Transdermal patch incorporating a polymer film incorporated with an active agent

• US 6,010,715 A
• Filed: 10/21/1997
• Issued: 01/04/2000
• Est. Priority Date: 04/01/1992
• Status: Expired due to Term

• Current Assignee: Mylan Technologies Incorporated (Pfizer Inc.)
• Original Assignee: Bertek, Inc. (Pfizer Inc.)
• Inventors: Weimann, Ludwig J., Pollock, Wayne C., Wick, John J.
• Primary Examiner(s): BROUILLETTE, D GABRIELLE
• Application Number:
  US08/954,861
• Time in Patent Office: 805 Days
• Field of Search: 424/448, 424/449, 427/2.31
• US Class Current: 424/448
• CPC Class Codes: A61K 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Abstract

Devices for the controlled release of an active agent to the skin or mucosa of a host are disclosed, which devices are laminates of a backing layer and a monolithic carrier layer formed from a melt blend of an active ingredient with a thermoplastic matrix polymer without first dissolving or suspending the polymer or active ingredient in a solvent therefor, so that the carrier layer is substantially free of residual solvent, wherein the thermoplastic matrix polymer has a melt temperature between about 170° C. and about 200° C. and is selected from polyether block amides, ethylene methacrylic acid copolymers, ethylene acrylic acid copolymers, copolymers of polyether prepolymers with polybutylene terephthalate, copolymers of polyether prepolymers with polyisobutylene terephthalate and polyether polyurethanes, the active ingredient is heat stable at the melt temperature of the matrix polymer and is selected from active agents, active agent enhancers and mixtures thereof, and the laminate is provided with means for affixing the laminate to the skin or mucosa of the host so that the active ingredient is continuously released from the carrier layer thereto. Methods for assembling the device are also disclosed.

Claims

1. A device for the controlled release of an active agent to the skin or mucosa of a host, said device comprising a laminate of:

(a) a monolithic carrier layer having a first surface and a second surface, said monolithic carrier layer comprising an active ingredient melt-blended with a thermoplastic matrix polymer and formed into said carrier layer without first dissolving or suspending said polymer or active ingredient in a solvent therefor, so that said carrier layer is substantially free of residual solvent, wherein said thermoplastic matrix polymer has a melt temperature between about 170°

C. and about 200°

C. and is selected from the group consisting of polyether block amides, ethylene methacrylic acid copolymers, ethylene acrylic acid copolymers, copolymers of polyether prepolymers with polybutylene terephthalate, copolymers of polyether prepolymers with polyisobutylene terephthalate and polyether polyurethanes, said polymer is capable of controllably releasing said active ingredient, and said active ingredient is heat stable at the melt temperature of said matrix polymer, and is selected from the group consisting of active agents, active agent enhancers, and mixtures thereof;

(b) a backing layer having an inner surface and an outer surface, wherein said second surface of said carrier layer and said inner surface of said backing layer are laminated together with an adhesive, so that said active ingredient cannot permeate from said second surface of said carrier layer through said outer surface of said backing layer; and

(c) a pressure-sensitive adhesive layer for affixing said laminate to said skin or mucosa of said host so that said active ingredient is capable of being continuously released from said first surface of said carrier layer thereto.

2. The laminate of claim 1, wherein said pressure-sensitive adhesive layer is affixed to said first surface of said carrier layer.

3. The laminate of claim 1, wherein said backing layer comprises an active ingredient impermeable material.

4. The laminate of claim 1, wherein said adhesive laminating the inner surface of said backing layer to said second surface of said carrier layer is active ingredient impermeable.

5. The laminate of claim 1, further comprising means for controlling the rate at which said active ingredient is released from said first surface of said carrier layer to said skin or mucosa of said host.

6. The laminate of claim 5, wherein said rate-controlling means comprises an active ingredient permeable adhesive layer affixed to said first surface of said carrier layer and adapted to adhere said first surface of said carrier layer to said skin or mucosa of said host, wherein said adhesive layer is capable of controlling the rate at which said active ingredient is released from said first surface of said carrier layer to said skin or mucosa.

7. The laminate of claim 5, wherein said rate-controlling means comprises a rate-controlling polymer layer affixed to said first surface of said carrier layer and adhered to said skin or mucosa of said host by an active ingredient permeable adhesive layer affixed to said rate-controlling polymer layer on the surface opposite said carrier layer.

