Patent Application
20150209564
1. Field of the Invention
The present invention pertains to an ultrasound device and ultrasound mediated therapeutic treatment methods.
2. Brief Description of the Prior Art
Conventional sonicators are designed to generate acoustic energy at intensities well in excess of FDA approved guidelines of 100 mW/cm2 for prolonged exposure and hence are unsafe and unable to efficiently generate ultrasound waves at low intensities and low pressure amplitudes. Furthermore, in order to generate prolonged high intensity acoustic output, these devices require large, heavy electronics to deliver large excitation voltages. Consequently, conventional sonicators are generally large, heavy, stationary structures that are not intended to be portable and do not provide a reasonable option for home treatment. While some ultrasound devices claim to be portable, at best they are bulky, unwieldy, rigid devices, easily weighing in excess of 40 lbs that and are not configured to be truly wearable or portable devices, such as a Band-Aid® like bandage or patch.
Conventional sonicators also do not enable control and adjustment of operational parameters, such as the duration of ultrasound administration, ultrasound frequency, ultrasound intensity, ultrasound pressure amplitude, transdermal delivery rate, and applied excitation voltage, and therefore do not allow for customized, individualized therapeutic treatment. Furthermore, these devices can also induce inertial cavitation resulting in potential tissue damage due to implosion of air voids near a cell wall or generation of free radicals. When used to mediate transdermal drug delivery, inertial cavitation can also cause the rupture of encapsulated drug molecules prior to passing through the epidermis. Consequently, conventional sonicators do not enable safe and intact drug delivery of encapsulated drug molecules.
For example, WO 97/04832 discloses a method for enhancing transdermal drug transport using low frequency ultrasound. The method involves using a portable sonicator capable of generating an acoustic intensity within the range of 12.5 mW/cm2 to 225 mW/cm2 and capable of generating an ultrasound frequency as low as 20 kHz. This reference, however, does not teach a transducer having a structure and capability to efficiently produce a low intensity acoustic output and low acoustic pressure amplitude from a minimal applied excitation voltage. Nor does it teach a truly wearable and portable device, such as a Band-Aid® like bandage or patch. Although the reference suggests using the sonicator for ultrasound mediated transdermal delivery of encapsulated drugs, it also does not demonstrate intact transdermal delivery of encapsulated drugs.
U.S. Pat. No. 6,190,315 discloses a method for transdermal transport of encapsulated drug molecules. The method involves applying low frequency ultrasound to the skin prior to and/or during transdermal delivery. Although the patent teaches that its transducer is capable of being operated at a frequency of 20 kHz to 2.5 MHz and capable of producing an ultrasound intensity of from 0 to 20 W/cm2, it fails to teach a transducer having a structure and capability to efficiently produce a low intensity acoustic output and low acoustic pressure amplitude from a minimal applied excitation voltage. Furthermore, the device requires a bench-top ultrasound generator or a bulky and unwieldy portable ultrasound generator; it therefore does not teach truly wearable and portable applications, such as a Band-Aid® like bandage or patch. Furthermore, although the reference suggests using ultrasound mediated transdermal delivery of encapsulated drugs, it does not demonstrate intact transdermal delivery of encapsulated drugs.
U.S. Pat. No. 6,322,532 discloses a sonophoresis apparatus for transdermal drug delivery. The apparatus includes a flexible metal disk that is continuously joined to a piezoelectric disk which operates in flexural mode to produce a cavitation effect. During operation, 30V to 300V is applied to the transducer assembly to generate an acoustic output. Although the patent discloses that 0.05 W/cm2 to 5 W/cm2 of power is required to operate the apparatus, it does not specify either the acoustic intensity or the acoustic pressure amplitude generated by the transducer assembly nor the amount of voltage necessary to achieve the acoustic intensity or pressure amplitude. Moreover, it does not teach intact transdermal delivery of encapsulated drugs.
U.S. Pat. No. 7,429,249 discloses a wearable kit that utilizes low intensity ultrasound to induce stable cavitation and microstreaming for use in facilitating treatment of bone fracture and wound healing. It further discloses that the ultrasonic waves transmitted by the kit may be about 10 kHz to about 10 MHz and have SATA intensities of from about 5 mW/cm2 to 500 mW/cm2. This patent, however, does not contemplate the use of encapsulated drug molecules to achieve intact ultrasound mediated drug delivery. Furthermore, although the kit is intended to be worn by a patient, it requires the use of an unwieldy harness to attach it to a patient and can be awkward to use. Moreover, the patent does not teach transducers having a structure and capability to efficiently produce a low intensity acoustic output and low acoustic pressure amplitude from a minimal applied excitation voltage.
