Claims for Patent: 9,925,147

Summary for Patent: 9,925,147

Title:	Method for treating secondary hyperparathyroidism in CKD
Abstract:	A stable, controlled release formulation for oral dosing of vitamin D compounds is disclosed. The formulation is prepared by incorporating one or more vitamin D compounds into a solid or semi-solid mixture of waxy materials. Oral dosage forms can be prepared by melt-blending the components described herein and filling gelatin capsules with the formulation.
Inventor(s):	Bishop; Charles W. (Miami Beach, FL), Tabash; Samir P. (Whitby, CA), Agudoawu; Sammy A. (Mississauga, CA), White; Jay A. (Newmarket, CA), Messner; Eric J. (Lake Forest, IL), Petkovich; P. Martin (Kingston, CA), Crawford; Keith H. (Lone Tree, CO)
Assignee:	OPKO RENAL, LLC (Miami, FL) OPKO IRELAND GLOBAL HOLDINGS, LIMITED (Grand Cayman, KY)
Application Number:	15/358,065
Patent Claims:	1. A method of treating secondary hyperparathyroidism in a human patient having Chronic Kidney Disease (CKD), comprising administering to the human patient having CKD an effective amount of a sustained release formulation of a 25-hydroxyvitamin D compound to treat the secondary hyperparathyroidism and reduce the patient's serum parathyroid hormone level, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 10 hours. 2. The method of claim 1, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 24 hours. 3. The method of claim 1, wherein the administration avoids transient increases in blood levels of 25-hydroxyvitamin D of greater than 3 ng/mL following a unit dose. 4. The method of claim 1, wherein the 25-hydrovitamin D compound is 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 5. The method of claim 1, wherein the sustained release formulation comprises 1 .mu.g to 1000 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 6. The method of claim 5, wherein the sustained release formulation comprises 1 .mu.g to 100 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 7. The method of claim 1, wherein the sustained release formulation comprises a waxy controlled release carrier. 8. The method of claim 1, wherein the sustained release formulation comprises a waxy controlled release carrier, a lipoidic agent, and an oily vehicle for the 25-hydroxyvitamin D compound. 9. The method of claim 1, comprising administering the sustained release formulation to deliver a dosage amount of the 25-hydroxyvitamin D compound from 1 to 100 .mu.g per day. 10. The method of claim 1, wherein the patient has CKD Stage 5. 11. The method of claim 1, wherein the patient has CKD Stage 1 or 2. 12. The method of claim 1, wherein the patient has CKD Stage 3 or 4. 13. A method of treating secondary hyperparathyroidism in a human patient having Chronic Kidney Disease (CKD), comprising administering to the human patient having CKD an effective amount of a sustained release formulation of a 25-hydroxyvitamin D compound to treat the secondary hyperparathyroidism and reduce the patient's serum parathyroid hormone level, such that the maximum serum concentration (Cmax) of 25-hydroxyvitamin D in a dose interval is reduced compared to the Cmax for an equivalent amount of the 25-hydroxyvitamin D compound administered by bolus IV injection and an equivalent amount of the 25-hydroxyvitamin D compound administered by immediate-release, oral dosing. 14. The method of claim 13, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 10 hours. 15. The method of claim 13, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 24 hours. 16. The method of claim 13, wherein the administration avoids transient increases in blood levels of 25-hydroxyvitamin D of greater than 3 ng/mL following a unit dose. 17. The method of claim 13, wherein the 25-hydrovitamin D compound is 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 18. The method of claim 13, wherein the sustained release formulation comprises 1 .mu.g to 1000 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 19. The method of claim 18, wherein the sustained release formulation comprises 1 .mu.g to 100 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 20. The method of claim 13, wherein the sustained release formulation comprises a waxy controlled release carrier. 21. The method of claim 13, wherein the sustained release formulation comprises a waxy controlled release carrier, a lipoidic agent, and an oily vehicle for the 25-hydroxyvitamin D compound. 22. The method of claim 13, comprising administering the sustained release formulation to deliver a dosage amount of the 25-hydroxyvitamin D compound from 1 to 100 .mu.g per day. 23. The method of claim 13, wherein the patient has CKD Stage 5. 24. The method of claim 13, wherein the patient has CKD Stage 1 or 2. 25. The method of claim 13, wherein the patient has CKD Stage 3 or 4. 26. A method of treating secondary hyperparathyroidism in a human patient having Chronic Kidney Disease (CKD), comprising administering to the human patient having CKD an effective amount of a sustained release formulation of a 25-hydroxyvitamin D compound to treat the secondary hyperparathyroidism and reduce the patient's serum parathyroid hormone level, such that the maximum change in serum concentration of 25-hydroxyvitamin D in a dose interval is reduced compared to the maximum change in serum concentration of 25-hydroxyvitamin D for an equivalent amount of the 25-hydroxyvitamin D compound administered by bolus IV injection and an equivalent amount of the 25-hydroxyvitamin D compound administered by immediate-release, oral dosing. 27. The method of claim 26, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 10 hours. 28. The method of claim 26, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 24 hours. 29. The method of claim 26, wherein the administration avoids transient increases in blood levels of 25-hydroxyvitamin D of greater than 3 ng/mL following a unit dose. 30. The method of claim 26, wherein the 25-hydrovitamin D compound is 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 31. The method of claim 26, wherein the sustained release formulation comprises 1 .mu.g to 1000 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 32. The method of claim 31, wherein the sustained release formulation comprises 1 .mu.g to 100 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 33. The method of claim 26, wherein the sustained release formulation comprises a waxy controlled release carrier. 34. The method of claim 26, wherein the sustained release formulation comprises a waxy controlled release carrier, a lipoidic agent, and an oily vehicle for the 25-hydroxyvitamin D compound. 35. The method of claim 26, comprising administering the sustained release formulation to deliver a dosage amount of the 25-hydroxyvitamin D compound from 1 to 100 .mu.g per day. 36. The method of claim 26, wherein the patient has CKD Stage 5. 37. The method of claim 26, wherein the patient has CKD Stage 1 or 2. 38. The method of claim 26, wherein the patient has CKD Stage 3 or 4. 39. A method of treating secondary hyperparathyroidism in a human patient having Chronic Kidney Disease (CKD), comprising administering to the human patient having CKD an effective amount of a sustained release formulation of a 25-hydroxyvitamin D compound to treat the secondary hyperparathyroidism and reduce the patient's serum parathyroid hormone level, such that the maximum serum concentration within 24 hours after administration of the 25-hydroxyvitamin D compound to the concentration 24 hours after administration (Cmax.sub.24hr/C.sub.24hr) is reduced compared to the Cmax.sub.24hr/C.sub.24hr for an equivalent amount of the 25-hydroxyvitamin D compound administered by bolus IV injection and an equivalent amount of the 25-hydroxyvitamin D compound administered by immediate-release, oral dosing. 40. The method of claim 39, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 10 hours. 41. The method of claim 39, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 24 hours. 42. The method of claim 39, wherein the administration avoids transient increases in blood levels of 25-hydroxyvitamin D of greater than 3 ng/mL following a unit dose. 43. The method of claim 39, wherein the 25-hydrovitamin D compound is 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 44. The method of claim 39, wherein the sustained release formulation comprises 1 .mu.g to 1000 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 45. The method of claim 44, wherein the sustained release formulation comprises 1 .mu.g to 100 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 46. The method of claim 39, wherein the sustained release formulation comprises a waxy controlled release carrier. 47. The method of claim 39, wherein the sustained release formulation comprises a waxy controlled release carrier, a lipoidic agent, and an oily vehicle for the 25-hydroxyvitamin D compound. 48. The method of claim 39, comprising administering the sustained release formulation to deliver a dosage amount of the 25-hydroxyvitamin D compound from 1 to 100 .mu.g per day. 49. The method of claim 39, wherein the patient has CKD Stage 5. 50. The method of claim 39, wherein the patient has CKD Stage 1 or 2. 51. The method of claim 39, wherein the patient has CKD Stage 3 or 4. 52. A method of treating secondary hyperparathyroidism in a human patient having Chronic Kidney Disease (CKD), comprising administering to the human patient having CKD an effective amount of a sustained release formulation of a 25-hydroxyvitamin D compound to treat the secondary hyperparathyroidism and reduce the patient's serum parathyroid hormone level, such that the elimination half-life (t.sub.1/2) of the 25-hydroxyvitamin D compound is increased compared to the t.sub.1/2 for an equivalent amount of the 25-hydroxyvitamin D compound administered by bolus IV injection and an equivalent amount of the 25-hydroxyvitamin D compound administered by immediate-release, oral dosing. 53. The method of claim 52, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 10 hours. 54. The method of claim 52, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 24 hours. 55. The method of claim 52, wherein the administration avoids transient increases in blood levels of 25-hydroxyvitamin D of greater than 3 ng/mL following a unit dose. 56. The method of claim 52, wherein the 25-hydrovitamin D compound is 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 57. The method of claim 52, wherein the sustained release formulation comprises 1 .mu.g to 1000 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 58. The method of claim 57, wherein the sustained release formulation comprises 1 .mu.g to 100 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 59. The method of claim 52, wherein the sustained release formulation comprises a waxy controlled release carrier. 60. The method of claim 52, wherein the sustained release formulation comprises a waxy controlled release carrier, a lipoidic agent, and an oily vehicle for the 25-hydroxyvitamin D compound. 61. The method of claim 52, comprising administering the sustained release formulation to deliver a dosage amount of the 25-hydroxyvitamin D compound from 1 to 100 .mu.g per day. 62. The method of claim 52, wherein the patient has CKD Stage 5. 63. The method of claim 52, wherein the patient has CKD Stage 1 or 2. 64. The method of claim 52, wherein the patient has CKD Stage 3 or 4. 