United States Patent:   6,002,961

Assignee:  Massachusetts Institute of Technology (Cambridge, MA)

Filed:  July 25, 1995

Applications of low-frequency (20 KHz) ultrasound enhances transdermal transport of high-molecular weight proteins. This method includes a simultaneous application of ultrasound and protein on the skin surface in order to deliver therapeutic doses of proteins across the skin. Examples demonstrate in vitro and in vivo administration of insulin (molecular weight 6,000 D), and in vitro administration of gamma interferon (molecular weight 17,000 D), and erythropoeitin (molecular weight 48,000 D).

DETAILED DESCRIPTION OF THE INVENTION

Sonophoresis:

As used herein, sonophoresis is the application of ultrasound to the skin on which a drug, most preferably proteinaceous in nature, alone or in combination with a carrier, penetration enhancer, lubricant, or other pharmaceutically acceptable agent for application to the skin, has been applied. As used herein, "low frequency" sonophoresis is ultrasound at a frequency that is less than 1 MHz, more typically in the range of 20 to 40 KHz, which is preferably applied in pulses, for example, 100 msec pulses every second at intensities in the range of between zero and 1 W/cm², more typically between 12.5 mW/cm² and 225 mW/cm².

Many ultrasound devices are available commercially which can be used in the method described herein. For example, the ultrasonic devices used by dentists to clean teeth have a frequency of between about 25 and 40 KHz. Commercially available portable ultrasound tooth-brushes make use of a small sonicator contained within the tooth-brush (Sonex International Corporation). This sonicator is portable and operates on rechargeable batteries. Small pocket-size sonicators carried by patients and used to "inject" drugs whenever required could be readily adapted from these devices. In addition, these devices could be potentially combined with sensors that can monitor drug concentrations in the blood to formulate a self-controlled drug (insulin, for example) delivery method that can potentially eliminate the attention required by the patient.

Devices typically used for therapeutic or diagnostic ultrasound operate at a frequency of between 1.6 and 10 MHz. These devices can also be modified for use at lower frequencies.

Drugs to be Administered.

Drugs to be administered include a variety of bioactive agents, but are preferably proteins or peptides. Specific examples include insulin, erythropoietin, and interferon. Other materials, including nucleic acid molecules such as antisense and genes encoding therapeutic proteins, synthetic organic and inorganic molecules including antiinflammatories, antivirals, antifungals, antibiotics, local anesthetics, and saccharides, can also be administered.

The drug will typically be administered in an appropriate pharmaceutically acceptable carrier having an absorption coefficient similar to water, such as an aqueous gel. Alternatively, a transdermal patch such as the one described in the examples can be used as a carrier. Drug can be administered in a gel, ointment, lotion, suspension or patch, which can incorporate anyone of the foregoing.

Administration of Drug

The drug is preferably administered to the skin at a site selected based on convenience to the patient as well as maximum drug penetration. For example, the arm, thigh, or stomach represent areas of relatively thin skin and high surface area, while the hands and feet are uneven and calloused. In the preferred embodiment, drug is applied to the site and ultrasound applied immediately thereafter.

Based on these calculations and the data in the following examples, one can calculate the required dosage and application regime for treatment of a patient, as follows. A typical diabetic patient (70 Kg weight) takes about 12 Units of insulin three times a day (total dose of about 36 Units per day: cited in `World Book of Diabetes in Practice` Krall, L. P. (Ed), Elsvier, 1988). If each insulin dose was to be delivered by sonophoresis in 1 hour, the required transdermal flux would be 12 U/hour. Note that 1 unit (1 U) of insulin corresponds approximately to 40 mg of insulin. The transdermal patch area used in these calculations is 40 cm² (the area of a transdermal Fentanyl patch [ALZA Corporation]). The donor concentrations used in these calculations are 100 U/ml in the case of insulin (commercially available insulin solution [Humulin]), 3.times.10⁷ in the case of .gamma.-interferon (typical concentration of interferon solution recommended by Genzyme Corporation), and 3.times.10⁵ U/ml in the case of erythropoeitin [Davis J., Arakawa T., Strickland T., Yphantis D., Biochemistry, 2633-2638, 1987].

A typical .gamma.-interferon dose given each time to patients suffering from cancer or viral infections is about 5.times.10⁶ U [(i) Grups J. W., Frohmuller H. G., Br. J. Med., 1989, 64 (3): 218-220, (ii) Parkin J. M., Eales L., Galazka A., Pinching A., Br. Med. J., 1987, 294: 1185-1186.] Similar doses of .alpha.interferon and .beta.-interferon have also been shown to enhance the immune response of patients suffering from viral infections and cancer (cited in `Clinical Applications of interferons and their inducers`, Ed. Stringfellow D., Marcel Dekker, New York, 1986). If this interferon dose was to be given by sonophoresis in 1 hour, the required transdermal flux would be 5.times.10⁶ U/hour. Note that 1 unit of .gamma.-interferon corresponds approximately to 1 pg of .gamma.-interferon.

A typical daily erythropoeitin dose given subcutaneously to anemic patients is about 400 U (cited in `Subcutaneous Erythropoeitin, Bommer J., Ritz E., Weinreich T., Bommer G., Ziegler T., Lancet, 406, 1988). If this dose was to be delivered in three steps, each involving sonophoresis for 1 hour, the transdermal flux required would be about 140 U/hour. Note that 1 unit of erythropoeitin corresponds approximately to 7.6 nanograms of erythropoeitin.

An optimal selection of ultrasound parameters, such as frequency, pulse length, intensity, as well as of non-ultrasonic parameters, such as ultrasound coupling medium, can be conducted to ensure a safe and efficacious application using the guidelines disclosed herein as applied by one of ordinary skill in the art.

Claim 1 of 6 Claims

1. A method for enhancing delivery of a drug in a single step across the skin into the blood using ultrasound wherein the ultrasound is applied by pulsing at a frequency of between 20 kHz and less than 1 MHz at an intensity not causing any irreversible skin damage for a period of time effective to deliver to the patient a therapeutic drug dosage into the blood.

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