Buprenorphine transdermal delivery system

Abstract

A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing self-adhesive layer structure having (A) a buprenorphine-impermeable backing layer, and (B) a buprenorphine-containing pressure-sensitive adhesive layer on the backing layer. The buprenorphine-containing adhesive layer comprises (a) at least one polymer-based pressure-sensitive adhesive, (b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, (c) a viscosity-increasing substance in an amount of about 0.1% to about 8% of the buprenorphine-containing pressure-sensitive adhesive layer, and (d) a carboxylic acid selected from oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof. The amount of the carboxylic acid is sufficient so that the analgesically effective amount of buprenorphine is solubilized in the carboxylic acid to form a mixture including the viscosity-increasing substance. This mixture forms dispersed deposits in the pressure-sensitive adhesive. The buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

Claims

1. A transdermal therapeutic system for transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, said adhesive layer comprising at least one polymer-based pressure-sensitive adhesive based on polysiloxanes, an analgesically effective amount of buprenorphine comprising buprenorphine base or a pharmaceutically acceptable salt thereof, a viscosity-increasing substance in an amount of about 0.1% to about 8% of said buprenorphine-containing pressure-sensitive adhesive layer, wherein the viscosity-increasing substance comprises polyvinylpyrrolidone, and a carboxylic acid comprising levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture including said viscosity-increasing substance, and wherein said carboxylic acid-, buprenorphine- and viscosity-increasing substance-containing mixture forms dispersed deposits in said pressure-sensitive adhesive, and wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

2. The transdermal therapeutic system of claim 1, wherein said buprenorphine-comprises buprenorphine base.

3. The transdermal therapeutic system of claim 1, wherein said polyvinylpyrrolidone is present in an amount of about 0.1% to about 7%, or of about 0.5% to about 5%, or of about 1% to about 4%, or of about 2% to about 3% of said buprenorphine-containing pressure-sensitive adhesive layer.

4. The transdermal therapeutic system of claim 1, wherein said polyvinylpyrrolidone is present in an amount of about 0.1% to about 7%.

5. The transdermal therapeutic system of claim 1, wherein said polyvinylpyrrolidone has a K-Value of at least about 5, or of at least about 10, or of at least about 15, or of at least about 20, or of at least about 50, or of at least about 80.

6. The transdermal therapeutic system of claim 1, wherein the polyvinylpyrrolidone has a K-Value of at least about 80.

7. The transdermal therapeutic system of claim 1, wherein said buprenorphine comprises buprenorphine base and said polyvinylpyrrolidone is present in an amount of about 1% to about 4%.

8. The transdermal therapeutic system of claim 1, wherein said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, or about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, or about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, or about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, or about 15 mg to about 32 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof.

9. The transdermal therapeutic system of claim 1, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2, or about 3 cm.sup.2 to about 9.5 cm.sup.2, or about 6 cm.sup.2 to about 19 cm.sup.2, or about 12 cm.sup.2 to about 28.5 cm.sup.2, or about 16 cm.sup.2 to about 38 cm.sup.2.

10. The transdermal therapeutic system of claim 1, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2 and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 5 μg/hr over about 168 hours of administration.

11. The transdermal therapeutic system of claim 1, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 3 cm.sup.2 to about 9.5 cm.sup.2, and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 10 μg/hr over about 168 hours of administration.

12. The transdermal therapeutic system of claim 1, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 6 cm.sup.2 to about 19 cm.sup.2 and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 20 μg/hr over about 168 hours of administration.

13. The transdermal therapeutic system of claim 1, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 12 cm.sup.2 to about 28.5 cm.sup.2, and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 30 μg/hr over about 168 hours of administration.

14. The transdermal therapeutic system of claim 1, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 16 cm.sup.2 to about 38 cm.sup.2, and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 40 μg/hr over about 168 hours of administration.

15. The transdermal therapeutic system of claim 1, wherein said buprenorphine comprises buprenorphine base and said system provides a mean cumulative skin permeation rate measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 μg/cm.sup.2-hr over a 168 hours test and/or provides a cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 220 μg/cm.sup.2 to 640 μg/cm.sup.2 over a time period of 168 hours.

16. The transdermal therapeutic system of claim 1, wherein said buprenorphine comprises buprenorphine base and said system provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 2 μg/cm.sup.2 to 10 μg/cm.sup.2 in the first 8 hours, 20 μg/cm.sup.2 to 80 μg/cm.sup.2 from hour 8 to hour 24, 20 μg/cm.sup.2 to 80 μg/cm.sup.2 from hour 24 to hour 32, 30 μg/cm.sup.2 to 120 μg/cm.sup.2 from hour 32 to hour 48, 40 μg/cm.sup.2 to 150 μg/cm.sup.2 from hour 48 to hour 72, 100 μg/cm.sup.2 to 300 μg/cm.sup.2 from hour 72 to hour 144, and 30 μg/cm.sup.2 to 100 μg/cm.sup.2 from hour 144 to hour 168.

17. The transdermal therapeutic system of claim 1, wherein said transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg.Math.hr/ml-cm.sup.2 over about 168 hours of administration after a single-dose administration to a subject population.

18. The transdermal therapeutic system of claim 1, wherein said buprenorphine base-containing pressure-sensitive adhesive layer comprises an anti-oxidant selected from the group consisting of ascorbyl palmitate, tocopherol and esters thereof, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, propyl gallate and mixtures thereof.

19. The transdermal therapeutic system of claim 18, wherein said anti-oxidant is ascorbyl palmitate and is present in an amount of from about 0.01 to about 0.5% of said buprenorphine-containing pressure-sensitive adhesive layer.

20. A set of two to five different transdermal therapeutic systems each in accordance with claim 1, wherein said first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; said second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 3 cm.sup.2 to about 9.5 cm.sup.2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; said third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 6 cm.sup.2 to about 19 cm.sup.2 and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; said fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 12 cm.sup.2 to about 28.5 cm.sup.2 and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and said fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 16 cm.sup.2 to about 38 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

21. A transdermal therapeutic system for transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, said adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive based on polysiloxanes or polyisobutylenes, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, c) a viscosity-increasing substance in an amount of about 0.1% to about 8% of said buprenorphine-containing pressure-sensitive adhesive layer, wherein the viscosity-increasing substance is polyvinylpyrrolidone, and d) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture including said viscosity-increasing substance, and wherein said carboxylic acid-, buprenorphine- and viscosity-increasing substance-containing mixture forms dispersed deposits in said pressure-sensitive adhesive, and wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

22. The transdermal therapeutic system of claim 21, wherein said buprenorphine is present in the form of buprenorphine base and/or wherein said carboxylic acid is levulinic acid.

23. The transdermal therapeutic system of claim 21, wherein said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid and said polymer-based pressure-sensitive adhesive is based on polysiloxanes.

24. The transdermal therapeutic system of claim 21, wherein said polyvinylpyrrolidone is present in an amount of about 0.1% to about 7%, or of about 0.5% to about 5%, or of about 1% to about 4%, or of about 2% to about 3% of said buprenorphine-containing pressure-sensitive adhesive layer.

25. The transdermal therapeutic system of claim 21, wherein the polyvinylpyrrolidone has a K-Value of at least about 80.

26. The transdermal therapeutic system of claim 21, wherein said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid, said polymer-based pressure-sensitive adhesive is based on polysiloxanes and said polyvinylpyrrolidone in an amount of about 1% to about 4%.

27. The transdermal therapeutic system of claim 21, wherein said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, or about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, or about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, or about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, or about 15 mg to about 32 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof.

28. The transdermal therapeutic system of claim 21, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2, or about 3 cm.sup.2 to about 9.5 cm.sup.2, or about 6 cm.sup.2 to about 19 cm.sup.2, or about 12 cm.sup.2 to about 28.5 cm.sup.2, or about 16 cm.sup.2 to about 38 cm.sup.2.

29. The transdermal therapeutic system of claim 21, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2 and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 5 μg/hr over about 168 hours of administration.

30. The transdermal therapeutic system of claim 21, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 3 cm.sup.2 to about 9.5 cm.sup.2, and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 10 μg/hr over about 168 hours of administration.

31. The transdermal therapeutic system of claim 21, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 6 cm.sup.2 to about 19 cm.sup.2 and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 20 μg/hr over about 168 hours of administration.

32. The transdermal therapeutic system of claim 21, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 12 cm.sup.2 to about 28.5 cm.sup.2, and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 30 μg/hr over about 168 hours of administration.

33. The transdermal therapeutic system of claim 21, wherein said buprenorphine-containing pressure-sensitive adhesive layer has a size that provides an area of release ranging from about 16 cm.sup.2 to about 38 cm.sup.2, and said amount of said buprenorphine contained in the transdermal therapeutic system ranges from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of the pharmaceutically acceptable salt thereof, wherein said transdermal therapeutic system provides a nominal mean release rate of about 40 μg/hr over about 168 hours of administration.

34. The transdermal therapeutic system of claim 21, wherein said buprenorphine is present in the form of buprenorphine base and said system provides a mean cumulative skin permeation rate measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 μg/cm.sup.2-hr over a 168 hours test and/or provides a cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 220 μg/cm.sup.2 to 640 μg/cm.sup.2 over a time period of 168 hours.

35. The transdermal therapeutic system of claim 21, wherein said buprenorphine is present in the form of buprenorphine base and said system provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 2 μg/cm.sup.2 to 10 μg/cm.sup.2 in the first 8 hours, 20 μg/cm.sup.2 to 80 μg/cm.sup.2 from hour 8 to hour 24, 20 μg/cm.sup.2 to 80 μg/cm.sup.2 from hour 24 to hour 32, 30 μg/cm.sup.2 to 120 μg/cm.sup.2 from hour 32 to hour 48, 40 μg/cm.sup.2 to 150 μg/cm.sup.2 from hour 48 to hour 72, 100 μg/cm.sup.2 to 300 μg/cm.sup.2 from hour 72 to hour 144, and 30 μg/cm.sup.2 to 100 μg/cm.sup.2 from hour 144 to hour 168.

36. The transdermal therapeutic system of claim 21, wherein said transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg.Math.hr/ml-cm.sup.2 over about 168 hours of administration after a single-dose administration to a subject population.

37. The transdermal therapeutic system of claim 21, wherein said buprenorphine base-containing pressure-sensitive adhesive layer comprises an anti-oxidant selected from the group consisting of ascorbyl palmitate, tocopherol and esters thereof, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, propyl gallate and mixtures thereof.

38. The transdermal therapeutic system of claim 37, wherein said anti-oxidant is ascorbyl palmitate and is present in an amount of from about 0.01 to about 0.5% of said buprenorphine-containing pressure-sensitive adhesive layer.

39. A method of treating pain in a patient comprising applying the transdermal therapeutic system of claim 21 to the skin of said patient.

40. The method claim 39, wherein said transdermal therapeutic system is applied on the skin of the patient for about 168 hours.

41. The method of claim 39, wherein said buprenorphine is present in the form of buprenorphine base and/or wherein said carboxylic acid is levulinic acid.

42. The method of claim 39, wherein said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid and said polymer-based pressure-sensitive adhesive is based on polysiloxanes.

43. The method of claim 39, wherein the polyvinylpyrrolidone has a K-Value of at least about 80.

44. The method of claim 39, wherein said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid, said polymer-based pressure-sensitive adhesive is based on polysiloxanes and said polyvinylpyrrolidone in an amount of about 1% to about 4%.

45. The method of claim 39, wherein said transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg.Math.hr/ml-cm.sup.2 over about 168 hours of administration after a single-dose administration to a subject population.

46. The transdermal therapeutic system of claim 21, wherein the polyvinylpyrrolidone comprises soluble polyvinylpyrrolidone.

47. The transdermal therapeutic system of claim 21, wherein the polyvinylpyrrolidone has a K-Value of at least about 5, or of at least about 10, or of at least about 15, or of at least about 20, or of at least about 50, or of at least about 80.

48. A set of two to five different transdermal therapeutic systems each in accordance with claim 21, wherein said first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; said second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 3 cm.sup.2 to about 9.5 cm.sup.2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; said third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 6 cm.sup.2 to about 19 cm.sup.2 and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; said fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 12 cm.sup.2 to about 28.5 cm.sup.2 and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and said fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing an area of release ranging from about 16 cm.sup.2 to about 38 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 depicts a microscopic picture of the matrix layer of Comparative Example 1.

(2) FIG. 2A depicts a microscopic picture of the buprenorphine base-containing adhesive mixture of Comparative Example 2.

(3) FIG. 2B depicts a microscopic picture of the matrix layer of Comparative Example 2.

(4) FIG. 3A depicts a microscopic picture of the buprenorphine base-containing adhesive mixture of Example 3.

(5) FIG. 3B depicts a microscopic picture of the matrix layer of Example 3.

(6) FIG. 4A depicts a microscopic picture of the buprenorphine base-containing adhesive mixture of Example 4.

(7) FIG. 4B depicts a microscopic picture of the matrix layer of Example 4.

(8) FIG. 5 depicts the mean in-vitro-dissolution of Comparative Example 1.