8. The laminate of claim 1, wherein said backing layer extends peripherally beyond said carrier layer about the entire periphery thereof, thereby defining an extended peripheral area of said backing layer, and said means for affixing said laminate to said skin or mucosa of said host comprises an adhesive layer adapted to adhere said extended peripheral area of said backing layer to said host'"'"'s skin or mucosa.

9. The laminate of claim 8, wherein said inner surface of said backing layer is affixed to said second surface of said carrier layer by said adhesive layer and said adhesive layer extends peripherally beyond said carrier layer about the entire periphery thereof coextensively with said extended peripheral area of said backing layer.

10. The laminate of claim 8, wherein said means for affixing said laminate to said skin or mucosa of said host further comprises an active ingredient permeable adhesive layer affixed to said first surface of said carrier layer.

11. The laminate of claim 8, further comprising means for controlling the rate at which said active agent is released from said first surface of said carrier layer to said skin or mucosa of said host.

12. The device of claim 1, further comprising a removable liner layer having a first surface and a second surface, said first surface of said liner layer comprising a releasable surface, a bottom layer comprising a first surface and a second surface, and a plurality of said laminates disposed between said first surface of said bottom layer and said first surface of said liner layer, wherein said backing layer of each of said laminates is affixed to said first surface of said bottom layer, said means for affixing each of said laminates to said skin or mucosa of said host is affixed to said liner layer, and said first surface of said liner layer is releasably heat sealed to said first surface of said bottom layer at least at a location between two of said laminate so as to physically separate at least two laminates prior to removal of said removable liner layer from said bottom layer, whereby removal of said removable liner layer eliminates said heat seal.

13. The laminate of claim 1, wherein said backing layer comprises one or more layers of an occlusive material, wherein each layer of material is independently selected from the group consisting of cellophane, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride copolymers, ethylene-vinyl acetate copolymer, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidene chloride, paper, cloth and aluminum foil.

14. The laminate of claim 13, wherein each layer of material is independently selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride and polyethylene terephthalate.

15. The laminate of claim 14, wherein each layer of material is independently selected from the group consisting of polyethylene terephthalate and polyvinylidene chloride.

16. The laminate of claim 1, wherein said pressure-sensitive adhesive layer is selected from the group consisting of polyisobutylene adhesives, silicon adhesives, acrylic adhesives and synthetic rubber adhesives.

17. The laminate of claim 16, wherein said acrylic pressure-sensitive adhesive comprises a polymer of alcohol esters of acrylic or methacrylic acid.

18. The laminate of claim 17, wherein said esters of polyacrylic acid and polymethacrylic acid are esters of alcohol selected from the group consisting of N-butanol, isopentanol, 2-methylbutanol, 1-methyl-butanol, 1-methylpentanol, 2-methylpentanol, 3-methylpentanol, 2-ethylbutanol, isooctanol, n-decanol and n-dodecanol.

19. The laminate of claim 18, wherein said esters of polyacrylic acid and polymethacrylic acid are copolymerized with one or more ethylenically unsaturated monomers selected from the group consisting of acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamide, N-alkoxymethyl methacrylamide, N-t-butylacrylamide, itaconic acid, vinyl acetate, N-branched alkyl malemic acid with alkyl groups from 10 to 24 carbon atoms and glycol diacrylates.

20. The laminate of claim 2, wherein said adhesive layer comprises a dermatologically acceptable pressure-sensitive adhesive selected from the group consisting of polyurethane elastomers, polyvinyl alcohol, polyvinyl ethers, polyvinyl pyrrolidone, polyvinyl acetate, urea formaldehyde resins, phenol formaldehyde resins, resorcinol formaldehyde resins, ethyl cellulose, methyl cellulose, nitrocellulose, cellulose acetate butyrate, carboxymethyl cellulose, guar gum, acacia gum, pectina gum, destria gum, gelatin and casein.

21. The laminate of claim 1, wherein said active ingredient comprises an active agent selected from the group consisting of psychoactive agents selected from the group consisting of nicotine, caffeine, mesocarb, mefexamide and cannabinals;

sedatives selected from the group consisting of diazepam, mepiridine, uldazepan, tybamate, metaclazepam and tetrabarbitol;

antidepressants selected from the group consisting of amitryptyline, imipramine, desipramine, nialamide, melitracen and isocarboxazid;

anticonvulsants selected from the group consisting of phenobarbitol, carbamazepine, methsuximide, 2-ethyl-2-phenylmalonamide and phenytoin;

steroids selected from the group consisting of progesterone, testosterone, pregnanediol, progestin and estradiol;

narcotic analgesics selected from the group consisting of codeine, morphine, analorphine and demeral;

analgesics selected from the group consisting of acetaminophen, aspirin and alprazolam;

antimicrobial agents selected from the group consisting of sulconazole, siccamin, silver sulfadiazene and bentiacide, tranquilizers;

antineoplastic agents selected from the group consisting of sulfosamide and rufocromomycin; and

antibiotic agents selected from the group consisting of tetrasycline, penicillin and atreptozocin.

