Sustained release formulations of nalbuphine

• US 8,394,812 B2
• Filed: 05/23/2008
• Issued: 03/12/2013
• Est. Priority Date: 08/24/2005
• Status: Active Grant

• Current Assignee: ENDO USA Incorporated
• Original Assignee: Penwest Pharmaceuticals Company (Endo International PLC)
• Inventors: Baichwal, Anand R., Goliber, Philip A., Carpanzano, Anthony E., Sciascia, Thomas, Diehl, Donald II, Vogler, Brian, Verbel, David, Au, Stanley
• Primary Examiner(s): PACKARD, BENJAMIN J
• Application Number:
  US12/154,496
• Publication Number:
  US 20090030026A1
• Time in Patent Office: 1,754 Days
• Field of Search: 514/279, 424/464
• US Class Current: 514/279
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• 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 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

Sustained release formulations of nalbuphine or pharmaceutically acceptable salts thereof; methods for making the sustained release formulations of nalbuphine or pharmaceutically acceptable salts thereof; and methods for using the sustained release formulations of nalbuphine or pharmaceutically acceptable salts thereof to treat patients suffering from pain are provided.

Claims

1. A sustained release oral solid dosage form comprising nalbuphine or a pharmaceutically acceptable salt thereof in a sustained release gel matrix delivery system, wherein the dosage form provides a mean T_max at about 1.77 to about 8.01 hours after oral administration to human subjects and maintains a plateau of a relatively constant blood serum level of nalbuphine during a dosage interval, in the form of a tablet.

2. The dosage form of claim 1, wherein the plateau has a duration of about 1 hours to about 12 hours.

3. The dosage form of claim 1, wherein the plateau has a duration of about 2 to about 10 hours.

4. The dosage form of claim 1, wherein the plateau has a duration of about 6 hours to about 9 hours.

5. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 7 to about 16 ng/ml.

6. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 8.58 ng/ml based on a 60 mg single dose.

7. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 7.17 ng/ml based on a 60 mg single dose.

8. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 7.920 ng/ml based on a 60 mg single dose.

9. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 7.750 ng/ml based on a 60 mg single dose.

10. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 12.87 ng/ml based on a 120 mg single dose.

11. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 14.1 ng/ml based on a 120 mg single dose.

12. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 11.3 ng/ml based on a 120 mg single dose.

13. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 13.4 ng/ml based on a 120 mg single dose.

14. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 14.2 ng/ml based on a 120 mg single dose.

15. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 12.5 ng/ml based on a 120 mg single dose.

16. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 15.574 ng/ml based on a 120 mg single dose.

17. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 12.498 ng/ml based on a 120 mg single dose.

18. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 12.903 ng/ml based on a 120 mg single dose.

19. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 12.700 ng/ml based on a 120 mg single dose.

20. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 13.265 ng/ml based on a 120 mg single dose.

21. The dosage form of claim 1, wherein the dosage form provides a mean C_max of about 15.59 ng/ml based on a 180 mg single dose.

22. The dosage form of claim 1, wherein the dosage form provides a blood serum level of nalbuphine at each time point in the plateau that ranges from about 75% to about 125% of the mean blood serum level in the plateau.

23. The dosage form of claim 1, wherein the dosage form provides a minimum blood serum level of nalbuphine observed during the plateau that is not more than 25% below the mean blood serum level for all time points in the plateau.

24. The dosage form of claim 22, wherein the minimum blood serum level is not more than 20% below the mean blood serum level for all time points in the plateau.

25. The dosage form of claim 22, wherein the minimum blood serum level is not more than 15% below the mean blood serum level for all time points in the plateau.

26. The dosage form of claim 1, wherein the dosage form provides a width at 50% of the height of the plasma concentration curve/time curve of nalbuphine about 10 hours based on a 60 mg single dose.

27. The dosage form of claim 1, wherein the dosage form provides a width at 50% of the height of the plasma concentration curve/time curve of nalbuphine of about 13 hours based on a 60 mg single dose.

28. The dosage form of claim 1, wherein the dosage form provides a width at 50% of the height of the plasma concentration curve/time curve of nalbuphine of about 17 hours based on a 120 mg single dose.

29. The dosage form of claim 1, wherein the dosage form provides a width at 50% of the height of the plasma concentration curve/time curve of nalbuphine of about 12 hours based on a 180 mg single dose.

