WO2023227940A2 - Dispositifs, systèmes et procédés d'administration de médicament et d'activation de cellule immunitaire - Google Patents

Dispositifs, systèmes et procédés d'administration de médicament et d'activation de cellule immunitaire Download PDF

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Publication number
WO2023227940A2
WO2023227940A2 PCT/IB2023/000289 IB2023000289W WO2023227940A2 WO 2023227940 A2 WO2023227940 A2 WO 2023227940A2 IB 2023000289 W IB2023000289 W IB 2023000289W WO 2023227940 A2 WO2023227940 A2 WO 2023227940A2
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WIPO (PCT)
Prior art keywords
range
chamber
ultrasound
mhz
liquid
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PCT/IB2023/000289
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English (en)
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WO2023227940A3 (fr
Inventor
Mor Cohen
Original Assignee
Mor Cohen
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Publication of WO2023227940A2 publication Critical patent/WO2023227940A2/fr
Publication of WO2023227940A3 publication Critical patent/WO2023227940A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/14—Female reproductive, genital organs
    • A61M2210/1475—Vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0039—Ultrasound therapy using microbubbles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0043—Ultrasound therapy intra-cavitary
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0073—Ultrasound therapy using multiple frequencies

Definitions

  • the present disclosure is related to devices, systems and methods for drug delivery. More particularly, the present disclosure is related to devices, systems, and methods for drug delivery through the use of ultrasound.
  • the vagina and cervix are female reproductive organs.
  • the vagina is an elastic muscular tube of 7 to 10 cm in length that extends from the vulva (female external genitalia) to the cervix of the uterus where it ends in an anterior and posterior fornix. Its net surface area is about 80 - 110 cm 2 .
  • the vagina does not contain any glands; rather, fluid transudates through the vaginal wall.
  • the vagina has multiple functions, including: (a) menstruation as a canal for menstrual fluid; (b) immune protection against harmful pathogens via acidic pH, the mucus layer and local flora; (c) reproduction functions as the receptacle for sperm and canal for parturition; and (d) sexual functions for sexual pleasure.
  • the cervix has also multiple functions including: (a) acts as a portal into the uterus through which sperm can enter to fertilize eggs; (b) during pregnancy, assists in keeping the baby in place until it is fully developed; and (c) maintains sterility of the upper female reproductive tract.
  • the cervix and all structures above it are sterile. By preventing bacterial invasion, this ultimately protects the uterine cavity and the upper genital tract.
  • vaginal delivery e.g. contraceptive hormones and prostaglandins
  • topical delivery e.g. spermicides, agents against urinary tract infections and Candida infections, anti-bacterial vaginosis medications, labor inducing agents, HPV infections etc
  • Drug delivery via the vagina is currently implemented or being developed via administration of a range of dosage forms to the vaginal canal: monolithic solid materials (e.g. intravaginal rings, IVRs) and soft, semi-solid materials (e.g. gels, creams, nanoparticles, nanofibers, nanogels, polymeric micelles, vaginal films suppositories, non-woven porous textile materials, dissolving tablets, and fiber-woven meshes).
  • monolithic solid materials e.g. intravaginal rings, IVRs
  • soft, semi-solid materials e.g. gels, creams, nanoparticles, nanofibers, nanogels, polymeric micelles, vaginal films suppositories, non
  • Vaginal rugae are structures of the vagina that are transverse ridges formed out of the supporting tissues and vaginal epithelium in females. Some conditions can cause the disappearance of vaginal rugae and are usually associated with childbirth and prolapse of pelvic structures. However, Vaginal "folds" or rugae, making the surfaces of these folds less accessible to drugs and drug carriers. While, drug distribution over the entire target surface of the vagina has been proven important for preventing and treating infections. [0009] Moreover, the mucus layer coating the vaginal epithelium presents a barrier to achieving uniform distribution and prolonged retention in the vaginal tract.
  • Mucus efficiently traps most particulates, including conventional polymeric nanoparticles (CPs), through both adhesive and steric interactions.
  • the efficiency with which mucus traps foreign pathogens and particulates implies that CPs would become trapped immediately upon contact with the lumenal mucus layer, preventing penetration into and, thus protection of, the rugae. Particles and pathogens trapped in the superficial lumenal mucus layer would be expected to be rapidly cleared from the tissue, limiting the retention time of mucoadhesive materials, such as CP.
  • vaginal drug distribution Some natural biological variability in vaginal size and epithelial thickness in users influences vaginal drug distribution. For example; drug spreading and vaginal drug distribution occur more rapidly as the anatomical size of the vagina diminishes.
  • Ultrasound has been shown to facilitate the delivery of drugs across the skin, promote gene therapy to targeted tissues, deliver chemotherapeutic drugs into tumors and deliver thrombolytic drugs into blood clots.
  • ultrasound has also been shown to facilitate the healing of wounds and bone fractures.
  • Cavitation is the formation of gas-filled cavities in liquids when the liquid's static pressure falls below the liquid's gas pressure. When subjected to increased pressure, these holes, known as "bubbles,” collapse and can even generate shock waves. Cavitation can be caused by ultrasonic vibration, among other causes.
  • cavitation is the effervescence caused by dissolved gases in sparkling wines and carbonated soft beverages. Cavitation in the engineering sense is characterized by an explosive growth and occurs at suitable combinations of low pressure and high speed in pipelines.
  • the present invention in some embodiments thereof, is directed to drug delivery and/or immune cell activation in the digestive tract and the reproductive system.
  • the objective of the invention is to overcome the deficiencies in the prior art.
  • the invention provides a system and a method for drug delivery and/or immune cell activation at a target site of a reproductive system or a digestive tract of a subject.
  • the composition is delivered to one or more target sites within the reproductive system of the subject. In some embodiments, the composition is delivered simultaneously to each of the one or more target sites. In some embodiments, the composition is delivered sequentially to each of the one or more target sites.
