Sonophoretic enhanced transdermal transport

Details Sonophoretic enhanced transdermal transport Sonophoretic enhanced transdermal transport

1999-01-08

2001-02-20

Winakur, Eric F. (Department: 3736)

Surgery

Diagnostic testing

Measuring or detecting nonradioactive constituent of body...

C604S022000

Reexamination Certificate

active

06190315

ABSTRACT:

FIELD OF THE INVENTION
The present invention generally relates to improved methods for transdermal transport using ultrasound. More specifically, methods are provided enabling repeated analyte extraction or dug delivery over a period of time following a single application of low frequency ultrasound.
BACKGROUND OF THE INVENTION
Transdermal drug delivery (TDD) offers several advantages over traditional delivery methods including injections and oral delivery. When compared to oral delivery, TDD avoids gastrointestinal drug metabolism, reduces first-pass effects, and provides sustained release of drugs for up to seven days, as reported by Elias, in
Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery
, Bronaugh, R. L. et al. (Eds), pages 1-12, Marcel Dekker, New York (1989).
The skin is a complex structure. There are at least four distinct layers of tissue: the nonviable epidermis (stratum corneum, SC), the viable epidermis, the viable dennis, and the subcutaneous connective tissue. Located within these layers are the skin's circulatory system, the arterial plexus, and appendages, including hair follicles, sebaceous glands, and sweat glands. The circulatory system lies in the dermis and tissues below the dennis. The capillaries do not actually enter the epidermal tissue but come within 150 to 200 microns of the outer surface of the skin. The highly-ordered structure of the lipid bilayers confers an impermeable character to the SC (Flynn, G. L., in
Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery
; Bronaugh, R. L. et al. (Eds.), pages 27-53, Marcel Dekker, New York, (1989). The word “transdermal” is used herein as a generic term. However, in actuality, transport of drugs occurs only across the epidermis where the drug is absorbed in the blood capillaries. In comparison to injections, TDD can reduce or eliminate the associated pain and the possibility of infection.
Several methods have been proposed to enhance transdermal drug transport, including the use of chemical enhancers, ie. the use of chemicals to either modify the skin structure or to increase the drug concentration in a transdermal patch (Burnette, R. R., in
Developmental Issues and Research Initiatives
; Hadgraft J., et al. (Eds.), pages 247-288, Marcel Dekker, New York (1989); Junginger, et al. in
Drug Permeation Enhancement
; Hsieh, D. S., (Eds.), pages 59-90; Marcel Dekker, New York (1994)) and the use of applications of electric fields to create transient transport pathways [electroporation] or to increase the mobility of charged drugs through the skin [iontophoresis] (Prausnitz,
Proc. Natl. Acad. Sci. USA
90: 10504-10508 (1993); Walters, K. A., in
Transdennal Drug Delivery: Developmental Issues and Research Initiatives
, Hadgraft J., Guy, R. H., (Eds.) Marcel Dekker, New York (1989)). Another approach that has been explored is the application of ultrasound.
Ultrasound has been shown to enhance transdermal transport of low-molecular weight drugs (molecular weight less than 500) across human skin, a phenomenon referred to as sonophoresis (Levy, J. Clin. Invest. 1989, 83, 2974-2078; Kost and Langer in “
Topical Drug Bioavailability, Bioequivalence, and Penetration
”; pp. 91-103, Shah V. P., M. H. I., Eds. (Plenum: New York, 1993); Frideman, R. M., “
Interferons: A Primer
”, Academic Press, New York, 1981). Although a variety of ultrasound conditions have been used for sonophoresis, the most commonly used conditions correspond to therapeutic ultrasound (frequency in the range of between one MHz and three MHz, and intensity in the range of between above zero and two W/cm
2
) (U.S. Pat. No. 4,767,402 to Kost, et al.). It is a common observation that the typical enhancement induced by therapeutic ultrasound is less than ten-fold. In many cases, no enhancement of transdermal drug transport has been observed upon ultrasound application. U.S. Pat. Nos. 5,458,140 and 5,445,611 to Eppstein et al. disclose the use of ultrasound at a frequency range of between 0.1 and 100 MHz, preferably between 3 and 30 MHz, in combination with chemical enhancers, to enhance skin permeability. The ultrasound was frequency, intensity and/or phase modulated. An increase in permeability was noted during application of the ultrasound but decreased to passive diffusion rates when ultrasound was discontinued (see Example 4 in both patents).
U.S. Pat. No. 5,323,769 to Bommannan discloses ultrasound enhanced delivery of molecules into and through the skin, in combination with chemical permeation enhancers. The ultrasound is applied at frequencies above 10 MHz. The ultrasound must be applied “relatively simultaneously” with the molecules being delivered, within at least six minutes, preferably within two minutes.
Application of low frequency (between approximately 20 and 200 kHz) ultrasound can dramatically enhance transdermal transport of molecules when applied directly to the drug or at the time of collection, as described in WO 97/04832 by Massachusetts Institute of Technology. Transdermal transport enhancement induced by low-frequency ultrasound was found to be as much as 1000-fold higher than that induced by therapeutic ultrasound.
There is a major medical need to extract analytes through the skin, such as in diabetes where it is desirable to measure blood glucose several times per day in order to optimize insulin treatment and thereby reduce the severe long-term complications of the disease. Currently, diabetics do this by pricking the highly vascularized fingertips with a lancet to perforate the skin, then milking the skin with manual pressure to produce a drop of blood, which is then assayed for glucose using a disposable diagnostic strip and a meter into which this strip fits. This method of glucose measurement has the major disadvantage that it is painful, so diabetics do not like to obtain a glucose measurement as often as is medically indicated.
Therefore, many groups are working on non-invasive and less invasive means to measure glucose, such as micro lancets that are very small in diameter, very sharp, and penetrate only to the interstitium (not to the blood vessels of the dermis). A small sample, from about 0.1 to two &mgr;l, of interstitial fluid is obtained through capillary forces for glucose measurements. Other groups have used a laser to breach the integrity of the stratum comeum and thereby make it possible for blood or interstitial fluid to diffuse out of such a hole or to be obtained through such a hole using pneumatic force (suction) or other techniques. An example of such a laser based sampling device is disclosed in U.S. Pat. No. 5,165,418 to Tankovich and WPI ACC No: 94-167045/20 by Budnik (assigned to Venisect, Inc.).
It would be of significant utility to be able to obtain a sample of blood, lymph, or interstitial fluid more quickly, using an easier procedure, and relatively noninvasively. It would also be advantageous to be able to repeatedly extract analyte or deliver drug transdermally over a period of time.
It is an object of the present invention to provide methods enabling repeated or continuous transdermal transport with minimal effort to permeabilize the skin.
SUMMARY OF THE INVENTION
Methods are described wherein the application of ultrasound is required only once for repeated or sustained transdermal extraction or delivery, over a period of time, rather than prior to each extraction or delivery. Examples demonstrate multiple sample extractions could be obtained over a time period of up to ten hours after a single ultrasound application to the collection site. The method is applicable to extraction of analyte, such as glucose, extraction, as well as for drug delivery. The method may also be applicable for enhancing permeation of cellular membranes.
In the preferred embodiment, low frequency ultrasound effective to permeabilize the skin or membrane is applied initially, alone or in combination with an enhancer followed by mechanical analyte extraction or drug delivery over a period of time. The initial application of ultrasound is effective to permeabilize the skin

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