(9) FIG. 6 depicts the mean in-vitro-dissolution of Comparative Example 2.

(10) FIG. 7 depicts the mean in-vitro-dissolution of Example 3.

(11) FIG. 8 depicts the mean in-vitro-dissolution of Example 4.

(12) FIG. 9 depicts the mean non-cumulative skin permeation rates for Comparative Examples 1 and 2 and Norspan®.

(13) FIG. 10 depicts the mean non-cumulative skin permeation rates for Examples 6, 7.1, 8 and BuTrans®.

(14) FIG. 11 depicts the mean non-cumulative skin permeation rates for Examples 7.1, 7.2 and BuTrans®.

(15) FIG. 12 depicts the mean non-cumulative skin permeation rates for Examples 7.2, 5.2 and BuTrans®.

(16) FIG. 13 depicts the mean non-cumulative skin permeation rate of the of the transdermal therapeutic systems. The area of release of the transdermal therapeutic system according to Example 5.2 is 14 cm.sup.2 and the area of release for BuTrans® is 25 cm.sup.2. The amount of buprenorphine base for Example 5.2 is 12.6 mg and the amount of buprenorphine base for BuTrans® is 20 mg.

DETAILED DESCRIPTION

(17) A microreservoir system including deposits of buprenorphine and a carboxylic acid dispersed in a hydrophobic pressure-sensitive adhesive layer provides high overall release rates during a seven-day administration period, thereby allowing a reduction of size and drug content of the TTS in comparison to the commercial product Norspan®. Such systems are described in the parallel patent application PCT/US2012/069242, corresponding to PCT/IB2012/002973, which is hereby incorporated by reference. In particular reference is made to Examples 1 to 4 in PCT/US2012/069242, corresponding to PCT/IB2012/002973. The manufacturing of several batches, however, shows a high variability in the performance. These systems provide high performance but are biphasic due to the dispersed deposits (1. phase) in the adhesive (2. phase). Without wishing to be bound to any theory, it is believed that the size and size distribution of the deposits influences the drug delivery. Large deposits release the drug too fast and provide for an undesired burst in the beginning of the dosing period and a failure of the system after three to four days. There is thus a need to sufficiently control the size and size distribution of the deposits.

(18) The production of a commercial transdermal product as disclosed herein requires a continuous coating and drying process to form the buprenorphine-containing pressure sensitive adhesive layer. Such coating is usually accomplished with a sufficiently sized roller coater and attached drying compartment. The buprenorphine-containing mixture to be coated is usually prepared batch wise, and is then stored for some time until the coater is ready to coat the mixture. The time between the preparation of the mixture and the coating of the mixture in a normal production routine can be almost zero, if after mixing/homogenizing the mass will be transferred to the coating station and is coated directly and may be as long as several days, e.g. four to six days, to store the mixture during the time of a failure of the coater or a weekend or other reasons for a coating process interruption. Thus the mixture must be sufficiently stable. A microreservoir system as described herein including two phases, namely the deposits and the adhesive surrounding the deposits which may change over time due to the fusion of individual deposits forming larger deposits. Thus the deposits must be hindered in fusing during the storing time between mixing and coating.

(19) Additionally, the shearing force applied to the coating mixture during coating in a roller coater is different and higher than on a laboratory scale coating technique like such as when using the Erichsen coater. But for commercial scale production, a roller coater is necessary to provide the necessary scale up and the necessary coating precision. However, the shear force in a roller coater causes additional fusion of the deposits. Thus the deposits must be hindered in fusing during the coating process using a roller coater.

TTS Structure

(20) According to a certain embodiment of the invention the transdermal therapeutic system for the transdermal administration of buprenorphine comprises a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, c) a viscosity-increasing substance in an amount of about 0.1% to about 8% of said buprenorphine-containing pressure-sensitive adhesive layer, and d) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture including said viscosity-increasing substance, and wherein the carboxylic acid-, buprenorphine- and viscosity-increasing substance-containing mixture forms dispersed deposits in the said pressure-sensitive adhesive, and
wherein said buprenorphine-containing pressure-sensitive adhesive layer is preferably the skin contact layer.

(21) Without wishing to be bound to any theory it is believed that the viscosity-increasing substance increases the viscosity of the deposits (inner phase) within the adhesive solution (outer phase) during the production and within the adhesive matrix (outer phase) during the storage of the dried buprenorphine-containing layer.

(22) Useful viscosity-increasing substances may be selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and microcrystalline cellulose, high molecular mass polyacrylic acids and/or their salts and/or their derivatives such as esters, polyvinylpyrrolidone, in particular soluble polyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate, tragacanth, xanthan gum, bentonite, carageenan and guar gum. A preferred viscosity-increasing substance is polyvinylpyrrolidone.

(23) In certain embodiments of the invention the viscosity-increasing substance is present in an amount of about 0.1% to about 7%, or in an amount of about 0.5% to about 5%, preferably in an amount of about 1% to about 4%, more preferably in an amount of about 2% to about 3% of the buprenorphine-containing pressure-sensitive adhesive layer.

(24) According to a certain independent embodiments of the invention wherein the structure is concerned, the transdermal therapeutic system for the transdermal administration of buprenorphine comprises a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, c) soluble polyvinylpyrrolidone, and d) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture including said polyvinylpyrrolidone, and wherein the carboxylic acid-, buprenorphine- and polyvinylpyrrolidone-containing mixture forms dispersed deposits in the said pressure-sensitive adhesive, and
wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

(25) Without wishing to be bound to any theory it is believed that the polyvinylpyrrolidone having a K-Value of at least 5, at least 10, at least 15, at least 20, at least 50, or a K-Value of at least 80 is in particular beneficial in increasing the viscosity of the deposits (inner phase) within the adhesive solution (outer phase) during the production and within the adhesive matrix (outer phase) during the storage of the dried buprenorphine-containing layer. The increase in viscosity si beneficial because the deposits are thereby hindered in fusing during the storing time between mixing and coating.

(26) In certain embodiments of the invention the transdermal therapeutic system for the transdermal administration of buprenorphine comprises a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the adhesive layer comprising a) at least one pressure-sensitive adhesive based on polysiloxane, b) an analgesically effective amount of buprenorphine base, c) soluble polyvinylpyrrolidone in an amount of about 1% to about 4% of the buprenorphine base-containing pressure-sensitive adhesive layer, wherein the polyvinylpyrrolidone has K-Value of at least about 80, and d) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a mixture including said polyvinylpyrrolidone, and wherein the levulinic acid-, buprenorphine base- and polyvinylpyrrolidone-containing mixture forms dispersed deposits in the said pressure-sensitive adhesive, and
wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer.

(27) According to a certain other embodiment of the invention alternatively the buprenorphine-containing pressure-sensitive adhesive layer comprises an additional skin contact layer.

(28) According to certain embodiments of the invention, the TTS comprises in addition to the buprenorphine-containing self-adhesive layer structure attached thereto a larger active agent-free self-adhesive layer structure, e.g., a peripheral adhesive or overlying adhesive, for enhancing the adhesive properties of the overall transdermal therapeutic system. Said active agent-free self-adhesive layer structure comprises also a backing layer. In certain embodiments, this additional layer is beige colored. The active agent-free pressure-sensitive adhesive layer of polymer-based pressure-sensitive adhesive is e.g., based on polyacrylates or polysiloxanes. The area of said second active agent-free self-adhesive layer structure adds to the overall size of the TTS but does not add to the area of release. The pressure-sensitive adhesive in the active agent-containing and the active agent-free self-adhesive layer structures may be the same or different. If the adhesive in the active agent-free self-adhesive layer is different from that of the buprenorphine-containing layer, then pressure-sensitive adhesives selected from the group of polyacrylate-based or polyisobutylene-based pressure-sensitive adhesives can be used, and polyacrylate based pressure-sensitive adhesives are preferred, in particular pressure-sensitive adhesives based on an acrylate-vinylacetate polymer, e.g., such as those available from Henkel under the tradename Duro Tak®, e.g., Duro Tak® 387 2051. Such pressure-sensitive adhesives are provided in an organic solution of ethyl acetate and heptane. Such pressure-sensitive adhesives provide a 180° Peel at 20 minutes of at least about 20 N/25 mm, and at 24 minutes of at least about 25 N/25 cm, and at one week of at least about 30 N/25 mm and a Loop tack of at least 15 N/25 mm.sup.2, or of at least 20 N/25 mm.sup.2, or of at least 22 N/25 mm.sup.2.

Active Agent

(29) The TTS according to the invention comprises an analgesically effective amount of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts may be selected from those known in the art, such as the hydrochloride, sulphate, phosphate, tartrate, maleinate, oxalate, acetate and lactate salts. According to a preferred embodiment of the invention the active agent is included in the form of buprenorphine base. The term buprenorphine base, however, does not exclude interactions, including complexation between the buprenorphine base and other ingredients of the buprenorphine-containing layer e.g. levulinic acid.

(30) An analgesically effective amount may vary from about 1 mg to about 50 mg, in particular from about 2 mg to about 30 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt, or from about 2 mg to about 25 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. According to certain embodiments, the TTS contains according to five different dosages from about 1 mg to about 4 mg, or from about 3.5 mg to about 8 mg, or from about 6.5 mg to about 16 mg, or from about 11.5 mg to about 24 mg, or from about 15 mg to about 32 mg of buprenorphine base or a an equimolar amount of a pharmaceutically acceptable salt thereof, or the TTS contains according to five different dosages from about 1 mg to about 4.5 mg, or about 3 mg, or from about 4 mg to about 9 mg, or about 6 mg, or from about 8 mg to about 14 mg, or about 12 mg, or from about 15 mg to about 20 mg, or about 18 mg or from about 20 mg to about 28 mg, or about 24 mg of buprenorphine base or a an equimolar amount of a pharmaceutically acceptable salt thereof. Further dosages are provided by transdermal therapeutic systems containing smaller or greater amounts, e.g., from about 5.5 mg to about 13 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

Pressure-Sensitive Adhesive

(31) The pressure-sensitive adhesives used for the present invention are polymer-based pressure-sensitive adhesives. Such polymer-based pressure-sensitive adhesives may e.g., be based on polysiloxanes or polyisobutylenes. For the present invention polysiloxane-based pressure-sensitive adhesives are preferred. Such polysiloxanes adhesives need, unlike other organic pressures-sensitive adhesives, no additives like antioxidants, stabilizers, plasticizers, catalysts or other potentially extractable ingredients. These pressure-sensitive adhesives provide for suitable tack for quick bonding to various skin types, including wet skin, suitable adhesive and cohesive qualities, long lasting adhesion to the skin of up to 7 days, a high degree of flexibility, a permeability to moisture, and compatibility to many actives and film-substrates. It is possible to provide them with sufficient amine resistance and therefore enhanced stability in the presence of amines. Such pressure-sensitive adhesives are based on a resin-in-polymer concept wherein, by condensation reaction of silanol end blocked polydimethylsiloxane with a silica resin, a polysiloxane is prepared which for amine stability the residual silanol functionality is additionally capped with trimethylsiloxy groups. The dimethiconol content contributes to the viscous component of the visco-elastic behavior, and impacts the wetting and the spreadability properties of the adhesive. The resin acts as a tackifying and reinforcing agent, and participates in the elastic component. The correct balance between dimethiconol and resin provides for the correct adhesive properties.

(32) The adhesive strength of the polysiloxanes may be sufficient for the desired skin contact. In certain embodiments of the invention a plasticizer or a tackifying agent is incorporated into the formulation to improve the adhesive characteristics of the pressure-sensitive adhesive layer. It may be advantageous in an individual case to improve the tack by adding small amounts of tackifiers such as polyterpenes, rosin derivatives, or silicone oils. In preferred embodiments, the tackifying agent is a silicone oil (e.g., 360 Medical Fluid, available from Dow Corning Corporation, Midland, Mich.).

(33) The pressure-sensitive adhesives are supplied and used in solvents like heptane, ethyl acetate or volatile silicone fluids. For the present invention heptane is preferred. The solids content is usually between 60 and 80%.

(34) The preferred pressure-sensitive adhesives based on polysiloxanes in accordance with the invention are characterized by a solution viscosity at 25° C. and 60% solids content in heptane of more than about 150 mPa s, or from about 200 mPa s to about 700 mPa s, in particular from about 350 mPa s to about 600 mPa s, more preferred from about 480 mPa s to about 550 mPa s, or most preferred of about 500 mPa s or alternatively from about 400 mPa s to about 480 mPa s, or most preferred of about 450 mPa s. Theses may also be characterized by a complex viscosity at 0.01 rad/s at 30° C. of less than about 1×10.sup.9 Poise, or from about 1×10.sup.5 to about 9×10.sup.8 Poise, or more preferred from about 1×10.sup.5 to about 1×10.sup.7 Poise, or most preferred about 5×10.sup.6 Poise, or alternatively more preferred from about 2×10.sup.7 to about 9×10.sup.8 Poise, or most preferred about 1×10.sup.8 Poise.

