Transdermal pressure sensitive adhesive drug delivery system

• US 6,174,546 B1
• Filed: 05/01/2000
• Issued: 01/16/2001
• Est. Priority Date: 02/21/1997
• Status: Expired due to Fees

• Current Assignee: Adhesives Research Inc.
• Original Assignee: Adhesives Research Inc.
• Inventors: Therriault, Donald J., Stutzman, Barbara A., Zajaczkowski, Michael J.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Seidleck, Brian K.
• Application Number:
  US09/562,450
• Time in Patent Office: 260 Days
• Field of Search: 424/448, 424/449
• US Class Current: 424/448
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: C08F 290/04 Polymers provided for in subclasses C08C or C08F
• CPC Class Codes: C08F 290/044 Polymers of aromatic monomers as defined in group C08F12/00
• CPC Class Codes: C08F 290/046 Polymers of unsaturated carboxylic acids or derivatives thereof
• CPC Class Codes: C08L 51/00 Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds for ABS polymers C08L55/02; Compositions of derivatives of such polymers
• CPC Class Codes: C09J 151/00 Adhesives based on graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds based on ABS polymers C09J155/02; Adhesives based on derivatives of such polymers

Abstract

A transdermal drug delivery system is provided which includes an optionally crosslinked macromer-reinforced (meth)acrylic ester base copolymer pressure sensitive adhesive wherein the macromer includes repeat hydrophilic units.

Claims

1. A pressure sensitive adhesive drug delivery composition for use in the transdermal administration of a pharmacologically active agent comprised of a homogeneous admixture of a hydrophilic macromer reinforced copolymer and a pharmacologically active agent, said copolymer comprising the crosslinked reaction product of:

(1) at least one A monomer consisting of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol, said alcohol having from 1 to 30 carbon atoms, wherein at least about 30 percent by weight of said A monomer consists of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol having at least 12 carbon atoms, and said at least one A monomer exhibiting an average number of carbon atoms in the alcohol portion of the total (meth)acrylic acid esters of at least 10,

(2) optionally at least one B monomer,

(3) optionally a polymeric graft moiety C having a T_g greater than 20°

C., and

(4) a graft macromer D containing hydrophilic repeat units.

2. The composition of claim 1 wherein said graft moiety C is a polymerized monoalkenyl-substituted aromatic hydrocarbon.

3. The composition of claim 2 wherein said polymerized monoalkenyl-substituted aromatic hydrocarbon comprises polystyrene.

4. The composition of claim 1 wherein said at least one A monomer comprises an ester of (meth)acrylic acid with a non-tertiary alcohol selected from the group consisting of 1-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, 1-decanol, and 1-dodecanol.

5. The composition of claim 1 wherein the A monomer is present in the copolymer in an amount within the range of from about 20 to 80 percent by weight.

6. The composition of claim 1 wherein the B monomer is present in the copolymer in an amount within the range of from about 3 to 30 percent by weight.

7. The composition of claim 1 wherein the D macromer is present in the copolymer in an amount within the range of from about 5 to 60 percent by weight.

8. The composition of claim 1 wherein a B monomer is present selected from the group consisting of hydroxy(C_1-5)alkyl acrylates, hydroxy(C_1-5)alkyl methacrylates, dihydroxy(C_1-5)alkyl acrylates, dihydroxy(C_1-5)alkyl methacrylates and mixtures thereof.

9. The composition of claim 1 wherein said B monomer is selected from the group consisting of acrylamide, methacrylamide, N-methylacrylamide, N-ethylacrylamide, N-methylolacrylamide, N-hydroxyethylacrylamide, diacetone acrylamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, N-ethyl-N-aminoethyl acrylamide, N-ethyl-N-hydroxyethylacrylamide, N,N-dimethylolacrylamide, N,N-dihydroxyethylacrylamide and mixtures thereof.

10. The composition of claim 1 wherein said macromer D is defined by the formula X—

(Y)_p—

Z—

R, wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, Z is a homo- or copolymeric moiety containing hydrophilic repeat units, R is a terminal group, and p is 0 or 1.

