Claims for Patent: 4,704,282

Summary for Patent: 4,704,282

Title:	Transdermal therapeutic system having improved delivery characteristics
Abstract:	A transdermal therapeutic system using a subsaturated matrix is provided having improved approved release characteristics. Reinforcing means preferably in the form of a fabric are embedded in the upper surface of the subsaturated matrix. At least a portion of the reinforcing means is selected such that the active agent to be delivered to the skin has a solubility, C.sub.r therein which is lower than the initial solubility C.sub.o of the agent in the matrix. In addition, the relationship between the diffusion coefficients of the agent in the matrix D.sub.m and the portion of reinforcing means D.sub.r and the solubilities is given by the relationship: D.sub.r .multidot.C.sub.r <D.sub.m .multidot.C.sub.o. In operation the agent dissolved in the reinforcing means acts as a secondary reservoir improving the release characteristics of the system. Specific embodiments of the invention are particularly adapted for scrotal and labial delivery of drugs such as testosterone and progesterone.
Inventor(s):	Campbell; Patricia S. (Palo Alto, CA), Eckenhoff; James B. (Los Altos, CA)
Assignee:	Alza Corporation (Palo Alto, CA)
Application Number:	06/626,095
Patent Claims:	1. A subsaturated transdermal therapeutic system having improved release characteristics comprising, in combination: (a) a matrix containing an active agent to be dispensed therefrom at an initial concentration, C.sub.o, no greater than the saturation concentration of the agent in the matrix; (b) reinforcing means within the matrix, at least a portion of said reinforcing means being a solvent for said agent, said portion of said reinforcing means having a solubility for said agent, C.sub.r, less than the initial concentration of the agent in the matrix and wherein the diffusion coefficient of said agent in said matrix is D.sub.m, the diffusion coefficient of said agent in the solvent portion of said reinforcing means is D.sub.r and the values of D.sub.m, D.sub.r, C.sub.o and C.sub.r are selected such that: 2. The transdermal therapeutic system of claim 1 wherein D.sub.r .multidot.C.sub.r is at least 10% less than D.sub.m .multidot.C.sub.o. 3. The transdermal therapeutic system of claim 2 wherein said reinforcing means comprises a fabric imbedded in the body distal portion of the system. 4. The transdermal therapeutic system of claim 3 wherein the overall thickness of said system is in the range of from about 2-10 mils. 5. A transdermal therapeutic system according to claim 1 particularly adapted for application to sensitive skin surfaces for an extended time period wherein said reinforcing means comprises fibrous means imbedded in the body distal surface of said matrix and said matrix is adherent to said sensitive skin surfaces with a peel strength sufficiently high to maintain said system in place for said extended time period and sufficiently low to be removed without discomfort. 6. The system of claim 5 wherein the peel strength of said material from skin is in the range of 1-20 gm/cm. 7. The system of claim 5 wherein the overall thickness of the system is in the range of 2-10 mils. 8. The system of claim 7 wherein said agent is selected from the group consisting of testosterone and progesterone and and said matrix comprises an ethylene/vinyl acetate copolymer containing from about 40 to 60% vinyl acetate and said system is from about 2-10 mils thick. 9. A method of transdermal administration of an agent which comprises applying a system according to claim 7 to the scrotum of a male subject or the labia of a female subject and maintaining said system in place for an extended period of time. 10. A method of transdermal administration of an agent which comprises applying a system according to claim 8 to the scrotum of a male subject or the labia of a female subject and maintaining said system in place for an extended period of time. 11. The transdermal therapeutic system of claim 1 wherein said reinforcing means comprise fibrous reinforcing means. 12. The transdermal therapeutic system of claim 11 wherein said fibrous reinforcing means are imbedded in the skin distal surface of said matrix. 13. The transdermal therapeutic system of claim 11 wherein the solvent portion of said reinforcing means is a coating on the fibers forming said reinforcing means. 14. The transdermal therapeutic system of claim 12 wherein the solvent portion of said reinforcing means is a coating on fibers forming said reinforcing means. 15. This system according to claim 8 wherein said agent is testosterone. 16. The system of claim 8 wherein said agent is progesterone. 17. The transdermal therapeutic system of claim 8 wherein said reinforcing means comprises fibrous reinforcing means. 18. The transdermal therapeutic system of claim 17 wherein said fibrous reinforcing means are imbedded in the skin distal surface of said matrix. 19. The transdermal therapeutic system of claim 18 wherein the solvent portion of said reinforcing means is a coating on the fibers forming said reinforcing means. 