Clear aqueous solution
The present invention provides a stable and clear aqueous liquid preparation containing (3-{2-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]ethyl}-5-methyl-1,2-benzisoxazol-6-yl) oxyacetic acid or a pharmaceutically acceptable salt thereof as an active ingredient, and bensalkonium chloride represented by the formula: [C 6 H 5 CH 2 N(CH 3 ) 2 R]Cl wherein R is an alkyl group having 8-18 carbon atoms.
1. An aqueous liquid preparation comprising: (1) (3-{2-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]ethyl}-5-methyl-1,2-benzisoxazol-6-yl)oxyacetic acid or a pharmaceutically acceptable salt thereof, and (2) one benzalkonium chloride or a mixture of benzalkonium chlorides, wherein benzalkonium chloride is represented by the formula:
[C 6 H 5 CH 2 N(CH 3 ) 2 R]Cl
wherein R is an alkyl group having 8-18 carbon atoms, wherein the transmittance of the aqueous liquid preparation at wavelength 600 nm is not less than 98%, and
wherein the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 8 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 10 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.003 w/v % or higher than 0.01 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 12 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 14 carbon atoms,
wherein the one benzalkonium chloride has a concentration other than 0.001 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 16 carbon atoms,
wherein the mixture of the benzalkonium chlorides has a total concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the aqueous liquid preparation when the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms, and (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, or
wherein the mixture of the benzalkonium chlorides has a total concentration of 0.003 w/v % relative to the total amount of the aqueous liquid preparation when the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms, (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and (iii) a third benzalkonium chloride wherein R is an alkyl group having 16 carbon atoms.
2. The aqueous liquid preparation according to claim 1 , wherein (3-{2-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]ethyl}-5-methyl-1,2-benzisoxazol-6-yl)oxyacetic acid or a pharmaceutically acceptable salt thereof has a concentration selected from the range of the lower limit concentration of about 0.0001 w/v % and the upper limit concentration of about 0.05 w/v % relative to the total amount of the aqueous liquid preparation.
3. The aqueous liquid preparation according to claim 1 , wherein R is an alkyl group having 8 carbon atoms, and the one benzalkonium chloride contained therein has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the aqueous liquid preparation.
4. The aqueous liquid preparation according to claim 1 , wherein R is an alkyl group having 10 carbon atoms, and the one benzalkonium chloride contained therein has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the aqueous liquid preparation.
5. The aqueous liquid preparation according to claim 1 , wherein R is an alkyl group having 12 carbon atoms, and the one benzalkonium chloride contained therein has a concentration of less than 0.003 w/v % or higher than 0.01 w/v % relative to the total amount of the aqueous liquid preparation.
6. The aqueous liquid preparation according to claim 1 , wherein R is an alkyl group having 14 carbon atoms, and the one benzalkonium chloride contained therein has a concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the aqueous liquid preparation.
7. The aqueous liquid preparation according to claim 1 , wherein R is an alkyl group having 16 carbon atoms, and the one benzalkonium chloride contained therein has a concentration other than 0.001 w/v % relative to the total amount of the aqueous liquid preparation.
8. The aqueous liquid preparation according to claim 1 , wherein R of the one benzalkonium chloride is an alkyl group having 18 carbon atoms.
9. The aqueous liquid preparation according to claim 1 , wherein the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms and (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and wherein the total concentration of the benzalkonium chloride mixture relative to the total amount of the aqueous liquid preparation is less than 0.001 w/v % or higher than 0.002 w/v %.
