TRANSDERMAL ANALGESIC SYSTEMS WITH REDUCED ABUSE POTENTIAL

CLAIMS We Claim : 1. A transdermal system for administering an analgesic through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising an analgesic, the analgesic being selected from the group consisting of fentanyl and analogs thereof; (b) an antagonist reservoir comprising an antagonist for said analgesic ;STDC0557 (c) a barrier layer, said barrier layer separating said antagonist reservoir from said analgesic reservoir, said barrier layer being substantially impermeable to said analgesic and to said antagonist, wherein the system (i) substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days; and (ii) provides release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic when the system is subject to abuse.

2. The system of claim 1 further comprising an antagonist release rate controlling means.

3. The system of claim 2 wherein said antagonist release rate controlling means substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days; and provides release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic when the system is subject to abuse.

4. A transdermal system for administering an analgesic through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising an analgesic, the analgesic being selected from the group consisting of fentanyl and analogs thereof; (b) an antagonist reservoir comprising an antagonist for said analgesic ;

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(c) a barrier layer, said barrier layer separating said antagonist reservoir from said analgesic reservoir, said barrier layer being substantially impermeable to said analgesic and to said antagonist, wherein the system (i) substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days;STDC0221 and (ii) provides release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic upon ingestion or substantial immersion of the system in the solvent.

5. The system of claim 4 further comprising an antagonist release rate controlling means.

6. The system of claim 5 wherein said antagonist release rate controlling means substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days; and provides release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic upon ingestion or substantial immersion of the system in the solvent.

7. The system of claim 3 or claim 6 further wherein the antagonist release rate controlling means is disposed on the skin distal surface of the antagonist reservoir.

8. The system of claim 7 wherein the antagonist release rate controlling means is selected from a group consisting of a layer, a membrane, a film, a coating, a sheet, and a deposit on the antagonist reservoir.

9. The system of claim 8 wherein the antagonist release rate controlling means is selected from a group consisting of a rate control layer, a rate control membrane, a porous membrane and a microporous membrane.

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10. The system of any of the preceding claims, wherein said analgesic reservoir comprises an amount of analgesic sufficient to induce and maintain analgesia in a human patient for a period of at least three days.

11. The system of claim 10 wherein said analgesic reservoir comprises an amount of dissolved fentanyl or analog thereof sufficient to induce and maintain analgesia for 3-7 days.

12. The system of any of the preceding claims, wherein said analgesic reservoir comprises a single phase formulation free of undissolved components.

13. The system of any of the preceding claims wherein the analgesic reservoir is formed from an adhesive polymer.

14. The system of claim 13 wherein said analgesic reservoir comprises a polymer having a solubility for fentanyl and analogs thereof of about 1 wt% to about 25wt%.

15. The system of claim 14 wherein the reservoir comprises about 0.05 to about 1.75 mg/cm2 of fentanyl or analogs thereof.

16. The system of claim 14 wherein the analgesic reservoir further comprises a permeation enhancer.

17. The system of claim 11, wherein the analgesic reservoir comprises a polymeric matrix comprising about 5 wt% to about 50 wt% of the analgesic, and optionally a permeation enhancer.

18. The system of claim 17 comprising an aqueous gel comprising up to about 1 wt% of the analgesic, about 25 wt% permeation enhancer, and 1-10% gelling agent.

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19. The system of claim 17 further comprising an analgesic release rate controlling means disposed between the analgesic reservoir and the skin, wherein said release rate controlling means is less permeable to the analgesic than to the permeation enhancer.

20. The system of any of the preceding claims, wherein said antagonist reservoir is disposed adjacent the skin distal surface of the barrier layer and the analgesic reservoir is disposed adjacent the skin proximal surface of the barrier layer.

21. The system of any of the preceding claims, wherein said antagonist reservoir comprises the antagonist dispersed within a polymer.

22. The system of any of the preceding claims, wherein the system exhibits a standardized Cmax of about 0.01 to about 0.2 ng/ml-cm2.

23. The system of any of the preceding claims, wherein the system exhibits a normalized Cmax of about 3.3 to about 82.5 ng/ml- (mg/h).

24. The system of any of the preceding claims, wherein the system exhibits an in vivo steady-state analgesic flux of about 0.1 to about 10 ug/h-cm2.