20. A transdermal therapeutic system particularly adapted for application to sensitive skin surfaces for an extended time period comprising, in combination: (a) a matrix containing an active agent to be dispensed therefrom at an initial concentration, C.sub.o, no greater than the saturation concentration of said agent in the matrix and having a diffusion coefficient of said agent in said matrix, D.sub.m ; (b) fibrous reinforcing means imbedded in the body distal surface of said matrix, at least the exterior portion of said fibrous reinforcing means being a solvent for said agent having a solubility for said agent, C.sub.r, less than C.sub.o, and having a diffusion coefficient for said agent in said portion, D.sub.r ; (c) said agent, matrix and exterior portion of said fibrous reinforcing means are selected such that: and (d) said matrix being adherent to said sensitive skin surface with a peel strength sufficiently high to allow said system to remain in place for said extended time period and sufficiently low to the removed without discomfort. 21. The transdermal therapeutic system of claim 20 wherein D.sub.r .multidot.C.sub.r is at least 10% less than D.sub.m .multidot.C.sub.o. 22. The transdermal therpeutic system of claim 20 wherein the overall thickness of said system is in the range of 2-10 mils. 23. The transdermal therapeutic system of claim 20 wherein said matrix is selected from the group consisting of ethylene/vinyl acetate copolymer, natural rubbers, synthetic rubbers, and low density polyethylene. 24. The transdermal therapeutic system for claim 21 wherein said exterior portion of said reinforcing means is selected form the group consisting of polyolefins and polyarylamides. 25. The transdermal therapeutic system of claim 22 wherein said agent is selected from the group consisting of progesterone, testosterone and hydrocortisone. 26. The transdermal therapeutic system of claim 23 wherein said matrix is selected from the group consisting of ethylene/vinyl acetate copolymers and styrene-butadiene block copolymers, said exterior portion of said reinforcing means is selected from the group consisting of polyolefins and polyarylamides. 27. The transdermal therapeutic system of claim 26 wherein said agent is selected from the group consisting of progesterone, testosterone and hydrocortisone. 28. The transdermal therapeutic system of claim 26 wherein said matrix is an ethylene/vinyl acetate copolymer and said exterior portion of said reinforcing means is polyethylene. 29. The transdermal therapeutic system of claim 26 wherein said matrix is a styrene-butadiene block copolymer and said exterior portion of said reinforcing means is a polyarylamide. 30. The transdermal therapeutic system of claim 27 wherein said matrix is an ethylene/vinyl acetate copolymer and said exterior portion of said reinforcing means is polyethylene. 31. The transdermal therapeutic system of claim 27 wherein said matrix is a styrene-butadiene block copolymer and said exterior portion of said reinforcing means is a polyarylamide. 32. The transdermal therapeutic system claim 30 wherein said agent is progesterone. 33. The transdermal therapeutic system of claim 30 wherein said agent is testosterone. 34. The transdermal therapeutic system of claim 31 wherein said agent is hydrocortisone. 35. The transdermal therapeutic system of claim 8 wherein said agent is testosterone. 36. The transdermal therapeutic system of claim 1 wherein said agent is testosterone. 37. A method for testosterone replacement in hypogonadic males which comprises applying the system of claim 35 to the scrotum of a hypogonadic male and maintaining said system in testosterone transfering relationship to said scrotum for at least about 8 hours. 38. A method for testosterone replacement in hypogonadic males which comprises applying the system of claim 36 to the scrotum of a hypogonadic male and maintaining said system in testosterone transfering relationship to said scrotum for at least about 8 hours. 39. The method of claim 37 wherein said system is maintained in place for about 24 hours and is replaced with a fresh system upon removal whereby continuous testosterone replacement is obtained. 40. The method of claim 38 wherein said system is maintained in place for about 24 hours and is replaced with a fresh system upon removal whereby continuous testosterone replacement is obtained. 41. The system of claim 20 wherein said agent is testosterone and said matrix is an ethylene/vinyl acetate copolymer having from about 40%-60% vanyl acetate. 42. A method for testosterone replacement in hypogonadic males which comprises applying the system of claim 41 to the scrotum of a hypogonadic male and maintaining said system in testosterone transfering relationship to said scrotum for at least about 8 hours. 43. The method of claim 42 wherein said system is maintained in place for about 24 hours and is replaced with a fresh system upon removal whereby continuous testosterone replacement is obtained.