Patent EA-001958-B1 (EA)
Title: Eprosartan dihydrate and a process for its production and formulation
Inventor: PALEPU NAGESWARA R
IPC: A61K31/40
Filed: 1997-03-26
Abstract: 1. A compound which is (E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dihydrate. 2. A process for the preparation of the compound according to Claim 1 which comprises recrystallizing the anhydrous form of (E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate from an aqueous solution containing an acid. 3. The process according to Claim 2 wherein the acid is methanesulfonic acid. 4. A process for the preparation of the compound according to Claim 1 which comprises: (i) mixing the anhydrous form of (E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate with one or more pharmaceutically acceptable excipients; (ii) granulating the mixture with water; and (iii) drying the granulation to a predetermined water content. 5. The process according to Claim 4 wherein the pharmaceutically acceptable excipient is selected from the group consisting of diluents, fillers, binders, disintegrants and lubricants. 6. A process for the preparation of a solid dosage form containing the compound according to Claim 1 which comprises: (i) producing granules containing (E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dihydrate; and (ii) blending said granules with other pharmaceutically acceptable excipients, and (iii) filling into a capsule or compressing into a tablet. 7. A process for the preparation of a solid dosage form containing the compound according to Claim 1 which comprises: (i) storing the anhydrous form of (E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate at a relative humidity of 98% or higher at ambient or high temperatures for 8 days or longer; (ii) producing granules containing the dihydrate and (iii) blending said granules with other pharmaceutically acceptable excipients and (iii) filling into a capsule or compressing into a tablet. 8. A process for the preparation of a solid dosage form containing the compound according to Claim 1 which comprises: (i) recrystallizing the anhydrous form of (E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate from an aqueous solution containing an acid; (ii) producing granules containing the dihydrate and (iii) blending said granules with other pharmaceutically acceptable excipients and (iii) filling into a capsule or compressing into a tablet. 9. The process according to Claim 8 wherein the acid is methanesulfonic acid. 10. A pharmaceutical composition comprising the compound according to Claim 1, and a pharmaceutically acceptable carrier. 11. A pharmaceutical composition comprising the compound according to Claim 1, a pharmaceutically acceptable carrier and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel blocker, a β-adrenoceptor blocker, a renin inhibitor, and an angiotensin converting enzyme inhibitor. 12. The pharmaceutical composition according to Claim 11 wherein the second pharmaceutically active compound is a diuretic. 13. The pharmaceutical composition according to Claim 12 wherein the diuretic is hydrochlorothiazide. 14. The pharmaceutical composition according to Claim 11 wherein the second pharmaceutically active compound is a loop diuretic. 15. The pharmaceutical composition according to Claim 14 wherein the loop diuretic is furosemide. 16. The pharmaceutical composition according to Claim 11 wherein the second pharmaceutically active compound is a calcium channel blocker. 17. The pharmaceutical composition according to Claim 16 wherein the calcium channel blocker is nifedipine. 18. The pharmaceutical composition according to Claim 11 wherein the second pharmaceutically active compound is a β-adrenoceptor blocker. 19. The pharmaceutical composition according to Claim 18 wherein the β-adrenoceptor blocker is propranolol. 20. The pharmaceutical composition according to Claim 11 wherein the second pharmaceutically active compound is an angiotensin converting enzyme inhibitor. 21. The pharmaceutical composition according to Claim 20 wherein the angiotensin converting enzyme inhibitor is captopril or enalapril. 22. The pharmaceutical composition according to Claim 11 wherein the second pharmaceutically active compound is a renin inhibitor. 23. The pharmaceutical composition according to Claim 22 wherein the renin inhibitor is enalkinen. 24. A method of blocking angiotensin II receptors which comprises administering to a subject in need thereof an effective amount of the compound according to Claim 1. 25. A method of treating hypertension which comprises administering to a subject in need thereof an effective amount of the compound according to Claim 1. 26. A method of treating hypertension which comprises administering stepwise or in physical combination the compound according to Claim 1 and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel blocker, a β-adrenoceptor blocker, a renin inhibitor, and an angiotensin converting enzyme inhibitor. 27. The method according to Claim 26 wherein the second pharmaceutically active compound is a diuretic. 28. The method according to Claim 27 wherein the diuretic is hydrochlorothiazide. 29. The method according to Claim 26 wherein the second pharmaceutically active compound is a loop diuretic. 30. The method according to Claim 29 wherein the loop diuretic is furosemide. 31. The method according to Claim 26 wherein the second pharmaceutically active compound is a calcium channel blocker. 32. The method according to Claim 31 wherein the calcium channel blocker is nifedipine. 33. The method according to Claim 26 wherein the second pharmaceutically active compound is a β-adrenoceptor blocker. 34. The method according to Claim 33 wherein the β-adrenoceptor blocker is proranolol. 35. The method according to Claim 26 wherein the second pharmaceutically active compound is an angiotensin converting enzyme inhibitor. 36. The method according to Claim 35 wherein the angiotensin converting enzyme inhibitor is captopril or enalapril. 37. The method according to Claim 26 wherein the second pharmaceutically active compound is a renin inhibitor. 38. The method according to Claim 37 wherein the renin inhibitor is enalkinen. 39. A method of treating congestive heart failure which comprises administering to a subject in need thereof an effective amount of the compound according to Claim 1. 40. A method of treating renal failure which comprises administering to a subject in need thereof an effective amount of the compound according to Claim 1. 41. A compound according to Claim 1 for use as a medicament. 42. The use of a compound according to Claim 1 in the manufacture of a medicament for the treatment of diseases in which blockade of the angiotensin II receptor is indicated. 43. The use of a compound according to Claim 1 in the manufacture of a medicament for the treatment of hypertension. 44. The use of a compound according to Claim 1 in the manufacture of a medicament for the treatment of congestive heart failure. 45. The use of a compound according to Claim 1 in the manufacture of a medicament for the treatment of renal failure. 46. The use of a compound according to Claim 1 and a diuretic in the manufacture of a medicament for the treatment of hypertension. 47. The use according to Claim 46 wherein the diuretic is hydrochlorothiazide. 48. The use according to Claim 46 wherein the diuretic is furosemide. 49. The use of a compound according to Claim 1 and a calcium channel blocker in the manufacture of a medicament for the treatment of hypertension. 50. The use according to Claim 49 wherein the calcium channel blocker is nifedipine. 51. The use of a compound according to Claim 1 and a β-adrenoceptor blocker in the manufacture of a medicament for the treatment of hypertension. 52. The use according to Claim 51 wherein the β-adrenoceptor blocker is propranolol. 53. The use of a compound according to Claim 1 and a renin inhibitor in the manufacture of a medicament for the treatment of hypertension. 54. The use according to Claim 53 wherein the renin inhibitor is enalkinen. 55. The use of a compound according to Claim 1 and an angiotensin converting enzyme inhibitor in the manufacture of a medicament for the treatment of hypertension. 56. The use according to Claim 55 wherein the angiotensin converting enzyme inhibitor is captopril or enalapril.