  • the target site is selected from the vagina, the cervix, the uterus, the anus, and any combination thereof.
  • the purpose of the treatment is to treat vaginal Candida, bacterial infections, HPV virus and any other infections and any combination thereof.
  • exemplary treatment is performed in the treatment of endometriosis.
  • the purpose of the treatment is to increase the success rate of in vitro fertilization (“IVF”) or natural pregnancy.
  • IVF in vitro fertilization
  • the composition comprising a liquid and one or more active agents.
  • the one or more active agents are selected from the group consisting of: therapeutic agent, diagnostic agent and/or prophylactic agent.
  • the one or more active agents are selected from the group consisting of: anti-fungal, anti- bacterial, an antibiotic, antiviral, a hormone, a steroid, chemotherapeutic agent, a surfactant, a cytotoxic agent, an anti neoplastic agent, a chemotherapeutic agent, a f3-agonist, an immune-modulating agent, anti -metastatic agent, an anticoagulant, a probiotic, and a prebiotic.
  • the liquid has a half-life that is in a range of between 250 milliseconds and 10 hours when positioned within the reproductive system or the digestive tract.
  • cloud cavitation ensures highly effective drug spreading and vaginal/ cervix drug distribution.
  • At least one nozzle has a diameter that is in a range of from 1 micron to 1 centimeter.
  • at least one of an upstream pressure or a downstream pressure is between 0.01 MPa to 100 MPa.
  • a device includes a probe body configured to be held by a user; a chamber defined within the probe body, wherein the chamber is configured to contain a liquid; at least one hole extending from within the chamber to an exterior of the probe body, wherein the at least one hole is configured to deliver the liquid contained within the chamber from within the chamber to a target site; and at least one ultrasound element configured to emit ultrasound waves so as to facilitate delivery of the liquid to the target site.
  • the at least one hole has a size in the range of 1 micron to 1 centimeter.
  • the at least one hole is positioned at least one of a side of the probe body or a tip of the probe body.
  • the at least one ultrasound element is configured to emit ultrasound waves having a frequency in a range of from 0.5 MHz to 5 MHz.
  • the at least one ultrasound element is configured to emit ultrasound waves having an intensity in a range of from 0.5 W/cm2 to 1.5 W7cm2.
  • the at least one ultrasound element is configured to emit ultrasound waves at least one of toward the chamber or toward an exterior of the probe body.
  • the ultrasound waves are configured to induce cavitation in the liquid.
  • a method includes providing a device including: a probe body configured to be held by a user; a chamber defined within the probe body, wherein the chamber is configured to contain a liquid; a liquid contained within the chamber; at least one hole extending from within the chamber to an exterior of the probe body, wherein the at least one hole is configured to deliver the liquid contained within the chamber from within the chamber to a target site; and at least one ultrasound element configured to emit ultrasound waves so as to facilitate delivery of the liquid to the target site; positioning the device at a target site of a patient; and operating the device to emit ultrasound waves while dispensing the liquid from within the chamber via the at least one hole.
  • the target site includes at least one of a vagina, a uterus, a cervix, or an anus.
  • the liquid includes an active agent.
  • the active agent comprises at least one of a therapeutic agent, a diagnostic agent, or a prophylactic agent.
  • the ultrasound waves promote stable cavitation within the liquid.
  • the ultrasound waves have a frequency that is in a range of from 0.5 MHz to 5 MHz.
  • the ultrasound waves are configured to stimulate immune cell activity at the target site.
  • the ultrasound waves are configured to lower a viscosity of mucus.
  • Figure 1A shows an exemplary embodiment of a device.
  • Figure IB shows an exemplary embodiment of a device.
  • Figure 2A shows an exemplary embodiment of a device.
  • Figure 2B shows an exemplary embodiment of a device.
  • Figure 2C shows an exemplary embodiment of a device.
  • Figure 3A shows an exemplary embodiment of a device.
  • Figure 3B shows an exemplary embodiment of a device.
  • Figure 4 shows an exemplary embodiment of a device.
  • Figure 5A shows an exemplary embodiment of a device.
  • Figure 5B shows an exploded view of the exemplary embodiment of a device shown assembled in Figure 5A.
  • Figure 5C shows the exemplary embodiment of a device shown in Figure 5A as integrated into an exemplary embodiment of a treatment system.
  • the term “real-time” is directed to an event/action that can occur instantaneously or almost instantaneously in time when another event/action has occurred.
  • the “real-time processing,” “real-time computation,” and “real-time execution” all pertain to the performance of a computation during the actual time that the related physical process (e.g., a user interacting with an application on a mobile device) occurs, in order that results of the computation can be used in guiding the physical process.
  • events and/or actions in accordance with the present disclosure can be in real-time and/or based on a predetermined periodicity of at least one of: nanosecond, several nanoseconds, millisecond, several milliseconds, second, several seconds, minute, several minutes, hourly, several hours, daily, several days, weekly, monthly, etc.
  • exemplary embodiments relate to devices, systems, and methods that enhance localized drug delivery and/or activation of immune cells through the use of therapeutic ultrasound energy, such as energy optimized to heat tissue, cause cavitation, or stabilize cavitation.
  • exemplary devices, systems, and methods include an ultrasound device to generate the therapeutic ultrasound.
  • therapeutic ultrasonic energy such as energy adapted to heat tissue, produce cavitation, or stabilize cavitation, improves localized drug delivery and/or activation of immune cells.
  • a probe including at least one piezoelectric element is utilized to apply therapeutic ultrasound energy and to release a drug to a target site.
  • a probe including at least one piezoelectric element is utilized to apply therapeutic ultrasound energy and to release bubbles in order to activate immune cells at a target site.
  • Figures 1A and IB show an exemplary device 100 for enhancing drug delivery and/or activating immune cells through the use of ultrasound.
  • the device 100 includes a probe 103.
