Method and apparatus for enhancement of transdermal transport

• US 20040236268A1
• Filed: 03/05/2004
• Published: 11/25/2004
• Est. Priority Date: 01/08/1998
• Status: Active Grant

• Current Assignee: Echo Therapeutics Incorporated
• Original Assignee: Sontra Medical, Inc. (Echo Therapeutics Incorporated)
• Inventors: Elstrom, Tuan A., Mitragotri, Samir S., Warner, Nicholas F., Kost, Joseph, Kellogg, Scott C.
• Granted Patent: US 8,287,483 B2
• Time in Patent Office: Days
• US Class Current: 604/20
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/411 Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
• CPC Class Codes: A61B 5/415 the glands, e.g. tonsils, adenoids or thymus
• CPC Class Codes: A61B 5/418 lymph vessels, ducts or nodes
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• 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

According to the present invention, a method for enhancing transdermal transport is disclosed. The method includes the steps of increasing a permeability of an area of a membrane with a permeabilizing device. The membrane may be, inter alia, biologic skin or synthetic skin. The permeabilizing device may be an ultrasound-producing device. A substance is transported into and through the area of the membrane. The substance may be a drug, a vaccine, or a component of interstitial fluid.

Claims

1. A method for enhancing transdermal transport, comprising:

increasing a permeability of an area of a membrane with a permeabilizing device using low frequency ultrasound;

monitoring the permeability of the area of membrane;

transporting a substance into and through the area of membrane.

2. The method of claim 1, wherein the step of increasing a permeability of an area of membrane with a permeabilizing device comprises:

applying electricity to the area of membrane;

measuring at least one electrical parameter of the area of membrane; and

controlling the permeabilizing device based on the at least one electrical parameter.

3. The method of claim 1, wherein the step of increasing a permeability of an area of membrane with the permeabilizing device comprises:

creating a volume of fluid adjacent the area of membrane, said fluid having an initial concentration of a first substance; and

applying the permeabilizing device to the area of membrane.

4. The method of claim 3, wherein the step of monitoring the permeability of the area of membrane comprises:

monitoring changes in the concentration of the first substance; and

controlling the permeabilizing device based on the changes in the concentration of the substance.

5. The method of claim 1, wherein the step of increasing a permeability of an area of membrane with a permeabilizing device comprises:

creating a volume of fluid adjacent the area of membrane;

determining a reference value for an electrical parameter of the volume of fluid; and

applying the permeabilizing device to the area of membrane.

6. The method of claim 5, wherein the created volume fluid is selected from the group consisting of a liquid, a gel, and a solid.

7. The method of claim 5, wherein the step of monitoring the permeability of the area of membrane comprises:

monitoring changes in the electrical parameter of the volume of fluid; and

controlling the permeabilizing device based on the changes in the electrical parameter of the volume of fluid.

8. The method of claim 1, wherein the step of increasing a permeability of an area of membrane with a permeabilizing device comprises:

providing a first electrode in electrical contact with a first area of membrane;

providing a second electrode in electrical contact with a second area of membrane;

measuring an initial conductivity between said electrodes; and

applying the permeabilizing device to said first area of membrane.

9. The method of claim 8, wherein the step of monitoring the permeability of the area of membrane comprises:

measuring a second conductivity between said first and second electrodes;

processing said initial conductivity and said second conductivity to establish information on a time-variation of membrane conductance;

calculating at least one parameter describing a kinetics of membrane conductance changes responsive to said information; and

terminating said application of said permeabilizing device in response to a desired value for said at least one parameter.

10. The method of claim 1, wherein the step of transporting a substance across an outer surface of the area of membrane comprises:

extracting an analyte of a body fluid from or through said area of membrane;

receiving said analyte; and

sensing the presence of said at least one analyte in said body fluid.

11. The method of claim 1, wherein the substance is a drug.

12. The method of claim 1, wherein the substance is a vaccine.

13. The method of claim 1, wherein the substance includes at least one component of interstitial fluid.

15. The method of claim 1, wherein the permeabilizing device is a device that produces a force selected from the group consisting of chemical, electroporation, mechanical, disrupting, tape stripping, and laser forces.

16. The method of claim 1, wherein the membrane is selected from the group consisting of biologic skin and synthetic skin.

14. (Cancelled).

17. A method for enhancing a permeability of an area of skin comprising:

increasing the permeability of the area of skin with a skin permeabilizing device;

applying electricity to the area of skin;

measuring at least one electrical parameter of the area of skin; and

controlling the skin permeabilizing device based on the at least one electrical parameter.

18. The method of claim 17, further comprising:

applying electricity to the area of skin before increasing the permeability of the area of skin with a skin permeabilizing device; and

measuring a baseline for the at least one electrical parameter.

19. The method of claim 17, wherein the step of applying electricity to the area of skin comprises:

applying a first source having a first frequency to the area of skin; and

applying a second source having a second frequency to the area of skin.

