Claims
- 1. A controlled release pharmaceutical composition for oral use comprising midodrine (ST 1085) or a pharmaceutically acceptable salt thereof and/or its active metabolite desglymidodrine (ST 1059) or a pharmaceutically acceptable salt thereof,
the composition being adapted to release midodrine and/or desglymidodrine in such a manner that a relatively fast peak plasma concentration of desglymidodrine is obtained and that a therapeutically effective plasma concentration of desglymidodrine is maintained for at least about 9 hours such as, e.g. at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, or at least about 14 hours.
- 2. A controlled release pharmaceutical composition according to claim 1, wherein the relatively fast peak plasma concentration of desglymidodrine is obtained about 15 min—6 hours such as, e.g. about 0.5-6 hours, about 1-6, about 2-5.5 or about 2.5-5.2 hour after oral administration.
- 3. A composition according to claim 1, wherein the plasma concentration of desglymidodrine is maintained at a therapeutically active level for about 4.5-14 hours such as, e.g. about 5-14 hours, about 6-14 hours, about 7-14 hours, about 8-13 hours, about 9-13 hours, about 10-14 hours, about 10-13 hours, or for at least about 4.5 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours or at least about 14 hours.
- 4. A composition according to claim 1, wherein the plasma concentration of desglymidodrine is maintained at a relatively constant level for about 4.5-16 hours such as, e.g., 4.5-14 hours or such as, e.g. for at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, or at least about 11 hours.
- 5. A composition according to claim 4, wherein the relatively constant level n is ±60%, such as, eg., n±50%, n±40%, and wherein n is the plasma concentration in ng/ml and monitored in healthy persons.
- 6. A composition according to claim 1 containing midodrine or a pharmaceutically acceptable salt thereof.
- 7. A composition according to claim 6, wherein a peak plasma concentration of midodrine is obtained 15-90 min after oral administration.
- 8. A composition according to claim 6, wherein the plasma concentration of midodrine after oral administration is maintained at a relatively constant level for about 0.7-4 hours such as, e.g. at least about 0.7 hours, at least about 1 hours, at least about 1.2 hours, at least about 1.3 hours, at least about 1.4 hours, at least about 1.5 hours, at least about 1.6 hours, at least about 1.7 hours, at least about 1.8 hours, at least about 2 hours, at least about 3 hours, or at least about 4 hours.
- 9. A composition according to claim, 8, wherein the relatively constant level m is ±60% such as, e.g. m±50%, or m±40%, and wherein m is the plasma concentration in ng/ml and monitored in healthy persons.
- 10. A composition according to claim 6, wherein the release pattern of midodrine from the composition—when tested in vitro using Dissolution Method I or II described herein and employing a basket according to USP and Ph. Eur, 100 rpm, 600 ml 1 N hydrochloric acid as dissolution medium and a temperature of 37° C.—is:
1-15% w/w is released from the composition within the first 30 min after start of the test, 10-35% (25%) w/w is released about 30 min after start of the test, 15-40% (35%) w/w is released about 1 hour after start of the test 20-50% (39%) w/w is released about 2 hours after start of the test, 20-55% (47%) w/w is released about 3 hours after start of the test, 25-75% such as, e.g., 25-65% (53%) w/w is released about 4 hours after start of the test, 30-74% (66%) w/w is released about 6 hours after start of the test, 40-85% (80%) w/w is released about 8 hours after start of the test, 65-100% (93%) w/w is released about 10 hours after start of the test, 90-110% (100%) w/w is released about 12 hours after start of the test.
- 11. A composition according to claim 6, wherein the release pattern of midodrine from the composition—when tested in vitro using Dissolution Method III or IV described herein and employing a basket according to USP and Ph. Eur. 100 rpm, a first dissolution medium with a pH of about 1.0 for the first 2 hours of the testing followed by a second dissolution medium with a pH of about 6.0 for the next 5.5 hours and finally a third dissolution medium with a pH of about 7.5 until the end of the testing, and a temperature of 37° C.—is:
1-15% w/w is released from the composition within the first 30 min after start of the test, 10-35% (25%) w/w is released about 30 min after start of the test, 15-40% (35%) w/w is released about 1 hour after start of the test 20-50% (39%) w/w is released about 2 hours after start of the test, 20-55% (47%) w/w is released about 3 hours after start of the test, 25-75% such as, e.g., 25-65% (53%) w/w is released about 4 hours after start of the test, 30-74% (66%) w/w is released about 6 hours after start of the test, 40-95% such as, e.g., 45-85% (80%) w/w is released about 8 hours after start of the test, 65-100% (93%) w/w is released about 10 hours after start of the test, 75-110% (100%) w/w is released about 12 hours after start of the test.
