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WO2024049667A1 - Dispositif ultrasonore ingérable à efficacité volumique élevée à faible puissance pour administration d'agents thérapeutiques - Google Patents

Dispositif ultrasonore ingérable à efficacité volumique élevée à faible puissance pour administration d'agents thérapeutiques Download PDF

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Publication number
WO2024049667A1
WO2024049667A1 PCT/US2023/030685 US2023030685W WO2024049667A1 WO 2024049667 A1 WO2024049667 A1 WO 2024049667A1 US 2023030685 W US2023030685 W US 2023030685W WO 2024049667 A1 WO2024049667 A1 WO 2024049667A1
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WO
WIPO (PCT)
Prior art keywords
ultrasound
sensor
ingestible capsule
capsule
transducer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2023/030685
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English (en)
Inventor
Scott Kellogg
Tuan Elstrom
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suono Bio Inc
Original Assignee
Suono Bio Inc
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Filing date
Publication date
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Publication of WO2024049667A1 publication Critical patent/WO2024049667A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • 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
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/05—General characteristics of the apparatus combined with other kinds of therapy
    • A61M2205/058—General characteristics of the apparatus combined with other kinds of therapy with 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3327—Measuring
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3331—Pressure; Flow
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/82—Internal energy supply devices
    • A61M2205/8206—Internal energy supply devices battery-operated

Definitions

  • the invention relates generally to devices and methods for ultrasonic delivery of an agent to an internal tissue.
  • Ingestible ultrasonic drug delivery devices or capsules have been developed to overcome the difficulty of delivering certain drugs via the GI tract. Such devices incorporate the use of an ultrasound transducer, a reservoir that stores the drug, and a power source, such as a battery and drive circuitry, that drives the transducer.
  • a power source such as a battery and drive circuitry
  • the utility of these fully self-contained devices is limited by a different set of technical obstacles.
  • the device must be small enough that it can be easily swallowed, yet large enough to accommodate the drug, transducer, drive circuitry, and battery.
  • Conventional capsule electronics are highly volume inefficient, generally requiring multiple chips, packaging, and wires. The physical dimensions and mechanical characteristics of the device also dictate its biocompatibility with the gastrointestinal tract.
  • the maximum size of a capsule’s rigid outer body is limited to the diameter of the smallest passage within the gastrointestinal tract.
  • silver-oxide button batteries occupy significant real estate volume within ingestible capsules and often become the deciding factor for the device size. These factors constrain the quantity of drug that can be delivered by all-in-one ingestible ultrasonic drug delivery devices. Another consideration is that the battery can severely damage internal tissue if it were to make electrical contact with the tissue. The alkaline solution within ingested silveroxide button batteries can cause severe tissue damage in the mouth, vocal cord, trachea, or esophagus. Therefore, the device must contain material to electrically insulate the battery, which further restricts the drug-loading capacity of the device. Consequently, these factors largely limit the therapeutic potential of drug delivery via ingestible ultrasonic devices.
  • aspects of the present disclosure may include a low power ingestible capsule drug delivery system for targeted or localized ultrasound-mediated drug delivery within the GI tract.
  • the low power high-volume efficiency ingestible capsule drug delivery system may comprise one or more energy storage device, piezoelectric transducer, ultrasound transducer driver, drug carrier/reser- voir, at least one drug payload, and or at least one diagnostic unit.
  • the energy storage device may comprise a biocompatible battery or a biocompatible capacitor, a biocompatible supercapacitor, combinations thereof, or the like.
  • the ultrasound transducer driver may comprise one or integrated circuit (IC) or application-specific integrated circuit (ASIC) further comprising one or more internal resistor, transistor, bipolar transistor, field effect transistor (FET), capacitor, inductor, a finite state machine (FSM), and FPGA.
  • the said IC may function in conjunction with an external inductor or capacitor.
  • a crystal clock provides timing for the IC and an FSM for function control.
  • the said IC may comprise one or more drivers further comprising at least one charge-discharging unit.
  • the said IC may comprise one or more drivers further comprising at least one charge pump or switched-capacitor DC -DC boost converter unit.
  • the said IC may comprise one or more drivers further comprising at least one half-bridge transducer driver unit.
  • the battery may be cast into the rear part of the backing of said piezoelectric transducer which may be used to form the shape of a generated ultrasound emission.
  • the electronics is integrated in one single ASIC which is mounted directly on a piezoelectric transducer.
  • the low power high-volume efficiency capsule may contain at least one piezoelectric transducer configured to operate in one or more modes, including but not limited to, thickness vibration, radial vibration, transverse vibration, combinations thereof, or the like.
  • the ingestible capsule can perform one or more low power operations with high-volume efficiency incorporating a minimum number of electrical components for generating an ultrasound motive force, ultrasound field gradient, sonophoretic force, acoustic streaming, or cavitation within the GI tract using low frequency ultrasound.
  • aspects of the present disclosure can include a method for generating an ultrasound motive force, ultrasound field gradient, sonophoretic force, acoustic streaming, or cavitation using a low power high-volume efficiency ingestible capsule drug delivery system for targeted or localized ultrasound-mediated drug delivery within the GI tract.
  • the method may comprise the use of one or more techniques for device operation using one or more biocompatible compact energy storage device, including but not limited to, a battery, a capacitor, a supercapacitor, combinations thereof, or the like.
  • the method may comprise the adiabatic charging of a piezoelectric transducer from a low voltage to a high voltage, preferably using an on-chip charge pump, boost converter, or inductive pump for high-volume efficiency and reduction of energy consumption.
  • the method may comprise the use of a half-bridge transducer driver.
  • the method comprises the use of one or more wave excitation, including but not limited to, a square wave, using one or more IC with a minimum number of components for high-volume efficiency and low power consumption.
  • the method may comprise the use of the piezoelectric transducer itself as storage capacitor.
  • the said transducer is slowly charged by a high voltage generation block, whereafter it is rapidly discharged to create one or more intermittent or continuous emission of ultrasound, preferably low frequency ultrasound to generate cavitation in an oral cavity or GI tract.
  • the method comprises the use of one or single edge excitation to reduce the complexity of the electronics of the low power and high-volume efficient ingestible capsule.
  • the ingestible capsule drug delivery system may comprise a diagnostic unit containing a sensor suite to determine the location of the capsule during transit through the GI tract.
  • the sensor suite comprises one or more physical, chemical, or bio-responsive sensor, including but not limited to, a pH, temperature, pressure, gas (e g., O2) chemical, biochemical, immuno-reactive, ultrasound, electromagnetic, magnetic field, CCD array, electrochemical, gravimetric, accelerometer, combinations thereof, or the like.