  • the probe 103 includes at least one ultrasound transducer 101.
  • the at least one ultrasound transducer 101 includes at least one piezoelectric element.
  • the at least one ultrasound transducer 101 is configured (e.g., positioned and oriented) so as to emit ultrasound waves 105 toward target tissue (e.g., toward the environment surrounding the probe 103).
  • the probe 103 includes a chamber 106 formed within the probe 103.
  • the probe 103 includes at least one hole 102 extending from the chamber 106 to the exterior of the probe 103, through which a liquid (e.g., containing a medication and/or bubbles) positioned within the chamber 106 can be extracted.
  • the probe 103 includes a fluid propulsion element 104 positioned within the chamber 106.
  • the fluid propulsion element 104 has a size complementary to that of the chamber 106 such that motion of the fluid propulsion element 104 along the chamber 106 causes a liquid that is positioned within the chamber 106 to be extracted (e.g., to flow) through the at least one hole 102 to thereby treat target tissue.
  • the fluid propulsion element 104 includes a piston.
  • the at least one hole 102 is positioned in different locations.
  • a plurality of the holes 102 are arrayed in a row longitudinally along the probe 103. In other embodiments similar to the embodiment shown in Figure IB, different numbers of rows (e g., two rows, three rows, etc.) are present. In other embodiments, a plurality the holes 102 are positioned in other arrangements on the probe 103 (e.g., in a helical pattern, in a randomized pattern, etc.).
  • the at least one ultrasound transducer 101 is positioned in different locations.
  • a plurality of the ultrasound transducer 101 e.g., three of the ultrasound transducer 101
  • different numbers of the ultrasound transducer 101 e.g., one ultrasound transducer 101, two ultrasound transducers 101, etc.
  • a plurality of the ultrasound transducer 101 each extend longitudinally along the probe 103 and are separated from one another about the circumference of the probe 103.
  • two of the ultrasound transducer 101 are included. Tn other embodiments similar to the embodiment shown in Figure IB, different numbers of the ultrasound transducer 101 (e.g., one ultrasound transducer 101, three ultrasound transducers 101, etc.).
  • Figures 2A, 2B, and 2C show an exemplary device 200 for enhancing drug delivery and/or activating immune cellsthrough the use of ultrasound.
  • the device 100 includes a probe 203.
  • the probe 203 includes at least one ultrasound transducer 201.
  • the at least one ultrasound transducer 201 includes at least one piezoelectric element.
  • the probe 203 includes a chamber 206 formed within the probe 203.
  • the chamber 206 is configured to contain a liquid (e.g., containing a medication and/or bubbles) positioned therein.
  • the probe 203 includes at least one hole 202 extending from the chamber 206 to the exterior of the probe 203, through which a liquid (e.g., containing a medication and/or containing bubbles) positioned within the chamber 206 can be extracted.
  • the at least one ultrasound transducer 201 is configured (e.g., positioned and oriented) so as to emit ultrasound waves 205 toward a liquid (e g., containing a medicine and/or bubles) positioned within the chamber 206.
  • the probe 203 includes a fluid propulsion element 204 positioned within the chamber 206.
  • the fluid propulsion element 204 has a size complementary to that of the chamber 206 such that motion of the fluid propulsion element 204 along the chamber 206 causes a liquid that is positioned within the chamber 206 to be extracted (e.g., to flow) through the at least one hole 202 to thereby treat target tissue.
  • the fluid propulsion element 204 includes a piston.
  • the at least one hole 202 is positioned in different locations.
  • a plurality of the holes 202 are arrayed circumferentially around the exterior of the probe 203 in two rows.
  • different numbers of rows e.g., one row, three rows, etc.
  • a plurality of the holes 202 are arrayed in a row longitudinally along the probe 203.
  • different numbers of rows e g., two rows, three rows, etc.
  • a single one of the hole 202 is positioned at a tip of the probe 203.
  • a plurality the holes 202 are positioned in other arrangements on the probe 203 (e.g., in a helical pattern, in a randomized pattern, etc ).
  • the at least one ultrasound transducer 201 is positioned in different locations.
  • a plurality of the ultrasound transducer 201 e.g., three of the ultrasound transducer 201 are separated from one another longitudinally along the probe 203.
  • different numbers of the ultrasound transducer 201 e.g., one ultrasound transducer 201, two ultrasound transducers 201, etc.
  • a plurality of the ultrasound transducer 201 each extend longitudinally along the probe 203 and are separated from one another about the circumference of the probe 203.
  • the probe 203 includes an ultrasound transducer 201 that is cylindrical and is configured to thereby emit the ultrasound waves 205 toward a liquid that is present within the chamber 206.
  • Figures 3A and 3B show an exemplary device 300 for enhancing drug delivery and/or activating immune cells through the use of ultrasound.
  • the device 300 includes a probe 303.
  • the probe 303 includes at least one ultrasound transducer 301.
  • the at least one ultrasound transducer 301 includes at least one piezoelectric element.
  • the probe 303 includes a chamber 306 formed within the probe 303.
  • the probe 303 includes at least one hole 302 extending from the chamber 306 to the exterior of the probe 303, through which a liquid (e.g., containing a medication and/or bubbles) contained within the chamber 306 can be extracted.
  • a liquid e.g., containing a medication and/or bubbles
  • the at least one ultrasound transducer 301 is configured (e.g., positioned and oriented) so as to emit ultrasound waves 305 toward target tissue (e.g., toward the environment surrounding the probe 103) and also toward a liquid (e.g., containing a medication and/or bubbles) contained within the chamber 306.
  • the probe 303 includes a fluid propulsion element 104 positioned within the chamber 306.
  • the fluid propulsion element 304 has a size complementary to that of the chamber 306 such that motion of the fluid propulsion element 304 along the chamber 306 causes a liquid that is positioned within the chamber 306 to be extracted (e.g., to flow) through the at least one hole 302 to thereby treat target tissue.