In view of the aforementioned deficiencies, there is a need to develop a portable, truly wearable, lightweight, ultrasound device that efficiently and safely enables non-invasive generation of low intensity and low pressure amplitude ultrasound waves for various therapeutic purposes. Additionally, there is a need to develop an improved method for ultrasound mediated transdermal drug delivery which permits intact transdermal delivery of encapsulated drug molecules.
In a first aspect, the invention is directed to an ultrasound device for therapeutic treatment including an ultrasound transducer and a driving means that supplies an excitation voltage to the ultrasound transducer. The transducer has a piezoelectric element, a first cover and a second cover, wherein each cover has a concave configuration and wherein the piezoelectric element is positioned within a cavity formed by the opposing first and second covers.
In a second aspect, the invention is directed to a drug delivery system including an ultrasound device that facilitates transdermal drug delivery and an encapsulated drug positioned proximate to an ultrasound transducer. The ultrasound device includes an ultrasound transducer operatively associated with a driving means. The ultrasound transducer has a piezoelectric element, a first cover and a second cover, wherein each cover has a concave configuration and wherein the piezoelectric element is positioned within a cavity formed by the opposing first and second covers.
In a third aspect, the invention is directed to various therapeutic methods of using ultrasonic waves to treat a patient. The methods involve producing ultrasonic waves having an acoustic pressure amplitude of about 30 kPa to about 55 kPa upon applying an excitation voltage of about 10V to about 30V to a piezoelectric element of an ultrasound device positioned proximate to an epidermal surface for ultrasound mediated therapy.
a) is a perspective view of an exemplary embodiment of one embodiment of the ultrasound device of the present invention.
b) is a close-up of the ultrasound applicator array of
a) shows one embodiment of a modular ultrasound applicator.
b) shows another embodiment of a modular ultrasound applicator configured as a parallelogram.
a) is a schematic diagram showing a cross-sectional view of a transducer at an initial state of rest (Stage 0) and subsequently contracted (Stage 1) to achieve a maximum vertical displacement and minimum radial extension corresponding to a positive cycle (peak) of excitation.
b) is a schematic diagram showing a cross-sectional view of a transducer at an initial state of rest (Stage 0) and subsequently expanded (Stage −1) to achieve a maximum radial extension and minimum vertical displacement corresponding to a negative cycle (peak) of excitation.
c) is a two dimensional symmetric model of a portion of the transducer operating at its fundamental mode of vibration showing a maximum displacement amplitude at the center.
a) is a block diagram of an exemplary driving means.
b) is a schematic diagram of another driving means operatively associated with an ultrasound applicator.
a) is a schematic diagram illustrating air voids within the stratum corneum.
b) is a schematic diagram illustrating the formation of passageways from the air voids of
For illustrative purposes, the principles of the present invention are described by referencing various exemplary embodiments. Although certain embodiments of the invention are specifically described herein, one of ordinary skill in the art will readily recognize that the same principles are equally applicable to, and can be employed in other systems and methods. Before explaining the disclosed embodiments of the present invention in detail, it is to be understood that the invention is not limited in its application to the details of any particular embodiment shown. Additionally, the terminology used herein is for the purpose of description and not of limitation. Furthermore, although certain methods are described with reference to steps that are presented herein in a certain order, in many instances, these steps may be performed in any order as may be appreciated by one skilled in the art; the novel method is therefore not limited to the particular arrangement of steps disclosed herein.
It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Furthermore, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. The terms “comprising”, “including”, “having” and “constructed from” can also be used interchangeably.
For purposes of the present invention, the term “stable cavitation” as used herein refers to air voids that have a tendency to increase in size and vibrate without imploding. The air voids vibrate when exposed a pressure field but do not implode. In stable cavitation a collection of air voids tend to operate in a relatively stable manner as long as a pressure field capable of producing rectified diffusion exits.
As used herein, the term “inertial cavitation” refers to the oscillation and violent collapse of air voids induced by an applied pressure field, usually at the air voids' resonance frequency. When the air voids implode near a cell wall, they exert a concentrated, high pressure force against the cell wall, which can destroy tissue and denature proteins in the cell. In addition to causing tissue damage, inertial cavitation may also generate free radicals.
As used herein, the terms “intact delivery,” “intact transdermal drug delivery,” or “delivery of intact encapsulated drugs” refers to the delivery of an analyte to a subcutaneous location, wherein the analyte has substantially the same ratio of chemical components and substantially the same concentration as prior to being administered by ultrasound mediated transdermal delivery. Intact drug delivery may be achieved using specific ultrasound frequency and acoustic field parameters such as for instance pressure amplitude or intensity and encapsulated drug s that substantially prevent analyte leakage during transdermal delivery thereby enabling analyte delivery in a predetermined concentration. Preferably, intact drug delivery limits analyte leakage from the vesicle to a maximum of about 10% or less, more preferably, about 6% or less, and most preferably, by about 4% or less.