22. The laminate of claim 21, wherein said active agent comprises nicotine.

23. The laminate of claim 7, wherein said rate-controlling polymer layer comprises a material selected from the group consisting of polypropylene, polyethylene, ethylene vinyl acetate, polyether polyurethanes, polyether block amides, ethylene methacrylic acid copolymers, ethylene acrylic acid copolymers and copolymers of polyether prepolymers and polybutylene terephthalate and polyisobutylene terephthalate.

24. The device of claim 12, wherein said releasable surface comprises a siliconized coating.

25. The device of claim 12, wherein said liner layer comprises one or more layers, wherein each layer is independently selected from the group consisting of paper, thermoplastic polymers and metal foils.

26. The device of claim 12, wherein said bottom layer comprises one or more polymeric materials selected from the group consisting of polyethylene, polypropylene, polyvinylidene chloride, polyethylene terephthalate, polyesters and polyamides.

27. The device of claim 26, wherein said bottom layer comprises polyethylene.

28. The laminate of claim 7, wherein one or more of said rate-controlling polymer layer and either of said active agent permeable adhesive layers further comprise an active agent enhancer.

29. The laminate of claim 28, wherein said active agent enhancer is melt-blended with one or more of said rate-controlling polymer layer and either of said active agent permeable adhesive layers and is heat-stable at a melt temperature between about 170°

C. and about 200°

C.

30. The laminate of claim 29, wherein said active agent enhancer is selected from the group consisting of monovalent, saturated and unsaturated aliphatic and cycloaliphatic alcohols having 6 to 12 carbon atoms, aliphatic and cycloaliphatic hydrocarbons, cycloaliphatic and aromatic aldehydes and ketones, N,N-di (lower alkyl) acetamides, aliphatic and cycloaliphatic esters, N,N-di (lower alkyl) sulfoxides, essential oils, nitrated aliphatic and cycloaliphatic hydrocarbons, salicylates, polyalkylene glycol silicates, aliphatic acids, terpenes, surfactants and siloxanes.

31. The laminate of claim 1, wherein said active ingredient further comprises a heat-resistant liquid carrier compatible with said thermoplastic matrix polymer.

32. The laminate of claim 1, wherein said active ingredient of said monolithic carrier layer comprises said active agent enhancer, and said laminate further comprises a rate-controlling polymer layer having an inner surface and an outer surface, said rate-controlling polymer layer comprising an active agent melt-blended with a thermoplastic rate-controlling polymer capable of controllably releasing said active agent, wherein said active agent is heat-stable at the melt-temperature of said rate-controlling polymer, and wherein said inner surface of said rate-controlling polymer layer is affixed to said first surface of said carrier layer;

and said means for affixing said laminate to said skin or mucosa of said host comprises an adhesive layer affixed to said outer surface of said rate-controlling polymer layer and permeable to said active agent and said active agent enhancer so that said active agent enhancer is continuously released from said first surface of said carrier layer through said rate-controlling polymer layer and then released with said active agent from said outer surface of said rate-controlling polymer layer through said active agent permeable adhesive layer to said skin or mucosa of said host.

33. The laminate of claim 32, wherein said active agent comprises estradiol.

34. The laminate of claim 33, wherein said active agent enhancer comprises mineral oil.

35. A process for assembling a device for the controlled release of an active agent to the skin or mucosa of a host, which process includes the steps of:

(a) melt-blending at a temperature range between about 170°

C. and about 200°

C. (1) a thermoplastic matrix polymer capable of controllably releasing an active ingredient and having a melt temperature within said temperature range, said polymer being selected from the group consisting of polyether block amides, ethylene methacrylic acid copolymers, ethylene acrylic acid copolymers, copolymers of polyether prepolymers with polybutylene terephthalate, copolymers of polyether prepolymers with polyisobutylene terephthalate and polyether polyurethanes, and (2) an active ingredient that is heat stable at the melt temperature of said matrix polymer, so that a melt-blend of said active ingredient and said thermoplastic matrix polymer is formed, wherein said active ingredient is selected from the group consisting of active agents, active agent enhancers and mixtures thereof;