  • the fluid propulsion element 304 includes a piston.
  • the at least one hole 302 is positioned in different locations.
  • a plurality of the holes 302 are arrayed circumferentially around the exterior of the probe 303 in two rows.
  • different numbers of rows e.g., one row, three rows, etc.
  • a plurality of the holes 302 are arrayed in a row longitudinally along the probe 303.
  • different numbers of rows e.g., two rows, three rows, etc.
  • a plurality the holes 302 are positioned in other arrangements on the probe 303 (e.g., in a helical pattern, in a randomized pattern, etc.).
  • the at least one ultrasound transducer 301 is positioned in different locations.
  • a plurality of the ultrasound transducer 301 e.g., three of the ultrasound transducer 301 are separated from one another longitudinally along the probe 303.
  • different numbers of the ultrasound transducer 301 e.g., one ultrasound transducer 301, two ultrasound transducers 301, etc.
  • a plurality of the ultrasound transducer 301 each extend longitudinally along the probe 303 and are separated from one another about the circumference of the probe 303.
  • Figure 4 shows an exemplary device 400 for enhancing drug delivery and/or activating immune cells through the use of ultrasound.
  • the device 400 includes a probe 403.
  • the probe 403 includes at least one ultrasound transducer 401.
  • the at least one ultrasound transducer 401 includes at least one piezoelectric element.
  • the at least one ultrasound transducer 401 includes a plurality of the ultrasound transducer 401.
  • the at least one ultrasound transducer 401 is configured (e.g., positioned and oriented) so as to emit ultrasound waves 405 such that the ultrasound waves focus at a focal point 410.
  • the probe 403 includes a chamber 406 formed within the probe 403.
  • the probe 403 includes at least one hole 402 extending from the chamber 406 to the exterior of the probe 403, through which a liquid (e.g., containing a medication and/or bubbles) contained within the chamber 406 can be extracted.
  • the probe 403 includes a fluid propulsion element 404 positioned within the chamber 406.
  • the fluid propulsion element 404 has a size complementary to that of the chamber 406 such that motion of the fluid propulsion element 404 along the chamber 406 causes a liquid that is positioned within the chamber 406 to be extracted (e.g., to flow) through the at least one hole 402 to thereby treat target tissue.
  • the fluid propulsion element 404 includes a piston.
  • the at least one hole 402 is positioned in different locations.
  • a plurality of the holes 402 are arrayed circumferentially around the circumference of the probe 403 in a row that is positioned proximate to a tip of the probe 403.
  • different numbers of rows e.g., two rows, three rows, etc.
  • the holes 402 are positioned along a length of the probe 403 (e.g., in a manner similar to that shown in Figure IB), are positioned in a helical pattern, are positioned in a randomized pattern, etc.
  • the at least one ultrasound transducer 401 is positioned in different locations.
  • a single one of the ultrasound transducer 401 is positioned proximate to a tip of the probe 403 and is configured to deliver ultrasound waves 405 having a focal point 410 as described above.
  • different numbers of the ultrasound transducer 401 e.g., two ultrasound transducers 401, three ultrasound transducers 401, etc.
  • are present e.g., are arrayed about a circumference of the probe 403 and/or along a length of the probe 403 and are configured to deliver ultrasound waves 405 having a focal point 410 as described above.
  • Figures 5A and 5B show assembled and exploded views, respectively, of an exemplary device 500 for enhancing drug delivery and/or activating immune cells through the use of ultrasound.
  • the device 500 includes an ultrasound transducer 510.
  • the ultrasound transducer 510 includes at least one piezoelectric element.
  • the ultrasound transducer 510 defines a chamber 512 therein.
  • the ultrasound transducer 510 includes at least one hole 514 extending from within the chamber 512 to an exterior of the ultrasound transducer 510.
  • the device 500 includes a sleeve 520.
  • the sleeve 520 surrounds the ultrasound transducer 510 when the device 500 is assembled (e.g., as shown in Figure 5A).
  • the sleeve 520 includes a material that transmits ultrasound energy (e.g., latex, silicone, polyethylene terephthalate, polyurethane, polydimethylsiloxane, polyethylene, mylar, fused silica, polytetrafluoroethylene, polypropylene, polycarbonate, or polystyrene).
  • the sleeve 520 includes a plurality of microchannels 522 extending therethrough (only one of the microchannels 522 specifically identified in Figures 5A and 5B for clarity).
  • the microchannels 522 are positioned so as to receive liquid dispersed from the chamber 512 through the at least one hole 514 and disperse the liquid to a target area at which the device 500 is positioned. In some embodiments, the microchannels 522 are positioned so as to disperse a liquid in all substantially directions around the device 500. In some embodiments, the device 500 includes a fluid propulsion element 530 positioned within the chamber 512 when the device 500 is assembled.
  • the fluid propulsion element 530 has a size complementary to that of the chamber 512 such that motion of the fluid propulsion element 530 along the chamber 512 causes a liquid that is positioned within the chamber 512 to be extracted (e.g., to flow) through the at least one hole 514 and the microchannels 522 to thereby treat target tissue.
  • the fluid propulsion element 530 includes a piston.
  • the device 500 includes a handle 540 that is configured to be manipulated by a user so as to position the device 500 in a target location.
  • Figure 5C shows the device 500 as incorporated into a treatment system 550.
  • the treatment system 550 is suitable for use, for example, in a clinical setting.
  • the treatment system 550 includes a control system 560 communicatively coupled to the device 500 via a coupling 570 (e.g., a cord as shown in Figure 5C; in other embodiments the device 500 is communicatively coupled to the control system 560, such as using near field communication, personal area networking, wireless networking, etc.).
  • a coupling 570 e.g., a cord as shown in Figure 5C; in other embodiments the device 500 is communicatively coupled to the control system 560, such as using near field communication, personal area networking, wireless networking, etc.
