Drug-containing adhesive composite transdermal delivery device

• US 5,626,866 A
• Filed: 10/17/1995
• Issued: 05/06/1997
• Est. Priority Date: 03/07/1994
• Status: Expired due to Term

• Current Assignee: Theratech, Inc. (Dynatronics Corporation)
• Original Assignee: Theratech, Inc. (Dynatronics Corporation)
• Inventors: Borsadia, Suresh, Heiber, Werner, Venkateshwaran, Srinivasan, Ebert, Charles D.
• Primary Examiner(s): KRASS, FREDERICK F
• Application Number:
  US08/544,110
• Time in Patent Office: 567 Days
• Field of Search: 424/447, 424/448, 424/449
• US Class Current: 424/447
• CPC Class Codes: A61K 9/703 characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
• CPC Class Codes: A61K 9/7061 Polyacrylates

Abstract

A method for making a transdermal drug delivery device for heat sensitive and volatile drugs is disclosed. The device contains a drug-containing adhesive composite layer having an impermeable backing material laminated to the distal surface thereof and a proximal peelable impermeable backing material adapted for removal for administering a drug to the skin or mucosa laminated to the proximal surface thereof. The method comprising the steps of providing first and second adhesive laminates each comprising a drug permeable adhesive layer having laminated to one surface one of said backing materials and having the opposing surface exposed. The drug, in gelled form and optionally containing additives such as enhancers and preservatives, is extruded onto at least one exposed surface of the first or second adhesive laminate followed by laminating together the exposed surfaces of the first and second adhesive laminate such that the adhesive layers and gelled drug are combined to form the drug-containing adhesive composite layer having the distal and proximal surfaces covered by the respective backing materials. The adhesives used in making up the laminates may be the same or different provided the drug is compatible with the adhesive. The process is particularly adaptable to the formulation of nicotine-containing patches. Drug delivery devices made according to the disclosed method and a method of using these drug delivery devices are also described.

Claims

1. A method for making a transdermal or transmucosal drug delivery device including a drug-containing adhesive composite layer consisting essentially of first and second drug permeable adhesive layers containing a drug in gel form, said composite layer having a distal backing material impermeable to said drug laminated to the distal surface of said composite layer and a proximal peelable film which is substantially impermeable to said drug and adapted for removal for administering a drug to the skin or mucosa laminated to the proximal surface of said composite layer, said method comprising the steps of:

(a) providing a first adhesive laminate comprising said first adhesive layer having laminated to one surface thereof said distal backing material and having the opposing surface of said first adhesive layer exposed;

(b) providing a second adhesive laminate comprising said second adhesive layer having laminated to one surface thereof said proximal peelable film and having the opposing surface of said second adhesive layer exposed;

(c) extruding said drug, in gel form, onto at least one exposed surface of said first or second adhesive laminate; and

(d) laminating together the exposed surfaces of said first adhesive laminate and said second adhesive laminate, at least one of which contains said extruded gelled drug, such that said first and second adhesive layers and said gelled drug are combined to form said drug-containing adhesive composite layer having said distal backing material covering one surface thereof and said proximal peelable film covering the opposite surface thereof.

2. The method of claim 1 wherein the extruding of said gelled drug and said laminating together of said exposed surfaces of said laminates is a continuous process.

3. The method of claim 2 wherein the extrusion and lamination steps occur substantially simultaneously.

4. The method of claim 1 wherein said drug has a melting point, decomposes or is deactivated at a temperature below about 100°

C.

5. The method of claim 4 wherein said temperature is below about 75°

C.

6. The method of claim 1 wherein said drug is nicotine or an acid addition salt thereof.

7. The method of claim 6 wherein said drug is nicotine base.

8. The method of claim 1 wherein said drug is gelled by the addition of a minor amount of a member selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose and an acrylic thickener.

9. The method of claim 8 wherein the adhesive comprising said first and second adhesive layers is a member selected from the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, ethylenevinylacetate copolymers, polysiloxanes, polyacrylates, polyurethanes, polyether block amide copolymers, and mixtures thereof.

10. The method of claim 9 wherein the adhesives comprising said first and second adhesive layers are different.

11. The method of claim 10 wherein said drug has greater permeability in the adhesive comprising the first adhesive layer than in the adhesive comprising the second adhesive layer, thereby making the second adhesive layer rate limiting as to diffusion of the drug out of the device to the skin or mucosa.

12. The method of claim 10 wherein said drug has greater permeability in the adhesive comprising the second adhesive layer than in the adhesive comprising the first adhesive layer, thereby providing for quick release of the drug from the second adhesive layer and sustained release from the first adhesive layer.

