Aqueous liquid preparation

Abstract

To provide formulation technology concerning an aqueous liquid preparation comprising brinzolamide and / or a salt thereof.SOLUTION: An aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08-0.12 w / v% brimonidine tartrate, and timolol and / or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous liquid preparation having improved photostability of brinzolamide and / or a salt thereof, and also to an aqueous suspension preparation having improved stability of suspended particles of brinzolamide and / or a salt thereof. [Background technology]

[0002] Brinzolamide is known as a carbonic anhydrase inhibitor, which acts to reduce intraocular pressure by suppressing the production of aqueous humor, and is used to treat glaucoma and ocular hypertension.

[0003] In recent years, in order to enhance the therapeutic effect of glaucoma and ocular hypertension, preparations using brinzolamide and / or its salts in combination with other active ingredients have been proposed. For example, Patent Document 1 reports that ocular diseases such as glaucoma can be effectively treated by administering brimonidine and brinzolamide simultaneously or separately. In addition, Patent Document 2 discloses a multi-dose ophthalmic composition containing brimonidine tartrate and brinzolamide. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 6,316,441 [Patent Document 2] International Publication No. 2010 / 148190 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a formulation technology relating to an aqueous liquid preparation containing brinzolamide and / or a salt thereof. [Means for solving the problem]

[0006] The present inventors have found that an aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and timolol and / or a salt thereof improves the photostability of brinzolamide and / or a salt thereof. Furthermore, the present inventors have found that when the aqueous liquid preparation is an aqueous suspension in which brinzolamide and / or a salt thereof exists as suspended particles, the stability of the suspended particles improves.

[0007] The present inventors have also found that an aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and carteolol and / or a salt thereof improves the photostability of brinzolamide and / or a salt thereof. Furthermore, the present inventors have found that when the aqueous liquid preparation is an aqueous suspension in which brinzolamide and / or a salt thereof exists as suspended particles, the stability of the suspended particles improves.

[0008] Furthermore, the present inventors have found that an aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and a β-blocker improves the photostability of brinzolamide and / or a salt thereof. Furthermore, the present inventors have found that when the aqueous liquid preparation is an aqueous suspension in which brinzolamide and / or a salt thereof exists as suspended particles, the stability of the suspended particles improves.

[0009] The present invention was completed based on these findings and through further investigation.

[0010] As one embodiment of the present invention, the following aqueous liquid formulation and method are provided. Item 1-1. An aqueous liquid preparation comprising brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and timolol and / or a salt thereof. Item 1-2. The aqueous liquid preparation according to Item 1-1, which is an aqueous suspension. Item 1-3. The aqueous liquid preparation according to Item 1-1 or 1-2, wherein the concentration of the brimonidine tartrate is 0.1 w / v %. Item 1-4. The aqueous liquid preparation according to any one of Items 1-1 to 1-3, wherein the brinzolamide and / or a salt thereof is brinzolamide. Item 1-5. The aqueous liquid preparation according to any one of Items 1-1 to 1-4, wherein the concentration of the brinzolamide and / or a salt thereof is 0.1 to 3 w / v %. Item 1-6. The aqueous liquid preparation according to any one of Items 1-1 to 1-5, wherein the concentration of the brinzolamide and / or a salt thereof is 1 w / v %. Item 1-7. The aqueous liquid preparation according to any one of Items 1-1 to 1-6, wherein the timolol and / or a salt thereof is timolol maleate. Item 1-8. The aqueous liquid preparation according to any one of Items 1-1 to 1-7, wherein the concentration of the timolol and / or a salt thereof is 0.1 to 1.5 w / v %. Item 1-9. The aqueous liquid preparation according to any one of Items 1-1 to 1-8, wherein the concentration of the timolol and / or a salt thereof is 0.68 w / v %. Item 1-10. The aqueous liquid preparation according to any one of Items 1-1 to 1-9, further comprising sodium chloride. Item 1-11. The aqueous liquid preparation according to Item 1-10, wherein the concentration of the sodium chloride is 0.01 to 0.2 w / v %. Item 1-12. The aqueous liquid preparation according to Item 1-10 or 1-11, wherein the concentration of the sodium chloride is 0.02 to 0.1 w / v %. Item 1-13. The aqueous liquid preparation according to Item 1-10 or 1-11, wherein the concentration of the sodium chloride is 0.08 to 0.12 w / v %. Item 1-14. An aqueous liquid preparation comprising brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% of brimonidine tartrate, timolol and / or a salt thereof, and 0.01 to 0.2 w / v% of sodium chloride. Item 1-15. The aqueous liquid preparation according to any one of Items 1-1 to 1-14, further comprising benzalkonium chloride. Item 1-16. The aqueous liquid preparation according to Item 1-15, wherein the concentration of the benzalkonium chloride is 0.0001 to 0.01 w / v %. Item 1-17. The aqueous liquid preparation according to any one of Items 1-1 to 1-16, further comprising a thickening agent. Item 1-18. The aqueous liquid preparation according to Item 1-17, wherein the thickening agent is a carboxyvinyl polymer. Item 1-19. The aqueous liquid preparation according to Item 1-17 or 1-18, wherein the concentration of the thickening agent is 0.1 to 1 w / v %. Item 1-20. The aqueous liquid preparation according to any one of Items 1-1 to 1-19, further comprising a nonionic surfactant. Item 1-21. The aqueous liquid preparation according to Item 1-20, wherein the nonionic surfactant is tyloxapol. Item 1-22. The aqueous liquid preparation according to Item 1-20 or 1-21, wherein the concentration of the nonionic surfactant is 0.005 to 0.1 w / v %. Item 1-23. The aqueous liquid preparation according to any one of Items 1-1 to 1-22, further comprising a buffer. Item 1-24. The aqueous liquid preparation according to Item 1-23, wherein the buffer is boric acid and / or a salt thereof. Item 1-25. The aqueous liquid preparation according to Item 1-23, wherein the buffer is boric acid. Item 1-26. The aqueous liquid preparation according to any one of Items 1-23 to 1-25, wherein the concentration of the buffer is 0.01 to 2 w / v %. Item 1-27. The aqueous liquid preparation according to any one of Items 1-1 to 1-26, further comprising a chelating agent. Item 1-28. The aqueous liquid preparation according to Item 1-27, wherein the chelating agent is citric acid and / or a salt thereof. Item 1-29. The aqueous liquid preparation according to Item 1-27, wherein the chelating agent is edetic acid and / or a salt thereof. Item 1-30. The aqueous liquid preparation according to any one of Items 1-27 to 1-29, wherein the concentration of the chelating agent is 0.001 to 0.2 w / v %. Item 1-31. The aqueous liquid preparation according to any one of Items 1-1 to 1-30, which has a pH of 4 to 8. Item 1-32. The aqueous liquid preparation according to any one of Items 1-1 to 1-31, which is contained in a transparent container. Item 1-33. The aqueous liquid preparation according to any one of Items 1-1 to 1-32, which is an eye drop. Item 1-34. The aqueous liquid preparation according to any one of Items 1-1 to 1-33, which is used for the treatment of glaucoma or ocular hypertension. Item 1-35. The aqueous liquid preparation according to any one of Items 1-1 to 1-34, which has improved photostability. Item 1-36. The aqueous liquid preparation according to any one of Items 1-1 to 1-35, which has improved thermal stability. Item 1-37. The aqueous liquid preparation according to any one of Items 1-1 to 1-36, which has improved photostability and improved thermal stability. Item 1-38. The aqueous liquid preparation according to Item 1-35 or 1-37, wherein the improved photostability indicates that the remaining rate of brinzolamide and / or a salt thereof after exposure to light of total near-ultraviolet radiation energy is about 95% or more. Item 1-39. The aqueous liquid preparation according to Item 1-35 or 1-37, wherein the improved photostability indicates that the amount of RRT0.1 impurity formed after exposure to light of total near-ultraviolet radiation energy is 0.5% or less. Item 1-40. The aqueous liquid preparation according to any one of Items 1-35 and 1-37, wherein the improved photostability indicates that the residual rate of brinzolamide and / or a salt thereof after exposure to light of total near-ultraviolet radiation energy is about 95% or more, and the amount of RRT0.1 impurity formed after exposure to light of total near-ultraviolet radiation energy is 0.5% or less. Item 1-41. The light intensity of the total near ultraviolet radiation energy is 200 W·h / m 2 The aqueous liquid preparation according to any one of Items 1-38 to 1-40, wherein Item 1-42. The aqueous liquid preparation according to Item 1-36 or 1-37, wherein the improved thermal stability is indicated by a maximum particle size of suspended particles of 15 μm or less after storage at 60° C. for 4 weeks. Item 1-43. The aqueous liquid preparation according to Item 1-36 or 1-37, wherein the improved thermal stability is indicated by a maximum particle size of suspended particles of 10 μm or less after storage at 60° C. for 4 weeks. Item 1-44. A composition comprising brinzolamide, brimonidine tartrate, timolol maleate, benzalkonium chloride, sodium chloride, a carboxyvinyl polymer, tyloxapol, and boric acid; The concentration of the brinzolamide is 0.1 to 3 w / v %, The concentration of the brimonidine tartrate is 0.1 w / v%; The concentration of the timolol maleate is 0.1 to 1.5 w / v%, The concentration of the benzalkonium chloride is 0.0001 to 0.01 w / v%, The concentration of the sodium chloride is 0.01 to 0.2 w / v%, The concentration of the carboxyvinyl polymer is 0.1 to 1 w / v %, The concentration of the tyloxapol is 0.005 to 0.1 w / v%, The concentration of the boric acid is 0.01 to 2 w / v %, An aqueous suspension having a pH of 4 to 8. Item 1-45. A method for photostabilizing brinzolamide and / or a salt thereof, comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous liquid preparation. Item 1-46. A method for suppressing a decrease in the content of brinzolamide and / or a salt thereof due to exposure to light, comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous liquid preparation. Item 1-47. A method for suppressing the production of an RRT0.1 impurity due to light exposure, comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous liquid preparation. Item 1-48. A method for stabilizing suspended particles in an aqueous suspension containing brimonidine and / or a salt thereof, the method comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% of brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous suspension. Item 1-49. A method for suppressing an increase in particle size of suspended particles in an aqueous suspension containing brimonidine and / or a salt thereof, the method comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % of brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous suspension.

