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Last Updated: October 31, 2020

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Claims for Patent: 10,357,502

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Summary for Patent: 10,357,502
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. (Miami, FL)
Assignee: OPKO IRELAND GLOBAL HOLDINGS, LTD. (Grand Cayman, KY)
Application Number:15/990,352
Patent Claims: 1. A stabilized 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 in an extended release lipophilic matrix, the lipophilic matrix further comprising a cellulosic stabilizing agent to stabilize the matrix against changes in dissolution release characteristics over time; wherein the cellulosic stabilizing agent is a cellulose ether and is present in an amount of about 5 wt % to about 30 wt % of the stabilized formulation, wherein the formulation is characterized by providing a mean t.sub.max of the vitamin D compound in adult humans following an initial, single dose, in a range of 4 to 96 hours.

2. The stabilized formulation of claim 1, wherein the mean t.sub.max is at least 18 hours.

3. The stabilized formulation of claim 2, wherein the mean t.sub.max is in a range of 18 to 30 hours.

4. The stabilized formulation of claim 2, wherein the mean t.sub.max is at least 20 hours.

5. The stabilized formulation of claim 2, wherein the mean t.sub.max is at least 24 hours.

6. The stabilized formulation of claim 2, wherein the mean t.sub.max is at least 28 hours.

7. The stabilized formulation of claim 1, wherein the lipophilic matrix comprises a wax.

8. The stabilized formulation of claim 7, wherein the lipophilic matrix comprises paraffin wax.

9. The stabilized formulation according to claim 1, further comprising an emulsifier.

10. The stabilized formulation according to claim 9, wherein the emulsifier has a HLB value less than 7.

11. The stabilized formulation according to claim 10, wherein the emulsifier comprises glycerol monostearate.

12. The stabilized formulation according to claim 1, further comprising an absorption enhancer.

13. The stabilized formulation according to claim 12, wherein the absorption enhancer has a HLB value in a range of about 13 to about 18.

14. The stabilized formulation according to claim 12, wherein the absorption enhancer is a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides.

15. The stabilized formulation according to claim 1, further comprising an oily vehicle.

16. The stabilized formulation according to claim 15, wherein the oily vehicle comprises mineral oil.

17. The stabilized formulation according to claim 1, wherein the lipophilic matrix comprises a wax, an oil, an emulsifier, and an absorption enhancer.

18. The stabilized formulation according to claim 1, wherein the formulation comprises 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.

19. The stabilized formulation according to claim 18, wherein the vitamin D compound comprises 25-hydroxyvitamin D.sub.3.

20. The stabilized formulation according to claim 1, wherein the cellulose ether comprises one or more of methylcellulose, hydroxyl propyl methylcellulose, hydroxyl ethyl methylcellulose, hydroxyl ethyl cellulose, and hydroxyl propyl cellulose.

21. The stabilized formulation according to claim 20, wherein the cellulose ether comprises hydroxyl propyl methylcellulose.

22. An extended release dosage form in the form of a capsule, tablet, sachet, or dragee comprising a stabilized formulation according to claim 1.

23. An extended release capsule for extended release of 25-hydroxyvitamin D.sub.3 in the gastrointestinal tract of a subject which ingests the capsule, the capsule containing 25-hydroxyvitamin D.sub.3 in an extended release, wax-based matrix, the matrix comprising paraffin, mineral oil, an emulsifier, and a cellulose ether, wherein the cellulose ether is present in an amount of about 5 wt % to about 30 wt % of the capsule, wherein the extended release capsule is characterized by providing a mean t.sub.max of the vitamin D compound in adult humans following an initial, single dose, in a range of 18 to 30 hours.

24. The stabilized formulation of claim 1, wherein the formulation is further characterized by providing a mean baseline-adjusted in vivo C.sub.x per microgram of 25-hydroxyvitamin D administered to humans in a range of about 0.0133 ng/mL to about 0.04 ng/mL.

25. The stabilized formulation of claim 24, wherein the formulation, following storage for 3 months at 25.degree. C. and 60% RH, provides a C.sub.max within 80% to 125% of the mean of the fresh product.

26. The stabilized formulation of claim 1, wherein the formulation is further characterized by a baseline-adjusted AUC.sub.0-6 wk of the administered vitamin D compound having a mean of about 700 ngd/mL, when administered to adult humans having CKD Stage 3 with secondary hyperparathyroidism and vitamin D insufficiency, and at daily oral doses of 30 mcg.

27. The stabilized formulation of claim 26, wherein the formulation comprises 30 mcg 25-hydroxyvitamin D.sub.3.

28. A method of administering a stabilized 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 in an extended release lipophilic matrix, the lipophilic matrix further comprising a cellulosic stabilizing agent to stabilize the matrix against changes in dissolution release characteristics over time; wherein the cellulosic stabilizing agent is a cellulose ether and is present in an amount of about 5 wt % to about 30 wt % of the stabilized formulation, comprising administering an effective amount of the formulation to a human patient to provide a baseline-adjusted AUC.sub.0-inf following a dose in a range of 52 ngh/mL to less than 34,500 ngh/mL.

29. The method of claim 28, comprising administering an effective amount of the formulation to a human patient to provide a baseline-adjusted AUC.sub.0-inf following a dose in a range of 52 ngh/mL to about 12,000 ngh/mL.

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