- 12. A composition according to claim 6, wherein the release pattern of midodrine from the composition—when tested in vitro employing any of Dissolution Method I, II, III or IV as described herein,—is as follows (±30% w/w such as, e.g., ±25%, ±20%, ±15% or ±10% of the values stated below):
about 25% w/w is released about 30 min after start of the test, about 35% w/w is released about 1 hour after start of the test, about 39% w/w is released about 2 hours after start of the test, about 47% w/w is released about 3 hours after start of the test, about 53-56% such as, e.g., about 53% w/w is released about 4 hours after start of the test, about 66-72% such as, e.g., about 66% w/w is released about 6 hours after start of the test, about 80-85% w/w is released about 8 hours after start of the test, about 93% w/w is released about 10 hours after start of the test, about 100% w/w is released about 12 hours after start of the test.
- 13. A composition according to claim 6, wherein the release pattern of midodrine from the composition—when tested in vitro employing any of Dissolution Method I, II, III or IV as described herein—is:
1-15% w/w is released from the composition within the first 30 min after start of the test, 10-35% (25%) w/w is released about 30 min after start of the test, 15-40% (35%) w/w is released about 1 hour after start of the test, 20-50% (39%) w/w is released about 2 hours after start of the test, 20-55% (47%) w/w is released about 3 hours after start of the test, 25-75% such as 25-65% (53%) w/w is released about 4 hours after start of the test, 30-74% (66%) w/w is released about 6 hours after start of the test, 35-85% (75%) w/w is released about 7 hours after start of the test, 45-95% (90%) w/w is released about 8 hours after start of the test, 65-100% (97%) w/w is released about 10 hours after start of the test, 90-110% (100%) w/w is released about 12 hours after start of the test.
- 14. A composition according to claim 6, wherein the release pattern of midodrine from the composition—when tested in vitro employing any of Dissolution Method I, II, III or IV as described herein—is:
1-15% w/w is released from the composition within the first 30 min after start of the test, 15-35% (25%) w/w is released about 30 min after start of the test, 20-40% (35%) w/w is released about 1 hour after start of the test, 25-50% (39%) w/w is released about 2 hours after start of the test, 30-55% (47%) w/w is released about 3 hours after start of the test, 40-75% such as, e.g., 40-65% (53%) w/w is released about 4 hours after start of the test, 50-74% (66%) w/w is released about 6 hours after start of the test, 60-85% (75%) w/w is released about 7 hours after start of the test, 70-95% (90%) w/w is released about 8 hours after start of the test, 80-100% (97%) w/w is released about 10 hours after start of the test, 90-110% (100%) w/w is released about 12 hours after start of the test.
- 15. A composition according to claim 6, wherein the release pattern of midodrine from the composition—when tested in vitro employing any of Dissolution Method I, II, III or IV as described herein—is as follows (±30% w/w, ±20% w/w, ±10% w/w, ±7.5% w/w or ±5% w/w of the values stated below):
about 25% w/w is released about 30 min after start of the test, about 35% w/w is released about 1 hour after start of the test, about 39% w/w is released about 2 hours after start of the test, about 47% w/w is released about 3 hours after start of the test, about 53% w/w is released about 4 hours after start of the test, about 66 w/w is released about 6 hours after start of the test, about 75% w/w is released about 7 hours after start of the test, about 80% w/w is released about 8 hours after start of the test, about 90% w/w is released about 10 hours after start of the test, about 100% w/w is released about 12 hours after start of the test.
- 16. A composition according to claim 6, wherein the release pattern of midodrine from the composition—when tested in vitro employing any of Dissolution Method I, II, III or IV as described herein—is as follows (±30% w/w, ±20% w/w, ±10% w/w, ±7.5% w/w or ±5% w/w of the values stated below):
about 28% w/w is released about 30 min after start of the test, about 35% w/w is released about 1 hour after start of the test, about 41% w/w is released about 2 hours after start of the test, about 45% w/w is released about 3 hours after start of the test, about 55% w/w is released about 4 hours after start of the test, about 70 w/w is released about 6 hours after start of the test, about 78% w/w is released about 7 hours after start of the test, about 90% w/w is released about 8 hours after start of the test, about 95% w/w is released about 10 hours after start of the test, about 100% w/w is released about 12 hours after start of the test.