[0011] In addition, as another embodiment of the present invention, there are provided the following aqueous liquid preparations and methods. Item 2-1. An aqueous liquid preparation comprising brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and carteolol and / or a salt thereof. Item 2-2. The aqueous liquid preparation according to Item 2-1, which is an aqueous suspension. Item 2-3. The aqueous liquid preparation according to Item 2-1 or 2-2, wherein the concentration of the brimonidine tartrate is 0.1 w / v %. Item 2-4. The aqueous liquid preparation according to Items 2-1 to 2-3, wherein the brinzolamide and / or a salt thereof is brinzolamide. Item 2-5. The aqueous liquid preparation according to any one of Items 2-1 to 2-4, wherein the concentration of the brinzolamide and / or a salt thereof is 0.1 to 3 w / v %. Item 2-6. The aqueous liquid preparation according to any one of Items 2-1 to 2-5, wherein the concentration of the brinzolamide and / or a salt thereof is 1 w / v %. Item 2-7. The aqueous liquid preparation according to any one of Items 2-1 to 2-6, wherein the carteolol and / or a salt thereof is carteolol hydrochloride. Item 2-8. The aqueous liquid preparation according to any one of Items 2-1 to 2-7, wherein the concentration of the carteolol and / or a salt thereof is 0.5 to 1.5 w / v %. Item 2-9. The aqueous liquid preparation according to any one of Items 2-1 to 2-8, wherein the concentration of the carteolol and / or a salt thereof is 1 w / v %. Item 2-10. The aqueous liquid preparation according to any one of Items 2-1 to 2-9, further comprising sodium chloride. Item 2-11. The aqueous liquid preparation according to Item 2-10, wherein the concentration of the sodium chloride is 0.01 to 0.2 w / v %. Item 2-12. The aqueous liquid preparation according to Item 2-10 or 2-11, wherein the concentration of the sodium chloride is 0.02 to 0.1 w / v %. Item 2-13. The aqueous liquid preparation according to Item 2-10 or 2-11, wherein the concentration of the sodium chloride is 0.08 to 0.12 w / v %. Item 2-14. The aqueous liquid preparation according to any one of Items 2-1 to 2-13, further comprising benzalkonium chloride. Item 2-15. The aqueous liquid preparation according to Item 2-14, wherein the concentration of the benzalkonium chloride is 0.0001 to 0.01 w / v %. Item 2-16. The aqueous liquid preparation according to any one of Items 2-1 to 2-15, further comprising a thickening agent. Item 2-17. The aqueous liquid preparation according to Item 2-16, wherein the thickener is a carboxyvinyl polymer. Item 2-18. The aqueous liquid preparation according to Item 2-16 or 2-17, wherein the concentration of the thickening agent is 0.1 to 1 w / v %. Item 2-19. The aqueous liquid preparation according to any one of Items 2-1 to 2-18, further comprising a nonionic surfactant. Item 2-20. The aqueous liquid preparation according to Item 2-19, wherein the nonionic surfactant is tyloxapol. Item 2-21. The aqueous liquid preparation according to Item 2-19 or 2-20, wherein the concentration of the nonionic surfactant is 0.005 to 0.1 w / v %. Item 2-22. The aqueous liquid preparation according to any one of Items 2-1 to 2-21, further comprising a buffer. Item 2-23. The aqueous liquid preparation according to Item 2-22, wherein the buffer is boric acid and / or a salt thereof. Item 2-24. The aqueous liquid preparation according to Item 2-22, wherein the buffer is boric acid. Item 2-25. The aqueous liquid preparation according to any one of Items 2-22 to 2-24, wherein the concentration of the buffer is 0.01 to 2 w / v %. Item 2-26. The aqueous liquid preparation according to any one of Items 2-1 to 2-25, further comprising a chelating agent. Item 2-27. The aqueous liquid preparation according to Item 2-26, wherein the chelating agent is citric acid and / or a salt thereof. Item 2-28. The aqueous liquid preparation according to Item 2-26, wherein the chelating agent is edetic acid and / or a salt thereof. Item 2-29. The aqueous liquid preparation according to any one of Items 2-26 to 2-28, wherein the concentration of the chelating agent is 0.001 to 0.2 w / v %. Item 2-30. The aqueous liquid preparation according to any one of Items 2-1 to 2-29, which has a pH of 4 to 8. Item 2-31. The aqueous liquid preparation according to any one of Items 2-1 to 2-30, which is filled in a transparent container. Item 2-32. The aqueous liquid preparation according to any one of Items 2-1 to 2-31, which is an eye drop. Item 2-33. The aqueous liquid preparation according to any one of Items 2-1 to 2-32, which is used for the treatment of glaucoma or ocular hypertension. Item 2-34. The aqueous liquid preparation according to any one of Items 2-1 to 2-33, which has improved photostability. Item 2-35. The aqueous liquid preparation according to any one of Items 2-1 to 2-34, which has improved thermal stability. Item 2-36. The aqueous liquid preparation according to any one of Items 2-1 to 2-35, which has improved photostability and improved thermal stability. Item 2-37. The aqueous liquid preparation according to Item 2-34 or 2-36, wherein the improved photostability indicates that the remaining rate of brinzolamide and / or a salt thereof after exposure to light of total near-ultraviolet radiation energy is about 95% or more. Item 2-38. The aqueous liquid preparation according to Item 2-34 or 2-36, wherein the improved photostability indicates that the amount of RRT0.1 impurity formed after exposure to light of total near-ultraviolet radiation energy is 0.5% or less. Item 2-39. The aqueous liquid preparation according to Item 2-34 or 2-36, wherein the improved photostability indicates that the residual rate of brinzolamide and / or a salt thereof after exposure to light of total near-ultraviolet radiation energy is about 95% or more, and the amount of RRT0.1 impurity formed after exposure to light of total near-ultraviolet radiation energy is 0.5% or less. Item 2-40. The light intensity of the total near-ultraviolet radiant energy is 200 W·h / m 2 The aqueous liquid preparation according to any one of Items 2-37 to 2-39, wherein Item 2-41. The aqueous liquid preparation according to Item 2-35 or 2-36, wherein the improved thermal stability is demonstrated by the maximum particle size of suspended particles being 15 μm or less after storage at 60° C. for 4 weeks. Item 2-42. The aqueous liquid preparation according to Item 2-35 or 2-36, wherein the improved thermal stability is demonstrated by the maximum particle size of suspended particles being 10 μm or less after storage at 60° C. for 4 weeks. Item 2-43. A composition comprising brinzolamide, brimonidine tartrate, carteolol hydrochloride, benzalkonium chloride, sodium chloride, a carboxyvinyl polymer, tyloxapol, and boric acid; The concentration of the brinzolamide is 0.1 to 3 w / v %, The concentration of the brimonidine tartrate is 0.1 w / v%; The concentration of the carteolol hydrochloride is 0.5 to 1.5 w / v%, The concentration of the benzalkonium chloride is 0.0001 to 0.01 w / v%, The concentration of the sodium chloride is 0.01 to 0.2 w / v%, The concentration of the carboxyvinyl polymer is 0.1 to 1 w / v %, The concentration of the tyloxapol is 0.005 to 0.1 w / v%, The concentration of the boric acid is 0.01 to 2 w / v %, An aqueous suspension having a pH of 4 to 8. Item 2-44. A method for photostabilizing brinzolamide and / or a salt thereof, comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and carteolol and / or a salt thereof to obtain an aqueous liquid preparation. Item 2-45. A method for suppressing a decrease in the content of brinzolamide and / or a salt thereof due to exposure to light, comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and carteolol and / or a salt thereof to obtain an aqueous liquid preparation. Item 2-46. A method for stabilizing suspended particles in an aqueous suspension containing brimonidine and / or a salt thereof, the method comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and carteolol and / or a salt thereof to obtain an aqueous suspension. Item 2-47. A method for stabilizing suspended particles in an aqueous suspension containing brimonidine and / or a salt thereof, the method comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % of brimonidine tartrate, and carteolol and / or a salt thereof to obtain an aqueous suspension, and suppressing an increase in particle size of the suspended particles.

[0012] Furthermore, as still another embodiment of the present invention, there are provided the following aqueous liquid preparations and methods. Item 3-1. An aqueous liquid preparation comprising brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and a β-blocker. Item 3-2. The aqueous liquid preparation according to Item 3-1, which is an aqueous suspension. Item 3-3. The aqueous liquid preparation according to Item 3-1 or 3-2, wherein the concentration of the brimonidine tartrate is 0.1 w / v %. Item 3-4. The aqueous liquid preparation according to any one of Items 3-1 to 3-3, wherein the brinzolamide and / or a salt thereof is brinzolamide. Item 3-5. The aqueous liquid preparation according to any one of Items 3-1 to 3-4, wherein the concentration of the brinzolamide and / or a salt thereof is 0.1 to 3 w / v %. Item 3-6. The aqueous liquid preparation according to any one of Items 3-1 to 3-5, wherein the concentration of the brinzolamide and / or a salt thereof is 1 w / v %. Item 3-7. The aqueous liquid preparation according to any one of Items 3-1 to 3-6, wherein the β-blocker is at least one selected from the group consisting of timolol, carteolol, befunolol, nipradilol, betaxol, levobunolol, and metipranolol. Item 3-8. The aqueous liquid preparation according to any one of Items 3-1 to 3-7, wherein the β-blocker is carteolol and / or a salt thereof. Item 3-9. The aqueous liquid preparation according to any one of Items 3-1 to 3-7, wherein the β-blocker is carteolol hydrochloride. Item 3-10. The aqueous liquid preparation according to any one of Items 3-1 to 3-9, wherein the concentration of the β-blocker is 0.1 to 1.5 w / v %. Item 3-11. The aqueous liquid preparation according to Item 3-8 or 3-9, wherein the concentration of the carteolol and / or a salt thereof is 0.8 to 1.2 w / v %. Item 3-12. The aqueous liquid preparation according to any one of Items 3-1 to 3-11, further comprising sodium chloride. Item 3-13. The aqueous liquid preparation according to Item 3-12, wherein the concentration of the sodium chloride is 0.01 to 0.2 w / v %. Item 3-14. The aqueous liquid preparation according to Item 3-12, wherein the concentration of the sodium chloride is 0.02 to 0.1 w / v %. Item 3-15. The aqueous suspension according to Item 3-12 or 3-13, wherein the concentration of the sodium chloride is 0.08 to 0.12 w / v %. Item 3-16. An aqueous liquid preparation comprising brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % of brimonidine tartrate, a β-blocker, and 0.01 to 0.2 w / v % of sodium chloride. Item 3-17. The aqueous liquid preparation according to any one of Items 3-1 to 3-16, further comprising benzalkonium chloride. Item 3-18. The aqueous liquid preparation according to Item 3-17, wherein the concentration of the benzalkonium chloride is 0.0001 to 0.01 w / v %. Item 3-19. The aqueous liquid preparation according to any one of Items 3-1 to 3-18, further comprising a thickening agent. Item 3-20. The aqueous liquid preparation according to Item 3-19, wherein the thickener is a carboxyvinyl polymer. Item 3-21. The aqueous liquid preparation according to Item 3-19 or 3-20, wherein the concentration of the thickening agent is 0.1 to 1 w / v %. Item 3-22. The aqueous liquid preparation according to any one of Items 3-1 to 3-21, further comprising a nonionic surfactant. Item 3-23. The aqueous liquid preparation according to Item 3-22, wherein the nonionic surfactant is tyloxapol. Item 3-24. The aqueous liquid preparation according to Item 3-22 or 3-23, wherein the concentration of the nonionic surfactant is 0.005 to 0.1 w / v %. Item 3-25. The aqueous liquid preparation according to any one of Items 3-1 to 3-24, further comprising a buffer. Item 3-26. The aqueous liquid preparation according to Item 3-25, wherein the buffer is boric acid and / or a salt thereof. Item 3-27. The aqueous liquid preparation according to Item 3-25, wherein the buffer is boric acid. Item 3-28. The aqueous liquid preparation according to any one of Items 3-25 to 3-27, wherein the concentration of the buffer is 0.01 to 2 w / v %. Item 3-29. The aqueous liquid preparation according to any one of Items 3-1 to 3-28, further comprising a chelating agent. Item 3-30. The aqueous liquid preparation according to Item 3-29, wherein the chelating agent is citric acid and / or a salt thereof. Item 3-31. The aqueous liquid preparation according to Item 3-29, wherein the chelating agent is edetic acid and / or a salt thereof. Item 3-32. The aqueous liquid preparation according to any one of Items 3-29 to 3-31, wherein the concentration of the chelating agent is 0.001 to 0.2 w / v %. Item 3-33. The aqueous liquid preparation according to any one of Items 3-1 to 3-32, which has a pH of 4 to 8. Item 3-34. The aqueous liquid preparation according to any one of Items 3-1 to 3-33, which is filled in a transparent container. Item 3-35. The aqueous liquid preparation according to any one of Items 3-1 to 3-34, which is an eye drop. Item 3-36. The aqueous liquid preparation according to any one of Items 3-1 to 3-35, which is used for the treatment of glaucoma or ocular hypertension. Item 3-37. The aqueous liquid preparation according to any one of Items 3-1 to 3-36, which has improved photostability. Item 3-38. The aqueous liquid preparation according to any one of Items 3-1 to 3-37, which has improved thermal stability. Item 3-39. The aqueous liquid preparation according to any one of Items 3-1 to 3-38, which has improved photostability and improved thermal stability. Item 3-40. The aqueous liquid preparation according to Item 3-37 or 3-39, wherein the improved photostability indicates that the remaining rate of brinzolamide and / or a salt thereof after exposure to light of total near-ultraviolet radiation energy is about 95% or more. Item 3-41. The aqueous liquid preparation according to Item 3-37 or 3-39, wherein the improved photostability indicates that the amount of RRT0.1 impurity formed after exposure to light of total near-ultraviolet radiation energy is 0.5% or less. Item 3-42. The aqueous liquid preparation according to Item 3-37 or 3-39, wherein the improved photostability indicates that the residual rate of brinzolamide and / or a salt thereof after exposure to light of total near-ultraviolet radiation energy is about 95% or more, and the amount of RRT0.1 impurity formed after exposure to light of total near-ultraviolet radiation energy is 0.5% or less. Item 3-43. The light intensity of the total near-ultraviolet radiant energy is 200 W·h / m 2 The aqueous liquid preparation according to any one of Items 3-40 to 3-42, wherein Item 3-44. The aqueous liquid preparation according to Item 3-38 or 3-39, wherein the improved thermal stability is indicated by a maximum particle size of suspended particles of 15 μm or less after storage at 60° C. for 4 weeks. Item 3-45. The aqueous liquid preparation according to Item 3-38 or 3-39, wherein the improved thermal stability is indicated by a maximum particle size of suspended particles of 10 μm or less after storage at 60° C. for 4 weeks. Item 3-46. A composition comprising brinzolamide, brimonidine tartrate, a beta-blocker, benzalkonium chloride, sodium chloride, a carboxyvinyl polymer, tyloxapol, and boric acid; The concentration of the brinzolamide is 0.1 to 3 w / v %, The concentration of the brimonidine tartrate is 0.1 w / v%; The concentration of the β-blocker is 0.1 to 1.5 w / v%, The concentration of the benzalkonium chloride is 0.0001 to 0.01 w / v%, The concentration of the sodium chloride is 0.01 to 0.2 w / v%, The concentration of the carboxyvinyl polymer is 0.1 to 1 w / v %, The concentration of the tyloxapol is 0.005 to 0.1 w / v%, The concentration of the boric acid is 0.01 to 2 w / v %, An aqueous suspension having a pH of 4 to 8. Item 3-47. A method for photostabilizing brinzolamide and / or a salt thereof, comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and a β-blocker to obtain an aqueous liquid preparation. Item 3-48. A method for suppressing a decrease in the content of brinzolamide and / or a salt thereof due to exposure to light, comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and a β-blocker to obtain an aqueous liquid preparation. Item 3-49. A method for suppressing the production of an RRT0.1 impurity due to light exposure, comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and a β-blocker to obtain an aqueous liquid preparation. Item 3-50. A method for stabilizing suspended particles in an aqueous suspension containing brimonidine and / or a salt thereof, the method comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and a β-blocker to obtain an aqueous suspension. Item 3-51. A method for suppressing an increase in particle size of suspended particles in an aqueous suspension containing brimonidine and / or a salt thereof, the method comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and a β-blocker to obtain an aqueous suspension. [Effects of the Invention]

