WO2004066903A2 - Active drug delivery in the gastrointestinal tract - Google Patents
Active drug delivery in the gastrointestinal tract Download PDFInfo
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- WO2004066903A2 WO2004066903A2 PCT/IL2004/000093 IL2004000093W WO2004066903A2 WO 2004066903 A2 WO2004066903 A2 WO 2004066903A2 IL 2004000093 W IL2004000093 W IL 2004000093W WO 2004066903 A2 WO2004066903 A2 WO 2004066903A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
- A61B1/04—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor combined with photographic or television appliances
- A61B1/041—Capsule endoscopes for imaging
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/07—Endoradiosondes
- A61B5/073—Intestinal transmitters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14539—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring pH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
- A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
- A61N1/303—Constructional details
- A61N1/306—Arrangements where at least part of the apparatus is introduced into the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
- A61B5/0004—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by the type of physiological signal transmitted
- A61B5/0008—Temperature signals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
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- 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
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
Definitions
- the present invention relates to an oral drug delivery system and, more particularly, to an ingestible capsule which acts as a medication carrier and which enhances the absorption of the medication through the gastrointestinal wall.
- the absorption of a drug (or of a drug precursor) into the systemic circulation is determined by the physicochemical properties of the drug, its formulations, and the route of administration, whether oral, rectal, topical, by inhalation, or by intravenous administration.
- Oral administration includes swallowing, chewing, sucking, as well as buccal administration, i.e., placing a drug between the gums and cheek, and sublingual administration, i.e., placing a drug under the tongue.
- buccal administration i.e., placing a drug between the gums and cheek
- sublingual administration i.e., placing a drug under the tongue.
- a prerequisite to absorption is drug dissolution.
- Absorption of orally-administered drugs into the internal environment generally occurs almost exclusively in the small intestine.
- the small intestine is lined with a layer of epithelial cells joined by tight junctions, hi order to pass from the lumen of the small intestine into the internal environment and, therefrom into the systemic circulation, a dissolved drug must either pass through the semi-permeable membranes of the epithelial cells (transcellular passage), or through the tight junctions between the epithelial cells.
- the rate of transcellular passage is generally low except for small, lipid-soluble molecules.
- the tight junctions generally prevent the passage of most dissolved molecules.
- a drug may cross the biological barrier by passive diffusion, or by other naturally-occurring transfer modes, for example, facilitated passive diffusion, active transport, or pinocytosis.
- a drug may be artificially assisted to cross the biological barrier.
- passive diffusion transport depends on the concentration gradient of the solute across the biological barrier. Since the drug molecules are rapidly removed by the systemic circulation, drug concentration in the blood in the vicinity of the administration site is low compared with that at the administration site, producing a large concentration gradient. The drug diffusion rate is directly proportional to that gradient. The drug diffusion rate also depends on other parameters, for example, the molecule's lipid solubility and size. Because the cell membrane is lipoid, lipid-soluble drugs diffuse more rapidly than relatively lipid-insoluble drugs.
- a carrier component combines reversibly with a substrate molecule at the cell membrane exterior.
- the carrier- substrate complex diffuses rapidly across the membrane, releasing the substrate at the interior surface. This process is characterized by selectivity and saturability: The carrier is operative only for substrates with a relatively specific molecular configuration, and the process is limited by the availability of carriers.
- Active transport which is another naturally occurring transfer mode, appears to be limited to drugs that are structurally similar to endogenous substances. Active transport is characterized by selectivity and saturability and requires energy expenditure by the cell. It has been identified for various ions, vitamins, sugars, and amino acids.
- Electrotransport refers generally to electrically induced passage of a drug (or a drug precursor) through a biological barrier.
- Iontophoresis involves the electrically induced transport of charged ions, by the application of low-level, direct current (DC) to a solution of the medication. Since like electrical charges repel, the application of a positive current drives positively charged drug molecules away from the electrode and into the tissues; similarly, a negative current will drive negatively charge ions into the tissues.
- DC direct current
- Iontophoresis is an effective and rapid method of delivering water-soluble, ionized medication.
- the drug molecule itself is not water-soluble, it may be coated with a coating (for example, sodium lauryl sulfate (SLS)), that may form water-soluble entities.
- SLS sodium lauryl sulfate
- Electroosmosis involves the movement of a solvent with the agent through a membrane under the influence of an electric field.
- Electrophoresis is based on migration of charged species in an electromagnetic field. Ions, molecules, and particles with charge carry current in solutions when an electromagnetic field is imposed. Movement of a charged species tends to be toward the electrode of opposite charge. The voltages for continuous electrophoresis are rather high (several hundred volts) .
- Electroporation is a process in which a biological barrier is subjected to a high- voltage alternating-current (AC) surge, or pulse.
- the AC pulse creates temporary pores in the biological membrane, specifically between cells.
- the pores allow large molecules, such as proteins, DNA, RNA, and plasmids to pass through the biological barrier.
- Iontophoresis, electroosmosis, and electrophoresis are diffusion processes, in which diffusion is enhanced by electrical or electromagnetic driving forces.
- electroporation physically punctures the biological barriers, along cell boundaries, enabling passage of large molecules through the epithelium.
- electrotransport refers to at least one, and possibly a combination of the aforementioned transport mechanisms, which supplement the naturally-occurring transfer modes.
- Sonophoresis devices are described, for example, in US Patents 6,002,961, 6,018,678, and 6,002,961 to Mitragotri et al., US Patents 6,190,315 and 6,041,253 to Kost et al, US Patent 5,947,921 to Johnson et al., and US Patents 6,491,657 and 6,234,990 to Rowe et al., all of whose disclosures are incorporated herein by reference.
- Ablation is another method of facilitating drug passage through a biological barrier.
- ablation techniques include laser ablation, cryogenic ablation, thermal ablation, microwave ablation, radiofrequency ablation, liquid jet ablation, or electrical ablation.
- US patent 6,471,696 to Berube et al. describes a microwave ablation catheter, which may be used as a drug delivery device.
- US Patent 6,443,945 to Marchitto et al. describes a device for pharmaceutical delivery using laser ablation.
