Ultrasound enhancement of transdermal drug delivery

• US 4,767,402 A
• Filed: 07/08/1986
• Issued: 08/30/1988
• Est. Priority Date: 07/08/1986
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Levy, Drora, Langer, Robert S., Kost, Joseph
• Primary Examiner(s): Rosenbaum, C. Fred
• Assistant Examiner(s): Costantino, Mario
• Application Number:
  US06/883,111
• Time in Patent Office: 784 Days
• Field of Search: 604/22, 604/890, 604/891, 604/896, 604/897, 604/306, 604/49, 604/93, 604/28, 604/289, 604/290, 604/304, 604/66, 128/24 A, 128/328, 128/804
• US Class Current: 604/22
• 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 35/00 Devices for applying media, e.g. remedies, on the human body devices for handling toiletry or cosmetic substances A45D; absorbent pads, e.g. swabs, A61F13/15
• CPC Class Codes: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis

Abstract

The present invention is a method using ultrasound to enhance permeation of molecules through the skin and into the blood stream, at a controlled rate. Depending on the drug being infused through the skin, the rate of permeation is increased as well as the efficiency of transfer. Drugs which may not be effective under other conditions, for example, due to degradation within the gastrointestinal tract, can be effectively conveyed transdermally into the circulatory system by means of ultrasound.

Claims

1. A method for enhancing and controlling transdermal infusion of molecules comprising:

(a) selecting the molecules having a low rate of permeability through the skin to be infused;

(b) applying to the skin said molecules in a medium with an absorption coefficient similar to that of water;

(c) applying ultrasound to said molecules in said medium at a frequency of between 20 kHz and 10 MHz and an intensity of between 0 and 3 W/cm² ; and

(d) varying the frequency and intensity over time to transdermally infuse said molecules at an optimal rate into the circulatory system without delay or damaging the skin, wherein the optimal rate is determined by measurements of a physiological fluid.

2. This method of claim 1 wherein the ultrasound frequency is applied at between 0.5 MHz and 1.5 MHz and an intensity of between 2 and 4 W/cm².

3. The method of claim 1 wherein the ultrasound is applied for less than 10 minutes.

4. The method of claim 1 further comprising suspending the molecules to be applied in an aqueous gel.

5. The method of claim 1 further comprising constructing a transdermal drug patch formed of a support, adhesive, a drug-containing matrix and a protective covering for applying the molecules to the skin.

6. The method of claim 1 wherein the ultrasound is applied continuously.

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

8. The method of claim 1 further comprising selecting said molecule from the group of molecules consisting of proteins, drugs, antigens, vitamins, inorganic compounds, organic compounds, and combinations thereof, wherein said molecule has a biological effect when infused into the circulatory system.

9. The method of claim 1 further comprising measuring the temperaure of the skin where the ultrasound is applied.

10. The method of claim 9 wherein the ultrasound is applied at a frequency and intensity over a period of time which does not cause an increase in skin temperature of more than 2°

C.

11. The method of claim 1 further comprising measuring the concentration of said molecules in a physiological fluid during or immediately after administration of the ultrasound.

12. The method of claim 1 further comprising measuring the concentrations of said molecule in the physiological fluid over time, determining the rate of transdermal transfer for said molecules at specific frequencies, intensities and times of ultrasound application, wherein the molecules are subsequently infused using ultrasound at the frequency, intensity and time of application determined to yield a specific concentration.