  • control system 560 includes a combination of hardware and software configured to control operation of the device 500 as described herein (e.g., to control the timing and pressure applied by the fluid propulsion element 530, to control the ultrasound transducer 510 to emit ultrasound waves at desired settings, etc.).
  • the device 500 as incorporated into a treatment system 550 in a clinical setting is configured to deliver treatment at a higher intensity level (e.g., supplying a liquid with a higher pressure, emitting ultrasound waves with a higher intensity) than a standalone device.
  • an exemplary device includes a fluid propulsion element that includes a balloon.
  • a balloon is positioned within a chamber (e.g., the chamber 106, 206, 306, 406, or 512) in a manner similar to that described above with respect to the fluid propulsion elements 104, 204, 304, 404, and 530.
  • a balloon is configured to inflate within a chamber so as to disperse a liquid from within the chamber through at least one hole (e.g., the holes 102, 202, 302, 402, and 514 described above).
  • a balloon is configured to inflate upon being triggered by a user (e.g., by actuation of a button or other trigger that causes a fluid to flow into the balloon to thereby cause the balloon to inflate).
  • inclusion of a balloon in a fluid propulsion element provides advantageous performance in relation to homogeneous dispersion of a liquid.
  • Exemplary embodiments described above have been described with reference to ultrasound transducers having specific shapes (e.g., ringshaped, annular, tubular, etc.), and specific positions within the respective devices.
  • the specific shapes and locations described herein are only exemplary and other embodiments may have ultrasound transducers having other shapes and/or other locations within the respective devices.
  • exemplary devices, systems, and methods perform drug delivery and/or activate immune cells through the use of cavitation.
  • the cavitation is induced by ultrasound transducers as described above.
  • the cavitation is stable cavitation.
  • stable cavitation is characterized by sustained small amplitude oscillations of a bubble about its equilibrium.
  • the phenomenon of bubbles expanding and shrinking in size but not collapsing occurs as the acoustic pressure waves (e.g., pressure waves resulting from ultrasound emission as described herein) create a low- pressure area inside the liquid, causing gas bubbles to form and remain in place.
  • the bubbles then remain stationary or move slowly in the same direction as the sound waves, creating a stable environment in which they can exist.
  • stable cavitation enhances drug delivery.
  • oscillation of gas microbubbles is used to increase the diffusion of drugs through cell membranes, thus improving drug delivery and uptake.
  • stable cavitation is used to alter vascular permeability, thereby allowing for increased extravasation of nanoparticles for targeted drug delivery.
  • stable cavitation is used to stimulate ion channels and receptors, alter cell permeability, and modify action potentials of cells, thus providing an efficient means of drug delivery to cells.
  • low-intensity ultrasound activates immune cells.
  • low-intensity ultrasound triggers immune cells to release natural antimicrobial peptides (“AMPs”).
  • AMPs natural antimicrobial peptides
  • low-intensity ultrasound enhances production of lactic acid by Lactobacillus.
  • application of ultrasound e g., through the use of one of the devices 100, 200, 300, 400, or 500
  • bubbles refers to bubbles having a diameter in the range of 10 to 50 microns.
  • nanobubbles refers to bubbles having a diameter on the order of nanometers or single-digit micrometers, such as bubbles having a diameter in the range of 50 nanometers to 10 microns.
  • micro-nanobubbles encompasses both microbubbles and nanobubbles (e.g., bubbles having a diameter in the range of 50 nanometers to 50 microns).
  • the size of micro-nanobubbles affects the resonance frequency when exposed to ultrasound frequencies in the low MHz range, typically between one and ten microns in diameter. In some embodiments, as the size of bubbles decreases, the bubbles will experience resonance at higher ultrasound frequencies.
  • bubbles having a diameter of 12 microns experience resonance at a frequency of about 0.5 MHz
  • bubbles having a diameter of 8 microns experience resonance at a frequency of about 1 MHz
  • bubbles having a diameter of 6 microns experience resonance at a frequency of about 1.5 MHz
  • bubbles having a diameter of 4 microns experience resonance at a frequency of about 3 MHz
  • bubbles having a diameter of 2 microns experience resonance at a frequency of about 4 MHz.
  • bubbles may grow and contract during different phases of a cycle; for example, in some embodiments, bubbles may grow under negative pressure and contract under positive pressure.
  • the ultrasound frequency is tuned to thereby control the size of the micro-nanobubbles.
  • the specific bubble sizes and frequencies mentioned above are only exemplary and various embodiments may also use other frequencies and/or other bubble sizes without departing from the exemplary
  • Endogenous bubbles are naturally-occurring pockets of gas within tissues, and they generally require higher acoustic pressures to be effective.
  • exogenous bubbles are externally-administered and possess a much lower cavitation threshold.
  • the lower cavitation threshold of exogenous bubbles allows for greater concentration of ultrasound energy, resulting in the release of energy at the target site and increased drug delivery.
  • exogenous microbubbles enable sonoporation to take place at relatively low-pressure amplitudes, further enhancing the targeted treatment of tumors.
  • bubbles or cavitating nuclei can be formed by one or more of: (1) application of ultrasound waves to create tiny cavities in a liquid, which then fill with gas, through a process called sonoporation; the gas-filled cavities can then be used to deliver drugs or other molecules directly into cells, creating lysosome bubbles; (2) microfluidics that a combination of microchannels and pumps to create nanobubbles filled with gas; (3) electrocoalescence, which is a process that uses an electric field to create nanobubbles filled with gas; (4) bubble injection, which is a process that uses a syringe to inject a gas into a liquid, forming nanobubbles; (5) addition of CO2, N2, NO, O2, and/or other gases to a liquid in suitable concentrations to create nanobubbles filled with gas; and/or (6) addition of a substance (e.g., a substance including one or more suitable chemicals) to a liquid prior to injection.
  • a substance e.g., a substance including one or more suitable chemicals
  • the substance added to a liquid to facilitate formation of micro-nanobubbles includes a surfactant.
