Claims for Patent: 10,220,047

Summary for Patent: 10,220,047

Title:	Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
Abstract:	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.
Inventor(s):	Petkovich; P. Martin (Kingston, CA), Melnick; Joel Z. (Wilmette, IL), White; Jay A. (Newmarket, CA), Tabash; Samir P. (Whitby, CA), Bishop; Charles W. (Miami Beach, FL), Peers; Susan (Toronto, CA), Strugnell; Stephen A. (Bay Harbor Islands, FL)
Assignee:	OPKO IRELAND GLOBAL HOLDINGS, LTD. (Grand Cayman, KY)
Application Number:	14/866,155
Patent Claims:	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.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof. 13. The pharmaceutical formulation of claim 12, wherein the 25-hydroxyvitamin D compound is 25-hydroxyvitamin D.sub.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.sub.3, 25-hydroxyvitamin D.sub.2, or a combination thereof. 34. The method of claim 33, wherein the 25-hydroxyvitamin D comprises 25-hydroxyvitamin D.sub.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.

Details for Patent 10,220,047

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2034-08-07