  • the methods for targeted drug delivery comprises calculating the time of transit to activate the said piezoelectric transducer to produce cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery comprises the use of an internal clock of said IC to activate the said piezoelectric transducer to produce, for example, cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise the calculation of a transit time to activate the said piezoelectric transducer to produce cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise the determination of a pH, a pH change, a pH gradient to activate the said piezoelectric transducer to produce cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise the determination of a body temperature, a body temperature change, a temperature gradient to activate the said piezoelectric transducer to produce cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise determining a combination of a body temperature, pH, and or O2, temperature and pH and O2 change, or temperature, pH, or O2 gradient to activate the said piezoelectric transducer to produce, including but not limited to, cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the said system and methods for targeted or localized ultrasound-mediated drug delivery within the GI tract preferably combine the functionalities of the diagnostic sensor suite and the capabilities to generate one or more adjustable controlled drug release profiles of one or more drug payload from said drug reservoir.
  • the present disclosure provides methods of administering a therapeutic agent to a GI tissue of a subject by transporting the ingestible capsule to at least one specific location of the GI and the payload containing an encapsulated or non-encapsu- lated therapeutic agent that is activated by an ultrasound transducer within the capsule for control- released, pulsatile, non-pulsatile, intermittent, digital, or continuous local or targeted delivery of said agent from the payload or reservoir into GI tissue of the subject.
  • said drug reservoir is configured to releasably retain at least one encapsulated therapeutic agent.
  • the ultrasound transducer may be positioned to transduce ultrasound waves in a particular direction relative to the reservoir of the ingestible capsule.
  • the ultrasound transducer may be positioned to transduce ultrasound waves toward the reservoir.
  • the ultrasound transducer is positioned to transduce ultrasound waves away from the reservoir.
  • the ultrasound transducer is positioned to produce omnidirectional ultrasound waves through the reservoir.
  • the reservoir is configured to releasably retain a liquid comprising a therapeutic agent or encapsulated therapeutic agent.
  • the ultrasound transducer of the ingestible capsule may produce an ultrasound signal with a defined frequency or within a defined frequency range.
  • the ultrasound transducer may produce an ultrasound signal of from about 10 kHz to about 10 MHz, from about 10 kHz to about 1 MHz, from about 10 kHz to about 100 kHz, from about 20 kHz to about 80 kHz, from about 20 kHz to about 60 kHz, or from about 30 kHz to about 50 kHz.
  • the ultrasound transducer may produce an ultrasound signal of less than 100 kHz, less than 80 kHz, less than 60 kHz, or less than 50 kHz.
  • the ultrasound transducer may produce an ultrasound signal of about 20 kHz, about 25 kHz, about 30 kHz, about 35 kHz, about 40 kHz, about 45 kHz, about 50 kHz, about 55 kHz, or about 60 kHz.
  • the transducer comprises at least one, directional, planar, spherical, hemispherical, or omni-directional transducer.
  • the ingestible capsule may have a defined size or length.
  • the ingestible capsule may have the longest dimension of less than about 3.0 cm, about 2.75 cm, about 2.5 cm, about 2.25 cm, about 2.0 cm, about 1.75 cm, or about 1.5 cm.
  • the ingestible capsule may have a transverse dimension of less than about 1.2 cm, about 1.1 cm, about 1.0 cm, about 0.9 cm, or about 0.8 cm.
  • the ingestible capsule comprises a magnetic component.
  • the magnetic component may comprise a ferromagnet or magnetic microparticles.
  • one or more permanent magnet may be positioned about a subject to attract the ingestible capsule to a specific location of the GI tract.
  • the low power ingestible capsule drug delivery system further comprises a magnetic component to enable attraction to said external permanent to retain and secure the ingestible at a specific location within a GI tract.
  • the present disclosure provides methods of administering a therapeutic agent to a GI tissue of a subject by orally administering to a subject an ingestible capsule.
  • the therapeutic agent is encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, catalytic, piezo-catalytic, or ultrasound-responsive polymeric carrier, including but not limited to, microbubble, nanobubble, nanodroplet, nano emulsion, nanofiber, vesicle, micelle, or hydrogel sphere or coating.
  • the ingestible capsule may comprise one or more payload or reservoir containing at least one therapeutic agent encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, or ultrasound-responsive polymeric carrier.
  • the ingestible capsule may comprise one or more reservoir or payload containing at least one therapeutic agent encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, catalytic, piezo-catalytic, or ultrasound-responsive polymeric carrier.
  • the ingestible capsule may comprise a coating or scaffold on at least one internal or external surface, said coating or scaffold contains at least one therapeutic agent encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, catalytic, piezo-catalytic, or ultrasound-responsive polymeric carrier.
  • the ingestible capsule may contain an iron oxide particle-based biocompatible gel with a controlled architecture that can release its payload containing an encapsulated or non-encapsulated therapeutic agent when exposed to at least one AC magnetic field.
  • FIG. l is a pictorial of a low power ingestible capsule drug delivery system for targeted ultrasound-mediated drug delivery within the GI tract, according to an embodiment of the present disclosure.
  • FIG. 2 is a block diagram of a design of an IC for activating a piezoelectric transducer for low power battery operated ingestible capsule, according to an embodiment of the present disclosure.
  • FIG. 3 is a simplified schematic of an inductive boost converter, according to an embodiment of the present disclosure.
  • FIG. 4 is a simplified schematic of a discharge block of the low power battery operated ingestible capsule, according to an embodiment of the present disclosure.
  • FIG. 5 is a diagram of a miniaturized transducer driver comprising a charge pump and a half-bridge transducer driver, according to an embodiment of the present disclosure.
  • FIG. 6 is a block diagram of a method for targeted drug delivery using a low power ingestible capsule, according to an embodiment of the present disclosure.
  • FIG 7 is a block diagram of a single-chip multi-sensor diagnostic unit, according to an embodiment of the present disclosure.
  • the term “includes” means includes but is not limited to, the term “including” means including but not limited to.
  • volume efficiency means the amount of function per unit volume displaced by a capsule or device.
  • aspects of the present disclosure can include a low power ingestible capsule drug delivery system for targeted or localized ultrasound-mediated drug delivery within the GI tract.
  • the high- volume efficiency low power ingestible capsule drug delivery system may comprise one or more low power energy storage device, piezoelectric transducer, ultrasound transducer driver, drug car- rier/reservoir, at least one drug payload, and optionally a diagnostic unit.
  • the diagnostic unit further comprises a sensor suite to determine the location of the capsule during transit through the GI tract and for subsequent activation of the piezoelectric transducer at a targeted location.
  • the in- gestible capsule can perform one more high efficiency low power operations with high-volume efficiency incorporating a minimum number of electrical components for generating an ultrasound motive force, ultrasound field gradient, sonophoretic force, acoustic streaming, or cavitation within the GI using low frequency ultrasound.
  • the high volume efficiency low power ingestible capsule drug delivery system 102 may comprise one or more energy storage device 104, piezoelectric transducer 106, ultrasound transducer driver 108, drug carrier/reservoir 110, at least one drug payload 112, and or at least one diagnostic unit 114.
  • the energy storage device may comprise a biocompatible battery or a biocompatible capacitor, a biocompatible supercapacitor, combinations thereof, or the like.