13. The method of claim 10 wherein at least one of the members selected from the group consisting of the first adhesive layer and the second adhesive layer comprises a composite adhesive layer having a proximal adhesive stratum and a distal adhesive stratum in which the adhesives comprising the proximal stratum and the distal stratum have different permeabilities to said drug, thereby affecting the delivery of the drug by the device.

14. The method of claim 9 wherein the adhesives comprising said first and second adhesive layers are the same.

15. The method of claim 14 wherein said adhesive is selected from the group consisting of crosslinked and uncrosslinked acrylic copolymers.

16. The method of claim 9 wherein the gelled drug also contains an antioxidant.

17. The method of claim 3 wherein the gelled drug includes a member selected from the group consisting of penetration enhancers, anti-irritants, and solubilizing agents.

18. The method of claim 17 wherein the gelled drug includes a penetration enhancer for facilitating transport of the drug through the skin or mucosa.

19. The method of claim 18 wherein the penetration enhancer is a member selected from the group consisting of a solvent and a cell-envelope disordering compound and mixtures thereof.

20. The method of claim 19 wherein said solvent is a member selected from the group consisting of water, diols, C₁ -C₃ alkanols, DMSO, dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-alkylazacycloheptan-2-ones and 1-arylazacycloalkyl-2-ones and the cell-envelope disordering compound is a member selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters.

21. A transdermal or transmucosal drug delivery device including a drug-containing adhesive composite layer consisting essentially of first and second drug permeable adhesive layers containing a drug in gel form, said composite layer having a distal backing material impermeable to said drug laminated to the distal surface of said composite layer and a proximal peelable film which is substantially impermeable to said drug adapted for removal for administering a drug to the skin or mucosa laminated to the proximal surface of said composite layer, said drug-containing adhesive composite layer being formed by a method comprising the steps of:

(a) providing a first adhesive laminate comprising said first adhesive layer having laminated to one surface thereof said distal backing material and having the opposing surface of said first adhesive layer exposed;

(b) providing a second adhesive laminate comprising said second adhesive layer having laminated to one surface thereof said proximal peelable film and having the opposing surface of said second adhesive layer exposed;

(c) extruding said drug, in gel form, onto at least one exposed surface of said first or second adhesive laminate; and

(d) laminating together the exposed surfaces of said first adhesive laminate and said second adhesive laminate, at least one of which contains said extruded gelled drug, such that said first and second adhesive layers and said gelled drug are combined to form said drug containing adhesive composite layer having said distal backing material covering one surface thereof and said proximal peelable film covering the opposite surface thereof.

22. The device of claim 21 wherein the extruding of said gelled drug and said laminating together of said exposed surfaces of said laminates is a continuous process.

23. The device of claim 22 wherein the extrusion and lamination steps occur substantially simultaneously.

24. The device of claim 21 wherein said drug has a melting point, decomposes or is deactivated at a temperature below about 100°

C.

25. The device of claim 24 wherein said temperature is below about 75°

C.

26. The device of claim 21 wherein said drug is nicotine or an acid addition salt thereof.

27. The device of claim 26 wherein said drug is nicotine base.

28. The device of claim 21 wherein said drug is gelled by the addition of a minor amount of a member selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose and an acrylic thickener.

29. The device of claim 28 wherein the adhesive comprising said first and second adhesive layers is a member selected from the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, ethylenevinylacetate copolymers, polysiloxanes, polyacrylates, polyurethanes, polyether block amide copolymers, and mixtures thereof.

30. The device of claim 29 wherein the adhesives comprising said first and second adhesive layers are different.

31. The device of claim 30 wherein said drug has greater permeability in the adhesive comprising the first adhesive layer than in the adhesive comprising the second adhesive layer, thereby making the second adhesive layer rate limiting as to diffusion of the drug out of the device to the skin or mucosa.

32. The device of claim 30 wherein said drug has greater permeability in the adhesive comprising the second adhesive layer than in the adhesive comprising the first adhesive layer, thereby providing for quick release of the drug from the second adhesive layer and sustained release from the first adhesive layer.

33. The device of claim 30 wherein at least one of the members selected from the group consisting of the first adhesive layer and the second adhesive layer comprises a composite adhesive layer having a proximal adhesive stratum and a distal adhesive stratum in which the adhesives comprising the proximal stratum and the distal stratum have different permeabilities to said drug thereby affecting the delivery of the drug by the device.

34. The device of claim 29 wherein the adhesives comprising said first and second adhesive layers are the same.

35. The device of claim 34 wherein said adhesive is selected from the group consisting of crosslinked and uncrosslinked acrylic copolymers.

36. The device of claim 29 wherein the gelled drug also contains an antioxidant.

37. The device of claim 23 wherein the gelled drug includes a member selected from the group consisting of penetration enhancers, anti-irritants, and solubilizing agents.