11. The composition of claim 10 wherein Z is selected from the group consisting of a polyalkylene oxide radical, a polyethyloxazoline radical, a polyacrylic acid radical, a polyvinyl alcohol radical, a polyvinylpyrrolidone radical, a polyvinylcaprolactam radical and a polymethylvinyl ether radical.

12. The composition of claim 1 wherein said macromer D is defined by the formula:

13. The composition of claim 12 wherein said macromer D is defined by the formula

wherein R₁ is hydrogen or C_1-5 alkyl, R is a terminal group, and n is an integer from 5 to 30.

14. The composition of claim 1 wherein said A monomer comprises a monomeric (meth)acrylic acid ester of a non-tertiary alcohol which has from 12 to 18 carbon atoms.

15. The composition of claim 1 wherein said macromer D is selected from the group consisting of ethoxylated and propoxylated hydroxy (C_1-5 alkyl) (meth)acrylate, poly(2-ethyl-2-oxazoline), polyacrylic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl caprolactam and polymethylvinyl ether mono(meth)acrylate.

16. The composition of claim 1 wherein a B monomer is present comprising an N-vinyl lactam monomer selected from the group consisting of N-vinyl-2-pyrrolidone, 5-methyl-N-vinyl-2-pyrrolidone, 5-ethyl-N-vinyl-2-pyrrolidone, 3,3-dimethyl-N-vinyl-2-pyrrolidone, 3-methyl-N-vinyl-2-pyrrolidone, 3-ethyl-N-vinyl-2-pyrrolidone, 4-methyl-N-vinyl-2-pyrrolidone, 4-ethyl-N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam, N-vinyl-2-caprolactam, and mixtures thereof.

17. The composition of claim 1 wherein said copolymer comprises the reaction product of at least one A monomer, at least one N-vinyl lactam B monomer, at least one polymeric graft moiety C and a graft macromer D.

18. The composition of claim 1 or 17 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.

19. The composition of claim 1 wherein said macromer D is 2-carboxy(C_1-5)alkyl acrylate.

20. The composition of claim 1 wherein said macromer D is defined by the formula:

wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, R is a terminal group, m is an integer of from 2 to 6, n is an integer of up to 300, and p is 0 or 1.

21. The composition of claim 20 wherein said macromer D is defined by the formula:

wherein R₁ is hydrogen or C_1-5 alkyl, m is 2 or 3, n is 4 to 30, and R is H, OH, C_1-5 alkyl or nonyl-phenol.

22. The composition of claim 20 wherein R is OH, C_1-5 alkyl, or nonyl-phenol.

23. The composition of claim 20 wherein n is an integer of from 4 to 30.

71. The composition of any one of claims 1-9 wherein a percutaneous penetration enhancer is present in said admixture.

24. A transdermal delivery system for administering a pharmacologically active agent comprising a flexible backing material impermeable to said active agent and a pressure sensitive adhesive layer on at least a portion of said backing material for adhesion of said transdermal delivery system to the skin, said pressure sensitive adhesive being in homogeneous admixture with said active agent, said pressure sensitive adhesive comprising a crosslinked graft macromer reinforced copolymer formed by the reaction of:

(1) at least one A monomer consisting of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol, said alcohol having from 1 to 30 carbon atoms, wherein at least about 30 percent by weight of said A monomer consists of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol having at least 12 carbon atoms, and said at least one A monomer exhibiting an average number of carbon atoms in the alcohol portion of the total (meth)acrylic acid esters of at least 10,

(2) optionally at least one B monomer,

(3) optionally a polymeric graft moiety C having a T_g greater than 20°

C., and

(4) a graft macromer D containing hydrophilic repeat units.

25. The delivery system of claim 24 wherein said graft moiety C is a polymerized monoalkenyl-substituted aromatic hydrocarbon.

26. The delivery system of claim 25 wherein said polymerized monoalkenyl-substituted aromatic hydrocarbon comprises polystyrene.

