Effect of electric field and ultrasound for transdermal drug delivery

• US 20040210184A1
• Filed: 05/05/2004
• Published: 10/21/2004
• Est. Priority Date: 12/18/1995
• Status: Abandoned Application

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Mitragotri, Samir S., Pliquett, Uwe, Langer, Robert S., Kost, Joseph, Weaver, James C.
• Application Number:
  US10/839,571
• Publication Number:
  US 20040210184A1
• Time in Patent Office: Days
• US Class Current: 604/20
• CPC Class Codes: A61B 5/14514 using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
• CPC Class Codes: A61K 41/0047 Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• 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
• CPC Class Codes: A61N 1/0412 Specially adapted for transcutaneous electroporation, e.g. including drug reservoirs
• CPC Class Codes: A61N 1/042 Material of the electrode
• CPC Class Codes: A61N 1/0428 Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
• 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
• CPC Class Codes: A61N 1/327 for enhancing the absorption properties of tissue, e.g. by electroporation

Abstract

Transdermal transport of molecules during sonophoresis (delivery or extraction) can be further enhanced by application of an electric field, for example, electroporation or iontophoresis. In a preferred embodiment the ultrasound is low frequency ultrasound which induces cavitation of the lipid layers of the stratum corneum (SC). This method provides higher drug transdermal fluxes, allows rapid control of transdermal fluxes, and allows drug delivery or analyte extraction at lower ultrasound intensities than when ultrasound is applied in the absence of an electric field.

Claims

1. A method for enhancing transdermal transport of compounds comprising administering to the skin an effective amount of low frequency ultrasound to induce cavitation of the skin to enhance transport without increasing skin temperature more than about two degrees Centrigrade in combination with an effective amount of an electric field selected from the group consisting of iontophoresis and electroproration to enhance transport.

3. The method of claim 1 wherein the ultrasound is administered at a frequency of 1 MHz or less.

4. The method of claim 1 wherein the intensity of the ultrasound is less than 2.5 W/cm².

5. The method of claim 1 wherein the intensity of the ultrasound is less than 1.5 W/cm².

6. The method of claim 1 wherein the ultrasound is administered in combination with agents enhancing solubility of the compounds to be transported in combination with agents enhancing the fluidity of lipid bilayers.

8. The method of claim 1 wherein the compound to be transported is a drug the patient is in need of.

9. The method of claim 1 wherein the compound to be transported is an analyte to be measured.

10. The method of claim 1 wherein the electric field is pulsed.

11. The method of claim 1 wherein the ultrasound is pulsed.

15. The method of claim 1, wherein the electric field is iontophoresis.

16. The method of claim 1, wherein the electric field is electroporation.

17. The method of claim 1, wherein the ultrasound is applied simultaneously with the electric field.

18. The method of claim 1, wherein the ultrasound is applied before the electric field.

19. The method of claim 1, wherein the ultrasound is administered at a frequency equivalent to between 20 and 40 kHz.

20. The method of claim 1 wherein the frequency is less than 1 MHz, the intensity is in the range of between zero and 1 W/cm².

2. (Canceled).

7. (Canceled).

12. An apparatus, comprising a means for applying low frequency ultrasound to induce cavitation of the skin to enhance transport without increasing skin temperature more than about two degrees Centrigrade and a means for applying ant electric field in a form selected from the group consisting of iontophoresis and electroporation to skin in an amount effective to enhance transport of molecules trough the skin without damaging the skin.

13. The apparatus of claim 12 further comprising a reservoir for a compound to be transported.

14. The apparatus of claim 12 further comprising a reservoir for collection of an analyte to be measured.

21. The apparatus of claim 12, which can administer ultrasound at a frequency equivalent to between 20 kHz and 40 kHz.

22. The apparatus of claim 12 wherein the apparatus can administer ultrasound at a frequency less than 1 MHz, with an intensity in the range of between zero and 1 W/cm².

23. The apparatus of claim 12, wherein the electric field is iontophoresis.

24. The apparatus of claim 12, wherein the electric field is electroporation.