38. The device of claim 37 wherein the gelled drug includes a penetration enhancer for facilitating transport of the drug through the skin or mucosa.

39. The device of claim 38 wherein the penetration enhancer is a member selected from the group consisting of a solvent and a cell-envelope disordering compound and mixtures thereof.

40. The device of claim 39 wherein said solvent is a member selected from the group consisting of water, diols, C₁ -C₃ alkanols, DMSO, dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-alkylazacycloheptan-2-ones and 1-arylazacycloalkyl-2-ones and the cell-envelope disordering compound is a member selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters.

41. A method of delivering a drug through the skin or mucosa of an individual comprising;

(a) providing a transdermal or transmucosal drug delivery device including a drug-containing adhesive composite layer consisting essentially of first and second drug permeable adhesive layers containing a drug in gel form, said composite layer having a distal backing material impermeable to said drug laminated to the distal surface of said composite layer and a proximal peelable film that is substantially impermeable to said drug adapted for removal for administering a drug to the skin or mucosa laminated to the proximal surface of said composite layer, said drug-containing adhesive composite layer being formed by a method comprising the steps of;

(1) providing a first adhesive laminate comprising said first adhesive layer having laminated to one surface thereof said distal backing material and having the opposing surface of said first adhesive layer exposed;

(2) providing a second adhesive laminate comprising said second adhesive layer having laminated to one surface thereof said proximal peelable film and having the opposing surface of said second adhesive layer exposed;

(3) extruding said drug, in gel form, onto at least one exposed surface of said first or second adhesive laminate; and

(4) laminating together the exposed surfaces of said first adhesive laminate and said second adhesive laminate, at least one of which contains said extruded gelled drug, such that said first and second adhesive layers and said gelled drug are combined to form said drug containing adhesive composite layer having said distal backing material covering one surface thereof and said proximal peelable film covering the opposite surface thereof;

(b) removing said proximal peelable film from said device and bringing said skin or mucosa into contact with the proximal surface of said adhesive composite layer.

42. The method of claim 41 wherein the extruding of said gelled drug and said laminating together of said exposed surfaces of said laminates is a continuous process.

43. The method of claim 42 wherein the extrusion and lamination steps occur substantially simultaneously.

44. The method of claim 41 wherein said drug has a melting point, decomposes or is deactivated at a temperature below about 100°

C.

45. The method of claim 44 wherein said temperature is below about 75°

C.

46. The method of claim 41 wherein said drug is nicotine or an acid addition salt thereof.

47. The method of claim 46 wherein said drug is nicotine base.

48. The method of claim 41 wherein said drug is gelled by the addition of a minor amount of a member selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose and an acrylic thickener.

49. The method of claim 48 wherein the adhesive comprising said first and second adhesive layers is a member selected from the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, ethylenevinylacetate copolymers, polysiloxanes, polyacrylates, polyurethanes, polyether block amide copolymers, and mixtures thereof.

50. The method of claim 49 wherein the adhesives comprising said first and second adhesive layers are different.

51. The method of claim 50 wherein said drug has greater permeability in the adhesive comprising the first adhesive layer than in the adhesive comprising the second adhesive layer, thereby making the second adhesive layer rate limiting as to diffusion of the drug out of the device to the skin or mucosa.

52. The method of claim 50 wherein said drug has greater permeability in the adhesive comprising the second adhesive layer than in the adhesive comprising the first adhesive layer, thereby providing for quick release of the drug from the second adhesive layer and sustained release from the first adhesive layer.

53. The method of claim 50 wherein at least one of the members selected from the group consisting of the first adhesive layer and the second adhesive layer comprises a composite adhesive layer having a proximal adhesive stratum and a distal adhesive stratum in which the adhesives comprising the proximal stratum and the distal stratum have different permeabilities to said drug thereby affecting the delivery of the drug by the device.

54. The method of claim 49 wherein the adhesives comprising said first and second adhesive layers are the same.

55. The method of claim 54 wherein said adhesive is selected from the group consisting of crosslinked and uncrosslinked acrylic copolymers.

56. The method of claim 49 wherein the gelled drug also contains an antioxidant.

57. The method of claim 43 wherein the gelled drug includes a member selected from the group consisting of penetration enhancers, anti-irritants, and solubilizing agents.

58. The method of claim 57 wherein the gelled drug includes a penetration enhancer for facilitating transport of the drug through the skin or mucosa.

59. The method of claim 58 wherein the penetration enhancer is a member selected from the group consisting of a solvent and a cell-envelope disordering compound and mixtures thereof.

60. The method of claim 59 wherein said solvent is a member selected from the group consisting of water, diols, C₁ -C₃ alkanols, DMSO, dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-alkylazacycloheptan-2-ones and 1-arylazacycloalkyl-2-ones and the cell-envelope disordering compound is a member selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters.