Methods and devices for providing prolonged drug therapy

• US 9,029,416 B2
• Filed: 08/12/2003
• Issued: 05/12/2015
• Est. Priority Date: 11/12/1996
• Status: Expired due to Fees

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Lam, Andrew C., Shivanand, Padmaja, Ayer, Atul D., Hatamkhany, Zahedeh, Gupta, Suneel K., Guinta, Diane R., Christopher, Carol A., Saks, Samuel R., Hamel, Lawrence G., Wright, Jeri D., Weyers, Richard G.
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US10/638,977
• Publication Number:
  US 20050025831A1
• Time in Patent Office: 4,291 Days
• Field of Search: 514/532
• US Class Current: 514/532
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• 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 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092

Abstract

Methods and devices for maintaining a desired therapeutic drug effect over a prolonged therapy period are provided. In particular, oral dosage forms that release drug within the gastrointestinal tract at an ascending release rate over an extended time period are provided. The dosage forms may additionally comprise an immediate-release dose of drug.

Claims

1. An osmotic dosage form comprising:

a capsule-shaped longitudinally compressed tablet core containing a plurality of layers wherein drug is contained in at least one layer and at least one other layer comprises a suitable fluid-expandable polymer, and wherein said drug is a CNS-stimulant drug selected from the group consisting of methylphenidate, d-threo-methylphenidate, amphetamine, dextroamphetamine, methamphetamine, and pemoline;

a semipermeable wall surrounding said longitudinally compressed tablet core to thereby form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting said semipermeable wall into said compartment; and

an orifice formed through said semipermeable wall and into said longitudinally compressed tablet core to permit drug to be released from within said compartment into said external fluid environment.

2. The dosage form described in claim 1 wherein said longitudinally compressed tablet core comprises two layers and wherein said orifice is formed through said semipermeable wall at a location adjacent to said layer wherein said drug is contained.

3. The dosage form described in claim 2 additionally comprising an immediate-release dose of a drug applied as a coating onto the outer surface of said osmotic dosage form.

4. The dosage form described in claim 1 wherein said longitudinally compressed tablet core comprises three layers and a portion of said drug is contained within a first layer and the remaining portion of said drug is contained within a second layer, wherein the concentration of drug contained within said first layer is less than the concentration of drug contained within said second layer, and wherein said fluid-expandable polymer is contained within a third layer and said orifice is formed through said semipermeable wall at a location adjacent to said first layer.

5. The dosage form described in claim 4 further comprising an immediate-release dose of a drug applied as a coating onto the outer surface of said osmotic dosage form.

6. The dosage form described in claim 1 wherein said CNS-stimulant drug is methylphenidate.

7. The dosage form described in claim 5 wherein said coating comprises an antidegradation agent.

8. The dosage form described in claim 7 wherein said antidegradation agent is phosphoric acid.

9. The dosage form described in claim 1 wherein said semipermeable membrane comprises cellulose acetate and a flux-enhancing agent.

10. The dosage form described in claim 9 wherein said flux-enhancing agent is a copolymer of ethylene and propylene oxide.

11. A dosage form comprising:

a first drug layer comprising drug, wherein said drug is a CNS-stimulant drug selected from the group consisting of methylphenidate, d-threo-methylphenidate, amphetamine, dextroamphetamine, methamphetamine, and pemoline, or a pharmaceutically acceptable salt thereof;

a second drug layer comprising an additional quantity of said drug, wherein the quantity of said drug in said second layer is greater than the quantity of said drug in the first layer;

a third layer comprising a composition that expands and displaces the first drug layer followed by the second drug layer from the dosage form;

a wall that surrounds the three layers, which wall is permeable to fluid and impermeable to drug; and

a passageway in the wall communicating with the first drug layer for delivering the first drug layer followed by the second drug layer from the dosage form wherein said drug layers and wall are shaped and adapted to interact cooperatively such that drug is released from the dosage form at an ascending release rate

beginning with a first periodic interval that begins at time t=0 and continuing up to at least about 5.5 hours following administration of said dosage form.

12. The dosage form of claim 11 wherein said drug is methylphenidate hydrochloride.

13. The dosage form of claim 11 further comprising a drug layer overcoat.

14. The dosage form of claim 11 wherein the third layer further comprises at least one osmagent.

15. The dosage form of claim 14 wherein at least about 35% of the third layer comprises an osmagent.

16. The dosage form of claim 15 wherein the osmagent is sodium chloride.

17. The dosage form of claim 11 wherein said wall further comprises an immediate-release dosage of the drug applied as a coating onto the outer surface.

18. The dosage form of claim 17 wherein the coating comprises an antidegradation agent.

19. The dosage form of claim 18 wherein the antidegradation agent is phosphoric acid.

20. The dosage form of claim 11 wherein said wall further comprises cellulose acetate and a flux-enhancing agent.

21. The dosage form of claim 20 wherein the flux enhancing agent is a copolymer of ethylene and propylene oxide.

22. A dosage form comprising a capsule shaped tablet core comprising two layers, wherein:

a first of said two layers comprises a portion of drug, wherein the drug is methylphenidate or pharmaceutically acceptable salt thereof,

a second of said layers comprises a suitable fluid-expanding polymer and is adjacent said first layer,

a semipermeable membrane surrounding the capsule shaped tablet core to form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting the semipermeable membrane into the compartment, and

an orifice formed through the semipermeable membrane and into the capsule shaped tablet core at a location adjacent to the first layer to permit the drug to be released from within the compartment into the external fluid environment, and wherein the dosage form releases the drug at an ascending release rate

beginning with a first periodic interval that begins at time t=0 and continuing up to at least about 5.5 hours following administration of said dosage form.

