US-12622868-B2 - Devices, systems, and methods for facilitating tissue delivery of drug

Abstract

Devices and methods are provided for administering a drug to a biological tissue in a patient, such as by intracellular and/or dermal delivery. The device includes a piezoelectric pulse generator; and an array of microneedle electrodes electrically coupled to the piezoelectric pulse generator, wherein the device, following insertion of the microneedle electrodes into the biological tissue, is configured to generate and deliver one or more electrical pulses through the microneedle electrodes effective to electroporate cells in the biological tissue and enable delivery of a drug into the electroporated cells.

Inventors

• Mohammed Saad Bhamla
• Gaurav Byagathvalli
• Dengning Xia
• Mark R. Prausnitz

Assignees

• GEORGIA TECH RESEARCH CORPORATION

Dates

Publication Date

20260512

Application Date

20210528

Claims (20)

1. 1 . A device for use in administering a drug into or across a biological tissue in a patient, comprising: a piezoelectric pulse generator; and an array of microneedle electrodes electrically coupled to the piezoelectric pulse generator, wherein the device, following insertion of the microneedle electrodes into the biological tissue, is configured to generate and deliver one or more electrical pulses through the microneedle electrodes effective to electroporate cells in the biological tissue and enable delivery of a drug into the electroporated cells, and wherein the piezoelectric pulse generator comprises: a piezoelectric crystal; a mechanism configured to strike a surface of the piezoelectric crystal effective to generate the one or more electrical pulses; and electrical connections configured to conduct the one or more electrical pulses to the microneedle electrodes.
2. 2 . The device of claim 1 , further comprising (i) a base from which the array of microneedle electrodes extend, and (ii) a housing which is connected to the base and contains the piezoelectric pulse generator.
3. 3 . The device of claim 1 , wherein the device further comprises the drug and is configured to release the drug to the biological tissue.
4. 4 . The device of claim 3 , wherein the drug is coated onto the microneedle electrodes.
5. 5 . The device of claim 3 , wherein: the drug is stored in one or more reservoirs in the device, at least a portion of the microneedle electrodes each includes a hollow bore or a groove on its surface, and the device includes one or more conduits which are in fluid communication with the one or more reservoirs and the hollow bores or grooves of the microneedle electrodes for passage of the drug.
6. 6 . The device of claim 1 , wherein the drug is in the form of particles that contain the drug.
7. 7 . The device of claim 1 , wherein the microneedle electrodes extend from one or more metal plates which are configured to conduct the electrical pulses from the piezoelectric pulse generator to the microneedle electrodes.
8. 8 . The device of claim 7 , wherein a linear array of the microneedle electrodes extends from one edge of each of the metal plates.
9. 9 . The device of claim 7 , wherein the one or more metal plates are two or more plates which are parallel to each other and spaced apart from one another.
10. 10 . The device of claim 1 , wherein the microneedle electrodes extend from a single metal plate, and the array is a two-dimensional array.
11. 11 . The device of claim 1 , wherein the microneedle electrodes extend from at least one non-electrically conductive plate and wherein electrical connections are provided between the microneedle electrodes and configured to conduct the one or more electrical pulses from the piezoelectric pulse generator to the microneedle electrodes.
12. 12 . The device of claim 11 , wherein the electrical connections are located on a surface of the at least one non-electrically conductive plate.
13. 13 . The device of claim 11 , wherein the electrical connections cross from a first side of the at least one non-electrically conductive plate to an opposed second side of the plate through holes in the at least one non-electrically conductive plate.
14. 14 . The device of claim 1 , wherein the microneedle electrodes each comprise a non-electrically conductive core and a conductive electrode material the covers at least part of a surface of the microneedle core.
15. 15 . The device of claim 1 , wherein the mechanism of the piezoelectric pulse generator comprises a spring-latch hammer.
16. 16 . The device of claim 1 , wherein the piezoelectric crystal comprises lead zirconate titanate (PZT), silicon nitride, barium titanate, quartz, zinc oxide, or sodium tungstate.
17. 17 . The device of claim 15 , further comprising (i) a toggle switch with a wedge controlling latch configured to release a hammer driven by decompression of a spring, and (ii) a metal pin disposed between the hammer and the piezoelectric crystal.
18. 18 . The device of claim 1 , further comprises a casing for the piezoelectric crystal, wherein the electrical connections consist of a lower electrode and a side electrode, which extends from the casing.
