Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
Methods, compositions, and kits for adjunctive therapy using 25-hydroxyvitamin D are disclosed. The 25-hydroxyvitamin D may be administered with an agent that increases the risk of hypocalcemia, such as cinacalcet or a salt thereof, and/or an anticancer agent. The adjunctive therapy is effective to treat and prevent iatrogenic hypocalcemia and/or secondary hyperparathyroidism, as well as delay cancer progression and the time to a post-treatment skeletal related event.
1. A pharmaceutical formulation for oral administration comprising (a) a core region comprising a 25-hydroxyvitamin D compound in a matrix that releasably binds and controllably releases the 25-hydroxyvitamin D compound and (b) an outer region comprising an agent that increases the risk of hypocalcemia, wherein the agent that increases the risk of hypocalcemia comprises cinacalcet or a salt thereof.
2. The pharmaceutical formulation of claim 1 , wherein the matrix comprising the 25-hydroxyvitamin D compound comprises a wax, an emulsifier, an absorption enhancer, and a stabilizing agent.
3. The pharmaceutical formulation of claim 2 , wherein the matrix comprising the 25-hydroxyvitamin D compound includes about 20 wt % paraffin, about 20 wt % to about 25 wt % glycerol monostearate, about 10 wt % a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides, about 30 wt % to about 35 wt % mineral oil, and about 10 wt % to about 15 wt % hydroxyl propyl methylcellulose.
4. The pharmaceutical formulation of claim 1 , characterized by an in vitro dissolution profile providing release of the 25-hydroxyvitamin D compound of about 20% to about 40% at 2 hours, at least 35% at 6 hours, and at least 70% at 12 hours.
5. The pharmaceutical formulation of claim 4 , characterized by an in vitro dissolution profile providing release of the agent that increases the risk of hypocalcemia of at least 50% at 30 minutes.
6. The pharmaceutical formulation of claim 1 , wherein the formulation comprises a capsule having a hard shell.
7. The pharmaceutical formulation of claim 1 , wherein the formulation comprises a soft capsule.
8. The pharmaceutical formulation of claim 1 , comprising the agent that increases the risk of hypocalcemia disposed in a first capsule shell and the 25-hydroxyvitamin D compound disposed in second capsule shell, the second capsule shell being disposed within the first capsule shell.
9. The pharmaceutical formulation of claim 1 , comprising the agent that increases the risk of hypocalcemia in granular form.
10. The pharmaceutical formulation of claim 1 , wherein the agent that increases the risk of hypocalcemia is disposed within a coating.
11. The pharmaceutical formulation of claim 1 , wherein the agent that increases the risk of hypocalcemia is formulated for rapid release.
12. The pharmaceutical formulation of claim 1 , wherein the 25-hydroxyvitamin D compound is 25-hydroxyvitamin D 2 , 25-hydroxyvitamin D 3 , or a combination thereof.
13. The pharmaceutical formulation of claim 12 , wherein the 25-hydroxyvitamin D compound is 25-hydroxyvitamin D 3 .
14. The pharmaceutical formulation of claim 1 , comprising the 25-hydroxyvitamin D compound in an amount between about 1 mcg and about 1000 mcg.
15. The pharmaceutical formulation of claim 1 , comprising the 25-hydroxyvitamin D compound in an amount between about 1 mcg and about 100 mcg.
16. The pharmaceutical formulation of claim 1 , comprising the agent that increases the risk of hypocalcemia in an amount between about 1 mg and about 100 mg.
17. The pharmaceutical formulation of claim 1 , wherein the cinacalcet or salt thereof comprises cinacalcet HCl.
18. The pharmaceutical formulation of claim 1 , further comprising a disintegrant, optionally in an amount of about 1 wt % to 10 wt %.
19. The pharmaceutical formulation of claim 1 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises from about 10% to about 40% by weight of cinacalcet or a salt thereof, from about 45% to about 85% by weight of at least one diluent, and from about 1% to about 10% by weight of at least one disintegrant, optionally further comprising from about 1% to about 5% by weight of at least one binder, wherein the percentage by weight is relative to the total weight of the region.
20. The pharmaceutical formulation of claim 1 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
(a) from about 10% to about 40% by weight of cinacalcet or salt thereof;
(b) from about 40% to about 75% by weight of microcrystalline cellulose;
(c) from about 5% to about 35% by weight of starch;
(d) from about 1% to about 10% by weight of crospovidone;
(e) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and
(f) from about 0.05% to about 1.5% by weight of magnesium stearate;
wherein the percentage by weight is relative to the total weight of the region.
21. The pharmaceutical formulation of claim 1 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
(a) from about 10% to about 40% by weight of cinacalcet or salt thereof;
(b) from about 40% to about 75% by weight of microcrystalline cellulose;
(c) from about 1% to about 5% by weight of povidone;
(d) from about 5% to about 35% by weight of starch;
(e) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and
(f) from about 0.05% to about 1.5% by weight of magnesium stearate;
wherein the percentage by weight is relative to the total weight of the region.
22. The pharmaceutical formulation of claim 1 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
(a) from about 10% to about 40% by weight of cinacalcet or salt thereof;
(b) from about 40% to about 75% by weight of microcrystalline cellulose;
(c) from about 15% to about 50% by weight of starch;
(d) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and
(e) from about 0.05% to about 1.5% by weight of magnesium stearate;
wherein the percentage by weight is relative to the total weight of the region.