(b) forming said melt-blend into a monolithic carrier layer having a first surface and a second surface without first dissolving or suspending said polymer or said active ingredient in a solvent therefor, so that said carrier layer is substantially free of residual solvents;

(c) laminating said second surface of said carrier layer to the inner surface of a backing layer with an adhesive, so that a laminate of said carrier layer and said backing layer is formed wherein said active ingredient cannot permeate from said second surface of said carrier layer to said outer surface of said backing layer; and

(d) providing said laminate with a pressure-sensitive adhesive layer for securing said laminate to said skin or mucosa of said host so that said active ingredient is controllably released from said first surface of said carrier layer thereto.

36. The process of claim 35, wherein said forming step comprises calendaring said melt-blend into a monolithic carrier layer.

37. The process of claim 35, wherein said forming step comprises compression molding said melt-blend into a monolithic carrier layer.

38. The process of claim 35, wherein said forming step comprises injection molding said melt-blend into a monolithic carrier layer.

39. The process of claim 35, wherein said forming step comprises thermoforming said melt-blend into a monolithic carrier layer.

40. The process of claim 35, wherein said step of providing said laminate with a pressure sensitive adhesive layer for securing said laminate to said skin or mucosa of said host comprises the step of applying an active ingredient permeable adhesive layer to the first surface of said carrier layer.

41. The process of claim 35, wherein said step of providing a backing layer comprises the steps of providing a backing layer having a greater surface area than said carrier layer and laminating said second surface of said carrier layer to said inner surface of said backing layer so that said greater surface area of said backing layer extends peripherally beyond said carrier layer about the entire periphery thereof so as to create an extended peripheral area of said backing layer, and said step of providing said laminate with a pressure sensitive adhesive layer for securing said first surface of said carrier layer to said skin or mucosa of said host comprises the step of coating said inner surface of said extended peripheral area of said backing layer with said pressure sensitive adhesive layer.

42. The process of claim 41, wherein said step of coating of said inner surface of said extended peripheral area of said backing layer comprises coating the entirety of said inner surface of said backing layer with an adhesive layer prior to laminating said inner surface of said backing layer to said second surface of said carrier layer, so that when said second surface of said carrier layer is laminated to said inner surface of said backing layer, said layers are secured by said adhesive layer.

43. The process of claim 35, wherien said second surface of said carrier layer is laminated to said inner surface of said backing layer with an active agent impermeable adhesive.

44. The process of claim 35, further comprising the step of affixing to said first surface of said carrier layer means for controlling the rate at which said active ingredient is released from said first surface of said carrier layer to said skin or mucosa of said host.

45. The process of claim 44, wherein said affixing step comprises coating said first surface of said carrier layer with an active agent permeable adhesive layer capable of controlling said rate at which said active ingredient is released from said first surface of said carrier layer to said skin or mucosa of said host and laminating a rate-controlling polymer layer to said first surface of said carrier layer.

46. The process of claim 45, wherein said step of providing said laminate with a pressure sensitive adhesive layer for securing said laminate to said skin or mucosa of said host comprises coating said rate-controlling polymer layer on the surface opposite said carrier layer with an active ingredient permeable adhesive layer.

47. The process of claim 35, further comprising the steps of:

(a) providing a removable liner layer having a first surface and a second surface, wherein said first surface of said liner layer is a releasable surface;

(b) providing a bottom layer having a first surface and a second surface;

(c) disposing a plurality of said laminates between said first surface of said bottom layer and said first surface of said liner layer, wherein said backing layer of each of said laminate is affixed to said first surface of said bottom layer and said means for securing each of said laminate to said skin or mucosa of said host is affixed to said liner layer; and

(d) releasably heat sealing said first surface of said liner layer to said first surface of said bottom layer at least at a location between at least two laminates so as to physically separate said laminates prior to removal of said removable liner layer from said bottom layer, whereby removal of said liner layer eliminates said heat seal.

48. The process of claim 47, wherein said backing layer of each of said laminates are affixed to said first surface of said bottom layer by an adhesive layer having a coefficient of adhesion less than the coefficient of adhesion of said means for securing said laminate to said skin or mucosa of said host of each of said laminate.

