Ultrasonic transdermal drug delivery system

• US 5,421,816 A
• Filed: 10/14/1992
• Issued: 06/06/1995
• Est. Priority Date: 10/14/1992
• Status: Expired due to Fees

• Current Assignee: Endodermic Medical Technologies Company
• Original Assignee: Endodermic Medical Technologies Company
• Inventors: Lipkovker, Lev M.
• Primary Examiner(s): Cohen, Lee S.
• Assistant Examiner(s): GILBERT, SAMUEL G
• Application Number:
  US07/961,113
• Time in Patent Office: 965 Days
• Field of Search: 128/633, 128/635, 128/736, 128/767, 128/24 AA, 128/804, 604/20, 604/22, 604/289, 604/290, 604/890.1, 604/892.1, 601/2, 607/154
• US Class Current: 604/20
• CPC Class Codes: A61M 2037/0007 having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
• CPC Class Codes: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis

Abstract

Ultrasonic energy is used to release a stored drug and forcibly move the drug through the skin of an organism into the blood stream. A housing (81) includes a cavity (67) defined by an assembly of ultrasonic transducers (65) and separated from the skin by a polymeric membrane (69) that stores the drug to be delivered. The ultrasonic transducer assembly includes a flat, circular ultrasonic transducer (85) that defines the top of a truncated cone and a plurality of transducer segments (87a, 87b, 87c, 87d . . . ) that define the walls of the cone. The resonant frequency of the planar transducer is lower than the resonant frequency of the transducer segments. The planar, flat, circular transducer generates fixed frequency (5 KHz-1 MHz range) ultrasonic stimuli impulses for a predetermined period of time (10-20 seconds). Between the stimuli pulse periods, the transducer segments receive variable frequency ultrasonic pumping pulses. Preferably, the variable frequency ultrasonic pumping pulses lie in the 50 MHz-300 MHz range. The variable frequency ultrasonic pumping pulses are applied to opposed transducer segments. The transducer segments create beams that impinge on the skin at an oblique angle and create a pulsating wave. Further, the variable frequency ultrasonic pumping pulses are applied to opposing transducer segments in a rotating manner to create pulsating waves in the skin in a variety of directions. The stimuli pulses cause the planar transducer to produce an ultrasonic wave that excites the local nerves in the way that trauma (heat, force) excites the local nerves. The nerve excitation opens the epidermal/dermal junction membrane and the capillary endothelial cell joints. The variable frequency ultrasonic pumping pulses cause the transducer segments to produce ultrasonic waves in both the polymeric membrane and the skin. The ultrasonic waves pump the drug first through the polymeric membrane and then through, skin openings into the underlying blood vessels.

Claims

1. An ultrasonic transdermal drug delivery system comprising:

(a) a housing;

(b) an ultrasonic transducer assembly mounted in said housing, said ultrasonic transducer assembly including a stimuli transducer and at least one drug delivery transducer, said stimuli and said at least one drug delivery transducer oriented so as to at least partially define a reservoir having an open side for storing a pharmaceutical to be delivered;

(c) a membrane whose porosity is controllable by ultrasonic waves positioned to close the open side of said reservoir;

(d) attachment means for attaching said transdermal drug delivery system to an organism having a skin such that said membrane faces said skin and separates said reservoir from said skin; and

(e) electronic control means coupled to said stimuli transducer and said at least one drug delivery transducer for causing said stimuli transducer to emit ultrasonic stimuli pulses having a frequency for a predetermined period of time and, subsequent to said predetermined period of time, causing said at least one drug delivery transducer to emit variable frequency ultrasonic pumping pulses that cause the pharmaceutical stored in said reservoir to be forcibly moved through said membrane to said skin and into said skin.

2. The ultrasonic transdermal drug delivery system claimed in claim 1, wherein said at least one drug delivery transducer is oriented such that said variable frequency ultrasonic pumping pulses intersect said skin at an oblique angle.

3. The ultrasonic transdermal drug delivery system claimed in claim 2 wherein the frequency of said ultrasonic stimuli pulses lie in a range of 5 KHz-1 MHz.

4. The ultrasonic transdermal drug delivery system claimed in claim 3 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

5. The ultrasonic transdermal drug delivery system claimed in claim 4 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

6. The ultrasonic transdermal drug delivery system claimed in claim 5 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

7. The ultrasonic transdermal drug delivery system claimed in claim 2 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

8. The ultrasonic transdermal drug delivery system claimed in claim 7 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

9. The ultrasonic transdermal drug delivery system claimed in claim 8 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

10. The ultrasonic transdermal drug delivery system claimed in claim 2, wherein said reservoir includes walls that define a truncated geometric shape and said ultrasonic drug delivery system includes a plurality of drug delivery transducer segments, said plurality of drug delivery transducer segments forming at least a part of the walls of said reservoir.