[0013] In one embodiment of the present invention, an aqueous liquid preparation contains brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and timolol and / or a salt thereof, thereby suppressing a decrease in the brinzolamide content and the production of the RRT0.1 impurity even when exposed to light, and improving the photostability of brinzolamide and / or a salt thereof. Furthermore, when the aqueous liquid preparation is an aqueous suspension containing brinzolamide and / or a salt thereof as suspended particles, it is possible to suppress an increase in the particle size of the suspended particles over time, and improve the stability of the suspended particles.

[0014] In another embodiment of the present invention, an aqueous liquid preparation contains brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and carteolol and / or a salt thereof, thereby preventing a decrease in the brinzolamide content and preventing the formation of the RRT0.1 impurity even when exposed to light, thereby improving the photostability of brinzolamide and / or a salt thereof. Furthermore, when the aqueous liquid preparation is an aqueous suspension containing brinzolamide and / or a salt thereof as suspended particles, it is possible to prevent an increase in the particle size of the suspended particles of brinzolamide and / or a salt thereof over time, thereby improving the stability of the suspended particles.

[0015] In yet another embodiment of the present invention, an aqueous liquid preparation contains brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and a β-blocker, thereby preventing a decrease in the brinzolamide content and preventing the formation of the RRT0.1 impurity even when exposed to light, thereby improving the photostability of brinzolamide and / or a salt thereof. Furthermore, when the aqueous liquid preparation is an aqueous suspension containing brinzolamide and / or a salt thereof as suspended particles, it is possible to prevent an increase in the particle size of the suspended particles over time, thereby improving the stability of the suspended particles. DETAILED DESCRIPTION OF THE INVENTION

[0016] 1.Definition It should be understood that the terms used herein are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0017] As used herein, the term "aqueous liquid preparation" refers to a liquid preparation containing water as a base.

[0018] As used herein, the term "aqueous suspension" refers to a liquid preparation in which poorly soluble particles (suspension particles) are dispersed in water. Aqueous suspensions are a concept encompassed by aqueous liquid preparations. Brinzolamide and / or its salts have extremely low solubility in water, so in aqueous suspensions containing brinzolamide and / or its salts, brinzolamide and / or its salts become suspended particles.

[0019] As used herein, "brinzolamide" refers to a compound known as a carbonic anhydrase inhibitor, (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl-2H-thieno[3,2,e]-1,2-thiazine-6-sulfonamide 1,1-dioxide.

[0020] As used herein, "brimonidine" is a compound known as an adrenergic α2 receptor agonist, and refers to 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine.

[0021] As used herein, the term "β-blocker" refers to a drug that blocks at least one of the β1, β2, and β3 receptors among the adrenergic receptors of the sympathetic nerve. β-blockers include both β1-selective and non-β1-selective types, and further include those having intrinsic sympathomimetic activity (ISA) or α-blocking action in addition to the β-blocking action.

[0022] As used herein, "timolol" is a compound known as a β-blocker, and refers to (2S)-1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)-2-propanol.

[0023] As used herein, " carteolol" is a compound known as a β-blocker, and refers to 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydroquinolin-2(1H)-one.

[0024] As used herein, the "RRT0.1 impurity" is a substance corresponding to a peak observed at a relative retention time (RRT) of 0.1 with respect to brinzolamide when HPLC measurement is performed under the conditions described in "<HPLC conditions>" in the column of Examples after exposure of an aqueous solution containing brinzolamide and / or its salt to light (the main decomposition product of brinzolamide). The relative retention time is the value obtained by dividing the retention time of the target impurity peak by the retention time of brinzolamide. The "RRT0.1 impurity" is an impurity generated from brinzolamide and / or its salt.

[0025] As used herein, "photostability of brinzolamide and / or a salt thereof" refers to the degree to which the generation of RRT0.1 impurities caused by light exposure of an aqueous liquid preparation containing brinzolamide and / or a salt thereof is suppressed and / or the degree to which the content of brinzolamide and / or a salt thereof is not reduced by light exposure. "Photostabilization of brinzolamide and / or a salt thereof" refers to improving the photostability of brinzolamide and / or a salt thereof, and "a method for photostabilizing brinzolamide and / or a salt thereof" refers to a method for improving the photostability of brinzolamide and / or a salt thereof. For example, if the residual rate of brinzolamide and / or its salts is 95% or more and / or the amount of RRT0.1 impurity formed (relative to the labeled rate of brinzolamide and / or its salts) is 0.5% or less after irradiating an aqueous liquid preparation containing brinzolamide and / or its salts with light of total near-ultraviolet radiant energy, it can be said that the "photostability of brinzolamide and / or its salts" is improved and "photostabilization of brinzolamide and / or its salts" is achieved. More specifically, if the aqueous liquid preparation containing brinzolamide and / or its salts is irradiated with light of total near-ultraviolet radiant energy of 200 W·h / m 2 When the residual rate of brinzolamide and / or its salt is 95% or more after irradiation with light, and / or when the amount of RRT0.1 impurity produced (relative to the labeled ratio of brinzolamide and / or its salt) is 0.5% or less, it can be said that the "photostability of brinzolamide and / or its salt" is improved and that the "photostabilization of brinzolamide and / or its salt" is achieved.

[0026] In this specification, expressions such as "suppressing the decrease in the content of brinzolamide and / or its salts due to light exposure" refer to suppressing the decrease in the content of brinzolamide and / or its salts due to light exposure, and "a method for suppressing the decrease in the content of brinzolamide and / or its salts due to light exposure" refers to a method for suppressing the decrease in the content of brinzolamide and / or its salts due to light exposure. For example, if the remaining rate of brinzolamide and / or its salts is 95% or more after irradiating an aqueous liquid preparation containing brinzolamide and / or its salts with light of total near-ultraviolet radiation energy, it can be said that "suppressing the decrease in the content of brinzolamide and / or its salts due to light exposure" has been achieved. More specifically, when an aqueous liquid preparation containing brinzolamide and / or its salts is irradiated with light of total near-ultraviolet radiation energy of 200 W·h / m 2 If the remaining rate of brinzolamide and / or its salts is 95% or more after irradiation with light, it can be said that "reduction in the content of brinzolamide and / or its salts due to light exposure is suppressed."

[0027] As used herein, expressions such as "suppression of the formation of the RRT0.1 impurity due to light exposure" refer to suppressing the formation of the RRT0.1 impurity due to light exposure of an aqueous liquid preparation containing brinzolamide and / or its salts, and a "method for suppressing the formation of the RRT0.1 impurity due to light exposure" refers to a method for suppressing the formation of the RRT0.1 impurity due to light exposure of an aqueous liquid preparation containing brinzolamide and / or its salts. For example, if the amount of RRT0.1 impurity formed (relative to the labeled ratio of brinzolamide and / or its salts) is 0.5% or less after irradiating an aqueous liquid preparation containing brinzolamide and / or its salts with light of total near-ultraviolet radiation energy, it can be said that "suppression of the formation of the RRT0.1 impurity due to light exposure" has been achieved. More specifically, when a total near-ultraviolet radiation energy of 200 W·h / m is applied to an aqueous liquid preparation containing brinzolamide and / or its salts, the amount of RRT0.1 impurity formed is 0.5% or less. 2 If the amount of RRT0.1 impurity produced (relative to the labeled ratio of brinzolamide and / or its salts) is 0.5% or less after irradiation with light, it can be said that "the production of RRT0.1 impurity due to light exposure is suppressed."

[0028] In the present invention, the "residual rate of brinzolamide and / or its salt" and the "generation amount of RRT0.1 impurity (relative display rate with respect to brinzolamide and / or its salt)" are values determined according to the conditions described in "<HPLC conditions>" and "<Calculation of residual rate of brinzolamide and generation amount of RRT0.1 impurity>" in the column of Examples.