49. The process of claim 35, wherein said backing layer comprises one or more layers of an occlusive material, wherein each layer of material is independently selected from the group consisting of cellophane, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride copolymers, ethylene-vinyl acetate copolymer, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidine chloride, paper, cloth and aluminum foil.

50. The process of claim 49, wherein said backing layer comprises an active ingredient impermeable material.

51. The process of claim 35, wherein said pressure-sensitive adhesive layer is selected from the group consisting of polyisobutylene adhesives, silicone adhesives, acrylic adhesives and synthetic rubber adhesives.

52. The process of claim 51, wherein said acrylic pressure-sensitive adhesive comprises a polymer of alcohol esters of acrylic or methacrylic acid.

53. The process of claim 52, wherein said esters of polyacrylic acid and polymethacrylic acid are esters of alcohols selected from the group consisting of N-butanol, isopentanol, 2-methylbutanol, 1-methylbutanol, 1-methylpentanol, 2-methylpentanol, 3-methylpentanol, 2-ethylbutanol, isooctanol, n-decanol and n-dodecanol.

54. The process of claim 53, wherein said esters of polyacrylic acid and polymethacrylic acid are copolymerized with one or more ethylenically unsaturated monomers selected from the group consisting of acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamide, N-alkoxymethyl methacrylamide, N-t-butylacrylamide, itaconic acid, vinyl acetate, N-branched alkyl malemic acid with alkyl groups from 10 to 24 carbon atoms and glycol diacrylates.

55. The process of claim 40, wherein said active ingredient permeable adhesive layer comprises a dermatologically acceptable pressure-sensitive adhesive selected from the group consisting of polyurethane elastomers, polyvinyl alcohol, polyvinyl ethers, polyvinyl pyrrolidone, polyvinyl acetate, urea formaldehyde resins, phenol formaldehyde resins, resorcinol formaldehyde resins, ethyl cellulose, methyl cellulose, nitrocellulose, cellulose acetate butyrate, carboxymethyl cellulose, guar gum, acacia gum, pectina gum, destria gum, gelatin and casein.

56. The process of claim 35, wherein said active ingredient comprises an active agent selected from the group consisting of psychoactive agents selected from the group consisting of nicotine, caffeine, mesocarb, mefexamide and cannabinols;

sedatives selected from the group consisting of diazepam, mepiridine, uldazepam, tybamate, metaclazepam and tetrabarbitol;

antidepressants selected from the group consisting of amitryptyline, imipramine, desipramine, nialamide, melitracen and isocarboxazid;

anticonvulsants selected from the group consisting of phenobarbitol, carbamazepine, methsuximide, 2-ethyl-2-phenylmalonamide and phenytoin;

steroids selected from the group consisting of progesterone, testosterone, pregnanediol, progestin and estradiol;

narcotic analgesics selected from the group consisting of codeine, morphine, analorphine and demeral;

analgesics selected from the group consisting of acetaminophen, aspirin and alprazolam;

antimicrobial agents selected from the group consisting of sulconazole, siccamin, silver sulfadiazene and bentiacide, tranquilizers;

antineoplastic agents selected from the group consisting of sulfosamide and rufocromomycin; and

antibiotic agents selected from the group consisting of tetracycline, penicillin and streptozocin.

57. The process of claim 56, wherein said active agent comprises nicotine.

58. The process of claim 45, wherein said rate-controlling polymer layer comprises a material selected from the group consisting of polypropylene, polyethylene, ethylene vinyl acetate, polyether polyurethanes, ethylene methacrylic acid copolymers, ethylene acrylic acid copolymers, polyether block amides, and copolymers of polyether prepolymers and polybutylene terephthalate and polyisobutylene terephthalate.

59. The process of claim 47, wherein said releasable surface comprises a siliconized coating.

60. The process of claim 47, wherein said liner layer comprises one or more layers, wherein each layer is independently selected from the group consisting of paper, thermoplastic polymers and metal foils.

61. The process of claim 47, wherein said bottom layer comprises one or more polymeric materials selected from the group consisting of polyethylene, polypropylene, polyvinylidene chloride, polyethylene terephthalate, polyesters and polyamides.

