WO1994008655B1 - Ultrasonic transdermal drug delivery system - Google Patents

Ultrasonic transdermal drug delivery system

Info

Publication number
WO1994008655B1
WO1994008655B1 PCT/US1993/009798 US9309798W WO9408655B1 WO 1994008655 B1 WO1994008655 B1 WO 1994008655B1 US 9309798 W US9309798 W US 9309798W WO 9408655 B1 WO9408655 B1 WO 9408655B1
Authority
WO
WIPO (PCT)
Prior art keywords
ultrasonic
pulses
drug delivery
delivery system
variable frequency
Prior art date
Application number
PCT/US1993/009798
Other languages
French (fr)
Other versions
WO1994008655A3 (en
WO1994008655A2 (en
Filing date
Publication date
Priority claimed from US07/961,113 external-priority patent/US5421816A/en
Application filed filed Critical
Priority to EP93923872A priority Critical patent/EP0684856A1/en
Priority to AU53591/94A priority patent/AU678781B2/en
Priority to JP6510246A priority patent/JPH08502424A/en
Publication of WO1994008655A2 publication Critical patent/WO1994008655A2/en
Publication of WO1994008655A3 publication Critical patent/WO1994008655A3/en
Publication of WO1994008655B1 publication Critical patent/WO1994008655B1/en
Priority to KR1019950701445A priority patent/KR950703383A/en

Links

Abstract

A transdermal drug delivery system that uses ultrasonic energy to release a stored drug and forcibly move the drug through the skin of an organism into the blood stream of the organism is disclosed. The transdermal drug delivery system includes a housing (81) having a cavity (67) for storing the drug to be delivered. The cavity is defined by an assembly of ultrasonic transducers (65) and is separated from the skin by a polymeric membrane (69). 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. Located between the transducer assembly and the cavity is a drug-impermeable laminate (77) that also functions as a focusing lens for the transducers. Control electronics (63) and a power source (61) are also stored in the housing. In operation, the planar, flat, circular transducer generates fixed frequency (5KHz-1MHz 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. The transducer segments create beams that impinge on the skin at an oblique angle and create a pulsating wave. A skin temperature sensor is included to prevent the ultrasonic signals from overheating the skin. The system may also include an infrared (IR) or laser transducer for enhancing the operation of the drug delivery system by heating the skin and creating additional ultrasonic waves. Both open loop and closed loop (feedback) versions are provided. The closed loop version includes a sensor for sensing drug delivery effectiveness and using the resulting information to control the rate of drug delivery. The sensor uses ultrasonic energy to remove fluid from the skin for analysis.

