Pharmaceutical compositions for treating or preventing pain

• US 9,433,625 B2
• Filed: 04/03/2014
• Issued: 09/06/2016
• Est. Priority Date: 07/08/2009
• Status: Active Grant

• Current Assignee: LOCL Pharma, Inc. (Charleston Laboratories, Inc.)
• Original Assignee: LOCL Pharma, Inc. (Charleston Laboratories, Inc.)
• Inventors: Bosse, Paul, Ameling, John, Schachtel, Bernard, Takigiku, Ray
• Primary Examiner(s): Arnold, Ernst V
• Application Number:
  US14/244,455
• Publication Number:
  US 20140308349A1
• Time in Patent Office: 887 Days
• US Class Current: 1/1
• 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 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• 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: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Methods and compositions are provided which comprise effective amounts of one or more analgesics, such as hydrocodone or acetaminophen, and an antiemetic, such as promethazine, to treat or prevent pain in a subject, and to reduce or prevent an adverse effect associated with the analgesics.

Claims

1. A pharmaceutical composition in the form of a tablet comprising two layers, wherein the tablet comprises

(1) a layer formulated for immediate release comprising:

(a) 5 mgs to 30 mgs of an antiemetic;

(b) about 75 mgs to about 150 mgs of silicified microcrystalline cellulose;

(c) about 10 mgs to about 20 mgs of croscarmellose sodium; and

(d) about 0.5 mgs to about 2 mgs of magnesium stearate; and

(2) a layer formulated for controlled release comprising;

(a) about 200 mgs to about 1000 mgs of a non-opioid analgesic;

(b) about 0.5 mgs to about 20 mgs of an opioid analgesic;

(c) about 75 mgs to about 250 mgs of silicified microcrystalline cellulose;

(d) about 10 mgs to about 40 mgs of hydroxypropyl methylcellulose;

(e) about 0.5 mgs to 5 mgs of magnesium stearate; and

(f) about 0.5 mgs to about 5 mgs of stearic acid.

2. The pharmaceutical composition of claim 1, wherein the tablet has a hardness of about 7, 8, 9, 10, 11, 12, 13, 14, or 15 kilaponds (kp).

3. The pharmaceutical composition of claim 1, wherein the tablet has a hardness of about 15 kp.

4. The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine, aprepitant, dronabinol, perphenazine, palonosetron, metoclopromide, domperidone, prochlorperazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, thiethylperazine, thioproperazine, tropisetron, droperidol, haloperidol, diphenhydramine, midazolam, lorazepam, hyoscine, dexamethasone, emetrol, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine hydrochloride.

7. The pharmaceutical composition of claim 1, wherein the antiemetic is present in an amount of about:

5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, or 25 mgs.

8. The pharmaceutical composition of claim 1, wherein the antiemetic is present in the amount of about 12.5 mgs.

9. The pharmaceutical composition of claim 1, wherein the opioid analgesic is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, codeine, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, tramadol, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 1, wherein the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 1, wherein the opioid analgesic is hydrocodone bitartrate.

12. The pharmaceutical composition of claim 1, wherein the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition of claim 1, wherein the opioid analgesic is oxycodone hydrochloride.

14. The pharmaceutical composition of claim 1, wherein the opioid analgesic is present in an amount of about:

1, 1.5, 2.5, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 mgs.

15. The pharmaceutical composition of claim 1, wherein the opioid analgesic is present in an amount of about 7.5 mgs.

16. The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is acetaminophen, aspirin, ibuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is acetaminophen.

18. The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is present in an amount of :

300, 305, 310, 315, 320, 325, 330, 335, 340, 345, or 350 mgs.

19. The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is acetaminophen and is present in an amount of about 325 mgs.

20. The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof, the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof, and the non-opioid analgesic is acetaminophen or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of claim 20, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, about 7.5 mg, or about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 402 mg.

22. The pharmaceutical composition of claim 20, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

23. The pharmaceutical composition of claim 20, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 7.5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

24. The pharmaceutical composition of claim 20 wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

25. The pharmaceutical composition of any one of claims 22-24, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg.

26. The pharmaceutical composition of claim 1, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof, the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof, and the non-opioid analgesic is acetaminophen or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical composition of claim 26, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, about 7.5 mg, or about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 402 mg.

28. The pharmaceutical composition of claim 26, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

29. The pharmaceutical composition of claim 26, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 7.5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

30. The pharmaceutical composition of claim 26, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

31. The pharmaceutical composition of any one of claims 28-30, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg.

32. The pharmaceutical composition of any one of claims 1, 2, 3, 4-19, 20-24, and 26-30, wherein the layer formulated for controlled release further comprises about 5 mgs to about 25 mgs of croscarmellose sodium.

33. The pharmaceutical composition of claim 31, wherein the layer formulated for controlled release comprises from about 8 mgs to about 12 mgs of croscarmellose sodium.

74. The pharmaceutical composition of claim 1, wherein the tablet further comprises an effective amount of an abuse deterrent agent.