20. The method of claim 19, wherein the step of measuring a first electrical parameter comprises:

measuring the at least one electrical parameter at the first frequency; and

measuring the at least one electrical parameter at the second frequency.

21. The method of claim 17, further comprising:

coupling a first electrode with the area of skin;

coupling a second electrode with the skin; and

measuring the at least one electrical parameter using the first electrode and the second electrode.

22. The method of claim 21, wherein the first electrode is coupled with a portion of stratum corneum of the area of skin.

23. The method of claim 22, wherein the second electrode is coupled with a portion of epidermis over which the stratum corneum has been removed.

24. The method of claim 22, wherein the second electrode is coupled with a portion of stratum corneum of the skin.

25. The method of claim 21, wherein at least one of the first and second electrode is coupled through a conductive medium.

26. The method of claim 25, wherein the conductive medium a gel.

27. The method of claim 25, wherein the conductive medium is a liquid.

28. The method of claim 21, wherein the second electrode is placed on the skin.

29. The method of claim 17, further comprising:

comparing the at least one electrical parameter with the baseline, and

wherein the step of controlling the skin permeabilizing device comprises discontinuing the application of the skin permeabilizing device based on the comparison.

30. The method of claim 19, wherein the first source comprises a voltage source having a frequency of about 10 Hz.

31. The method of claim 19, wherein the second source comprises a voltage source having a frequency of about 1 kHz.

32. The method of claim 17, wherein the parameter is selected from the group consisting of impedance, conductance, capacitance, current, and voltage.

33. The method of claim 17, wherein said skin permeabilizing device comprises an ultrasound-producing device.

34. The method of claim 20, wherein the step of controlling the skin permeabilizing device comprises decreasing a characteristic of the skin permeabilizing device when the measurement of the at least one electrical parameter at the first frequency and, the measurement of the at least one electrical parameter at the second frequency differ by less than a predetermined amount, the characteristic selected from the group consisting of intensity and duty cycle.

35. The method of claim 19, wherein the step of controlling the skin permeabilizing device comprises decreasing a characteristic of the skin permeabilizing device when a rate of change between the one electrical parameters reaches a predetermined value, the characteristic selected from the group consisting of intensity and duty cycle.

36. An apparatus for enhancing permeability of an area of skin comprising:

a skin permeabilizing device configured to increase a permeability of the area of skin;

an electrical source operable to apply electricity to the area of skin;

a circuit to measure at least one electrical parameter of the area of skin; and

a controller responsive to the circuit and operable to control the skin permeabilizing device.

37. The apparatus of claim 36, wherein the electrical source comprises:

a first source having a first frequency; and

a second source having a second frequency.

38. The apparatus of claim 37, wherein the circuit measures the at least one electrical parameter of the area of skin at the first frequency and at the second frequency.

39. The apparatus of claim 36, further comprising:

a first electrode coupled on the area of skin; and

a second electrode positioned on the skin;

wherein the circuit measures the first parameter of the area of skin between the first electrode and the second electrode.

40. The apparatus of claim 39, wherein the first electrode comprises an electrode that is coupled to a portion of stratum corneum of the area of skin.

41. The apparatus of claim 40, wherein the second electrode comprises an electrode that is positioned on a portion of epidermis over which the stratum corneum has been removed.

42. The apparatus of claim 39, wherein the first electrode comprises an electrode having a first surface area and coupled to a portion of stratum corneum of the area of skin.

43. The apparatus of claim 42, wherein the second electrode comprises an electrode having a second surface area positioned on a portion of stratum corneum of the skin, and further wherein the second surface area is substantially larger than the first surface area.

44. The apparatus of claim 40, wherein the controller compares the measurement of the at least one electrical parameter at the first frequency with the measurement of the at least one electrical parameter at the second frequency and turns off the skin permeabilizing device when they differ by less than about a predetermined amount.

45. The apparatus of claim 37, wherein the first source comprises a voltage source having a frequency of about 10 Hz.

46. The apparatus of claim 37, wherein the second source comprises a voltage source having a frequency of about 1 kHz.

47. The apparatus of claim 38, wherein the parameter is selected from the group consisting of impedance, conductance, capacitance, current, and voltage.

48. The apparatus of claim 37, wherein the controller compares the measurement of the at least one electrical parameter at the first frequency with the measurement of the at least one electrical parameter at the second frequency and decreases an intensity of the skin permeabilizing device source when they differ by less than about a predetermined amount.

49. The apparatus of claim 38, wherein the controller compares the measurement of the at least one electrical parameter at the first frequency with the measurement of the at least one electrical parameter at the second frequency and decreases a duty cycle of the skin permeabilizing device source when they differ by less than about a predetermined amount.