The present invention is directed to a portable, truly wearable, lightweight ultrasound device that produces ultrasound waves for customized therapeutic treatment. Also, the invention is directed to methods for using the ultrasound device to treat wounds, stimulate tissue and enable substantially intact transdermal drug delivery of encapsulated drugs. Predicated on the importance of administering low intensity, low pressure amplitude, low frequency ultrasound waves generated from a minimal excitation voltage, the invention enables safe, effective and energy efficient ultrasound mediated therapy, and particularly, intact transdermal drug delivery. The invention also enables customization of ultrasound treatment and provides an ultrasound device that is easily portable, comfortably worn and easy to use, enabling effective therapeutic treatment and improved patient compliance.
a) shows an exemplary ultrasound device 100 including an ultrasound applicator 10 and an operatively associated driving means 30 positioned within or mounted to housing 50. Ultrasound applicator 10 has one or more transducers 12 adapted to efficiently generate a sufficient amount of acoustic energy to enable therapeutic treatment from a relatively low excitation voltage supplied by driving means 30. Transducers 12, shown in
Ultrasound device 100 preferably also enables a user or healthcare provider to control and adjust one or more parameters of driving means 30 in order to customize the therapeutic treatment. In an exemplary embodiment, ultrasound device 100 is configured as a flexible, lightweight, compact, portable, energy efficient device that can be comfortably worn by an individual and enables customized therapeutic treatment.
b) shows an exemplary ultrasound applicator 10 of the present invention. As illustrated, ultrasound applicator 10 preferably includes a plurality of transducers 12 arranged in an array and operatively associated with driving means 30. In an exemplary embodiment, ultrasound applicator 10 may include about 1 to about 36 transducers 12, preferably about 4 to about 25 transducers, more preferably, about 4 to about 16 transducers, and most preferably about 9 to about 16 transducers forming an array. Preferably transducers 12 may be arranged in a series of rows and columns, such as a 2×2, 3×3 or 4×4 array, in a staggered pattern, in a radial pattern, in a series of concentric circles, or any arrangement that would facilitate therapeutic treatment. Preferably, the surface area of ultrasound device 100 occupied by one or more transducers 12 can be adapted to comply with and conform to the clinical application. Preferably, the surface area of ultrasound device 100 occupied by transducers 12, preferably ultrasound applicator 10, is about 200 mm2 to about 3600 mm2, preferably, about 200 mm2 to about 1000 mm2, more preferably, about 200 mm2 to about 6400 mm2, and most preferably about 1600 mm2 to about 3600 mm2.
In one embodiment, transducers 12 can be directly mounted to a surface of housing 50. For example, each transducer 12 may be potted within an opening or recess of housing 50 with an appropriate hardness controlled epoxy mixture in order to electrically insulate transducers 12, to electrically isolate covers 16, 18 and to encapsulate transducer 12 in a waterproof and structurally stable enclosure.
Optionally, as shown in
As shown in
The modular ultrasound applicator 10 may be separate from driving means 30. For example, modular ultrasound applicator 10 may be attached and/or worn by an individual, and driving means 30 may be removably connected to modular ultrasound applicator 10 to supply an excitation voltage.
a) shows a modular ultrasound applicator 10 comprising three segments 23 including four separate transducers 12 two of which are positioned at opposite ends of each segment 23. The frame 23 is arranged in a first unfolded orientation. Frame 23 can be subsequently folded to form another configuration, such as a triangle.
b) shows another ultrasound applicator 10 having five segments 23 arranged to form a parallelogram, wherein one of the segments 23 functions as a locking mechanism that attaches to and fixes two corners of the parallelogram to one another, thereby preventing the unfolding of frame 22. Additionally, two or more of these modular ultrasound applicators 10 may be coupled together to form different configurations.
In an exemplary embodiment, modular ultrasound applicator 10 includes a frame 22, configured as an elongated flexible wire body, and a plurality of transducers 12 mounted to the flexible, wire body of frame 22. In this embodiment, transducers 12 may be attached to and positioned on a patient in any desired configuration or arrangement. A thin film may be placed over ultrasound applicator 10 and wrapped around a portion of the patient to retain transducers 12 in a fixed position. Ultrasound applicator 10 may be then detachably connected to driving means 2 in order to initiate ultrasound therapy.
The structure of transducer 12 is best shown in
As shown in
First and second covers 16, 18 are preferably constructed from a highly flexible, electrically conductive material. Exemplary materials include metals, such as brass, copper, aluminum, stainless steel or titanium. In one embodiment, first cover 16 may be constructed from a different material or in a different thickness and may consequently have different flexibility properties than second cover 18.