11. The ultrasonic transdermal drug delivery system claimed in claim 10, wherein said truncated geometric shape is a truncated cone, and wherein said stimuli transducer defines the small end of said truncated cone and said membrane closes the larger end of said truncated cone.

12. The ultrasonic transdermal drug delivery system claimed in claim 11 wherein the frequency of said ultrasonic stimuli pulses lie in a range of 5 KHz-1 MHz.

13. The ultrasonic transdermal drug delivery system claimed in claim 12 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

14. The ultrasonic transdermal drug delivery system claimed in claim 13 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

15. The ultrasonic transdermal drug delivery system claimed in claim 14 wherein variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

16. The ultrasonic transdermal drug delivery system claimed in claim 11 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

17. The ultrasonic transdermal drug delivery system claimed in claim 16 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

18. The ultrasonic transdermal drug delivery system claimed in claim 17 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

19. The ultrasonic transdermal drug delivery system claimed in claim 11 including a drug-impermeable laminate located between said reservoir and said stimuli transducer and said plurality of drug delivery transducer segments.

20. The transdermal drug delivery system claimed in claim 19, wherein said drug-impermeable laminate also functions as a focusing lens for said stimuli transducer and said plurality of drug delivery transducer segments.

21. The ultrasonic transdermal drug delivery system claimed in claim 20 wherein the frequency of said ultrasonic stimuli pulses lie in a range of 5 KHz-1 MHz.

22. The ultrasonic transdermal drug delivery system claimed in claim 21 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

23. The ultrasonic transdermal drug delivery system claimed in claim 22 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

24. The ultrasonic transdermal drug delivery system claimed in claim 23 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

25. The ultrasonic transdermal drug delivery system claimed in claim 20 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

26. The ultrasonic transdermal drug delivery system claimed in claim 25 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

27. The ultrasonic transdermal drug delivery system claimed in claim 26 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

28. The ultrasonic transdermal drug delivery system claimed in claim 20, wherein said plurality of drug delivery transducer segments total an even number, and wherein pairs of drug delivery transducer segments are positioned on opposite sides of said truncated cone.

29. The ultrasonic transdermal drug delivery system claimed in claim 28 wherein said pairs of drug delivery transducer segments positioned on opposite sides of said truncated cone are simultaneously energized to emit variable frequency ultrasonic pumping pulses.

30. The ultrasonic transdermal drug delivery system claimed in claim 29 wherein the frequency of said ultrasonic stimuli pulses lie in a range of 5 KHz-1 MHz.

31. The ultrasonic transdermal drug delivery system claimed in claim 30 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

32. The ultrasonic transdermal drug delivery system claimed in claim 31 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

33. The ultrasonic transdermal drug delivery system claimed in claim 32 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

34. The ultrasonic transdermal drug delivery system claimed in claim 29 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

35. The ultrasonic transdermal drug delivery system claimed in claim 34 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

36. The ultrasonic transdermal drug delivery system claimed in claim 35 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

37. The ultrasonic transdermal drug delivery system claimed in claim 29 wherein sequential pairs of opposed drug delivery transducer segments are simultaneously energized to emit variable frequency ultrasonic pumping pulses rotating about the central axis of said truncated cone.

38. The ultrasonic transdermal drug delivery system claimed in claim 37 wherein the frequency of said ultrasonic stimuli pulses lie in a range of 5 KHz-1 MHz.

39. The ultrasonic transdermal drug delivery system claimed in claim 38 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

40. The ultrasonic transdermal drug delivery system claimed in claim 39 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

41. The ultrasonic transdermal drug delivery system claimed in claim 40 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

42. The ultrasonic transdermal drug delivery system claimed in claim 37 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

43. The ultrasonic transdermal drug delivery system claimed in claim 42 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

44. The ultrasonic transdermal drug delivery system claimed in claim 43 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

45. The ultrasonic transdermal drug delivery system claimed in claim 2, 11, 20, 29 or 37 including an energy emitter mounted in said housing adjacent said transducer assembly, said energy emitter connected to said electronic control means, said electronic control means also controlling said energy emitter such that said energy emitter produces further stimuli pulses at predetermined intervals during the period of time said variable frequency ultrasonic pumping pulses are being produced by said drug delivery transducer segments.

46. The ultrasonic transdermal drug delivery system claimed in claim 45, wherein said energy emitter is an infrared (IR) emitter.

47. An ultrasonic transdermal drug delivery system as claimed in claim 45, wherein said energy emitter is a laser emitter.