[0029] In the present specification, the "stability of suspended particles" means the degree of suppressing the increase in the particle diameter of the suspended particles of brinzolamide and / or its salt by storage for a certain period. The "stabilization of suspended particles" means improving the stability of the suspended particles of brinzolamide and / or its salt, and the "method for stabilizing suspended particles" means a method for improving the stability of the suspended particles of brinzolamide and / or its salt. For example, when the maximum particle diameter of the suspended particles is 15 μm or less after storing an aqueous preparation containing brinzolamide and / or its salt for a certain period, it can be said that the "stability of suspended particles" is improved and the "stabilization of suspended particles" is achieved. More specifically, when the maximum particle diameter of the suspended particles is 15 μm or less after storing an aqueous preparation containing brinzolamide and / or its salt in the dark at 60°C for 4 weeks, it can be said that the "stability of suspended particles" is improved and the "stabilization of suspended particles" is achieved.

[0030]

[0013] In this specification, expressions such as "suppressing an increase in particle size of suspended particles over time" and "suppressing an increase in particle size of suspended particles" refer to suppressing an increase in the particle size of suspended particles of brinzolamide and / or a salt thereof dispersed in an aqueous suspension after storage for a certain period of time, and a "method for suppressing an increase in particle size of suspended particles" refers to a method for suppressing an increase in the particle size of suspended particles of brinzolamide and / or a salt thereof. For example, if an aqueous suspension containing brinzolamide and / or a salt thereof has a maximum particle size of 15 μm or less after storage for a certain period of time, it can be said that "suppressing an increase in the particle size of suspended particles over time" and "suppressing an increase in the particle size of suspended particles" have been achieved. More specifically, if the maximum particle size of the suspended particles in an aqueous liquid preparation containing brinzolamide and / or a salt thereof is 15 μm or less after storage in a dark place at 60°C for 4 weeks, it can be said that "the increase in particle size of suspended particles over time is suppressed" and "the increase in particle size of suspended particles is suppressed."

[0031] In this specification, the "maximum particle size of suspended particles" refers to the particle size (D) at which the total volume percentage obtained by integrating the volume percentage of particles starting from the smallest particle size in the volume-based particle size distribution of suspended particles of brinzolamide and / or its salt obtained using a laser diffraction particle size distribution analyzer is 99.999%. 99.999 )

[0032] In this specification, the "median diameter of suspended particles" refers to the particle diameter (D) at which the total volume ratio, obtained by integrating the volume ratio of particles starting from the smallest particle diameter, reaches 50% when the volume-based particle size distribution of suspended particles of brinzolamide and / or its salt is determined using a laser diffraction particle size distribution analyzer. 50 )

[0033] As used herein, "glaucoma" refers to a disease characterized by functional and structural abnormalities of the eye, which have characteristic changes in the optic nerve and visual field, and in which optic nerve damage can usually be improved or prevented by sufficient reduction of intraocular pressure.

[0034] As used herein, the term "ocular hypertension" refers to a condition in which intraocular pressure exceeds the normal value (approximately 10 to 20 mmHg) even though no clear lesion is found in the optic nerve.

[0035] As used herein, "treatment" refers to the alleviation, amelioration or slowing of the rate of progression of a disease or symptom.

[0036] 2. Description of the Preferred Embodiment Although the following description of preferred embodiments is given, it should be understood that these embodiments are merely examples of the present invention and that the scope of the present invention is not limited to such preferred embodiments. It should also be understood that those skilled in the art can easily make modifications, changes, etc. within the scope of the present invention by referring to the preferred examples described below. Those skilled in the art can combine any of these embodiments as appropriate.

[0037] 3. Water-based liquid A Because eye drops are administered directly to the ocular mucosa, they must ensure high safety. They must maintain the stability of the active ingredient even when exposed to light, while suppressing the formation of impurities (decomposition products). In particular, when developing prescription drugs, if the concentration of impurities generated in photostability tests under specified conditions exceeds a certain level, the structure of the impurity must be identified and safety assessments and management of potential carcinogenic risks must be conducted (PMSB / ELD Notification No. 0624001, "Revision of the Guidelines for Impurities in Pharmaceuticals Containing New Active Ingredients," and PMSB / ELD Notification No. 0214-1, "Guidelines for the Evaluation and Management of DNA-Reactive (Mutagenic) Impurities in Pharmaceuticals to Reduce Potential Carcinogenic Risk"). In developing eye drops, this obligation typically arises when the impurity concentration exceeds 1.0%. Therefore, eye drop formulations must maintain the stability of the active ingredient and sufficiently suppress the formation of impurities in photostability tests.

[0038] Furthermore, in eye drops in suspension form, if the suspended particles become too large, problems such as discomfort or eye irritation may occur when the particles are administered, so quality that can maintain a stable particle size is required.

[0039] The present inventors have conducted various studies on the stability of aqueous liquid preparations containing brinzolamide and / or a salt thereof and have found that when the aqueous liquid preparation is exposed to light, impurities (RRT0.1 impurities described in the above section "1. Definitions") are generated, resulting in a decrease in the brimonidine content. Furthermore, the present inventors have found that when the aqueous liquid preparation containing brinzolamide and / or a salt thereof is an aqueous suspension, Ostwald ripening occurs, causing the particle size of the suspended particles (brinzolamide and / or a salt thereof) to increase over time.

[0040] Under these circumstances, the present inventors have conducted further studies and have found that an aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and timolol and / or a salt thereof can suppress a decrease in the brinzolamide content and the formation of the RRT0.1 impurity even when exposed to light, thereby improving the photostability of brinzolamide and / or a salt thereof. Furthermore, the present inventors have also found that when the aqueous liquid preparation is an aqueous suspension containing brinzolamide and / or a salt thereof as suspended particles, it can suppress an increase in the particle size of the suspended particles over time, improving the stability of the suspended particles.

[0041] That is, in one embodiment, the present invention provides an aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and timolol and / or a salt thereof (hereinafter, also referred to as "aqueous liquid preparation A"). Aqueous liquid preparation A of the present invention will be described below.

[0042] [Brinzolamide and / or its salts] Aqueous liquid preparation A of the present invention contains brinzolamide and / or a salt thereof. The salt of brinzolamide is not particularly limited as long as it is pharmaceutically acceptable, and specific examples thereof include hydrochloride and acetate.

[0043] In the aqueous liquid preparation A of the present invention, either brinzolamide or a salt thereof may be used alone or in combination. Among brinzolamide and a salt thereof, brinzolamide is preferred.

[0044] In the aqueous liquid preparation A of the present invention, the content of brinzolamide and / or a salt thereof is not particularly limited and may be appropriately determined depending on the severity of the symptoms of the patient to be treated, the amount to be administered per dose, etc., and may be, for example, 0.1 to 3 w / v%, preferably 0.5 to 2 w / v%, more preferably 1 w / v%. In this specification, the concentration of brinzolamide and / or a salt thereof is the concentration converted to brinzolamide unless otherwise specified.

[0045] [Brimonidine tartrate] Aqueous liquid preparation A of the present invention contains 0.08 to 0.12 w / v% brimonidine tartrate. Aqueous liquid preparation A of the present invention contains the above-mentioned amount of brimonidine tartrate and also contains timolol and / or a salt thereof described below, which improves the photostability of brinzolamide and / or a salt thereof and, when it is an aqueous suspension, makes it possible to suppress an increase in the particle size of suspended particles over time.

[0046] In the aqueous liquid preparation A of the present invention, the content of brimonidine tartrate may be 0.08 to 0.12 w / v %, preferably 0.09 to 0.11 w / v %, more preferably 0.1 w / v %.

[0047] [Timolol and / or its salts] Aqueous liquid preparation A of the present invention contains timolol and / or a salt thereof. In aqueous liquid preparation A of the present invention, timolol and / or a salt thereof, together with the predetermined amount of brimonidine tartrate, contribute to improving the photostability of brinzolamide and / or a salt thereof and, when in the form of an aqueous suspension, to suppressing an increase in the particle size of suspended particles of brinzolamide and / or a salt thereof over time.

[0048] The salt of timolol is not particularly limited as long as it is pharmaceutically acceptable, and specific examples thereof include organic acid salts such as maleate, fumarate, acetate, tartrate, citrate, succinate, mesylate, besylate, and tosylate; inorganic acid salts such as hydrochloride, nitrate, sulfate, hydrobromide, and hydroiodide; and the like. Timolol and / or its salts may be in the form of a solvate such as a hydrate.

[0049] In the aqueous liquid preparation A of the present invention, either timolol or a salt thereof may be used alone or in combination. Among timolol and its salts, timolol maleate is preferred.

[0050] In the aqueous liquid preparation A of the present invention, the content of timolol and / or a salt thereof is not particularly limited, and may be, for example, 0.1 to 1.5 w / v%, preferably 0.3 to 1.1 w / v%, more preferably 0.5 to 0.9 w / v%, and particularly preferably 0.68 w / v%. In this specification, the concentration of timolol and / or a salt thereof is the concentration converted into timolol maleate unless otherwise specified.

[0051] [Sodium chloride] Aqueous liquid preparation A of the present invention may contain sodium chloride. When aqueous liquid preparation A of the present invention contains sodium chloride, the content thereof is not particularly limited, and may be, for example, 0.01 to 0.2 w / v%. From the viewpoint of further improving the effect of inhibiting the decrease in brimonidine content and the formation of RRT0.1 impurity after light exposure and further increasing the photostability of brinzolamide and / or a salt thereof, the content of sodium chloride in aqueous liquid preparation A of the present invention is preferably 0.02 to 0.1 w / v%, more preferably 0.05 to 0.1 w / v%, even more preferably 0.07 to 0.1 w / v%, even more preferably 0.08 to 0.12 w / v%, 0.08 to 0.1 w / v%, or 0.09 to 0.1 w / v%, and particularly preferably 0.1 w / v%.

[0052] [Benzalkonium chloride] Aqueous liquid preparation A of the present invention may contain benzalkonium chloride. When aqueous liquid preparation A of the present invention contains benzalkonium chloride, the formation of the RRT0.1 impurity after exposure to light can be more effectively suppressed, and the photostability of brinzolamide and / or a salt thereof can be further improved.

[0053] When benzalkonium chloride is contained in the aqueous liquid preparation A of the present invention, the content thereof is not particularly limited, and may be, for example, 0.0001 to 0.01 w / v%, preferably 0.0005 to 0.01 w / v%, more preferably 0.001 to 0.005 w / v%, and even more preferably 0.005 w / v%.

[0054] [Thickening agent] The aqueous liquid preparation A of the present invention may contain a thickener, if necessary. The type of thickener used in the aqueous liquid preparation A of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polycarbophil and its salts, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and sodium carboxymethyl cellulose. These thickeners may be used alone or in combination of two or more. Among these thickeners, a preferred example is carboxyvinyl polymer, and commercially available products such as "Carbopol 974PNF," "Carbopol 971PNF," "Carbopol 71GNF," "Carbopol 5984EP," and "Carbopol 980NF" manufactured by Lubrizol Advanced Materials are used.

[0055] When a thickening agent is contained in the aqueous liquid preparation A of the present invention, the content thereof may be appropriately set depending on the type of thickening agent used, and may be, for example, 0.1 to 1 w / v%, preferably 0.2 to 0.8 w / v%, more preferably 0.3 to 0.6 w / v%, and even more preferably 0.4 w / v%.

[0056] [Surfactants] The aqueous liquid preparation A of the present invention may contain a surfactant if necessary. The type of surfactant used in the aqueous liquid preparation A of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxynol, etc.; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine, etc.; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, etc.; cationic surfactants such as alkylpyridinium salts and alkylamine salts, etc. These surfactants may be used alone or in combination of two or more. Among these surfactants, nonionic surfactants are preferred, and tyloxapol is more preferred.