- US Patent 4,869,248 to Narula describes a catheter for performing localized thermal ablation, for purposes of drug administration.
- US Patents 6,148,232 and 5,983,135 to Avrahami describe drug delivery systems using electrical ablation. The disclosures of all of these patents are incorporated herein by reference.
- Oral drug administration is a common drug delivery route.
- Drug bioavailability of orally administered drugs i.e., the degree to which the drug is available to the target tissue, is affected by drug dissolution, drug degradation in the gastrointestinal (GI) tract, and drug absorption.
- GI gastrointestinal
- Drug dissolution is affected by whether the drug is in salt, crystal, or hydrate form.
- disintegrants and other excipients such as diluents, lubricants, surfactants (substances which increase the dissolution rate by increasing the wettability, solubility, and dispersibility of the drug), binders, or dispersants are often added during manufacture.
- Drug degradation in the GI tract is due to GI secretions, low pH values, and degrading enzymes. Since luminal pH varies along the GI tract, the drug must withstand different pH values. Interaction with blood, food staff, mucus, and bile may also affect the drug.
- Reactions that may affect the drug, and reduce bioavailability include: (a) complex formations, for example, between tetracycline and polyvalent metal ions; (b) hydrolysis by gastric acid or digestive enzymes, for example, penicillin and chloramphenicol palmitate hydrolysis; (c) conjugation in the gut wall, for example, sulfoconjugation of isoproterenol; (d) adsorption to other drugs, for example, digoxin and cholestyramine; and (e) metabolism by luminal microflora.
- Drug absorption of orally-administered drugs relates to transport of drugs across biological barriers presented by the epithelial cells in the GI tract.
- the nature of intestinal epithelium tends to inhibit drug absorption.
- the intestinal epithelium of the small intestine is formed as a series of finger-like projections, called intestinal villi. These are covered by columnar epithelium, carpeted with microvilli.
- the epithelial cells along the microvilli are strongly bound to each other, by tight junctions, also called the zona occludens.
- the tight junctions seal the internal environment of the body from the intestinal lumen.
- the size of gaps between tight junctions in humans is about 8 nm in the jejunum, and about 0.3 nm in the ileum and the colon. Therefore, particles with diameters greater than about 11.5 angstrom and/or several thousand daltons generally cannot penetrate the gaps.
- MDR which is a major cause of cancer treatment failure, is a phenomenon whereby cancer cells develop a broad resistance to a wide variety of chemotherapeutic drugs.
- MDR has been associated with overexpression of P-glycoprotein or multidrug resistance- associated protein (MRP), two transmembrane transporter molecules which act as pumps to remove toxic drugs from tumor cells.
- MRP multidrug resistance- associated protein
- P-glycoprotein acts as a unidirectional efflux pump in the membrane of acute myeloid leukemia (AML) cells and lowers the intracellular concentration of cytotoxic agents, by pumping them out of leukemic cells. Yet it confers resistance to a variety of chemotherapy drugs, including daunorubicin.
- Ingestible radio pills which are ingestible capsules containing a transmitter and other electrical components are known.
- researchers at Heidelberg University developed a pill for monitoring pH of the GI tract. (Noller, H. G., "The Heidelberg Capsule Used For the Diagnosis of Peptic Diseases," Aerospace Medicine, Feb., 1964, pp.
- US Patent 4,844,076 to Lesho et al. issued July 1989, entitled, "Ingestible size continuously transmitting temperature monitoring pill,” whose disclosure is incorporated herein by reference, describes a temperature responsive transmitter, encapsulated in an ingestible size capsule.
- the capsule is configured to monitor average body temperature, internally.
- the ingestible size temperature pill can be configured in a rechargeable embodiment. In this embodiment the pill uses the inductive coil in the tank circuit as the magnetic pickup to charge a rechargeable nickel cadmium battery.
- US Patent 5,279,607 to Schentag et al. entitled, "Telemetry capsule and process,” whose disclosure is incorporated herein by reference, describes an ingestible capsule and a process for delivery, particularly repeatable delivery, of a medicament to the alimentary canal.
- the ingestible capsule is an essentially non-digestible capsule, which contains an electric energy emitting means, a radio signal transmitting means, a medicament storage means and a remote actuatable medicament releasing means.
- the capsule signals a remote receiver as it progresses through the alimentary tract in a previously mapped route and upon reaching a specified site is remotely triggered to release a dosage of medicament.
- PCT Publication WO 97/31679 further discloses that USSR Inventor's Certificate No. 1223922, Int. CI. A 61 N 1/36, Bulletin No. 14, by Pekarasky et al., entitled, "Gastrointestinal tract Electrostimulator,” which is incorporated herein by reference, describes a swallowable capsule adapted for electrostimulation of the alimentary tract, as post-surgical therapy, as a prophylactic measure of alimentary tract diseases, or for the promotion of peristalsis, which is further adapted for the dispensing of medication.
- US Patent 5,604,531 to Iddan et al. entitled, "In vivo video camera system,” whose disclosure is incorporated herein by reference, describes a video camera system, encapsulated within an ingestible capsule, arranged to pass through the entire digestive tract, operating as an autonomous video endoscope.
- the ingestible capsule includes a camera system and an optical system for imaging an area of interest onto the camera system, and a transmitter, which relays the video output of the camera system to an extracorporeal reception system.
- a light source is located within a borehole of the optical system.
- US Patent Application 2001/0035902 to Iddan et al. entitled, "Device and system for in vivo imaging,” whose disclosure is incorporated herein by reference, describes a system and method for obtaining in vivo images.
- the system contains an imaging system and an ultra low power radio frequency transmitter for transmitting signals from a CMOS imaging camera to a receiving system located outside a patient.
- US Patent 6,428,469 to Iddan et al. entitled, "Energy management of a video capsule,” whose disclosure is incorporated herein by reference, describes an energy saving device for acquiring in vivo images of the gastro-intestinal tract.
- the device such as an autonomous capsule, includes at least one imaging unit, a control unit connected to the imaging unit, and a power supply connected to the control unit.
- the control unit includes a switching unit, and an axial motion detector connected to the switching unit, which disconnects the power supply thereby preventing the acquisition of redundant images.