48. The ultrasonic transdermal drug delivery system claimed in claim 45, including temperature sensing means, said temperature sensing means including a temperature sensing device positioned in said housing for sensing the temperature of the skin of said organism when said transdermal drug delivery system is attached by said attachment means to an organism having a skin, said temperature sensing device connected to said electronic control means for preventing said electronic control means from causing said stimuli transducer to emit ultrasonic stimuli pulses if the temperature sensed by said temperature sensing means exceeds a predetermined parameter.

49. The ultrasonic transdermal drug delivery system as claimed in claim 48, wherein said electronic control means is inhibited from energizing said energy emitter if the temperature sensed by said temperature sensing means exceeds predetermined parameter.

50. The ultrasonic transdermal drug delivery system claimed in claim 20, 29 or 37, wherein said drug delivery reservoir is part of a canister that also includes said membrane and said drug-impermeable laminate.

51. The ultrasonic transdermal drug delivery system as claimed in claims 2, 11, 20, 29 or 37, including a substance concentration sensor for withdrawing fluid from said organism and analyzing said fluid to determine the concentration of a particular component of said fluid, and wherein said electronic means controls the delivery of drugs based on said concentration determination.

52. The ultrasonic transdermal drug delivery system claimed in claim 51, wherein said substance concentration sensor includes:

(a) an ultrasonic sensor transducer for generating ultrasonic sensing pulses when energized;

(b) energizing means for energizing said ultrasonic sensor transducer;

(c) focusing means, including a cavity adjacent the skin of said organism when said transdermal drug delivery system is attached by said attachment means to an organism having skin, for focusing the ultrasonic sensing pulse is generated by said ultrasonic sensor transducer into said organism, said ultrasonic sensing pulses focused by said focusing means causing fluid to be withdrawn from said organism through said skin into said cavity;

(d) a substance sensing transducer mounted in said cavity for sensing a substance in said fluid; and

(e) analysis means coupled to said substance sensing transducer for determining the concentration of said substance sensed by said substance sensing transducer.

53. The ultrasonic transdermal drug delivery system claimed in claim 52, wherein said ultrasonic sensor transducer is planar and lies in a plane parallel to a surface of the skin of said organism.

54. The ultrasonic transdermal drug delivery system claimed in claim 53, wherein said focusing means is a plano-concave lens positioned such that the concave side of said lens faces the skin of said organism and said ultrasonic sensor transducer is located on the plano side of said plano-concave lens.

55. The ultrasonic transdermal drug delivery system claimed in claim 54, wherein said substance sensing transducer is an ISFET.

56. The ultrasonic transdermal drug delivery system claimed in claim 54, wherein said substance sensing transducer is a sandwich formed of a polyvinylidene fluoride film located between two layers of conductive material.

57. The ultrasonic transdermal drug delivery system claimed in claim 52, wherein said focusing lens is a plano-concave means positioned such that the concave side of said lens faces the skin of said organism and said transducer is located on the plano side of said plano-concave lens.

58. The ultrasonic transdermal drug delivery system claimed in claim 57 wherein the frequency of said ultrasonic stimuli pulses lie in a range of 5 KHz-1 MHz.

59. The ultrasonic transdermal drug delivery system claimed in claim 58 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

60. The ultrasonic transdermal drug delivery system claimed in claim 59 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

61. The ultrasonic transdermal drug delivery system claimed in claim 60 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-360 MHz range.

62. The ultrasonic transdermal drug delivery system claimed in claim 61 wherein the frequency of said ultrasonic sensing pulses lie in a range of 3 MHz-50 MHz.

63. The ultrasonic transdermal drug delivery system claimed in claim 57 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in a range of 50 MHz-300 MHz.

64. The ultrasonic transdermal drug delivery system claimed in claim 63 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

65. The ultrasonic transdermal drug delivery system claimed in claim 64 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

66. The ultrasonic transdermal drug delivery system claimed in claim 65 wherein the frequency of said ultrasonic sensing pulses lie in a range of 3 MHz-50 MHz.

67. A transdermal drug delivery method comprising the steps of:

(a) placing a reservoir containing a pharmaceutical on a region of the skin of an organism having a skin;

(b) applying ultrasonic stimuli pulses to said skin in the region where said reservoir is placed for a first predetermined period of time;

(c) applying variable frequency ultrasonic drug delivery pulses to said skin in said region where said reservoir is placed for a second predetermined period of time subsequent to said first predetermined period of time; and

(d) sequentially repeating the steps of applying ultrasonic stimuli pulses followed by the step of applying variable frequency ultrasonic drug delivery pulses to the skin of said organism.

68. The method claimed in claim 67, wherein said ultrasonic stimuli pulses are applied perpendicular to said skin.

69. The method claimed in claim 68, wherein said variable frequency ultrasonic drug delivery pulses are applied to said skin at an oblique angle.