[0057] When a surfactant is contained in the aqueous liquid preparation A of the present invention, the content thereof may be appropriately set depending on the type of surfactant used, etc., and may be, for example, 0.005 to 0.1 w / v%, preferably 0.01 to 0.1 w / v%, more preferably 0.02 to 0.1 w / v%, and even more preferably 0.025 to 0.1 w / v%.

[0058] [Buffer] The aqueous liquid preparation A of the present invention may contain a buffer, if necessary. The type of buffer used in the aqueous liquid preparation A of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include borate buffer, citrate buffer, phosphate buffer, Tris buffer, tartrate buffer, acetate buffer, amino acid buffer, etc.

[0059] Specific examples of boric acid buffers include boric acid and / or salts thereof. Examples of boric acid salts include, but are not limited to, alkali metal salts such as sodium salts (e.g., borax) and potassium salts, as long as they are pharmaceutically acceptable. Examples include alkali metal salts such as calcium salts and magnesium salts; aluminum salts; and organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. Boric acid and / or its salts may also be in the form of a hydrate, such as borax. As the boric acid buffer, one type may be selected from boric acid and its salts and used alone, or two or more types may be used in combination. Among boric acid and its salts, at least one of boric acid and borax is preferred, and boric acid is more preferred.

[0060] Specific examples of citrate buffers include citric acid and / or salts thereof. The salts of citric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like. The salts of citric acid may also be in the form of solvates such as hydrates. As the citrate buffer, one selected from citric acid and its salts may be used alone, or two or more may be used in combination.

[0061] Specific examples of phosphate buffers include phosphoric acid and / or salts thereof. Phosphate salts are not particularly limited as long as they are pharmaceutically acceptable, and examples include dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Phosphate salts may also be in the form of solvates such as hydrates. Phosphate buffers may be used singly or in combination of two or more, selected from phosphoric acid and salts thereof.

[0062] Specific examples of Tris buffers include trometamol and / or salts thereof. The salts of trometamol are not particularly limited as long as they are pharmaceutically acceptable, and examples include organic acid salts such as acetate salts; and inorganic acid salts such as hydrochloride and sulfonate salts. As the Tris acid buffer, one selected from trometamol and its salts may be used alone, or two or more may be used in combination. Among trometamol and its salts, trometamol is preferred.

[0063] Specific examples of tartaric acid buffers include tartaric acid and / or salts thereof. Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like. Furthermore, the salts of tartaric acid may be in the form of solvates such as hydrates. As the tartaric acid buffer, one selected from tartaric acid and its salts may be used alone, or two or more may be used in combination.

[0064] Specific examples of acetate buffers include acetic acid and / or salts thereof. The salts of acetic acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Furthermore, the salts of acetic acid may be in the form of a solvate such as a hydrate. As the acetate buffer, one selected from acetic acid and its salts may be used alone, or two or more may be used in combination.

[0065] Specific examples of the amino acid buffer include acidic amino acids and / or their salts. Specific examples of the acidic amino acids include aspartic acid and glutamic acid. The salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts. One of the acidic amino acids and salts thereof may be selected and used alone as the amino acid buffer, or two or more of them may be used in combination.

[0066] These buffers may be used alone or in combination of two or more. Among these buffers, boric acid buffers (boric acid and / or borax) are preferred from the viewpoint of more effectively suppressing the decrease in viscosity over time.

[0067] When a buffering agent is contained in the aqueous liquid preparation A of the present invention, the content thereof may be appropriately set depending on the type of buffering agent used, etc., and may be, for example, 0.01 to 2 w / v%, preferably 0.05 to 1 w / v%, more preferably 0.1 to 0.5 w / v%.

[0068] [Chelating agent] The aqueous liquid preparation A of the present invention may contain a chelating agent, if necessary. The type of buffer used in the aqueous liquid preparation A of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, and salts thereof. The salt form is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts. These chelating agents may also be in the form of solvates, such as hydrates. These chelating agents may be used alone or in combination of two or more. Among these chelating agents, preferred examples include edetic acid, citric acid, and salts thereof.

[0069] When a chelating agent is contained in the aqueous liquid preparation A of the present invention, the content thereof may be appropriately set depending on the type of buffer used, etc., and may be, for example, 0.001 to 0.2 w / v%, preferably 0.01 to 0.1 w / v%, more preferably 0.02 to 0.05 w / v%.

[0070] [Other additives] In addition to the above-mentioned components, the aqueous liquid preparation A of the present invention may contain additives such as an isotonic agent (other than sodium chloride), a polyhydric alcohol, a preservative (other than benzalkonium chloride), a cooling agent, a stabilizer, a pH adjuster, etc., as necessary.

[0071] The isotonicity agent (other than sodium chloride) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; and metal salts such as potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. These isotonicity agents may be used alone or in combination of two or more.

[0072] The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, glycerin, etc. These polyhydric alcohols may be used alone or in combination of two or more.

[0073] The preservative is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate, polyhexanide (polyhexaethylenebiguanide), alkylpolyaminoethylglycine hydrochloride, dehydroacetic acid or a salt thereof, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polidronium chloride, thimerosal, dibutylhydroxytoluene, etc. These preservatives may be used alone or in combination of two or more.

[0074] The cooling agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include 1-menthol, borneol, camphor, eucalyptus oil, etc. These cooling agents may be used alone or in combination of two or more.

[0075] The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene, etc. These stabilizers may be used alone or in combination of two or more.

[0076] The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, and sodium carbonate. These pH adjusters may be used alone or in combination of two or more.

[0077] The concentrations of these additives may be appropriately set depending on the types of additives used and the properties to be imparted to the aqueous liquid preparation.

[0078] [Other pharmacological ingredients] The aqueous liquid preparation A of the present invention may optionally contain pharmacological ingredients other than brinzolamide and / or its salts, brimonidine tartrate, and timolol and / or its salts. Examples of such pharmacological ingredients include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetics such as pilocarpine hydrochloride; anticholinesterase agents such as distigmine bromide; sympathomimetics such as dipivefrin hydrochloride; beta-blockers such as carteolol hydrochloride, betaxolol hydrochloride, nipradilol, levobunolol hydrochloride, befunolol hydrochloride, and metipranolol hydrochloride; and alpha-blockers such as bunazosin hydrochloride. These pharmacological ingredients may be used alone or in combination of two or more. The concentrations of these pharmacological ingredients may be appropriately determined depending on the type of pharmacological ingredient used and the desired efficacy.

[0079] Furthermore, one embodiment of aqueous liquid preparation A of the present invention includes an embodiment in which brinzolamide and / or a salt thereof, brimonidine tartrate, and timolol and / or a salt thereof are contained as directly active ingredients for treating glaucoma or ocular hypertension, and no other active ingredients are contained.

[0080] [pH] The pH of aqueous liquid preparation A of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and may be, for example, 4 to 8. When aqueous liquid preparation A of the present invention is an eye drop, the pH is preferably 5 to 8, more preferably 6 to 7, even more preferably 6.1 to 6.9, and particularly preferably 6.2 to 6.8, from the viewpoint of further reducing irritation to the eyes that can be applied to the ocular mucosa.

[0081] [Osmotic pressure] The osmotic pressure of aqueous liquid preparation A of the present invention is not particularly limited as long as it is applicable to the intended use. When aqueous liquid preparation A of the present invention is an ophthalmic solution, the osmotic pressure can be 250 to 350 mOsm / kg.

[0082] The osmotic pressure ratio of aqueous liquid preparation A of the present invention is not particularly limited as long as it is applicable to the intended use. For example, when aqueous liquid preparation A of the present invention is an ophthalmic solution, the osmotic pressure ratio is 0.85 to 1.15. From the viewpoint of alleviating eye irritation, the osmotic pressure ratio is preferably 0.9 to 1.1, more preferably 1.0.

[0083] [Form of formulation] Aqueous liquid preparation A of the present invention may be any of an aqueous suspension containing brinzolamide and / or a salt thereof as suspended particles, an aqueous solution in which all of the formulated ingredients are dissolved or solubilized, an aqueous emulsion, etc., but a preferred example is an aqueous suspension. When aqueous liquid preparation A of the present invention is an aqueous suspension, it also has the effect of suppressing an increase in the particle size of the suspended particles over time.

[0084] [Photostability of Brinzolamide and / or its salts] Aqueous liquid preparation A of the present invention has improved photostability of brinzolamide and / or a salt thereof, and can suppress the production of the RRT0.1 impurity even when exposed to light, thereby suppressing a decrease in the content of brinzolamide and / or a salt thereof.

[0085] An example of the photostability of aqueous liquid preparation A of the present invention is that the amount of RRT0.1 impurity generated (relative to Brinzolamide and / or its salts) after the preparation is placed in a transparent container and irradiated with light having a total near-ultraviolet radiation energy of 0.5% or less, preferably less than 0.5%, and more preferably less than 0.2%. Another example of the photostability of aqueous liquid preparation A of the present invention is that the amount of RRT0.1 impurity generated (relative to Brinzolamide and / or its salts) after the preparation is placed in a transparent container and irradiated with light having a total near-ultraviolet radiation energy of 200 W·h / m 2 The amount of RRT0.1 impurity produced after irradiation with light (expressed ratio relative to brinzolamide and / or a salt thereof) is 0.5% or less, preferably less than 0.5%, and more preferably less than 0.2%.

[0086] Another example of the photostability of aqueous liquid preparation A of the present invention is when the residual rate of brinzolamide and / or a salt thereof after being placed in a transparent container and irradiated with light of a total near-ultraviolet radiation energy is about 95% or more, preferably 96% or more, more preferably 97% or more, 98% or more, or 99% or more, and even more preferably 100%. Another example of the photostability of aqueous liquid preparation A of the present invention is when the residual rate of brinzolamide and / or a salt thereof after being placed in a transparent container and irradiated with light of a total near-ultraviolet radiation energy of 200 W·h / m 2 The residual rate of brinzolamide and / or a salt thereof after irradiation with light is about 95% or more, preferably 96% or more, more preferably 97% or more, 98% or more, or 99% or more, and even more preferably 100%.

[0087] [Stability of suspended particles of brinzolamide and / or its salts] When the aqueous liquid preparation A of the present invention is an aqueous suspension, the stability of the particle size of the suspended particles of brinzolamide and / or a salt thereof is improved, and an increase in the particle size of the suspended particles over time can be suppressed.

[0088] When aqueous liquid preparation A of the present invention is an aqueous suspension, the stability of the suspended particles may be such that the maximum particle size of the suspended particles after storage for a certain period of time is 15 μm or less, preferably 14 μm or less, more preferably 12 μm or less or 11 μm or less, and even more preferably 10 μm or less. When aqueous liquid preparation A of the present invention is an aqueous suspension, the stability of the suspended particles may be such that the maximum particle size of the suspended particles after storage for 4 weeks at 60° C. in a dark place is 15 μm or less, preferably 14 μm or less, more preferably 12 μm or less or 11 μm or less, and even more preferably 10 μm or less.

[0089] Another example of the stability of suspended particles that can be exhibited when aqueous liquid preparation A of the present invention is an aqueous suspension is that the median diameter of suspended particles after storage for a certain period of time is 4 μm or less, preferably 0.5 to 4 μm, more preferably 0.5 to 3 μm, and even more preferably 1 to 2 μm. Another example of the stability of suspended particles that can be exhibited when aqueous liquid preparation A of the present invention is an aqueous suspension is that the median diameter of suspended particles after storage in a dark place at 60°C for 4 weeks is 4 μm or less, preferably 0.5 to 4 μm, more preferably 0.5 to 3 μm, and even more preferably 1 to 2 μm.