  • said biocompatible energy devices may incorporate one or more anode, cathode, and electrolytes to be biodegradable or safe for ingestion.
  • the anode-cathode-electrolyte combinations can be but not limited to: Mg/Fe/PCL/NaCl composite activated H2O, Mg/CuCl/SGF, Zn-Mg/Cu/SGF, Zn/SGF, AC-XMnCF/H O 1 MNa SCh, or Melanin/ XMnCh 1 MNa SCE.
  • energy storage device 104 may be a battery encapsulated for compatibility using, for example, Parylene deposited as a thin fdm.
  • the ultrasound transducer driver 108 may comprise one or integrated circuit (IC) 116 or ASIC further comprising one or more internal resistor, transistor, bipolar transistor, FET, capacitor, inductor, a finite state machine (FSM), or Field Programmable Gate Array (FPGA).
  • the said IC 116 may function in combination with an external inductor 118.
  • a crystal clock provides timing for the IC and an FSM for function control.
  • the said IC 116 may comprise one or more drivers further comprising at least one charge-discharging unit.
  • the battery 144 is cast into the rear part of the backing of ultrasound transducer 106 which may be used to form the shape of a generated ultrasound emission.
  • the low power high-volume efficiency capsule 102 may contain at least one piezoelectric transducer 106 configured to operate in one or more modes, including but not limited to, thickness vibration, radial vibration, transverse vibration, combinations thereof, or the like.
  • the ingestible capsule 102 can perform one or more high efficiency low power operations with high- volume efficiency incorporating a minimum number of electrical components for generating ultrasonic energy or intensity within the GI using low frequency ultrasound.
  • the transducer 106 delivers ultrasound energy at a frequency optimal for promoting entry of the therapeutic agent 112 into the tissue of the GI tract.
  • the ultrasound transducer 106 may produce an ultrasound signal of from about 10 kHz to about 10 MHz, from about 10 kHz to about 1 MHz, from about 10 kHz to about 100 kHz, from about 20 kHz to about 80 kHz, from about 20 kHz to about 60 kHz, or from about 30 kHz to about 50 kHz.
  • the ultrasound transducer 106 may produce an ultrasound signal of less than 100 kHz, less than 80 kHz, less than 60 kHz, or less than 50 kHz.
  • the ultrasound transducer 106 may produce an ultrasound signal of about 20 kHz, about 25 kHz, about 30 kHz, about 35 kHz, about 40 kHz, about 45 kHz, about 50 kHz, about 55 kHz, or about 60 kHz.
  • the design of the ingestible capsule 102 enables the transducer 106 to produce ultrasound energy at a desired power, frequency, or intensity.
  • the ingestible capsule 102 may have a defined size or length.
  • the ingestible capsule 102 may have the longest dimension of less than about 3.0 cm, about 2.75 cm, about 2.5 cm, about 2.25 cm, about 2.0 cm, about 1.75 cm, or about 1.5 cm.
  • the ingestible capsule 102 may have a transverse dimension of less than about 1.2 cm, about 1.1 cm, about 1.0 cm, about 0.9 cm, about 0.8 cm, about 0.7 cm, about 0.6 cm, or about 0.5 cm.
  • the ingestible capsule 102 may have a radial dimension of less than about 1.2 cm, about 1.1 cm, about 1.0 cm, about 0.9 cm, about 0.8 cm, about 0.7 cm, about 0.6 cm, or about 0.5 cm.
  • IC 202 comprises a control block 204, a boost converter 206, a discharge unit 208, and an oscillator 210.
  • control block 204 controls the functionality of the IC 202 whereby parameters are set via digital inputs.
  • boost convert 206 is used to generate a high voltage on the piezoelectric transducer 212 prior to excitation with the use of an external or off-chip inductor 214.
  • discharge unit 208 activates the production of one or more ultrasound pulse or emission generated by one or more discharge of piezoelectric transducer 212 Tn various embodiments, the control of the functionality of IC 202 is handled by a finite state machine (FSM).
  • the FSM relates all switching activities to its input clock signal derived from oscillator 210.
  • the core of the FSM can be, but not limited to a n-bit counter.
  • the output signals of the FSM controls one or more complete operational cycle of the chip.
  • the control of the functionality of IC 202 is handled by an FPGA.
  • aspects of the present disclosure may include an ultrasonic transducer driver that can overcome the dynamic range limitations of a low voltage battery supply by using an on-chip boost converter in combination with one external inductor to generate the required high voltage for excitation of the transducer.
  • the transducer itself is used as a storage capacitor, whereafter it is rapidly discharged to generate an ultrasound pulse.
  • the transducer is slowly charged by a high voltage generation block, whereafter it is rapidly discharged using one or more discharge controller to create an ultrasound pulse. This approach doesn’t require an external storage capacitor leading to a reduction in size, power consumption, number of transistors, and chip area.
  • FIG. 3 a simplified schematic 300 of an inductive boost converter is shown, according to various embodiments.
  • pumping is performed with a high voltage transistor M9302.
  • transistor M7304 is on and transistor M8 306 is off.
  • charge n 308 is pulled high so that M8 306 grounds the supply side of the inductor 310, equivalent to inductor 214 of FIG. 2, to prevent current built up in the inductor during the discharge of the piezoelectric transducer 312, equivalent to transducer 212 of FIG. 2, connected to the output of the pump.
  • M7 304 and M8 308 are driven with unbalanced inverter chains to ensure that they are never carrying a short circuit current during switching.
  • the transducer 312 is slowly charged by the high voltage generation block, whereafter it is rapidly discharged using one or more discharge block to create one or more ultrasound pulse.
  • discharge unit 208 of FIG. 2 can be divided two or more equivalents block 402.
  • the division into blocks enables the adjustment of used discharge transistor size to the connected piezoelectric transducer 212 of FIG. 2.
  • the main component in the block can be a 12000/3 _m discharge transistor Ml 404.
  • Ml 404 can be a high voltage thin oxide n-channel transistor At a gate voltage of 3.6V, the transistor achieves a peak current of about 1 A.
  • the gate capacitance presented by Ml is large, and care should be taken to use an appropriate transistor scaling to drive the gate.
  • a discharge is initiated by a high level on the pulse input, which propagates through the AND gate Al 406 to the buffers and to the discharge transistor Ml 404 which starts to discharge the node out.
  • the task of the discharge control is to turn the discharge transistor Ml 404 off immediately when the out node has been discharged, to avoid holding the transducer clamped to ground level.
  • a key component to achieve this is the controllable level shifter M2/M3 408 which transforms the high voltage on the out node to a level appropriate for the low voltage CMOS logic.
  • the gate node of the inverter M4/M5 410 will hold a value of VDD - VGSM3 as long as the out node remains over approximately VDD - VGSM3 + VDS,sat M3.
  • the level shifter 408 is turned on only when a discharge is initiated.
  • the gate node of M4/M5 410 starts to drop as it is pulled down by M2 when M3 turns off.