- US Patent 6,632,216 to Houzego et al. which is incorporated herein by reference, describes an ingestible device for delivering a substance to a chosen location in the GI tract.
- the device includes a receiver of electromagnetic radiation for powering an openable part of the device to an opened position for dispensing of the substance.
- the receiver includes a coiled wire that couples the energy field, the wire having an air or ferrite core.
- the device optionally includes a latch defined by a heating resistor and a fusible restraint.
- the device may also include a flexible member that may serve one or both the functions of activating a transmitter circuit to indicate dispensing of the substance, and restraining of a piston used for expelling the substance.
- PCT Publication WO 02/094369 to Walla which is incorporated herein by reference, describes a device for applying substances such as medicaments having a liquid, ointment or gel-like consistency through the skin, especially by means of iontophoresis. The resorption of the substance occurs by application of a DC current.
- the publication also describes a capsular, hermetically sealed container for insertion into body orifices, which has at least two electrodes for generating a continuous electric field on its outer side. A device for receiving the substance to be applied is provided above the electrodes.
- the container is positioned to be in contact with the mucous membrane and/or the skin in a body orifice, especially in the urogenital, vaginal, and/or anal tract, and/or in the cavities of the mouth, ear, and/or nose.
- US Patent 5,217,449 to Yuda et al. which is incorporated herein by reference, describes a capsule having an outer cylinder and a piston movable in the outer cylinder, the piston being activated by an externally given signal so as to discharge a medicine to the outside of the capsule or to suck a humor for a sampling purpose.
- the capsule has a remote-controllable means including a normally-opened lead switch which connects a power supply to an activating means in response to an externally given magnetic signal thereby initiating activation of the capsule.
- US Patent 5,464,395 to Faxon et al. which is incorporated herein by reference, describes a catheter for delivering therapeutic and/or diagnostic agents directly into the tissue surrounding a bodily passageway.
- the catheter comprises at least one needle cannula able to be projected outboard of the catheter so as to deliver the desired agents to the tissue.
- the catheter also preferably includes one or more inflatable balloons.
- US Patent 4,239,040 to Hosoya et al. which is incorporated herein by reference, describes a capsule for discharging drugs into a body or collecting samples from the body.
- the capsule comprises an external cylinder having slidably mounted therein an internal cylinder.
- the internal cylinder is retained by a meltable thread at one end of the external cylinder against the biasing force of a compression spring.
- the spring effects sliding of the internal cylinder to the other end of the external cylinder, and, during this sliding movement, a drug is pushed out of the external cylinder ahead of the moving internal cylinder or a body sample is withdrawn into the external cylinder behind the moving internal cylinder.
- An electric circuit including a tunable receiver responds to an externally-transmitted electric signal to energize a heater for melting the thread to thereby effect sliding movement of the internal cylinder at the desired time.
- US Patent 4,425,117 to Hugemann et al. which is incorporated herein by reference, describes a capsule for the release of a substance at a defined or desired location in the alimentary tract.
- the capsule has a separating wall therein, which forms a first chamber and a second chamber, the first chamber having a hole in a wall thereof.
- a compression spring in a compressed state, is affixed to a body located in the second chamber.
- a needle is mounted on the compression spring facing the separation wall.
- a resonant circuit in the second chamber is tuned to an electromagnetic field of high frequency.
- the resonant circuit has a coupling coil, positioned around the body, a capacitor, connected to the other end of the coil and extending away from the first chamber, and a resistance wire, attached to the coupling coil and the capacitor.
- a fuse wire is connected to the compression spring, extends through the longitudinal passageway of the body and is connected to the body end facing away from the first chamber. The fuse wire contacts the resistance wire.
- a balloon in the expanded state is positioned in the first chamber. When the device is subjected to an external electromagnetic field having the high frequency to which the resonant circuit is tuned, the fuse wire heats up and breaks. The compressed spring is released pushing the pomt of the needle through the separating wall and the balloon, which bursts releasing any substance contained in the first chamber.
- US Patent 4,507,115 to Kambara et al. which is incorporated herein by reference, describes a capsule that comprises a capsule body having a chamber formed inside and a communicating path for communicating the chamber with outside, a movable member arranged in the chamber and movable between a liquid-receiving position at which the volume of said chamber is made largest and a liquid-pushing position at which the volume of said chamber is made smallest, and a coiled operating member made of shape memory alloy heated by ultrasonic wave to move the movable member to liquid-receiving and - pushing positions selectively.
- US Patent 5,951,538 to Joshi et al which is incorporated herein by reference, describes a controlled delivery device for holding and administering a biologically active agent.
- the device includes a housing having a first end portion, a second end portion, and a port associated with the housing. Enclosed within the housing is a displacing member, a chemical or electrochemical gas generating cell, and activation and control circuitry.
- the electrochemical or chemical cell generates gas within the housing, forcing the displacing member against the beneficial agents contained within the housing and forcing the beneficial agents through an outlet port and into a body cavity at a predetermined rate.
- An anchoring mechanism may be associated with the housing for securing the housing inside the body cavity.
- US Patents 5,167,626 and 5,170,801 to Casper at al. which are incorporated herein by reference, describe a capsule for releasing a substance at a defined location in the GI tract.
- the body of the capsule defines one or more apertures in the circumferential wall thereof, and a sleeve valve rotatably positioned therein has one or more corresponding apertures in the circumferential wall thereof.
- the sleeve valve comprises a coil and electrically connected heatable resistor which are operatively associated with an actuator member formed of a shape memory alloy responsive to heat and which will move from a non-heated first shape to a heated second shape.
- Actuator stop means are provided in the capsule body for being engaged by the actuator member during movement from the non-heated first shape to the heated second shape so that the actuator member movement serves to rotate the sleeve valve to an open position.
- PCT Publication WO 01/45552 to Houzego et al which is incorporated herein by reference, describes a closure member for a substance reservoir of a site-specific drug delivery capsule (SSDC).
- the SSDC includes a retainer that provides a non-linear force resisting opening of the closure member.