(35) Suitable pressure-sensitive adhesives based on polysiloxanes may be obtained from Dow Corning® BIO-PSA Standard Silicone Adhesives. Preferred are the BIO-PSA 7 4301 and BIO-PSA 7 4201 Silicone Adhesives. According to certain embodiments BIO-PSA 7 4301 is preferred and according to certain other embodiments BIO-PSA 7 4201 is preferred. To avoid excessive cold flow, BIO-PSA 7 4201 is preferred. BIO-PSA 4201 has a solution viscosity at 25° C. and about 60% solids content in heptane of 450 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 1×10.sup.8 Poise. BIO-PSA 4301 has a solution viscosity at 25° C. and about 60% solids content in heptane of 500 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 5×10.sup.6 Poise.

(36) The pressure-sensitive adhesive layer of the TTS of the invention may further comprise in addition to the above mentioned ingredients a), b), c) and d), (i.e. the polymer-based pressure-sensitive adhesive, the buprenorphine, the viscosity-increasing substance/the polyvinylpyrrolidone and the carboxylic acid selected from the group of oleic acid, linoleic acid, linolenic acid and levulinic acid as described herein), other various excipients or additives, selected, for example, from the group of solubilizers, fillers, tackifiers, substances which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability, pH regulators, and preservatives.

(37) Substances which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability are known to the skilled worker and the substance appropriate for the respective active agents must—if necessary—be found by means of permeation studies. Some examples are polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives such as allantoin; polar solvents such as dimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamine, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide, and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate; and higher molecular weight aliphatic surfactants such as lauryl sulfate salts. Other agents include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate. The TTS of the invention may additionally comprise according to certain embodiments (in which the pressure-sensitive adhesive layer comprises a) the polymer-based pressure-sensitive adhesive, b) the buprenorphine, c) the viscosity-increasing substance/the polyvinylpyrrolidone and d) levulinic acid or linolenic acid or mixtures of both as the carboxylic acid as described herein) oleic and linoleic acids as substances influencing the barrier properties of the stratum corneum in the sense of increasing the active agent permeability.

(38) Such substances as described in the previous paragraph may be included in a TTS and may be present in an amount of about 1% to about 10% by weight. In a preferred embodiment of the present invention such additional substances are however not necessary. According to an embodiment of the invention the TTS does not comprise such additional substances as mentioned in the previous paragraph.

(39) In addition to the carboxylic acid selected from oleic acid, linoleic acid, linolenic acid, levulinic acid, the solubility of the drug can be further altered by the optional addition of an agent that increases the solubility of drug or inhibits drug crystallization in the transdermal composition, such as vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives.

(40) Fillers such as silica gels, titanium dioxide and zinc oxide may be used in conjunction with the polymer in order to influence certain physical parameters, such as cohesion and bond strength, in the desired way.

(41) Further one or more anti-oxidants can be added. The anti-oxidant may be selected from the group consisting of tocopherol, esters thereof, e.g. α-tocopherol acetate, ascorbyl palmitate, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or propyl gallate, preferably ascorbyl palmitate. The antioxidant may be conveniently present in an amount of from about 0.01 to about 0.5%, e.g. 0.05 to 0.30, e.g. 0.18% or 0.2% of the buprenorphine-containing pressure-sensitive adhesive layer.

Buprenorphine-Containing Self-Adhesive Layer Structure

(42) In accordance with the invention, the buprenorphine-containing self-adhesive layer structure comprises a buprenorphine-impermeable backing layer, and a buprenorphine-containing pressure-sensitive adhesive layer coated thereon. In a preferred embodiment, the buprenorphine-containing self-adhesive layer structure consists of these two elements.

(43) The buprenorphine-containing pressure-sensitive adhesive layer may be coated at any dry weight, but is preferably coated at a dry weight of more than about 6 mg/cm.sup.2 (about 60 g/m.sup.2), or of more than about 8 mg/cm.sup.2 (about 80 g/m.sup.2), or ranging from about 6 mg/cm.sup.2 (about 60 g/m.sup.2) to about 14 mg/cm.sup.2 (about 140 g/m.sup.2), or from about 8 mg/cm.sup.2 (about 80 g/m.sup.2) to about 14 mg/cm.sup.2 (about 140 g/m.sup.2). Specifically, the dry weight is more than about 10 mg/cm.sup.2 (about 100 g/m.sup.2), or ranges from about 10 mg/cm.sup.2 (about 100 g/m.sup.2) to about 13 mg/cm.sup.2 (about 130 g/m.sup.2), or ranges from about 11.5 mg/cm.sup.2 (about 115 g/m.sup.2) to about 12.5 mg/cm.sup.2 (about 125 g/m.sup.2), or is specifically about 12 mg/cm.sup.2 (about 120 g/m.sup.2).

(44) The dry buprenorphine-containing pressure-sensitive adhesive layer preferably contains buprenorphine base, but may contain an equimolar amount of a pharmaceutically acceptable salt. According to the invention, preferably more than 5%, or more than about 6%, or more than about 7%, or more than about 8%, or more than about 9%, or from about 6% to about 20%, or from about 7% to about 20%, or from about 8% to about 20%, or from about 9% to about 20%, or from about 6% to about 15%, or from about 7% to about 15%, or from about 8 to about 15%, or from about 9 to about 15% buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt based on the total dry weight of the dry buprenorphine-containing pressure-sensitive adhesive layer is contained in the dry buprenorphine-containing pressure-sensitive adhesive layer. In a specific embodiment, about 10% buprenorphine base is contained in the dry buprenorphine-containing pressure-sensitive adhesive layer.

(45) Preferably, the TTS contains in the pressure-sensitive adhesive layer more than about 0.55 mg/cm.sup.2, or more than about 0.6 mg/cm.sup.2, or more than about 0.7 mg/cm.sup.2, or more than about 0.8 mg/cm.sup.2, or more than about 0.9 mg/cm.sup.2, or more than about 1 mg/cm.sup.2, or more than about 1.1 mg/cm.sup.2, buprenorphine base, or from about 0.55 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 0.6 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 0.7 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 0.8 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 0.9 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 1 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 1.1 mg/cm.sup.2 to about 2 mg/cm.sup.2 buprenorphine base or contains about 1.2 mg/cm.sup.2 buprenorphine base. The TTS may also contain equimolar amounts of pharmaceutically acceptable salts.

(46) In order to provide the desired delivery rate of buprenorphine, a carboxyclic acid is present. The carboxylic acid may be selected from the group consisting of C.sub.3 to C.sub.24 carboxylic acids including oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, wherein levulinic acid is preferred. Alternatively or in addition, a substance selected from the group consisting of alcohols and esters may be present. The buprenorphine is in mixture with, e.g., dissolved in, the carboxylic acid, e.g., the levulinic acid, and this mixture, e.g., solution, is dispersed in the form of small deposits, e.g., droplets, in the matrix layer. Buprenorphine, with its known physicochemical properties, namely its poor solubility, its comparatively high melting point of 216° C., and its high molecular weight, tends readily towards crystallization. For this reason, a solubilizer with at least one acidic group (alternatively with an alcoholic or ester group) is used in order to prevent the buprenorphine from crystallizing during the storage of the pharmaceutical form. Buprenorphine and levulinic acid have an extremely low solubility in polysiloxanes. As a consequence of this, it is possible to solubilize buprenorphine in levulinic acid and to disperse this mixture in the form of small deposits (e.g. droplets) in a matrix layer prepared on the basis of polysiloxanes as described herein.

(47) Levulinic acid is sparingly soluble in the organic solvents of the adhesives. Consequently, the liquid mixture of buprenorphine and levulinic acid can be dispersed in the solution of the adhesive, with the dispersion being retained following removal of the solvent. In a matrix layer of this kind, the solubility of the buprenorphine is dependent virtually only on the amount of the levulinic acid.

(48) The amount of the dispersed mixture of buprenorphine, e.g., buprenorphine base, and the carboxylic acid, e.g., levulinic acid, can be up to about 40% by weight, it being preferred not to exceed about 25% or about 20% by weight and ranges from about 15% to about 25%, or from about 15% to about 20%, or from about 17% to about 20%. The size of the deposit, e.g., droplet (diameter) itself ought preferably not to exceed about 150 μm, or ranges from about 1 to about 150 μm, preferably from about 1 to about 50 μm, or from about 5 to about 50 μm, or from about 1 to about 25 μm or from about 5 to about 25 μm. The preferred size is dependent, furthermore, on the thickness of the matrix layer.

(49) Since the carboxylic acid, e.g., the levulinic acid, can likewise be absorbed through the skin, the amount in the TTS becomes less as the time of application elapses, and leads to a reduction of the solubility of buprenorphine. As a result, the decrease in the thermodynamic activity of buprenorphine due to depletion is compensated by the reduced drug solubility in the buprenorphine/levulinic acid deposits.

(50) According to the invention the dry buprenorphine-containing pressure-sensitive adhesive layer contains more than about 5%, or more than about 6%, or more than about 7%, or more than about 8%, or more than about 9%, or from about 6% to about 20%, or from about 7% to about 20%, or from about 8 to about 20%, or from about 9 to about 20%, or from about 5% to about 15%, or from about 6% to about 15%, or from about 6% to about 9%, or from about 9% to about 15% carboxylic acid, e.g., levulinic acid based on the total dry weight of the dry buprenorphine-containing pressure-sensitive adhesive layer. In a specific embodiment the dry buprenorphine-containing pressure-sensitive adhesive layer contains from about 6% to about 11% levulinic acid, or from about 6% to about 9% or from about 9% to about 15% levulinic acid, or about 7% levulinic acid or about 10% levulinic acid. According to a specific embodiment the pressure-sensitive adhesive layer contains the same %-amount of levulinic acid and buprenorphine base or equimolar amounts of pharmaceutically acceptable salts. According to another specific embodiment, the pressure-sensitive adhesive layer contains less %-amount of levulinic acid than it contains %-amount of buprenorphine base or equimolar amounts of pharmaceutically acceptable salts.

(51) According to a specific embodiment, the pressure-sensitive adhesive layer contains more than about 9% to about 15% buprenorphine base and from about 6% to about 9% levulinic acid or from more than about 9% to about 15% buprenorphine base, and from about 9% to about 15% levulinic acid based on the total dry weight.

(52) According to a certain embodiment, the pressure-sensitive adhesive layer is coated at a dry weight of from about 10 mg/cm.sup.2 to about 14 mg/cm.sup.2, or from about 11.5 mg/cm.sup.2 to about 12.5 mg/cm.sup.2, or is about 12 mg/cm.sup.2, and the dry pressure-sensitive adhesive layer contains from about 7% to about 13% or from about 8% to about 12%, or from about 9% to about 11% or about 10% buprenorphine base and from about 6% to about 8%, or about 7% levulinic acid. In a specific embodiment the dry pressure-sensitive adhesive layer has a dry weight of about 12 mg/cm.sup.2 and contains about 7% levulinic acid and about 10% buprenorphine base.

(53) According to a certain other embodiment, the pressure-sensitive adhesive layer is coated at a dry weight of from about 10 mg/cm.sup.2 to about 14 mg/cm.sup.2, or from about 11.5 mg/cm.sup.2 to about 12.5 mg/cm.sup.2, or is about 12 mg/cm.sup.2, and the dry pressure-sensitive adhesive layer contains from about 7% to about 13% or from about 8% to about 12%, or from about 9% to about 11% or about 10% buprenorphine base and from about 8 to about 12% or about 10% levulinic acid. In a specific embodiment, the dry pressure-sensitive adhesive layer has a dry weight of about 12 mg/cm.sup.2, and contains about 10% levulinic acid and about 10% buprenorphine base.

(54) In accordance with the above, the TTS contains more than about 0.55 mg/cm.sup.2, or more than about 0.6 mg/cm.sup.2, or more than about 0.7 mg/cm.sup.2, or more than about 0.8 mg/cm.sup.2, or more than about 0.9 mg/cm.sup.2, or more than about 1 mg/cm.sup.2, or more than about 1.1 mg/cm.sup.2 buprenorphine base or from about 0.6 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 0.7 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 0.8 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 0.9 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 1 mg/cm.sup.2 to about 2 mg/cm.sup.2, or from about 1.1 mg/cm.sup.2 to about 2 mg/cm.sup.2 buprenorphine base or contains about 1.2 mg/cm.sup.2 buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. In certain embodiments, buprenorphine base is preferred. According to a specific embodiment, the pressure-sensitive adhesive layer contains the same amounts of levulinic acid and buprenorphine base. According to another specific embodiment, the pressure-sensitive adhesive layer contains less levulinic acid than it contains buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

(55) According to a certain embodiment of the invention, the pressure-sensitive adhesives in the buprenorphine-containing layer and in the active agent-free layer are different, and the adhesive in the active agent-free layer is a pressure-sensitive adhesive based on polyacrylates. According to certain other embodiments, the adhesive in the active agent-containing and the active agent-free layer are the same and are an amine-resistant pressure-sensitive adhesive based on polysiloxane. According to certain embodiments, the polysiloxane is a product of the condensation reaction of silanol endblocked polydimethylsiloxane with a silica resin and the residual silanol functionality is capped with trimethylsiloxy groups and characterized by a solution viscosity at 25° C. and about 60% solids content in heptanes of about 500 mPa s or of about 450 mPa s. According to certain embodiments, the buprenorphine-containing pressure-sensitive adhesive layer is coated at a dry weight of about 12 mg/cm.sup.2 and contains about 10% buprenorphine base and about 10% levulinic acid.