Each cover 16, 18 has a concave configuration relative to the piezoelectric element 14 including a base 24 and a substantially dome shaped central region, defined by an apex 26 and one or more inclined side walls 28 connecting base 24 to apex 26. In the embodiment shown in
Preferably, the length of inclined wall 28 between apex 26 and base 24 is about 0.1 mm to about 5 mm, more preferably, about 0.1 mm to about 2 mm and most preferably, about 0.2 mm to about 1 mm. In one embodiment, inclined wall 28 may move between a first position, wherein inclined wall 28 is substantially perpendicular to base 24, and a second position, wherein inclined wall 28 is substantially parallel to base 24. In another embodiment, the angle of inclination, α, between side wall 28 and base 24, as shown in
During flexural operation, piezoelectric material 14 contracts to a smaller diameter causing the angle of inclination between base 24 and side wall 28 of the covers to decrease as piezoelectric element 14, as illustrated in
First and second concave covers 16, 18 directly face and oppose one another so as to form a cavity 20 for receiving piezoelectric element 14. Piezoelectric element 14 is positioned between first and second covers 16, 18, dividing cavity 20 into two separate compartments, as best illustrated in
The structure and properties of transducer 12 enables the efficient generation of low acoustic intensity and low pressure amplitude ultrasound waves from a nominal applied excitation voltage. Preferably, transducer 12 enables the generation of FDA approved, acoustic intensities of about 0.1 mW/cm2 to about 100 W/cm2, more preferably, about 10 mW/cm2 to about 100 mW/cm2, more preferably, about 50 mW/cm2 to about 100 mW/cm2, and most preferably, about 60 mW/cm2 to about 100 mW/cm2 and low acoustic pressure amplitudes of about 5 kPa to about 100 kPa, preferably, about 5 kPa to about 80 kPa, more preferably about 30 kPa to about 55 kPa, and most preferably, about 40 kPa to about 55 kPa, at a low frequency of about 10 kHz to about 200 kHz, preferably, about 10 kHz to about 150 kHz, more preferably, 10 kHz to about 100 kHz and most preferably, about 20 kHz to about 100 kHz upon application of an initial excitation voltage of less than about 30V, preferably, less than about 20V and more preferably, less than about 10 V.
The energy efficiency of transducer 12 is dependent in part upon the material, geometry and dimensions of piezoelectric element 14, the material, structure and acoustic impedance of covers 16, 18, the volume and shape of cavity 20, how transducers 12 are mounted to housing 50 and the electrical matching network. Additionally, the generated ultrasound intensity, pressure amplitude and frequency is dependent upon the material, thickness and diameter of piezoelectric element 14, and the material, shape, cavity depth, outer diameter and apex diameter of first and second covers 16, 18.
Ultrasound device 100 further includes a driving means 30, such as a electronic driving module, operatively associated with and connected to ultrasound applicator 10 through a matching network, such as inductors and/or resistors having various configurations and/or arrangements, and via electrical leads 32. Electrical leads 32 may be directly connected to piezoelectric element 14 or may be connected to first cover 16, second cover 18 or conductive bonding agent 15 to deliver an excitation voltage to transducers 12. In the embodiment shown in
An oscillator 34 is connected to power source 33 and may include one or more components, such as a pulse repetition frequency generator 38 and frequency generator 40, for generating an electrical charge, as shown in
Driving means 30 and ultrasound applicator 10 are positioned within or otherwise mounted to housing 50 of ultrasound device 100. As shown in
Alternatively, housing 50 can also be constructed as a rigid structure, as shown in
In one embodiment, flexible housing 50 includes one or more straps 52 to facilitate the removable attachment of ultrasound device 100 to a patient. To ensure that ultrasound device 100 is adequately secured to a patient, strap 52 may include a fastener 54 to removably attach strap 52 to a portion of ultrasound device 100 or to another strap 52 of ultrasound device 100. In the embodiments shown in
Optionally, ultrasound device 100 may further include a reservoir located within housing 50. Reservoir may contain a viscous medium, such as a gel, to increase acoustic coupling and facilitate ultrasound transmission. In one embodiment, reservoir may be located adjacent to ultrasound applicator 10, wherein the viscous medium is applied to a surface of transducers 12 upon manually squeezing reservoir or upon activating a pump.