- the non-linear force is described as ensuring that the closure member unseals the reservoir only when an opening force exceeds a maximal value of the resisting force, thereby preventing premature or accidental emptying of the reservoir.
- the preferred means of providing the resistive force is a rolling, elastomeric o-ring that additionally seals the closure member into an aperture.
- a catheter which includes a shaft having an infusion lumen extending therethrough, wherein the proximal end of the shaft connected to a pressurized fluid source capable of generating a transient pressure of more than 1000 psi.
- the distal end of the shaft includes a nozzle having an injection port in fluid communication with the infusion lumen such that fluid from the pressurized fluid source may be delivered to the heart tissue at a sufficiently high exit velocity to partially penetrate the heart tissue.
- US Patent 6,369,039 to Palasis et al. which is incorporated herein by reference, describes a method for site-specifically delivering a therapeutic agent to a target location within a body cavity, vasculature or tissue.
- the method comprises: providing a medical device having a substantially saturated solution of therapeutic agent associated therewith; introducing the medical device into the body cavity, vasculature or tissue; releasing a volume of the solution of therapeutic agent from the medical device at the target location at a pressure of from about 0 to about 5 atmospheres for a time of up to about 5 minutes; and withdrawing the medical device from the body cavity, vasculature or tissue.
- the patent also describes a system for delivering a therapeutic agent to a body cavity, vasculature or tissue, comprising a medical device having a substantially saturated solution of the therapeutic agent associated therewith.
- PCT Publication WO 02/098501 to Keisari et al. which is incorporated herein by reference, describes a method for treating tumor tissue, including applying to cells of the tumor tissue electrical field pulses having a strength, a repetition frequency, and a pulse width selected capable of inducing endocytosis-mediated cell death, thereby treating the tumor tissue.
- Patents 3,485,235 to Felson, 3,315,660 to Abella, 3,118,439 to Perrenoud, and 3,057,344 to Abella et al. which are incorporated herein by reference, describe capsules for insertion into the GI tract for treatment and/or diagnostic purposes.
- an ingestible active drug-delivery system comprises electrical and/or mechanical means to enhance the absorption of a drug provided to the gastrointestinal (GI) tract.
- GI gastrointestinal
- such means includes a device for performing electrotransport of the drug, in order to actively deliver the drug through the wall of the GI tract.
- such means includes a mechanical driving mechanism that actively drives the drug through the wall of the GI tract.
- the drug-delivery system comprises a pill-shaped and -sized capsule that comprises the delivery means, and holds the drug until it is released to the GI tract.
- the active driving of the drug through the GI tract wall is accomplished by: (a) driving the drug through the wall by passage of the drug through tight junctions of the epithelial layer of the small intestine, and/or (b) driving the drug through the wall by penetrating the epithelial cells themselves.
- a therapeutically-significant portion of the drug is thereby passed into direct contact with the capillary supply of the GI tract, and therefrom into the systemic circulation. It is noted that this embodiment therefore typically allows entry into the bloodstream of drag molecules which would normally be largely excluded (e.g., due to size or chemical properties).
- the drug-delivery system comprises a mechanism that is operative to be responsive to its environment, such as, for example, a pH-sensitive coating.
- the coating is typically configured, using techniques known in the art, to dissolve upon entering a small intestine of a patient.
- the environmentally-responsive mechanism comprises, for example, a sensor (such as an electronic sensor) a timer, a transmitter / receiver, or a camera.
- the dissolving of the coating triggers activation of the driving means, which, in turn, actively drives drug through the wall of the GI tract wall.
- the coating is configured to dissolve in a pH range typical of the small intestine.
- the coating is applied at a first thickness over a first portion of the capsule, and at a second thickness over a second portion of the capsule.
- different types of coatings are applied to different portions of the capsule, e.g., in order to provide for the respective portions of the capsule to be exposed to the small intestine at different times.
- the driving mechanism comprises a gas generator and a movable member, such as a membrane.
- the membrane moves within the capsule in response to the generation of gas by the generator.
- the movable member comprises a piston.
- a movable member is not provided, but instead the gas generator acts directly on the drug.
- the dissolving of the coating activates the gas generator to release a gas that deflects the membrane. This deflection, in turn, applies pressure to the drug, driving it out of the capsule (typically through an orifice thereof), through the epithelial layer of the GI tract, and into contact with the capillary circulation of the GI tract.
- the gas generator comprises a power source, such as a battery, having positive and negative poles thereof coupled to respective electrodes.
- a power source such as a battery
- One of the electrodes is typically in contact with a liquid, such as a saline solution contained within the capsule.
- the solution is typically in contact with or otherwise mechanically coupled to the membrane.
- Another one of the electrodes is typically mounted to an external surface of the capsule, within the coating.
- the capsule comprises an electrode having a first electrode contact electrically coupled to the solution, and a second electrode contact mounted to the outer surface of the capsule.
- the coating typically has very low electrical conductivity, and can be generally considered to act as an electrical insulator.
- the current drain from the battery is minimal or essentially zero.
- the externally-mounted electrode and the externally-mounted electrode contact are electrically coupled via the ion-rich fluids naturally present in the small intestine.
- a current is thereby able to flow, powered by the battery, from the electrode in contact with the saline solution, via the solution, to the electrode contact electrically coupled to the solution.
- the flow of the current through the solution is associated with electrolysis of the water, and generates a gas. The gas generated by this process deflects the membrane and forces the drug out of the orifice, as described hereinabove.
- the gas generator comprises a hydrophilic membrane and a substance typically adjacent to the hydrophilic membrane.
- the hydrophilic membrane is typically embedded in or otherwise coupled to the outer surface of the capsule.
- the substance is typically disposed within the capsule, and has the characteristic of rapidly releasing gas upon contact with the fluid of the GI tract.
- the hydrophilic membrane is protected from the fluid of the GI tract by the coating until the capsule arrives at a suitable region of the GI tract, such as a portion of the small intestine having a particular pH. At this point, the coating dissolves, and the hydrophilic membrane allows passage of the GI tract fluid into the capsule, where it contacts the substance. Gas is released rapidly in response to the reaction of the GI tract fluid with the substance. In turn, the drug is ejected at high pressure and velocity through the orifice and through the wall of the small intestine.