10. The aqueous liquid preparation according to claim 1 , further comprising a surfactant.
11. The aqueous liquid preparation according to claim 10 , wherein the surfactant is tyloxapol.
12. An ophthalmic solution comprising: (1) (3-{2-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]ethyl}-5-methyl-1,2-benzisoxazol-6-yl)oxyacetic acid or a pharmaceutically acceptable salt thereof, and (2) one benzalkonium chloride or a mixture of benzalkonium chlorides, wherein benzalkonium chloride is represented by the formula:
[C 6 H 5 CH 2 N(CH 3 ) 2 R]Cl
wherein R is an alkyl group having 8-18 carbon atoms,
wherein the transmittance of the opthalamic solution at wavelength 600 nm is not less than 98%, and
wherein the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the opthalamic solution when R is an alkyl group having 8 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the opthalamic solution when R is an alkyl group having 10 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.003 w/v % or higher than 0.01 w/v % relative to the total amount of the opthalamic solution when R is an alkyl group having 12 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the opthalamic solution when R is an alkyl group having 14 carbon atoms,
wherein the one benzalkonium chloride has a concentration other than 0.001 w/v % relative to the total amount of the opthalamic solution when R is an alkyl group having 16 carbon atoms,
wherein the mixture of the benzalkonium chlorides has a total concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the opthalamic solution when the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms and (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, or
wherein the mixture of the benzalkonium chlorides has a total concentration of 0.003 w/v % relative to the total amount of the opthalamic solution when the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms, (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and (iii) a third benzalkonium chloride wherein R is an alkyl group having 16 carbon atoms.
13. A method of preparing the aqueous liquid preparation of claim 1 comprising: adding one benzalkonium chloride or a mixture of benzalkonium chlorides, wherein benzalkonium chloride is represented by the formula:
[C 6 H 5 CH 2 N(CH 3 ) 2 R]Cl
wherein R is an alkyl group having 8-18 carbon atoms to an aqueous liquid solution comprising (3-{2-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]ethyl}-5-methyl-1,2-benzisoxazol-6-yl)oxyacetic acid or a pharmaceutically acceptable salt thereof, and
wherein the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 8 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % when R is an alkyl group having 10 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.003 w/v % or higher than 0.01 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 12 carbon atoms,
wherein the one benzalkonium chloride has a concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 14 carbon atoms,
wherein the one benzalkonium chloride has a concentration other than 0.001 w/v % relative to the total amount of the aqueous liquid preparation when R is an alkyl group having 16 carbon atoms,
wherein the mixture of the benzalkonium chlorides has a total concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the aqueous liquid preparation when the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms and (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, or
wherein the mixture of the benzalkonium chlorides has a total concentration of 0.003 w/v % relative to the total amount of the aqueous liquid preparation when the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms, (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and (iii) a third benzalkonium chloride wherein R is an alkyl group having 16 carbon atoms, and
wherein the transmittance of the aqueous liquid preparation at wavelength 600 nm is not less than 98%.
14. The method according to claim 13 , wherein R is an alkyl group having 8 carbon atoms and the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the aqueous liquid preparation.
15. The method according to claim 13 , wherein R is an alkyl group having 10 carbon atoms and the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the aqueous liquid preparation.
16. The method according to claim 13 , wherein R is an alkyl group having 12 carbon atoms and the one benzalkonium chloride has a concentration of less than 0.003 w/v % or higher than 0.01 w/v % relative to the total amount of the aqueous liquid preparation.
17. The method according to claim 13 , wherein R is an alkyl group having 14 carbon atoms and the one benzalkonium chloride has a concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the aqueous liquid preparation.
18. The method according to claim 13 , wherein R is an alkyl group having 16 carbon atoms and the one benzalkonium chloride has a concentration other than 0.001 w/v % relative to the total amount of the aqueous liquid preparation.
19. The method according to claim 13 , comprising adding the one benzalkonium chloride wherein R is an alkyl group having 18 carbon atoms.
20. The method according to claim 13 , comprising adding the mixture of benzalkonium chlorides, wherein the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms and (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and the total concentration of the benzalkonium chloride mixture is less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the aqueous liquid preparation.
21. The aqueous liquid preparation according to claim 1 , wherein the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms, (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and (iii) a third benzalkonium chloride wherein R is an alkyl group having 16 carbon atoms, and the total concentration of the benzalkonium chloride mixture relative to the total amount of the aqueous liquid preparation is 0.003 w/v %.