65. A method of treating secondary hyperparathyroidism in a human patient having Chronic Kidney Disease (CKD), comprising administering to the human patient having CKD an effective amount of a sustained release formulation of a 25-hydroxyvitamin D compound to treat the secondary hyperparathyroidism and reduce the patient's serum parathyroid hormone level, such that the time for the plasma concentration of the 25-hydroxyvitamin D compound to reach its maximum in a dose interval following administration (Tmax) is increased compared to the Tmax for an equivalent amount of the 25-hydroxyvitamin D compound administered by bolus IV injection and an equivalent amount of the 25-hydroxyvitamin D compound administered by immediate-release, oral dosing. 66. The method of claim 65, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 10 hours. 67. The method of claim 65, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 24 hours. 68. The method of claim 65, wherein the administration avoids transient increases in blood levels of 25-hydroxyvitamin D of greater than 3 ng/mL following a unit dose. 69. The method of claim 65, wherein the 25-hydrovitamin D compound is 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 70. The method of claim 65, wherein the sustained release formulation comprises 1 .mu.g to 1000 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 71. The method of claim 70, wherein the sustained release formulation comprises 1 .mu.g to 100 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 72. The method of claim 65, wherein the sustained release formulation comprises a waxy controlled release carrier. 73. The method of claim 65, wherein the sustained release formulation comprises a waxy controlled release carrier, a lipoidic agent, and an oily vehicle for the 25-hydroxyvitamin D compound. 74. The method of claim 65, comprising administering the sustained release formulation to deliver a dosage amount of the 25-hydroxyvitamin D compound from 1 to 100 .mu.g per day. 75. The method of claim 65, wherein the patient has CKD Stage 5. 76. The method of claim 65, wherein the patient has CKD Stage 1 or 2. 77. The method of claim 65, wherein the patient has CKD Stage 3 or 4. 78. A method of administering a 25-hydroxyvitamin D compound to a patient wherein the maximum serum concentration of 25-hydroxyvitamin D in a dose interval (Cmax) is reduced as compared to Cmax for both an equivalent amount of the 25-hydroxyvitamin D compound administered by bolus IV injection and an equivalent amount of the 25-hydroxyvitamin D compound administered by immediate-release, oral dosing; and wherein the maximum change in serum concentration of 25-hydroxyvitamin D in a dose interval is reduced as compared to the maximum change in serum concentration of 25-hydroxyvitamin D in a dose interval for both an equivalent amount of the 25-hydroxyvitamin D compound administered by bolus IV injection and an equivalent amount of the 25-hydroxyvitamin D compound administered by immediate-release, oral dosing; and wherein the time for the plasma concentration of the 25-hydroxyvitamin D compound to reach its maximum in a dose interval following administration (Tmax) is reduced as compared to Tmax for both an equivalent amount of the 25-hydroxyvitamin D compound administered by bolus IV injection and an equivalent amount of the 25-hydroxyvitamin D compound administered by immediate-release, oral dosing. 79. The method of claim 78, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 10 hours. 80. The method of claim 78, wherein the sustained release of the 25-hydroxyvitamin D compound is effected over a period of at least 24 hours. 81. The method of claim 78, wherein the administration avoids transient increases in blood levels of 25-hydroxyvitamin D of greater than 3 ng/mL following a unit dose. 82. The method of claim 78, wherein the 25-hydrovitamin D compound is 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 83. The method of claim 78, wherein the sustained release formulation comprises 1 .mu.g to 1000 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 84. The method of claim 83, wherein the sustained release formulation comprises 1 .mu.g to 100 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 85. The method of claim 78, wherein the sustained release formulation comprises a waxy controlled release carrier. 86. The method of claim 78, wherein the sustained release formulation comprises a waxy controlled release carrier, a lipoidic agent, and an oily vehicle for the 25-hydroxyvitamin D compound. 87. The method of claim 78, comprising administering the sustained release formulation to deliver a dosage amount of the 25-hydroxyvitamin D compound from 1 to 100 .mu.g per day. 88. The method of claim 78, wherein the patient has CKD Stage 5. 89. The method of claim 78, wherein the patient has CKD Stage 1 or 2. 90. The method of claim 78, wherein the patient has CKD Stage 3 or 4. 91. A formulation for sustained release of a 25-hydroxyvitamin D compound, wherein release of the 25-hydroxyvitamin D compound from the formulation is sustained for at least four hours. 92. The formulation of claim 91, wherein the release of the 25-hydroxyvitamin D compound from the formulation is sustained for at least 10 hours. 93. The formulation of claim 91, wherein the release of the 25-hydroxyvitamin D compound from the formulation is sustained for at least 24 hours. 94. The formulation of claim 91, wherein the 25-hydrovitamin D compound is 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 95. The formulation of claim 91, comprising 1 .mu.g to 1000 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 96. The formulation of claim 95, comprising 1 .mu.g to 100 .mu.g 25-hydrovitamin D.sub.3 per unit dose. 97. The formulation of claim 91, comprising a waxy controlled release carrier. 98. The formulation of claim 91, comprising a waxy controlled release carrier, a lipoidic agent, and an oily vehicle for the 25-hydroxyvitamin D compound.