- 17. A composition according to claim 6, wherein the release pattern of midodrine from the composition—when tested in vitro employing any of Dissolution Method I, II, III or IV as described herein—is as follows (±30% w/w, ±20% w/w, ±10% w/w, ±7.5% w/w or ±5% w/w of the values stated below):
about 20% w/w is released about 30 min after start of the test, about 20% w/w is released about 1 hour after start of the test, about 20% w/w is released about 2 hours after start of the test, about 20% w/w is released about 3 hours after start of the test, about 25% w/w is released about 4 hours after start of the test, about 45 w/w is released about 6 hours after start of the test, about 75% w/w is released about 7 hours after star of the test, about 90% w/w is released about 8 hours after start of the test, about 95% w/w is released about 10 hours after start of the test, about 100% w/w is released about 12 hours after start of the test.
- 18. A composition according to claim 1 containing desglymidodrine or a pharmaceutically acceptable salt thereof and wherein the release pattern of desglymidodrine follows the patterns claimed for midodrine in any of claims 10-17.
- 19. A composition according to claim 1 containing midodrine or a pharmaceutically acceptable salt thereof and desglymidodrine or a pharmaceutically acceptable salt thereof and wherein the release pattern of the sum of midodrine and desglymidodrine calculated on a molar basis follows the patterns claimed for midodrine in any of claims 10-17.
- 20. A composition according to claim 6, wherein the release rate of midodrine—When tested in vitro employing any of Dissolution Method I, II, III or IV—follows a curve which has a shape corresponding to
i) a relatively fast first initial release followed by ii) a steady release or a slower release than in step i) above, which is followed by iii) a second rise in release rate and, finally, iv) a decline in release rate.
- 21. A composition according to claim 20, wherein the second rise in release rate takes place 5-10 hours such as, e.g., about 5-9 hours, about 6-8 hours after start of the dissolution test.
- 22. A composition according to claim 21, wherein the second rise in release rate takes place 6.5-9 hours after start of the dissolution test simulating the time it takes to reach the colon after oral administration.
- 23. A composition according to claim 20, wherein the steady release period starts about 1-3 hours after start of the dissolution test.
- 24. A composition according to claim 20, wherein the steady release is maintained for at least 2 hours such as, e.g. at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours such as about 6-8 hours.
- 25. A composition according to claim 6, wherein the release rate of midodrine—when tested in vitro employing dissolution apparatus 2 (paddle) according to USP and Ph. Eur, 100 rpm, 0.1 N hydrochloric acid as dissolution medium or any of Dissolution Method I, II, III or IV as described herein and a temperature of 37° C.—in %/hour is as follows (±10-40% such as, e.g. ±10-30% or ±10%, ±15% or ±20% of the values stated below):
about 35%/hour about 30 min after start of the test (range e.g. 15-40%/hour), about 12%/hour about 1 hour after start of the test (range e.g 4-15%/hour), about 6%/hour about 2 hours after start of the test (range e.g. 2-10%/hour), about 7%/hour about 3 hours after start of the test (range e.g. 2-10%/hour), about 6.5%/hour about 4 hours after start of the test (range e.g. 2-15%/hour), about 7.5%/hour about 6 hours after start of the test (range e.g. 2-30% such as, e.g., 2-10%/hour), about 10%/hour about 8 hours after start of the test (range e.g. 2-15%/hour), about 2%/hour about 10 hours after start of the test (range e.g. 0-10%/hour), about 1%hour about 12 hours after start of the test (range e.g. 0-10%/hour).
- 26. A composition according to claim 1 containing desglymidodrine or a pharmaceutically acceptable salt thereof and wherein the release rate of desglymidodrine follows the patterns claimed for midodrine in any of claims 20-25.
- 27. A composition according to claim 1 containing midodrine or a pharmaceutically acceptable salt thereof and desglymidodrine or a pharmaceutically acceptable salt thereof and wherein the release rate of the sum of midodrine and desglymidodrine calculated on a molar basis follows the patterns claimed for midodrine in any of claims 20-25.
- 28. A composition according to any of the preceding claims for administration once or twice daily.
- 29. A composition according to claim 6, wherein the W50 of midodrine (defined as corresponding to the time the plasma concentration curve is or is above 50% of the Cmax value) is from about 1 to about 9 hours such as, e.g. from about 1.3 to about 8 hours such as, e.g. at least about 1.4 hours, at least about 1.5 hours, or at least about 1.7 hours.
