Methods for delivering agents using alternating current

• US 6,512,950 B2
• Filed: 02/13/2001
• Issued: 01/28/2003
• Est. Priority Date: 02/18/2000
• Status: Expired due to Fees

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: University of Utah Research Foundation (State of Utah)
• Inventors: Song, Yang, Li, S. Kevin, Zhu, Honggang, Higuchi, William I.
• Primary Examiner(s): Derakshani, Philippe
• Application Number:
  US09/783,138
• Publication Number:
  US 20010044592A1
• Time in Patent Office: 714 Days
• Field of Search: 604/20, 128/803
• US Class Current: 604/20
• CPC Class Codes: A61N 1/0432 Anode and cathode
• CPC Class Codes: A61N 1/044 Shape of the electrode
• CPC Class Codes: A61N 1/0448 Drug reservoir
• CPC Class Codes: A61N 1/325 for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body electrodes for external use A61N1/0428

Abstract

A variety of methods for transporting different agents such as pharmaceutical agents, nutrients and genetic materials across a tissue are provided. The methods utilize an AC signal to maintain a substantially constant electrical state in a region of the tissue through which transport occurs, thereby allowing agent to be transported across the tissue in a controlled and predictable manner. Certain methods include an optional AC or DC prepulse signal to initially achieve the target electrical state. An optional DC offset signal can also be included to assist in promoting transfer of the agent. The methods have utility in a variety of different clinical settings and applications.

Claims

1. A method of delivering an agent across a tissue, comprising.

(a) supplying one or more electrical signals, the one or more electrical signals comprising an AC signal;

(b) applying the AC signal to the tissue; and

(c) adjusting the AC signal so as to maintain a substantially constant electrical state within a region of the tissue, wherein maintenance of the substantially constant electrical state facilitates delivery of the agent.

2. The method of claim 1, wherein the AC signal is adjusted to maintain a substantially constant state of electroporation in the region of the tissue throughout the time period in which the agent is delivered.

3. The method of claim 1, wherein the electrical state is electrical conductance or electrical resistance and the AC signal is adjusted to maintain a substantially constant electrical conductance or electrical resistance in the region of the tissue throughout the time period in which the agent is delivered.

4. The method of claim 1, wherein the waveform of the AC signal is symmetric.

5. The method of claim 1, wherein the waveform of the AC signal is asymmetric.

6. The method of claim 1, wherein the waveform of the AC signal is a square-waveform, a sine-waveform, a saw-tooth waveform, or trapezoidal waveform.

7. The method of claim 1, wherein the frequency of the AC signal is at least about 1 Hz.

8. The method of claim 1, wherein the frequency of the AC signal is in the range of about 1 Hz to about 1 kHz.

9. The method of claim 7, wherein the frequency of the AC signal is in the range of about 1 kHz to about 10 kHz.

10. The method of claim 7, wherein the frequency of the AC signal is in the range of about 10 kHz to 30 kHz.

11. The method of claim 1, wherein the one or more electrical signals comprise an electrical prepulse applied to the tissue prior to the AC signal to induce electroporation within the region.

12. The method of claim 1, wherein the voltage of the electrical prepulse is in the range of about 1 to about 90 V.

13. The method of claim 12, wherein the voltage of the electrical prepulse is in the range of about 9 to about 30 V.

14. The method of claim 12, wherein the voltage of the electrical prepulse is in the range of about 30 to about 40 V.

15. The method of claim 12, wherein the voltage of the electrical prepulse is in the range of about 40 to about 90 V.

16. The method of claim 12, wherein the electrical prepulse is a DC prepulse.

17. The method of claim 12, wherein the electrical prepulse is an AC prepulse.

18. The method of claim 12, wherein the electrical prepulse is a DC prepulse.

19. The method of claim 12, wherein the electrical prepulse is an AC prepulse.

20. The method of claim 1, wherein delivery of the agent is via passive diffusion through the electroporated region.

21. The method of claim 1, wherein:

.

(a) the one or more electrical signals further comprise a DC offset signal; and

(b) applying comprises applying the DC signal to the tissue, wherein the DC offset signal is effective to promote delivery of the agent through the region.

22. The method of claim 21, wherein the DC offset signal is applied substantially continuously during delivery of the agent and is of a voltage or current effective to control the rate of delivery of the agent through the region.

23. The method of claim 21, wherein the voltage of the DC offset signal is in the range of about 0.1 V to about 5 V and the current range is about 0.01 to 0.5 mA/cm².

24. The method of claim 21, wherein the AC signal and the DC offset signal are provided simultaneously.

25. The method of claim 21, wherein the DC offset signal is applied after initiation of the AC signal.

26. The method of claim 21, wherein the DC offset signal is applied utilizing two electrodes in contact with the tissue and the direction of current flow of the DC offset signal is periodically reversed between the two electrodes.

