Controlled Release Formulations and Associated Methods

• US 20080020039A1
• Filed: 07/19/2006
• Published: 01/24/2008
• Est. Priority Date: 07/19/2006
• Status: Active Grant

• Current Assignee: Watson Laboratories, Inc. (Connecticut) (Abbvie Incorporated)
• Original Assignee: Watson Laboratories, Inc. (Connecticut) (Abbvie Incorporated)
• Inventors: Melaku, Teshome, Parikh, Nilesh H.
• Granted Patent: US 8,765,178 B2
• Time in Patent Office: Days
• US Class Current: 424/472
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• 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 25/04 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]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/04 for decreasing, blocking or antagonising the activity of the hypothalamic hormones
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

A pharmaceutical formulation having a geometric configuration that affects the release characteristics of active agents contained therein and associated methods are provided. In one aspect, a sustained release oral dosage pharmaceutical tablet may include a first layer having a first active agent, where the first layer is disposed between two adjacent controlled release layers, at least one of the adjacent layers including at least one second active agent. The two adjacent layers are arranged such that they cover a portion of the first layer. The two adjacent layers may be separate layers or they may be joined into a single continuous layer, depending on the overall configuration and geometric design of the oral dosage form.

Claims

1. A sustained release oral dosage pharmaceutical tablet, comprising:

a first layer including a first active agent, the first layer disposed between two adjacent controlled release layers, at least one of said adjacent layers including at least one second active agent, the two adjacent layers covering a portion of the first layer.

2. The tablet of claim 1, wherein a portion of the two adjacent layers are joined into a single continuous layer.

3. The tablet of claim 1, wherein the two adjacent layers cover substantially the entire first layer around a peripheral edge thereof.

4. The tablet of claim 1, wherein the first active agent is an opioid agonist.

5. The tablet of claim 1, wherein the opioid agonist is a member selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methylmorphine, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, ohmefentanyl, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, pholcodine, piminodine, piritramide, propheptazine, promedol, profadol, properidine, propiram, propoxyphene, remifentanyl, sufentanyl, tramadol, tilidine, and salts, isomers, and combinations thereof.

6. The tablet of claim 5, wherein the opioid agonist is hydrocodone.

7. The tablet of claim 1, wherein the second active agent is a non-opioid analgesic.

8. The tablet of claim 7, wherein the non-opioid analgesic is a member selected from the group consisting of acetaminophen, aspirin, a non-steroidal anti-inflammatory drug, a cyclooxegenase inhibitor, an NMDA receptor antagonists, a muscle relaxant, a GABA receptor agonist, and combinations thereof.

9. The tablet of claim 1, wherein the first active agent is hydrocodone and the second active agent is acetaminophen.

10. The tablet of claim 1, further comprising an immediate release layer having a third active agent.

11. The tablet of claim 10, wherein the third active agent and either of the first active agent and the second active agent are the same.

12. The tablet of claim 10, wherein the first active agent is hydrocodone, the second active agent is acetaminophen, and the third active agent is hydrocodone.

13. The tablet of claim 10, wherein the immediate release layer is an immediate release coating substantially surrounding the pharmaceutical tablet.

14. The tablet of claim 1, wherein the two adjacent layers are erodible layers.

15. The tablet of claim 1, wherein the two adjacent layers are swellable layers.

16. The tablet of claim 1, wherein each of the two adjacent layers contain the same second active agent.

17. A sustained release oral dosage pharmaceutical tablet for administration to a subject, comprising:

a first layer including a first active agent to be released over a sustained period of time; and

at least two adjacent layers including at least one second active agent to be released in a controlled manner, said at least two adjacent layers being configured to regulate fluid access to a portion of the first layer, thereby controlling release of the first active agent from the first layer over the sustained period of time.

18. The tablet of claim 17, wherein the at least two adjacent layers are configured to expose only a peripheral edge of the first layer from which the first active agent is released.

19. The tablet of claim 18, wherein the at least two adjacent layers are configured such that the peripheral edge of the first layer provides constant release of the first active agent.

20. The tablet of claim 17, wherein the first active agent is hydrocodone and the second active agent is acetaminophen.

21. The tablet of claim 20, wherein the configuration of the first layer and the at least two adjacent layers provides a T_max hydrocodone serum concentration occurring at about 3 hours or more after administration of the tablet to the subject.

22. The tablet of claim 20, wherein the configuration of the first layer and the at least two adjacent layers provides a T_max hydrocodone serum concentration at from about 3 hours to about 8 hours after administration of the tablet to the subject.

23. The tablet of claim 20, wherein the configuration of the first layer and the at least two adjacent layers provides a T_max hydrocodone serum concentration at from about 4 hours to about 8 hours after administration of the tablet to the subject.

24. The tablet of claim 20, wherein the configuration of the first layer and the at least two adjacent layers provides a T_max hydrocodone serum concentration at from about 4 hours to about 6 hours after administration of the tablet to the subject.

25. The tablet of claim 20, wherein fluid access is regulated in an amount sufficient to release the first active agent at a rate of from about 30% to about 45% after about 1 hour, from about 43% to about 75% after about 2 hours, and from about 80% to about 100% after about 4 hours.

26. The tablet of claim 20, wherein fluid access is regulated in an amount sufficient to release the first active agent at a rate of from about 37% to about 44% after about 1 hour, from about 60% to about 73% after about 2 hours, and from about 85% to about 97% after about 4 hours.