Claims

94/08655 AMENDED CLAIMS PCT/US93/09798[received by the International Bureau on 11 August 1994 (11.08.94); original claims 1, 4, 6, 7, 9, 10, 13, 15, 16, 18, 22, 24, 25, 27-29, 31, 33, 34, 36, 37, 39,41, 42, 44, 45, 48-50, 52, 59, 61-63, 65, 66, 77-82, 85, 86, 88, 91, 93, 96, 98101 , 104, 105, 107, 111, 113, 119, 121, 125 and 127 amended; remaining claims unchanged (15 pages)]The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
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 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 a 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 the 5KHz-lMHz range.
4. The ultrasonic transdermal drug delivery system claimed in Claim 3 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in the 50MHz-300MHz range.
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 50MHz-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 the 50MHz-300MHz range.
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 50MHz-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 the 5KHz-lMHz range.
13. The ultrasonic transdermal drug delivery system claimed in Claim 12 wherein the frequency of said variable frequency ultrasonic pumping pulses he in the 50MHz-300MHz range.
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 50MHz-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 the 50MHz-300MHz range.
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 50MHz-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 the 5KHz-lMHz range.
22. The ultrasonic transdermal drug delivery system claimed in Claim 21 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in the 50MHz-300MHz range.
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 50MHz-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 the 50MHz-300MHz range.
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 50MHz-300MHz range.
28. The ultrasonic transdermal drug delivery system claimed in Claim 20, wherein the number of said plurality of drug delivery transducers is 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 the 5KHz-lMHz range.
31. The ultrasonic transdermal drug delivery system claimed in Claim 30 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in the 50MHz-300MHz range.
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 50MHz-300MHz range.
34. The ultrasonic transdermal drug delivery system claimed in Claim 29 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in the 50MHz-300MHz range.
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 50MHz-300MHz 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 the 5KHz-lMHz range.
39. The ultrasonic transdermal drug delivery system claimed in Claim 38 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in the 50MHz-300MHz range.
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 50MHz-300MHz range.
42. The ultrasonic transdermal drug delivery system claimed in Claim 37 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in the 50MHz-300MHz range.
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 50MHz-300MHz 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 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 means for preventing said electronic 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 a 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 membrane.
51. The ultrasonic transdermal drug delivery system as claimed in Claims 2, 11, 20, 92 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 a skin, for focusing the ultrasonic sensing pulses 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 the surface of the skin of said organism.
54. The ultrasonic transdermal drug delivery system claimed in Claim 53 wherein said focusing lens 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 piano 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 lens positioned such that the concave side of said lens faces the skin of said organism and said transducer is located on the piano 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 the 5KHz-lMHz range.
59. The ultrasonic transdermal drug delivery system claimed in Claim 58 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in the 50MHz-300MHz range.
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 50MHz-300MHz range.
62. The ultrasonic transdermal drug delivery system claimed in Claim 61 wherein the frequency of said ultrasonic sensing pulses lie in the 3MHz-50MHz range.
63. The ultrasonic transdermal drug delivery system claimed in Claim 57 wherein the frequency of said variable frequency ultrasonic pumping pulses lie in the 50MHz-300MHz range.
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 50MHz-300MHz range.
66. The ultrasonic transdermal drug delivery system claimed in Claim 65 wherein the frequency of said ultrasonic sensing pulses lie in the 3MHz-50MHz range.
67. A noninvasive apparatus for withdrawing fluid from an organism and determining the concentration of a substance in the fluid, said noninvasive apparatus comprising:
(a) a container;
(b) attachment means for attaching said container to the skin of an organism;
(c) an ultrasonic transducer positioned in said container for generating ultrasonic energy when energized;
(d) energizing means for energizing said ultrasonic transducer;
