Surgery – Means for introducing or removing material from body for... – With means for cutting – scarifying – or vibrating tissue
Reexamination Certificate
2001-07-26
2003-09-16
Mendez, Manuel (Department: 3763)
Surgery
Means for introducing or removing material from body for...
With means for cutting, scarifying, or vibrating tissue
Reexamination Certificate
active
06620123
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to transdermal molecular transportation. More specifically, this invention relates to methods and apparatus for producing homogenous cavitation in a transdermal transport system.
BACKGROUND OF THE INVENTION
Drugs are routinely administered either orally or by injection. The effectiveness of most drugs relies on achieving a certain concentration in the bloodstream. Although some drugs have inherent side effects which cannot be eliminated in any dosage form, many drugs exhibit undesirable behaviors that are specifically related to a particular route of administration. For example, drugs may be degraded in the GI tract by the low gastric pH, local enzymes or interaction with food or drink within the stomach. The drug or disease itself may forestall or compromise drug absorption because of vomiting or diarrhea. If a drug entity survives its trip through the GI tract, it may face rapid metabolism to pharmacologically inactive forms by the liver, the first-pass effect. Sometimes the drug itself has inherent undesirable attributes such as a short half-life, high potency or a narrow therapeutic blood level range.
Recently, efforts aimed at eliminating some of the problems of traditional dosage forms involve transdermal delivery of the drugs (TDD). Topical application has been used for a very long time, mostly in the treatment of localized skin diseases. Local treatment, however, only require that the drug permeate the outer layers of the skin to treat the diseased state, with little or no systemic accumulation. Transdermal delivery systems are designed for, inter alia, obtaining systemic blood levels, and topical drug application. For purposes of this application, the word “transdermal” is used as a generic term to describe the passage of substances to and through the skin.
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. Maibach, H. I. (Ed), pp 1-12, Marcel Dekker, New York, 1989.
The transport of drugs through the skin is complex since many factors influence their permeation. These include the skin structure and its properties, the penetrating molecule and its physical-chemical relationship to the skin and the delivery matrix, and the combination of the skin, the penetrant, and the delivery system as a whole. Particularly, 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 dermis, 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 dermis. The capillaries do not actually enter the epidermal tissue but come within 150 to 200 microns of the outer surface of the skin.
In comparison to injections, TDD can reduce or eliminate the associated pain and the possibility of infection. Theoretically, the transdermal route of drug administration could be advantageous in the delivery of many therapeutic drugs, including proteins, because many drugs, including proteins, are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake, proteins such as interferon are cleared rapidly from the blood and need to be delivered at a sustained rate in order to maintain their blood concentration at a high value, and transdermal devices are easier to use than injections.
In spite of these advantages, very few drugs and no proteins or peptides are currently administered transdermally for clinical applications because of the low skin permeability to drugs. This low permeability is attributed to the SC, the outermost skin layer which consists of flat, dead cells filled with keratin fibers (keratinocytes) surrounded by lipid bilayers. 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., Maibach, H. I. (Ed), pages 27-53, Marcel Dekker, New York 1989). Several methods have been proposed to enhance transdermal drug transport, including the use of chemical enhancers, i.e. 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., Guy, R. H., Eds., Marcel Dekker: 1989; pp. 247-288; Junginger, et al. in
Drug Permeation Enhancement
; Hsieh, D. S., Eds., pp. 59-90; Marcel Dekker, Inc. 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
Transdermal Drug Delivery: Developmental Issues and Research Initiatives
, Ed. Hadgraft J., Guy, R. H., Marcel Dekker, 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., Maibach H. I., Eds. (Plenum: New York, 1993); Frideman, R. M., “
Interferons: A Primer
”, Academic Press, New York, 1981). For example, U.S. Pat. No. 4,309,989 to Fahim and U.S. Pat. No. 4,767,402 issued to Kost et al. both describe the use of ultrasound in conjunction with transdermal drug delivery. U.S. Pat. No. 4,309,989 discloses the topical application of a medication using ultrasound with a coupling agent such as oil. Ultrasound at a frequency of at least 1000 kHz and a power of one to three W/cm
2
was used to cause selective localized intracellular concentration of a zinc containing compound for the treatment of herpes simplex virus.
U.S. Pat. No. 4,309,989, the disclosure of which is specifically incorporated by reference, discloses the use of ultrasound for enhancing and controlling transdermal permeation of a molecule, including drugs, antigens, vitamins, inorganic and organic compounds, and various combinations of these substances, through the skin and into the circulatory system. Ultrasound having a frequency between about 20 kHz. and 10 MHz. and having an intensity between about 0 and 3 W/cm
2
is used essentially to drive molecules through the skin and into the circulatory system. A significant drawback to this system is that the resultant enhanced permeability only occurs while the ultrasound is being applied to the skin. Thus, the skin is often damaged due to over exposure to the ultrasound.
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
) (such as that described in the Kost et al. patent). 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. Accordingly, a better selection of ultrasound techniques is needed to induce a higher enhancement of transdermal drug transport by sonophoresis.
Application of low-frequency (between approximately 20 and 200 kHz) ultrasound can dramatically enhance transdermal transport of drugs, as described in PCT/US96/12244 by Massachusetts Institute of Technology. Transdermal transport enhancement induce
Kellogg Scott C.
Kost Joseph
Mitragotri Samir S.
Warner Nicholas F.
Hunton & Williams LLP
Mendez Manuel
Sontra Medical Inc.
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