25. The system of any of the preceding claims which is bioequivalent to DURAGESICO transdermal fentanyl system.

26. The system of any of the preceding claims which is pharmacologically equivalent to DURAGESICs transdermal fentanyl system.

27. The system of any of the preceding claims, wherein the analgesic is a fentanyl analog and the analog is selected from the group consisting of alfentanil, lofentanil, remifentanil, sufentanil and trefentanil ; and the antagonist is selected from the group consisting of naltrexone, methylnaltrexone, naloxone, nalbuphine,

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nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan, cyclozocine and pharmaceutically acceptable salts thereof.

28. The system of claim 25, wherein the analgesic is fentanyl and upon ingestion or immersion of the system in a solvent for a period of time, the system substantially provides a release rate ratio of the antagonist to the analgesic of at about 0.5 : 1 to about 20: 1.

29. The system of claim 26, wherein the analgesic is sufentanil and upon ingestion or immersion of the system in a solvent for a period of time, the system substantially provides a release rate ratio of the antagonist to the analgesic of at least about 4: 1 30. The system of claim 28 or claim 29, wherein the antagonist is naltrexone.

31. A transdermal system for administering an analgesic through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising an amount of analgesic sufficient to induce and maintain analgesia in a human patient, wherein the analgesic is fentanyl or an analog thereof; (b) an antagonist reservoir comprising an antagonist for said analgesic, wherein the antagonist in a form that is not releasable through the barrier layer, the antagonist being releasable from system upon being ingested or substantially immersed in a solvent;STDC0797 (c) a barrier layer, said barrier layer separating said antagonist reservoir from said analgesic reservoir, said barrier layer being substantially impermeable to said analgesic and to said antagonist; and (d) an antagonist release rate controlling means disposed on the skin distal surface of the antagonist reservoir, wherein said antagonist release rate controlling means substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days, and

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further wherein the antagonist release rate controlling means provides release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic when the system is subject to abuse.

32. A transdermal system for administering an analgesic through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising an amount of analgesic sufficient to induce and maintain analgesia in a human patient, wherein the analgesic is fentanyl or an analog thereof; (b) an antagonist reservoir comprising an antagonist for said analgesic, wherein the antagonist in a form that is not releasable through the barrier layer, the antagonist being releasable from system upon being ingested or substantially immersed in a solvent;STDC0797 (c) a barrier layer, said barrier layer separating said antagonist reservoir from said analgesic reservoir, said barrier layer being substantially impermeable to said analgesic and to said antagonist; and (d) an antagonist release rate controlling means disposed on the skin distal surface of the antagonist reservoir, wherein said antagonist release rate controlling means substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days, and further wherein the antagonist release rate controlling means provides release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic upon ingestion or substantial immersion of the system in the solvent.

33. The system of claim 31 or claim 32 wherein the antagonist release rate controlling means is selected from a group consisting of a layer, a membrane, a film, a coating, a sheet, and a deposit on the antagonist reservoir.

34. The system of claim 33 wherein the antagonist release rate controlling means is selected from a group consisting of a rate control layer, a rate control membrane, a porous membrane and a microporous membrane.

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35. The system of any of the preceding claims 31-34, wherein said analgesic reservoir comprises an amount of analgesic sufficient to induce and maintain analgesia in a human patient for a period of at least three days.

36. The system of claim 35 wherein said analgesic reservoir comprises an amount of dissolved fentanyl or analog thereof sufficient to induce and maintain analgesia for 3-7 days.

37. The system of any of the preceding claims 31-36, wherein said analgesic reservoir comprises a single phase formulation free of undissolved components.

38. The system of any of the preceding claims 31-37 wherein the analgesic reservoir is formed from an adhesive polymer.

39. The system of claim 38 wherein said analgesic reservoir comprises a polymer having a solubility for fentanyl and analogs thereof of about 1 wt% to about 25wt%.

40. The system of claim 39 wherein the reservoir comprises about 0.05 to about 1.75 mg/cm2 of fentanyl or analogs thereof.

41. The system of any of the preceding claims 31-40 wherein the analgesic reservoir further comprises a permeation enhancer.

42. The system of claim 36, wherein the analgesic reservoir comprises a polymeric matrix comprising about 5 wt% to about 50 wt% of the analgesic, and optionally a permeation enhancer.

43. The system of claim any of the preceding claims 31-42, wherein said antagonist reservoir comprises the antagonist dispersed within a polymer.

