Method and device for drug delivery

• US 20080281297A1
• Filed: 06/21/2007
• Published: 11/13/2008
• Est. Priority Date: 03/19/2007
• Status: Active Grant

• Current Assignee: InsuLine Medical Ltd.
• Original Assignee: InsuLine Medical Ltd.
• Inventors: Pesach, Benny, Bitton, Gabriel, Nagar, Ron, Weiss, Ram
• Granted Patent: US 9,220,837 B2
• Time in Patent Office: Days
• US Class Current: 604/890.1
• CPC Class Codes: A61B 18/08 by means of electrically-heated probes
• CPC Class Codes: A61B 18/14 Probes or electrodes therefor
• CPC Class Codes: A61B 18/1477 Needle-like probes
• CPC Class Codes: A61B 18/1492 having a flexible, catheter-like structure, e.g. for heart ablation A61B18/1477 takes precedence
• CPC Class Codes: A61B 18/18 by applying electromagnetic radiation, e.g. microwaves radiation therapy A61N5/00
• CPC Class Codes: A61B 18/20 using laser
• CPC Class Codes: A61B 2018/1425 Needle
• CPC Class Codes: A61F 7/007 characterised by electric heating
• CPC Class Codes: A61M 2005/1581 Right-angle needle-type devices
• CPC Class Codes: A61M 2005/1726 the body parameters being measured at, or proximate to, the infusion site
• CPC Class Codes: A61M 2039/1022 additionally providing electrical connection
• CPC Class Codes: A61M 2205/05 combined with other kinds of therapy
• CPC Class Codes: A61M 2205/051 with radiation therapy
• CPC Class Codes: A61M 2205/052 infrared
• CPC Class Codes: A61M 2205/058 with ultrasound therapy
• CPC Class Codes: A61M 2205/8206 battery-operated
• CPC Class Codes: A61M 5/1413 Modular systems comprising interconnecting elements
• CPC Class Codes: A61M 5/14244 adapted to be carried by the patient, e.g. portable on the body
• CPC Class Codes: A61M 5/158 Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
• CPC Class Codes: A61M 5/16831 Monitoring, detecting, signalling or eliminating infusion flow anomalies low-level float-valves causing cut-off A61M5/40; indicating or recording presence, absence or direction of flow in general G01P13/0066
• CPC Class Codes: A61M 5/1723 : using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00
• CPC Class Codes: A61M 5/20 : Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically A61M5/142 , A61M5/46 take precedence; hypodermic projectiles F42B12/54
• CPC Class Codes: A61M 5/422 : Desensitising skin
• CPC Class Codes: A61N 1/30 : Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
• CPC Class Codes: A61N 2005/0645 : Applicators worn by the patient
• CPC Class Codes: A61N 7/00 : Ultrasound therapy lithotripsy A61B17/22, A61B17/225; massage using supersonic vibration A61H23/00 ; using ultrasound for introducing media into the body A61M37/0092

Abstract

A method and a device for a delivery of a chemical substance to the body of the patient are provided. The device includes an infusion catheter configured to be inserted into a tissue, a catheter securing element configured to be adhered to the skin of the patient and further configured to secure the infusion catheter to the skin, a drug delivery pump configured to infuse a drug into the infusion catheter for delivery to a drug infused region on the body of the patient, and a treatment element configured to apply a treatment to the drug infused region to improve pharmacodynamics of the drug during a period of delivery of the drug to the patient.

Claims

1. A device for delivery of a therapeutic substance to the body of a patient, comprising:

an infusion catheter configured to be inserted into a tissue of a patient, wherein a volume surrounding the insertion site comprises an infused region;

a catheter securing element configured to be adhered to the skin of the patient and further configured to secure the infusion catheter to the skin;

a treatment element configured to apply a treatment to the vicinity of the infused region to modify the pharmacodynamic profile of the substance.

2. The device according to claim 1, wherein the pharmacodynamic profile is modified either before, during and/or after a period of delivery of the substance to the patient.

3. The device according to claim 1, further comprising a delivery pump configured to infuse the substance into the infusion catheter for delivery to the infused region on the body of the patient.

4. The device according to claim 1, wherein the treatment element is further configured to modify absorption of the substance into at least one of the blood system and the lymphatic system of the patient during and/or following the period of delivery of the substance to the patient.

