Claims for Patent: 9,861,644

Summary for Patent: 9,861,644

Title:	Stabilized modified release vitamin D formulation and method of administering same
Abstract:	A stabilized formulation for controlled release of a vitamin D compound is disclosed. The formulation comprises one or both of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 and a cellulosic compound. The stabilized formulations exhibit a stable dissolution profile following exposure to storage conditions and demonstrate improved pharmacokinetic parameters compared to unstabilized formulations.
Inventor(s):	White; Jay A. (Newmarket, CA), Tabash; Samir P. (Whitby, CA), Agudoawu; Sammy A. (Mississauga, CA), Melnick; Joel Z. (Wilmette, IL)
Assignee:	OPKO IRELAND GLOBAL HOLDINGS, LTD. (Grand Cayman, KY)
Application Number:	14/213,285
Patent Claims:	1. A stabilized capsule formulation for extended release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation, the formulation comprising a mixture of: one or both of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3; a lipophilic matrix comprising an emulsifier; and an effective amount of a cellulosic stabilizing agent to maintain a difference of less than 30% between the amount of vitamin D compound released at any given time point after four hours during in vitro dissolution after two months exposure to storage conditions of 25.degree. C. and 60% relative humidity and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions, wherein the cellulosic stabilizing agent is hydroxypropyl methylcellulose (HPMC), and the HPMC is present in an amount greater than 5 wt % and up to about 30 wt % of the formulation. 2. A stabilized oral capsule formulation for extended release of a vitamin D compound, said formulation comprising a mixture of: one or both of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3; a wax matrix comprising an emulsifier; and an effective amount of a cellulosic stabilizing agent to maintain a difference of less than 30% between the amount of vitamin D compound released at any given time point after four hours during in vitro dissolution testing after exposure for two months to storage conditions of 25.degree. C. and 60% relative humidity and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions, wherein the cellulosic stabilizing agent is hydroxypropyl methylcellulose (HPMC), and the HPMC is present in an amount greater than 5 wt % and up to about 30 wt % of the formulation. 3. A stabilized capsule formulation for extended release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation, said formulation comprising a mixture of: an active-loaded wax matrix comprising one or both of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 and an emulsifier; and a cellulosic stabilizing agent, wherein the cellulosic stabilizing agent is hydroxypropyl methylcellulose (HPMC), and the HPMC is present in an amount greater than 5 wt % and up to about 30 wt % of the formulation; wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after two months exposure to storage of 25.degree. C. and 60% relative humidity that varies at any given dissolution time point compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions by 30% or less in the absence of the cellulosic stabilizing agent. 4. In a capsule formulation comprising a 25-hydroxyvitamin D compound, a lipophilic matrix, and an emulsifier for extended release of the 25-hydroxyvitamin D compound in the gastrointestinal tract of a subject which ingests the formulation, the improvement comprising an effective amount of a cellulosic compound admixed in the formulation to maintain a change of less than 30% in the amount of 25-hydroxyvitamin D released during in vitro dissolution after exposure to storage conditions of at least one month at 25.degree. C. and 60% relative humidity at any given dissolution time point after four hours compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions, wherein the cellulosic compound is hydroxypropyl methylcellulose (HPMC), and the HPMC is present in an amount greater than 5 wt % and up to about 30 wt % of the formulation. 5. The stabilized capsule formulation according to claim 1, wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions for 2 months at 25.degree. C. and 60% relative humidity that varies at any given dissolution time point after four hours compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions, by 25% or less. 6. The stabilized capsule formulation according to claim 1, wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after exposure to storage conditions for one month at 40.degree. C. and 75% relative humidity that varies at any given dissolution time point after four hours compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions, by 30% or less. 7. The stabilized oral capsule formulation according to claim 2, wherein the matrix comprises a wax matrix comprising a controlled release agent, a lipophilic emulsifier, and an absorption enhancer. 8. The stabilized oral capsule formulation according to claim 7, wherein the controlled release agent comprises paraffin. 9. The stabilized oral capsule formulation according to claim 7, wherein the lipophilic emulsifier has a HLB value less than 7. 10. The stabilized oral capsule formulation according to claim 9, wherein the lipophilic emulsifier comprises glycerol monostearate. 11. The stabilized oral capsule formulation according to claim 7, wherein the absorption enhancer has a HLB value in a range of about 13 to about 18. 12. The stabilized oral capsule formulation according to claim 11, wherein the absorption enhancer comprises lauroyl polyoxylglycerides. 13. The stabilized capsule formulation according to claim 1, wherein the vitamin D compound comprises 25-hydroxyvitamin D.sub.3. 14. The stabilized oral capsule formulation according to claim 7, further comprising an oily vehicle. 