(56) According to certain embodiments, the area of release ranges from about 1 cm.sup.2 to about 38 cm.sup.2, or is less than 25 cm.sup.2, or less than 22 cm.sup.2, or ranges from about 1.5 to about 25 cm.sup.2, or from about 1.5 to about 22 cm.sup.2, or from about 1.5 to about 20 cm.sup.2, or is about 3 cm.sup.2, or about 6 cm.sup.2, or about 10 cm.sup.2, or about 15 cm.sup.2 or about 20 cm.sup.2.

(57) According to certain embodiments, the TTS contains from about 1 mg to about 32 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or from about 1 mg to about 28 mg, or from about 2 mg to about 25 mg, or from about 2 mg to about 24 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. Considering five different increasing dosage strengths, the TTS in specific cases preferably contains a) from about 1 mg to about 4 mg, or from about 1 mg to about 4.5 mg, preferably from about 1 mg to about 3.5 mg, or from about 2 mg to about 4 mg, more preferably from about 1 mg to about 3 mg, or from about 2.5 mg to about 4 mg, or about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or b) from about 3.5 mg to about 8 mg, or from about 4 mg to about 9 mg, preferably from about 3.5 mg to about 7 mg, or from about 5 mg to about 8 mg, more preferably from about 3.5 mg to about 6 mg, or from about 5 mg to about 7 mg, or about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or c) from about 6.5 mg to about 16 mg, or from about 8 mg to about 14 mg, preferably from about 6.5 mg to about 14 mg, or from about 10 mg to about 14 mg, more preferably from about 6.5 mg to about 11 mg, or from about 11 mg to about 13 mg, or about 12 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or d) from about 11.5 mg to about 24 mg, or from about 15 mg to about 20 mg, preferably from about 11.5 mg to about 21 mg, or from about 16 mg to about 19 mg, more preferably from about 11.5 mg to about 14 mg, or from about 17 mg to about 19 mg, or about 18 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or e) from about 15 mg to about 32 mg, or from about 20 mg to about 28 mg, preferably from about 15 mg to about 28 mg, or from about 21 mg to about 26 mg, more preferably from about 15 mg to about 24 mg, or from about 22 mg to about 25 mg, or about 24 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.
Correspondingly the area of release ranges from about 1 cm.sup.2 to about 38 cm.sup.2, or from 1.5 cm.sup.2 to about 24 cm.sup.2, or ranges from 1.5 cm.sup.2 to about 22 cm.sup.2, or ranges from 1.5 cm.sup.2 to about 20 cm.sup.2 and with respect to the five specific preferred dosage strengths a) to e) a) ranges from about 1 cm.sup.2 to about 4.8 cm.sup.2, or from about 1.5 cm.sup.2 to about 5.5 cm.sup.2, preferably from about 1 cm.sup.2 to about 4.5 cm.sup.2, or from about 2 cm.sup.2 to about 4 cm.sup.2, more preferably from about 2.5 cm.sup.2 to about 4 cm.sup.2, or from about 2 cm.sup.2 to about 3 cm.sup.2, or is about 2.5 cm.sup.2, or b) ranges from about 3 cm.sup.2 to about 9.5 cm.sup.2, or from about 3 cm.sup.2 to about 9 cm.sup.2, preferably from about 3 cm.sup.2 to about 9 cm.sup.2, or from about 4.5 cm.sup.2 to about 7.5 cm.sup.2, more preferably from about 5 cm.sup.2 to about 8 cm.sup.2, or from about 4.5 cm.sup.2 to about 6 cm.sup.2, or is about 5 cm.sup.2, or c) ranges from about 6 cm.sup.2 to about 19 cm.sup.2, or from about 6 cm.sup.2 to about 14 cm.sup.2, preferably from about 6 cm.sup.2 to about 18 cm.sup.2, or from about 8 cm.sup.2 to about 12 cm.sup.2, more preferably from about 10 cm.sup.2 to about 16 cm.sup.2, or from about 9 cm.sup.2 to about 11 cm.sup.2, or is about 10 cm.sup.2, or d) ranges from about 12 cm.sup.2 to about 28.5 cm.sup.2, or from about 13 cm.sup.2 to about 17 cm.sup.2, preferably from about 12 cm.sup.2 to about 27 cm.sup.2, or from about 13 cm.sup.2 to about 16 cm.sup.2, more preferably from about 17 cm.sup.2 to about 23 cm.sup.2, or from about 14 cm.sup.2 to about 16 cm.sup.2, or is about 15 cm.sup.2, or e) ranges from about 16 cm.sup.2 to about 38 cm.sup.2, or from about 16 cm.sup.2 to about 24 cm.sup.2, preferably or from about 16 cm.sup.2 to about 35 cm.sup.2, or from about 17 cm.sup.2 to about 22 cm.sup.2, more preferably from about 23.5 cm.sup.2 to about 32 cm.sup.2, or from about 18 cm.sup.2 to about 21 cm.sup.2, or is about 20 cm.sup.2. A further TTS providing a dosage strength between strength b) and c) contains from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and the area of release ranges from about 5 cm.sup.2 to about 14 cm.sup.2, preferably from about 5 cm.sup.2 to about 13.5 cm.sup.2.
In such embodiments the dry pressure-sensitive adhesive layer preferably comprises a pressure-sensitive adhesive based on polysiloxanes and has preferably a dry weight of about 6 mg/cm.sup.2, 7.5 mg/cm.sup.2, 8 mg/cm.sup.2, 9 mg/cm.sup.2, 10.5 mg/cm.sup.2, or 12 mg/cm.sup.2 and contains 10% buprenorphine base.

(58) According to certain preferred embodiments, the TTS contains with respect to five dosage strengths a) to e) the following amounts of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides the following corresponding area of release ranges:

(59) a)

(60) TABLE-US-00001 about 1 cm.sup.2 to about 1 cm.sup.2 to about 2.5 cm.sup.2 to a) about 4.8 cm.sup.2 about 4.5 cm.sup.2 about 4 cm.sup.2 about 1 mg to X X X about 4 mg about 1 mg to X X X about 3.5 mg about 1 mg to X X X about 3 mg
b)

(61) TABLE-US-00002 about 3 cm.sup.2 to about 3 cm.sup.2 to about 5 cm.sup.2 to b) about 9.5 cm.sup.2 about 9 cm.sup.2 about 8 cm.sup.2 about 3.5 mg to X X X about 8 mg about 3.5 mg to X X X about 7 mg about 3.5 mg to X X X about 6 mg
c)

(62) TABLE-US-00003 about 6 cm.sup.2 to about 6 cm.sup.2 to about 10 cm.sup.2 to c) about 19 cm.sup.2 about 18 cm.sup.2 about 16 cm.sup.2 about 6.5 mg to X X X about 16 mg about 6.5 mg to X X X about 14 mg about 6.5 mg to X X X about 11 mg
d)

(63) TABLE-US-00004 about 12 cm.sup.2 to about 12 cm.sup.2 to about 17 cm.sup.2 to d) about 28.5 cm.sup.2 about 27 cm.sup.2 about 23 cm.sup.2 about 11.5 mg X X X to about 24 mg about 11.5 mg X X X to about 21 mg about 11.5 mg X X X to about 14 mg
e)

(64) TABLE-US-00005 about 16 cm.sup.2 to about 16 cm.sup.2 to about 23.5 cm.sup.2 e) about 38 cm.sup.2 about 35 cm.sup.2 to about 32 cm.sup.2 about 15 mg to X X X about 32 mg about 15 mg to X X X about 28 mg about 15 mg to X X X about 24 mg
The further TTS providing the dosage strength between strength b) and c) provides from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and the area of release ranges from about 5 cm.sup.2 to about 14 cm.sup.2, or
from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and the area of release ranges from about 5 cm.sup.2 to about 13.5 cm.sup.2.

Set of Transdermal Therapeutic Systems

(65) For the treatment of pain a patient needs to be titrated to the individual dose of buprenorphine to adequately control the pain. In order to meet the individual requirements five different dosage strengths are provided in accordance with the invention.

(66) According to one aspect, the invention relates to a set of two (first and second, or second and third, or third and fourth, or fourth and fifth TTS, or any other combination of two of the five different dosage strengths), three (first to third, or second to fourth or third to fifth TTS, or any other combination of three of the five different dosage strengths), four (first to fourth or second to fifth TTS, or any other combination of four of the five different dosage strengths) or five (first to fifth TTS) different transdermal therapeutic systems in accordance with the invention, wherein: the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2, or from about 1.5 cm.sup.2 to about 5.5 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg, or from about 1 mg to about 4.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and

(67) the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm.sup.2 to about 9.5 cm.sup.2, or from about 3 cm.sup.2 to about 9 cm.sup.2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg, or from about 4 mg to about 9 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm.sup.2 to about 19 cm.sup.2, or from about 6 cm.sup.2 to about 14 cm.sup.2 and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg, or from about 8 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm.sup.2 to about 28.5 cm.sup.2, or from about 13 cm.sup.2 to about 17 cm.sup.2 and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg, or from about 15 mg to about 20 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm.sup.2 to about 38 cm.sup.2, or from about 16 cm.sup.2 to about 24 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 32 mg, or from about 20 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. The set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by one or more further transdermal therapeutic system(s) which may provide smaller, greater or intermediate areas of release and amounts of buprenorphine compared with the five different transdermal therapeutic systems described above, preferably the set of two to five different transdermal therapeutic systems is expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm.sup.2 to about 14 cm.sup.2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, providing an intermediate transdermal therapeutic system between the second and the third transdermal therapeutic system. Alternatively, one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by such a further transdermal therapeutic system.

(68) The invention relates also to set of transdermal therapeutic systems, wherein:

(69) the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm.sup.2 to about 4.5 cm.sup.2, or from about 2 cm.sup.2 to about 4 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg, or from about 1 mg to about 3.5 mg, or from about 2 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm.sup.2 to about 9 cm.sup.2, or from about 4.5 cm.sup.2 to about 7.5 cm.sup.2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg, or from about 3.5 mg to about 7 mg, or from about 5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm.sup.2 to about 18 cm.sup.2, or from about 8 cm.sup.2 to about 12 cm.sup.2 and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg, or from about 6.5 mg to about 14 mg, or from about 10 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm.sup.2 to about 27 cm.sup.2, or from about 13 cm.sup.2 to about 16 cm.sup.2 and contains an amount of said buprenorphine from about 11.5 mg to about 21 mg, or from about 11.5 mg to about 24 mg, or from about 16 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm.sup.2 to about 35 cm.sup.2, or from about 17 cm.sup.2 to about 22 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 32 mg, or from about 15 mg to about 28 mg, or from about 21 mg to about 26 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. The set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by one or more further transdermal therapeutic system(s) which may provide smaller, greater or intermediate areas of release and amounts of buprenorphine compared with the five different transdermal therapeutic systems described above, preferably the set of two to five different transdermal therapeutic systems is expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm.sup.2 to about 13.5 cm.sup.2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, providing an intermediate transdermal therapeutic system between the second and the third transdermal therapeutic system. Alternatively, one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by such a further transdermal therapeutic system.

(70) The invention relates also to set of different transdermal therapeutic, wherein:

(71) the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2.5 cm.sup.2 to about 4 cm.sup.2, or from about 2 cm.sup.2 to about 3 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 3 mg, or from about 2.5 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm.sup.2 to about 8 cm.sup.2, or from about 4.5 cm.sup.2 to about 6 cm.sup.2 and contains an amount of said buprenorphine from about 3.5 mg to about 6 mg, or from about 5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 10 cm.sup.2 to about 16 cm.sup.2, or from about 9 cm.sup.2 to about 11 cm.sup.2 and contains an amount of said buprenorphine from about 6.5 mg to about 11 mg, or from about 11 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 17 cm.sup.2 to about 23 cm.sup.2, or from about 14 cm.sup.2 to about 16 cm.sup.2 and contains an amount of said buprenorphine from about 11.5 mg to about 14 mg, or from about 17 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 23.5 cm.sup.2 to about 32 cm.sup.2, or from about 18 cm.sup.2 to about 21 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 24 mg, or from about 22 mg to about 25 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. The set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by one or more further transdermal therapeutic system(s) which may provide smaller, greater or intermediate areas of release and amounts of buprenorphine compared with the five different transdermal therapeutic systems described above, preferably the set of two to five different transdermal therapeutic systems is expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm.sup.2 to about 13.5 cm.sup.2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, providing an intermediate transdermal therapeutic system between the second and the third transdermal therapeutic system. Alternatively, one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by such a further transdermal therapeutic system.