  • surfactants are a type of molecule that are able to reduce the surface tension of liquids, allowing for the formation of nanobubbles.
  • nanobubbles are much smaller than regular bubbles (e.g., having a diameter on the order of nanometers or micrometers, as described above).
  • the surfactant includes one or more of sodium dodecyl sulfate (“SDS”), polysorbate 20, polysorbate 80, sodium lauryl sulfate, polyoxyethylene alkyl ether, cetyltrimethylammounium bromide (“CTAB”), cocoamphocarboxyglycinate (“CAPB”), deoxycholate (“DOC”), polyethylene glycol (“PEG”), sodium dodecylbenzenesulfonate (“SDBS”), or dodecylphosphocholine (“DSPC”).
  • SDS sodium dodecyl sulfate
  • polysorbate 20 polysorbate 80
  • sodium lauryl sulfate sodium lauryl sulfate
  • polyoxyethylene alkyl ether cetyltrimethylammounium bromide (“CTAB”), cocoamphocarboxyglycinate (“CAPB”), deoxycholate (“DOC”), polyethylene glycol (“PEG”), sodium dodecylbenzenesulfonate
  • nanobubbles are able to remain stable in liquid solutions.
  • the surfactant molecules provide a protective layer on the surface of the nanobubbles, thereby enhancing the stability of the nanobubbles.
  • a substance added to the liquid to induce formation of micro- nanobubbles includes a fatty acid.
  • the fatty acid creates micro- nanobubbles when added to the liquid.
  • the fatty acid includes a chain of carbon atoms that includes between three and 24 carbon atoms.
  • the fatty acid includes no double bonds, one double bond, two double bonds, or three double bonds.
  • the number of carbon atoms in the fatty acid affects the bubble size by influencing the surface tension of the liquid.
  • the fatty acid is selected in order to control the surface tension of the liquid and to thereby control the size of the bubbles.
  • micro-nanobubbles include a protective outer layer and a hydrophobic gas core.
  • the protective layer includes a phospholipid such as dipalmitoylphosphatidylcholine (“DPPC”) or distearoylphosphatidylcholine (“DSPC”), which is mixed with polyethylene glycol (“PEG”)-functionalized lipids such as polyethylene glycol, (PEG)ylated lipids, PEG stearate and cholesterol.
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC distearoylphosphatidylcholine
  • PEG polyethylene glycol
  • the hydrophobic core includes an inert gas, such as octafluoropropane, perfluorobutane, perfluorohexane, sulfur hexafluoride, or nitrogen, which reduce dissolution and increase stability.
  • the oxygen is incorporated into the hydrophobic core. Tn some embodiments, oxygen is incorporated to facilitate tumor treatments.
  • properties of the micro-nanobubbles are specifically customized in order to facilitate linking the microbubbles with different payloads.
  • the microbubbles are customized through the use of crosslinking groups, electrostatic charges, lipids such as dioleoyl-3-trimethylammonium propane (“DOTAP”) and distearoyl-3-trimethylammonium-propane chloride (“DSTAP”), and PEG- coated, N-hydroxysuccinimide (“NHS”)-functionalized microbubbles.
  • DOTAP dioleoyl-3-trimethylammonium propane
  • DSTAP distearoyl-3-trimethylammonium-propane chloride
  • NHS N-hydroxysuccinimide
  • targeting capabilities are added to the micro-nanobubbles by attaching multiple ligands.
  • micro-nanobubble-liposome complexes have lower stability than some other nanoparticles, and are stabilized by using 5% biotinylated PEG surface chains with liposomes of 100 nm diameter.
  • the liposomes consist of PEGylated lipids, biotinylated and PEGylated lipids, and 22-(N-(7-Nitrobenz-2-Oxa-l,3-Diazol-4-yl) Amino)-23,24-Bisnor-5- C noir-3p-Ol (NBD) fluorescent cholesterol.
  • nanoparticles have a size in the range of between 10 nm and 200 nm, which results in minimal renal and immune clearance.
  • cavitating nuclei are particles that form tiny bubbles or cavitation nuclei when they come in contact with a liquid.
  • cavitating nuclei are formed when particles such as proteins, lipids, or polymers come into contact with a liquid. In some embodiments, this contact results in the formation of tiny bubbles or cavitation nuclei.
  • these bubbles can then be used to transport drugs directly to target sites in the body, allowing for more efficient delivery. In some embodiments, such bubbles are also used to trigger an immune response (e.g., to stimulate activation of immune cells).
  • a probe may include a chamber containing a liquid.
  • the liquid includes one or more constituents, which may include one or more of a surfactant, a fatty acid, nanoparticles, a polymer, a protein, a drug, and/or a carrier.
  • ultrasound as described herein is applied to enhance fertility and promote fertilization.
  • the viscosity of cervicovaginal mucus is a contributing factor to fertility for women.
  • Low viscosity mucus is considered more favorable for fertility because it allows sperm to travel more easily, thereby increasing the chances of successful fertilization.
  • Low viscosity mucus is also more hospitable to sperm, providing them with the nutrients they need to survive and swim to the egg.
  • low viscosity mucus helps to protect sperm from the acidic environment of the vagina, increasing their survival rate and improving fertility.
  • lowering the viscosity of mucus promotes fertility.
  • ultrasound as applied as described herein disrupts the mucosal structure, thereby reducing the viscosity of mucus and promoting fertility.
  • reduction of the viscosity of mucus also has the effect of allowing bubbles (e.g., microbubbles or nanobubbles) and/ active agents (e.g., drugs, therapeutic agents, nanoparticles, lysosomes) to penetrate the mucus and enter the underlying tissues.
  • a treatment method includes positioning any of the exemplary devices described herein in the reproductive tract, the anal tract, or the digestive tract to thereby deliver a composition (e.g., a composition including medication) to a target site.
