Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
1999-03-30
2002-11-19
Mendez, Manuel (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C606S015000
Reexamination Certificate
active
06484052
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to techniques for drug delivery, and more specifically, it relates to the use of acoustic waves for the enhancement of drug delivery.
2. Description of Related Art
Ultrasound-enhanced drug delivery has been postulated to work through a variety of mechanisms. Most notably, ultrasound produces cavitation bubbles, which are thought to disrupt the lipid bilayer membrane of cells (Mitragotri, et al. Pharm Res 1996; 13: 411-420). This disruption can cause channels to form, which can temporarily increase a cell's permeability to certain drug compounds. The concentration of compounds which normally have low diffusion rates into the cell can be increased. Transdermally (across the skin), it has been shown that the permeability of disordered lipid bilayers can be up to 5000-fold higher than the diffusion coefficients in normal lipid bilayers (Mitragotri 1996). Other compounds, to which the cell is usually impermeable, can also be driven into the cell through the use of ultrasound.
Extracorporeal (transdermal) application of ultrasound is inappropriate when deeper penetration of the ultrasound is required for enhanced drug delivery in remote locations. In the current transdermal method, the drug of interest is applied to the skin and ultrasound is generated through the placement of a piezoelectric transducer on the skin. This ultrasound could be focused into deeper structures, similar to ultrasound imaging transducers. However, it is difficult to assess or control dosimetry to deeper structures with this method and the ultrasound does not penetrate through gas filled organs or high density tissues such as bone. If one transducer is used, a high amount of power is necessary to generate the required ultrasound in the underlying tissues. The high power needed can cause thermal damage to the skin. An array of transducers could be used to focus onto a single point beneath the skin. However, the amount of heat and stress produced as the ultrasound waves converge, may produce damage to the underlying tissue, including those that are not intended to be treated. Local generation of ultrasound solves many of these potential problems. However, the use of traditional piezoelectric materials such as PZT induce other complications. These materials need electrical stimulation, which is undesirable to deliver inside the body. Further, the large size of the piezoelectric materials required to achieve necessary ultrasound magnitudes, forbids certain in vivo applications. The present invention, with its local generation and delivery of optically generated ultrasound, facilitates the delivery of ultrasound at required intensities into remote locations.
U.S. Pat. No. 4,767,402, issued Aug. 30, 1988, titled “Ultrasound Enhancement Of Transdermal Drug Delivery” is directed to a method using 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. The frequency and intensity of ultrasonic energy which is applied, the media between the ultrasonic applicator and the skin, and the length of time of exposure are determined according to the type of skin and the substance to be diffused transdermally. Levels of the diffused molecules in the blood and urine measured over a period of time are initially used to determine under what conditions adequate transfer occurs. In general, the frequency range of the ultrasound is between 20 kHz and 10 MHz, with intensities between 0 and 3 W/cm<2>. Intensity is decreased as the frequency is decreased to prevent damage to the skin. The preferred range of frequencies is between 0.5 MHz and 1.5 MHz and the preferred range of intensities is between 2 and 4 W/cm<2>. Exposure is for between 1 and 10 minutes for most medical uses. The ultrasound may be pulsed or continuous. However, the frequency, intensity and time of exposure are interdependent as well as a function of the molecule being diffused and the nature of the skin at the site of exposure. One way of determining the maximum limit of exposure is to measure skin temperature, decreasing or stopping the treatment when the temperature of the skin rises one to two degrees Centigrade.
In U.S. Pat. No. 5,386,837, issued Feb. 7, 1995, titled “Method For Enhancing Delivery Of Chemotherapy Employing High-Frequency Force Fields” pulse shocks of high-frequency wave energy (e.g. RF, microwave, high-energy infra-red or laser electromagnetic wave energy or ultrasonic acoustic wave energy), rather than DC electric pulses, are employed to non-invasively produce, with minimal or, if desired, a controlled amount of temperature rise in a patient's body tissues, force fields of an intensity sufficient to create transient pores in the plasma membranes of targeted cells, such as tumor or other diseased cells, through which chemotherapeutic agents can easily be delivered, enter and taken up by these targeted cells, even for (1) deep-seated cells (e.g., the cells of a deep-seated tumor) or (2) non-localized diseased cells (e.g., metastasized tumor cells) within a patient's body.
U.S. Pat. No. 5,421,816, issued Jun. 6, 1995, titled “Ultrasonic Transdermal Drug Delivery System” described the use of Ultrasonic energy to release a stored drug and forcibly move the drug through the skin of an organism into the blood stream. A housing (81) includes a cavity (67) defined by an assembly of ultrasonic transducers (65) and separated from the skin by a polymeric membrane (69) that stores the drug to be delivered. The ultrasonic transducer assembly includes a flat, circular ultrasonic transducer (85) that defines the top of a truncated cone and a plurality of transducer segments (
87
a
,
87
b
,
87
c
,
87
d
. . . ) that define the walls of the cone. The resonant frequency of the planar transducer is lower than the resonant frequency of the transducer segments. The planar, flat, circular transducer generates fixed frequency (5 KHz-1 MHz range) ultrasonic stimuli impulses for a predetermined period of time (10-20 seconds). Between the stimuli pulse periods, the transducer segments receive variable frequency ultrasonic pumping pulses. Preferably, the variable frequency ultrasonic pumping pulses lie in the 50 MHz-300 MHz range. The variable frequency ultrasonic pumping pulses are applied to opposed transducer segments. The transducer segments create beams that impinge on the skin at an oblique angle and create a pulsating wave. Further, the variable frequency ultrasonic pumping pulses are applied to opposing transducer segments in a rotating manner to create pulsating waves in the skin in a variety of directions. The stimuli pulses cause the planar transducer to produce an ultrasonic wave that excites the local nerves in the way that trauma (heat, force) excites the local nerves. The nerve excitation opens the epidermal/dermal junction membrane and the capillary endothelial cell joints. The variable frequency ultrasonic pumping pulses cause the transducer segments to produce ultrasonic waves in both the polymeric membrane and the skin. The ultrasonic waves pump the drug first through the polymeric membrane and then through, skin openings into the underlying blood vessels. The control electronics apply ultrasonic stimuli pulses to the skin by energizing the stimuli transducer at a first frequency, preferably lying in the 5 KHz-1 MHz range for a predetermined period of time (10-20 seconds). Between the stimuli pulse periods, the control electronics apply variable frequency ultrasonic pumping pulses to the skin by energizing the pumping transducer segments. Preferably, the frequency of the variable frequency ultrasonic pumping pulses lie in the 50 MHz-300 MHz range
U.S. Pat. No. 5,445,611, issued Aug. 29, 1995, titled “Enhancement Of Transdermal Delivery With Ultrasound And Chemical Enhancers” discloses a method of enhancing the permeability of the skin or mucosa to a biolog
Campbell Heather L.
Da Silva Luiz
Visuri Steven R.
Mendez Manuel
The Regents of the University of California
Thompson Alan H.
Wooldrige John P.
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