[0090] [Application areas] Aqueous liquid preparation A of the present invention is prepared into pharmaceutical compositions for various uses, such as ophthalmology, dentistry, otolaryngology, dermatology, etc., and used as a topical administration preparation. One embodiment of aqueous liquid preparation A of the present invention is a composition for ophthalmology, dentistry, otolaryngology, or dermatology, preferably an aqueous liquid preparation for ophthalmology.

[0091] Specific examples of aqueous ophthalmic solutions include eye drops, eyewashes, solutions for contact lenses, injections, etc. Among these, eye drops are preferred.

[0092] [Applications / Dosage / Directions] Aqueous liquid preparation A of the present invention exhibits carbonic anhydrase inhibitory activity due to brinzolamide and / or a salt thereof, adrenergic α2 receptor agonist activity due to brimonidine tartrate, and β-receptor blocking activity due to timolol and / or a salt thereof, and therefore, in one embodiment, aqueous liquid preparation A of the present invention is provided as an eye drop solution and can be suitably used for the treatment of glaucoma or ocular hypertension.

[0093] When the aqueous liquid preparation A of the present invention is used as an eye drop, several drops may be instilled into the eye once or multiple times a day. In one embodiment of the aqueous liquid preparation A of the present invention, one drop is instilled into the eye twice a day.

[0094] [container] The container for containing aqueous liquid preparation A of the present invention is not particularly limited, and any conventional container for containing pharmaceutical compositions may be used. For example, if aqueous liquid preparation A of the present invention is an eye drop solution, a conventional eye drop container may be used. The material for the container for containing aqueous liquid preparation A of the present invention is not particularly limited, and the container may be made of glass or plastic. When a plastic container is used for containing aqueous liquid preparation A of the present invention, the constituent material of the plastic container is not particularly limited, and examples include one or a blend of two or more of polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polyarylate, polyimide, and cyclic olefin copolymer (COC). The material for the container body (the component forming the storage portion for containing the aqueous liquid preparation) is preferably polyethylene or polypropylene, more preferably polyethylene.

[0095] A suitable example of a container for containing the aqueous liquid preparation A of the present invention is a transparent container. The transparent container may be either colorless and transparent or colored and transparent, as long as it has sufficient transparency to allow the interior to be visually observed without interfering with the insoluble foreign matter inspection method. Specifically, the transparent container has a maximum light transmittance of 10% or more in the wavelength range of 400 to 800 nm. Here, the maximum light transmittance in the wavelength range of 400 to 800 nm is a value obtained by measuring the light transmittance at wavelengths from 400 nm to 800 nm at wavelength intervals of 5 nm using an ultraviolet-visible spectrophotometer and determining the maximum of the measured transmittance values. From the viewpoint of further improving interior visibility, the maximum light transmittance of the transparent container in the wavelength range of 400 to 800 nm is 10% or more, preferably 20% or more, particularly preferably 30% or more, and even more preferably 40% or more. The upper limit of the maximum transmittance of light in the wavelength region of 400 to 800 nm is, for example, 80% or less, preferably 70% or less, more preferably 60% or less, and particularly preferably 50% or less.

[0096] Furthermore, in a transparent container, the transparent region may be provided over the entire container, or may be provided over at least a portion of the container, as long as the internal visibility necessary for insoluble foreign matter testing, checking the remaining liquid volume, etc., is ensured. For example, a transparent container may have a non-colorless, transparent region in part for the purpose of displaying the product name, ingredient names, expiration date, precautions, etc. In one embodiment of a transparent container, the transparent region occupies 5% or more, preferably 7% or more, more preferably 10% or more, and even more preferably 15% or more of the side surface of the container (the outer surface of the main body excluding the area covered by the lid). Furthermore, in a transparent container, the transparent region may be covered with a covering member such as a shrink label or a tack label, as long as the transparent region is ensured.

[0097] [Manufacturing method] The aqueous liquid preparation A of the present invention may be prepared according to a known preparation method depending on the dosage form, etc., and can be prepared, for example, by the method described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition.

[0098] Specifically, the method for producing aqueous liquid preparation A of the present invention includes a step of blending brinzolamide and / or a salt thereof, brimonidine tartrate, timolol and / or a salt thereof, and other ingredients as needed, in a pharmaceutically acceptable aqueous medium. The pharmaceutically acceptable aqueous medium means a pharmaceutically acceptable aqueous medium, such as purified water. In the blending step, the order in which the ingredients are blended is not particularly limited, and the ingredients may be blended sequentially in any order or simultaneously. Furthermore, during or after the blending step, a sterilization step such as filter sterilization, filtration sterilization, dry heat sterilization, electron beam sterilization, or gamma ray sterilization may be performed as needed.

[0099] 4. Method A for photostabilizing brinzolamide and / or its salt In another embodiment of the present invention, there is provided a method for photostabilizing brinzolamide and / or a salt thereof (hereinafter, also referred to as "photostabilization method A"), which comprises the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous liquid preparation. According to the photostabilization method A of the present invention, in an aqueous liquid preparation containing brinzolamide and / or a salt thereof, a decrease in the brimonidine content and the generation of the RRT0.1 impurity due to light exposure can be suppressed, and the photostability of brinzolamide and / or a salt thereof can be improved.

[0100] The types, concentrations, etc. of brimonidine and / or a salt thereof, brimonidine tartrate, and timolol and / or a salt thereof used in photostabilization method A of the present invention are as described above in "3. Aqueous liquid preparation A." In addition, other components that can be incorporated into the aqueous liquid preparation in photostabilization method A of the present invention, as well as the pH, osmotic pressure, formulation, field of application, container, etc. of the aqueous liquid preparation are also as described above in "3. Aqueous liquid preparation A."

[0101] Since the photostabilization method A of the present invention can suppress a decrease in the brimonidine content due to light exposure, one embodiment of the photostabilization method A of the present invention can also be carried out as a method for suppressing a decrease in the brinzolamide and / or a salt thereof content due to light exposure. Furthermore, since the photostabilization method A of the present invention can suppress the formation of the RRT0.1 impurity due to light exposure, another embodiment of the photostabilization method A of the present invention can also be carried out as a method for suppressing the formation of the RRT0.1 impurity due to light exposure.

[0102] 5. Method A for stabilizing suspended particles of brinzolamide and / or its salt In another embodiment of the present invention, there is provided a method for stabilizing suspended particles in an aqueous suspension containing brinzolamide and / or a salt thereof, the method comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous suspension (hereinafter, this method may be referred to as "Method A for stabilizing suspended particles"). According to Method A for stabilizing suspended particles of the present invention, an increase in particle size of suspended particles over time can be suppressed in an aqueous suspension containing brimonidine and / or a salt thereof, and an aqueous suspension having excellent formulation stability can be provided.

[0103] The types, concentrations, etc. of brimonidine and / or a salt thereof, brimonidine tartrate, and timolol and / or a salt thereof used in method A for stabilizing suspended particles of the present invention are as described above in the section "3. Aqueous liquid preparation A." In method A for stabilizing suspended particles of the present invention, other components that can be blended in the aqueous liquid preparation, as well as the pH, osmotic pressure, fields of application, container, etc. of the aqueous liquid preparation are also as described above in the section "3. Aqueous liquid preparation A."

[0104] The method A for stabilizing suspended particles of the present invention can suppress an increase in particle size of suspended particles of brinzolamide and / or a salt thereof over time, and therefore, in one embodiment, the method A for stabilizing suspended particles of the present invention can also be carried out as a method for suppressing an increase in particle size of suspended particles in an aqueous suspension containing brinzolamide and / or a salt thereof.

[0105] 6. Water-based liquid B The present inventors have conducted research into techniques for improving the stability of aqueous liquid preparations containing brinzolamide and / or a salt thereof, and have found that an aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and carteolol and / or a salt thereof is stable. liquid The present inventors have also found that, when the aqueous liquid preparation is an aqueous suspension containing brinzolamide and / or a salt thereof as suspended particles, an increase in the particle size of the suspended particles over time can be suppressed.

[0106] That is, in another embodiment, the present invention provides an aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and carteolol and / or a salt thereof (hereinafter, also referred to as "aqueous liquid preparation B"). Aqueous liquid preparation B of the present invention will be described below.

[0107] In aqueous liquid preparation B of the present invention, the type and concentration of brinzolamide and / or a salt thereof, and the concentration of brimonidine tartrate are as described in the above section "3. Aqueous liquid preparation A."

[0108] In aqueous liquid preparation B of the present invention, carteolol and / or a salt thereof, together with the predetermined amount of brimonidine tartrate, contribute to improving the photostability of brinzolamide and / or a salt thereof and inhibiting the increase in particle size of suspended particles of brinzolamide and / or a salt thereof over time when the preparation is an aqueous suspension. The carteolol salt is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include inorganic acid salts such as hydrochloride. In aqueous liquid preparation B of the present invention, either carteolol or a salt thereof may be used alone or in combination. Among aqueous liquid preparation B and its salts, carteolol hydrochloride is preferred. The content of carteolol and / or a salt thereof in aqueous liquid preparation B of the present invention is not particularly limited, and may be, for example, 0.5 to 1.5 w / v%, preferably 0.7 to 1.3 w / v%, more preferably 0.8 to 1.2 w / v%, and particularly preferably 1 w / v%. In this specification, concentrations of carteolol and / or its salts are concentrations converted into carteolol hydrochloride unless otherwise specified.

[0109] [Form of formulation] Aqueous liquid preparation B of the present invention may be any of an aqueous suspension containing brinzolamide and / or a salt thereof as suspended particles, an aqueous solution in which all of the formulated ingredients are dissolved or solubilized, an aqueous emulsion, etc., and a preferred example is an aqueous suspension. When aqueous liquid preparation B of the present invention is an aqueous suspension, it also has the effect of suppressing an increase in the particle size of the suspended particles over time.

[0110] Regarding aqueous liquid preparation B of the present invention, other ingredients that can be added, pH, osmotic pressure, light stability of brinzolamide and / or a salt thereof, stability of suspended particles of brinzolamide and / or a salt thereof, field of application, use / dosage / administration, container, production method, etc. are as described in the above section "3. Aqueous liquid preparation A."

[0111] 7. Method B for stabilizing brinzolamide and / or its salts with light In yet another embodiment of the present invention, there is provided a method for photostabilizing brinzolamide and / or a salt thereof (hereinafter, also referred to as "photostabilization method B"), which comprises the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and carteolol and / or a salt thereof to obtain an aqueous liquid preparation. According to photostabilization method B of the present invention, in an aqueous liquid preparation containing brinzolamide and / or a salt thereof, a decrease in the brimonidine content and the generation of the RRT0.1 impurity due to light exposure can be suppressed, and the photostability of brinzolamide and / or a salt thereof can be improved.

[0112] The types, concentrations, etc. of brimonidine and / or salts thereof and brimonidine tartrate used in photostabilization method B of the present invention are as described in the above section "3. Aqueous liquid preparation A." Furthermore, the types, concentrations, etc. of carteolol and / or salts thereof used in photostabilization method B of the present invention are as described in the above section "6. Aqueous liquid preparation B." Furthermore, other components that can be incorporated into the aqueous liquid preparation in photostabilization method B of the present invention, as well as the pH, osmotic pressure, formulation form, field of application, container, etc. of the aqueous liquid preparation are also as described in the above section "3. Aqueous liquid preparation A."