27. The method of claim 1, wherein:

(a) the one or more electrical signals further comprise an electrical prepulse and a DC offset signal;

(b) applying comprises

(i) applying the electrical prepulse to the tissue prior to the AC signal to induce electroporation within the region; and

(ii) applying the DC offset signal to the tissue, wherein the DC offset signal is effective to promote delivery of the agent through the region.

28. The method of claim 27, wherein the voltage of the electrical prepulse is in the range of about 1 to about 90 V.

29. The method of claim 28, wherein the electrical prepulse is a DC prepulse.

30. The method of claim 28, wherein the electrical prepulse is an AC prepulse.

31. The method of claim 27, wherein the DC offset signal is applied utilizing two electrodes in contact with the tissue and the direction of current flow of the DC offset signal is periodically reversed between the two electrodes.

32. The method of claim 27, wherein the DC offset signal is applied substantially continuously during delivery of the agent and is of a voltage or current effective to maintain a substantially constant rate of delivery of the agent through the region.

33. The method of claim 27, wherein the conductance or resistance within the region is maintained within a range that is approximately 20% of a target conductance or resistance.

34. The method of claim 33, wherein the range is approximately 10% of the target conductance or resistance.

35. The method of claim 34, wherein the range is approximately 5% of the target conductance or resistance.

36. The method of claim 35, wherein the range is approximately 1% of the target conductance or resistance.

37. The method of claim 1, wherein the human tissue is skin.

38. The method of claim 1, wherein the human tissue is mucosal membrane.

39. The method of claim 1, wherein the tissue is an animal tissue other than a human tissue.

40. The method of claim 1, wherein the tissue is a plant tissue.

41. The method of claim 1, wherein the region has an area in the range of about 1 cm² to about 200 cm².

42. The method of claim 41, wherein the region has an area in the range of about 5 cm to about 100 cm².

43. The method of claim 42, wherein the region has an area in the range of about 5 cm to about 30 cm².

44. The method of claim 1, wherein the agent is a pharmacologically active agent.

45. The method of claim 44, wherein the pharmacologically active agent is selected from the group consisting of analeptic agents;

analgesic agents;

anesthetic agents;

antiasthmatic agents;

antiarthritic agents;

anticancer agents;

anticholinergic agents;

anticonvulsant agents;

antidepressant agents;

antidiabetic agents;

antidiarrheal agents;

antiemetic agents;

antihelminthic agents;

antihistamines;

antihyperlipidemic agents;

antihypertensive agents;

anti-infective agents;

antiinflammatory agents;

antimigraine agents;

antineoplastic agents;

antiparkinsonism drugs;

antipruritic agents;

antipsychotic agents;

antipyretic agents;

antispasmodic agents;

antitubercular agents;

antiulcer agents;

antiviral agents;

anxiolytic agents;

appetite suppressants;

attention deficit disorder and attention deficit hyperactivity disorder drugs;

cardiovascular agents including calcium channel blockers, antianginal agents, central nervous system (“

CNS”

) agents, beta-blockers and antiarrhythmic agents;

central nervous system stimulants;

diuretics;

genetic materials;

hormonolytics;

hypnotics;

hypoglycemic agents;

immunosuppressive agents;

muscle relaxants;

narcotic antagonists;

nicotine;

nutritional agents;

parasympatholytics;

peptide drugs;

psychostimulants;

sedatives;

steroids;

smoking cessation agents;

sympathomimetics;

tranquilizers;

vasodilators;

β

-agonist;

a tocolytic agent; and

combinations thereof.

46. The method of claim 45, wherein the pharmacologically active agent is a pharmacologically active metabolite of the pharmacologically active agent.

47. The method of claim 45, wherein the pharmacologically active agent is contained in a liquid formulation comprising a vehicle suitable for transdermal drug delivery.

48. The method of claim 45, wherein the pharmacologically active agent comprises two or more pharmacologically active agents administered in combination.

49. The method of claim 1, wherein the agent is a nucleic acid.

50. A method of delivering an agent across a human tissue, comprising.

(a) supplying one or more electrical signals, the one or more electrical signals comprising an AC signal;

(b) applying the AC signal to the human tissue, wherein the tissue is human skin or mucosal tissue; and

(c) adjusting the AC signal so as to maintain a substantially constant state of electroporation within a region of the tissue, wherein maintenance of the substantially constant state of electroporation facilitates delivery of the agent.

51. The method of claim 50, further comprising applying an electrical prepulse to the tissue prior to the AC signal to induce electroporation within the region.

52. The method of claim 50, further comprising applying a DC offset signal effective to promote delivery of the agent through the region to the tissue.

53. The method of claim 51, further comprising applying a DC offset signal effective to promote delivery of the agent through the region to the tissue.