34. A method of treating or preventing pain in a subject in need thereof, comprising:

orally administering to a subject in need thereof in a dosing interval of 4 to 6 hours, as needed, a pharmaceutical composition in the form of a tablet comprising two layers, wherein the tablet comprises;

(1) a layer formulated for immediate release comprising;

(a) 5 mgs to 30 mgs of an antiemetic;

(b) about 75 mgs to about 150 mgs of silicified microcrystalline cellulose;

(c) about 10 mgs to about 20 mgs of croscarmellose sodium; and

(d) about 0.5 mgs to about 2 mgs of magnesium stearate; and

(2) a layer formulated for controlled release comprising;

(a) about 200 mgs to about 1000 mgs of a non-opioid analgesic;

(b) about 0.5 mgs to about 20 mgs of an opioid analgesic;

(c) about 75 mgs to about 250 mgs of silicified microcrystalline cellulose;

(d) about 10 mgs to about 40 mgs of hydroxypropyl methylcellulose;

(e) about 0.50 mgs to 5 mgs of magnesium stearate; and

(f) about 0.5 mgs to about 5 mgs of stearic acid,

wherein the pharmaceutical composition provides an effective amount of the opioid analgesic and the non-opioid analgesic to treat or prevent pain in the subject in need thereof, and an effective amount of the antiemetic to reduce or prevent an adverse effect associated with the opioid analgesic in the subject in need thereof.

35. The method of claim 34, wherein the subject has a reduction in the adverse effect associated with the opioid analgesic.

36. The method of claim 34, wherein the adverse effect associated with the opioid analgesic is nausea, vomiting, constipation, itching, gastric upset, or skin rash.

37. The method of claim 34, wherein the subject is about age 65 or older.

38. The method of claim 34, wherein the pain is associated with a headache.

39. The method of claim 38, wherein the headache is a migraine headache, cluster headache, hemicrania continua headache, chronic headache, tension headache or chronic tension headache.

40. The method of claim 34, wherein the pain is associated with photophobia.

41. The method of claim 34, wherein the antiemetic is promethazine, aprepitant, dronabinol, perphenazine, palonosetron, metoclopromide, domperidone, prochlorperazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, thiethylperazine, thioproperazine, tropisetron, droperidol, haloperidol, diphenhydramine, midazolam, lorazepam, hyoscine, dexamethasone, emetrol, or a pharmaceutically acceptable salt thereof.

42. The method of claim 34, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof.

43. The method of claim 34, wherein the antiemetic is promethazine hydrochloride.

44. The method of claim 34, wherein the antiemetic is present in an amount of about:

5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20 mgs.

45. The method of claim 34, wherein the antiemetic is present in an amount of about 12.5 mgs.

46. The method of claim 34, wherein the opioid analgesic is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, codeine, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, tramadol, or a pharmaceutically acceptable salt thereof.

47. The method of claim 34, wherein the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof.

48. The method of claim 34, wherein the opioid analgesic is hydrocodone bitartrate.

49. The method of claim 34, wherein the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof.

50. The method of claim 34, wherein the opioid analgesic is oxycodone hydrochloride.

51. The method of claim 34, wherein the opioid analgesic is present in an amount of about:

1, 1.5, 2.5, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 mgs.

52. The method of claim 34, wherein the opioid analgesic is present in an amount of about 7.5 mgs.

53. The method of claim 34, wherein the non-opioid analgesic is acetaminophen, aspirin, ibuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, or a pharmaceutically acceptable salt thereof.

54. The method of claim 34, wherein the non-opioid analgesic is acetaminophen.

55. The method of claim 34, wherein the non-opioid analgesic is present in an amount of:

300, 305, 310, 315, 320, 325, 330, 335, 340, 345, or 350 mgs.

56. The method of claim 34, wherein the non-opioid analgesic is acetaminophen and is present in an amount of about 325 mgs.

57. The method of claim 34, wherein the adverse effect is nausea or vomiting.

58. The method of claim 34, wherein the subject has a reduction in incidence of nausea or vomiting.

59. The method of claim 34, wherein the subject has a reduction in intensity of nausea or vomiting.

60. The method of claim 34, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof, the opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof, and the non-opioid analgesic is acetaminophen or a pharmaceutically acceptable salt thereof.

61. The method of claim 60, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, about 7.5 mg, or about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 402 mg.

62. The method of claim 60, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

63. The method of claim 60, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 7.5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

64. The method of claim 60, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the hydrocodone or the pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

65. The method of any one of claims 62-64, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg.

66. The method of claim 34, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof, the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof, and the non-opioid analgesic is acetaminophen or a pharmaceutically acceptable salt thereof.

67. The method of claim 66, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, about 7.5 mg or about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 402 mg.

68. The method of claim 66, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

69. The method of claim 66, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 7.5 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

70. The method of claim 66, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg or about 25 mg, wherein the oxycodone or the pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, and wherein the acetaminophen or the pharmaceutically acceptable salt thereof is present in an amount of about 325 mg.

71. The method of any one of claims 68-70, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in an amount of about 12.5 mg.

72. The method of any one of claims 34-36, 37-40, 41-59, 60-64, and 66-70, wherein the layer formulated for controlled release of the tablet further comprises about 5 mgs to about 25 mgs of croscarmellose sodium.

73. The method of claim 72, wherein the layer formulated for controlled release of the tablet comprises from about 8 mgs to about 12 mgs of croscarmellose sodium.

75. The method of claim 34, wherein the tablet further comprises an effective amount of an abuse deterrent agent.