Chemical and physical enhancers and ultrasound for transdermal drug delivery

• US 5,947,921 A
• Filed: 12/18/1995
• Issued: 09/07/1999
• Est. Priority Date: 12/18/1995
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Johnson, Mark E., Pishko, Michael, Langer, Robert S., Mitragotri, Samir S., Kost, Joseph, Blankschtein, Daniel
• Primary Examiner(s): Bockelman, Mark
• Application Number:
  US08/574,377
• Time in Patent Office: 1,359 Days
• Field of Search: 604/20, 604/22, 604/49, 128/760, 128/637, 601/2
• US Class Current: 604/22
• 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 1/325 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 providing chemical enhancers which increase the solubility of the compound to be transported and/or lipid bilayer solubility, and/or additional driving forces for transport, such as mechanical or osmotic pressure, magnetic fields, 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 and other forces or concentrations than that required if each means of enhancing transport is used individually.

Claims

1. A method for enhancing transdermal transport of compounds comprising administering to the skin an effective amount of ultrasound in combination with linoleic acid in an ethanol solution.

4. The method of claim 1 wherein the combination is linoleic acid in an ethanol solution.

2. A method for enhancing transdermal transport of compounds comprising administering to the skin an effective amount of ultrasound in combination with a magnetic force field to transport the compound through the skin.

3. The method claim 2 comprising administering to the skin an effective amount of ultrasound and magnetic force in combination with an agent enhancing solubility of the compounds to be transported and an agent enhancing the fluidity of lipid bilayers.

5. The method of claim 2 wherein the ultrasound is administered at a frequency of between 20 kHz and 40 kHz.

6. The method of claim 2 wherein the ultrasound is administered at a frequency of 1 MHz or less.

7. The method of claim 2 wherein the intensity of the ultrasound is less than 2.5 W/cm².

8. The method of claim 2 wherein the intensity of the ultrasound is less than 1.5 W/cm².

9. The method of claim 2 wherein the ultrasound is administered in combination with an electric force field selected from the group consisting of electroporation and iontophoresis.

10. The method of claim 2 wherein the ultrasound is administered in combination with a mechanical or osmotic force field.

11. The method of claim 2 wherein the ultrasound is administered in combination with iontophoresis.

12. The method of claim 2 wherein the compound to be transported is a drug the patient is in need of.

13. The method of claim 2 wherein the compound to be transported is an analyte to be measured.