PHARMACEUTICAL DOSAGE FORMS COMPRISING POLY(E-CAPROLACTONE)

• US 20110165248A1
• Filed: 09/17/2009
• Published: 07/07/2011
• Est. Priority Date: 09/18/2008
• Status: Abandoned Application

• Current Assignee: Meridith Lee Machonis
• Original Assignee: Meridith Lee Machonis
• Inventors: Machonis, Meridith Lee
• Application Number:
  US13/055,535
• Publication Number:
  US 20110165248A1
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The present invention relates to pharmaceutical dosage forms, for example to pharmaceutical dosage forms comprising poly(ε-caprolactone), and processes of manufacture, uses, and methods of treatment thereof.

Claims

1. A solid oral extended release pharmaceutical dosage form, comprising a melt formed multi particulate extended release matrix formulation, comprising at least one poly(ε

-caprolactone), and at least one active agent.

2. The solid oral extended release pharmaceutical dosage form of claim 1, wherein the melt is formed by an extrusion method.

3. The solid oral extended release pharmaceutical dosage form of claim 1, wherein the melt is formed by a casting method.

4. The solid oral extended release pharmaceutical dosage form of claim 1, wherein the melt is formed by an injection molding method.

5. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein at least one poly(ε

-caprolactone) has an approximate number average molecular weight of at least about 10,000.

6. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the at least one poly(ε

-caprolactone) has an approximate number average molecular weight of at least about 37,000.

7. The solid oral extended release pharmaceutical dosage form according to claim 5, wherein the at least one poly(ε

-caprolactone) has an approximate number average molecular weight of between about 10,000 to about 80,000.

8. The solid oral extended release pharmaceutical dosage form according to claim 6, wherein the at least one poly(ε

-caprolactone) has an approximate number average molecular weight of between about 37,000 and about 80,000.

9. The solid oral extended release pharmaceutical dosage form according to claim 1, comprising at least a first poly(ε

-caprolactone) with an approximate number average molecular weight of between about 10,000 and about 25,000 and a second poly(ε

-caprolactone) with an approximate number average molecular weight of between about 37,000 and about 80,000.

10. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein poly(ε

-caprolactone) is present at an amount of at least about 50 weight-% of the extended release matrix formulation.

11. The solid oral extended release pharmaceutical dosage form according to claim 10, wherein poly(ε

-caprolactone) is present at an amount of at least about 60 weight-% of the extended release matrix formulation.

12. The solid oral extended release pharmaceutical dosage form according to claim 10, wherein poly(ε

-caprolactone) is present at an amount of between about 50 and about 90 weight-% of the extended release matrix formulation.

13. The solid oral extended release pharmaceutical dosage form according to according to claim 1, wherein the least one poly(ε

-caprolactone) has an approximate number average molecular weight of between about 37,000 and about 80,000 and is present at an amount of between about 50 and about 90 weight-% of the extended release matrix formulation.

14. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the multi particulates have a diameter in the range of about 0.1 to about 3 mm.

15. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the extended release matrix formulation further comprises at least one polyethylene glycol.

16. The solid oral extended release pharmaceutical dosage form according to claim 15, wherein the polyethylene glycol is present at an amount of between about 1 and about 20 weight-%

17. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the extended release matrix formulation further comprises at least one high molecular weight polyethylene oxide.

18. The solid oral extended release pharmaceutical dosage form according to claim 17, wherein high molecular weight polyethylene oxide has a molecular weight of between about 1,000,000 and about 10,000,000, based on rheological measurements.

19. The solid oral extended release pharmaceutical dosage form according to claim 17, wherein high molecular weight polyethylene oxide is present at an amount of between about 5 and about 35 weight-%.

20. The solid oral extended release pharmaceutical dosage form according to claim 17, wherein a high molecular weight polyethylene oxide is used which has been screened with a screen with a size of 1/10 or less of the average diameter of the resulting melt formed multi particulate extended release formulation.

21. The solid oral extended release pharmaceutical dosage form according to claim 17, wherein a high molecular weight polyethylene oxide is used which has been screened with a 100 US mesh screen or a finer screen.

22. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the extended release matrix formulation further comprises at least one poloxamer.

23. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein active agent is an opioid analgesic.

24. The solid oral extended release pharmaceutical dosage form according to claim 23, wherein the opioid analgesic is selected from the group of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiarnbutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφ

hine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures of any of the foregoing.

25. The solid oral extended release pharmaceutical dosage form of claim 24, wherein the opioid analgesic is selected from the group of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone or pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures of any of the foregoing.

26. The solid oral extended release pharmaceutical dosage form of claim 25, wherein the opioid analgesic is oxycodone hydrochloride and the dosage form comprises from about 5 mg to about 500 mg of oxycodone hydrochloride.

27. The solid oral extended release pharmaceutical dosage form of claim 26, wherein the dosage form comprises 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30, mg, 40 mg, 45 mg, 50 mg, 60 mg, or 80 mg, 90 mg, 100 mg, 120 mg or 160 mg of oxycodone hydrochloride.

28. The solid oral extended release pharmaceutical dosage form of claim 27, wherein the opioid analgesic is oxycodone hydrochloride having a 14-hydroxycodeinone level of less than about 25 ppm.

29. The solid oral extended release pharmaceutical dosage form of claim 25, wherein the opioid analgesic is oxymorphone hydrochloride and the dosage form comprises from about 1 mg to about 500 mg of oxymorphone hydrochloride.

30. The solid oral extended release pharmaceutical dosage form of claim 29, wherein the dosage form comprises 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg 60 mg, or 80 mg, 90 mg, 100 mg, 120 mg or 160 mg of oxymorphone hydrochloride.

31. The solid oral extended release pharmaceutical dosage form of claim 25, wherein the opioid analgesic is hydromorphone hydrochloride and the dosage form comprises from about 1 mg to about 100 mg of hydromorphone hydrochloride.

32. The solid oral extended release pharmaceutical dosage form of claim 31, wherein the dosage form comprises 2 mg, 4 mg, 5 mg, 8 mg, 12 mg, 15 mg, 16 mg, 24 mg, 25 mg, 32 mg, 48 mg, 50 mg, 64 mg or 75 mg of hydromorphone hydrochloride.

33. The solid oral extended release pharmaceutical dosage form of claim 1, which contains active in immediate release form.

34. The solid oral extended release pharmaceutical dosage form of claim 33, wherein the same or different active agents are in extended release and in immediate release forms.

35. The solid oral extended release pharmaceutical dosage form according to any one of claim 1, wherein the dosage form provides release rates of the active agent in-vitro when measured by the USP Basket Method at 100 rpm at 900 ml simulated gastric fluid at 37°

C., between about 12.5% and about 55% (by wt) active agent released after 1 hour, between about 25% and about 65% (by wt) active agent released after 2 hours, between about 45% and about 85% (by wt) active agent released after 4 hours and between about 55% and about 95% (by wt) active agent released after 6 hours.

36. The solid oral extended release pharmaceutical dosage form of claim 35, wherein the active agent is oxycodone hydrochloride.

37. The solid oral extended release pharmaceutical dosage form of claim 35, wherein the active agent is hydromorphone hydrochloride.

38. The solid oral extended release pharmaceutical dosage form of claim 35, wherein the active agent is oxymorphone hydrochloride.

39. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the dosage form provides release rates of the active agent in-vitro when measured by the USP Basket Method at 100 rpm at 900 ml simulated gastric fluid at 37°

C. between about 10% and about 30% (by wt) active agent released after 2 hour, about 40% and about 75% (by wt) active agent released after 8 hours and no less than about 80% (by wt) active agent released after 22 hours.

40. The solid oral extended release pharmaceutical dosage form of claim 39, wherein the active agent is hydromorphone hydrochloride.

41. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the dosage form provides an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid comprising 40% ethanol at 37°

C., characterized by the percent amount of active agent released at 1 hour of dissolution that deviates no more than about 20% points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid at 37°

C. without ethanol.

42. The solid oral extended release pharmaceutical dosage form according to claim 41, wherein the percent amount of active agent released at 1 hour of dissolution deviates no more than about 10% points.

43. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the dosage form provides after milling an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid at 37°

C., characterized by the percent amount of active agent released at 1 hour of dissolution that increases no more than about 20% points when compared to the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid at 37°

C. without milling.

44. The solid oral extended release pharmaceutical dosage form according to claim 43, wherein the percent amount of active agent released at 1 hour of dissolution increases no more than about 10% points.

45. The solid oral extended release pharmaceutical dosage form according to claim 43, wherein the percent amount of active agent released at 1 hour of dissolution decreases when oral compared to the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid at 37°

C. without milling.

46. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the dosage form provides after grinding an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid at 37°

C., characterized by the percent amount of active agent released at 1 hour of dissolution that increases no more than about 20% points when compared to the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid at 37°

C. without grinding.

47. The solid oral extended release pharmaceutical dosage form according to claim 46, wherein the percent amount of active agent released at 1 hour of dissolution increases no more than about 10% points.

48. The solid oral extended release pharmaceutical dosage form according to claim 46, wherein the percent amount of active agent released at 1 hour of dissolution decreases when compared to the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid at 37°

C. without grinding.

49. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the dosage form after milling provides an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid comprising 40% ethanol at 37°

C., characterized by the percent amount of active agent released at 1 hour of dissolution that deviates no more than about 20% points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without ethanol at 37°

C. without milling.

50. The solid oral extended release pharmaceutical dosage form according to claim 49, wherein the percent amount of active agent released at 1 hour of dissolution deviates no more than about 10% points.

51. The solid oral extended release pharmaceutical dosage form according to claim 1, wherein the dosage form after grinding provides an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid, comprising 40% ethanol, at 37°

C., characterized by the percent amount of active agent released at 1 hour of dissolution that deviates no more than about 20% points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without ethanol at 37°

C. without grinding.

52. The solid oral extended release pharmaceutical dosage form according to claim 51, wherein the percent amount of active agent released at 1 hour of dissolution deviates no more than about 10% points.

53. The solid oral extended release pharmaceutical dosage form according to claim 41, wherein the active agent is oxycodone hydrochloride.

54. The solid oral extended release pharmaceutical dosage form according to claim 41, wherein the active agent is hydromorphone hydrochloride.

55. The solid oral extended release pharmaceutical dosage form according to claim 41, wherein the active agent is oxymorphone hydrochloride.

58. A method of treatment wherein a solid oral extended release pharmaceutical dosage form according to claim 1 is administered for treatment of pain to a patient in need thereof, wherein the dosage form comprises an opioid analgesic.

56. A solid oral extended release pharmaceutical dosage form which is resistant to milling and grinding.

57. The solid oral extended release pharmaceutical dosage form according to claim 56, wherein the dosage form is resistant to alcohol extraction.

59-60. -60. (canceled)

61. A process of preparing a solid oral extended release pharmaceutical dosage form comprising the steps of:

melting and blending the poly(ε

-caprolactone) (PCL) and optionally other ingredients except the active agent on a Thermodyne Hot Plate (temperature range 90°

-160°

C.) to obtain a mixture;

adding the active agent to the mixture on the Thermodyne Hot Plate (temperature range about 90°

-about 160°

C.) until the mixture appeared homogeneous to obtain a blend;

placing the molten blend on a stainless steel plate and pressing with a second stainless steel plate and cooling to room temperature to obtain a sheet with a given thickness; and

pelletizing the sheet by cutting into pellets.

62. The process of claim 61, wherein the thickness of the sheet is approximately 2 mm and the pellets have approximately 2 mm in length and width.

65. A solid oral extended release pharmaceutical dosage form obtainable by a process according to claim 61.

63. A process of preparing a solid oral extended release pharmaceutical dosage form comprising the steps of:

screening active agent, poly(ε

-caprolactone) and optionally other ingredients through a #20 US mesh screen;

blending the screened materials at ambient temperature;

extruding the screened and blended materials in a twin screw extruder fitted with a die and set on counter-rotation with zone (barrel) temperatures ranged from about 18°

C. to about 110°

C. to obtain stands;

cooling the strands to ambient temperature; and

pelletizing the cooled strands into pellets.

64. The process of claim 63, further comprising screening a polyethylene oxide through a #100 US mesh screen or finer.