5. The device according to claim 1, wherein the tissue comprises a blood vessel.

6. The device according to claim 1, wherein the pharmacodynamic profile of the substance is modified to enable a faster onset of action of the substance infused into the infused region.

7. The device according to claim 1, wherein the pharmacodynamic profile of the substance is modified to enable a faster peak of action of the substance infused into the infused region.

8. The device according to claim 1, wherein the pharmacodynamic profile of the substance is modified to enable a faster clearance of the substance from the infused region to the circulatory system of the patient.

9. The device according to claim 1, wherein the pharmacodynamic profile of the substance is modified to improve the repeatability of the pharmacodynamics profile in response to therapeutic substance infusion.

10. The device according to claim 1, wherein the pharmacodynamic profile of the substance is modified to reduce a variability of absorption of the substance into the blood system and/or lymphatic system of the patient.

11. The device according to claim 1, wherein the pharmacodynamic profile of the substance is modified to reduce a variability of onset of action of the substance.

12. The device according to claim 1, wherein the pharmacodynamic profile of the substance is modified to reduce a variability of time to peak of action of the substance.

13. The device according to claim 1, wherein the pharmacodynamic profile of the substance is modified to reduce a variability of the clearance of the substance from the infused region to the circulatory system of the patient.

14. The device according to claim 1, wherein the substance is insulin, insulin analogues or insulin mimetics.

15. The device according to claim 14, wherein the treatment is applied during and/or after an infusion of a insulin bolus dose.

16. The device according to claim 14, wherein the treatment is applied short time before, during and/or after an infusion of a insulin bolus dose.

17. The device according to claim 1, further comprising a processing unit for controlling at least one of the treatment device and a delivery pump for delivering the substance to the infusion catheter.

18. The device according to claim 17, wherein processing unit is disposed in delivery pump.

19. The device according to claim 17, wherein processing unit is disposed in an enclosure adjacent to delivery pump.

20. The device according to claim 17, wherein processing unit is disposed in an enclosure attached to delivery pump.

21. The device according to claim 14, further comprising a sensor for detecting an infusion of an insulin bolus.

22. The device according to claim 14, comprising a sensor for measuring insulin flow in the catheter.

23. The device according to claim 15, further comprising a processing unit configured to initiate the treatment device to apply the treatment upon detection of the insulin bolus.

24. The device according to claim 23, wherein the sensor comprises an electromagnetic sensing element for measuring an electromagnetic emission of a delivery pump for delivering the substance to the infusion catheter.

25. The device according to claim 1, wherein the treatment device includes a processing unit and wherein a substance delivery pump and substance reservoir are provided in the same housing.

26. The device according to claim 1, wherein the treatment device comprises a heater to heat the infused region.

27. The device according to claim 26, wherein said heater is attached to the skin around said insertion sight.

28. The device according to claim 26, wherein said heater is attached to the skin around said securing device.

29. The device according to claim 26, wherein said heater is U shaped.

30. The device according to claim 26, wherein the heater does not heat the substance prior to the substance being infused into an end of the infusion catheter or prior to being infused into the infusion region.

31. The device according to claim 3, wherein the delivery pump further comprises a reservoir, and wherein the treatment device comprises a heater to heat the infused region without heating the substance reservoir.

32. The device according to claim 1, wherein the treatment device comprises a heater to heat the infused region without heating the substance above a limiting temperature prior to infusion of the substance into the infused region, or prior to the substance being infused into an end of the infusion catheter.

33. The device according to claim 1, wherein the treatment device comprises a heater, and wherein the heater heats the infused region without heating a reservoir and associated tubing of a delivery pump above a limiting temperature.

34. The device according to claim 1, further comprising a temperature sensor configured to indicate a temperature of the substance prior to infusion into the infused region.

35. The device according to claim 34, further comprising a processing unit configured to verify that the substance is not heated above a limiting temperature prior to the substance being infused into the infused region.

36. The device according to claim 31, further comprising a thermal insulation configured to be disposed between the treatment device and the reservoir and further configured to prevent heating of the substance in the reservoir above a limiting temperature.

37. The device according to claim 3, wherein the treatment element and substance delivery pump and substance reservoir are enclosed into the same housing.

38. The device according to claim 33, wherein the limiting temperature is about 37 degrees C.

39. The device according to claim 1, wherein the treatment device is provided in the catheter securing element.

40. The device according to claim 1, wherein the treatment device is provided between the catheter securing element and the skin of the patient.