(72) In a further aspect of the invention a transdermal therapeutic system selected from a set of transdermal therapeutic systems as described in the previous paragraphs is provided wherein buprenorphine is present in the form of buprenorphine base and wherein

(73) the first transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 6.25 cm.sup.2 and providing a nominal mean release rate of about 5 μg/hr over about 168 hours of administration,
the second transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 12.5 cm.sup.2 and providing a nominal mean release rate of about 10 μg/hr over about 168 hours of administration,
the third transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 25 cm.sup.2 and providing a nominal mean release rate of about 20 μg/hr over about 168 hours of administration,
the fourth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 37.5 cm.sup.2 and providing a nominal mean release rate of about 30 μg/hr over about 168 hours of administration,
the fifth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 50 cm.sup.2 and providing a nominal mean release rate of about 40 μg/hr over about 168 hours of administration,
the further transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 18.75 cm.sup.2 and providing a nominal mean release rate of about 15 μg/hr over about 168 hours of administration,
wherein the reference product is prepared by the following steps: 1. mixing of 1,139 g of a 47.83% polyacrylate solution of a self-crosslinked acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (solvent: ethyl acetate:heptanes:isopropanol:toluene:acetylacetonate in the ratio of 37:26:26:4:1), 100 g of levulinic acid, 150 g of oleyl oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate, and 100 g of buprenorphine base to provide a mixture; 2. stirring the mixture of step 1 for about 2 hours and controlling the dissolution of all solids visually whereas controlling the evaporation loss by reweighing and replenishing the possible solvent loss by ethyl acetate; 3. subsequently applying the mixture on a transparent polyester film in such a manner that the mass per unit area of the dry adhesive layer amounts to about 80 g/m.sup.2 wherein the polyester film is rendered removable by means of siliconization and serves as protective layer; 4. removing the solvents of the mixture applied on a transparent polyester film in step 3 by drying with heated air which is led over a moist lane resulting in evaporation of the solvents, but also in melting of the levulinic acid and covering the adhesive film with a polyester foil; 5. punching the area of release of 6.25 cm.sup.2, 12.5 cm.sup.2, 18.75 cm.sup.2, 25 cm.sup.2, 37.5 cm.sup.2 and 50 cm.sup.2, respectively, by means of suitable cutting tools and removing the edges left between the individual systems.

(74) According to one aspect, the invention relates to a transdermal therapeutic system described as first transdermal therapeutic system in the previous paragraphs wherein buprenorphine is present in the form of buprenorphine base and which is when tested in a comparative clinical study bioequivalent to the commercial product BuTrans®, also known as Norspan®, having an area of release of 6.25 cm.sup.2.

(75) According to one aspect, the invention relates to a transdermal therapeutic system described as second transdermal therapeutic system in the previous paragraphs wherein buprenorphine is present in the form of buprenorphine base and which is when tested in a comparative clinical study bioequivalent to the commercial product BuTrans®, also known as Norspan®, having an area of release of 12.5 cm.sup.2.

(76) According to one aspect, the invention relates to a transdermal therapeutic system described as third transdermal therapeutic system in the previous paragraphs wherein buprenorphine is present in the form of buprenorphine base and which is when tested in a comparative clinical study bioequivalent to the commercial product BuTrans®, also known as Norspan®, having an area of release of 25 cm.sup.2.

(77) According to one aspect, the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:

(78) a first transdermal therapeutic system providing a size of the area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2 and containing an amount of said buprenorphine from 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 μg/hr and/or providing a mean AUCt of more than 7,000 pg.Math.hr/ml, preferably more than 8,000 pg.Math.hr/ml, or of from more than 7,000 pg.Math.hr/ml to about 16,000 pg.Math.hr/ml, or of from more than 8,000 pg.Math.hr/ml to about 16,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population;
a second transdermal therapeutic system providing a size of the area of release ranging from about 3 cm.sup.2 to about 9.5 cm.sup.2 and containing an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 10 μg/hr and/or providing a mean AUCt of more than 14,000 pg.Math.hr/ml, preferably of more than 16,000 pg.Math.hr/ml, or of from more than 14,000 pg.Math.hr/ml to about 32,000 pg.Math.hr/ml, or of from more than 16,000 pg.Math.hr/ml to about 32,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a third transdermal therapeutic system providing a size of the area of release ranging from about 6 cm.sup.2 to about 19 cm.sup.2 and containing an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg.Math.hr/ml, preferably of more than 32,000 pg.Math.hr/ml, or of from more than 28,000 pg.Math.hr/ml to about 64,000 pg.Math.hr/ml, or of from more than 32,000 pg.Math.hr/ml to about 64,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system providing a size of the area of release ranging from about 12 cm.sup.2 to about 28.5 cm.sup.2 and containing an amount of said buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg.Math.hr/ml, preferably of more than 48,000 pg.Math.hr/ml, or of from more than 42,000 pg.Math.hr/ml to about 96,000 pg.Math.hr/ml, or of from more than 48,000 pg.Math.hr/ml to about 96,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system providing a size of the area of release ranging from about 16 cm.sup.2 to about 38 cm.sup.2 and containing an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg.Math.hr/ml, preferably of more than 64,000 pg.Math.hr/ml, or of from more than 62,000 pg.Math.hr/ml to about 128,000 pg.Math.hr/ml, or of from more than 64,000 pg.Math.hr/ml to about 128,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a further transdermal therapeutic system providing a size of the area of release ranging from about 5 cm.sup.2 to about 14 cm.sup.2 and containing an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 15 μg/hr and/or providing a mean AUCt of more than 22,000 pg.Math.hr/ml, preferably of more than 24,000 pg.Math.hr/ml, or of from more than 22,000 pg.Math.hr/ml to about 48,000 pg.Math.hr/ml, or of from more than 24,000 pg.Math.hr/ml to about 48,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population.

(79) According to one aspect, the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:

(80) a first transdermal therapeutic system providing a size of the area of release ranging from about 1 cm.sup.2 to about 4.5 cm.sup.2 and containing an amount of said buprenorphine from 1 mg to about 4 mg, or from 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 μg/hr and/or providing a mean AUCt of more than 7,000 pg.Math.hr/ml, preferably more than 8,000 pg.Math.hr/ml, or of from more than 7,000 pg.Math.hr/ml to about 16,000 pg.Math.hr/ml, or of from more than 8,000 pg.Math.hr/ml to about 16,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population;
a second transdermal therapeutic system providing a size of the area of release ranging from about 3 cm.sup.2 to about 9 cm.sup.2 and containing an amount of said buprenorphine from about 3.5 mg to about 8 mg, or from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 10 μg/hr and/or providing a mean AUCt of more than 14,000 pg.Math.hr/ml, preferably of more than 16,000 pg.Math.hr/ml, or of from more than 14,000 pg.Math.hr/ml to about 32,000 pg.Math.hr/ml, or of from more than 16,000 pg.Math.hr/ml to about 32,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a third transdermal therapeutic system providing a size of the area of release ranging from about 6 cm.sup.2 to about 18 cm.sup.2 and containing an amount of said buprenorphine from about 6.5 mg to about 16 mg, or from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg.Math.hr/ml, preferably of more than 32,000 pg.Math.hr/ml, or of from more than 28,000 pg.Math.hr/ml to about 64,000 pg.Math.hr/ml, or of from more than 32,000 pg.Math.hr/ml to about 64,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system providing a size of the area of release ranging from about 12 cm.sup.2 to about 27 cm.sup.2 and containing an amount of said buprenorphine from about 11.5 mg to about 24 mg, or from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg.Math.hr/ml, preferably of more than 48,000 pg.Math.hr/ml, or of from more than 42,000 pg.Math.hr/ml to about 96,000 pg.Math.hr/ml, or of from more than 48,000 pg.Math.hr/ml to about 96,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system providing a size of the area of release ranging from about 16 cm.sup.2 to about 35 cm.sup.2 and containing an amount of said buprenorphine from about 15 mg to about 32 mg, or from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg.Math.hr/ml, preferably of more than 64,000 pg.Math.hr/ml, or of from more than 62,000 pg.Math.hr/ml to about 128,000 pg.Math.hr/ml, or of from more than 64,000 pg.Math.hr/ml to about 128,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a further transdermal therapeutic system providing a size of the area of release ranging from about 5 cm.sup.2 to about 13.5 cm.sup.2 and containing an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 15 μg/hr and/or providing a mean AUCt of more than 22,000 pg.Math.hr/ml, preferably of more than 24,000 pg.Math.hr/ml, or of from more than 22,000 pg.Math.hr/ml to about 48,000 pg.Math.hr/ml, or of from more than 24,000 pg.Math.hr/ml to about 48,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population.

(81) According to one aspect, the invention relates a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:

(82) a first transdermal therapeutic system providing a size of the area of release ranging from about 2.5 cm.sup.2 to about 4 cm.sup.2 and containing an amount of said buprenorphine from 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 μg/hr and/or providing a mean AUCt of more than 7,000 pg.Math.hr/ml, preferably more than 8,000 pg.Math.hr/ml, or of from more than 7,000 pg.Math.hr/ml to about 16,000 pg.Math.hr/ml, or of from more than 8,000 pg.Math.hr/ml to about 16,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population;
a second transdermal therapeutic system providing a size of the area of release ranging from about 5 cm.sup.2 to about 8 cm.sup.2 and containing an amount of said buprenorphine from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 10 μg/hr and/or providing a mean AUCt of more than 14,000 pg.Math.hr/ml, preferably of more than 16,000 pg.Math.hr/ml, or of from more than 14,000 pg.Math.hr/ml to about 32,000 pg.Math.hr/ml, or of from more than 16,000 pg.Math.hr/ml to about 32,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a third transdermal therapeutic system providing a size of the area of release ranging from about 10 cm.sup.2 to about 16 cm.sup.2 and containing an amount of said buprenorphine from about 6.5 mg to about 11 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg.Math.hr/ml, preferably of more than 32,000 pg.Math.hr/ml, or of from more than 28,000 pg.Math.hr/ml to about 64,000 pg.Math.hr/ml, or of from more than 32,000 pg.Math.hr/ml to about 64,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system providing a size of the area of release ranging from about 17 cm.sup.2 to about 23 cm.sup.2 and containing an amount of said buprenorphine from about 11.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg.Math.hr/ml, preferably of more than 48,000 pg.Math.hr/ml, or of from more than 42,000 pg.Math.hr/ml to about 96,000 pg.Math.hr/ml, or of from more than 48,000 pg.Math.hr/ml to about 96,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system providing a size of the area of release ranging from about 23.5 cm.sup.2 to about 32 cm.sup.2 and containing an amount of said buprenorphine from about 15 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg.Math.hr/ml, preferably of more than 64,000 pg.Math.hr/ml, or of from more than 62,000 pg.Math.hr/ml to about 128,000 pg.Math.hr/ml, or of from more than 64,000 pg.Math.hr/ml to about 128,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a further transdermal therapeutic system providing a size of the area of release ranging from about 5 cm.sup.2 to about 13.5 cm.sup.2 and containing an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 15 μg/hr and/or providing a mean AUCt of more than 22,000 pg.Math.hr/ml, preferably of more than 24,000 pg.Math.hr/ml, or of from more than 22,000 pg.Math.hr/ml to about 48,000 pg.Math.hr/ml, or of from more than 24,000 pg.Math.hr/ml to about 48,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population.

Release Characteristic

(83) In accordance with the invention, the TTS is further characterized by the skin permeation rate determined by in vitro experiments carried out with the Franz diffusion cell (e.g., a 9 ml Franz diffusion cell), using human split thickness skin. Skin from cosmetic surgeries (female breast, date of birth 1989) can be used. A dermatone is used to prepare skin to a thickness of 800 μm, with an intact epidermis, in accordance with the OECD Guideline (adopted Apr. 13, 2004). Due to the prolonged test (168 hours) 800 μm skin is used instead of the recommended 200 to 400 μm skin. The receptor medium used is a phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent is used at a temperature of 32±1° Example formulations with an area of 1.163 cm.sup.2 are punched from laminates, and in the present examples are each tested against 1.163 cm.sup.2 samples of the commercial product Norspan®. The concentrations of buprenorphine in the acceptor medium of the Franz cell are measured.

(84) The TTS according to the invention provides a mean cumulative skin permeation rate of more than about 1.3 μg/cm.sup.2-hr, or more than about 1.5 μg/cm.sup.2-hr or more than about 1.7 μg/cm.sup.2-hr over a 168 hours test, or of more than about 2 μg/cm.sup.2-hr over a 168 hours test, or of more than about 2.5 μg/cm.sup.2-hr over a 168 hours test, or of more than 2.7 μg/cm.sup.2-hr over a 168 hours test, or of more than about 3 μg/cm.sup.2-hr over a 168 hours test, or from about 1.3 μg/cm.sup.2-hr to about 4 μg/cm.sup.2-hr, or from about 1.7 μg/cm.sup.2-hr to about 4 μg/cm.sup.2-hr, or from about 2 μg/cm.sup.2-hr to about 4 μg/cm.sup.2-hr, or from about 2.5 μg/cm.sup.2-hr to about 4 μg/cm.sup.2-hr, or from about 2.7 μg/cm.sup.2-hr to about 4 μg/cm.sup.2-hr, or from about 3 μg/cm.sup.2-hr to about 4 μg/cm.sup.2-hr, over a 168 hours test. The commercial product BuTrans® provides a mean cumulative skin permeation rate of about 1.7 μg/cm.sup.2-hr over a 168 hours test in said test.