27. The tablet of claim 20, wherein fluid access is regulated in an amount sufficient to release the first active agent at a rate of from about 39% to about 42% after about 1 hour, from about 65% to about 70% after about 2 hours, and from about 87% to about 94% after about 4 hours.

28. A method for controlling drug release from an oral dosage tablet administered to a subject, comprising:

regulating exposure of a first active agent containing layer in the tablet to the subject'"'"'s gastrointestinal fluid by placing said first layer between two adjacent controlled release layers having at least one second active agent.

29. The method of claim 28, wherein the first layer is placed between the two adjacent controlled release layers such that only a peripheral edge of the first layer is exposed.

30. The method of claim 29, wherein the first active agent is released at a constant rate from the peripheral edge as the two adjacent layers erode or swell.

31. The method of claim 28, wherein a portion of the first active agent is released prior to substantial erosion or swelling of the two adjacent layers.

32. The method of claim 28, further comprising allowing erosion or swelling of the two adjacent layers to expose additional surface area of the first layer to the subject'"'"'s gastrointestinal environment.

33. The method of claim 28, further comprising delivering an immediate release third active agent from the oral dosage tablet.

34. The method of claim 33, wherein the third active agent and either of the first active agent and the second active agent is the same.

35. A method of limiting release acceleration of an active agent from a pharmaceutical formulation when said formulation is exposed to alcohol, comprising:

regulating fluid access to a portion of a first layer containing said active agent by placing said first layer in contact with at least one adjacent layer that regulates the first layer'"'"'s exposure to alcohol.

36. The method of claim 35, wherein regulating fluid access further comprises:

placing the first layer between two adjacent layers, said adjacent layers controlling fluid access to a majority of the first layer'"'"'s surface area.

37. The method of claim 35, wherein the at least one adjacent layer contains at least one second active agent.

38. The method of claim 37, wherein the at least one second active agent is a non-opioid analgesic.

39. The method of claim 38, wherein the non-opioid analgesic is a member selected from the group consisting of acetaminophen, aspirin, a non-steroidal anti-inflammatory drug, a cyclooxegenase inhibitor, an NMDA receptor antagonists, a muscle relaxant, a GABA receptor agonist, and combinations thereof.

40. The method of claim 39, wherein the non-opioid analgesic is acetaminophen.

41. The method of claim 37, wherein the first active agent is hydrocodone and the second active agent is acetaminophen.

42. The method of claim 35, wherein the first active agent is an opioid agonist.

43. The method of claim 42, wherein the opioid agonist is a member selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methylmorphine, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, ohmefentanyl, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, pholcodine, piminodine, piritramide, propheptazine, promedol, profadol, properidine, propiram, propoxyphene, remifentanyl, sufentanyl, tramadol, tilidine, and salts, isomers, and combinations thereof.

44. The method of claim 42, wherein the opioid agonist is hydrocodone.

45. A pharmaceutical tablet that limits alcohol-induced accelerated release of an active agent, comprising:

a first layer including a first active agent, the first layer disposed between two adjacent layers, at least one of which includes at least one second active agent, the two adjacent layers covering a portion of the first layer such that, in an alcohol containing environment, alcohol access to the first layer is regulated by the two adjacent layers.

49. The pharmaceutical tablet of claim 45, wherein the two adjacent layers cover a portion of the first layer such that the tablet provides a release rate of the first active agent into an in vitro solution of from about 37% to about 48% after about 1 hour, from about 65% to about 75% after about 2 hours, and from about 90% to about 100% after about 4 hours, said in vitro solution including about 5% ethanol.

50. The pharmaceutical tablet of claim 45, wherein the two adjacent layers cover a portion of the first layer such that the tablet provides a release rate of the first active agent into an in vitro solution of from about 40% to about 46% after about 1 hour, from about 68% to about 73% after about 2 hours, and from about 90% to about 98% after about 4 hours, said in vitro solution including about 5% ethanol.

46. A pharmaceutical tablet that limits alcohol-induced accelerated release of an active agent, comprising:

a first layer including a first active agent, the first layer disposed between two adjacent layers, at least one of which includes at least one second active agent, the two adjacent layers covering a portion of the first layer such that the tablet provides a release rate of the first active agent into an in vitro solution of from about 30% to about 50% after about 1 hour, from about 45% to about 75% after about 2 hours, and from about 80% to about 100% after about 4 hours, said in vitro solution including up to about 40% ethanol.

47. The pharmaceutical tablet of claim 46, wherein the in vitro solution includes about 5% ethanol.

48. The pharmaceutical tablet of claim 46, wherein the in vitro solution includes about 40% ethanol.

51. A sustained release oral dosage pharmaceutical tablet, comprising:

a first layer including a first active agent, the first layer disposed between two adjacent layers, at least one of which includes at least one second active agent, the two adjacent layers covering a portion of the first layer in order to control release of the first active agent, such that after about 1 hour from about 30% to about 45% is released, after about 2 hours, from about 43% to about 75% is released, and after about 4 hours, from about 80% to about 100% after about 4 hours is released.

52. The pharmaceutical tablet of claim 51, wherein the two adjacent layers covering a portion of the first layer control release of the first active agent at a rate of from about 37% to about 44% after 1 hour, from about 60% to about 73% after 2 hours, and from about 85% to about 97% after about 4 hours, into an in vitro solution.

53. The pharmaceutical tablet of claim 51, wherein the two adjacent layers covering a portion of the first layer control release of the first active agent at a rate of from about 39% to about 42% after 1 hour, from about 65% to about 70% after 2 hours, and from about 87% to about 94% after about 4 hours.