41. The device according to claim 1, wherein the treatment device is disposed into catheter securing element.

42. The device according to claim 1, wherein the treatment device comprises an intra catheter electrical heater.

43. The device according to claim 1, wherein the treatment device is configured to heat the infused region using optical radiation.

44. The device according to claim 1, further comprising a temperature sensor provided adjacent to the skin of the patient and proximal to an insertion point of the infusion catheter.

45. The device according to claim 1, further comprising a temperature sensor configured to be embedded into the infusion catheter and further configured to be proximal to the infused region.

46. The device according to claim 1, where the treatment device comprises a heater and wherein the device is configured to regulate heating of the infused region to stabilize a temperature of the substance infused tissue region at a pre-determined temperature.

47. The device according to claim 46, wherein the predetermined temperature is between about 37 degrees C. and about 42 degrees C.

48. The device according to claim 46, wherein the predetermined temperature is between about 37 degrees C. and about 39 degrees C.

49. The device according to claim 46, wherein the predetermined temperature is between about 32 degrees C. and about 37 degrees C.

50. The device according to claim 14, wherein treatment device comprises a heater, and wherein the treatment device provides heat subsequent to an infusion of an insulin bolus dose for a period of between about 10 minutes and about 30 minutes.

51. The device according to claim 14, wherein treatment device comprises a heater, and wherein the treatment device provides heat subsequent to an infusion of an insulin bolus dose for a period of between about 1 minutes and about 10 minutes.

52. The device according to claim 1, wherein the treatment device comprises a heater and wherein heat is produced at a power of between about 0.25 watts and about 2 watts.

53. The device according to claim 1, wherein the treatment device comprises a heater and wherein the treatment device operates between on and off states to produce a predetermined stable temperature at the infused region.

54. The device according to claim 1, wherein the treatment device comprises a heater and wherein the treatment device power is regulated to produce a predetermined stable temperature at the infused region.

55. The device according to claim 54, wherein the treatment element is configured to be embedded into the catheter securing element, wherein the catheter securing element is configured to be connected to a delivery pump using at least one electrical wire and at least one tube.

56. The device according to claim 55, further comprising a connector housing configured to connect said at least one electrical wire and at least one tube.

57. The device according to claim 56, wherein the connector housing is configured to be adjacent to the treatment element.

58. The device according to claims 56, wherein the connector housing is configured to be adjacent to the drug delivery pump.

59. The device according to claim 56, further comprising a cap configured to seal the connector housing when the connector housing is disconnected.

60. The device according to claim 54, further comprising a temperature sensor in the treatment element and wherein an electrical wire connects the temperature sensor to a delivery pump.

61. The device according to claim 1, wherein the treatment element is configured to be combined with the catheter securing element and/or a delivery pump.

62. The device according to claim 1, wherein the catheter securing element is disposable and the treatment element is reusable.

63. The device according to claim 1, wherein the catheter securing element is disposable and the treatment element is disposable.

64. The device according to claim 1, wherein the catheter securing element and treatment element are disposed in the same housing.

65. The device according to claim 64, wherein the catheter securing element combined with treatment element in the same disposable housing.

66. The device according to claim 1, wherein the treatment device comprises an optical radiation device configured to irradiate the infused region with optical radiation.

67. The device according to claim 1, wherein the treatment device comprises a micro-wave generator or emitter configured to irradiate the infused region with micro-wave radiation.

68. The device according to claim 1, wherein the treatment device is a radio frequency electromagnetic radiation generator or emitter configured to irradiate the infused region with radio frequency electromagnetic radiation.

69. The device according to claim 1, wherein the treatment device comprises a vibration device configured to vibrate the infused region.

70. The device according to claim 69, wherein the treatment device is configured to massage the infused region with vibrations.

71. The device according to claim 1, wherein the treatment device is a vacuum device and is configured to apply suction to the infused region.

72. The device according to claim 1, wherein the treatment device comprises and electric field generator or emitter configured to apply an electric field to the infused region.

73. The device according to claim 1, wherein the treatment device comprises a magnetic field generator or emitter configured to apply magnetic field to the infused region.

74. The device according to claim 1, wherein the treatment device comprises an acoustic signal generator or emitter configured to apply acoustic stimulation to the infused region.