27. The delivery system of claim 24 wherein said at least one A monomer comprises an ester of (meth)acrylic acid with a non-tertiary alcohol selected from the group consisting of 1-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-pentanol, 2-imethyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, 1-decanol, and 1-dodecanol.

28. The delivery system of claim 24 wherein the A monomer is present in the copolymer in an amount within the range of from about 20 to 80 percent by weight.

29. The delivery system of claim 24 wherein a B monomer is present in the copolymer in an amount within the range of from about 3 to 30 percent by weight.

30. The delivery system of claim 24 wherein the D macromer is present in the copolymer in an amount within the range of from about 5 to 60 percent by weight.

31. The delivery system of claim 24 wherein a B monomer is present selected from the group consisting of hydroxy(C_1-5)alkyl acrylates, hydroxy(C_1-5)alkyl methacrylates, dihydroxy(C_1-5)alkyl acrylates, dihydroxy(C_1-5)alkyl methacrylates and mixtures thereof.

32. The composition of claim 24 wherein said B monomer is selected from the group consisting of acrylamide, methacrylamide, N-methylacrylamide, N-ethylacrylamide, N-methylolacrylamide, N-hydroxyethylacrylamide, diacetone acrylamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, N-ethyl-N-aminoethyl acrylamide, N-ethyl-N-hydroxyethylacrylamide, N,N-dimethylolacrylamide, N,N-dihydroxyethylacrylamide and mixtures thereof.

33. The delivery system of claim 24 wherein said macromer D is defined by the formula X—

(Y)_p—

Z—

R, wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, Z is a homo- or copolymeric moiety containing hydrophilic repeat units, R is a terminal group, and p is 0 or 1.

34. The delivery system of claim 33 wherein Z is selected from the group consisting of a polyalkylene oxide radical, a polyethyloxazoline radical, a polyacrylic acid radical, a polyvinyl alcohol radical, a polyvinylpyrrolidone radical, a polyvinylcaprolactam radical and a polymethylvinyl ether radical.

35. The delivery system of claim 24 wherein said macromer D is defined by the formula:

36. The delivery system of claim 35 wherein said macromer D is defined by the formula

wherein R₁ is hydrogen or C_1-5 alkyl, R is a terminal group, and n is an integer from 5 to 30.

37. The delivery system of claim 24 wherein said A monomer comprises a monomeric (meth)acrylic acid ester of a non-tertiary alcohol which has from 12 to 18 carbon atoms.

38. The delivery system of claim 24 wherein said macromer D is selected from the group consisting of ethoxylated and propoxylated hydroxy (C_1-5 alkyl) (meth)acrylate, poly(2-ethyl-2-oxazoline), polyacrylic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl caprolactam and polymethylvinyl ether mono(meth)acrylate.

39. The delivery system of claim 24 wherein a B monomer is present comprising an N-vinyl lactam monomer selected from the group consisting of N-vinyl-2-pyrrolidone, 5-methyl-N-vinyl-2-pyrrolidone, 5-ethyl-N-vinyl-2-pyrrolidone, 3,3-dimethyl-N-vinyl-2-pyrrolidone, 3-methyl-N-vinyl-2-pyrrolidone, 3-ethyl-N-vinyl-2-pyrrolidone, 4-methyl-N-vinyl-2-pyrrolidone, 4-ethyl-N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam, N-vinyl-2-caprolactam, and mixtures thereof.

40. The delivery system of claim 24 wherein said copolymer comprises the reaction product of at least one A monomer, at least one N-vinyl lactam B monomer, at least one polymeric graft moiety C and a water-soluble or water-dispersible macromer D.

41. The delivery system of claim 24 or 40 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.

42. The delivery system of claim 24 wherein said macromer D is 2-carboxy(C_1-5)alkyl acrylate.

43. The delivery system of claim 24 wherein said macromer D is defined by the formula:

wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, R is a terminal group, m is an integer of from 2 to 6, n is an integer of up to 300, and p is 0 or 1.

44. The delivery system of claim 43 wherein said macromer D is defined by the formula:

wherein R₁ is hydrogen or C_1-5 alkyl, m is 2 or 3, n is 4 to 30, and R is H, OH, C_1-5 alkyl or nonyl-phenol.