- the gas generator comprises a hydrophilic membrane, as described hereinabove, and two electrodes typically but not necessarily embedded in the casing of the capsule.
- the electrodes typically comprise different metals.
- a conductor electrically couples the electrodes to one another.
- the conductor and the electrodes are encased within an insulator, and, in combination, constitute a galvanic cell.
- the gas generator comprises a hydrophilic membrane and one or more gas-releasing elements.
- the gas-releasing elements react with the acidic GI tract fluid passing through the hydrophilic membrane after the dissolving of the coating. This reaction rapidly releases gas, and drives the drug through the orifice of the capsule and through the epithelial layer of the small intestine.
- the driving mechanism comprises a piston and a piston driver.
- the piston driver comprises a mechanical spring.
- the piston driver comprises a source of compressed air.
- the capsule is typically stored with the piston driver in the tense state. The piston driver is prevented from releasing its energy by a portion of the coating that is disposed in a position within the capsule that inhibits motion of the piston. After ingestion of the capsule and the dissolving of the coating in the small intestine, the portion of the coating is exposed to the acidic environment of the small intestine, and dissolves as well, thereby freeing the piston. After the piston is released, the piston driver drives the piston to force the drug through the orifice and through the wall of the small intestine.
- the capsule comprises a drug stored in powder form.
- a hydrophilic membrane in addition to any uses it may have in activating the driving mechanism as described hereinabove, allows fluid from the GI tract to mix with the drug.
- the capsule is configured to facilitate this mixing prior to activation of the driving mechanism.
- this pre-mixing of the drug with the GI tract fluid is brought about by setting a first thickness of the coating to be lower in a region surrounding the hydrophilic membrane than a second thickness of the coating in a region surrounding the driving mechanism. In this manner, the pH-sensitive coating over the hydrophilic membrane essentially completely dissolves, allowing the GI tract fluid to enter the capsule and mix with the drug.
- the portion of the coating over the driving mechanism is not yet sufficiently small to cause the activation of the driving mechanism. Subsequently, the portion of the coating over the driving mechanism also dissolves, causing the activation of the driving mechanism. This activation causes the (now substantially liquefied) drug to be (a) driven out of the orifice and (b) driven through the wall of the small intestine by the mechanical force applied thereto by the driving mechanism.
- the capsule comprises a hollow needle located adjacent to the orifice and in communication with the drug.
- one or more elastic elements hold the hollow needle generally within the capsule, such that the sharp tip of the needle does not extend past the coating, and, typically, does not extend past the outer surface of the capsule.
- the elastic elements may comprise springs, spring-like mechanical elements, or compressed air.
- the capsule comprises a bio-sensor that detects a biological or physiological parameter, and activates the driving mechanism responsive thereto.
- the bio-sensor may comprise one or more of the following: an enzymatic sensor, a temperature sensor, a pH sensor, or a timer (the timer typically comprising chemicals that react in a known manner to activate the driving mechanism at a predetermined time following an event such as the patient squeezing the capsule or the patient ingesting the capsule).
- the capsule comprises a camera, which records an image of the GI tract for on-board analysis and, if appropriate, activation of the driving mechanism in response to the image.
- the capsule comprises a transmit / receive unit, adapted to transmit a signal responsive to an image recorded by the camera and/or responsive to a reading by the bio-sensor.
- the transmitted data are typically analyzed in real-time, and a decision is made (e.g., by a physician or by a computer external to the patient) whether and when to administer drag.
- an electrically- assisted drag-delivery system comprising: a biologically inert and biologically compatible device, comprising: a power supply; a control component, in power communication with the power supply; and at least one apparatus for electrically assisted drug transport, the apparatus being in signal communication with the control component and in power communication with the power supply; and a drag, attached to the device.
- the drug further includes pharmaceutically acceptable additives for absorption enhancement.
- the drag further includes pharmaceutically acceptable additives for improved bioavailability.
- the drag further includes pharmaceutically acceptable additives for controlled release.
- the drag further includes pharmaceutically acceptable additives for pH-dependent controlled release. • According to an additional aspect of the present invention, the drag further includes pharmaceutically acceptable additives for time-dependent controlled release.
- the at least one apparatus for electrically assisted drag transport comprises an apparatus for at least one electrotransport process.
- the apparatus for electrotransport is further operative to enhance peristalsis, by electrostimulation.
- the apparatus for electrically assisted drug transport comprises an apparatus for at least two electrotransport processes.
- the at least one apparatus for electrically assisted drug transport comprises an apparatus for sonophoresis.
- the at least one apparatus for electrically assisted drug transport comprises an apparatus for at least one ablation process.
- the at least one apparatus for electrically assisted drug transport comprises an apparatus for at least two processes, selected from the group consisting of electrotransport, sonophoresis, and ablation.
- the device includes at least one self-expansible portion, for making good contact with the gastrointestinal (GI) walls.
- the power supply is a galvanic cell, which uses GI fluids as an electrolyte.
- the device further defines a drug-dispensing cavity.
- the drug-dispensing cavity is adapted for controlled release.
- the drug-dispensing cavity is adapted for pH-dependent controlled release.
- the drug-dispensing cavity is self-expansible, to make better contact with the GI walls.
- the device includes a pH sensor. According to an additional aspect of the present invention, the device includes a telemetry system for communicating with an extracorporeal station.
- the device is ingestible.
- the device is attached to a catheter.
- the device includes an imaging apparatus.
- a method of oral drug delivery comprising: orally inserting a drag into the GI tract; and inducing transport through the GI walls, by a method selected from the group consisting of at least one electrotransport process, sonophoresis, at least one ablation process, and a combination thereof.
- apparatus for drag administration including: an ingestible capsule, which includes: a drag, stored by the capsule; an environmentally-sensitive mechanism, adapted to change a state thereof responsive to a disposition of the capsule within a gastrointestinal tract of a subj ect; and a driving mechanism, which, in response to a change of state of the environmentally-sensitive mechanism, is adapted to drive the drag directly through an endothelial layer of the gastrointestinal tract.