- 30. A composition according to any of the preceding claims, wherein the W50 of desglymidodrine (defined as corresponding to the time the plasma concentration curve is or is above 50% of the Cmax value is from about 5 to about 12 hours such as, e.g. from about 6 to about 11 hours such as, e.g. at least about 7 hours.
- 31. A composition according to any of the preceding claims, wherein Tmax is increased with a factor of at least 2 when compared with a plain Gutron® tablet administered in the same dose and where Tmax is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
- 32. A composition according to any of the preceding claims, wherein MRT (mean residence time) is increased with a factor of at least 2 when compared with a plain Gutron® tablet administered in the same dose and where MRT is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
- 33. A composition according to any of the preceding claims, wherein W50 is increased with a factor of at least 2 such as, e.g., at least 2.5 when compared with a plain Gutron® tablet administered in the same dose and where W50 is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
- 34. A composition according to any of the preceding claims, wherein W75 (T>75% Tmax) is increased with a factor of at least 1.5 such as, e.g. at least 2 when compared with a plain Gutron® tablet administered in the same dose and where W75 T>75% Tmax) is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
- 35. A composition according to any of the preceding claims, wherein the MRT for midodrine is at least about 1.5 hours such as, e.g., at least about 2 hours, at least about 2.5 hours or at least about 3 hours.
- 36. A composition according to any of the preceding claims, wherein the MRT for desglymidodrine is at least about 6 hours such as, e.g., at least about 7 hours, at least about 7.5 hours, at least about 8 hours, at least about 8.5 hours, at least about 9 hours, or at least about 9.5 hours.
- 37. A composition according to any of the preceding claims, wherein midodrine is present in the form of (±)-2-amino-N-(β-hydroxy-2,5-dimethoxyphenethyl)acetamide, (+)2-amino-N-(β-hydroxy-2,5-dimethoxyphenethyl)acetamide, (−)-2-amino-N-(β-hydroxy-2,5-dimethoxyphenethyl)acetamide or mixtures thereof.
- 38. A composition according to any of the preceding claims, wherein midodrine is present in the racemic form (RS), in the enantiomeric form (R), in the enantiomeric form (S) or in mixtures thereof.
- 39. A composition according to claim 37 or 38, wherein at least 90% w/w such as, e.g., at least 95% w/w, at least 97% w/w, at least 98% w/w, at least 99% w/w of midodrine is present in the therapeutically active enantiomeric form.
- 40. A composition according to claim 39, wherein the therapeutically active enantiomeric form of midodrine is (−)-2-amino-N-(β-hydroxy-2,5-dimethoxyphenethyl)acetamide or the (R) form of midodrine.
- 41. A composition according to claim 1 containing the active metabolite desglymidodrine (ST 1059), wherein desglymidodrine is present in the form of (±)-α-(aminomethyl)-2,5-dimethoxy-benzenemethanol (±ST 1059), (+)-α-(aminomethyl)-2,5-dimethoxy-benzenemethanol (+ST 1059), (−)-α-(aminomethyl)-2,5-dimethoxy-benzonemethanol (−ST 1059) or mixtures thereof.
- 42. A composition according to claim 41, wherein desglymidodrine is present in the racemic form (RS), in the enantiomeric form (R), in the enantiomeric form (8) or in mixtures thereof.
- 43. A composition according to claim 41 or 42, wherein at least 90% w/w such as, e.g., at least 95% w/w, at least 97% w/w, at least 98% w/w, at least 99% w/w of desglymidodrine is present in the therapeutically active enantiomeric form.
- 44. A composition according to claim 43, wherein the therapeutically active enantiomeric form of desglymidodrine is (−)-α-(aminomethyl)-2,5dimethoxy-benzenemethanol (−ST 1059) or the (R) form of desglymidodrine ((R) ST 1059).
- 45. A composition according to any of the preceding claims, wherein midodrine and/or desglymidodrine are present in the form of a pharmaceutically acceptable salt such as a salt formed between midodrine and/or desglymidodrine and an inorganic acid such as e.g., a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a nitrite, a H3PO3 salt, a H3PO4 salt, a H2SO3 salt, a sulfate, a H2SO5 salt, or a salt formed between midodrine and/or desglymidodrine and an organic acid such as organic acids like e.g. H2CO3, acetic acid, C2H5COOH, C3H7COOH, C4H9COOH, (COOH)2, CH2(COOH)2, C2H6(COOH)2, C3H6(COOH)2, C4H8(COOH)2, C5H10(COOH)2, fumaric acid, maleic acid, lactic acid, citric acid, tartaric acid, ascorbic acid, benzoic acid, salicylic acid and phthalic acid.