  • the inverter M4/M5 410 switches and pulls the clock input of the D flip-flop high. This turns off the discharge transistor through the AND gate Al 406, as well as the sense circuit through AND gate A2 412. Before a new discharge cycle can be performed the D flip-flop has to be reset through reset.
  • a miniaturized transducer driver that can overcome the dynamic range limitations of a low voltage battery supply by using a DC-DC boost converter to generate the high voltage required by the system.
  • the transducer driver is used to generate high-energy HV pulses with the control signals of a digital control block and the power supply of the DC-DC boost converter.
  • FIG. 5 a diagram 400a of a miniaturized transducer driver comprising a charge pump and a half-bridge transducer driver is shown, according to various embodiments.
  • a miniaturized transducer driver comprises a battery 402a, an ASIC 404a, an off-chip digital control block 406a, and a PZT transducer 408a.
  • battery 402a may comprise a lithium-ion battery with a nominal voltage, for example, approximately 4V.
  • a half-bridge transducer driver 410a is used to drive the PZT transducer 408a, equivalent to transducer 106 of FIG. 1 to generate ultrasound.
  • the output of the half-bridge transducer driver 410a equals the voltage that is applied across the PZT transducer 408a.
  • digital control signals for ASIC 402a are generated by the digital control block 406a of an FPGA.
  • the control signals generated by the digital control block include a Clockl HS, Clockl LS for clock driver 412a and Clock2 HS, and Clock2 LS for clock driver 414a, said clock drivers driving charge pump 416a within the DC-DC boost converter 418a as well as the control signals LIUS HS for HV Level shifter 420a and LIUS LS for LS Gate Driver 422a the half-bridge transducer driver 410a.
  • transistor QI 424a is the high-side HS and transistor Q2 426a is the low side switch.
  • driver 410a may comprise of an internal bootstrap circuit, consisting of a diode DBOOT and a capacitor CBOOT, used to generate a bootstrap voltage VBOOT for HS Gate Driver 428a for the high-side operation of the half-bridge transducer driver 410a.
  • the DC-DC boost converter 420a is used to generate the high voltage VPP needed by the transducer driver to interface with the PZT transducer 408a.
  • the output wave of the half-bridge transducer may be designed to operate at one or more frequencies depending on a desired output, including the drug dispensing, transport, or generation of ultrasound energy or intensity to produce, including but not limited to, cavitation or sonophoresis.
  • aspects of the present disclosure may include methods for targeted or localized ultrasound- mediated drug delivery.
  • the targeted delivery methods may comprise the use of a diagnostic unit having a sensor suite to determine the location of the capsule during transit through the GI tract.
  • the method may comprise the use of a sensor suite containing one or more physical, chemical, or bio-responsive sensor, including but not limited to, a pH, temperature, pressure, gas, chemical, immune-reactive, ultrasound, electromagnetic, magnetic field, CCD array, optical sensor, electrochemical, gravimetric, combinations thereof, or the like.
  • the methods for targeted drug delivery may comprise calculating the time of transit to activate the said piezoelectric transducer to produce ultrasound energy, intensity, or cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise the use of an internal clock of said IC to activate the said piezoelectric transducer to produce ultrasound energy, intensity, or cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise the calculation of a transit time to activate the said piezoelectric transducer to produce ultrasound energy, intensity, or cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise the determination of a pH, a pH change, a pH gradient to activate the said piezoelectric transducer to produce ultrasound energy, intensity, or cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise the determination of a body temperature, a body temperature change, a temperature gradient to activate the said piezoelectric transducer to produce ultrasound energy, intensity, or cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the methods for targeted drug delivery may comprise the determination of a combination of a body temperature and or pH, temperature and pH change, or temperature and pH gradient to activate the said piezoelectric transducer to produce ultrasound energy, intensity, or cavitation using low frequency ultrasound for drug delivery to at a specific location of the GI.
  • the said system and methods for targeted or localized ultrasound-mediated drug delivery within the GI tract preferably combines the functionalities of the diagnostic sensor suite and the capabilities to generate one or more adjustable controlled drug release profiles of one or more drug payload from said drug reservoir.
  • the present disclosure provides methods of administering a therapeutic agent to a gastrointestinal tissue of a subject by transporting the ingestible capsule to at least one specific location of the GI and the payload containing an encapsulated or non-encapsulated therapeutic agent that is activated by an ultrasound transducer within the capsule for control-released, pulsatile, non-pulsatile, intermittent, digital, or continuous local or targeted delivery of said agent from the payload or reservoir into gastrointestinal tissue of the subject.
  • the method comprises the use of a temperature and a pH sensor from said diagnostic sensor suite to determine a specific location with the GI for activating said ultrasound transducer (e.g., 106 of FIG. 1).
  • said temperature sensor can be a silicon temperature sensor.
  • said pH sensor can be a ISFET sensor requiring low power consumption.
  • said chip may incorporated a sensor interface, a timer, and an FSM.
  • a patient swallows a capsule (Step 502), and the FSM is programmed for the capsule to analyze one or more GI landmarks, including but not limited to ingestion, pylorus, ileocecal valve, stomach, colon, or rectum.
  • ingestion is identified has having a rapid temperature rise and a rapid pH drop (> 3 pH values) (Step 504).
  • a determination to deliver (Step 504a) a targeted amount of drug using transducer 106 of FIG. 1 to produce ultrasound energy, intensity, or cavitation to propel one or more released drug 112 of FIG. 1 into a targeted region of GI tissue.
  • the pylorus location is identified by a rapid pH rise (> 3 pH values (Step 506).
  • a determination is made to deliver (Step 506a) a targeted amount of drug using transducer 106 of FIG. 1 to produce ultrasound energy, intensity, or cavitation to propel one or more released drug 112 of FIG. 1 into a targeted region of GI tissue.
  • ileocecal valve is identified by a rapid drop to ⁇ 6.5 pH (Step 508).
  • the senor suit can be implemented in a CMOS process, including but not limited to, a 0.6 pm or 0.18 pm CMOS process.
  • the single-chip multi-sensor diagnostic unit may comprise of a highly monolithic-integrated multimodal sensing system consisting of a capacitive based pressure sensor 602, a three-electrode electrochemical oxygen sensor 604, a solid-state based temperature sensor 606, their respective sensor interface circuits, a readout multiplexer 608, an analog-to-digital converter (ADC) 610, a digital controll er uni t 612, and a power management u nit 614.
  • ADC analog-to-digital converter
  • an interface circuit 616 for the capacitive pressure sensor includes a pseudo-differential sensor bridge, a two-stage capacitance-to-voltage converter (CVC) to convert the capacitance changes into voltage output, and a self-calibration circuit to auto-calculate the baseline for process variation compensation.
  • an oxygen sensor interface circuit has a negative feedback configuration operational amplifier as a potentiostat 618 and a transimpedance amplifier to convert the sensing current to output voltage.