- the drag is stored in the capsule in liquid form.
- the environmentally-sensitive mechanism is adapted to undergo the change of state when the capsule is in a small intestine of the subject.
- the environmentally-sensitive mechanism is adapted to undergo the change of state when the capsule is in a large intestine of the subject. h an embodiment, the environmentally-sensitive mechanism is adapted to undergo the change of state when the capsule is in a stomach of the subject.
- the environmentally-sensitive mechanism is essentially entirely biodegradable.
- the driving mechanism is essentially entirely biodegradable.
- the environmentally-sensitive mechanism includes a sensor adapted to sense an indication of a distance traveled by the capsule in the gastrointestinal tract, and the environmentally-sensitive mechanism is adapted to undergo the change of state responsive to the distance.
- the sensor includes an inertial sensor.
- At least 80% of the mass of the capsule is biodegradable.
- At least 95% of the mass of the capsule is biodegradable.
- essentially the entire capsule is biodegradable.
- the capsule includes a self-expansible portion, which is adapted to expand responsive to the change of state of the environmentally-sensitive mechanism.
- a characteristic diameter of the self-expansible portion is adapted to increase by at least 100%, responsive to the change of state of the environmentally-sensitive mechanism.
- the self-expansible portion is adapted to expand responsive to expansion of a gas within the self-expansible portion.
- the self-expansible portion is adapted to expand responsive to an inflow of fluid from the gastrointestinal tract.
- a characteristic diameter of the self-expansible portion immediately prior to expanding is smaller than a characteristic diameter of a portion of the gastrointestinal tract containing the capsule, and a characteristic diameter of the self-expansible portion following expanding is at least as large as a characteristic diameter of the portion of the gastrointestinal tract containing the capsule.
- the capsule includes an electrode on an outer surface of the self-expansible portion, and the driving mechanism is adapted to drive current through the electrode when the self-expansible portion is in an expanded state thereof.
- the self-expansible portion includes a first self-expansible portion, at a first end of the capsule, the capsule includes a second self-expansible portion, at a second end of the capsule, and the capsule includes an electrode on an outer surface of the second self-expansible portion.
- the capsule includes a third self-expansible portion, disposed between the first and second self-expansible portions.
- the capsule includes an electrode on an outer surface of the third self-expansible portion.
- the capsule contains no electrodes on an outer surface of the third self-expansible portion.
- the environmentally-sensitive mechanism includes a coating on a surface of the capsule.
- the coating includes a pH-sensitive coating.
- the pH-sensitive coating is sensitive to a pH that is characteristic of a small intestine.
- the coating is adapted to cover a portion of the driving mechanism, prior to the change of state, in a manner that substantially prevents contact of the driving mechanism with a first fluid of the gastrointestinal tract, and the coating is adapted to uncover the portion of the driving mechanism in response to the coating contacting a second fluid of the gastrointestinal tract.
- the driving mechanism is adapted to drive the drag directly through the endothelial layer of the gastrointestinal tract responsive to uncovering of the portion of the driving mechanism.
- the environmentally-sensitive mechanism includes a timer, adapted to change the state of the environmentally-sensitive mechanism responsive to a duration of the capsule in the gastrointestinal tract.
- the timer includes an electronic timer.
- the timer includes a chemical timer, adapted to change the state of the environmentally-sensitive mechanism responsive to a chemical reaction.
- the environmentally-sensitive mechanism includes a camera, adapted to image the gastrointestinal tract, and the driving mechanism is adapted to drive the drag through the endothelial layer in response to an image acquired by the camera.
- the capsule includes a control component, adapted to interpret the acquired image and activate the driving mechanism responsive thereto.
- the capsule includes a transmit/receive unit, adapted to transmit data responsive to the acquired image, to receive an instruction responsive to the transmission, and to activate the driving mechanism responsive to the instruction.
- the environmentally-sensitive mechanism includes a sensor, adapted to sense a characteristic of the gastrointestinal tract, and the driving mechanism is adapted to drive the drag through the endothelial layer in response to the sensed characteristic.
- the capsule includes a control component, adapted to interpret the sensed characteristic and activate the driving mechanism responsive thereto.
- the capsule includes a transmit/receive unit, adapted to transmit data responsive to the sensed characteristic, to receive an instruction responsive to the transmission, and to activate the driving mechanism responsive to the instruction.
- the sensor includes an enzymatic sensor.
- the senor includes an optical sensor.
- the senor includes a thermal sensor.
- the senor includes a pH sensor.
- the pH sensor is adapted to detect a pH between about 4.7 and about 6.5.
- the pH sensor is adapted to detect a pH between about 1.2 and about 3.5.
- the pH sensor is adapted to detect a pH between about 4.6 and about 6.0.
- the pH sensor is adapted to detect a pH between about 7.5 and about 8.0.
- the senor includes a sensor adapted to detect a pathological condition of the gastrointestinal tract. In an embodiment, the sensor includes a sensor adapted to detect bleeding in the gastrointestinal tract. In an embodiment, the sensor includes a sensor adapted to detect inflammation in the gastrointestmal tract.
- the capsule includes a needle including a sharp tip thereof, and the tip of the needle is adapted to contact the endothelial layer of the gastrointestinal tract in response to the change of state of the environmentally-sensitive mechanism.
- the needle is hollow.
- the needle is not hollow.
- the capsule includes an elastic element, adapted to maintain the sharp tip of the needle at an original position that is substantially within the capsule, prior to the change of state, in response to an action of the driving mechanism, the elastic element is adapted to change shape in a manner that permits the sharp tip of the needle to contact the endothelial layer of the gastrointestinal tract, and at a time after initiation of the driving of the drag through the endothelial layer, the elastic element is adapted to cause the sharp tip of the needle to withdraw to the original position.
- the driving mechanism is adapted to drive the needle to puncture the endothelial layer of the gastrointestinal tract at a puncture site, in response to the change of state of the environmentally-sensitive mechanism.
- the driving mechanism is adapted to drive the drug through the puncture site.
- the drug is stored in the capsule in powder form.
- the capsule is adapted to mix the drug in powder form with a fluid, in response to the change of state of the environmentally-sensitive mechanism.
