Patent EA-004871-B1 (EA)
Title: STABILIZED FORMULATIONS OF 6-HYDROXY-3-(4-[PIPERIDIN-1-YL) ETHOXY]PHENOXY)-2-(4-METHOXYPHENYL)BENZO[b]THIOPHENE AND SALTS THEREOF
Inventor: BASHORE FADIA NAJJAR
IPC: A61P25/00
Filed: 2001-04-30
Abstract: 1. A pharmaceutical formulation comprising 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene or a salt thereof; a stabilizing agent selected from methionine, acetylcysteine, cysteine or salts thereof in an amount sufficient to effect stabilization to decomposition; and pharmaceutically acceptable excipients. 2. A pharmaceutical formulation according to claim 1 wherein the stabilizing agent is present in said formulation in an amount of from about 0.01 to about 10 percent by weight of the total formulation. 3. A pharmaceutical formulation according to claim 2 wherein the stabilizing agent is present in said formulation in an amount of from about 0.05 to about 5.0 percent by weight of the total formulation. 4. A pharmaceutical formulation according to any one of claims 1-3 wherein the 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene is present as 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride. 5. A pharmaceutical formulation according to claim 4 wherein said 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride is crystalline 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride hydrate (F-I) having an X-ray diffraction d line spacing pattern which comprises the following peaks: 7.91 +- 0.2, 10.74 +- 0.2, 14.86 +-0.2, 15.92 +-0.2, 18.28 +- 0.2, and 20.58 +- 0.2 degree in 2theta; when obtained from a copper radiation source. 6. A pharmaceutical formulation according to claim 4 wherein said 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride is crystalline 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride hydrate (F-III) having an X-ray diffraction d line spacing pattern which comprises the following peaks: 4.63 +- 0.2, 7.82 +- 0.2, 9.29 +- 0.2, 13.97 +- 0.2, 17.62 +- 0.2, 20.80 +- 0.2 and 24.31 +- 0.2 degree in 2theta; when obtained at 25 +- 2 degree C and 35 +- 10% relative humidity from a copper radiation source. 7. A pharmaceutical formulation according to claim 4 wherein said 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride is crystalline 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride hydrate (F-V) having an X-ray diffraction pattern which comprises at least one of the following peaks: 7.3 +- 0.2, 15.5 +- 0.2, 15.9 +- 0.2 and 17.6 0.2 degree in 26 when obtained from a copper radiation source. 8. A pharmaceutical formulation according to claim 7 wherein said X-ray diffraction pattern further comprises the following peaks: 17.9 +- 0.2, 18.2 +- 0.2, 18.9 +- 0.2, and 21.5 +- 0.2 degree in 2theta when obtained from a copper radiation source. 9. A pharmaceutical formulation according to any one of claims 1-8 wherein the stabilizing agent is cysteine, or a salt thereof. 10. A pharmaceutical formulation according to any one of claims 1-8 wherein the stabilizing agent is cysteine hydrochloride. 11. A pharmaceutical formulation according to any one of claims 1-8 wherein the stabilizing agent is L-cysteine hydrochloride monohydrate. 12. A pharmaceutical formulation according to any one of claims 1-8 wherein the stabilizing agent is methionine, or a salt thereof. 13. A pharmaceutical formulation according to any one of claims 1-8 wherein the stabilizing agent is acetylcysteine, or a salt thereof. 14. A pharmaceutical formulation according to any one of claims 1-13 which is a tablet. 15. A pharmaceutical formulation according to any one of claims 1-13 which is a capsule. 16. A pharmaceutical formulation according to any one of claims 4-8 containing 20-23 mg, preferably approximately 21.53 mg, of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride, and 0.2-0.8 mg, preferably approximately 0.5 mg, of cysteine hydrochloride. 17. A pharmaceutical formulation according to claim 16 which is a tablet weighing 220-280 mg, preferably approximately 250 mg. 18. A pharmaceutical formulation any one of claims 4-8 containing 5.3-5.9 mg, preferably approximately 5.62 mg, of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride, and 0.2-0.3 mg, preferably approximately 0.25 mg, of cysteine hydrochloride. 19. A pharmaceutical formulation according to claim 18 which is a tablet weighing 120-130 mg, preferably approximately 125 mg. 20. A pharmaceutical formulation according to anyone of claims 16-19 wherein the cysteine hydrochloride is L-cysteine hydrochloride monohydrate. 