23. The pharmaceutical formulation of claim 1 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
(a) from about 10% to about 40% by weight of cinacalcet or salt thereof;
(b) from about 40% to about 75% by weight of microcrystalline cellulose;
(c) from about 1% to about 5% by weight of povidone;
(d) from about 1% to about 10% by weight of a disintegrant selected from the group consisting of croscarmellose, sodium starch glycolate, crosslinked cellulose, crosslinked polymers, crosslinked starches, and combinations thereof;
(e) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and
(f) from about 0.05% to about 1.5% by weight of magnesium stearate;
wherein the percentage by weight is relative to the total weight of the region.
24. The pharmaceutical formulation of claim 1 , wherein the region comprising the agent that increases the risk of hypocalcemia comprises:
(a) from about 10% to about 40% by weight of cinacalcet or salt thereof;
(b) from about 40% to about 75% by weight of microcrystalline cellulose;
(c) from about 1% to about 5% by weight of a binder selected from the group consisting of gelatin, acacia, tragacanth, alginic acid, cellulose, methyl cellulose, ethyl cellulose, HPMC, HPC, sodium carboxy methyl cellulose, PEG, PVA, polymethacrylate, polyvinylcaprolactam, and combinations thereof;
(d) from about 5% to about 35% by weight of starch;
(e) from about 1% to about 10% by weight of crospovidone;
(f) from about 0.05% to about 1.5% by weight of colloidal silicon dioxide; and
(g) from about 0.05% to about 1.5% by weight of magnesium stearate;
wherein the percentage by weight is relative to the total weight of the region.
25. A method of managing iatrogenic hypocalcemia and secondary hyperparathyroidism in a patient receiving therapy with cinacalcet or a salt thereof, comprising administering to said patient a pharmaceutical formulation of claim 1 .
26. The method of claim 25 , wherein the patient has impaired renal function, optionally associated with Chronic Kidney Disease Stage 1, 2, 3, 4, or 5.
27. The method of claim 25 , wherein the patient is receiving dialysis.
28. The method of claim 25 , wherein the patient is not on dialysis.
29. The method of claim 25 , wherein the effective amount of 25-hydroxyvitamin D is effective to restore or maintain the patient's serum calcium level to at least about 8.0 mg/dL, optionally in a range of about 8.3 mg/dL to about 11.6 mg/dL.
30. The method of claim 25 , wherein the effective amount of 25-hydroxyvitamin D is effective to safely increase the patient's serum level of 25-hydroxyvitamin D to at least 30 ng/mL, optionally in a range of about 30 ng/mL to about 100 ng/mL.
31. The method of claim 25 , wherein the effective amount of 25-hydroxyvitamin D is effective to decrease the patient's serum parathyroid hormone level, optionally by 30% or more.
32. The method of claim 25 , wherein the effective amount of 25-hydroxyvitamin D is administered in an oral modified release formulation, optionally a sustained release formulation.
33. The method of claim 25 , wherein the 25-hydroxyvitamin D comprises 25-hydroxyvitamin D 3 , 25-hydroxyvitamin D 2 , or a combination thereof.
34. The method of claim 33 , wherein the 25-hydroxyvitamin D comprises 25-hydroxyvitamin D 3 .
35. The method of claim 25 , wherein the 25-hydroxyvitamin D is administered in a dosage of 1 mcg to 1000 mcg per day.
36. The method of claim 25 , wherein the cinacalcet or salt thereof comprises cinacalcet HCl.
37. The method of claim 25 , wherein the patient is receiving cinacalcet administered in a dosage of 1 mg to 400 mg per day.
38. A method of treating secondary hyperparathyroidism in Chronic Kidney Disease in a patient on dialysis comprising administering to said patient the formulation of claim 1 comprising an effective amount of a 25-hydroxyvitamin D compound by modified release and an effective dose of cinacalcet or a salt thereof in an amount of less than 360 mg daily, wherein said effective amount of cinacalcet is a reduced dose compared to the effective dose of cinacalcet in the absence of said 25-hydroxyvitamin D administration.
39. The method of claim 38 , comprising an initial dose of cinacalcet in a range of about 20 mg to about 25 mg once daily.
40. A method of treating hypercalcemia in a patient with parathyroid carcinoma, comprising administering to said patient the formulation of claim 1 comprising an effective amount of a 25-hydroxyvitamin D compound by modified release and an effective dose of cinacalcet or a salt thereof in an amount of less than 360 mg daily, wherein said effective amount of cinacalcet or a salt thereof is a reduced dose compared to the effective dose of cinacalcet in the absence of said 25-hydroxyvitamin D administration.
41. A method of treating severe hypercalcemia in a patient with primary hyperparathyroidism who is unable to undergo parathyroidectomy, comprising administering to said patient the formulation of claim 1 comprising an effective amount of a 25-hydroxyvitamin D compound by modified release and an effective dose of cinacalcet or a salt thereof in an amount of less than 360 mg daily, wherein said effective amount of cinacalcet or a salt thereof is a reduced dose compared to the effective dose of cinacalcet in the absence of said 25-hydroxyvitamin D administration.
42. The method of claim 40 , comprising an initial dose of cinacalcet in a rage of about 20 mg to about 25 mg once daily.
43. The method of claim 40 , wherein the effective amount of 25-hydroxyvitamin D is in a range of about 100 mcg to about 300 mcg.