- the fluid includes fluid of the gastrointestinal tract
- the capsule is adapted to mix the drag in powder form with the gastrointestinal tract fluid, in response to the change of state of the environmentally-sensitive mechanism.
- the fluid includes fluid stored within the capsule, separately from the drug in powder form, and the capsule is adapted to mix the drag in powder form with the fluid stored within the capsule, in response to the change of state of the environmentally-sensitive mechanism.
- the driving mechanism includes a control component, a first electrode, a second electrode, and a third electrode
- the control component is adapted to drive an iontophoretic current between the first and second electrodes
- the control component is adapted to drive an electropulsation current through the third electrode
- the driving mechanism includes a control component, a first electrode, and a second electrode
- the control component is adapted to drive a current between the first and second electrodes in response to the change of state of the environmentally-sensitive mechanism.
- the environmentally-sensitive mechanism includes a coating on a surface of the capsule.
- the driving mechanism includes the first and second electrodes and no other electrodes. In an embodiment, the driving mechanism includes more than three electrodes. h an embodiment, the control component is adapted to configure the current to ablate at least a portion of the endothelial layer of the gastrointestinal tract.
- control component includes a battery.
- the battery is biodegradable.
- the battery includes zinc and manganese dioxide.
- the driving mechanism includes a third electrode, and the control component is adapted to drive a current between the first and third electrodes in response to the change of state of the environmentally-sensitive mechanism.
- the first electrode is physically disposed on the capsule between the second electrode and the third electrode.
- control component is adapted to configure the current driven between the first and second electrodes to be substantially identical to the current driven between the first and third elecfrodes.
- control component is adapted to configure the current driven between the first and second electrodes to consist essentially of an iontophoretic current
- control component is adapted to configure the current driven between the first and third electrodes to consist essentially of an electropulsation current.
- control component is adapted to drive the current between the first and second electrodes at a level sufficient to iontophoretically drive the drug through the endothelial layer of the gastrointestinal tract.
- control component is adapted to configure a voltage drop between the first and second electrodes to be less than about 3 volts.
- control component is adapted to configure the current to be substantially DC.
- control component is adapted to configure the current to have a characteristic frequency less than about 50 Hz. In an embodiment, the control component is adapted to configure the current to have a characteristic frequency less than about 5 Hz. In an embodiment, the control component is adapted to configure the current to have an amplitude less than about 5 mA. In an embodiment, the control component is adapted to configure the current to have an amplitude greater than about 0.5 mA.
- control component is adapted to configure the current to increase conduction of the drag through tight junctions of the endothelial layer of the gastrointestinal tract by means of electropulsation.
- control component is adapted to configure a voltage drop between the first and second electrodes to be between about 3 and about 12 volts.
- the control component is adapted to configure a voltage drop between the first and second electrodes to be between about 12 and about 50 volts. In an embodiment, the control component is adapted to configure the current to have a characteristic frequency less than about 300 Hz. In an embodiment, the control component is adapted to configure the current to have a characteristic frequency less than about 100 Hz. In an embodiment, the control component is adapted to configure the current to have a characteristic frequency greater than about 1 Hz. In an embodiment, the control component is adapted to configure the current to have a characteristic frequency greater than about 10 Hz. In an embodiment, the control component is adapted to configure the current to have a characteristic frequency less than about 20 Hz. In an embodiment, the control component is adapted to configure the current to have a characteristic frequency greater than about 10 Hz. In an embodiment, the control component is adapted to configure the current to:
- the current includes an iontophoretic current and an electropulsation current
- the control component is adapted to drive the iontophoretic current between the first and second electrodes
- the control component is adapted to drive the electropulsation current between the first and second electrodes.
- the control component is adapted to configure the current to have a high-frequency component and a low-frequency component.
- the control component is adapted to configure the high-frequency component and the low- frequency component to have frequencies that are respectively greater than and less than 5 Hz.
- the control component is adapted to drive the high-frequency component and the low-frequency component at the same time.
- the control component is adapted to drive the high-frequency component prior to driving the low-frequency component.
- control component is adapted to initiate driving the high-frequency component at least 30 seconds prior to driving the low-frequency component.
- driving mechanism includes a piston and a piston driver, and the piston driver is adapted to drive the piston to drive the drug from the capsule.
- the piston driver includes a compressed gas that is adapted to expand in response to the change of state of the environmentally-sensitive mechanism.
- the piston driver includes a spring-like mechanical element.
- the driving mechanism includes a gas generator, which, in response to the change of state of the environmentally-sensitive mechanism, is adapted to generate a gas which on expansion thereof performs work on the drag in a manner that drives the drag from the capsule and directly through the endothelial layer of the gastrointestinal tract.
- the gas generator is adapted to generate, within about 1 minute, a pressure change of at least 0.2 atmosphere within the capsule, in response to the change of state of the environmentally-sensitive mechanism.
- the gas generator is adapted to generate, within about 20 minutes, a pressure change of at least 0.2 atmosphere within the capsule, in response to the change of state of the environmentally-sensitive mechanism.
- the capsule includes a flexible membrane between the gas generator and the drag, the membrane is adapted to be deflected in response to the generation of the gas, and the membrane, in response to being deflected, is adapted to drive the drug through the endothelial layer of the gastrointestinal tract.
- the gas generator is in a common compartment with the drag, and the gas generated by the gas generator, in direct contact with the drag, drives the drag from the capsule and directly through the endothelial layer of the gastrointestinal tract.
- the gas generator is adapted to generate a pressure change of at least about 0.1 atmosphere within the capsule, in response to the change of state of the environmentally-sensitive mechanism.
- the gas generator is adapted to configure the pressure change to be less than about 5 atmospheres, in response to the change of state of the environmentally-sensitive mechanism.
- the gas generator is adapted to configure the pressure change to be between about 0.5 and 3 atmospheres, in response to the change of state of the environmentally-sensitive mechanism. In an embodiment, the gas generator is adapted to configure the pressure change to occur during less than about 1 minute. In an embodiment, the gas generator is adapted to configure the pressure change to occur over a time period having a duration between about 1 and 10 minutes. In an embodiment, the gas generator is adapted to configure the pressure change to occur over a time period having a duration between about 10 and 120 minutes.
