unstable. In this test example, the thermal stability of ketotifen fumarate was evaluated by examining the degree of yellowing of the test solution. Specific experimental procedures 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 3 types of pH (specifically, a solution of pH 6.2, pH 7.0, and pH 7.5) by adjusting the compounding quantity of borax appropriately. Each test solution immediately after preparation was visually confirmed to be colorless and transparent. Thereafter, each test solution was filled in 8 ml into a 10 ml glass vial, sealed, and stored at 70 ° C. for 1 week under light shielding. One week later, measurement of absorbance at 405 nm (A405) was performed for each test solution. As a blank group, the absorbance value of A405 of purified water was also measured at the same time. The degree of yellowing of each test solution was examined by calculating the value obtained by subtracting the absorbance value of A405 of the blank group from the absorbance value of A405 of each test solution.

  The results are shown in FIG. As apparent from FIG. 1, in the test solution 1 containing ketotifen fumarate but not containing pranoprofen, yellowing was not confirmed at pH 6.2, but when pH reached 7.0 or more. It was confirmed to cause significant yellowing. And, in the test solution 2 containing pranoprofen together with ketotifen fumarate, significant yellowing of a clear level is visually apparent at any pH, and it is clear that the degree of yellowing will be a problem in formulation Met. In addition, it was found that even when dibutyl hydroxytoluene was further blended, when the pH was 7.0 or more, the suppression effect against yellowing was hardly observed or conversely significantly deteriorated (Test solution 4). Further, although not shown in FIG. 1, yellowing was not observed at all at any pH in the test solution 3 containing pranoprofen but not containing ketotifen fumarate.

  On the other hand, surprisingly, in the test solution 4 in which dibutyl hydroxytoluene was added in addition to ketotifen fumarate and pranoprofen, and the pH was further adjusted to 6.2, the absorbance value of the A405 of the test solution decreased remarkably Also, even when visually observed, yellowing was not recognized at all. Therefore, according to the present invention, it is possible to obtain an aqueous composition which is extremely stable to heat and which is pharmaceutically excellent while coexisting ketotifen and / or a salt thereof with pranoprofen and / or a salt thereof. It became clear.

Test Example 2: Thermal Stability Evaluation (2)
Each test solution was adjusted according to Table 2 below to evaluate the heat stability of ketotifen fumarate. Specific experimental procedures 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 of 2 types of pH (specifically, pH 6.5 and 7.0) by adjusting the compounding quantity of borax suitably. Moreover, also about each test liquid of this test example, it confirmed visually that all the test liquids immediately after preparation are colorless and transparent. Thereafter, each test solution was filled in 8 ml into a 10 ml glass vial, sealed, and stored at 70 ° C. for 1 week under light shielding. One week later, measurement of absorbance at 405 nm (A405) was performed for each test solution. As a blank group, the absorbance value of A405 of purified water was also measured at the same time. The degree of yellowing of each test solution was examined by calculating the value obtained by subtracting the absorbance value of A405 of the blank group from the absorbance value of A405 of each test solution.

  The results are shown in FIG. As is clear from FIG. 2, in the test solution 5 containing ketotifen fumarate but not containing pranoprofen, significant yellowing occurred when the pH was 7.0, as in Test Example 1 above. And, in the test solution 6 containing pranoprofen together with ketotifen fumarate, significant yellowing at a visible level was confirmed at any pH. Moreover, in the test liquid 7 which further mix | blended dibutyl hydroxytoluene, the suppression effect with respect to yellowing was not recognized at all at pH 7.0. On the other hand, in addition to ketotifen fumarate and pranoprofen, in addition to dibutyl hydroxytoluene, in the test solution 7 with a pH of 6.5, the absorbance value of the A405 of the test solution is extremely low, and it is yellowish visually Did not recognize at all.

Test Example 3: Thermal Stability Evaluation (3)
Each test solution described in Table 3 below was prepared to have two kinds of pH (specifically, pH 6.2 and 7.0) by adjusting the amount of borax appropriately. Subsequently, the heat stability of fumaric acid ketotifen was evaluated in the same manner as in Test Example 2 except that the filling amount in the glass head space vial was changed from 8 ml to 5 ml for each test solution.

  The results are shown in FIG. As is clear from FIG. 3, even when the compounding amount of ketotifen fumarate was 0.0345 w / v%, the same tendency as in the above-mentioned Test Example 1-2 was observed. That is, in the case of pH 7.0, the effect of suppressing yellowing was not observed at all even when dibutylhydroxytoluene was further added together with ketotifen fumarate and pranoprofen, but in the case of pH 6.2, fumar It was found that the yellowing caused by the coexistence of the acid ketotifen 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 to have a predetermined pH by appropriately adjusting the amount of borax blended, and a method similar to the above-mentioned Test Example 2 using a glass head space vial The heat stability of ketotifen fumarate was evaluated for each test solution.

  The results are shown in FIG. Also from this result, as in the case of Test Example 1-3 above, significant yellowing occurs even when dibutyl hydroxytoluene is further blended with ketotifen fumarate and pranoprofen at pH 7.0. It confirmed (test liquid 13). On the other hand, even when ketotifen fumarate and pranoprofen were made to coexist, it was found that a remarkable yellowing inhibitory effect was obtained when the pH was made to be 6.5 or less after adding dibutylhydroxytoluene. (Test solution 11, 12). In addition, when polysorbate 80 is used as a nonionic surfactant (dilution solution 12) under conditions of containing dibutylhydroxytoluene in addition to ketotifen fumarate and pranoprofen and having a pH of 6.5 (test solution 12) When the oil 60 was used (Test solution 14), both showed remarkable yellowing suppression effects.

  In addition, when dibutyl hydroxytoluene is further added to fumaric acid ketotifen and pranoprofen and a polyhydric alcohol (glycerin or propylene glycol) is contained under the condition of pH 6.5 (test solutions 12 and 16) The yellowing suppression effect was enhanced as compared with the case where the alcohol was not contained (Test solution 15). In particular, when glycerin was contained as a polyhydric alcohol (Test solution 12), the yellowing suppression effect was significantly improved.

(General consideration)
From the above results, it is possible to significantly suppress the heat instability of ketotifen fumarate caused by pranoprofen by blending dibutylhydroxytoluene and setting the pH of the aqueous composition to 6.5 or less, and thus high temperature It has been found that a pharmaceutically excellent aqueous composition is obtained which does not cause yellowing even under conditions. In addition, in order to obtain the thermal stability improving effect of ketotifen fumarate much more remarkably, it was also recognized that it is beneficial to combine glycerin as a polyhydric alcohol.

Formulation Example: According to the formulation described in Table 5, eye drops (Examples 1-12) are prepared.

Claims (1)

(A) at least one member selected from the group consisting of ketotifen and its salt, (B) at least one member selected from the group consisting of pranoprofen and its salt, and (C) dibutyl hydroxytoluene And (A) at least one selected from the group consisting of ketotifen and a salt thereof is 0.01 to 1 w / v% with respect to the total amount of the aqueous composition, and the pH is 6.5 or less An aqueous composition characterized by being.

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