30. The dosage form of claim 1, wherein the median T_max ranges from about 1.5 to about 8.0 hours.

31. The dosage form of claim 20, wherein the median T_max is about 1.5 hours based on a 60 mg single dose.

32. The dosage form of claim 20, wherein the median T_max is about 3.5 hours based on a 60 mg single dose.

33. The dosage form of claim 20, wherein the median T_max is about 6.0 hours based on a 120 mg single dose.

34. The dosage form of claim 20, wherein the median T_max is about 8.0 hours based on a 180 mg single dose.

35. The dosage form of claim 1, wherein the mean AUC_(0-t) ranges from about 75.95 ng*h/ml to about 200.63 ng*h/ml.

36. The dosage form of claim 35, wherein the mean AUC_(0-t) is about 75.95 ng*h/ml based on a 60 mg single dose.

37. The dosage form of claim 35, wherein the mean AUC_(0-t) is about 78.73 ng*h/ml based on a 60 mg single dose.

38. The dosage form of claim 35, wherein the mean AUC_(0-t) is about 154.39 ng*h/ml based on a 120 mg single dose.

39. The dosage form of claim 35, wherein the mean AUC_(0-t) is about 200.63 ng*h/ml based on a 180 mg single dose.

40. The dosage form of claim 1, wherein the mean AUC_(0-inf) ranges from about 83.87 ng*h/ml to about 213.22 ng*h/ml.

41. The dosage form of claim 35, wherein the mean AUC_(0-inf) is about 83.87 ng*h/ml based on a 60 mg single dose.

42. The dosage form of claim 35, wherein the mean AUC_(0-inf) is about 90.70 ng*h/ml based on a 60 mg single dose.

43. The dosage form of claim 35, wherein the mean AUC_(0-inf) is about 170.75 ng*h/ml based on a 120 mg single dose.

44. The dosage form of claim 35, wherein the mean AUC_(0-inf) is about 213.22 ng*h/ml based on a 180 mg single dose.

47. The dosage form of claim 1, which comprises a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof for the treatment of pain.

48. The dosage form of claim 1, wherein the sustained release delivery system comprises at least one hydrophilic compound in an amount from about 5% to about 80% by weight.

49. The dosage form of claim 1, wherein the sustained release delivery system comprises at least one hydrophilic compound in an amount from about 5% to about 80% by weight and at least one pharmaceutical diluent.

50. The dosage form of claim 1, wherein the sustained release delivery system comprises at least one hydrophilic compound in an amount from about 5% to about 80% by weight, a cross-linking agent, and at least one pharmaceutical diluent.

51. The dosage form of claim 1, wherein the sustained release delivery system comprises a hydrophilic compound selected from gums, cellulose ethers, acrylic resins, polyvinyl pyrrolidone, protein-derived compounds, and mixtures thereof.

52. The dosage form of claim 1, wherein the gel matrix comprises a gum selected from xanthan, tragacanth, pectins, acacia, karaya, alginates, agar, guar, hydroxypropyl guar, carrageenan, locust bean gums, gellan gums, hydroxyalkyl celluloses, carboxyalkyl celluloses, and mixtures thereof.

53. The dosage form of claim 1, which comprises from about 1 mg to about 200 mg nalbuphine hydrochloride.

54. The dosage form of claim 53, wherein the sustained release delivery system comprises about 10 mg to about 420 mg.

55. The dosage form of claim 54, wherein the sustained release delivery system comprises a hydrophilic compound selected from gums, cellulose ethers, acrylic resins, polyvinyl pyrrolidone, protein-derived compounds, and mixtures thereof.

45. A method of treating pain in a human in need thereof, comprising:

administering an oral solid gel matrix dosage form comprising a therapeutically effective amount of nalbuphine or a pharmaceutically acceptable salt thereof in a sustained release delivery system, wherein the dosage form provides a mean T_max at about 1.77 to about 8.01 hours after oral administration to human subjects and maintains a plateau of a relatively constant blood serum level of nalbuphine which does not consistently increase or decrease during a dosage interval, in the form of a tablet.

46. The method of claim 45, wherein the pain is associated with acute pain, chronic pain, nociceptive pain, neuropathic pain, visceral pain, idiopathic pain and any combinations thereof.

56. A sustained release oral tablet, comprising from about 1 mg to about 200 mg nalbuphine (based on its hydrochloride salt) or a pharmaceutically acceptable salt thereof in a sustained release gel matrix delivery system comprising at least one hydrophilic compound, wherein the dosage form provides one or more peaks in blood serum level of nalbuphine concentration followed by a plateau region of a relatively constant blood serum level of nalbuphine during a dosage interval after oral administration of the tablet to a human subject.

57. The sustained release oral tablet of claim 56, wherein the sustained release gel matrix delivery system comprises from about 12% to about 42% locust bean gum;

from about 8% to about 28% xanthan gum;

from about 20% to about 70% mannitol; and

from about 5% to about 20% calcium sulfate dihydrate.