- 46. A composition according to any of the preceding claims in liquid form.
- 47. A composition according to any of claims 1-45 in the form of a solid dosage form.
- 48. A composition according to claim 47 in the form of tablets, capsules, sachets, solid dispersion, crystals and the like.
- 49. A composition according to claim 48, which comprises at least two parts such as at least a first and a second part, each part contains midodrine and/or, if present, desglymidodrine and the first part being adapted to release midodrine and/or, if present, desglymidodrine, in a controlled manner during the first 0-14 such as, e.g. 0-11 hours or 0-8 hours after oral intake and the second part being adapted to release midodrine and/or, if present, desglymidodrine, starting at least 6 hours after oral intake.
- 50. A composition according to claim 49, wherein at least one of the at least two parts is present in the composition in the form of a multiplicity of individual units such as, e.g. pellets or minitablets.
- 51. A composition according to claim 49, wherein the two parts of the at least two parts are present in the composition in the form of a multiplicity of individual units such as, e.g. pellets or minitablets, and the two parts are in admixture.
- 52. A composition according to claim 49 in multiple unit dosage form.
- 53. A composition according to claim 52 in the form of a multiple unit dosage form, wherein at least one of the at least two parts comprising at least two different types of pellets, the first type of pellets corresponding to a first fraction and the second type of pellets corresponding to a second fraction.
- 54. A composition according to claim 52, wherein the at least two parts of the composition comprise at least two different types of pellets, the first type of pellets corresponding to the first part and the second type of pellets corresponding to the second part.
- 55. A composition according to claim 52 in the form of a multiple unit dosage form comprising at least two different types of minitablets, the first type of minitablets corresponding to the first part and the second type of minitablets corresponding to the second part.
- 56. A composition according to claim 52 in the form of a multiple unit dosage form, wherein the first or the second part is in the form of minitablets.
- 57. A composition according to claim 52, wherein the first or the second part is in the form of pellets.
- 58. A composition according to claim 49, wherein the at least two fractions is present in a tablet.
- 59. A composition according to claim 58, wherein the tablet is a multilayer tablet and the at least first and the second part are each comprised in a layer in the tablet.
- 60. A composition according to claim 49 further comprising a third part adapted to release midodrine and, if present, desglymidodone relatively fast from the composition.
- 61. A composition according to claim 49 further comprising a fourth part adapted to release midodrine and/or desglymidodrine from the composition 6-10 hours after oral intake.
- 62. A composition according to claim 49 further comprising a fourth part adapted to release midodrine and/or desglymidodrine from the composition in the colon after oral intake.
- 63. A composition according to claim 61 or 62, wherein the third and/or, if present, the fourth part comprise pellets or minitablets or are a layer in or on a tablet.
- 64. A composition according to claim 49, wherein the first part has a release kinetic corresponding to a zero or a first order release, a mixture of zero and first order release, or any other order of release such as, e.g. 1½, second, third or fourth order release.
- 65. A composition according to claim 49 wherein the second part has a release kinetic corresponding to a zero or a first order release, a mixture of zero and first order release, or any other order of release such as, e.g. 1½, second, third or fourth order release.
- 66. A composition according to claim 60, wherein the third fraction has a release kinetic, which corresponds to that of a plain release tablet.
- 67. A composition according to any of claims 1-66, wherein the composition comprises one or more further active drug substance(s).
- 68. A method for treating a patient suffering from orthostatic hypotension and/or urinary incontinence such as urinary stress incontinence, the method comprising administering an effective amount of midodrine and/or desglymidodrine in the form of a controlled release composition according to any of claim 1-67 to a patient in need thereof.
- 69. A method according to claim 68, wherein an administration takes place at wake-up time.
- 70. A method according to claim 68, wherein an administration takes place in the morning.
- 71. A method according to claim 68, wherein an administration takes place at in the middle of the day and in the form of 1-2 tablets.
- 72. A method according to any of claims 68-71, wherein the administration takes place 1-3 times daily.
- 73. A method according to any of claims 68-71, wherein the administration takes place 1 or 2 times daily.
- 74. A method according to any of claims 68-71, wherein the administration takes place once daily.
Priority Claims (1)
Number |
Date |
Country |
Kind |
PA 2000 00549 |
Mar 2000 |
DK |
|
Parent Case Info
[0001] This application claims priority to U.S. Provisional Application No. 60/203,783, filed May 12, 2000 and is incorporated herein introduction by reference.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60203783 |
May 2000 |
US |