[0113] Since the photostabilization method B of the present invention can suppress a decrease in the brimonidine content due to light exposure, one embodiment of the photostabilization method B of the present invention can also be carried out as a method for suppressing a decrease in the brinzolamide and / or a salt thereof content due to light exposure. Furthermore, since the photostabilization method B of the present invention can suppress the formation of the RRT0.1 impurity due to light exposure, another embodiment of the photostabilization method B of the present invention can also be carried out as a method for suppressing the formation of the RRT0.1 impurity due to light exposure.

[0114] 8. Method B for stabilizing suspended particles of brinzolamide and / or its salt In yet another embodiment of the present invention, there is provided a method for stabilizing suspended particles in an aqueous suspension containing brinzolamide and / or a salt thereof, the method comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % of brimonidine tartrate, and carteolol and / or a salt thereof to obtain an aqueous suspension (hereinafter, this method may be referred to as "method B for stabilizing suspended particles"). According to method B for stabilizing suspended particles of the present invention, an increase in particle size of suspended particles over time can be suppressed in an aqueous suspension containing brimonidine and / or a salt thereof, and an aqueous suspension having excellent formulation stability can be provided.

[0115] In method B for stabilizing suspended particles of the present invention, the type and concentration of brinzolamide and / or a salt thereof and the concentration of brimonidine tartrate used are as described above in section "3. Aqueous liquid preparation A." In method B for stabilizing suspended particles of the present invention, the type and concentration of carteolol and / or a salt thereof used are as described above in "6. Aqueous liquid preparation B." In method B for stabilizing suspended particles of the present invention, other components that can be incorporated into the aqueous suspension, the pH, osmotic pressure, fields of application, containers, etc. of the aqueous suspension are also as described above in section "3. Aqueous liquid preparation A."

[0116] The method B for stabilizing suspended particles of the present invention can suppress the increase in particle size of suspended particles of brinzolamide and / or a salt thereof over time, and therefore, in one embodiment, the method B for stabilizing suspended particles of the present invention can also be carried out as a method for suppressing the increase in particle size of suspended particles in an aqueous suspension containing brinzolamide and / or a salt thereof.

[0117] 9. Water-based liquid C The present inventors have investigated techniques for improving the stability of aqueous liquid preparations containing brinzolamide and / or a salt thereof, and have found that an aqueous suspension containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and a β-blocker can suppress the decrease in brimonidine content and the formation of the RRT0.1 impurity even when exposed to light, thereby improving the photostability of brinzolamide and / or a salt thereof. Furthermore, the present inventors have also found that when the aqueous liquid preparation is an aqueous suspension containing brinzolamide and / or a salt thereof as suspended particles, it can suppress the increase in particle size of the suspended particles over time.

[0118] That is, in yet another embodiment, the present invention provides an aqueous liquid preparation containing brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and a β-blocker (hereinafter, also referred to as "aqueous liquid preparation C"). Aqueous liquid preparation C of the present invention will be described below.

[0119] In aqueous liquid preparation C of the present invention, the type and concentration of brinzolamide and / or a salt thereof, and the concentration of brimonidine tartrate are as described in the above section "3. Aqueous liquid preparation A."

[0120] In the aqueous liquid preparation C of the present invention, the β-blocker, together with the predetermined amount of brimonidine tartrate, contributes to suppressing the increase in particle size of suspended particles of brinzolamide and / or its salt over time. The type of β-blocker used in the aqueous liquid preparation C of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples include timolol, carteolol, betaxolol, nipradilol, levobunolol, befunolol, metipranolol, and salts thereof. Specific examples of salt forms of β-blockers include timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, nipradilol, levobunolol hydrochloride, befunolol hydrochloride, metipranolol hydrochloride, etc. In the aqueous liquid preparation C of the present invention, one β-blocker may be used alone, or two or more β-blockers may be used in combination.

[0121] The content of the β-blocker in aqueous liquid preparation C of the present invention is not particularly limited, but may be, for example, 0.5 to 1.5 w / v%. More specifically, when the β-blocker is timolol and / or a salt thereof, the content of timolol and / or a salt thereof in aqueous liquid preparation C of the present invention is preferably 0.3 to 1.1 w / v%, more preferably 0.5 to 0.9 w / v%, and particularly preferably 0.68 w / v%. In this specification, the content of timolol and / or a salt thereof is the content converted to timolol maleate unless otherwise specified. Furthermore, when the β-blocker is carteolol and / or a salt thereof, the content of carteolol and / or a salt thereof in aqueous liquid preparation C of the present invention is preferably 0.7 to 1.3 w / v%, more preferably 0.8 to 1.2 w / v%, and particularly preferably 1 w / v%. In this specification, the content of carteolol and / or a salt thereof is the content converted into carteolol hydrochloride unless otherwise specified.

[0122] Regarding aqueous liquid preparation C of the present invention, other ingredients that can be added, pH, osmotic pressure, dosage form, light stability of brinzolamide and / or a salt thereof, stability of suspended particles of brinzolamide and / or a salt thereof, application field, use / dosage / administration, container, production method, etc. are as described in the above section "3. Aqueous liquid preparation A."

[0123] 10. Method C for stabilizing brinzolamide and / or its salts with light Another embodiment of the present invention provides a method for photostabilizing brinzolamide and / or a salt thereof (hereinafter, also referred to as "photostabilization method C"), which comprises the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v% brimonidine tartrate, and a β-blocker to obtain an aqueous liquid preparation. According to photostabilization method C of the present invention, in an aqueous liquid preparation containing brinzolamide and / or a salt thereof, a decrease in the brinzolamide content and the generation of the RRT0.1 impurity due to light exposure can be suppressed, and the photostability of brinzolamide and / or a salt thereof can be improved.

[0124] The types, concentrations, etc. of brinzolamide and / or a salt thereof and brimonidine tartrate used in photostabilization method C of the present invention are as described in the above section "3. Aqueous liquid preparation A." Furthermore, the types, concentrations, etc. of the β-blockers used in photostabilization method C of the present invention are as described in the above section "9. Aqueous liquid preparation C." Furthermore, other components that can be incorporated into the aqueous liquid preparation in photostabilization method C of the present invention, as well as the pH, osmotic pressure, formulation form, field of application, container, etc. of the aqueous liquid preparation are also as described in the above section "3. Aqueous liquid preparation A."

[0125] Since the photostabilization method C of the present invention can suppress a decrease in the brinzolamide content due to light exposure, one embodiment of the photostabilization method C of the present invention can also be carried out as a method for stabilizing the content of brinzolamide and / or a salt thereof. Furthermore, since the photostabilization method C of the present invention can suppress the formation of the RRT0.1 impurity due to light exposure, another embodiment of the photostabilization method C of the present invention can also be carried out as a method for suppressing the formation of the RRT0.1 impurity.

[0126] 11. Method C for stabilizing suspended particles of brinzolamide and / or its salt In yet another embodiment of the present invention, there is provided a method for stabilizing suspended particles in an aqueous suspension containing brinzolamide and / or a salt thereof, the method comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % brimonidine tartrate, and a β-blocker to obtain an aqueous suspension (hereinafter, this method may be referred to as "method C of stabilizing suspended particles"). According to method C of stabilizing suspended particles of the present invention, it is possible to suppress an increase in particle size of suspended particles over time in an aqueous suspension containing brimonidine and / or a salt thereof, and to provide an aqueous suspension having excellent formulation stability.

[0127] In the method C for stabilizing suspended particles of the present invention, the type and concentration of brinzolamide and / or a salt thereof and the concentration of brimonidine tartrate used are as described in the above section "3. Aqueous liquid preparation A." In the method C for stabilizing suspended particles of the present invention, the type and concentration of the β-blocker used are as described in the above section "9. Aqueous liquid preparation C." In addition, in the method C for stabilizing suspended particles of the present invention, other components that can be blended in the aqueous suspension, the pH, osmotic pressure, fields of application, container, etc. of the aqueous suspension are also as described in the above section "3. Aqueous liquid preparation A."

[0128] The method C for stabilizing suspended particles of the present invention can suppress the increase in particle size of suspended particles of brinzolamide and / or a salt thereof over time, and therefore, in one embodiment, the method C for stabilizing suspended particles of the present invention can also be carried out as a method for suppressing the increase in particle size of suspended particles in an aqueous suspension containing brinzolamide and / or a salt thereof. [Example]

[0129] The present invention will be specifically described below with reference to examples, but the present invention should not be construed as being limited to the following examples.

[0130] Test Example 1: Evaluation of photostability of brinzolamide 1. Preparation of aqueous suspension Aqueous suspensions (ophthalmic solutions) with the compositions shown in Tables 1 to 6 were prepared. The specific manufacturing procedures are as follows. First, a carboxyvinyl polymer was dispersed in an aqueous sodium chloride solution to prepare a carboxyvinyl polymer aqueous solution. Next, predetermined amounts of brimonidine tartrate, timolol maleate, carteolol hydrochloride, boric acid, tyloxapol, benzalkonium chloride, and the carboxyvinyl polymer aqueous solution were added to purified water to obtain a solution. After adjusting the pH to 6.5 with sodium hydroxide, a predetermined amount of brinzolamide was added and the mixture was stirred for one day to obtain an aqueous suspension in which brinzolamide was dispersed in particulate form.

[0131] 2. Method for evaluating the photostability of Brinzolamide 3 mL of the obtained aqueous suspension was placed in a 5-mL colorless transparent container, and irradiated with light having a total near-ultraviolet radiation energy of 200 W·h / m 2 The aqueous suspension before and after light irradiation was subjected to HPLC under the following conditions to analyze the brinzolamide content and the amount of RRT0.1 impurities generated. The colorless transparent container used was made of polyethylene, polypropylene, or glass. The 5-mL colorless transparent polyethylene container is the container used for 0.1% sodium hyaluronate eye drops "Sensyu" (formerly 0.1% tear balance eye drops, manufacturer and distributor: Chisso Pharmaceutical Co., Ltd.), and the 5-mL colorless transparent polypropylene container is the container used for 1% azithromycin eye drops (manufacturer and distributor: Chisso Pharmaceutical Co., Ltd.). For the 5-mL colorless transparent glass container, the product of Daiwa Special Glass Co., Ltd. was used.

[0132] <HPLC Conditions> · Preparation of sample solution 0.5 g of each aqueous suspension was accurately weighed, and purified water was added to make exactly 5 mL to obtain a sample solution.

[0133] · Preparation of standard solution Approximately 0.01 g of brinzolamide was accurately weighed, and an aqueous methanol solution (volume ratio of methanol to purified water is 4:1) was added to make exactly 10 mL to obtain a standard solution.