45. The delivery system of claim 43 wherein R is OH, C_1-5 alkyl or nonyl-phenol.

46. The delivery system of claim 43 wherein n is an integer of from 4 to 30.

70. The delivery system of any one of claims 24-32 wherein a percutaneous penetration enhancer is present in said admixture.

47. In a transdermal delivery system for administering a pharmacologically active agent comprising a flexible backing material and a pressure sensitive adhesive layer for adhesion of said transdermal delivery system to the skin, said pharmacologically active agent being contained within either a reservoir attached to said backing material or within a matrix layer between said backing material and said pressure sensitive adhesive layer, the improvement wherein said pressure sensitive adhesive comprises an optionally crosslinked graft macromer reinforced copolymer formed by the reaction of:

(1) at least one A monomer consisting of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol, said alcohol having from 1 to 30 carbon atoms, wherein at least about 30 percent by weight of said A monomer consists of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol having at least 12 carbon atoms, and said at least one A monomer exhibiting an average number of carbon atoms in the alcohol portion of the total (meth)acrylic acid esters of at least 10,

(2) optionally at least one B monomer,

(3) optionally a polymeric graft moiety C having a T_g greater than 20°

C., and

(4) a graft macromer D containing hydrophilic repeat units.

48. The delivery system of claim 47 wherein said graft moiety C is a polymerized monoalkenyl-substituted aromatic hydrocarbon.

49. The delivery system of claim 48 wherein said polymerized monoalkenyl-substituted aromatic hydrocarbon comprises polystyrene.

50. The delivery system of claim 47 wherein said at least one A monomer comprises an ester of (meth)acrylic acid with a non-tertiary alcohol selected from the group consisting of 1-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, 1-decanol, and 1-dodecanol.

51. The delivery system of claim 47 wherein the A monomer is present in the copolymer in an amount within the range of from about 20 to 80 percent by weight.

52. The delivery system of claim 47 wherein a B monomer is present in the copolymer in an amount within the range of from about 3 to 30 percent by weight.

53. The delivery system of claim 47 wherein the D macromer is present in the copolymer in an amount within the range of from about 5 to 60 percent by weight.

54. The delivery system of claim 47 wherein a B monomer is present selected from the group consisting of hydroxy(C_1-5)alkyl acrylates, hydroxy(C_1-5)alkyl methacrylates, dihydroxy(C_1-5)alkyl acrylates, dihydroxy(C_1-5)alkyl methacrylates and mixtures thereof.

55. The composition of claim 47 wherein said B monomer is selected from the group consisting of acrylamide, methacrylamide, N-methylacrylamide, N-ethylacrylamide, N-methylolacrylamide, N-hydroxyethylacrylanide, diacetone acrylamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, N-ethyl-N-aminoethyl acrylamide, N-ethyl-N-hydroxyethylacrylamide, N,N-dimethylolacrylamide, N,N-dihydroxyethylacrylamide and mixtures thereof.

56. The delivery system of claim 47 wherein said macromer D is defined by the formula X—

(Y)_p—

Z—

R, wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, Z is a homo- or copolymeric moiety containing hydrophilic repeat units, R is a terminal group, and p is 0 or 1.

57. The delivery system of claim 56 wherein Z is selected from the group consisting of a polyalkylene oxide radical, a polyethyloxazoline radical, a polyacrylic acid radical, a polyvinyl alcohol radical, a polyvinylpyrrolidone radical, a polyvinylcaprolactam radical and a polymethylvinyl ether radical.

58. The delivery system of claim 47 wherein said macromer D is defined by the formula:

59. The delivery system of claim 58 wherein said macromer D is defined by the formula

wherein R₁ is hydrogen or C_1-5 alkyl, R is a terminal group, and n is an integer from 5 to 30.

60. The delivery system of claim 47 wherein said A monomer comprises a monomeric (meth)acrylic acid ester of a non-tertiary alcohol which has from 12 to 18 carbon atoms.