In an exemplary embodiment, ultrasound device 100 is a light-weight, compact, easily portable device having a flexible housing 50. Preferably, ultrasound device 100 weighs about 200 grams or less, preferably, about 100 grams or less. Additionally, ultrasound applicator 100 preferably weighs about 60 grams or less, more preferably, about 40 grams or less and most preferably, about 15 grams or less. When using a modular ultrasound applicator, such as that of
Ultrasound device 100 of the present invention offers a number of advantages. By virtue of the novel structure of the piezoelectric transducers 10, ultrasound device 100 is capable of efficiently producing ultrasound waves having a low intensity of about 0.1 mW/cm2 to about 100 mW/cm2 and low acoustic pressure amplitude of about 5 kPa to about 100 kPa at a low frequency of about 10 kHz to about 200 kHz upon application of a minimum excitation voltage of about 30V or less. The structure and flexibility of transducer 12 substantially enhances the excitation voltage to ultrasound wave pressure amplitude efficiency, enabling the applicator to generate ultrasound waves having large amplitudes from relatively minimal voltage input. Operational safety is also enhanced by avoiding inertial cavitation, applying a low excitation voltage and generating ultrasound waves at low intensity and low pressure within FDA-approved guidelines that permits long term ultrasound exposure without undesirable side effects. Additionally the invention enables a healthcare provider or user to control and adjust the operating parameters of ultrasound device 100 to customize therapeutic treatment. Moreover, the lightweight, compact, flexible structure of ultrasound device 100, which preferably has a bandage or patch like design, is configured to be a portable, comfortable, discrete and truly wearable ultrasound delivery means. The invention therefore provides a safe, efficient, customized, non-invasive, pain-free, portable and wearable ultrasound mediated therapeutic treatment.
During operation, an electrical charge generated by driving means 2 is supplied to piezoelectric elements 14 of each transducer 12. Upon application of an initial excitation voltage of about 10V to about 30V, disk-shaped piezoelectric element 14 vibrates in a flexural mode, radially contracting, as illustrated in
Upon application of an initial, low excitation voltage, ultrasound applicator 10 generates low intensity and low pressure amplitude ultrasound waves at a low frequency to allow for therapeutic treatment. To enable safe, FDA-approved ultrasound mediated therapeutic treatment, ultrasound applicator 10 preferably generates ultrasound waves having a pressure amplitude of about 55 kPa or less and a low acoustic intensity of about 100 mW/cm2 or less at a frequency of about 200 kHz or less. In an exemplary embodiment, ultrasound applicator 10 preferably generates ultrasound waves having a low acoustic intensity of about 0.1 mW/cm2 to about 100 mW/cm2, more preferably, about 10 mW/cm2 to about 100 mW/cm2, more preferably, about 50 mW/cm2 to about 100 mW/cm2, and most preferably, about 60 mW/cm2 to about 100 mW/cm2 and a low pressure amplitude of about 5 kPa to about 100 kPa, preferably, about 5 kPa to about 80 kPa and more preferably, about 30 kPa to about 55 kPa and most preferably, about 40 kPa to about 55 kPa at a low frequency of about 10 kHz to about 200 kHz, preferably, about 10 kHz to about 150 kHz, more preferably, 10 kHz to about 100 kHz and most preferably, about 20 kHz to about 100 kHz upon applying initial excitation voltage of about 30V or less, preferably about 20V or less and more preferably, about 10 V or less. In an exemplary embodiment, ultrasound device 100 generates an acoustic intensity output to applied voltage ratio of at least about 0.37 mW/cm2/V or better, preferably, about 2.7 mW/cm2/V or better, and most preferably, about 14.28 mW/cm2/V or better, more preferably, about 29 mW/cm2/V or better and most preferably, about 67 mW/cm2/V or better. In an exemplary embodiment, ultrasound device 100 can have an excitation voltage to ultrasound wave amplitude efficiency of at least 20V:55 kPa/100 mWcm2, preferably an excitation voltage to ultrasound wave amplitude efficiency of up to about 7V:55 kPa/100 mWcm2. Ultrasound device 100 can also generates a pressure amplitude to applied voltage ratio of at least about 0.2 kPa/V or better, preferably, about 1.5 kPa/V or better, more preferably, about 7.8 kPa/V or better, more preferably, about 15 kPa/V or better, and most preferably, about 40 kPa/V. Ultrasound applicator 10 can also generate a continuous or pulsed ultrasound waves.
When ultrasound applicator 10 is positioned adjacent to an epidermal surface, the flexural vibration of transducers 12 induces acoustic tissue interactions that enable ultrasound mediated therapeutic treatment. Without wishing to be bound by theory, it is believed that the generated ultrasound waves: induce a substantial amount of stable cavitation within a patient's epidermal tissue and/or causes formation of sonopores through the epidermal tissue due to acoustic tissue interactions, such as applied radiation forces, acoustic streaming, shear stress or combinations thereof, that can induce different bioeffects on a cell membrane and cytoskeleton, sufficient to achieve a therapeutic effect and/or facilitate transdermal drug delivery. Preferably, transducers 12 may be operated at an acoustic intensity, pressure amplitude and frequency to generate a frequency, acoustic pressure amplitude and acoustic intensity sufficient to achieve and maintain substantial stable cavitation. Additionally, transducers 12 are preferably operated at an acoustic intensity, pressure amplitude and frequency that do not induce inertial cavitation, which can cause cellular tissue damage and inhibit intact drug delivery, as discussed in greater detail below.
