Controlled Release Formulations of Opioids

• US 20110195989A1
• Filed: 02/09/2011
• Published: 08/11/2011
• Est. Priority Date: 02/09/2010
• Status: Abandoned Application

• Current Assignee: Qrxpharma Ltd.
• Original Assignee: Qrxpharma Ltd.
• Inventors: Rudnic, Edward M., Pace, Gary W., Iglesia, Felix de la, Berry, Joseph, Vachon, Michael
• Application Number:
  US13/024,319
• Publication Number:
  US 20110195989A1
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

Pharmaceutical formulations containing opioid components that each has a release profile. The components may provide immediate or controlled release of the opioid. The invention is also directed to methods of controlling release of one or more opioid compounds and methods of treating pain.

Claims

1. A pharmaceutical formulation for treatment of pain in a human, comprising one or more opioid components, wherein:

(a) the one or more opioid components comprise one or more release profiles;

(b) at least one of the opioid components is a controlled release opioid component comprising an opioid, wherein the opioid is oxycodone or a salt thereof;

wherein the pharmaceutical formulation provides a time to maximum oxycodone, or a salt thereof, plasma concentration (T_max) of about 4.5 to about 8 hours after repeated administration.

2. The pharmaceutical formulation of claim 1, wherein the controlled release opioid component further comprises one or more additional opioids selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.

3. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 2 mg of oxycodone, or a salt thereof, provides an area-under-the-curve for between about 0 and about 24 hours (AUC₂₄) of about 14.7 ng·

hr/mL to about 23.0 ng·

hr/mL after single administration.

4. The pharmaceutical formulation of claim 3, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 2 mg and has an AUC₂₄ that is proportional to the 2 mg AUC₂₄.

5. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 2 mg of oxycodone, or a salt thereof, provides a mean maximum oxycodone, or a salt thereof, plasma concentration (C_max) of about 1 to about 3 ng/mL after repeated administration through steady-state conditions.

6. The pharmaceutical formulation of claim 5, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 2 mg and has a C_max that is proportional to the 2 mg C_max.

7. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 5 mg of oxycodone, or a salt thereof, provides an area-under-the-curve for between about 0 and about 24 hours (AUC₂₄) of about 40.2 ng·

hr/mL to about 62.8 ng·

hr/mL after single administration.

8. The pharmaceutical formulation of claim 7, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 5 mg and has an AUC₂₄ that is proportional to the 5 mg AUC₂₄.

9. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 5 mg of oxycodone, or a salt thereof, provides a mean maximum oxycodone, or a salt thereof, plasma concentration (C_max) of about 3 to about 7 ng/mL after repeated administration through steady-state conditions.

10. The pharmaceutical formulation of claim 9, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 5 mg and has a C_max that is proportional to the 5 mg C_max.

11. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 10 mg of oxycodone, or a salt thereof, provides an area-under-the-curve for between about 0 and about 24 hours (AUC₂₄) of about 80.5 ng·

hr/mL to about 125.9 ng·

hr/mL after single administration.

12. The pharmaceutical formulation of claim 11, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 10 mg and has an AUC₂₄ that is proportional to the 10 mg AUC₂₄.

13. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 10 mg of oxycodone, or a salt thereof, provides a mean maximum oxycodone, or a salt thereof, plasma concentration (C_max) of about 5 to about 15 ng/mL after repeated administration through steady-state conditions.

14. The pharmaceutical formulation of claim 13, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 10 mg and has a C_max that is proportional to the 10 mg C_max.

15. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 20 mg of oxycodone, or a salt thereof, provides an area-under-the-curve for between about 0 and about 24 hours (AUC₂₄) of about 166.0 ng·

hr/mL to about 259.3 ng·

hr/mL after single administration.

16. The pharmaceutical formulation of claim 15, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 20 mg and has an AUC₂₄ that is proportional to the 20 mg AUC₂₄.

17. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 20 mg of oxycodone, or a salt thereof, provides a mean maximum oxycodone, or a salt thereof, plasma concentration (C_max) of about 10 to about 30 ng/mL after repeated administration through steady-state conditions.

18. The pharmaceutical formulation of claim 17, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 20 mg and has a C_max that is proportional to the 20 mg C_max.

19. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 40 mg of oxycodone, or a salt thereof, provides an area-under-the-curve for between about 0 and about 24 hours (AUC₂₄) of about 338.5 ng·

hr/mL to about 528.9 ng·

hr/mL after single administration.

20. The pharmaceutical formulation of claim 19, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 40 mg and has an AUC₂₄ that is proportional to the 40 mg AUC₂₄.

21. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 40 mg of oxycodone, or a salt thereof, provides a mean maximum oxycodone, or a salt thereof, plasma concentration (C_max) of about 25 to about 55 ng/mL after repeated administration through steady-state conditions.

22. The pharmaceutical formulation of claim 21, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 40 mg and has a C_max that is proportional to the 40 mg C_max.

23. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 80 mg of oxycodone, or a salt thereof, provides an area-under-the-curve for between about 0 and about 24 hours (AUC₂₄) of about 868.4 ng·

hr/mL to about 1356.9 ng·

hr/mL after single administration.

24. The pharmaceutical formulation of claim 23, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 80 mg and has an AUC₂₄ that is proportional to the 80 mg AUC₂₄.

25. The pharmaceutical formulation of claim 1, wherein the formulation, when containing a total dose of about 80 mg of oxycodone, or a salt thereof, provides a mean maximum oxycodone, or a salt thereof, lasma concentration (C_max) of about 50 to about 110 ng/mL after repeated administration through steady-state conditions.

26. The pharmaceutical formulation of claim 25, formulated for a total dose of oxycodone, or a salt thereof, that is different from about 80 mg and has a C_max that is proportional to the 80 mg C_max.

27. The pharmaceutical formulation of claim 1, comprising a second controlled release opioid component.

28. The pharmaceutical formulation of claim 27, wherein the second controlled release opioid component comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.

29. The pharmaceutical formulation of claim 1, comprising an immediate-release opioid component.

30. The pharmaceutical formulation of claim 29, where the immediate-release opioid component comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.

31. The pharmaceutical formulation of claim 30, wherein the opioid in the immediate-release opioid component is morphine or a salt thereof.

32. The pharmaceutical formulation of claim 31, wherein the total morphine, or salt thereof, and the total oxycodone, or salt thereof, in the formulation are in a ratio of about 3:

2, morphine or salt thereof to oxycodone or salt thereof, by weight.

33. The pharmaceutical formulation of claim 1, comprising a second opioid component and a third opioid component, wherein:

(a) the second opioid component is an immediate-release opioid component and comprises an opioid having kappa agonist activity; and

(b) the third opioid component is a controlled release opioid component and comprises an opioid having mu agonist activity.

34. The pharmaceutical formulation of claim 33, wherein the opioid having kappa agonist activity is oxycodone or a salt thereof.

35. The pharmaceutical formulation of claim 33, wherein the opioid having mu agonist activity is morphine or a salt thereof.

36. The pharmaceutical formulation of claim 1, wherein the controlled release opioid component comprises morphine or a salt thereof.

37. The pharmaceutical formulation of claim 36, wherein the controlled release opioid component comprises morphine or salt thereof and oxycodone or salt thereof in an amount of about 3:

2 by weight.

38. The pharmaceutical formulation of claim 1, wherein dissolution of the formulation releases about 0 to about 20% of the oxycodone, or a salt thereof, after two hours as measured in a USP type I apparatus at about 37°

C. in water at about 50 rpm.

39. The pharmaceutical formulation of claim 1, wherein dissolution of the formulation releases about 15 to about 60% of the oxycodone, or a salt thereof, after four hours as measured in a USP type I apparatus at about 37°

C. in water at about 50 rpm.

40. The pharmaceutical formulation of claim 1, wherein dissolution of the formulation releases about 25 to about 80% of the oxycodone, or a salt thereof, after six hours as measured in a USP type I apparatus at about 37°

C. in water at about 50 rpm.

41. The pharmaceutical formulation of claim 1, wherein dissolution of the formulation releases about 35 to about 85% of the oxycodone, or a salt thereof, after eight hours as measured in a USP type I apparatus at about 37°

C. in water at about 50 rpm.

42. The pharmaceutical formulation of claim 1, wherein dissolution of the formulation releases about 45 to about 95% of the oxycodone, or a salt thereof, after ten hours as measured in a USP type I apparatus at about 37°

C. in water at about 50 rpm.

43. The pharmaceutical formulation of claim 1, wherein dissolution of the formulation releases about 60 to about 100% of the oxycodone, or a salt thereof, after twelve hours as measured in a USP type I apparatus at about 37°

C. in water at about 50 rpm.

44. A method of controlling release of one or more compounds having opioid receptor agonist activity for absorption in a human, wherein the method comprises administering a pharmaceutical formulation comprising one or more components, wherein:

(a) the one or more opioid components comprise one or more release profiles;

(b) at least one of the opioid components is a controlled release opioid component comprising an opioid, wherein the opioid is oxycodone or a salt thereof;

wherein the pharmaceutical formulation provides a time to maximum oxycodone, or a salt thereof, plasma concentration (T_max) of about 4.5 to about 8 hours after repeated administration.

45. A method of treating pain in a human, comprising administering a pharmaceutical formulation comprising one or more components, wherein:

(a) the one or more opioid components comprise one or more release profiles;

(b) at least one of the opioid components is a controlled release opioid component comprising an opioid, wherein the opioid is oxycodone or a salt thereof;

wherein the pharmaceutical formulation provides a time to maximum oxycodone, or a salt thereof, plasma concentration (T_max) of about 4.5 to about 8 hours after repeated administration.