  • a treatment method includes positioning any of the exemplary devices described herein in the reproductive tract, the anal tract, or the digestive tract and delivering ultrasound to thereby activate immune cells.
  • a method includes delivering a composition to one or more target sites within a reproductive system of a subject.
  • the composition is delivered simultaneously to each of the one or more target sites.
  • the composition is delivered sequentially to each of the one or more target sites.
  • a method includes delivering a composition and/or delivering ultrasound to thereby treat diabetic ulcers.
  • the target site includes the vagina, the cervix, the uterus, or a combination thereof.
  • a method includes application of a device as described herein to thereby treat a vaginal Candida infection, a bacterial infection, an HPV viral infection, another viral infection, or a combination of infections.
  • a method includes application of a device as described herein to thereby improve the likelihood of success of attempts at pregnancy, insemination, or in vitro fertilization implantation.
  • a method includes application of ultrasound using a device as described herein to enhance the delivery of drugs or other therapeutic agents to thereby increase the effectiveness of treatments for infertility or contraception.
  • a method includes application of ultrasound using a device as described herein to thereby improve the accuracy of drug targeting, thereby improving the efficacy of drug delivery and improving safety by reducing the risk of off-target effects.
  • At least one ultrasound transducer has a pipe shape, a tube shape, or an annular shape.
  • at least one ultrasound transducer includes one or more piezoelectric elements.
  • at least one piezoelectric element has a square shape, a rectangular shape, an annular shape, or a circular shape.
  • At least one ultrasound transducer has a diameter that is at least 0.2 cm, or is at least 0.25 cm, or is at least 0.3 cm. In any of the embodiments described herein, at least one ultrasound transducer has a diameter that is in a range of from 0.2 cm to 5 cm, or is in a range of from 0.25 cm to 5 cm, or is in a range of from 0.3 cm to 5 cm.
  • At least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 5 MHz. Tn some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1 MHz to 5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1.5 MHz to 5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2 MHz to 5 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2.5 MHz to 5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 3 MHz to 5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 3.5 MHz to 5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 4 MHz to 5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 4.5 MHz to 5 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 4.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1 MHz to 4.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1.5 MHz to 4.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2 MHz to 4.5 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2.5 MHz to 4.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 3 MHz to 4.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 3.5 MHz to 4.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 4 MHz to 4.5 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 4 MHz. Tn some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1 MHz to 4 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1.5 MHz to 4 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2 MHz to 4 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2.5 MHz to 4 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 3 MHz to 4 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 3.5 MHz to 4 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 3.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1 MHz to 3.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1.5 MHz to 3.5 MHz. Tn some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2 MHz to 3.5 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2.5 MHz to 3.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 3 MHz to 3.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 3 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1 MHz to 3 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1.5 MHz to 3 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2 MHz to 3 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2.5 MHz to 3 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 2.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1 MHz to 2.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1.5 MHz to 2.5 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 2 MHz to 2.5 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 2 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1 MHz to 2 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1.5 MHz to 2 MHz. In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 1.5 MHz.
  • the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 1 MHz to 1 .5 MHz Tn some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having a frequency that is in a range of from 0.5 MHz to 1 MHz.
  • At least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 0.03 W/cm 2 to 3 W/ cm 2 . In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 0.75 W/cm 2 to 3 W/cm 2 . In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 1.5 W/cm 2 to 3 W/cm 2 .
  • the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 2.25 W/cm 2 to 3 W/cm 2 . In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 0.03 W/cm 2 to 2.25 W/cm 2 . Tn some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 0.75 W/ cm 2 to 2.25 W/cm 2 . In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 1.5 W/cm 2 to 2.25 W/cm 2 .
  • the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 0.03 W/cm 2 to 1.5 W/cm 2 . In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 0.75 W/cm 2 to 1.5 W/cm 2 . In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 0.03 W/cm 2 to 0.75 W/ cm 2 . In some embodiments, the at least one ultrasound transducer is configured to emit ultrasound waves having an intensity that is in a range of from 0.03 W/cm 2 to 0.1 W/ cm 2
  • At least one ultrasound transducer is configured to emit ultrasound waves in a pulsed mode and having a duty cycle that is in a range of from 1% to 50%, or that is in a range of from 10% to 50%, or that is in a range of from 20% to 50%, or that is in a range of from 30% to 50%, or that is in a range of from 40% to 50%, or that is in a range of from 1% to 40%, or that is in a range of from 10% to 40%, or that is in a range of from 20% to 40%, or that is in a range of from 30% to 40%, or that is in a range of from 1% to 30%, or that is in a range of from 10% to 30%, or that is in a range of from 20% to 30%, or that is in a range of from 1% to 10%, or that is in a range of from 10% to 20%, or that is in a range of from 1% to 10%
  • At least one hole has a size that is in a range of from 1 pm to 10,000 pm (i.e., 1 cm) [, or is in a range of from 2,000 pm to 10,000 pm, or is in a range of from 4,000 pm to 10,000 pm, or is in a range of from 6,000 pm to 10,000 pm, or is in a range of from 8,000 pm to 10,000 pm, or is in a range of from 1 pm to 8,000 pm, or is in a range of from 2,000 pm to 8,000 pm, or is in a range of from 4,000 pm to 8,000 pm, or is in a range of from 6,000 pm to 8,000 pm, or is in a range of from 1 pm to 6,000 pm, or is in a range of from 2,000 pm to 6,000 pm, or is in a range of from 4,000 pm to 6,000 pm, or is in a range of from 1 pm to 6,000 pm, or is in a range of from 2,000 pm to 6,000 pm, or is in a range of from 4,000 pm to 6,000 pm, or is in a
  • the number, size, and arrangement of holes varies depending on the design of the device.
  • a device includes many microscopic holes (e.g., between 1 and 2,000 pm); in some embodiments, a device includes a single large hole (e.g., 0.5 cm) that feeds liquid to multiple smaller channels.