61. The delivery system of claim 47 wherein said macromer D is selected from the group consisting of ethoxylated and propoxylated hydroxy (C_1-5 alkyl) (meth)acrylate, poly(2-ethyl-2-oxazoline), polyacrylic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl caprolactam and polymethylvinyl ether mono(meth)acrylate.

62. The delivery system of claim 47 wherein a B monomer is present comprising an N-vinyl lactam monomer selected from the group consisting of N-vinyl-2-pyrrolidone, 5-methyl-N-vinyl-2-pyrrolidone, 5-ethyl-N-vinyl-2-pyrrolidone, 3,3-dimethyl-N-vinyl-2-pyrrolidone, 3-methyl-N-vinyl-2-pyrrolidone, 3-ethyl-N-vinyl-2-pyrrolidone, 4-methyl-N-vinyl-2-pyrrolidone, 4-ethyl-N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam, N-vinyl-2-caprolactam, and mixtures thereof.

63. The delivery system of claim 47 wherein said copolymer comprises the reaction product of at least one A monomer, at least one N-vinyl lactam B monomer, at least one polymeric graft moiety C and a water-soluble or water-dispersible macromer D.

64. The delivery system of claim 63 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.

65. The delivery system of claim 47 wherein said macromer D is 2-carboxy(C_1-5)alkyl acrylate.

66. The delivery system of claim 47 wherein said macromer D is defined by the formula:

wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, R is a terminal group, m is an integer of from 2 to 6, n is an integer of up to 300, and p is 0 or 1.

67. The delivery system of claim 66 wherein said macromer D is defined by the formula:

wherein R₁ is hydrogen or C_1-5 alkyl, m is 2 or 3, n is 4 to 30, and R is H, OH, C_1-5 alkyl or nonyl-phenol.

68. The delivery system of claim 66 wherein R is OH, C_1-5 alkyl or nonyl-phenol.

69. The delivery system of claim 66 wherein n is an integer of from 4 to 30.

72. The delivery system of any one of claims 47-55 wherein a percutaneous penetration enhancer is present in admixture with said pressure sensitive adhesive.

73. A pressure sensitive adhesive composition for use in the transdermal administration of a pharmacologically active agent comprised of an admixture of a hydrophilic macromer reinforced copolymer, a percutaneous penetration enhancer and a pharmacologically active agent, said copolymer comprising the reaction product of:

(1) at least one A monomer consisting of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol, said alcohol having from 1 to 30 carbon atoms, wherein at least about 30 percent by weight of said A monomer consists of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol having at least 12 carbon atoms, and said at least one A monomer exhibiting an average number of carbon atoms in the alcohol portion of the total (meth)acrylic acid esters of at least 10,

(2) optionally at least one B monomer,

(3) optionally a polymeric graft moiety C having a T_g greater than 20°

C., and

(4) a graft macromer D containing hydrophilic repeat units.

74. The composition of claim 73 wherein a polymeric graft moiety C is present.

75. The composition of claim 74 wherein a graft moiety C is present comprising a polymerized monoalkenyl-substituted aromatic hydrocarbon.

76. The composition of claim 74 wherein said polymerized monoalkenyl-substituted aromatic hydrocarbon comprises polystyrene.

77. The composition of claim 73 wherein said at least one A monomer comprises an ester of (meth)acrylic acid with a non-tertiary alcohol selected from the group consisting of 1-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, 1-decanol, and 1-dodecanol.

78. The composition of claim 73 wherein said A monomer comprises a (meth)acrylic acid ester of a non-tertiary alcohol which has from 12 to 18 carbon atoms.

79. The composition of claim 73 wherein the A monomer is present in the copolymer in an amount within the range of from about 20 to 80 percent by weight.

80. The composition of claim 73 wherein a B monomer is present in the copolymer in an amount within the range of from about 3 to 30 percent by weight.

81. The composition of claim 73 wherein the D macromer is present in the copolymer in an amount within the range of from about 5 to 60 percent by weight.