(e) focusing means, including a cavity adjacent the skin of an organism when said container is attached to the skin of an organism, for focusing the ultrasonic energy generated by said ultrasonic transducer into said organism, said ultrasonic energy focused by said focusing means causing fluid to be withdrawn from said organism through said skin into said cavity;
(f) a substance sensing transducer mounted in said cavity for sensing a substance in said fluid; and
(g) analysis means coupled to said substance sensing transducer for determining the concentration of said substance sensed by said substance sensing transducer.
68. The noninvasive apparatus claimed in Claim 67 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.
69. The noninvasive apparatus claimed in Claim 67, wherein said ultrasonic transducer is planar and lies in a plane parallel to the surface of the skin of said organism when said container is attached to the skin of an organism.
70. The noninvasive apparatus claimed in Claim 69 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.
71. The noninvasive apparatus claimed in Claim 69, wherein said focusing lens is a plano-concave lens positioned such that the concave side of said lens faces said skin of an organism when said container is attached to the skin of an organism and said ultrasonic transducer is located on the piano side of said plano-concave lens.
72. The noninvasive apparatus claimed in Claim 71 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.
73. The noninvasive apparatus claimed in Claim 67, 69 or 71, wherein said substance sensing transducer is an ISFET.
74. The noninvasive apparatus claimed in Claim 73 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.
75. The noninvasive apparatus claimed in Claim 67, 69 or 71, wherein said substance sensing transducer is a sandwich formed of a polyvinylidene fluoride film located between two layers of conductive material.
76. The noninvasive apparatus claimed in Claim 74 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.
77. A transdermal drug delivery method comprising the steps of:
(a) placing a reservoir containing a pharmaceutical on 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.
78. The method claimed in Claim 77, wherein said ultrasonic stimuli pulses are applied perpendicular to said skin.
79. The method claimed in Claim 78, wherein said variable frequency ultrasonic drug delivery pulses are applied to said skin at an oblique angle.
80. The method claimed in Claim 79, wherein a pair of variable frequency ultrasonic drug delivery pulses are simultaneously applied to said skin at oblique angles from opposed directions.
81. The method claimed in Claim 80, wherein said pair of obliquely applied variable frequency ultrasonic drug delivery pulses are applied in a rotating manner about a common center.
82. The method claimed in Claim 77, 78, 79, 80 or 81, wherein said ultrasonic stimuli pulses have a frequency falling in the frequency range of 5KHz-lMHz.
83. The method claimed in Claim 82, wherein said variable frequency ultrasonic drug delivery pulses fall in the frequency range of 50MHz-300MHz.
84. The method claimed in Claim 83 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.
85. The method claimed in Claim 84 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.
86. The method claimed in Claim 77, 78, 79, 80 or 81, wherein the frequency of said variable frequency ultrasonic drug delivery pulses fall in the frequency range of 50MHz-300MHz.
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 50MHz-300MHz range.
89. The method claimed in Claim 77, 78, 79, 80 or 81, 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.
90. The method claimed in Claim 89, wherein said ultrasonic stimuli pulses have a frequency falling in the range of 5KHz-lMHz.
91. The method claimed in Claim 90, wherein the frequency of said variable frequency ultrasonic drug delivery pulses fall in the frequency range of 50MHz-300MHz.
92. The method claimed in Claim 91 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.
93. The method claimed in Claim 92 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.
94. The method claimed in Claim 93, wherein said additional stimuli pulses are infrared energy pulses.
95. The method claimed in Claim 93, wherein said additional stimuli pulses are laser pulses.
96. The method claimed in Claim 89, wherein the frequency of said variable frequency ultrasonic drug delivery pulses fall in the frequency range of 50MHz-300MHz.
97. The method claimed in Claim 96 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.
98. The method claimed in Claim 97 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.
99. The method claimed in Claim 98, wherein said additional stimuli pulses are infrared energy pulses.
100. The method claimed in Claim 98, wherein said additional stimuli pulses are laser pulses.
101. The method claimed in Claim 89 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.
102. The method claimed in Claim 77, 78, 79, 80 or 81, 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 dehvery pulses to said organism.
103. The method claimed in Claim 102, wherein said step of withdrawing fluid from said organism is performed in a noninvasive manner.
104. The method claimed in Claim 103, wherein said ultrasonic stimuli pulses have a frequency falling in the frequency range of 5KHz-lMHz.