70. The method claimed in claim 69, wherein a pair of variable frequency ultrasonic drug delivery pulses are simultaneously applied to said skin at oblique angles from opposed directions.

71. The method claimed in claim 70, wherein said pair of obliquely applied variable frequency ultrasonic drug delivery pulses are applied in a rotating manner about a common center.

72. The method claimed in claim 67, 68, 69, 70 or 71, wherein said ultrasonic stimuli pulses have a frequency in a range of 5 KHz-1 MHz.

73. The method claimed in Claim 72, wherein said variable frequency ultrasonic drug delivery pulses have a frequency in a range of 50 MHz-300 MHz.

74. The method claimed in claim 73 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

75. The method claimed in claim 74 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

76. The method claimed in claim 67, 68, 69, 70 or 71, wherein said variable frequency ultrasonic drug delivery pulses have a frequency in a range of 50 MHz-300 MHz.

77. The method claimed in claim 76 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

78. The method claimed in claim 77 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

79. The method claimed in claim 67, 68, 69, 70 or 71, including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

80. The method claimed in claim 79, wherein said ultrasonic stimuli pulses have a frequency in a range of 5 KHz-1 MHz.

81. The method claimed in claim 80, wherein said variable frequency ultrasonic drug delivery pulses have a frequency in a range of 50 MHz-300 MHz.

82. The method claimed in claim 81 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

83. The method claimed in claim 82 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

84. The method claimed in claim 83, wherein said further stimuli pulses are infrared energy pulses.

85. The method claimed in claim 83, wherein said further stimuli pulses are laser pulses.

86. The method claimed in claim 79, wherein said variable frequency ultrasonic drug delivery pulses have a frequency in a range of 50 MHz-300 MHz.

87. The method claimed in claim 86 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

88. The method claimed in claim 87 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

89. The method claimed in claim 88, wherein said further stimuli pulses are infrared energy pulses.

90. The method claimed in claim 88, wherein said further stimuli pulses are laser pulses.

91. The method claimed in claim 79 including the steps of detecting the temperature of the skin of said organism and terminating the application of said further stimuli pulses when the temperature of the skin of said organism exceeds a predetermined parameter.

92. The method claimed in claim 67, 68, 69, 70 or 71, including the steps of:

withdrawing fluid from said organism; and

using the results of said determination to control the application of said ultrasonic stimuli pulses and said ultrasonic drug delivery pulses to said organism.

93. The method claimed in claim 92, wherein said step of withdrawing fluid from said organism is performed in a noninvasive manner.

94. The method claimed in claim 93, wherein said ultrasonic stimuli pulses have a frequency in a range of 5 KHz-1 MHz.

95. The method claimed in claim 94, wherein said variable frequency ultrasonic drug delivery pulses have a frequency in a range of 50 MHz-300 MHz.

96. The method claimed in claim 95 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

97. The method claimed in claim 96 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

98. The method claimed in claim 97, including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

99. The method claimed in claim 98, wherein said further stimuli pulses are infrared energy pulses.

100. The method claimed in claim 98, wherein said further stimuli pulses are laser pulses.

101. The method claimed in claim 94, wherein said variable frequency ultrasonic drug delivery pulses have a frequency in a range of 50 MHz-300 MHz.

102. The method claimed in claim 101 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

103. The method claimed in claim 102 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

104. The method claimed in claim 103, including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

105. The method claimed in claim 104, wherein said further stimuli pulses are infrared energy pulses.

106. The method claimed in claim 104, wherein said further stimuli pulses are laser pulses.

107. The method claimed in claim 93, wherein said substep of withdrawing fluid from said organism comprises the substeps of creating a cavity above the skin of said organism and applying ultrasonic sensing pulses to the skin of said organism beneath said cavity.

108. The method claimed in claim 107, wherein said ultrasonic stimuli pulses have a frequency in a range of 5 KHz-1 MHz.

109. The method claimed in claim 108, wherein said variable frequency ultrasonic drug delivery pulses have a frequency in a range of 50 MHz-300 MHz.

110. The method claimed in claim 109, wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

111. The method claimed in claim 110, wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

112. The method claimed in claim 111, including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

113. The method claimed in claim 112, wherein said further stimuli pulses are infrared energy pulses.

114. The method claimed in claim 112, wherein said further stimuli pulses are laser pulses.

115. The method claimed in claim 107, wherein said variable frequency ultrasonic drug delivery pulses have a frequency in a range of 50 MHz-300 MHz.

116. The method claimed in claim 115, wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

117. The method claimed in claim 116, wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50 MHz-300 MHz range.

118. The method claimed in claim 117, including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

119. The method claimed in claim 118, wherein said further stimuli pulses are infrared energy pulses.

120. The method claimed in claim 118, wherein said further stimuli pulses are laser pulses.