50. A method for enhancing permeability of an area of skin comprising:

creating a volume of fluid adjacent the area of skin, said fluid having an initial concentration of a first substance;

applying a skin permeabilizing device to the area of skin;

monitoring changes in the concentration of the first substance; and

controlling the skin permeabilizing device based on the changes in the concentration of the substance.

51. The method of claim 50, wherein the volume of fluid is selected from the group consisting of a liquid, a gel, and a solid.

52. The method of claim 50, wherein the first substance comprises an analyte.

53. The method of claim 52, wherein the step of controlling the skin permeabilizing device comprises discontinuing the application of the skin permeabilizing device when the concentration of analyte in the volume of fluid increases to a predetermined concentration.

54. The method of claim 50, wherein the step of controlling the skin permeabilizing device comprises discontinuing the application of the skin permeabilizing device when a rate of increase of analyte in the volume of fluid reaches a predetermined concentration.

55. The method of claim 50, wherein the step of controlling the skin permeabilizing device comprises decreasing a characteristic of the skin permeabilizing device when the concentration of analyte in the volume of fluid increases to a predetermined concentration, said characteristic selected from the group consisting of intensity and duty cycle.

56. The method of claim 50, wherein the first substance comprises a benign molecule and the initial concentration comprises a concentration higher than that found in the body.

57. The method of claim 56, wherein the step of controlling the skin permeabilizing device comprises discontinuing the application of the skin permeabilizing device when the concentration of the benign molecule in the volume of fluid decreases to a predetermined concentration.

58. The method of claim 56, wherein the step of controlling the skin permeabilizing device comprises discontinuing the application of the skin permeabilizing device when the rate of change in the concentration of the benign molecule in the volume of fluid reaches a predetermined value.

59. The method of claim 56, wherein the step of controlling the skin permeabilizing device comprises decreasing an intensity of the skin permeabilizing device when the concentration of the benign molecule in the volume of fluid decreases to a predetermined concentration.

60. The method of claim 56, wherein the step of controlling the skin permeabilizing device comprises decreasing an intensity of the skin permeabilizing device when the rate of change in the concentration of the benign molecule in the volume of fluid reaches a predetermined value.

61. The method of claim 56, wherein the step of controlling the skin permeabilizing device comprises decreasing the intensity of a duty cycle of the skin permeabilizing device when the concentration of the benign molecule in the volume of fluid decreases to a predetermined concentration.

62. A method for enhancing permeability of an area of skin comprising:

creating a volume of fluid adjacent the area of skin;

determining a reference value for an electrical parameter of the volume of fluid;

applying a skin permeabilizing device to the area of skin;

monitoring changes in the electrical parameter of the volume of fluid; and

controlling the skin permeabilizing device based on the changes in the electrical parameter of the volume of fluid.

63. The method of claim 62, wherein the volume of fluid is selected from the group consisting of a liquid, a gel, and a solid.

64. The method of claim 62, wherein the electrical parameter is conductivity.

65. A method for regulating the permeabilization of an area of skin, comprising:

providing a first electrode in electrical contact with a first area of skin;

providing a second electrode in electrical contact with a second area of skin;

measuring an initial conductivity between said electrodes;

applying a skin permeabilizing device to said first area of skin;

measuring a second conductivity between said first and second electrodes;

processing said initial conductivity and said second conductivity to establish information on a time-variation of skin conductance;

calculating at least one parameter describing a kinetics of skin conductance changes responsive to said information; and

terminating said application of said skin permeabilizing device in response to a desired value for said at least one parameter.

66. The method of claim 65, wherein said application of said skin permeabilizing device is continuous.

67. The method of claim 65, wherein said application of said skin permeabilizing device is discontinuous.

68. The method of claim 65, wherein said skin permeabilizing device comprises an ultrasound-producing device.

69. The method of claim 65, wherein said step of calculating at least one parameter describing a kinetics of skin conductance changes responsive to said information comprises:

determining a slope of said information on a time-variation of skin conductance; and

determining a point of inflection for said information on a time-variance of skin conductance.

70. The method of claim 67, further comprising the steps of

performing analog to digital conversion on said information on a time-variation of skin conductance;

and

filtering said digital data.

71. The method of claim 65, wherein said step of processing said initial conductivity and said second conductivity to establish information on a time-variation of skin conductance comprises fitting said information into the following equation:

72-157. -157. (cancelled)

158. A method for enhancing transdermal transport of a substance into or through an area in a membrane comprising:

a) determining the initial permeability in said area of said membrane by applying an electrical force to said area and measuring an electrical property that varies with permeability;

b) applying low frequency ultrasound permeabilization forces to said area;

c) monitoring changes in said electrical property that varies with permeability during the application of low frequency ultrasound forces;

d) discontinuing the application of said low frequency ultrasound permeabilization forces when the monitored electrical property reaches a value indicating the desired level of permeability; and

e) transporting said substance into and through said area of said membrane.

159. The method of claim 158, wherein the substance comprises an anesthetic.