Surgery – Means for introducing or removing material from body for... – With means for cutting – scarifying – or vibrating tissue
Reexamination Certificate
1999-06-10
2001-11-27
Seidel, Richard K. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
With means for cutting, scarifying, or vibrating tissue
C604S289000, C604S290000
Reexamination Certificate
active
06322532
ABSTRACT:
FIELD
The present invention relates to an improved sonophoresis method and apparatus for enhancing transport of a substance through a liquid and, in particular, enhancing permeation of a substance into and/or across a membrane, such as for transdermal/transmucosal drug delivery and non-invasive monitoring of body fluids.
BACKGROUND
The term “sonophoresis” refers to the use of acoustic, usually ultrasonic, wave energy to enhance the transport of a substance through a liquid medium. The acoustic compression waves induce “streaming” and/or “cavitation” in the liquid medium. Streaming is a phenomenon that occurs when an oscillation in a liquid or gaseous medium forces the medium molecules to convect away from the source, which results in a net flow of agent or drug away from the wave source. Cavitation refers to the formation of bubbles in a liquid subjected to intense vibrations. It is often associated, for example, with the action of a propeller blade moving through water. In that context, cavitation is considered undesirable because it can cause erosive pitting of the propeller blade. However, cavitation may also be intentionally generated using high intensity acoustic waves, and there is a wide range of circumstances where it may be desired to do so. For example, cavitation can be useful in the context of such things as ultrasonic cleaning, and electroplating and electrochemistry processes.
One particularly important area where sonophoresis has been used is in the context of transdermal and transmucosal drug delivery. Conventional passive transdermal/transmucosal drug delivery systems are often ineffective at delivering large molecules into and/or across the dermal and mucosal membranes. It has been found, however, that transmembranal sonophoresis (i.e., the use of sonophoresis to enhance diffusion of a substance across a membrane) can be effectively used for transdermal/transmucosal drug delivery. U.S. Pat. Nos. 4,780,212, 4,767,402, and 4,948,587 to Kost, et al., U.S. Pat. No. 5,618,275 to Bock, U.S. Pat. No. 5,656,016 to Ogden, and U.S. Pat. No. 5,722,397 to Eppstein (all hereby incorporated by reference) disclose various sonophoresis systems.
In these conventional systems, sonophoresis is produced with a transducer made of a piezoelectric material that vibrates by simply expanding and contracting axially in response to an applied electrical voltage signal. When used for transdermal/transmucosal drug delivery, the waves generated by the sonophoresis transducer are applied to a drug-containing medium on the skin or mucosal tissue. By selecting piezoelectric material having an appropriate size and shape and applying a suitable voltage signal frequency, the resulting acoustic waves enhance permeation of the drug through the dermal/mucosal membrane.
The precise mechanism by which the acoustic waves help to enhance permeability through the skin/mucosal tissue is not fully understood. Without wishing to be bound by any theory, it is hypothesized that the acoustic waves cause microcavitation in the drug medium and the skin itself, and this action helps the drug molecules to diffuse into and through the skin. It is further hypothesized that the ordered lipid layers in parts of the skin may be temporarily disrupted by the acoustic waves, thus permitting molecules to pass. In any event, regardless of the mechanism(s) at work, the result is that the acoustic waves enhance passage of substances into and/or through the membrane.
There are two basic types of conventional sonophoresis transducer used. The first type is constructed of a converter and a horn section. The converter is made up of a stack of piezoelectric disks designed to vibrate in an axial direction. This so-called “horn type” of sonophoresis device, although potentially quite efficient at producing cavitation and permeation enhancement, is typically about 20 cm long and weighs as much as a kilogram. These large and heavy devices are cumbersome and obviously would not be desirable for many applications.
The second type of conventional sonophoresis transducer device does not have large converter and horn sections. It relies instead on only one or a small number of piezoelectric disk layers which, as with the horn type device, vibrate in a simple axial mode. Although these “disk type” of sonophoresis transducers can be relatively small and lightweight, they are generally not operated at resonance and thus are very inefficient, i.e., requiring a large amount of power to achieve suitable penetration enhancement. By way of comparison, for effective penetration enhancement a typical 20 cm long horn type device may only require on the order of about 0.1 to 0.2 watts/cm
2
of surface area of the relevant wave-generating surface (usually against the skin or mucosa); whereas a conventional disk type device of less than 2 cm or so thickness is estimated to require at least about an order of magnitude more power to achieve comparable results. Moreover, even if a suitable high power source is available to use with a disk type device, there may still be a serious problem with heat generation. Much of the energy used by a sonophoresis transducer operating in an axial vibration and non-resonant mode is converted into heat and when the amount of power required is too high relative to the size of the device, it can become so hot as to burn the user.
Hence, the two conventionally known types of sonophoresis transducer devices suffer two major disadvantages: they are unduly large and heavy and/or they are quite inefficient (i.e., requiring a relatively large amount of power to achieve suitable permeation enhancement). There is accordingly an important need for a more efficient wave-generating transducer to enhance diffusion and permeation for use in transdermal/transmucosal sonophoresis, as well as other applications.
SUMMARY
It has now been found that diffusion of a substance in a liquid medium via sonophoresis, and particularly diffusion into and/or through a membrane, can be efficiently enhanced using a “flexure mode” transducer instead of a simple axial mode transducer as in conventional sonophoresis systems. The improved sonophoresis system of the present invention, using a flexure mode transducer, is much smaller and more efficient than conventional systems, which is particularly useful in the context of transdermal/transmucosal sonophoresis because it allows for small, lightweight devices with relatively low power requirements.
Flexure mode transducers—which are well known in certain other contexts unrelated to the present invention—produce in response to an electrical voltage signal a vibrating flexing action, rather than a simple expansion and contraction action. Flexure mode transducers can have various designs. A typical flexure mode transducer has at least one flexible layer of material, such as aluminum or titanium, joined to a piezoelectric layer, such as a piezoceramic. When the piezoelectric layer expands and contracts in response to a voltage signal, the joined flexible layer (which does not likewise expand and contract) forces the device to flex in order to accommodate the dimensional changes of the piezoelectric layer. Moreover, by applying a proper voltage signal frequency to the flexure mode transducer, a resonant flexure vibration response can be attained, thereby efficiently producing the desired acoustic waves. A flexure mode transducer can, for example, in its simplest form comprise at least one flexible disk layer bonded to at least one piezoelectric material disk layer. Multiple layers of one or both materials may also be used. A construction of one flexible layer joined to one piezoelectric layer is sometimes referred to as a “unimorph; and a construction of one piezoelectric layer sandwiched between two flexible layers is sometimes referred to as a “bimorph”. The layers may be continuous or discontinuous. One variation is a ring design wherein the piezoelectric material forms a ring joined to the perimeter of a flexible disk layer. Radial or axial expansion and contraction of the piezoelectric ring in response to
D'Sa Joseph M.
Keister Jaimeson C.
3M Innovative Properties Company
Howard MarySusan
Ringsred Ted K.
Seidel Richard K.
Sprague Robert W.
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