(85) According to certain embodiments, the TTS provides a cumulative release as measured in a Franz diffusion cell as mentioned above of about 220 μg/cm.sup.2 to about 640 μg/cm.sup.2 over a time period of 168 hours, or of about 400 μg/cm.sup.2 to about 640 μg/cm.sup.2, or of about 450 μg/cm.sup.2 to about 640 μg/cm.sup.2, or of about 500 μg/cm.sup.2 to about 640 μg/cm.sup.2, or of about 600 μg/cm.sup.2 to about 640 μg/cm.sup.2 over a time period of 168 hours. The commercial product BuTrans® provides a cumulative release of about 250.7 μg/cm.sup.2 in said test. As can be seen from FIG. 13, comparable skin permeation rates are measured using the 25 cm.sup.2 BuTrans® TTS including 20 mg buprenorphine base and a TTS of an example in accordance with the invention with an area of 14 cm.sup.2 and including 12.6 mg buprenorphine base. This corresponds to about a 44% size reduction in area of release and a reduction of about 50% in the amount of used buprenorphine base.

(86) According to certain embodiments, the TTS provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell of

(87) 2 μg/cm.sup.2 to 10 μg/cm.sup.2 in the first 8 hours,

(88) 20 μg/cm.sup.2 to 80 μg/cm.sup.2 from hour 8 to hour 24,

(89) 20 μg/cm.sup.2 to 80 μg/cm.sup.2 from hour 24 to hour 32,

(90) 30 μg/cm.sup.2 to 120 μg/cm.sup.2 from hour 32 to hour 48,

(91) 40 μg/cm.sup.2 to 150 μg/cm.sup.2 from hour 48 to hour 72,

(92) 100 μg/cm.sup.2 to 300 μg/cm.sup.2 from hour 72 to hour 144, and

(93) 30 μg/cm.sup.2 to 100 μg/cm.sup.2 from hour 144 to hour 168.

(94) According to certain embodiments, the TTS provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell of

(95) 2 μg/cm.sup.2 to 6 μg/cm.sup.2 in the first 8 hours,

(96) 25 μg/cm.sup.2 to 60 μg/cm.sup.2 from hour 8 to hour 24,

(97) 25 μg/cm.sup.2 to 60 μg/cm.sup.2 from hour 24 to hour 32,

(98) 40 μg/cm.sup.2 to 100 μg/cm.sup.2 from hour 32 to hour 48,

(99) 50 μg/cm.sup.2 to 140 μg/cm.sup.2 from hour 48 to hour 72,

(100) 100 μg/cm.sup.2 to 280 μg/cm.sup.2 from hour 72 to hour 144, and

(101) 30 μg/cm.sup.2 to 100 μg/cm.sup.2 from hour 144 to hour 168.

(102) According to certain embodiments, the TTS provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell of

(103) 3 μg/cm.sup.2 to 6 μg/cm.sup.2 in the first 8 hours,

(104) 30 μg/cm.sup.2 to 50 μg/cm.sup.2 from hour 8 to hour 24,

(105) 30 μg/cm.sup.2 to 50 μg/cm.sup.2 from hour 24 to hour 32,

(106) 60 μg/cm.sup.2 to 90 μg/cm.sup.2 from hour 32 to hour 48,

(107) 100 μg/cm.sup.2 to 130 μg/cm.sup.2 from hour 48 to hour 72,

(108) 200 μg/cm.sup.2 to 280 μg/cm.sup.2 from hour 72 to hour 144, and

(109) 60 μg/cm.sup.2 to 100 μg/cm.sup.2 from hour 144 to hour 168.

(110) The commercial product BuTrans® provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell in the same setting of

(111) 2.1 μg/cm.sup.2 in the first 8 hours,

(112) 25.2 μg/cm.sup.2 from hour 8 to hour 24,

(113) 19.4 μg/cm.sup.2 from hour 24 to hour 32,

(114) 34.3 μg/cm.sup.2 from hour 32 to hour 48,

(115) 48.2 μg/cm.sup.2 from hour 48 to hour 72,

(116) 92.7 μg/cm.sup.2 from hour 72 to hour 144, and

(117) 28.5 μg/cm.sup.2 from hour 144 to hour 168.

Method of Treatment/Medical Use

(118) According to one aspect, the transdermal therapeutic system in accordance with the invention and as described above in detail is for use in a method of treating pain. The Method comprises in particular the application of the TTS for about 168 hours (corresponding to 7 days or one week) on the skin of a patient. According to other methods in accordance with the invention the TTS can be applied for more than about 96 hours corresponding to more than 4 days, or about 120 hours corresponding to 5 days and about 144 hours corresponding to 6 days. The application for about 168 hours is preferred.

(119) According to one aspect, the invention relates to a method of treatment wherein a set of five different transdermal therapeutic systems corresponding to different dosage strengths and corresponding different nominal mean release rates and/or mean release rates over about 168 hours of administration is used, wherein:

(120) the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1.5 cm.sup.2 to about 5.5 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 4.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm.sup.2 to about 9 cm.sup.2 and contains an amount of said buprenorphine from about 4 mg to about 9 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 8 to about 12 μg/hr or from about 9 to about 1 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm.sup.2 to about 14 cm.sup.2 and contains an amount of said buprenorphine from about 8 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 13 cm.sup.2 to about 17 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 20 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm.sup.2 to about 24 cm.sup.2 and contains an amount of said buprenorphine from about 20 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.

(121) The invention relates also to set of transdermal therapeutic systems, wherein:

(122) the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2 cm.sup.2 to about 4 cm.sup.2 and contains an amount of said buprenorphine from about 2 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 4.5 cm.sup.2 to about 7.5 cm.sup.2 and contains an amount of said buprenorphine from about 5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 8 cm.sup.2 to about 12 cm.sup.2 and contains an amount of said buprenorphine from about 10 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 13 cm.sup.2 to about 16 cm.sup.2 and contains an amount of said buprenorphine from about 16 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 17 cm.sup.2 to about 22 cm.sup.2 and contains an amount of said buprenorphine from about 21 mg to about 26 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.

(123) The invention relates also to set of different transdermal therapeutic, wherein:

(124) the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2 cm.sup.2 to about 3 cm.sup.2 and contains an amount of said buprenorphine from about 2.5 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 4.5 cm.sup.2 to about 6 cm.sup.2 and contains an amount of said buprenorphine from about 5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 9 cm.sup.2 to about 11 cm.sup.2 and contains an amount of said buprenorphine from about 11 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 14 cm.sup.2 to about 16 cm.sup.2 and contains an amount of said buprenorphine from about 17 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, or about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 18 cm.sup.2 to about 21 cm.sup.2 and contains an amount of said buprenorphine from about 22 mg to about 25 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.

(125) According to one aspect, the invention relates to a method of treating pain in a patient wherein said patient is treated with one appropriately selected TTS from a set of two (first and second, or second and third, or third and fourth, or fourth and fifth TTS, or any other combination of two of the five different dosage strengths), three (first to third, or second to fourth or third to fifth TTS, or any other combination of three of the five different dosage strengths), four (first to fourth or second to fifth TTS, or any other combination of four of the five different dosage strengths) or five (first to fifth TTS) different transdermal therapeutic systems corresponding to different dosage strengths and corresponding different nominal mean release rates and/or mean release rates over about 168 hours of administration is used, wherein:

(126) the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm.sup.2 to about 4.8 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm.sup.2 to about 9.5 cm.sup.2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 6 μg/hr, or of from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm.sup.2 to about 19 cm.sup.2 and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 11 μg/hr, or of from about 15 to about 25 μg/hr or at least about 16 μg/hr, or from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm.sup.2 to about 28.5 cm.sup.2 and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 21 μg/hr, or of from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm.sup.2 to about 38 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 31 μg/hr, or of from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration. The set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm.sup.2 to about 14 cm.sup.2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 11 μg/hr, or of from about 12 to about 18 μg/hr or from about 13.5 to about 16.5 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 15 μg/hr over about 168 hours of administration. Alternatively, one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by said transdermal therapeutic system.

(127) The invention relates also to a set of transdermal therapeutic systems, wherein:

(128) the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm.sup.2 to about 4.5 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg, or from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm.sup.2 to about 9 cm.sup.2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg, or from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 6 μg/hr, or of from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm.sup.2 to about 18 cm.sup.2 and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg, or from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 11 μg/hr, or of from about 15 to about 25 μg/hr or at least about 16 μg/hr, from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm.sup.2 to about 27 cm.sup.2 and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg, or from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 21 μg/hr, or of from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm.sup.2 to about 35 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 32 mg, or from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 31 μg/hr, or of from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration. The set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm.sup.2 to about 13.5 cm.sup.2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 11 μg/hr, or of from about 12 to about 18 μg/hr or from about 13.5 to about 16.5 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 15 μg/hr over about 168 hours of administration. Alternatively, one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by said transdermal therapeutic system. Alternatively, one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by said transdermal therapeutic system.

(129) The invention relates also to set of different transdermal therapeutic, wherein:

(130) the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2.5 cm.sup.2 to about 4 cm.sup.2 and contains an amount of said buprenorphine from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm.sup.2 to about 8 cm.sup.2 and contains an amount of said buprenorphine from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 6 μg/hr, or of from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 10 cm.sup.2 to about 16 cm.sup.2 and contains an amount of said buprenorphine from about 6.5 mg to about 11 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 11 μg/hr, or of from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 17 cm.sup.2 to about 23 cm.sup.2 and contains an amount of said buprenorphine from about 11.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 21 μg/hr, or of from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 23.5 cm.sup.2 to about 32 cm.sup.2 and contains an amount of said buprenorphine from about 15 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 31 μg/hr, or of from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.

(131) According to one aspect, the invention relates to a method of treating pain in a patient wherein a patient is treated with one appropriately selected TTS from a set of different transdermal therapeutic systems as described in the previous paragraphs, wherein:

(132) the first transdermal therapeutic system provides a mean AUCt of more than 7,000 pg.Math.hr/ml, preferably more than 8,000 pg.Math.hr/ml, or of from more than 7,000 pg.Math.hr/ml to about 16,000 pg.Math.hr/ml, or of from more than 8,000 pg.Math.hr/ml to about 16,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
the second transdermal therapeutic system provides a mean AUCt of more than 14,000 pg.Math.hr/ml, preferably of more than 16,000 pg.Math.hr/ml, or of from more than 14,000 pg.Math.hr/ml to about 32,000 pg.Math.hr/ml, or of from more than 16,000 pg.Math.hr/ml to about 32,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
the third transdermal therapeutic system provides a mean AUCt of more than 28,000 pg.Math.hr/ml, preferably of more than 32,000 pg.Math.hr/ml, or of from more than 28,000 pg.Math.hr/ml to about 64,000 pg.Math.hr/ml, or of from more than 32,000 pg.Math.hr/ml to about 64,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
the fourth transdermal therapeutic system provides a mean AUCt of more than 42,000 pg.Math.hr/ml, preferably of more than 48,000 pg.Math.hr/ml, or of from more than 42,000 pg.Math.hr/ml to about 96,000 pg.Math.hr/ml, or of from more than 48,000 pg.Math.hr/ml to about 96,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
the fifth transdermal therapeutic system provides a mean AUCt of more than 62,000 pg.Math.hr/ml, preferably of more than 64,000 pg.Math.hr/ml, or of from more than 62,000 pg.Math.hr/ml to about 128,000 pg.Math.hr/ml, or of from more than 64,000 pg.Math.hr/ml to about 128,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
the further transdermal therapeutic system provides a mean AUCt of more than 22,000 pg.Math.hr/ml, preferably of more than 24,000 pg.Math.hr/ml, or of from more than 22,000 pg.Math.hr/ml to about 48,000 pg.Math.hr/ml, or of from more than 24,000 pg.Math.hr/ml to about 48,000 pg.Math.hr/ml over about 168 hours of administration after a single-dose administration to a subject population.

(133) According to one aspect, the invention relates to a method of treatment described in the previous paragraphs, wherein the transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg.Math.hr/ml-cm.sup.2, or of more than 1,900 pg.Math.hr/ml-cm.sup.2, or of more than 2,300 pg.Math.hr/ml-cm.sup.2 over about 168 hours of administration after a single-dose administration to a subject population or provides a mean AUCt per area of release of from more than 1,700 pg.Math.hr/ml-cm.sup.2 to about 5,000 pg.Math.hr/ml-cm.sup.2, or of from more than 1,900 pg.Math.hr/ml-cm.sup.2 to about 5,000 pg.Math.hr/ml-cm.sup.2, or of from more than 2,300 pg.Math.hr/ml-cm.sup.2 to about 5,000 pg.Math.hr/ml-cm.sup.2 over about 168 hours of administration after a single-dose administration to a subject population.