15. The stabilized oral capsule formulation according to claim 14, wherein the oily vehicle comprises mineral oil. 16. The stabilized oral capsule formulation according to claim 15, wherein the formulation comprises about 20 wt % paraffin, about 20 wt % to about 25 wt % glycerol monostearate, about 10 wt % lauroyl polyoxylglycerides, about 30 wt % to about 35 wt % mineral oil, and about 10 wt % to about 15 wt % HPMC. 17. A The stabilized oral capsule formulation according to claim 7, wherein the formulation comprises glycerol monostearate in an amount in a range of about 20 wt % to about 25 wt %. 18. A The stabilized oral capsule formulation according to claim 7, wherein the formulation comprises one or more polyglycolized glycerides. 19. A The stabilized capsule formulation according to claim 1 comprising a dissolution profile providing a release of a 25-hydroxyvitamin D compound of less than 30% at 2 hours; greater than 45% at 6 hours; and greater than 80% at 12 hours. 20. A stabilized extended release oral capsule dosage form comprising a 25-hydroxyvitamin D compound, a lipophilic matrix, an emulsifier, and a cellulosic compound that increases the stability of the in vitro dissolution release profile of the dosage form wherein the cellulosic compound is hydroxypropyl methylcellulose (HPMC), and the HPMC is present in an amount greater than 5 wt % and up to about 30 wt % of the dosage form, wherein the dosage form comprises an in vitro dissolution profile providing release of the 25-hydroxyvitamin D compound of less than 30% at 100 to 140 minutes; greater than 45% at 5 to 7 hours; and greater than 80% at 11 to 13 hours. 21. A stabilized extended release oral capsule dosage form comprising a 25-hydroxyvitamin D compound, a lipophilic matrix, an emulsifier and a cellulosic compound that increases the stability of the in vitro dissolution release profile of the dosage form wherein the cellulosic compound is hydroxypropyl methylcellulose (HPMC), and the HPMC is present in an amount greater than 5 wt % and up to about 30 wt % of the dosage form, wherein the dosage form comprises 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. 22. A stabilized extended release capsule dosage form comprising a 25-hydroxyvitamin D compound, a lipophilic matrix, an emulsifier and a cellulosic compound that increases the stability of the in vitro dissolution release profile of the dosage form wherein the cellulosic compound is hydroxypropyl methylcellulose (HPMC), and the HPMC is present in an amount greater than 5 wt % and up to about 30 wt % of the dosage form, comprising a t.sub.max following administration of the dosage form to a human patient, of at least 4 hours. 23. A stabilized extended release capsule dosage form comprising a 25-hydroxyvitamin D compound, a lipophilic matrix, an emulsifier and a cellulosic compound that increases the stability of the in vitro dissolution release profile of the dosage form wherein the cellulosic compound is hydroxypropyl methylcellulose (HPMC), and the HPMC is present in an amount greater than 5 wt % and up to about 30 wt % of the dosage form, the dosage form providing a baseline-adjusted C.sub.max per microgram of 25-hydroxyvitamin D in a range of about 0.0133 ng/mL to about 0.04 ng/mL when administered to an adult human. 24. The stabilized oral capsule formulation according to claim 16, wherein the formulation comprises about 30 .mu.g to about 90 .mu.g 25-hydroxyvitamin D.sub.3, about 20 wt % paraffin, about 23 wt % glycerol monostearate, about 10 wt % lauroyl polyoxylglycerides, about 35 wt % mineral oil, and about 10 wt % HPMC. 25. The stabilized oral capsule formulation according to claim 24, wherein the formulation comprises 30 .mu.g 25-hydroxyvitamin D.sub.3. 26. The stabilized oral capsule formulation according to claim 24, wherein the formulation comprises 60 .mu.g 25-hydroxyvitamin D.sub.3. 27. The stabilized oral capsule formulation according to claim 24, wherein the formulation comprises 90 .mu.g 25-hydroxyvitamin D.sub.3. 28. The stabilized oral capsule formulation according to claim 16, wherein the formulation comprises about 30 .mu.g to about 90 .mu.g 25-hydroxyvitamin D.sub.3, about 20 wt % paraffin, about 23 wt % glycerol monostearate, about 10 wt % lauroyl polyoxylglycerides, about 30 wt % mineral oil, and about 15 wt % HPMC. 29. The stabilized oral capsule formulation according to claim 28, wherein the formulation comprises 30 .mu.g 25-hydroxyvitamin D.sub.3. 30. The stabilized oral capsule formulation according to claim 28, wherein the formulation comprises 60 .mu.g 25-hydroxyvitamin D.sub.3. 31. The stabilized oral capsule formulation according to claim 28, wherein the formulation comprises 90 .mu.g 25-hydroxyvitamin D.sub.3. 32. The stabilized extended release capsule dosage form of claim 22, wherein the dosage form comprises 100 .mu.g to 200 .mu.g 25-hydroxyvitamin D.sub.3. 33. The stabilized extended release capsule dosage form of claim 22, wherein the dosage form comprises an effective amount of a cellulosic stabilizing agent to maintain a difference of less than 30% between the amount of vitamin D compound released at any given time point after four hours during in vitro dissolution after six months exposure to storage conditions of 25.degree. C. and 60% relative humidity and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions. 34. The stabilized extended release capsule dosage form of claim 33, wherein the difference is less than 20%. 35. The stabilized extended release capsule dosage form of claim 22, wherein the dosage form comprises an effective amount of a cellulosic stabilizing agent to maintain a difference of less than 30% between the amount of vitamin D compound released at any given time point after four hours during in vitro dissolution after six months exposure to storage conditions of 40.degree. C. and 75% relative humidity and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions. 36. The stabilized extended release capsule dosage form of claim 35, wherein the difference is less than 20%.