21. A method for inhibiting a pathological condition selected from the group consisting of: uterine fibrosis, endometriosis, aortal smooth muscle cell proliferation, restenosis, breast cancer, uterine cancer, prostatic cancer or benign prostatic hyperplasia, bone loss, osteoporosis, cardiovascular disease, hyperlipidemia, CNS disorders, and Alzheimer's disease; which comprises administering to a mammal in need thereof, an effective amount of the pharmaceutical formulation of claim 1. 22. The method of claim 21 wherein the pathological condition is breast cancer. 23. The method of claim 21 wherein the pathological condition is osteoporosis. 24. The method of claim 21 wherein the pathological condition is endometrial cancer. 25. A pharmaceutical formulation according to any one of claims 1-20 for use in the treatment of the human or animal body by therapy. 26. Use of a pharmaceutical formulation according to any one of claims 1-20 in the manufacture of a medicament for the treatment of uterine fibrosis, endometriosis, aortal smooth muscle cell proliferation, restenosis, breast cancer, uterine cancer, prostatic cancer or benign prostatic hyperplasia, bone loss, osteoporosis, cardiovascular disease, hyperlipidemia, CNS disorders or Alzheimer's disease. 27. A method of stabilizing a pharmaceutical formulation comprising 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene or a salt thereof to decomposition which method comprises incorporating into said pharmaceutical formulation, in addition to a therapeutically effective amount of said hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene or a salt thereof and one or more pharmaceutically acceptable excipients, a stabilizing agent selected from methionine, acetylcysteine, cysteine, or salts thereof in an amount sufficient to effect stabilization to decomposition. 28. A method of claim 27 wherein the 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene is present as 6-hydroxy-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride. 29. A method according to claim 27 or 28 wherein the stabilizing agent is present in said formulation in an amount of from about 0.01 to about 10 percent by weight of the total formulation. 30. A method according to any one of claims 27-29 wherein the stabilizing agent is cysteine. 31. A method according to any one of claims 27-30 wherein the stabilizing agent is cysteine hydrochloride. 32. A method according to any one of claims 27-31, wherein the cysteine hydrochloride is L-cysteine hydrochloride monohydrate. 33. A method according to any one of claims 27-29 wherein the stabilizing agent is methionine. 34. A method according to any one of claims 27-29 wherein the stabilizing agent is acetylcysteine. 35. Use of crystalline 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride hydrate (F-I) having an X-ray diffraction d line spacing pattern which comprises the following peaks: 7.91 +- 0.2, 10.74 +- 0.2, 14.86 +- 0.2, +- 15.92 +- 0.2, 18.28 +- 0.2 and 20.58 +- 0.2 degree in 2theta; when obtained from a copper radiation source, in the manufacture of a medicament for the treatment of uterine fibrosis, endometriosis, aortal smooth muscle cell proliferation, restenosis, breast cancer, uterine cancer, prostatic cancer or benign prostatic hyperplasia, bone loss, osteoporosis, cardiovascular disease, hyperlipidemia, CNS disorders or Alzheimer's disease. 36. Use of crystalline 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride hydrate (F-III) having an X-ray diffraction d line spacing pattern which comprises the following peaks: 4.63 +- 0.2, 7.82 +- 0.2, 9.29 +- 0.2, 13.97 +- 0.2, 17.62 +- 0.2, 20.80 +- 0.2 and 24.31 +- 0.2 degree in 2theta; when obtained at 25 +- 2 degree C and 35 10% relative humidity from a copper radiation source, in the manufacture of a medicament for the treatment of uterine fibrosis, endometriosis, aortal smooth muscle cell proliferation, restenosis, breast cancer, uterine cancer, prostatic cancer or benign prostatic hyperplasia, bone loss, osteoporosis, cardiovascular disease, hyperlipidemia, CNS disorders or Alzheimer's disease. 37. Use of crystalline 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride hydrate (F-V) having an X-ray diffraction pattern which comprises at least one of the following peaks: 7.3 +- 0.2, 15.5 +- 0.2, 15.9 +- 0.2 and 17.6 +- 0.2 degree in 2theta when obtained from a copper radiation source, in the manufacture of a medicament for the treatment of uterine fibrosis, endometriosis, aortal smooth muscle cell proliferation, restenosis, breast cancer, uterine cancer, prostatic cancer or benign prostatic hyperplasia, bone loss, osteoporosis, cardiovascular disease, hyperlipidemia, CNS disorders or Alzheimer's disease. 38. Use according to claim 37 wherein said X-ray diffraction pattern further comprises the following peaks: 17.9 +- 0.2, 18.2 +- 0.2, 18.9 +- 0.2 and 21.5 +- 0.2 degree in 2theta when obtained from a copper radiation source.