75. The device according to claim 1, wherein the treatment device is configured to apply one more additional substances to the infused region wherein the second substance modifies the pharmacodynamic profile of the first substance.

76. The device according to claim 1, wherein the treatment device comprises double lumen catheter, wherein first lumen applies therapeutic substance to infused region and second lumen applies one more additional substance to the infused region wherein the second substance modifies the pharmacodynamic profile of the first substance.

77. The device according to claim 1, wherein the treatment device is configured to apply one more additional substances to the infused region wherein the second substance modifies absorption of first substance into the blood system and/or lymphatic system of the patient and/or promotes the clearance of first substance from the infusion site.

84. A method for infusing a drug into the body of the patient using a device according to claim 1, comprising:

improving the pharmacodynamics and/or pharmacokinetics of an infused drug in the body of the patient.

87. The device according to claim 1, further comprising a processing unit, wherein the catheter and/or the catheter securing element comprise a sensor that detects when the catheter is slightly pulled out of the tissue and wherein the processing unit that receives a signal from the sensor upon detection of the catheter securing element being pulled out of the tissue and alerts the user.

88. The device according to claim 1, further comprising a processing unit, wherein the catheter securing element includes a sensor that detects when the catheter securing element is disconnected from the skin;

and

wherein the processing unit receives a signal from the sensor upon detection of the catheter securing element being disconnected from the skin and alerts the user.

105. The device according to claim 1, further comprising an activator for manual activation of said treatment element.

106. The device according to claim 1, further comprising

a processing unit for controlling administration of the therapeutic substance;

and

a communication channel for communication between said treatment element and said processing unit.

107. The device according to claim 105, wherein said communication channel comprises wireless communication.

78. A device for regulating glucose level in the body of the patient, comprising

a glucose level sensor;

an insulin delivery device that infuses insulin into the body of the patient;

a treatment element configured to apply a treatment to the vicinity of insulin infused tissue; and

a processing unit configured to receive a glucose level reading from the glucose level sensor and further configured to control by way of an algorithm an infusion rate of insulin into the insulin infused tissue and the treatment element to regulate a glucose level in the body of the patient.

79. A device for regulating glucose level in the body of the patient, comprising

a glucose level sensor;

a delivery device that infuses insulin or other substances relevant for glucose level regulation into the patient;

a treatment element configured to apply a treatment to the vicinity of the delivery site; and

a processing unit configured to receive a glucose level reading from the glucose level sensor and further configured to control by way of an algorithm an infusion rate of insulin into the insulin infused tissue and the treatment element to regulate a glucose level in the body of the patient.

80. The device according to claim 79, wherein the faster onset of action of the substance infused into the infused region provided by said treatment device is used by said algorithm to improve the glucose regulation in the body of the patient.

81. The device according to claim 79, wherein the faster peak of action of the substance infused into the infused region provided by said treatment device is used by said algorithm to improve the glucose regulation in the body of the patient.

82. The device according to claim 79, wherein the faster clearance of the substance from the infused region to the circulatory system of the patient provided by said treatment device is used by said algorithm to improve the glucose regulation in the body of the patient.

83. The device according to claim 79, wherein the improved repeatability of the pharmacodynamic profile of the substance infused into the infused region provided by said treatment device is used by said algorithm to improve the glucose regulation in the body of the patient.

85. A device for delivery of a drug to the body of the patient, comprising

an infusion catheter configured to be inserted into a tissue;

a catheter securing element configured to be adhered to the skin of the patient and further configured to secure the infusion catheter to the skin;

a drug delivery pump configured to infuse a drug into the infusion catheter for delivery to a drug infused region on the body of the patient;

a sensor that detects if the catheter is slightly pulled out of the tissue; and

a processing unit that receives the signal from the sensor and configured to alert the user.

86. A device for delivery of a drug to the body of the patient, comprising:

an infusion catheter configured to be inserted into a tissue;

a catheter securing element configured to be adhered to the skin of the patient and further configured to secure the infusion catheter to the skin;

a drug delivery pump configured to infuse a drug into the infusion catheter for delivery to

a drug infused region on the body of the patient;

a sensor that detects if the catheter securing element is slightly disconnected from the skin; and

a processing unit that receives the signal from the sensor and configured to alert the user.