62. The laminate of claim 35, wherein said active agent enhancer is selected from the group consisting of monovalent, saturated and unsaturated aliphatic and cycloaliphatic alcohols having 6 to 12 carbon atoms, aliphatic and cycloaliphatic hydrocarbons, cycloaliphatic and aromatic aldehydes and ketones, N,N-di (lower alkyl) acetamides, aliphatic and cycloaliphatic esters, N,N-di (lower alkyl) sulfoxides, essential oils, nitrated aliphatic and cycloaliphatic hydrocarbons, salicylates, polyalkylene glycol silicates, aliphatic acids, terpenes, surfactants and siloxanes.

63. The process of claim 62, wherein said active agent enhancer comprises mineral oil.

64. The process of claim 45, further comprising the step of melt-blending said rate-controlling polymer layer with an active agent enhancer to promote the penetration of said active agent through said skin or mucosa of said host, prior to laminating said rate-controlling polymer layer to said first surface of said carrier layer, wherein said active agent enhancer is heat stable at a melt temperature between about 170°

C. and about 200°

C.

65. The process of claim 64, wherein said active agent enhancer is selected from the group consisting of monovalent, saturated and unsaturated aliphatic and cycloaliphatic alcohols having 6 to 12 carbon atoms, aliphatic and cycloaliphatic hydrocarbons, cycloaliphatic and aromatic aldehydes and ketones, N,N-di (lower alkyl) acetamides, aliphatic and cycloaliphatic esters, N,N-di (lower alkyl) sulfoxides, essential oils, nitrated aliphatic and cycloaliphatic hydrocarbons, salicylates, polyalkylene glycol silicates, aliphatic acids, terpenes, surfactants and siloxanes.

66. The process of claim 65, wherein said active agent enhancer comprises mineral oil.

67. The process of claim 46, further comprising the step of melt-blending said active ingredient permeable adhesive with an active agent enhancer to promote the penetration of said active agent through said skin or mucosa of said host, prior to coating said rate-controlling polymer layer on said surface opposite said carrier layer with said adhesive, wherein said active agent enhancer is heat stable at a melt temperature between about 170°

C. and about 200°

C., so that a melt-blend of said active agent enhancer and said adhesive is formed.

68. The process of claim 67, wherein said active agent enhancer is selected from the group consisting of monovalent, saturated and unsaturated aliphatic and cycloaliphatic alcohols having 6 to 12 carbon atoms, aliphatic and cycloaliphatic hydrocarbons, cycloaliphatic and aromatic aldehydes and ketones, N,N-di (lower alkyl) acetamides, aliphatic and cycloaliphatic esters, N,N-di (lower alkyl) sulfoxides, essential oils, nitrated aliphatic and cycloaliphatic hydrocarbons, salicylates, polyalkylene glycol silicates, aliphatic acids, terpenes, surfactants and siloxanes.

69. The process of claim 68, wherein said active agent enhancer comprises mineral oil.

70. The process of claim 35, wherein said active agent further comprises a heat-resistant liquid carrier compatible with said thermoplastic matrix polymer.

71. The process of claim 35, wherein said active ingredient melt-blended with said thermoplastic matrix polymer comprises said active agent enhancer, and said process further comprises the steps of:

(a) melt-blending a thermoplastic rate-controlling polymer capable of controllably releasing an active agent, with an active agent that is heat stable at the melt temperature of said rate-controlling polymer, so that a melt-blend of said active agent and said thermoplastic rate-controlling polymer is formed;

(b) forming said melt-blend of said active agent and said thermoplastic rate-controlling polymer into a rate-controlling polymer layer having an inner surface and an outer surface; and

(c) laminating said inner surface of said rate-controlling polymer layer to said first surface of said carrier layer;

wherein said step of providing said laminate with means for securing said laminate to said skin or mucosa of said host comprises coating said outer surface of said rate-controlling polymer layer with an adhesive layer permeable to said active ingredient, so that said active agent enhancer is capable of being continuously released from said first surface of said carrier layer through said rate-controlling polymer layer and then released with said active agent from said outer surface of said rate-controlling polymer layer through said adhesive layer to said skin or mucosa of said host.

72. The laminate of claim 71, wherein said active agent comprises estradiol.

73. The process of claim 64, wherein said laminating step comprises affixing said rate-controlling polymer layer to said first surface of said carrier layer with an active ingredient permeable adhesive layer.

74. The process of claim 73, further comprising the step of melt-blending said active agent permeable adhesive with said active agent enhancer to promote the penetration of said active agent through said skin or mucosa of said host, prior to affixing said rate-controlling polymer layer on said surface opposite said carrier layer with said adhesive, so that a melt-blend of said active agent enhancer and said adhesive is formed.