In one embodiment, ultrasound device 100 may be used to facilitate wound healing. Ultrasound applicator 10 is positioned against an epidermal tissue of a patient proximate to the site of the wound, and a viscous medium may be spread over the transducers 12 and/or the epidermal tissue to facilitate ultrasound transmission. Ultrasound device 10 can then be used to achieve a therapeutic effect by applying low intensity and low pressure amplitude ultrasound waves to the site of the wound and/or by transdermally administering a drug to facilitate wound healing, as discussed in greater detail below. Using controls 41, a user or healthcare provider may specify and/or control one of more of the ultrasound treatment duration, ultrasound frequency, acoustic intensity, acoustic pressure amplitude, transdermal delivery rate, and applied excitation voltage to enable customized wound treatment. Additionally, a healthcare provider or user may monitor the user's response to the treatment and adjust one or more of these operational parameters as necessary based on the user's response.
Ultrasound device 100 operates in the same manner as that described above. Without wishing to be bound by theory, it is believed that the applied acoustic intensity, acoustic pressure amplitude and frequency induces a sufficient amount of substantial stable cavitation and/or formation of sonopores that facilitate wound healing and does not cause inertial cavitation. The ultrasound waves may be applied for a sufficient period of time to enable or facilitate wound healing. In an exemplary embodiment, wound healing is monitored after each treatment using a near infrared optic device that provides diagnostic information about the healing progress. Based on this information, the clinician can make a decision as to increasing or decreasing the number of, duration of or other operational parameter of treatment. Using this method, ultrasound device 100 may be used to treat various types of wounds, including chronic wounds, such as ulcers, particularly chronic ulcers symptomatic of diabetes.
In another embodiment, ultrasound device 100 may be used to stimulate tissue, specifically nerve tissue and organs. In this embodiment, ultrasound applicator 10 is positioned against an epidermal tissue of a patient proximate to the tissue to be stimulated. Where the tissue is an organ or nerve, ultrasound applicator 10 may be positioned over the patient's skin directly above the tissue to be treated. A viscous medium may be spread over the transducers 12 and/or epidermal tissue to facilitate ultrasound transmission. Ultrasound device 10 may then be used to achieve a therapeutic effect by applying low intensity and low pressure amplitude ultrasound waves to the tissue. Using controls 41, a user or heath care provider may specify and/or control one or more of an ultrasound treatment duration, ultrasound frequency, acoustic intensity, acoustic pressure amplitude, transdermal delivery rate, and applied excitation voltage to enable customized therapeutic treatment. Additionally, a user or healthcare provider may adjust one or more of these operational parameters during treatment based on the user's response to the ultrasound therapy.
Without wishing to be bound by theory, it is believed that the applied low intensity, low pressure amplitude and s and low frequency ultrasound waves induces a sufficient amount of stable cavitation and/or formation of sonopores that facilitates tissue stimulation and does not cause inertial cavitation. The ultrasound waves may be applied for a sufficient period of time to enable or facilitate tissue stimulation. In an exemplary embodiment, tissue stimulation is monitored after each treatment using a near infrared optic device that provides diagnostic information about the degree of tissue stimulation. Based on this information, the clinician can make a decision as to increasing or decreasing the number of, duration of or other operational parameter of treatment. Using this method, ultrasound device 100 may be used to treat any nerve, including static nerves and nerves that have been damaged by diabetic neuropathy or trauma, such as the nerves within a patient's hands, legs, feet and other extremities, as well as treat organs having impaired functionality.
As discussed above, the invention is also directed to a novel method and system for transdermal drug delivery. In this embodiment, the drug delivery system including ultrasound device 100 and vesicle encapsulated analyte 70.
As best shown in
Vesicle 74 provides a protective shell that facilitates transdermal permeation, and may be used to control analyte release once the vesicle encapsulated drug 70 has reached a target site, such as a patient's blood stream. The nanoarchitecture of vesicle 74 is designed to ensure the safe delivery of analyte 72 to a target location in substantially the same concentration and molar ratio as is present prior to ultrasound mediated transdermal administration. Vesicle 74 may have a size and chemistry designed to achieve a membrane curvature, fluidity and bending rigidity that enables transdermal delivery without substantial leakage or rupture upon insonificiation. Preferably, vesicle 74 is constructed from lipids selected based on phase behavior, elastic modulus and membrane viscosity appropriate for the intended ultrasound mediated transdermal application and for the analyte to be delivered. Exemplary lipids used to construct vesicle 74 may include 1,2-dioleoyl-sn-glycerol-3-phosphocholine, 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine, 1,2 dipalmitoleoyl-sn-glycero-3-phosphocholine and 1,2-dimyrstoyl-sn-glycero-3-phosphocholine or combinations thereof. Vesicle 74 may be configured as a liposome, polymeric nanoparticles, polymersomes, microparticles, microcapsules, microspheres or similar encapsulation vehicles. Preferably, vesicle 74 may be configured as a uni-lamellar structure having a diameter of about 1 um or smaller, more preferably, about 300 nm or smaller and most preferably, about 100 nm or smaller. In an exemplary embodiment, vesicles 72 are constructed in accordance with nanoparticle critical design parameters that substantially prevent or minimize leakage or rupturing when exposed to low intensity and low pressure amplitude ultrasound waves at low frequencies and when exposed to stable cavitation. Preferably, vesicles 72 are deigned to substantially resist leakage or rupture when exposed to inertial cavitation.