  • the number, size, and arrangement of holes is selected in order to optimize a property of the liquid that passes through the holes (e.g., quantity of liquid that flows, pressure, size of bubbles, etc.), for a given purpose of the device.
  • a device in any of the embodiments described herein (e.g., the device 100, 200, 300, 400, or 500), includes a composition contained within a chamber (e.g., the chamber 106, 206, 306, 406, or 506).
  • the composition comprises a liquid.
  • the composition comprises a carrier and one or more active agents.
  • the one or more active agents includes one or more of a therapeutic agent, a diagnostic agent, and/or a prophylactic agent.
  • the one or more active agents include one or more of an anti-fungal, an anti-bacterial, an antibiotic, an antiviral, a hormone, a steroid, a chemotherapeutic agent, a surfactant , a cytotoxic agent, an antineoplastic agent, a P-agonist, an immune-modulating agent, an anti-metastatic agent, an anticoagulant, a probiotic, or a prebiotic.
  • the one or more active agents includes one or more substances that can enhance or activate immune cells in target tissue to facilitate the delivery of active agents through mucus, such as immunomodulatory peptides, cytokines, chemokines, and interleukins.
  • the one or more active agents includes one or more small molecules, nanoparticles, liposomes, or other drug delivery systems, delivery of which may be facilitated by ultrasound and/or micro-nanobubbles as described herein.
  • a device in any of the embodiments described herein (e.g., the device 100, 200, 300, 400, or 500), a device includes a fluid propulsion element (e.g., the fluid propulsion elements 104, 204, 304, 404, and 530, respectively) that is operative to induce an increased pressure in a liquid to thereby facilitate delivery of the liquid.
  • a fluid propulsion element e.g., the fluid propulsion elements 104, 204, 304, 404, and 530, respectively
  • the pressure is in a range of from 0.01 MPa to 100 MPa, or is in a range of from 1 MPa to 100 MPa, or is in a range of from 2 MPa to 100 MPa, or is in a range of from 5 MPa to 100 MPa, or is in a range of from 10 MPa to 100 MPa, or is in a range of from 20 MPa to 100 MPa, or is in a range of from 40 MPa to 100 MPa, or is in a range of from 60 MPa to 100 MPa, or is in a range of from 80 MPa to 100 MPa, or is in a range of from 0.01 MPa to 80 MPa, or is in a range of from 1 MPa to 80 MPa, or is in a range of from 2 MPa to 80 MPa, or is in a range of from 5 MPa to 80 MPa, or is in a range of from 10 MPa to 80 MPa, or is in a range of from 20 MPa to 80 MPa, or is in a range of a range of
  • the one or more active agents are used to deliver other therapeutic agents, such as recombinant proteins, antibodies, fusion proteins, nucleic acids, and gene therapy vectors.
  • ultrasound and/or micro-nanobubbles are applied as described herein to enhance or activate therapeutic strategies such as photodynamic therapy, gene therapy, and radiation therapy.
  • ultrasound and/or micro- nanobubbles are applied as described herein to image, diagnose, and/or monitor the delivery of drugs and other therapeutic agents in vivo.
  • the one or more active agents include a contrast agent, a radioisotopes, and/or a fluorescent dye that is provided to a target area for imaging, diagnosis, and/or monitoring purposes.
  • the one or more active agents include an active agent having a half-life within the reproductive system and/or within the digestive system that is in a range of between 250 milliseconds and 72 hours.
  • ultrasound and/or micro-nanobubbles as described herein are applied to ablate or disrupt tissue in the treatment of a condition requiring such ablation or disruption.
  • ultrasound waves are generated from an outer side of a transducer (e.g., are generated in a direction so as to be projected toward an exterior of a device including the transducer). In some embodiments, ultrasound waves are generated from an outer side of a transducer (e.g., are generated in a direction so as to be projected toward an interior of a device including the transducer, such as toward a liquid contained within a chamber of the device). In some embodiments, ultrasound waves are generated from an outer side of a transducer (e.g., are generated in a direction so as to be projected toward both an exterior and an interior of a device including the transducer).
  • a method practiced through use of any of the devices described herein facilitates drug delivery by providing improved liquid spreading.
  • distribution of a liquid through one or more holes as described above, together with application of ultrasound facilitates distribution of a drug across a target area.
  • liquid can be spread over a larger and uneven area using a pump or injection that produces pressure to push the liquid through small holes. This process allows for the liquid to be distributed more evenly across the desired area. The application of pressure to the liquid ensures that it is spread over the area in a uniform manner and does not pool in any one area. This process allows for the liquid to be evenly speared in area with folds or large area.
  • Cloud cavitation or cavitation jet is an innovative technology that uses ultrasound and nozzles to spread the liquid over a larger area in a shorter amount of time. This technology is based on the principles of cavitation, which is the formation and subsequent collapse of tiny bubbles in a liquid.
  • Ultrasound waves are used to generate the bubbles, and these bubbles are then directed through a nozzle which produces a jet of liquid.
  • the jet is powerful enough to carry the liquid over a great distance, reaching areas that would otherwise be unreachable due to the static pressure of the liquid.

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Abstract

La présente invention concerne un dispositif comprenant un corps de sonde configuré pour être tenu par un utilisateur; une chambre définie à l'intérieur du corps de sonde, la chambre étant configurée pour contenir un liquide; au moins un trou s'étendant de l'intérieur de la chambre à un extérieur du corps de sonde, le ou les trous étant configurés pour distribuer le liquide contenu à l'intérieur de la chambre depuis l'intérieur de la chambre vers un site cible; et au moins un élément ultrasonore configuré pour émettre des ondes ultrasonores de façon à faciliter la distribution du liquide au site cible.
PCT/IB2023/000289 2022-05-22 2023-05-22 Dispositifs, systèmes et procédés d'administration de médicament et d'activation de cellule immunitaire WO2023227940A2 (fr)

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