82. The composition of claim 73 wherein a B monomer is present selected from the group consisting of hydroxy(C_1-5)alkyl acrylates, hydroxy(C_1-5)alkyl methacrylates, dihydroxy(C_1-5)alkyl acrylates, dihydroxy(C_1-5)alkyl methacrylates and mixtures thereof.

83. The composition of claim 73 wherein a B monomer is present selected from the group consisting of acrylamide, methacrylamide, N-methylacrylamide, N-ethylacrylamide, N-methylolacrylamide, N-hydroxyethylacrylamide, diacetone acrylamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, N-ethyl-N-aminoethyl acrylamide, N-ethyl-N-hydroxyethylacrylamide, N,N-dimethylolacrylamide, N,N-dihydroxyethylacrylamide and mixtures thereof.

84. The composition of claim 73 wherein a B monomer is present comprising an N-vinyl lactam monomer selected from the group consisting of N-vinyl-2-pyrrolidone, 5-methyl-N-vinyl-2-pyrrolidone, 5-ethyl-N-vinyl-2-pyrrolidone, 3,3-dimethyl-N-vinyl-2-pyrrolidone, 3-methyl-N-vinyl-2-pyrrolidone, 3-ethyl-N-vinyl-2-pyrrolidone, 4-methyl-N-vinyl-2-pyrrolidone, 4-ethyl-N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam, N-vinyl-2-caprolactam, and mixtures thereof.

85. The composition of claim 73 wherein said macromer D is defined by the formula X—

(Y)_p—

Z—

R, wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, Z is a homo- or copolymeric moiety containing hydrophilic repeat units, R is a terminal group, and p is 0 or 1.

86. The composition of claim 85 wherein Z is selected from the group consisting of a polyalkylene oxide radical, a polyethyloxazoline radical, a polyacrylic acid radical, a polyvinyl alcohol radical, a polyvinylpyrrolidone radical, a polyvinylcaprolactam radical and a polymethylvinyl ether radical.

87. The composition of claim 85 wherein said macromer D is defined by the formula:

88. The composition of claim 85 wherein said macromer D is defined by the formula

wherein R₁ is hydrogen or C_1-5 alkyl, R is a terminal group, and n is an integer from 5 to 30.

89. The composition of claim 85 wherein said macromer D is defined by the formula:

wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, R is a terminal group, m is an integer of from 2 to 6, n is an integer of up to 300, and p is 0 or 1.

90. The composition of claim 73 wherein said copolymer comprises the reaction product of at least one A monomer, at least one N-vinyl lactam B monomer, at least one polymeric graft moiety C and a graft macromer D.

91. The composition of claim 85 wherein said copolymer comprises the reaction product of at least one A monomer, at least one N-vinyl lactam B monomer, at least one polymeric graft moiety C and a graft macromer D.

92. The composition of claim 73 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.

93. The composition of claim 90 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.

94. The composition of claim 91 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.

95. A transdermal delivery system for administering a pharmacologically active agent comprising a flexible backing material impermeable to said active agent and a pressure sensitive adhesive layer on at least a portion of said backing layer in admixture with a percutaneous penetration enhancer and a pharmacologically active agent, said pressure sensitive adhesive comprising a graft macromer reinforced copolymer formed by the reaction of:

(1) at least one A monomer consisting of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol, said alcohol having from 1 to 30 carbon atoms, wherein at least about 30 percent by weight of said A monomer consists of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol having at least 12 carbon atoms, and said at least one A monomer exhibiting an average number of carbon atoms in the alcohol portion of the total (meth)acrylic acid esters of at least 10,

(2) optionally at least one B monomer,

(3) optionally a polymeric graft moiety C having a T_g greater than 20°

C., and

(4) a graft macromer D containing hydrophilic repeat units.

96. The delivery system of claim 95 wherein a polymeric graft moiety C is present.

97. The delivery system of claim 95 wherein said graft moiety C is a polymerized monoalkenyl-substituted aromatic hydrocarbon.

98. The delivery system of claim 95 wherein said polymerized monoalkenyl-substituted aromatic hydrocarbon comprises polystyrene.