23. The dosage form of claim 22 wherein said drug comprises 100 ng and 500 mg of methylphenidate.

24. The dosage form of claim 22 that further comprises a drug layer overcoat.

25. The dosage form of claim 22 wherein the second layer further comprises at least one osmagent.

26. The dosage form of claim 22 that is a bi-layer dosage form comprising a drug layer and a push layer.

27. The dosage form of claim 26 wherein at least about 35% of the push layer comprises the osmagent.

28. The dosage form of claim 27 wherein the osmagent is sodium chloride.

29. The dosage form of claim 22 further comprising an outer surface and an immediate-release dosage of the drug applied as a coating onto the outer surface.

30. The dosage form of claim 29 wherein the coating comprises an antidegradation agent.

31. The dosage form of claim 30 wherein the antidegradation agent is phosphoric acid.

32. The dosage form of claim 22 wherein the semipermeable membrane further comprises cellulose acetate and a flux-enhancing agent.

33. The dosage form of claim 32 wherein the flux enhancing agent is a copolymer of ethylene and propylene oxide.

34. A method comprising orally administering an osmotic dosage form comprising:

a capsule-shaped longitudinally compressed tablet core containing a plurality of layers wherein drug is contained in at least one layer and at least one other layer comprises a suitable fluid-expandable polymer, wherein said drug is methylphenidate hydrochloride;

a semipermeable wall surrounding said longitudinally compressed tablet core to thereby form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting said semipermeable wall into said compartment; and

an orifice formed through said semipermeable wall and into said longitudinally compressed tablet core to permit drug to be released from within said compartment into said external fluid environment.

35. A method comprising orally administering a capsule shaped dosage form comprising:

a first drug layer comprising drug, wherein said drug is methylphenidate hydrochloride;

a second drug layer comprising an additional quantity of said drug, wherein the quantity of said drug in said second layer is greater than the quantity of said drug in the first layer;

a third layer comprising a composition that expands and displaces the first drug layer followed by the second drug layer from the dosage form;

a wall that surrounds the three layers, which wall is permeable to fluid and impermeable to drug; and

a passageway in the wall communicating with the first drug layer for delivering the first drug layer followed by the second drug layer from the dosage form wherein said drug layers and wall are shaped and adapted to interact cooperatively such that drug is released from the dosage form at an ascending release rate

beginning with a first periodic interval that begins at time t=0 and continuing up to at least about 5.5 hours following administration of said dosage form.

36. A method comprising orally administering a dosage form comprising a capsule shaped tablet core comprising two layers, wherein:

a first of said two layers comprises a portion of a drug, wherein said drug is methylphenidate hydrochloride,

a second of said layers comprises a suitable fluid-expanding polymer and is adjacent said first layer,

a semipermeable membrane surrounding the capsule shaped tablet core to form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting the semipermeable membrane into the compartment, and

an orifice formed through the semipermeable membrane and into the capsule shaped tablet core at a location adjacent to the first layer to permit the drug to be released from within the compartment into the external fluid environment, and wherein the dosage form releases the drug at an ascending release rate

beginning with a first periodic interval that begins at time t=0 and continuing up to at least about 5.5 hours following administration of said dosage form.

37. A dosage form comprising a capsule shaped tablet core comprising:

two layers, wherein a first of said two layers comprises a portion of drug, wherein said drug comprises-methylphenidate hydrochloride, and wherein a second of said layers comprises a suitable fluid-expanding polymer;

a semipermeable membrane that surrounds the capsule shaped tablet core to form a compartment that has an osmotic gradient that drives fluid from an external fluid environment contacting the semipermeable membrane into the compartment; and

an orifice that is formed through the semipermeable membrane at a location adjacent to the first layer that permits the drug to be released from the compartment into the external fluid environment,

wherein the dosage form releases the drug over a period comprising a first, second, and third sequential time intervals of equal duration, and

wherein the dosage form releases more of said drug during said second interval than during said first interval and more of said drug during said third interval than during said second interval.

38. The dosage form according to claim 37 wherein said period of release comprises a fourth sequential time interval, and wherein the dosage form releases more of said drug during said fourth interval than during said third interval.

39. The dosage form according to claim 37 further comprising an immediate-release dosage of the drug applied as a coating on an outer surface of the dosage form.

40. The dosage form according to claim 39 wherein the dosage form releases more of said drug during said second interval than during said first interval, not including drug released from said coating during said first interval.

41. The dosage form according to claim 40 wherein each of said time intervals is 30 minutes.

42. The dosage form according to claim 40 wherein each of said time intervals is 1 hour.

43. The dosage form according to claim 41 wherein the drug released during said first interval does not include any drug released from said capsule shaped tablet core.

44. The dosage form according to claim 42 wherein the drug released during said first interval does not include any drug released from said capsule shaped tablet core.

45. The dosage form according to claim 37 wherein said dosage form is configured for oral administration.

46. The dosage form according to claim 37 further comprising a third layer comprising an additional portion of said drug, wherein said third layer is disposed between said first layer and said second layer.