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44. The system of any of the preceding claims 31-43, wherein the system exhibits a standardized Cmax of about 0.01 to about 0.2 ng/ml-cm2.

45. The system of any of the preceding claims 31-44, wherein the system exhibits a normalized Cmax of about 3.3 to about 82.5 ng/ml- (mg/h).

46. The system of any of the preceding claims 31-45, wherein the system exhibits an in vivo steady-state analgesic flux of about 0.1 to about 10 pg/h-cm2.

47. The system of any of the preceding claims 31-46 which is bioequivalent to DURAGESICe transdermal fentanyl system.

48. The system of any of the preceding claims 31-46 which is pharmacologically equivalent to DURAGESICs transdermal fentanyl system.

49. The system of any of the preceding claims 31-48, wherein the fentanyl analog is selected from the group consisting of alfentanil, lofentanil, remifentanil, sufentanil and trefentanil ; and the antagonist is selected from the group consisting of naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan, cyclozocine and pharmaceutical acceptable salts thereof.

50. The system of claim 47, wherein the analgesic is fentanyl and upon ingestion or immersion of the system in a solvent for a period of time, the system substantially provides a release rate ratio of the antagonist to the analgesic of at about 0.5 : 1 to about 20: 1.

51. The system of claim 48, wherein the analgesic is sufentanil and upon ingestion or immersion of the system in a solvent for a period of time, the system substantially provides a release rate ratio of the antagonist to the analgesic of at least about 4: 1

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52. The system of claim 50 or claim 51, wherein the antagonist is naltrexone.

53. A transdermal system for administering fentanyl through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising a single phase polymeric composition free of undissolved components containing a polyacrylate adhesive having sufficient solubility for fentanyl to contain dissolved fentanyl in an amount sufficient to induce and maintain analgesia in a human for at least three days; (b) an antagonist reservoir comprising an antagonist for said analgesic, wherein the antagonist in a form that is not releasable through the barrier layer, the antagonist being releasable from system upon being ingested or substantially immersed in a solvent;STDC0797 (c) a barrier layer, said barrier layer separating said antagonist reservoir from said analgesic reservoir, said barrier layer being substantially impermeable to said analgesic and to said antagonist; and (d) an antagonist release rate controlling means disposed on the skin distal surface of the antagonist reservoir, wherein said antagonist release rate controlling means substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days, and further wherein the antagonist release rate controlling means provides release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic upon ingestion or substantial immersion of the system in the solvent.

54. A transdermal system for administering fentanyl through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising a single phase polymeric composition free of undissolved components containing a polyacrylate adhesive having sufficient solubility for fentanyl to contain dissolved fentanyl in an amount sufficient to induce and maintain analgesia in a human for at least three days;

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(b) an antagonist reservoir comprising an antagonist for said analgesic, wherein the antagonist in a form that is not releasable through the barrier layer, the antagonist being releasable from system upon being ingested or substantially immersed in a solvent;STDC0750 (c) a barrier layer, said barrier layer separating said antagonist reservoir from said analgesic reservoir, said barrier layer being substantially impermeable to said analgesic and to said antagonist; and (d) an antagonist release rate controlling means disposed on the skin distal surface of the antagonist reservoir, wherein said antagonist release rate controlling means substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days, and upon ingestion or immersion of the system in a solvent for a period of time, the antagonist release rate controlling means provides a release rate ratio of the antagonist to the analgesic of at about 0.5 : 1 to about 20: 1.

55. The system of claim 53 or 54 wherein (a) the analgesic reservoir comprises about 0.05 to about 1.75 mg/cm2 of fentanyl base; (b) the antagonist reservoir comprises about 0.2 to about 15 mg/cm2 of the antagonist dispersed in a polymer or a copolymer selected from the group consisting of polyolefin, polyethylene, polyoctene, polyvinyl acetate, polymethyl acrylate, polymethyl acrylate, polyethyl acrylate, polystyrene, polyethyleneoctene copolymers, ethylene-vinyl acetate copolymer (EVA), ethylenemethyl acrylate copolymers (EMA), ethylene-acrylic acid copolymer, and ethylene-ethylacrylate copolymer ;STDC0490 (c) the barrier layer comprises a comprises a polyester laminated to a polymer selected from the group consisting of polyurethane, polyethylene and ethylene copolymers ; and (d) the antagonist release rate controlling means is a microporous layer selected from the group consisting of microporous ultra high density polyethylene (UHDPE), microporous polypropylene, polyester capillary pore membrane, spun laced polyester, polypropylene and polyethylene.