As illustrated in
During operation, casing 76 containing the encapsulated drug dispersed viscous medium is coupled to ultrasound applicator 10 and positioned against an epidermal tissue of a patient. Using controls 41, a user or heath care provider may then specify and/or control one or more of an ultrasound treatment duration, ultrasound frequency, acoustic intensity, acoustic pressure amplitude, transdermal delivery rate, and applied excitation voltage to enable customized drug delivery. Additionally, a user or healthcare provider may adjust one or more of these operational parameters during drug delivery.
Without wishing to be bound by theory, it is believed that the applied low intensity, low pressure amplitude and low frequency ultrasound waves of the device induces a sufficient amount of stable cavitation and/or formation of sonopores to facilitate intact delivery of vesicle encapsulated analyte 70. It is further believed that the applied ultrasound waves do not cause inertial cavitation. Without wishing to be bound by theory, it is believed that stable cavitation induces rectified diffusion and pushes the vesicle encapsulated analyte 70 through the stratum corneum of a patient's skin.
Another mechanism of action by which the ultrasound device 100 enables transdermal transport involves the formation of sonopores when ultrasound field interacts with a tissue bilayer, which induces stretching and the pulling apart of the tissue membrane. This disrupts the structure of the stratum corneum, thereby forming pores or causing rupturing of the membrane enabling passage of the vesicle encapsulated analyte 70. This phenomenon is further explained in Krasovitski, B. et al., “Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects,” PNAS, 2011, herein incorporated by reference in its entirety.
The present invention therefore ensures substantially intact delivery of vesicle encapsulated analyte 70 to a target site, such as the blood stream, in a predetermined and preferably uniform concentration. Vesicle 74 enables analytes 72 to be transdermally delivered substantially intact and in sustained, clinically critical concentrations. Additionally, by operating ultrasound device 100 at a low acoustic intensities and a low frequency range, without inducing inertial cavitation, the invention enables stratum corneum penetration and sustained, stable drug delivery to a target site.
A study investigating the efficiency of the ultrasound device of the present invention to generate acoustic energy from a nominal applied voltage was performed. An ultrasound device 100 having an ultrasound applicator 10 including a 2×2 array of four piezoelectric transducers 12 was used. Voltages over a range of about 0V to 20V were applied to the piezoelectric elements 14 of the transducers 12. As shown in
In comparison,
An in vitro study was performed to evaluate the ability of the present invention to enable transdermal delivery of substantially intact encapsulated drugs. The study involved applying low intensity, low pressure amplitude ultrasound waves to mouse skin in order to mediate transdermal delivery of liposome encapsulated carboxyfluorescein (CF), a hydrophilic dye.
The liposomes were made from 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC), and the liposome encapsulated CF was prepared using the dehydration-rehydration technique described in Kirby, C. and G. Gregoriadis, “Dehydration rehydration vesicles: a simple method for high yield drug entrapment in liposome,” Nature Biotechnology, 1984, 2(11): p. 979-984, herein incorporated by reference. In this experiment, encapsulation efficiency of the CF was improved (about 10% to about 30% measured by titration) by minimizing the amount of rehydration buffer used, adjusting pH before rehydration to fully dissolve CF by minimizing the amount of rehydration buffer used, and by adjusting the pH to about 10 and subsequently adjusting the pH to about 7.4 before rehydration. The original encapsulation efficiency of CF was about 0.67% in 100 nm liposomes, using about 5.2 mg CF in the rehydration buffer (about 2.56 mM).
The same experimental setup was also used to evaluate the transdermal penetration of unencapsulated CF that was not exposed to ultrasound and the transdermal penetration of encapsulated CF that was not exposed to ultrasound
Table 1 shows the enhancement ratios, defined in equation 1 below, and delivery efficiency results from the experiment.
Test A shows the results for unencapsulated CF without the application of ultrasound. Test B shows the results for unencapsulated CF upon exposure to 4 hours of low frequency ultrasound. Test C shows the results for liposome encapsulated CF without the application of ultrasound. Tests D1-D2 show the results for liposome encapsulated CF after exposure to 20 minutes of low frequency ultrasound stimulation. Tests E1-3 show the results for liposome encapsulated CF upon exposure to 4 hours of low frequency ultrasound stimulation.