99. The delivery system of claim 95 wherein said at least one A monomer comprises an ester of (meth)acrylic acid with a non-tertiary alcohol selected from the group consisting of 1-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, 1-decanol, and 1-dodecanol.

100. The delivery system of claim 95 wherein said A monomer comprises a (meth)acrylic acid ester of a non-tertiary alcohol which has from 12 to 18 carbon atoms.

101. The delivery system of claim 95 wherein the A monomer is present in the copolymer in an amount within the range of from about 20 to 80 percent by weight.

102. The delivery system of claim 95 wherein a B monomer is present in the copolymer in an amount within the range of from about 3 to 30 percent by weight.

103. The delivery system of claim 95 wherein the D macromer is present in the copolymer in an amount within the range of from about 5 to 60 percent by weight.

104. The delivery system of claim 95 wherein a B monomer is present selected from the group consisting of hydroxy(C_1-5)alkyl acrylates, hydroxy(C_1-5)alkyl methacrylates, dihydroxy(C_1-5)alkyl acrylates, dihydroxy(C_1-5)alkyl methacrylates and mixtures thereof.

105. The composition of claim 95 wherein said B monomer is selected from the group consisting of acrylamide, methacrylamide, N-methylacrylamide, N-ethylacrylamide, N-methylolacrylamide, N-hydroxyethylacrylamide, diacetone acrylamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, N-ethyl-N-aminoethyl acrylamide, N-ethyl-N-hydroxyethylacrylamide, N,N-dimethylolacrylamide, N,N-dihydroxyethylacrylamide and mixtures thereof.

106. The delivery system of claim 95 wherein a B monomer is present comprising an N-vinyl lactam monomer selected from the group consisting of N-vinyl-2-pyrrolidone, 5-methyl-N-vinyl-2-pyrrolidone, 5-ethyl-N-vinyl-2-pyrrolidone, 3,3-dimethyl-N-vinyl-2-pyrrolidone, 3-methyl-N-vinyl-2-pyrrolidone, 3-ethyl-N-vinyl-2-pyrrolidone, 4-methyl-N-vinyl-2-pyrrolidone, 4-ethyl-N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam, N-vinyl-2-caprolactam, and mixtures thereof.

107. The delivery system of claim 95 wherein said macromer D is defined by the formula X—

(Y)_p—

Z—

R, wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, Z is a homo- or copolymeric moiety containing hydrophilic repeat units, R is a terminal group, and p is 0 or 1.

108. The delivery system of claim 107 wherein Z is selected from the group consisting of a polyalkylene oxide radical, a polyethyloxazoline radical, a polyacrylic acid radical, a polyvinyl alcohol radical, a polyvinylpyrrolidone radical, a polyvinylcaprolactam radical and a polymethylvinyl ether radical.

109. The delivery system of claim 107 wherein said macromer D is defined by the formula:

110. The delivery system of claim 109 wherein said macromer D is defined by the formula

wherein R₁ is hydrogen or C_1-5alkyl, R is a terminal group, and n is an integer from 5 to 30.

111. The delivery system of claim 107 wherein said macromer D is defined by the formula:

wherein X is a moiety copolymerizable with monomers A and B or capable of attachment to copolymerized monomers A and B, Y is a divalent linking group, R is a terminal group, m is an integer of from 2 to 6, n is an integer of up to 300, and p is 0 or 1.

112. The delivery system of claim 95 wherein said copolymer comprises the reaction product of at least one A monomer, at least one N-vinyl lactam B monomer, at least one polymeric graft moiety C and a water-soluble or water-dispersible macromer D.

113. The delivery system of claim 107 wherein said copolymer comprises the reaction product of at least one A monomer, at least one N-vinyl lactam B monomer, at least one polymeric graft moiety C and a water-soluble or water-dispersible macromer D.

114. The delivery system of claim 95 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.

115. The delivery system of claim 112 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.

116. The delivery system of claims 113 wherein said pharmacologically active agent is selected from the group consisting of estrogen, progestin and mixtures thereof.