Method for treating secondary hyperparathyroidism in CKD
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.
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 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
5. The method of claim 1 , wherein the sustained release formulation comprises 1 μg to 1000 μg 25-hydrovitamin D 3 per unit dose.
6. The method of claim 5 , wherein the sustained release formulation comprises 1 μg to 100 μg 25-hydrovitamin D 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 μg 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 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
18. The method of claim 13 , wherein the sustained release formulation comprises 1 μg to 1000 μg 25-hydrovitamin D 3 per unit dose.
19. The method of claim 18 , wherein the sustained release formulation comprises 1 μg to 100 μg 25-hydrovitamin D 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 μg 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 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
31. The method of claim 26 , wherein the sustained release formulation comprises 1 μg to 1000 μg 25-hydrovitamin D 3 per unit dose.
32. The method of claim 31 , wherein the sustained release formulation comprises 1 μg to 100 μg 25-hydrovitamin D 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 μg 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 24hr /C 24hr ) is reduced compared to the Cmax 24hr /C 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 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
44. The method of claim 39 , wherein the sustained release formulation comprises 1 μg to 1000 μg 25-hydrovitamin D 3 per unit dose.
45. The method of claim 44 , wherein the sustained release formulation comprises 1 μg to 100 μg 25-hydrovitamin D 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 μg 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 1/2 ) of the 25-hydroxyvitamin D compound is increased compared to the t 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 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
57. The method of claim 52 , wherein the sustained release formulation comprises 1 μg to 1000 μg 25-hydrovitamin D 3 per unit dose.
58. The method of claim 57 , wherein the sustained release formulation comprises 1 μg to 100 μg 25-hydrovitamin D 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 μg 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 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
70. The method of claim 65 , wherein the sustained release formulation comprises 1 μg to 1000 μg 25-hydrovitamin D 3 per unit dose.
71. The method of claim 70 , wherein the sustained release formulation comprises 1 μg to 100 μg 25-hydrovitamin D 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 μg 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 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
83. The method of claim 78 , wherein the sustained release formulation comprises 1 μg to 1000 μg 25-hydrovitamin D 3 per unit dose.
84. The method of claim 83 , wherein the sustained release formulation comprises 1 μg to 100 μg 25-hydrovitamin D 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 μg 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 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
95. The formulation of claim 91 , comprising 1 μg to 1000 μg 25-hydrovitamin D 3 per unit dose.
96. The formulation of claim 95 , comprising 1 μg to 100 μg 25-hydrovitamin D 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.