(134) According to one aspect, the invention relates to a method of treatment described in the previous paragraphs, wherein the transdermal therapeutic system provides an arithmetic mean t max of from about 60 hr to about 120 hr, preferably from about 66 hr to less than 108 hr, or from about 72 hr to about 96 hr after a single-dose administration to a subject population.

Method of Manufacture

(135) According to one further aspect, the invention relates to a method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising the steps of

(136) 1. providing a buprenorphine-containing adhesive mixture comprising

(137) a) buprenorphine base or a pharmaceutically acceptable salt thereof b) a carboxylic acid (e.g., levulinic acid), c) a viscosity increasing agent (e.g. polyvinylpyrrolidon) c) a polymer-based pressure-sensitive adhesive, and d) solvent (e.g., heptane and ethanol)
2. storing said mixture between 0 hours and 6 days
3. homogenizing said buprenorphine-containing adhesive mixture at a homogenizing speed of e.g. at least 1000 rpm (e.g. with a BECOMIX RW 30 Ex);
4. storing said homogenized mixture between 0 hours and 6 days,
5. coating said homogenized buprenorphine-containing adhesive mixture on a film (e.g., polyethylene terephthalate film) in an amount to provide the desired dry weight using a roller coater in an amount to provide the desired coating dry weight,
6. drying said coated buprenorphine-containing adhesive mixture to provide a buprenorphine-containing adhesive layer with the desired coating dry weight,
7. optionally laminating said buprenorphine-containing adhesive layer to a backing layer (e.g., Scotchpak 1220 from 3M) to provide an buprenorphine-containing self-adhesive layer structure,
8. optionally punching the individual systems from the buprenorphine-containing self-adhesive layer structure with the desired area of release, and
9. optionally adhering to the individual systems an active-free self-adhesive layer structure comprising also a backing layer and an active agent-free pressure-sensitive adhesive layer and which is larger than the individual systems of buprenorphine-containing self-adhesive layer structure.

(138) In step 1 of said method of manufacture preferably buprenorphine base, levulinic acid and polyvinylpyrrolidone are used and are dissolved in ethanol and subsequently suspended in a polymer-based pressure-sensitive adhesive based on polysiloxane in heptane to provide the buprenorphine-containing adhesive mixture or emulsion.

(139) The homogenization provides homogeneous mixtures and helps to provide narrower deposit size distributions. In combination with a viscosity-increasing substance in the deposits the size and size distribution of the deposits remains during the time between homogenization and coating and during coating. In particular the process is suitable for a commercial production skale.

(140) Homogenization speeds of e.g. at least 1000 rpm can be applied with a homogenizer, e.g. with a rotor-stator homogenizer (e.g. BECOMIX RW 30 Ex). In certain embodiments of the invention the homogenization speed is from about 1500 rpm to about 3800 rpm, or from about 1500 rpm to about 3000 rpm. The preferred homogenization speed is about 2000 rpm.

EXAMPLES

(141) The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention.

Comparative Example 1

(142) The composition of the buprenorphine base-containing adhesive mixture is summarized in Table 1 below.

(143) TABLE-US-00006 TABLE 1 Ingredient (Trade Name) Amt/unit (g) Buprenorphine base 7.00 Levulinic acid 4.90 Ascorbyl palmitate 0.175 Ethanol 3.80 Polysiloxane adhesive in n-heptane 79.57 Solids content of 73% by weight (BIO-PSA 7-4201 from Dow Corning Healthcare) n-heptane 4.56 Total 100.01

(144) In a suitable vessel, 7.00 g of buprenorphine were dissolved in 4.90 g of levulinic acid, 3.80 g of Ethanol and 0.175 g of Ascobyl palmitate by stirring until the buprenorphine was completely dissolved forming the buprenorphine solution. 79.57 g of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 4.56 g of heptane were added. The mixture was stirred to give 100.01 g of a buprenorphine-containing adhesive mixture with 7% of buprenorphine, with a solids content of 70% (buprenorphine base-containing adhesive mixture).

(145) The buprenorphine base-containing adhesive mixture was coated within less than 24 h after the buprenorphine containing mixture was finished on a polyethylene terephthalate film (e.g. Scotchpak from 3M) using an Erichsen coater and the solvent was removed by drying at approximately 50° C. for approx. 8 minutes.

(146) The coating thickness was chosen such that removal of the solvents results in a coating weight of the matrix layer of approx. 120 g/m.sup.2. This results in the 10% by weight of buprenorphine base, and 7% by weight of levulinic acid in this matrix layer. The dried film was laminated with the backing layer (e.g. polyethylenterephthalate (PET) foil 19 μm) to provide the buprenorphine-containing self-adhesive layer structure.

(147) Microscopic pictures were taken of the matrix layer using a Nikon S/N 237789 Microscope. FIG. 1 shows a microscopic picture of the matrix layer of Example 1.

Comparative Example 2

(148) The composition of the buprenorphine base-containing adhesive mixture is summarized in Table 2 below.

(149) TABLE-US-00007 TABLE 2 Ingredient (Trade Name) Amt/unit (kg) Buprenorphine base 1.890 Levulinic acid 1.323 Ethanol 0.945 Polysiloxane adhesive in n-heptane 21.489 Solids content of 73% by weight (BIO-PSA 7-4201 from Dow Corning Healthcare) n-heptane 1.353 Total 27

(150) In a stainless steel vessel, 1.890 kg of buprenorphine were dissolved in 1.323 kg of levulinic acid and 0.945 kg of ethanol by stirring until the buprenorphine was completely dissolved. With stirring, 21.489 kg of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 1.353 kg of heptane were added. The mixture was stirred to give 27 kg of a buprenorphine-containing adhesive mixture with 7% of buprenorphine, with a solids content of 70% (buprenorphine base-containing adhesive mixture).

(151) Within 24 hours the buprenorphine base-containing adhesive mixture was coated on a polyethylene terephthalate film (e.g., Scotchpak from 3M) using a pilot plant roll coater including a drying tunnel, several drying sections, an unwinding and laminating station. The solvent was removed by drying at approximately 30-50° C. The matrix layer remained within the drying tunnel at approx. 8 minutes. The coating thickness was chosen such that removal of the solvents results in a coating weight of the matrix layer of 120 g/m.sup.2. This results in the 10% by weight of buprenorphine base and 7% by weight of levulinic acid in this matrix layer. The dried film was laminated with the backing layer (e.g: polyethylenterephthalate (PET) film 19 μm) to provide the buprenorphine-containing self-adhesive layer structure.

(152) The individual systems (TTS) were then punched from the buprenorphine-containing self-adhesive layer structure.

(153) In specific embodiments a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active ingredient and has a preferably beige colored backing layer (overtape). This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the buprenorphine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes). The overtape including the TTS are then punched out by only punching the overtape and sealed into pouches of the primary packaging material.

(154) Microscopic pictures were taken of the buprenorphine base-containing adhesive mixture and of the matrix layer using a Nikon S/N 237789 Microscope. FIG. 2A shows a microscopic picture of the buprenorphine base-containing adhesive mixture of Comparative Example 2 and FIG. 2B shows a microscopic picture of the matrix layer of Comparative Example 2.

Example 3

(155) The composition of the buprenorphine base-containing adhesive mixture is summarized in Table 3 below.

(156) TABLE-US-00008 TABLE 3 Ingredient (Trade Name) Amt/unit (g) Buprenorphine base 7.44 Levulinic acid 5.24 Ascorbyl palmitate 0.14 Polyvinylpyrrolidone (PVP) 1.88 Ethanol 10.77 Polysiloxane adhesive in n-heptane 82.47 Solids content of 73% by weight (BIO-PSA 7-4201 from Dow Corning Healthcare) n-heptane 1.73 Total 109.67

(157) In a suitable vessel, 37.86 g of polyvinylpyrrolidone and 113.57 g of ethanol were dissolved to form a 25% PVP pre-solution. The prescribed amount of the PVP pre-solution, Levulinic acid and Ascorbyl palmitate were suspended with stirring and afterwards the remaining part of Ethanol and the Buprenorphine was added to form a buprenorphine containing solution by stirring until a solution is formed. 82.50 g of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 1.74 g of heptane were added. The mixture was stirred to give 109.67 g of a buprenorphine-containing adhesive mixture with 6.8% of buprenorphine, with a solids content of 68% (buprenorphine base-containing adhesive mixture).

(158) The buprenorphine base-containing adhesive mixture was coated within less than 24 h after the buprenorphine containing mixture was finished on a polyethylene terephthalate film (e.g. Scotchpak from 3M) using an Erichsen coater and the solvent was removed by drying in a first step at room temperature for approximately 10 minutes, followed by a second drying step at approximately 60° C. for approx. 10 minutes.

(159) The coating thickness was chosen such that removal of the solvents results in a coating weight of the matrix layer of approx. 120 g/m.sup.2. This results in the 10% by weight of buprenorphine base, 7% by weight of levulinic acid and 2.5% by weight of polyvinylpyrrolidone in this matrix layer. The dried film was laminated with the backing layer (e.g. polyethylenterephthalate (PET) foil 19 μm) to provide the buprenorphine-containing self-adhesive layer structure.

(160) Microscopic pictures were taken of the buprenorphine base-containing adhesive mixture and the matrix layer using a Nikon S/N 237789 Microscope. FIG. 3 shows a microscopic picture of the matrix layer of Example 3. FIG. 3A shows a microscopic picture of the buprenorphine base-containing adhesive mixture of Example 3 and FIG. 3B shows a microscopic picture of the matrix layer of Example 3.

Example 4

(161) The composition of the buprenorphine base-containing adhesive mixture is summarized in Table 4 below.

(162) TABLE-US-00009 TABLE 4 Ingredient (Trade Name) Amt/unit (kg) Buprenorphine base 1.368 Levulinic acid 0.958 Polyvinylpyrrolidone (PVP) 0.342 Ascorbyl palmitate 0.027 Ethanol 1.938 Polysiloxane adhesive in n-heptane 15.048 Solids content of 73% by weight (BIO-PSA 7-4201 from Dow Corning Healthcare) n-heptane 0.319 Total 20

(163) In a 101 vessel, 1.00 kg of polyvinylpyrrolidone and 3.00 g of ethanol were dissolved to form a 25% PVP pre-solution. In a homogenizing/mixing vessel: Becomix Lab mixer RW 30 Ex, 1.368 kg of PVP pre-solution, 0.958 kg levulinic acid, 0.027 kg of Ascorbyl palmitate and the main part of 0.912 kg of Ethanol were suspended by stirring. The prescribed amount of buprenorphine was weighed and added to the homogenizing/mixing vessel followed by rinsing the weighing container used for buprenorphine with the remaining part of Ethanol. The mixture was kept under stirring for at least 1 h until a buprenorphine containing solution was formed. 15.048 kg of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 0.319 kg of n-heptane were added to the mixing/homogenizing vessel The mixture was stirred for at least 2 h until a buprenorphine-containing adhesive mixture with 6.8% of buprenorphine, with a solids content of 68% (buprenorphine base-containing adhesive mixture) was formed.

(164) Within 24 hours the buprenorphine base-containing adhesive mixture was coated on a polyethylene terephthalate foil (e.g. Scotchpak from 3M) using a pilot plant roll coater including a drying tunnel, several drying sections, an unwinding and laminating station. The solvent was removed by drying at approximately 30-50° C. The matrix layer remained within the drying tunnel at approx. 8 minutes. The coating thickness was chosen such that removal of the solvents results in a coating weight of the matrix layer of 120 g/m.sup.2. This results in the 10% by weight of buprenorphine base and 7% by weight of levulinic acid and 2.5% by weight of polyvinylpyrrolidone in this matrix layer. The dried film was laminated with the backing layer (e.g. polyethylenterephthalate (PET) foil 19 μm) to provide the buprenorphine-containing self-adhesive layer structure.

(165) The individual systems (TTS) were then punched from the buprenorphine-containing self-adhesive layer structure.

(166) In specific embodiments a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active ingredient and has a preferably beige colored backing layer (overtape). This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the buprenorphine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes.

(167) The overtape including the TTS are then punched out by only punching the overtape and sealed into pouches of the primary packaging material.

(168) Microscopic pictures were taken of the buprenorphine base-containing adhesive mixture and of the matrix layer using a Nikon S/N 237789 Microscope. FIG. 4A shows a microscopic picture of the buprenorphine base-containing adhesive mixture of Example 4 and FIG. 4B shows a microscopic picture of the matrix layer of Example 4.

Example 5

(169) The composition of the buprenorphine base-containing adhesive mixture and the process of manufacture was as described for Example 4. After the mixing step forming a buprenorphine containing mixture, the buprenorphine base-containing adhesive mixture was additionally homogenized at a homogenizing speed of 2000 rpm-2500 rpm before coated on a polyethylene terephthalate film (e.g. Scotchpak from 3M).

(170) In Example 5, films with two different coating weights of the matrix layer were prepared:

(171) TABLE-US-00010 TABLE 5 Coating weight of the Example 5 matrix layer [g/m.sup.2] Example 5.1 120 Example 5.2 90

Example 6

(172) The composition of the buprenorphine base-containing adhesive mixture is summarized in Table 6 below.