[0134] · Set conditions For 10 μL of the sample solution and the standard solution, measurement was carried out by HPLC (High Performance Liquid Chromatograph: Prominence manufactured by Shimadzu Corporation) under the following conditions, and the peak areas of brinzolamide and impurities in each solution were measured by the automatic integration method. The measurement conditions of HPLC are as follows. detector : Ultraviolet absorptiometer (measurement wavelength: 230 nm) column : A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was filled with 5-μm octadecylsilylated silica gel for HPLC. <> Column oven temperature : 40 °C <> Mobile phase AApproximately 1.15 g of potassium dihydrogen phosphate and approximately 50 mg of sodium 1-heptanesulfonate were weighed and dissolved in 1680 mL of water. Dipotassium hydrogen phosphate was then added to adjust the pH to 6.0. 160 mL of methanol and 160 mL of acetonitrile were added to this solution, mixed, and filtered through a membrane filter. The filtered solution was used as mobile phase A. Mobile phase B Approximately 1.15 g of potassium dihydrogen phosphate and approximately 50 mg of sodium 1-heptanesulfonate were weighed and dissolved in 800 mL of water, followed by the addition of 600 mL of methanol and 600 mL of acetonitrile and mixing. This solution was filtered through a membrane filter. The filtered solution was used as mobile phase B. Gradient The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 1 to control the linear concentration gradient. flow rate : 0.5 mL / min [Table 1]

[0135] <Calculation of the residual rate of brinzolamide and the amount of RRT0.1 impurity produced> The remaining rate (%) of brinzolamide and the amount of impurities produced (%, expressed as a percentage of brinzolamide) were calculated according to the following formulas.

number

[0136] 3. Evaluation Results 3-1. Investigation of ingredients that improve the photostability of brinzolamide Table 2 shows the results of investigations into components that improve the photostability of brinzolamide. In the aqueous suspension containing brinzolamide alone (Comparative Example 1A), the residual rate of brinzolamide after exposure to light was low, and the RRT0.1 impurity was formed at a rate of 3.3%. In the aqueous suspension containing brinzolamide and either brimonidine tartrate or timolol maleate (Comparative Examples 2A or 3A), a slight improvement in the residual rate of brinzolamide and a decrease in the amount of RRT0.1 impurity formed were observed compared to Comparative Example 1A, but the photostability of brinzolamide was still insufficient. In contrast, in the aqueous suspension containing brinzolamide, brimonidine tartrate, and timolol maleate (Example 1A), the residual rate of brinzolamide remained at 100%, and the amount of RRT0.1 impurity formed was reduced to 0.15%, demonstrating improved photostability of brinzolamide. Furthermore, in the aqueous suspension containing brinzolamide, brimonidine tartrate, and carteolol hydrochloride (Example 2A), the residual rate of brinzolamide was as high as 98%, and the amount of RRT0.1 impurity produced was also reduced to 0.5%.

[0137] In other words, these results confirm that in order to improve the photostability of brinzolamide, it is important to contain at least brimonidine tartrate in combination with timolol maleate or carteolol hydrochloride in an aqueous liquid preparation containing brinzolamide.

[0138] [Table 2]

[0139] 3-2. Examination of the effect of container materials on the photostability of brinzolamide The results of an investigation into the effect of the container material on the photostability of Brinzolamide are shown in Table 3. When aqueous suspensions containing Brinzolamide alone were placed in any of the transparent containers made of polyethylene, polypropylene, and glass, the residual rate of Brinzolamide after exposure to light was low and the amount of RRT0.1 impurity formed was also large (Comparative Examples 1A to 1C). In contrast, when aqueous suspensions containing Brinzolamide, brimonidine tartrate, and timolol maleate were placed in any of the colorless transparent containers made of polyethylene, polypropylene, and glass, the residual rate of Brinzolamide was maintained at 100% and the amount of RRT0.1 impurity formed was reduced to less than 0.5%, thereby improving the photostability of Brinzolamide (Examples 1A to 1C).

[0140] That is, these results confirmed that the material of the colorless, transparent container that contains the aqueous liquid formulation has almost no effect on the photostability of brinzolamide.

[0141] [Table 3]

[0142] 3-3. Examination of the effect of brimonidine tartrate concentration on the photostability of brinzolamide The results of an investigation into the effect of brimonidine tartrate concentration on the photostability of brinzolamide are shown in Table 4. In an aqueous suspension containing brinzolamide and 0.2 w / v% brimonidine tartrate without timolol maleate, the residual rate of brinzolamide was 95% or more, but the amount of RRT0.1 impurity formed exceeded 0.5%, indicating insufficient photostability (Comparative Example 4C). In addition, in an aqueous suspension containing brimonidine tartrate and timolol maleate with 0.2 w / v% brimonidine tartrate, the residual rate of brinzolamide was 95% or more, but the amount of RRT0.1 impurity formed was 2.8%, indicating insufficient photostability (Comparative Example 5C). In contrast, in an aqueous suspension containing brinzolamide, brimonidine tartrate, and timolol maleate, when the brimonidine tartrate was 0.1 w / v%, the residual rate of brinzolamide was maintained at 100% and the amount of RRT0.1 impurity produced was reduced to less than 0.5%, thereby improving the photostability of brinzolamide (Example 1C).

[0143] In other words, these results confirmed that in order to improve the photostability of brinzolamide, it is important to incorporate a combination of brinzolamide, brimonidine tartrate, and timolol maleate, and to set the concentration of brimonidine tartrate to approximately 0.1 w / v% (specifically, 0.08 to 0.12 w / v%).

[0144] [Table 4]

[0145] 3-4. Examination of the effect of benzalkonium chloride on the photostability of brinzolamide The results of investigating the effect of benzalkonium chloride on the photostability of brinzolamide are shown in Table 5. When benzalkonium chloride was added to an aqueous suspension containing brinzolamide, brimonidine tartrate, and timolol maleate, the residual rate of brinzolamide was maintained at 100%, and the amount of RRT0.1 impurity produced was further reduced compared to when benzalkonium chloride was not added (Example 3C).

[0146] In other words, these results confirmed that the photostability of brinzolamide was further improved by further adding benzalkonium chloride to an aqueous suspension containing brinzolamide, 0.1 w / v% brimonidine tartrate, and timolol maleate.

[0147] [Table 5]

[0148] 3-5. Study on the effect of sodium chloride on the photostability of brinzolamide The results of an investigation into the effect of sodium chloride on the photostability of brinzolamide are shown in Table 6. When 0.1 w / v% sodium chloride was added to an aqueous suspension containing brinzolamide, brimonidine tartrate, and timolol maleate, an improved residual rate of brinzolamide and a reduced amount of RRT0.1 impurity were observed compared to when no sodium chloride was added or when 0.2 w / v% sodium chloride was added.

[0149] In other words, these results confirmed that the photostability of brinzolamide can be further improved by further adding approximately 0.1 w / v% (specifically, 0.08 to 0.12 w / v%) sodium chloride to an aqueous suspension containing brinzolamide, 0.1 w / v% brimonidine tartrate, and timolol maleate.

[0150] [Table 6]

[0151] Test Example 2: Evaluation of the stability of suspended particles 1. Preparation of aqueous suspension Aqueous suspensions (ophthalmic solutions) were prepared with the compositions shown in Tables 7 and 8. Brinzolamide was dispersed in particulate form in the aqueous suspensions. The specific preparation procedures for the aqueous suspensions were as described in Test Example 1 above.

[0152] 2. Methods for assessing the stability of suspended particles 3 mL of the obtained aqueous suspension was placed in a 5 mL colorless transparent glass container and stored in a dark place at 60°C for 4 weeks. The aqueous suspension before and after storage was subjected to laser diffraction particle size distribution measurement, and the cumulative 10% (D 20 ), 50% (median diameter, D 50 ), 90%(D 90 ), and 99.999% (maximum particle size, D 99.999 The measurement conditions were as follows: Equipment: Laser diffraction particle size distribution analyzer (SALD-2300, Shimadzu Corporation) -High concentration sample measurement unit Refractive index: 1.75-0.02i

[0153] 3. Evaluation Results 3-1. Study of components that stabilize the particle size of suspended particles Table 7 shows the results of an investigation into components that stabilize the particle size of suspended particles. In the aqueous suspension containing brinzolamide alone (Comparative Example 6), the particle size of the suspended particles significantly increased after storage. The aqueous suspension containing brinzolamide and brimonidine tartrate (Comparative Example 7) also failed to suppress the increase in particle size of the suspended particles after storage. Furthermore, the aqueous suspension containing brinzolamide and timolol maleate (Comparative Example 8) was able to suppress the increase in particle size of the suspended particles after storage compared to Comparative Example 5, but the maximum particle size of the suspended particles after storage still exceeded 15 μm. In contrast, the aqueous suspensions containing brinzolamide, brimonidine tartrate, and timolol maleate or carteolol hydrochloride (Examples 6 and 7) had a maximum particle size of 10 μm or less after storage, indicating that the particle size of the suspended particles was stabilized.

[0154] In other words, these results confirmed that in order to improve the stability of the particle size of brinzolamide suspension particles, it is important to contain at least brimonidine tartrate in combination with timolol maleate or carteolol hydrochloride in an aqueous liquid preparation containing brinzolamide.

[0155] [Table 7]

[0156] 3-2. Examination of the effect of brimonidine tartrate concentration on the stability of suspended particles The results of an investigation into the effect of brimonidine tartrate concentration on the stability of suspended particles are shown in Table 8. In an aqueous suspension containing brinzolamide, brimonidine tartrate, and timolol maleate, when the brimonidine tartrate concentration was 0.2 w / v%, the maximum particle size of the suspended particles after storage increased to 54 μm, indicating poor stability (Comparative Example 10). In contrast, in an aqueous suspension containing brimonidine tartrate and timolol maleate, when the brimonidine tartrate concentration was 0.1 w / v%, the maximum particle size of the suspended particles after storage was 10 μm or less, indicating improved stability of the particle size of the suspended particles (Example 6).

[0157] In other words, these results confirmed that in order to improve the stability of the particle size of suspended particles, it is important to contain a combination of brinzolamide, brimonidine tartrate, and timolol maleate, and to set the concentration of brimonidine tartrate to approximately 0.1 w / v% (specifically, 0.08 to 0.12 w / v%).

[0158] [Table 8]

Claims

1. An aqueous liquid preparation comprising brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % of brimonidine tartrate, and timolol and / or a salt thereof.

2. 2. The aqueous liquid preparation according to claim 1, wherein the concentration of the brimonidine tartrate is 0.1 w / v%.

3. 3. The aqueous liquid preparation according to claim 1, wherein the concentration of the brinzolamide and / or a salt thereof is 0.1 to 3 w / v %.

4. 3. The aqueous liquid preparation according to claim 1, wherein the concentration of the timolol and / or salt thereof is 0.1 to 1.5 w / v %.

5. 3. The aqueous liquid preparation according to claim 1, wherein the brinzolamide and / or a salt thereof is brinzolamide.

6. 3. The aqueous liquid preparation according to claim 1, wherein the timolol and / or a salt thereof is timolol maleate.

7. An aqueous liquid preparation comprising 0.1 to 3 w / v % brinzolamide, 0.08 to 0.12 w / v % brimonidine tartrate, and 0.1 to 1.5 w / v % timolol maleate.

8. The aqueous liquid preparation according to claim 1 or 7, further comprising benzalkonium chloride.

9. 9. The aqueous liquid preparation according to claim 8, wherein the concentration of the benzalkonium chloride is 0.0001 to 0.01 w / v %.

10. An aqueous liquid preparation comprising 0.1 to 3 w / v% brinzolamide, 0.08 to 0.12 w / v% brimonidine tartrate, 0.1 to 1.5 w / v% timolol maleate, and 0.0001 to 0.01 w / v% benzalkonium chloride.

11. 11. The aqueous liquid preparation according to claim 1, 7, or 10, which is an eye drop.

12. 11. The aqueous liquid preparation according to claim 1, 7, or 10, which is an aqueous suspension.

13. The aqueous liquid preparation according to claim 1 , 7 , or 10 , which is contained in a transparent container.

14. 11. The aqueous liquid preparation according to claim 1, 7, or 10, which is used for the treatment of glaucoma or ocular hypertension.

15. A method for photostabilizing brinzolamide and / or a salt thereof, comprising a step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % of brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous liquid preparation.

16. A method for stabilizing suspended particles in an aqueous suspension containing brimonidine and / or a salt thereof, the method comprising the step of blending brinzolamide and / or a salt thereof, 0.08 to 0.12 w / v % of brimonidine tartrate, and timolol and / or a salt thereof to obtain an aqueous suspension.

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