  • the solid-state temperature sensor has a bandgap reference and a proportional -to-absolute- temperature (PTAT) voltage generator 620 to sense the temperature variation and convert it into an output voltage.
  • PTAT proportional -to-absolute- temperature
  • multiplexer (MUX) 608 is used to feed the three sensing signals to the 10-bit successive approximation (SAR) ADC 610 to perform real-time data sampling and quantization in a time-multiplexed manner.
  • the digital controller circuit of controller unit 612 provides the configuration and control for the rest circuits, performs digital filtering of the sensor signals.
  • the power management circuit consists of low drop- out (LDO) voltage regulators to provide a 1.8 V voltage to supply the sensors and integrated circuits.
  • LDO low drop- out
  • the solid-state temperature sensor and integrated circuits may be fabricated using a 0.18-pm 1.8-V CMOS process.
  • the single-chip diagnostic unit may be used to perform one or more steps or methods described in FIG.
  • the single-chip diagnostic unit may be a stand-alone chip or may be combined with one or more said ASIC of the ingestible capsule of the present disclosure to minimize components and chip areas of the electronics resulting in the fabrication of a high efficiency low power and high-volume efficiency ingestible capsule.
  • An object of the present disclosure is the encapsulation of therapeutic agents with a liquid, mixture, scaffold, or responsive polymer for incorporation into a reservoir of ingestible capsule.
  • the therapeutic agent is encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, catalytic, piezo-catalytic, or ultrasound-responsive polymeric carrier, including but not limited to, microbubble, nanobubble, nanodroplet, nano emulsion, nanofiber, vesicle, micelle, or hydrogel sphere or coating.
  • microbubble, nanobubble, nanodroplet, nano emulsion, nanofiber, vesicle, micelle, or hydrogel sphere or coating of the present disclosure may be produced from, but not limited to, poly(lactic acid), poly(allyla- mine hydrochloride), perfluorocarbon, polyvinyl alcohol, poly(lactic-co-glycolic acid, perfluoroc- tanol-poly(lactic acid).
  • pH or ultrasound-responsive polymer may comprise a scaffold, gel, or vesicle produce from, but not limited to, self-assembled from a polyethylene oxide)- block-poly[2-(diethylamino)ethyl methacrylate-stat-2-tetrahydrofuranyloxy) ethyl methacrylate] [PEO-b-P(DEA-stat- TMA)] block copolymers, polyethylene glycol) (PEG) crosslinked glycol chitosan (GC), Pluronic copolymers, poly(N ,N-diethyl acrylamide) (pNNDEA), or the like.
  • a scaffold, gel, or vesicle produce from, but not limited to, self-assembled from a polyethylene oxide)- block-poly[2-(diethylamino)ethyl methacrylate-stat-2-tetrahydrofuranyloxy) ethyl methacrylate] [PEO-b-P(DEA-stat-
  • polymers for nucleic acid delivery includes, but not limited to, PS, poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), and polyplexes of cationic polymers, polyplexes of reporter gene DNA and polyethyleneimine (PEI), poly(l-lysine)/DNA (PLL/DNA), the like, or combination thereof.
  • the invention provides methods of administering a therapeutic agent to gastrointestinal tissue of a subject using the systems and devices described above.
  • the methods include delivering ultrasound energy to a liquid at a frequency that produces bubbles within the liquid and causes ultrasound energy, intensity, or cavitation of the bubbles.
  • gentle implosion of the bubbles produces shock waves that permeabilize cells and propel the agent from the liquid into the tissue.
  • the use of ultrasound to cause cavitation to deliver agents to tissue is described in, for example, Schoellhammer, C. M., Schroeder, A., Maa, R., Lauwers, G. Y., Swiston, A., Zervas, M., et al. (2015). Ultrasound-mediated gastrointestinal drug delivery.
  • the ultrasound signal may have a defined frequency.
  • the ultrasound signal may have a frequency of from about 10 kHz to about 10 MHz, from about 10 kHz to about 1 MHz, from about 10 kHz to about 100 kHz, from about 20 kHz to about 80 kHz, from about 20 kHz to about 60 kHz, or from about 30 kHz to about 50 kHz.
  • the ultrasound signal may have a frequency of less than 100 kHz, less than 80 kHz, less than 60 kHz, or less than 50 kHz.
  • the ultrasound signal may have a frequency of about 20 kHz, about 25 kHz, about 30 kHz, about 35 kHz, about 40 kHz, about 45 kHz, about 50 kHz, about 55 kHz, or about 60 kHz.
  • the ultrasound signal may have a defined intensity.
  • the ultrasound signal may have an intensity of from about 0.001 W/cm 2 to about 0.01 W/cm 2 , from about 0.024 W/cm 2 to about 0.04 W/cm 2 , from about 0.014 W/cm 2 to about 0.10 W/cm 2 , from about 0.10 W/cm 2 to about 0.5 W/cm 2 , from about 0.5 W/cm 2 to about .7500 W/cm 2 , or from about 0.75 W/cm 2 to about IW/cm 2 .
  • the ultrasound energy may be delivered as a pulse, i.e., it may be delivered over a brief, finite period to minimize damage to the agent being delivered by the ultrasound energy.
  • the pulse may be less than 20 minutes, less than 10 minutes, less than 5 minutes, or less than 10 minutes.
  • the pulse may be from about 10 seconds to about 3 minutes.
  • the pulse may be about 10 minutes, about 5 minutes, about 3 minutes, about 3 minutes, about 1 minute, about 30 seconds, about 20 seconds, or about 10 seconds.
  • the parameters of the ultrasound pulse such as the frequency and/or duration, may be selected so that damage to the agent is limited to a certain fraction or percentage of the agent.
  • the ultrasound energy may result in breakdown of less than about 95% of the agent, less than about 90% of the agent, less than about 80% of the agent, less than about 70% of the agent, less than about 60% of the agent, less than about 50% of the agent, less than about 40% of the agent, less than about 25% of the agent, or less than about 10% of the agent.
  • the parameters of the ultrasound pulse may be selected so that at least a minimum amount of the agent is transferred to the tissue.
  • the ultrasound energy may result in transfer of at least 1% of the agent, at least 2% of the agent, at least 5% of the agent, at least 10% of the agent, at least 20% of the agent, at least 30% of the agent, or at least 40% of the agent.
  • the methods may be used to deliver a therapeutic agent to a specific tissue in the GI tract.
  • the tissue may be buccal tissue, gingival tissue, labial tissue, esophageal tissue, gastric tissue, intestinal tissue, colorectal tissue, or anal tissue.
  • the therapeutic agent may be targeted to a particular tissue in the GI tract.
  • the therapeutic agent may be targeted to the stomach, small intestine, large intestine (colon), rectum, or at a duct that enters the GI tract, such as a pancreatic duct or a common bile duct.
  • the methods may include administering an ingestible capsule to the subject.
  • the ingestible capsule may be administered orally or rectally.
  • the ingestible capsule may be administered via a duct that enters the GI tract.
  • the methods may include positioning the ingestible capsule within the subjects GI tract.