22. The aqueous liquid preparation according to claim 1 , wherein the one benzalkonium chloride or the mixture of benzalkonium chlorides has a concentration selected from the range of the lower limit concentration of about 0.0001 w/v % and the upper limit concentration of about 5 w/v % relative to the total amount of the aqueous liquid preparation.
23. The aqueous liquid preparation according to claim 1 , further comprising a buffer.
24. The aqueous liquid preparation according to claim 10 , further comprising a buffer.
25. The ophthalmic solution according to claim 12 , wherein the (3-{2-[4-isopropyl-2-(4-trifluoromethyl)phenyl-5-thiazolyl]ethyl}-5-methyl-1,2-benzisoxazol-6-yl)oxyacetic acid or the pharmaceutically acceptable salt thereof has a concentration selected from the range of the lower limit concentration of about 0.0001 w/v % and the upper limit concentration of about 0.05 w/v % relative to the total amount of the aqueous liquid preparation.
26. The ophthalmic solution according to claim 12 , wherein R is an alkyl group having 8 carbon atoms, and the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the ophthalmic solution.
27. The ophthalmic solution according to claim 12 , wherein R is an alkyl group having 10 carbon atoms, and the one benzalkonium chloride has a concentration of less than 0.05 w/v % or higher than 0.1 w/v % relative to the total amount of the ophthalmic solution.
28. The ophthalmic solution according to claim 12 , wherein R is an alkyl group having 12 carbon atoms, and the one benzalkonium chloride has a concentration of less than 0.003 w/v % or higher than 0.01 w/v % relative to the total amount of the ophthalmic solution.
29. The ophthalmic solution according to claim 12 , wherein R is an alkyl group having 14 carbon atoms, and the one benzalkonium chloride has a concentration of less than 0.001 w/v % or higher than 0.002 w/v % relative to the total amount of the ophthalmic solution.
30. The ophthalmic solution according to claim 12 , wherein R is an alkyl group having 16 carbon atoms, and the one benzalkonium chloride has a concentration other than 0.001 w/v % relative to the total amount of the ophthalmic solution.
31. The ophthalmic solution according to claim 12 , wherein R of the one benzalkonium chloride is an alkyl group having 18 carbon atoms.
32. The ophthalmic solution according to claim 12 , wherein the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms and (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and the total concentration of the benzalkonium chloride mixture relative to the total amount of the ophthalmic solution is less than 0.001 w/v % or higher than 0.002 w/v %.
33. The ophthalmic solution according to claim 12 , wherein the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms, (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and (iii) a third benzalkonium chloride wherein R is an alkyl group having 16 carbon atoms, and the total concentration of the benzalkonium chloride mixture relative to the total amount of the ophthalmic solution is 0.003 w/v %.
34. The ophthalmic solution according to claim 12 , further comprising a surfactant.
35. The ophthalmic solution according to claim 34 , wherein the surfactant is tyloxapol.
36. The ophthalmic solution according to claim 12 , wherein the one benzalkonium chloride or the mixture of benzalkonium chlorides has a concentration selected from the range of the lower limit concentration of about 0.0001 w/v % and the upper limit concentration of about 5 w/v % relative to the total amount of the ophthalmic solution.
37. The ophthalmic solution according to claim 12 , further comprising a buffer.
38. The ophthalmic solution according to claim 34 , further comprising a buffer.
39. The method according to claim 13 , comprising adding the mixture of benzalkonium chlorides, wherein the mixture comprises (i) a first benzalkonium chloride wherein R is an alkyl group having 12 carbon atoms, (ii) a second benzalkonium chloride wherein R is an alkyl group having 14 carbon atoms, and (iii) a third benzalkonium chloride wherein R is an alkyl group having 16 carbon atoms, and the total concentration of the benzalkonium chloride mixture is 0.003 w/v % relative to the total amount of the aqueous liquid preparation.