A similar experiment set-up as described in Example 2 was used to investigate the effect of liposome size and viscosity on transdermal delivery. Unlike the experimental set-up in Example 2, the set-up here did not require a custom fixture for the ultrasound source as no ultrasound source was involved in this Example. Specifically, unassisted diffusion of drug filled liposomes constructed from 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC) and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC) through human skin samples were tested.
The liposomes were prepared using the dehydration-rehydration technique described in Kirby, C. and G. Gregoriadis, “Dehydration rehydration vesicles: a simple method for high yield drug entrapment in liposome,” Nature Biotechnology, 1984, 2(11): p. 979-984, herein incorporated by reference.
The results showed that by decreasing liposome size from 200 nm to 50 nm, there was a doubling of the delivery rate, irrespective of the type of liposome bilayer, e.g. DOPC v. DPPC, used. On the other hand, the type of liposome bilayer used effected delivery rate for a given vesicle size. In particular, DOPC bilayers exhibited twice the rate of delivery than DPPC bilayers at all vesicle sizes tested. This was attributed to the fact that DOPC bilayers are in the liquid disordered phase and therefore more fluid than the DPPC ones which are in the liquid ordered phase; clearly viscosity influences the passive diffusion rate.
Another study investigated the ability of specific liposomes to prevent leakage of an encapsulated analyte upon application of a low pressure amplitude ultrasound wave of about 55 kPa and an acoustic intensity of about 100 mW/cm2 at a frequency of about 17.9 kHz. In this experiment, an ultrasound applicator 10 having 4 transducers 12 arranged in a 2×2 array was positioned adjacent to a PetriDish 90 containing liposome encapsulated carboxyfluorescein (CF), as shown in
In this experiment, two liposomes were investigated. The liposomes were synthesized from two different lipid materials, namely 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC) and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC). DOPC formed a fluid membrane at skin temperature and had a Tm of about −20° C. DPPC formed a rigid membrane at skin temperature and had a Tm of about 42° C.
The liposomes were prepared using the dehydration-rehydration technique described in Kirby, C. and G. Gregoriadis, “Dehydration rehydration vesicles: a simple method for high yield drug entrapment in liposome,” Nature Biotechnology, 1984, 2(11): p. 979-984, herein incorporated by reference.
DPPC liposomes had a maximum leakage rate of about 3.3% when exposed to either pulsed or non-pulsed ultrasonic waves having a low pressure amplitude of about 55 kPa and an intensity of about 100 mW/cm2 at a frequency of about 17.9 kHz. These statistically insignificant, low leakage rates demonstrate that the applied acoustic energy does not cause significant leakage of CF from the liposome.
Twenty patients that had a venous ulcer for at least 6 weeks and larger than 1 cm2 and were between the ages of 18 and 65 were treated. Consenting subjects were randomly assigned to one of 4 different ultrasound treatment groups: 15 minutes of sham, 15 minutes of 20 kHz ultrasound, 45 minutes of 20 kHz ultrasound, or 15 minutes of 100 kHz ultrasound. All active treatments had an intensity of 100 mW/cm2 SPTP with a duty cycle of 50%. Five patients were enrolled in each group. Topical analgesic was applied to the wounds prior to each treatment. A non-invasive optical measurement (Diffuse Near Infrared Spectroscopy) was taken on the wound before and after ultrasound treatment to quantify oxy- and deoxy-hemoglobin concentrations. The ultrasound transducer of the invention was then applied to the wound with a small amount of sterile ultrasound gel as a coupling medium. The transducer was taped to the leg for the duration of the ultrasound treatment. In the case of the sham treatment, a non-functioning ultrasound device identical in form to the functioning ultrasound transducers was applied to the wound using the same procedure. A photograph was taken after each treatment to monitor changes in wound size. All treatments, measurements and photographs were taken prior to debridement by the physician.
1 out of the 5 wounds in the sham (non-treatment) group healed whereas 9 out of the 15 wounds sonicated healed in the 4 week time frame. The optimal group, which was 20 kHz treatment for 15 minutes, had 5 out of the 5 patients heal in 4 weeks, representing a 100% success rate. Every ultrasound treatment group had a higher healing rate than the control group.
The foregoing examples have been presented for the purpose of illustration and description and are not to be construed as limiting the scope of the invention in any way. The scope of the invention is to be determined from the claims appended hereto.
This invention was made with Government support under Contract No. R01 EB009670-02 awarded by the National Institutes of Health. The Government has certain rights to this invention.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US12/52615 | 8/28/2012 | WO | 00 | 2/27/2014 |
| Number | Date | Country | |
|---|---|---|---|
| 61530619 | Sep 2011 | US |
