Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
2000-10-17
2002-11-26
Look, Edward K. (Department: 3745)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S022000
Reexamination Certificate
active
06487447
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method and an apparatus for transdermal and/or intradermal delivery of drugs by sonoporation and more particularly to in-vivo transdermal and/or intradermal delivery of drugs.
BACKGROUND OF THE INVENTION
Transdermal and/or intradermal delivery of drugs offer several advantages over conventional delivery methods including oral and injection methods. It delivers a predetermined drug dose to a localized area with a controlled steady rate and uniform distribution, is non-invasive, convenient and painless.
Transdermal and/or intradermal delivery of drugs require transport of the drug molecules through the stratum corneum, i.e., the outermost layer of the skin. The stratum corneum (SC) provides a formidable chemical barrier to any chemical entering the body and only small molecules having a molecular weight of less than 500 Da (Daltons) can passively diffuse through the skin at rates resulting in therapeutic effects. A Dalton is defined as a unit of mass equal to {fraction (1/12)} the mass of a carbon-12 atom, according to “Steadman's Electronic Medical Dictionary” published by Williams and Wilkins (1996).
In co-pending patent application entitled “Method of forming micropores in skin”, incorporated herein by reference, sonoporation has been proposed as a method to facilitate transdermal and/or intradermal delivery of molecules larger than 500 Da and to increase the rate of drug delivery through the SC. The sonoporation apparatus described in the referenced application is not practical for in-vivo drug delivery and in particular for treating humans.
It would be advantageous to provide a method and an apparatus for in-vivo transdermal and/or intradermal delivery of any size drug molecules.
SUMMARY OF THE INVENTION
In general, in one aspect, the invention provides an apparatus for performing in-vivo sonoporation of a skin area and transdermal and/or intradermal delivery of a drug solution including a container having an end covered with a porous membrane and containing the drug solution and an ultrasound horn having a tip submerged in the drug solution. The ultrasound horn applies ultrasound radiation to the drug solution. The ultrasound radiation has a frequency in the range of 15 KHz and 1 MHz and is applied at an intensity, for a period of time and at a distance from said skin area effective to generate cavitation bubbles. The cavitation bubbles collapse and transfer their energy into the skin area thus causing the formation of pores in the skin area. The ultrasound radiation intensity and distance from the skin area are also effective in generating ultrasonic jets, which ultrasonic jets then drive the drug solution through the porous membrane and the formed pores into the skin area.
Implementations of the invention may include one or more of the following features. The membrane may have pores with a diameter of 100 micrometers. The membrane may be hydrophobic. The tip may be removable connected to the ultrasound horn and it may have a distal end surface, which is flat or concave. The distal end surface may have a plurality of depressions. The tip may also have a body having markings indicating the amount of the drug solution contained in the container. A removable protective film may cover the membrane. The container may have an outer wall, an inner wall and an absorbent wick placed between the inner and outer wall. The wick absorbs any excess drug solution that is not driven into the skin area through the formed pores and it may be made of highly absorbent and hydrophilic material such as absorbent cellulose material, polyvinyl alcohol sponge, Sodium Carboxy-Methyl Cellulose (CMC), blotting paper and any other spongy materials.
The container inner wall may have first and second grooves and tip may have a body having first and second grooves. The tip is inserted into the container and placed so that the first and second grooves of the tip body are opposite the first and second grooves of the container inner wall. This arrangement defines first and second spaces for accommodating first and second o-rings, respectively. The container may also have an inlet septum for filling it with the solution. The container may be a cylinder made of a transparent material and/or plastic material.
The ultrasound frequency may be 20 KHz and the ultrasound intensity may be in the range of 5 W/cm
2
and 55 W/ cm
2
. The tip may have a distal end located at a distance from the membrane in the range of 1 millimeter to 10 millimeters. The ultrasound radiation may be continuous or pulsed and it may be applied for a period of time in the range of about 30 seconds to 5 minutes, preferably 1 minute for continuous exposure or about 10 minutes to 20 minutes for pulsed exposure with a 5% duty cycle, respectively. The formed pores may have a diameter in the range of 1 micrometer to 100 micrometers.
In general, in another aspect, the invention features a method of performing in-vivo sonoporation of a skin area and transdermal and/or intradermal delivery of a drug solution. The method includes providing a container containing a predetermined amount of the drug solution and having a first end and a second end, the second end being covered with a porous membrane. Next a tip of an ultrasound horn is submerged in the drug solution through the first end of the container and then the porous membrane is placed in contact with the skin area. The ultrasound radiation is then turned on having a frequency in the range of 15 KHz and 1 MHz. The ultrasound radiation is applied with an intensity, for a period of time and at a distance from the skin area effective to generate cavitation bubbles. The cavitation bubbles collapse and transfer their energy into the skin area thus causing the formation of pores in the skin area. The ultrasound radiation intensity and distance from the skin area are also effective in generating ultrasonic jets, which ultrasonic jets then drive the drug solution through the porous membrane and the formed pores into the skin area.
Among the advantages of this invention may be one or more of the following. The apparatus allows a painless and rapid delivery of drugs through the skin for either topical or systemic therapy. The apparatus allows coupling of the ultrasound radiation to a container containing the drug solution without dampening the ultrasound intensity.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and description below. Other features, objects and advantages of the invention will be apparent from the following description of the preferred embodiments, the drawings and from the claims.
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Childs Richard
Weimann Ludwig
Elman Gerry J.
Elman & Associates
Leslie Michael
Look Edward K.
Ultra-Sonic Technologies, L.L.C.
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