  • the ingestible capsule may be positioned in proximity to an affected region of the GI tract, such as an ulcer or inflamed region.
  • the ingestible capsule may be positioned by applying a magnetic field to a portion of the subject’s GI tract from a device outside the subject’s body.
  • the magnetic field may be applied using the transmitter.
  • the magnetic field may be applied from a magnetic device that is separate from the transmitter.
  • the therapeutic agent may be any agent that provides a therapeutic benefit.
  • suitable agents include alpha-hydroxy formulations, ace inhibiting agents, analgesics, anesthetic agents, anthelmintics, anti-arrhythmic agents, antithrombotic agents, antiallergic agents, anti-angiogenic agents, antibacterial agents, antibiotic agents, anticoagulant agents, anticancer agents, antidiabetic agents, anti-emetics, antifungal agents, antigens, antihypertension agents, antihypotensive agents, antiinflammatory agents, antimicotic agents, antimigraine agents, anti-obesity agents, antiparkinson agents, antirheumatic agents, antithrombins, antiviral agents, antidepressants, antiepileptics, antihistamines, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antithyroid agents, anxiolytics, asthma therapies, astringents, beta blocking agents, blood products and substitutes, bronchospamolytic agents
  • agents may be of any chemical form.
  • agents may be biological therapeutics, such as nucleic acids, proteins, peptides, polypeptides, antibodies, or other macromolecules.
  • Nucleic acids include RNA, DNA, RNA/DNA hybrids, and nucleic acid derivatives that include non-naturally-occurring nucleotides, modified nucleotides, non-naturally-occurring chemical linkages, and the like. Examples of nucleic acid derivatives and modified nucleotides are described in, for example, International Publication WO 2018/118587, the contents of which are incorporated herein by reference.
  • Nucleic acids may be polypeptide-encoding nucleic acids, such as mRNAs and cDNAs. Nucleic acids may interfere with gene expression.
  • RNAi interfering RNAs
  • siRNAs and miRNAs examples include siRNAs and miRNAs.
  • miRNAs examples include siRNAs and miRNAs.
  • RNAi is known in the art and described in, for example, Kim and Rossi, Biotechniques. 2008 Apr; 44(5): 613-616, doi: 10.2144/000112792; and Wilson and Doudna, Molecular Mechanisms of RNA Interference, Annual Review of Biophysics 2013 42: 1, 217-239, the contents of each of which are incorporated herein by reference.
  • Agents may be organic molecules of non-biological origin. Such drugs are often called small-molecule drugs because they typically have a molecular weight of less than 2000 Daltons, although they may be larger. Agents may be combinations or complexes of one or more biological macromolecules and/or one or more small molecules.
  • agents may be nucleic acid complexes, protein complexes, protein-nucleic acid complexes, and the like.
  • the agent may exist in a multimeric or polymeric form, including homocomplexes and heterocomplexes.
  • an advantage of ultrasound-based delivery of therapeutic agents is the capacity to deliver large molecules, e.g., molecules having a molecular weight greater than 1000 Da.
  • the therapeutic agent may have a minimum size.
  • the antigen may have a molecular weight of > 100 Da, > 200 Da, > 500 Da, > 1000 Da, > 2000 Da, > 5000 Da, > 10,000 Da, > 20,000 Da, > 50,000 Da, or > 100,000 Da.
  • the therapeutic agent may be provided in a liquid that promotes delivery of the therapeutic agent using the devices or systems provided herein.
  • the liquid may facilitate ultrasound-induced cavitation, iontophoresis, sonoporation, magneto-sonoporation, or electroporation.
  • the liquid may be aqueous.
  • the liquid may contain ions.
  • the liquid may be an aqueous solution that contains one or more salts.
  • the liquid may contain a buffer.
  • the therapeutic agent may be formulated.
  • Formulations commonly used for delivery of biologic and small-molecule agents include drug crystals, gold particles, iron oxide particles, lipid- like particles, liposomes, micelles, microparticles, nanoparticles, polymeric particles, vesicles, viral capsids, viral particles, and complexes with other macromolecules that are not essential for the biological or biochemical function of the agent.
  • the therapeutic agent may be unformulated, i.e., it may be provided in a biologically active format that does not contain other molecules that interact with the agent solely to facilitate delivery of the agent.
  • the agent may be provided in a non-encapsulated form or in a form that is not complexed with other molecules unrelated to the function of the agent.
  • the agent may be a component of a gene editing system, such as a meganuclease, zinc finger nuclease (ZFN), a transcription activator-like effector-based nuclease (TALEN), or the clustered, regularly-interspersed palindromic repeat (CRISPR) system.
  • Meganucleases are endodeoxyribonucleases that recognize double-stranded DNA sequences of 12-40 base pairs. They can be engineered to bind to different recognition sequences to create customized nucleases that target particular sequences. Meganucleases exist in archaebacte- rial, bacteria, phages, fungi, algae, and plants, and meganucleases from any source may be used. Engineering meganucleases to recognize specific sequences is known in the art and described in, for example, Stoddard, Barry L.
  • ZFNs are artificial restriction enzymes that have a zinc finger DNA-binding domain fused to a DNA-cleavage domain. ZFNs can also be engineered to target specific DNA sequences. The design and use of ZFNs is known in the art and described in, for example, Carroll, D (2011) “Genome engineering with zinc-finger nucleases” Genetics Society of America 188 (4): 773-782, doi:10.1534/genetics.l 11.131433. PMC 3176093, PMID 21828278; Cathomen T, Joung JK (July 2008) "Zinc-finger nucleases: the next generation emerges" Mol. Ther.
  • TALENs are artificial restriction enzymes that have a TAL effector DNA-binding domain fused to a DNA cleavage domain. TALENs can also be engineered to target specific DNA sequences. The design and use of TALENs is known in the art and described in, for example, Boch J (February 2011) "TALEs of genome targeting” Nature Biotechnology 29 (2): 135-6, doi:10.1038/nbt.1767.
  • the CRISPR system is a prokaryotic immune system that provides acquired immunity against foreign genetic elements, such as plasmids and phages.
  • CRISPR systems include one or more CRISPR-associated (Cas) proteins that cleave DNA at clustered, regularly-interspersed palindromic repeat (CRISPR) sequences.
  • Cas proteins include helicase and exonuclease activities, and these activities may be on the same polypeptide or on separate polypeptides.
  • Cas proteins are directed to CRISPR sequences by RNA molecules.
  • a CRISPR RNA (crRNA) binds to a complementary sequence in the target DNA to be cleaved.
  • a transactivating crRNA binds to both the Cas protein and the crRNA to draw the Cas protein to the target DNA sequence. Not all CRISPR systems require tracrRNA. In nature crRNA and tracrRNA occur on separate RNA molecules, but they also function when contained a single RNA molecule, called a single guide RNA or guide RNA (gRNA). The one or more RNAs and one or more polypeptides assemble inside the cell to form a ribonucleoprotein (RNP).