105. The method claimed in Claim 104, wherein the frequency of said variable frequency ultrasonic drug dehvery pulses fall in the frequency range of 50MHz-300MHz.
106. The method claimed in Claim 105 wherein said variable frequency ultrasonic drug dehvery pulses are harmonics.
107. The method claimed in Claim 106 wherein said variable frequency ultrasonic drug dehvery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.
108. The method claimed in Claim 107, including the additional step of applying further stimuli pulses to the skin of said orgamsm during the period of time said variable frequency ultrasonic drug dehvery pulses are applied to said organism.
109. The method claimed in Claim 108, wherein said further stimuli pulses are infrared energy pulses.
110. The method claimed in Claim 108, wherein said further stimuli pulses are laser pulses.
111. The method claimed in Claim 104, wherein the frequency of said variable frequency ultrasonic drug dehvery pulses fall in the frequency range of 50MHz-300MHz.
112. The method claimed in Claim 111 wherein said variable frequency ultrasonic drug dehvery pulses are harmonics.
113. The method claimed in Claim 112 wherein said variable frequency ultrasonic drug dehvery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.
114. The method claimed in Claim 113, 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 dehvery pulses are applied to said organism.
115. The method claimed in Claim 114, wherein said further stimuli pulses are infrared energy pulses.
116. The method claimed in Claim 114, wherein said further stimuli pulses are laser pulses.
117. The method claimed in Claim 103, 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.
118. The method claimed in Claim 117, wherein said ultrasonic stimuli pulses have a frequency falling in the range of 5KHz-lMHz.
119. The method claimed in Claim 118, wherein the frequency of said variable frequency ultrasonic drug dehvery pulses fall in the frequency range of 50MHz-300MHz.
120. The method claimed in Claim 119, wherein said variable frequency ultrasonic drug dehvery pulses are harmonics.
121. The method claimed in Claim 120, wherein said variable frequency ultrasonic drug dehvery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.
122. The method claimed in Claim 121, 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 dehvery pulses are applied to said organism.
123. The method claimed in Claim 122, wherein said additional stimuli pulses are infrared energy pulses.
124. The method claimed in Claim 122, wherem said additional stimuli pulses are laser pulses.
125. The method claimed in Claim 117, wherein the frequency of said variable frequency ultrasonic drug dehvery pulses fall in the frequency range of 50MHz-300MHz.
126. The method claimed in Claim 125, wherein said variable frequency ultrasonic drug dehvery pulses are harmonics.
127. The method claimed in Claim 126, wherein said variable frequency ultrasonic drug dehvery pulses have a fundamental frequency that hes at the lower end of said 50MHz-3O0MHz range.
128. The method claimed in Claim 127, including the additional step of applying further stimuh pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug dehvery pulses are apphed to said organism.
129. The method claimed in Claim 128, wherein said additional stimuh pulses are infrared energy pulses.
130. The method claimed in Claim 128, wherein said additional stimuh pulses are laser pulses.
131. A noninvasive method of withdrawing a fluid from an organism and determining the concentration of a substance in the fluid, said noninvasive method comprising the steps of:
(a) creating a cavity juxtaposed against the skin of said organism;
(b) applying a focused beam of ultrasonic energy to the skin of said orgamsm in the region of said cavity to cause fluid to be withdrawn into said cavity; and
(c) analyzing fluid withdrawn into said cavity.
132. The method claimed in Claim 131, wherein the frequency of said focused beam of ultrasonic energy hes in the range of 3MHz-50MHz.
PCT/US1993/009798 1992-10-14 1993-10-13 Ultrasonic transdermal drug delivery system WO1994008655A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93923872A EP0684856A1 (en) 1992-10-14 1993-10-13 Ultrasonic transdermal drug delivery system
AU53591/94A AU678781B2 (en) 1992-10-14 1993-10-13 Ultrasonic transdermal drug delivery system
JP6510246A JPH08502424A (en) 1992-10-14 1993-10-13 Ultrasonic transdermal drug delivery system
KR1019950701445A KR950703383A (en) 1992-10-14 1995-04-14 ULTRASONIC TRANSDERMAL DRUG DELIVERY SYSTEM

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/961,113 US5421816A (en) 1992-10-14 1992-10-14 Ultrasonic transdermal drug delivery system
US07/961,113 1992-10-14

Publications (3)

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WO1994008655A2 WO1994008655A2 (en) 1994-04-28
WO1994008655A3 WO1994008655A3 (en) 1994-09-01
WO1994008655B1 true WO1994008655B1 (en) 1994-09-15

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US (2) US5421816A (en)
EP (1) EP0684856A1 (en)
JP (1) JPH08502424A (en)
KR (1) KR950703383A (en)
AU (1) AU678781B2 (en)
CA (1) CA2146010A1 (en)
WO (1) WO1994008655A2 (en)

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