89. A device for delivery of a drug to the body of the patient, comprising:

an infusion catheter configured to be inserted into a tissue;

a catheter securing element configured to be adhered to the skin of the patient and further configured to secure the infusion catheter to the skin;

a syringe configured to infuse a drug into the infusion catheter for delivery to a drug infused region on the body of the patient; and

a treatment element configured to apply a treatment to the vicinity of the drug infused region to modify a pharmacodynamics profile of the drug either before, during, and/or following a period of delivery of the drug to the patient.

90. The device according to claims 89, wherein the treatment device detects infusion of drug through the catheter and starts the treatment automatically.

91. The device according to claim 89, wherein the treatment device detects the syringe operation and starts the treatment automatically.

92. The device according to claim 89, wherein the treatment device detects the syringe vicinity and starts the treatment automatically.

93. The device according to claim 89, wherein the treatment device includes a button for manual operation of the treatment.

149. The device according to claim 89, wherein the treatment device is controlled by wireless communication.

150. The device according to claim 89, wherein the treatment device is controlled by a separate remote control.

151. The device according to claim 89, wherein the treatment device is controlled by a drug delivery pump remote control.

152. The device according to claim 89, wherein the treatment device communicates with a data storage unit.

153. The device according to claim 89, wherein the treatment device communicates with a cellular phone.

154. The device according to claim 89, wherein the treatment device is controlled by a drug delivery pump.

94. A device for delivery of a drug to the body of the patient, comprising:

a syringe configured to inject a drug into region on the body of the patient; and

a treatment element configured to apply a treatment to the vicinity of the drug injected region to improve pharmacodynamics profile of the drug during or following the drug injection to the patient.

95. A device for delivery of a drug to the body of the patient, comprising:

a syringe configured to inject a drug into region on the body of the patient; and

a treatment element configured to apply a treatment to the vicinity of the drug injected region to improve pharmacodynamics profile of the drug either a short time before, during and/or following the drug injection to the patient.

96. The device according to claim 95, wherein the treatment device detects injection of drug and starts the treatment automatically.

97. The device according to claim 95, wherein the treatment device detects the syringe vicinity and starts the treatment automatically.

98. The device according to claim 95, wherein the treatment device includes a button for manual operation of the treatment.

99. The device according to claim 95, wherein the treatment device is controlled by wireless communication.

100. The device according to claim 95, wherein the treatment device is controlled by a separate remote control.

101. The device according to claim 95, wherein the treatment device is controlled by a drug delivery pump remote control.

102. The device according to claim 95, wherein the treatment device communicates with a data storage unit.

103. The device according to claim 95, wherein the treatment device communicates with a cellular phone.

104. The device according to claim 95, wherein the treatment device is controlled by a drug delivery pump.

108. A method for treating a subject with a diabetic treatment agent, comprising:

infusing a diabetic treatment agent into the subject through a drug infusion device in combination with an energy from an energy source.

109. The method according to claim 108, wherein said infusing step further comprises

administering the energy to the subject at the region of infusion of the diabetic treatment agent.

110. The method according to claim 109, wherein the energy source is selected from a group consisting of:

heat, radiation, mechanical vibrations, suction, magnetic energy, ultrasound, light irradiation, RF irradiation, microwave irradiation and electrical stimulation.

111. The method according to claim 110, wherein the energy source is heat, and wherein the diabetic agent is selected from a group consisting of:

insulin, an insulin analog, and an insulin mimetic.

112. The method according to claim 111, wherein the step of administering the diabetic treatment agent further comprises

infusing insulin through an insulin pump device, wherein the insulin pump device includes the energy source.

113. The method according to claim 112, wherein the step of administering the energy further comprises

administering the energy while infusing insulin.

114. The method according to claim 113, wherein said step of administering the energy increases an onset of activation of insulin.

115. The method according to claim 113, further comprising:

measuring a level of glucose in the subject; and

determining a rate of administration of the insulin according to the level of glucose.

116. The method according to claim 113, wherein said administering the energy step further comprises

inducing a faster peak of action of insulin;

and

wherein said determining the rate of administration step is performed at least partially based on the faster peak of action to improve the glucose regulation in the body of the patient.

117. The method according to claim 116, wherein said administering the energy step further comprises

inducing a faster clearance of the insulin into the circulatory system of the patient;

and

wherein said determining said rate of administration step is performed at least partially based on the faster clearance of insulin.