19. 19 . The device of claim 18 , further comprising a cartridge that contains the array of microneedle electrodes and includes a first receptacle for mating engagement with the lower electrode and a second receptacle for mating engagement with the side electrode, the first and second receptacles being in electrical communication with the microneedle electrodes.
20. 20 . The device of claim 1 , wherein the array of microneedle electrodes is configured to be replaceable and disposable, and the piezoelectric pulse generator is configured to be reusable with a series of said arrays.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims benefit of U.S. Provisional Application No. 63/031,767, filed May 29, 2020, which is incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant number R01AI143844 awarded by the National Institutes of Health. The U.S. government has certain rights in this invention. BACKGROUND This invention is generally in the field of devices and methods for the administration of therapeutic and prophylactic agents to persons in need thereof, and more particularly to methods and devices for the introducing therapeutics, vaccines, nucleic acids, and the like into biological tissues and/or across tissue barriers, especially when the site of drug action is located within cells. Numerous formulations and devices have been investigated for delivery of drugs, nucleic acids, biologicals such as vaccines and therapeutic proteins through the skin and into cells. The stratum corneum of mammalian skin is an effective barrier, particularly for molecules larger than 500 Daltons, even when using penetration enhancers, ultrasound, electroporation or microneedles. Conventional devices using ultrasound and electroporation usually require costly technology, and in all cases require access to a continuous source of electric power such as AC power outlets or batteries. The plasma membrane is another effective barrier, particularly for molecules that are not normally taken up by active transport processes, even when nanoparticle, lipid, polymer and other formulations are used. This is especially important for drugs based on genetic material, such as DNA and RNA. The site of action of a DNA-based drug is typically within the cell nucleus. The site of action of a RNA-based drug is typically within the cell cytosol. A critical need therefore remains for an inexpensive device for dermal and intracellular drug delivery, which does not require adjunctive technology such as ultrasound generators and a continuous source of electric power such as AC power outlets or batteries, and which does not require chemical formulations that can have adverse side effects. BRIEF SUMMARY Electroporation-based drug delivery devices and methods are provided, which may overcome one or more of the foregoing problems associated with conventional devices and methods for administration of drugs to patients. In one aspect, a device is provided for use in administering a drug into or across a biological tissue in a patient. In embodiments, the device includes (i) a piezoelectric pulse generator; and (ii) an array of microneedle electrodes electrically coupled to the piezoelectric pulse generator, wherein the device, following insertion of the microneedle electrodes into the biological tissue, is configured to generate and deliver one or more electrical pulses, produced by the piezoelectric pulse generator, through the microneedle electrodes effective to electroporate cells in the biological tissue and enable delivery of a drug into the electroporated cells. In some embodiments, the device includes the drug and is configured to release the drug to the biological tissue. In some other embodiments, the drug is not provided as part of the device, and the drug is administered to the biological tissue from a separate source. The drug may be a therapeutic or prophylactic molecule larger than 500 Daltons, such as those including nucleic acids. In some embodiments, the drug is a vaccine, such as an RNA vaccine. In another aspect, a method is provided for delivering a drug into or across a biological tissue. In embodiments, the method includes (i) positioning the device, which includes an array of microneedle electrodes electrically coupled to a piezoelectric pulse generator, adjacent to a target tissue site in a biological tissue; (ii) inserting the microneedle electrodes into the target tissue site; (iii) activating the device to deliver one or more electrical pulses through the microneedle electrodes and into the target tissue site effective to electroporate cells at the target tissue site; (iv) and delivering the drug into tissues of the target tissue site. In some embodiments, the biological tissue is mammalian skin or a mucosal membrane. In some embodiments, the target tissue site comprises the dermis or epidermis. In some embodiments, the drug is administered to the target tissue site before, or contemporaneously with, delivery of the electrical pulse. In some embodiments, the drug is administered to the target tissue site from or through the microneedle electrodes. In some other embodiments, the drug is administered to the biological tissue from another part of the device or from a separate source. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is a plan view of a housing and piezoelectric pulse generator of a drug delivery system, according to one embodiment of the present disclosure FIG. 1B is an exploded view of a pie