  • RNP ribonucleoprotein
  • CRISPR systems are described, for example, in van der Oost, et al., CRISPR-based adaptive and heritable immunity in prokaryotes, Trends in Biochemical Sciences, 34(8):401-407 (2014); Garrett, et al., Archaeal CRISPR-based immune systems: exchangeable functional modules, Trends in Microbiol. 19(11):549-556 (2011); Makarova, et al., Evolution and classification of the CRISPR-Cas systems, Nat. Rev. Microbiol. 9:467-477 (2011); and Sorek, et al., CRISPR -Mediated Adaptive Immune Systems in Bacteria and Archaea, Ann. Rev. Biochem. 82:237-266 (2013), the contents of each of which are incorporated herein by reference.
  • Class 1 systems use multiple Cas proteins to degrade nucleic acids, while class 2 systems use a single large Cas protein.
  • Class 1 Cas proteins include CaslO, CaslOd, Cas3, Cas5, Cas8a, Cmr5, Csel, Cse2, Csfl, Csm2, Csxl 1, Csyl, Csy2, and Csy3.
  • Class 2 Cas proteins include C2cl, C2c2, C2c3, Cas4, Cas9, Cpfl, and Csn2.
  • CRISPR-Cas systems are powerful tools because they allow gene editing of specific nucleic acid sequences using a common protein enzyme.
  • a Cas protein By designing a guide RNA complementary to a target sequence, a Cas protein can be directed to cleave that target sequence.
  • Cas proteins Although naturally-occurring Cas proteins have endonuclease activity, Cas proteins have been engineered to perform other functions. For example, endonuclease-deactivated mutants of Cas9 (dCas9) have been created, and such mutants can be directed to bind to target DNA sequences without cleaving them. dCas9 proteins can then be further engineered to bind transcriptional activators or inhibitors.
  • CRISPR activators CRISPRa
  • CRISPR inhibitors CRISPR inhibitors
  • CRISPR systems can also be used to introduce sequence-specific epigenetic modifications of DNA, such acetylation or methylation.
  • modified CRISPR systems for purposes other than cleavage of target DNA are described, for example, in Dominguez, et al., Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation, Nat. Rev. Cell Biol. 17(1): 5- 15 (2016), which is incorporated herein by reference.
  • the agent may be any component of a CRISPR system, such as those described above.
  • the CRISPR component may be one or more of a helicase, endonuclease, transcriptional activator, transcriptional inhibitor, DNA modifier, gRNA, crRNA, or tra- crRNA.
  • the CRISPR component contain a nucleic acid, such as RNA or DNA, a polypeptide, or a combination, such as a RNP.
  • the CRISPR nucleic acid may encode a functional CRISPR component.
  • the nucleic acid may be a DNA or mRNA.
  • the CRISPR nucleic acid may itself be a functional component, such as a gRNA, crRNA, or tracrRNA.
  • the agent may include an element that induces expression of the CRISPR component.
  • expression of the CRISPR component may be induced by an antibiotic, such as tetracycline, or other chemical.
  • Inducible CRTSPR systems have been described, for example, in Rose, et al., Rapidly inducible Cas9 and DSB-ddPCR to probe editing kinetics, Nat. Methods, 14, pages 891-896 (2017); and Cao, et al., An easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targeting, Nucleic Acids Res. 14(19):el49 (2016), the contents of which are incorporated herein by reference.
  • the inducible element may be part of the CRISPR component, or it may be a separate component.
  • methods allow delivery of agents that promote wound healing.
  • the agent may promote healing by any mechanism.
  • the agent may facilitate one or more phases of the wound healing process; prevent infection, including bacterial or viral infection; or alleviate pain or sensitivity.
  • growth factors promote wound healing.
  • growth factors that promote wound healing include CTGF/CCN2, EGF family members, FGF family members, G-CSF, GM-CSF, HGF, HGH, HIF, histatin, hyaluronan, IGF, IL-1, IL-4, IL-8, KGF, lactoferrin, lysophosphatidic acid, NGF, a PDGF, TGF-P, and VEGF.
  • the EFG family includes 10 members: amphiregulin (AR), betacellulin (BTC), epigen, epiregulin (EPR), heparin- binding EGF-like growth factor (HB-EGF), neuregulin-1 (NRG1), neuregulin-2 (NRG2), neureg- ulin-3 (NRG3), neuregulin-4 (NRG4), or transforming growth factor-a (TGF-a).
  • the FGF family includes 22 members: FGF1, FGF2 (also called basic FGF or bFGF), FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF20, FGF21, FGF22, or FGF23.
  • PDGF exists in three forms: PDGF AA, PDGF AB, and PDGF BB.
  • the TGF-P family includes three forms: TGF-pi, TGF-P2, and TGF-P3.
  • agents that prevent infection have been used to treat wounds.
  • the agent may be an antimicrobial, antiviral, antibiotic, antifungal, or antiseptic.
  • exemplary agents include silver, iodine, chlorhexidine, hydrogen peroxide, lysozyme, peroxidase, defensins, cystatins, thrombospondin, and antibodies.
  • Nitric oxide donors such as glyceryl trinitrate and nitrite salts, are also useful to prevent infection and promote wound healing.
  • the methods are useful to treat conditions of the GI tract of a subject.
  • the condition may be any disease, disorder, or condition that affects the GI tract.
  • the disorder is a disorder of the esophagus, including, but not limited to, esophagitis - (candidal), gastroesophageal reflux disease (gerd); laryngopharyngeal reflux (also known as extraesophageal reflux disease/eerd); rupture (Boerhaave syndrome, Mallory- Weiss syndrome); UES - (Zenker's diverticulum); LES - (Barrett's esophagus); esophageal motility disorder - (nutcracker esophagus, achalasia, diffuse esophageal spasm); esophageal stricture; and megaesophagus.
  • esophagitis - candidal
  • gastroesophageal reflux disease gerd
  • laryngopharyngeal reflux also known as extraesophageal reflux disease/eerd
  • rupture Boerhaave syndrome, Mallory- Weiss syndrome
  • the disorder is a disorder of the stomach, including but not limited to gastritis (e.g., atrophic, Menetrier's disease, gastroenteritis); peptic (i.e., gastric) ulcer (e.g., Cushing ulcer, Dieulafoy's lesion); dyspepsia; emesis; pyloric stenosis; achlorhydria; gastropare- sis; gastroptosis; portal hypertensive gastropathy; gastric antral vascular ectasia; gastric dumping syndrome; and human mullular fibrillation syndrome (HMFS).