118. The method according to claim 117, wherein said administering the energy step further comprises

inducing an improved repeatability of the pharmacodynamic profile of insulin;

and

wherein said determining the rate of administration step is performed at least partially based on the improved repeatability of the pharmacodynamic profile of insulin.

119. A method for treating a subject with a treatment agent, comprising:

infusing a treatment agent into the subject while administering heat at or near a region of infusion on the subject.

120. The method according to claim 119, wherein the administering of the heat is configured to modify at least one parameter of the pharmacodynamic profile of the treatment agent.

121. A method for maintaining normal blood glucose in a subject, comprising:

infusing insulin into the subject while administering heat at or near the region of infusion.

122. A method for reducing variable blood level of a treatment agent in a subject, comprising:

infusing a treatment agent into the subject while administering heat at or near the region of infusion.

123. A system for delivery of a therapeutic substance to the body of a patient, comprising:

an administration device for infusing a therapeutic substance into a region of the body of the patient using a drug infusion device; and

a treatment element for applying a treatment to a vicinity of said region of the body of the patient.

124. The system according to claim 123, wherein said treatment element further comprises an energy source;

and

wherein the treatment is energy.

125. The system according to claim 124, wherein said energy source is selected from a group consisting of:

heat, radiation, mechanical vibrations, suction, magnetic energy, ultrasound, light irradiation, RF irradiation, microwave irradiation, and electrical stimulation.

126. The system according to claim 125, wherein said drug infusion device and said treatment element are configured to communicate to determine when to apply the treatment.

127. The system according to claim 126, wherein said communication between said drug infusion device and said treatment element is wireless.

128. The system according to claim 124, wherein said administration device and said treatment element are configured to be combined in a single device.

129. The system according to claim 124, wherein said administration device further comprises a sensor for determining when to apply the therapeutic substance.

130. A method for delivering a therapeutic substance to an infused region on the body of a patient, comprising:

applying a treatment to the vicinity of the infused region on the body of the patient to modify the pharmacodynamic profile of the substance.

131. The method according to claim 130, further comprising

modifying the pharmacodynamic profile of the substance to enable a faster onset of action of the substance infused into the infused region.

132. The method according to claim 130, further comprising

modifying the pharmacodynamic profile of the substance to enable a faster peak of action of the substance infused into the infused region.

133. The method according to claim 130, further comprising

modifying the pharmacodynamic profile of the substance to enable a faster clearance of the substance from the infused region to the circulatory system of the patient.

134. The method according to claim 130, further comprising

modifying the pharmacodynamic profile of the substance to improve the repeatability of the pharmacodynamics profile in response to therapeutic substance infusion.

135. The method according to claim 130, further comprising

modifying the pharmacodynamic profile of the substance to reduce a variability of absorption of the substance into the blood system and/or lymphatic system of the patient

136. The method according to claim 130, further comprising

modifying the pharmacodynamic profile of the substance to reduce a variability of onset of action of the substance.

137. The method according to claim 130, further comprising

modifying the pharmacodynamic profile of the substance to reduce a variability of time to peak of action of the substance.

138. The method according to claim 130, further comprising

modifying the pharmacodynamic profile of the substance to reduce a variability of the clearance of the substance from the infused region to the circulatory system of the patient.

139. The method according to claim 130, further comprising

using an optical radiation device, irradiating the infused region with optical radiation.

140. The method according to claim 130, further comprising

using a micro-wave generator or emitter, irradiating the infused region with micro-wave radiation.

141. The method according to claim 130, further comprising

using a radio frequency electromagnetic radiation generator or emitter, irradiating the infused region with radio frequency electromagnetic radiation.

142. The method according to claim 130, further comprising

using a vibration device, vibrating the infused region.

143. The method according to claim 142, wherein said vibrating further comprises

massaging the infused region using vibrations.

144. The method according to claim 130, further comprising

using a vacuum device, applying suction to the infused region.

145. The method according to claim 130, further comprising

using an electric field generator or emitter, applying an electric field to the infused region.

146. The method according to claim 130, further comprising

using a magnetic field generator or emitter, applying magnetic field to the infused region.

147. The method according to claim 130, further comprising

using an acoustic signal generator or emitter, applying acoustic stimulation to the infused region.

148. The method according to claim 130, further comprising

applying one more additional substances to the infused region wherein the second substance modifies the pharmacodynamic profile of the first substance.