(173) TABLE-US-00011 TABLE 6 Ingredient (Trade Name) Amt/unit (kg) Buprenorphine base 1.432 Levulinic acid 1.002 Polyvinylpyrrolidone 0.179 Ascorbylacid palmitate 0.029 Ethanol 1.014 Polysiloxane adhesive in n-heptane 15.997 Solids content of 73% by weight (BIO-PSA 7-4201 from Dow Corning Healthcare) n-heptane 0.346 Total 20

(174) In a 101 vessel, 1.00 kg of polyvinylpyrrolidone and 3.00 g of ethanol were dissolved to form a 25% PVP pre-solution. In a homogenizing/mixing vessel: Becomix Lab mixer RW 30 Ex, 0.716 kg of PVP pre-solution, 1.002 kg levulinic acid, 0.029 kg of Ascorbyl palmitate and the main part of 0.478 kg of Ethanol were suspended by stirring. The prescribed amount of buprenorphine was weighed and added to the homogenizing/mixing vessel followed by rinsing the weighing container used for buprenorphine with the remaining part of Ethanol. The mixture was kept under stirring for at least 1 h until a buprenorphine containing solution was formed. 15.997 kg of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 0.346 kg of n-heptane were added to the mixing/homogenizing vessel The mixture was stirred for at least 2 h until a buprenorphine-containing adhesive mixture with 7.2% of buprenorphine, with a solids content of 72% (buprenorphine base-containing adhesive mixture) was formed.

(175) Within 24 hours the buprenorphine base-containing adhesive mixture was coated on a polyethylene terephthalate film (e.g. Scotchpak from 3M) using a pilot plant roll coater including a drying tunnel, several drying sections, an unwinding and laminating station. The solvent was removed by drying at approximately 30-50° C. The matrix layer remained within the drying tunnel at approx. 8 minutes. The coating thickness was chosen such that removal of the solvents results in a specific coating weight of 120 g/m.sup.2.

(176) This results in the 10% by weight of buprenorphine base, 7% by weight of levulinic acid and 1.25% by weight of polyvinylpyrrolidone in this matrix layer. The dried film was laminated with the backing layer (e.g polyethylenterephthalate (PET) foil 19 μm) to provide the buprenorphine-containing self-adhesive layer structure.

(177) The individual systems (TTS) were then punched from the buprenorphine-containing self-adhesive layer structure. In specific embodiments a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active ingredient and has a preferably skin-colored backing layer. This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the buprenorphine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes).

(178) The overtape including the TTS are then punched out by only punching the overtape and sealed into pouches of the primary packaging material.

Example 7

(179) The composition of the buprenorphine base-containing adhesive mixture and the process of manufacture was as described for Example 6. After the mixing step forming a buprenorphine containing mixture, the buprenorphine base-containing adhesive mixture was additionally homogenized at a homogenizing speed of 2000 rpm-2500 rpm before coated on a polyethylene terephthalate film (e.g. Scotchpak from 3M).

(180) In Example 7, films with two different coating weights of the matrix layer were prepared:

(181) TABLE-US-00012 TABLE 7 Coating weight of the Example 7 matrix layer [g/m.sup.2] Example 7.1 120 Example 7.2 90

Example 8

(182) The composition of the buprenorphine base-containing adhesive mixture and the process of manufacture was as described for Example 6. After the mixing step forming a buprenorphine containing mixture, the buprenorphine base-containing adhesive mixture was additionally homogenized at a homogenizing speed of 3500 rpm-4000 rpm before coated on a polyethylene terephthalate film (e.g. Scotchpak from 3M).

Example 9

(183) In Example 9 the in-vitro dissolution of Comparative Examples 1 and 2, and Examples 3 and 4 were determined using the rotating cylinder apparatus of the Ph Eur/USP. The back of the TTS is affixed to the cylinder element using double sided adhesive tape. Following removal of the release liner, the cylinder is lowered into the dissolution medium (600 ml, degassed 0.9% sodium chloride solution at 32° C.) and rotated at 50 rpm. At 0.5, 2, 8 (or 5) and 24 hours, 4 ml samples are removed and analyzed by a reverse phase HPLC method using a mobile phase of 55:45% v/v acetonitrile:0.05 M potassium dihydrogen phosphate (adjusted to pH 3.5) and UV detection at 220 nm. The results are shown in Table 8 and FIGS. 5 to 8.

(184) TABLE-US-00013 TABLE 8 In vitro dissolution [%] (SD) Comparative Comparative Elapsed Example 1 Example 2 Example 3 Example 4 time (hr) n = 6 n = 6 n = 6 n = 3 0 0 0 0 0 0.5 15 (0.5) 51 (13.3)  8 (0.5) 6 (0)  2 22 (1.0) 59 (13.5) 14 (0.8) 12 (0)   5 29 (1.2) — 22 (1.1) — 8 — — — 24 (2.4) 24 51 (1.0) 95 (8.8) 52 (1.6) 44 (1.3)

Example 10

(185) In Example 10, the in-vitro skin permeation rates of Comparative Examples 1 and 2 and Norspan® were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 9 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female breast, date of birth 1987) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all examples Comparative Examples 1 and 2 and the commercial product Norspan®. Diecuts with an area of 1.163 cm.sup.2 were punched from Comparative Examples 1 and 2, and were each tested against diecuts of the commercial product Norspan®. The concentrations of buprenorphine in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured. The results are shown in Tables 9.1 to 9.4 and FIG. 9.

(186) TABLE-US-00014 TABLE 9.1 Non-cumulative release [μg/cm.sup.2] n = 3 (SD) Elapsed Comparative Comparative time (hr) Example 1 Example 2 Norspan ® 0 0 0 0 8 1.29 (1.71)  0.48 (0.23) 0.75 (0.10) 24 19.85 (17.70) 10.75 (2.90) 7.05 (5.31) 32 16.32 (11.50) 11.27 (2.56) 7.63 (0.68) 48 35.88 (18.39) 31.67 (5.81) 15.63 (1.70)  72 58.22 (17.37) 69.03 (9.19) 23.73 (2.05)  144 155.33 (15.27)  154.67 (6.41)  56.80 (3.723) 168 50.88 (2.60)  33.28 (3.47) 18.67 (1.3) 

(187) TABLE-US-00015 TABLE 9.2 Mean non-cumulative skin permeation rate [μg/cm.sup.2-hr] n = 3 (SD) Elapsed Comparative Comparative time (hr) Example 1 Example 2 Norspan ® 0 0 0 0 8 0.16 (0.21) 0.06 (0.03) 0.09 (0.01) 24 1.24 (1.11) 0.67 (0.18) 0.44 (0.33) 32 2.04 (1.44) 1.41 (0.32) 0.95 (0.08) 48 2.24 (1.15) 1.98 (0.36) 0.98 (0.11) 72 2.43 (0.72) 2.88 (0.38) 0.99 (0.09) 144 2.16 (0.21) 2.15 (0.09) 0.79 (0.05) 168 2.12 (0.11) 1.39 (0.14) 0.78 (0.05)

(188) TABLE-US-00016 TABLE 9.3 Cumulative release after 168 hours of release [μg/cm.sup.2] n = 3 (SD) Comparative Comparative Example 1 Example 2 Norspan ® 337.83 (82.62) 311.17 (14.25) 130.33 (14.05)

(189) TABLE-US-00017 TABLE 9.4 Mean cumulative skin permeation rate over 168 hours taking into account a lag time of 24 hours [μg/cm.sup.2-hr] Comparative Comparative Example 1 Example 2 Norspan ® 2.3 2.2 0.9

Example 11

(190) In Example 11, the in-vitro skin permeation rates of Examples 5 to 8 and BuTrans® were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 9 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female sample of abdomen region, date of birth 1983) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all examples 5 to 8 and the commercial product BuTrans®. Diecuts with an area of 1.163 cm.sup.2 were punched from examples 5 to 8, and were each tested against diecuts of the commercial product BuTrans®. The concentrations of buprenorphine in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32±1° C. were measured. The results are shown in Tables 10.1 to 10.7 and FIGS. 10 to 13.

(191) TABLE-US-00018 TABLE 10.1 Non-cumulative release [μg/cm.sup.2] n = 3 (SD) Elapsed Example Example Example time (hr) 6.1 7.1 8.1 BuTrans ® 0 0 0 0 0 8  1.9 (0.2)  4.4 (1.3)  3.5 (0.6)  2.1 (0.8) 24 26.0 (3.4) 45.0 (6.3) 33.5 (2.1) 25.2 (6.8) 32 22.9 (3.5) 34.0 (1.6) 27.1 (1.3) 19.4 (3.7) 48 47.8 (4.6) 61.4 (1.1) 51.6 (2.3) 34.3 (4.2) 72 78.4 (4.6) 88.3 (2.6) 79.6 (4.9) 48.2 (2.8) 144 193.3 (13.1) 203.3 (9.9)  192.3 (11.0) 92.7 (3.3) 168 69.8 (3.2) 75.7 (2.4) 68.0 (1.6) 28.5 (0.7)

(192) TABLE-US-00019 TABLE 10.2 Non-cumulative release [μg/cm.sup.2] n = 3 (SD) Elapsed Example Example time (hr) 7.2 5.2 BuTrans ® 0 0 0 0 8  2.5 (0.7)  2.8 (0.8)  2.1 (0.8) 24 30.1 (4.8) 35.6 (4.6) 25.2 (6.8) 32 27.2 (3.0) 30.4 (3.9) 19.4 (3.7) 48 56.2 (3.3) 62.7 (9.1) 34.3 (4.2) 72 89.0 (0.9)  96.9 (12.3) 48.2 (2.8) 144 203.7 (12.0) 216.3 (15.6) 92.7 (3.3) 168 66.6 (8.5) 70.5 (5.7) 28.5 (0.7)

(193) TABLE-US-00020 TABLE 10.3 Mean non-cumulative skin permeation rate [μg/cm.sup.2-hr] n = 3 (SD) Elapsed Example Example Example time (hr) 6.1 7.1 8.1 BuTrans ® 0 0 0 0 0 8 0.2 (0.0) 0.5 (0.2) 0.4 (0.1) 0.3 (0.1) 24 1.6 (0.2) 2.8 (0.4) 2.1 (0.1) 1.6 (0.4) 32 2.9 (0.4) 4.2 (0.2) 3.4 (0.2) 2.4 (0.5) 48 3.0 (0.3) 3.8 (0.1) 3.2 (0.1) 2.1 (0.3) 72 3.3 (0.3) 3.7 (0.1) 3.3 (0.2) 2.0 (0.1) 144 2.7 (0.2) 2.8 (0.1) 2.7 (0.2) 1.3 (0.0) 168 2.9 (0.1) 3.2 (0.1) 2.8 (0.1) 1.2 (0.0)

(194) TABLE-US-00021 TABLE 10.4 Mean non-cumulative skin permeation rate [μg/cm.sup.2-hr] n = 3 (SD) Elapsed Example Example time (hr) 7.2 5.2 BuTrans ® 0 0 0 0 8 0.3 (0.1) 0.4 (0.1) 0.3 (0.1) 24 1.9 (0.3) 2.2 (0.3) 1.6 (0.4) 32 3.4 (0.4) 3.8 (0.5) 2.4 (0.5) 48 3.5 (0.2) 3.9 (0.6) 2.1 (0.3) 72 3.7 (0.0) 4.0 (0.5) 2.0 (0.1) 144 2.8 (0.2) 3.0 (0.2) 1.3 (0.0) 168 2.8 (0.4) 2.9 (0.2) 1.2 (0.0)

(195) TABLE-US-00022 TABLE 10.5 Mean non-cumulative skin permeation rate [μg/cm.sup.2-hr] n = 3 (SD) and per area of release [μg/hr] Elapsed Sample Area of BuTrans ® time interval release Example Area of release (hr) (hr) (cm.sup.2) 5.2 (25 cm.sup.2) 0 0 0  0  8 8 0.4 (0.1) 0.3 (0.1) 10  3.5  6.7 14  4.9  6.7 24 16 2.2 (0.3) 1.6 (0.4) 10 22.2 39.4 14 31.1 39.4 32 8 3.8 (0.5) 2.4 (0.5) 10 38.0 60.7 14 53.1 60.7 48 16 3.9 (0.6) 2.1 (0.3) 10 39.2 53.6 14 54.8 53.6 72 24 4.0 (0.5) 2.0 (0.1) 10 40.4 50.2 14 56.5 50.2 144 72 3.0 (0.2) 1.3 (0.0) 10 30.0 32.2 14 42.1 32.2 168 24 2.9 (0.2) 1.2 (0.0) 10 29.4 29.7 14 41.1 29.7

(196) TABLE-US-00023 TABLE 10.6 Cumulative release after 168 hours of release [μg/cm.sup.2] n = 3 (SD) Example 5.2 BuTrans ® 515.3 (44.1) 250.7 (17.1)

(197) TABLE-US-00024 TABLE 10.7 Mean cumulative skin permeation rate over 168 hours taking into account a lag time of 24 hours [μg/cm.sup.2-hr] Example 5.2 BuTrans ® 3.6 1.7