  • gastritis e.g., atrophic, Menetrier's disease, gastroenteritis
  • peptic (i.e., gastric) ulcer e.g., Cushing ulcer, Dieulafoy's lesion
  • dyspepsia emesis
  • pyloric stenosis achlorhydria
  • the disorder is a disorder of the small intestine, including but not limited to, enteritis (duodenitis, jejuni tis, ileitis); peptic (duodenal) ulcer (curling's ulcer); malabsorption: celiac; tropical sprue; blind loop syndrome; Whipple's; short bowel syndrome; steatorrhea; milroy disease
  • the disorder is a disorder of the small intestine, including but not limited to, both large intestine and small intestine enterocolitis (necrotizing); inflammatory bowel disease (IBD); Crohn's disease; vascular; abdominal angina; mesenteric ischemia; angiodysplasia; bowel obstruction: ileus; intussusception; volvulus; fecal impaction; constipation; and diarrhea.
  • IBD inflammatory bowel disease
  • Crohn's disease vascular; abdominal angina; mesenteric ischemia; angiodysplasia
  • the disorder is a disorder of the small intestine, including but not limited to, accessory digestive glands disease; liver hepatitis (viral hepatitis, autoimmune hepatitis, alcoholic hepatitis); cirrhosis (PBC); fatty liver (Nash); vascular (hepatic veno-occlusive disease, portal hypertension, nutmeg liver); alcoholic liver disease; liver failure (hepatic encephalopathy, acute liver failure); liver abscess (pyogenic, amoebic); hepatorenal syndrome; peliosis hepatis; hemochromatosis; and Wilson's disease.
  • liver hepatitis viral hepatitis, autoimmune hepatitis, alcoholic hepatitis
  • PBC cirrhosis
  • fatty liver Naash
  • vascular hepatic veno-occlusive disease, portal hypertension, nutmeg liver
  • alcoholic liver disease liver failure (hepatic encephalopathy, acute liver
  • the disorder is a disorder of the pancreas, including, but not limited to, pancreas pancreatitis (acute, chronic, hereditary); pancreatic pseudocyst; and exocrine pancreatic insufficiency.
  • the disorder is a disorder of the large intestine, including but not limited to, appendicitis; colitis (pseudomembranous, ulcerative, ischemic, microscopic, collagenous, lymphocytic); functional colonic disease (IBS, intestinal pseudoobstruction/ogilvie syndrome); megacolon/toxic megacolon; diverticulitis; and diverticulosis.
  • colitis prseudomembranous, ulcerative, ischemic, microscopic, collagenous, lymphocytic
  • functional colonic disease IBS, intestinal pseudoobstruction/ogilvie syndrome
  • megacolon/toxic megacolon diverticulitis
  • diverticulosis a disorder of the large intestine
  • the disorder is a disorder of the large intestine, including but not limited to, gall bladder and bile ducts, cholecystitis; gallstones/cholecystolithiasis; cholesterolosis; Rokitansky-Aschoff sinuses; postcholecystectomy syndrome cholangitis (PSC, ascending); cho- lestasis/Mirizzi's syndrome; biliary fistula; haemobilia; and gallstones/cholelithiasis.
  • the disorder is a disorder of the common bile duct (including choledocholithiasis, biliary dyskinesia).
  • disorders which can be treated with the methods and devices included herein include acute and chronic immune and autoimmune pathologies, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, thyroidosis, graft versus host disease, scleroderma, diabetes mellitus, Graves' disease, Beschet' s disease; inflammatory diseases, such as chronic inflammatory pathologies and vascular inflammatory pathologies, including chronic inflammatory pathologies such as sarcoidosis, chronic inflammatory bowel disease, ulcerative colitis, and Crohn's pathology and vascular inflammatory pathologies, such as, but not limited to, disseminated intravascular coagulation, atherosclerosis, giant cell arteritis and Kawasaki's pathology; malignant pathologies involving tumors or other malignancies, such as, but not limited to leukemias (acute, chronic myelocytic, chronic lymphocytic and/or myelodyspastic syndrome); lymph
  • disorders which can be treated with the methods and devices included herein include acute and chronic immune and autoimmune pathologies, inflammatory diseases, infections and malignant pathologies involving, e.g., tumors or other malignancies.
  • the subject suffering from the GI condition may be any type of subject, such as an animal, for example, a mammal, for example, a human. Incorporation by Reference

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Abstract

L'invention concerne des systèmes et des procédés se rapportant à un système d'administration de médicament à capsule ingérable à faible puissance pour l'administration ciblée ou localisée d'un médicament à médiation par ultrasons à l'intérieur du tractus gastro-intestinal. Le système d'administration de médicament par capsule ingérable à faible consommation d'énergie à haut rendement peut comprendre un ou plusieurs dispositifs de stockage d'énergie à faible puissance, un transducteur piézoélectrique, un pilote de transducteur à ultrasons, un support/réservoir de médicament, au moins une charge utile de médicament et, éventuellement, une unité de diagnostic. L'unité de diagnostic peut, en outre, comprendre une suite de capteurs pour déterminer l'emplacement de la capsule pendant le transit à travers le tractus gastro-intestinal et pour l'activation ultérieure du transducteur piézoélectrique à un emplacement ciblé. La capsule ingérable peut effectuer une opération de faible puissance plus efficace avec une efficacité de volume élevé incorporant un nombre minimal de composants électriques pour générer une force motrice ultrasonore, un gradient de champ ultrasonore, une force sonophorétique, une diffusion en continu acoustique ou une cavitation à l'intérieur du GI à l'aide d'ultrasons basse fréquence.
PCT/US2023/030685 2022-08-31 2023-08-21 Dispositif ultrasonore ingérable à efficacité volumique élevée à faible puissance pour administration d'agents thérapeutiques Ceased WO2024049667A1 (fr)

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Citations (6)

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US20090306633A1 (en) * 2005-01-18 2009-12-10 Koninklijke Philips Electronics, N.V. Electronically controlled capsule
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US20140228715A1 (en) * 2011-05-13 2014-08-14 The General Hospital Corporation Method and Apparatus for Delivering a Substance
WO2019099681A1 (fr) * 2017-11-15 2019-05-23 Butterfly Network, Inc. Dispositif à ultrasons avec transducteurs ultrasonores micro-usinés piézoélectriques
US20190268078A1 (en) * 2006-09-06 2019-08-29 Innurvation Inc. System and method for acoustic data transmission

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Publication number Priority date Publication date Assignee Title
US8251929B2 (en) * 2005-01-10 2012-08-28 Chongqing Haifu (Hifu) Technology Co., Ltd. Integrated ultrasound therapy transducer assembly
US20090306633A1 (en) * 2005-01-18 2009-12-10 Koninklijke Philips Electronics, N.V. Electronically controlled capsule
US8597278B2 (en) * 2006-06-23 2013-12-03 MEDIMETRICS Personalized Drug Delivery B.V. Medicament delivery system and process
US20190268078A1 (en) * 2006-09-06 2019-08-29 Innurvation Inc. System and method for acoustic data transmission
US20140228715A1 (en) * 2011-05-13 2014-08-14 The General Hospital Corporation Method and Apparatus for Delivering a Substance
WO2019099681A1 (fr) * 2017-11-15 2019-05-23 Butterfly Network, Inc. Dispositif à ultrasons avec transducteurs ultrasonores micro-usinés piézoélectriques

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