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56. The system of any of the preceding claims 53-55, wherein the system exhibits a standardized Cmax of about 0.01 to about 0.2 ng/ml-cm2.

57. The system of any of the preceding claims 53-56, wherein the system exhibits a normalized Cmax of about 3.3 to about 82.5 ng/ml- (mg/h).

58. The system of any of the preceding claims 53-57 which is bioequivalent to DURAGESICO transdermal fentanyl system.

59. The system of any of the preceding claims 53-58, wherein the antagonist is naltrexone.

60. A transdermal system for administering sufentanil through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising a single phase polymeric composition free of undissolved components containing a polyacrylate adhesive having sufficient solubility for sufentanil to contain dissolved sufentanil in an amount sufficient to induce and maintain analgesia in a human for at least three days; (b) an antagonist reservoir comprising an antagonist for said analgesic, wherein the antagonist in a form that is not releasable through the barrier layer, the antagonist being releasable from system upon being ingested or substantially immersed in a solvent;STDC0830 (c) a barrier layer, said barrier layer separating said antagonist reservoir from said analgesic reservoir, said barrier layer being substantially impermeable to said analgesic and to said antagonist; and (d) an antagonist release rate controlling means disposed on the skin distal surface of the antagonist reservoir, wherein said antagonist release rate controlling means substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days, and further wherein the antagonist release rate controlling means provides release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the

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antagonist to the analgesic upon ingestion or substantial immersion of the system in the solvent.

61. A transdermal system for administering sufentanil through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising a single phase polymeric composition free of undissolved components containing a polyacrylate adhesive having sufficient solubility for sufentanil to contain dissolved sufentanil in an amount sufficient to induce and maintain analgesia in a human for at least three days; (b) an antagonist reservoir comprising an antagonist for said analgesic, wherein the antagonist in a form that is not releasable through the barrier layer, the antagonist being releasable from system upon being ingested or substantially immersed in a solvent;STDC0738 (c) a barrier layer, said barrier layer separating said antagonist reservoir from said analgesic reservoir, said barrier layer being substantially impermeable to said analgesic and to said antagonist; and (d) an antagonist release rate controlling means disposed on the skin distal surface of the antagonist reservoir, wherein said antagonist release rate controlling means substantially prevents release of the antagonist from the system upon securing the system to a human patient for a period of up to about 7 days, and upon ingestion or immersion of the system in a solvent for a period of time, the antagonist release rate controlling means provides a release rate ratio of the antagonist to the analgesic of at least about 4: 1.

62. The system of claim 60 or 61 wherein (a) the analgesic reservoir comprises about 0.05 to about 1.75 mg/cm2 of sufentanil base; (b) the antagonist reservoir comprises about 0.2 to about 15 mg/cm2 of the antagonist dispersed in a polymer or a copolymer selected from the group consisting of polyolefin, polyethylene, polyoctene, polyvinyl acetate, polymethyl acrylate, polymethyl acrylate, polyethyl acrylate, polystyrene, polyethyleneoctene copolymers, ethylene-vinyl acetate copolymer (EVA),

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ethylenemethyl acrylate copolymers (EMA), ethylene-acrylic acid copolymer, and ethylene-ethylacrylate copolymer ;STDC0457 (c) the barrier layer comprises a comprises a polyester laminated to a polymer selected from the group consisting of polyurethane, polyethylene and ethylene copolymers ; and (d) the antagonist release rate controlling means is a microporous layer selected from the group consisting of microporous ultra high density polyethylene (UHDPE), microporous polypropylene, polyester capillary pore membrane, spun laced polyester, polypropylene and polyethylene.

63. The system of any of the preceding claims 60-62, wherein the system exhibits a standardized Cmax of about 0.001 to about 0.05 ng/ml-cm2.

64. The system of any of the preceding claims 60-63, wherein the system exhibits a normalized Cmax of about 0.04 to about 10 ng/ml- (mg/h).

65. The system of any of the preceding claims 60-64 which is pharmacologically to DURAGESICs transdermal fentanyl system.

66. The system of any of the preceding claims 60-65, wherein the antagonist is naltrexone.