- the gas generator is adapted to facilitate entry into the capsule of fluid of the gastrointestinal tract in response to the change of state of the environmentally-sensitive mechamsm, and to generate the gas responsive to the entry of the gastrointestinal tract fluid into the capsule.
- the gas generator includes a substance, and the gas generator is adapted to generate the gas by causing contact of the gastrointestinal tract fluid with the substance, in response to the change of state of the environmentally-sensitive mechanism.
- the substance includes a substance selected from the list consisting of elemental sodium and elemental calcium.
- the gas generator includes a substance having a pH greater than 7, and the gas generator is adapted to generate the gas by facilitating contact between the substance and fluid of the gastrointestinal tract, in response to the change of state of the environmentally-sensitive mechanism.
- the substance includes sodium bicarbonate.
- the gas generator includes a membrane proximate the substance, which is adapted to facilitate entry of the gastrointestinal tract fluid into the capsule, through the membrane, in response to the change of state of the environmentally- sensitive mechanism.
- the membrane includes a hydrophilic membrane.
- the membrane is integral to an outer surface of the capsule.
- the gas generator includes a galvanic cell.
- the galvanic cell includes a first electrode including zinc and a second electrode including manganese dioxide.
- the galvanic cell includes first and second galvanic cell electrodes, which are adapted to pass current through fluid of the gastrointestinal tract at a level sufficient to electrolyze the fluid and generate the gas.
- the gas generator includes a membrane, which is adapted to facilitate entry of fluid of the gastrointestinal tract into the capsule, through the membrane, and into contact with the first and second galvanic cell electrodes, in response to the change of state of the environmentally-sensitive mechanism.
- an outer surface of the capsule is shaped so as to define an orifice having an edge, the edge of the orifice generally being in contact with a portion of the gastrointestinal tract at a time after the environmentally-sensitive mechanism changes state, and the gas generator and the drag are disposed within the capsule in such a manner that the generation of the gas drives the drag through the orifice and, therefrom, through the portion of the gastrointestinal tract.
- the capsule includes a seal, which blocks the orifice prior to the change of state of the environmentally-sensitive mechanism, and which is adapted to be removed from the orifice in response to the generation of the gas by the gas generator.
- the seal includes a plug, adapted to: be disposed within the orifice prior to the change of state of the environmentally- sensitive mechanism, resist ejection from the orifice during an initial rise in pressure within the capsule that occurs in response to the generation of the gas by the gas generator, and be ejected from the orifice when the pressure within the capsule surpasses a threshold pressure.
- the capsule is shaped such that a characteristic diameter of the orifice is between about 20 and about 400 microns. In an embodiment, the capsule is shaped such that the characteristic diameter of the orifice is between about 20 and about 50 microns. In an embodiment, the capsule is shaped such that the characteristic diameter of the orifice is between about 50 and about 300 microns.
- the gas generator includes an electrical power source, adapted to drive current through a fluid in a manner that causes the generation of the gas by electrolysis of the fluid.
- the power source includes first and second poles
- the gas generator includes the fluid
- the first pole of the power source is directly electrically coupled to the fluid
- the gas generator includes a coupling electrode, electrically coupled to the second pole of the power source
- the gas generator includes a second electrode, electrically coupled via the fluid to the first pole of the power source, and substantially electrically isolated from the coupling electrode prior to the change of state of the environmentally-sensitive mechanism
- the environmentally-sensitive mechanism is adapted, in response to the change of state, to establish electrical contact between the coupling electrode and the second electrode.
- the fluid includes fluid of the gastrointestinal tract
- the gas generator is adapted, in response to the change of state of the environmentally-sensitive mechanism, to drive the current through the fluid of the gastrointestinal tract.
- apparatus for administration of a drug including: an ingestible capsule adapted to store the drag, the capsule including: an environmentally-sensitive mechanism, adapted to change a state thereof responsive to a disposition of the capsule within a gastrointestinal tract of a subject; and a driving mechanism, which, in response to a change of state of the environmentally-sensitive mechanism, is adapted to drive the drag directly through an endothelial layer of the gastrointestinal tract.
- apparatus for administration of a drag including: an ingestible environmentally-sensitive mechanism, adapted to change a state thereof responsive to a disposition thereof within a gastrointestinal tract of a subj ect; and a driving mechanism, which, in response to a change of state of the environmentally-sensitive mechanism, is adapted to drive the drug directly through an endothelial layer of the gastrointestinal fract.
- apparatus including: a capsule adapted to travel through a gasfrointestinal fract of a subject, the capsule including: first and second electrodes; and a confrol component, adapted to drive, at each of a plurality of sites longitudinally distributed along the gastrointestinal tract, an iontophoretic current that travels from the first electrode, through an endothelial layer of the gasfrointestinal fract, and to the second electrode.
- the confrol component is adapted to drive the iontophoretic current while the capsule is in motion. In an embodiment, the confrol component is adapted to configure a voltage drop between the first and second electrodes to be less than about 3 volts, and to configure a characteristic frequency of the iontophoretic current to be less than about 5 Hz.
- the capsule includes a self-expansible portion, and the first electrode is disposed on an outer surface of the self-expansible portion.
- the capsule includes a second self-expansible portion, and the second electrode is disposed on an outer surface of the second self-expansible portion.
- the capsule includes a coating on an outer surface thereof, and the confrol component is adapted to initiate driving the iontophoretic current in response to a change of state of the coating.
- apparatus including: a capsule adapted to travel through a gasfrointestinal tract of a subject, the capsule including: first and second elecfrodes; and a confrol component, adapted to drive, at each of a plurality of sites longitudinally distributed along the gasfrointestinal tract, an electropulsation current that travels from the first electrode, through an endothelial layer of the gasfrointestinal tract, and to the second electrode.
- the confrol component is adapted to drive the electropulsation current while the capsule is in motion.
- the control component is adapted to configure a voltage drop between the first and second elecfrodes to be greater than about 3 volts, and to configure a characteristic frequency of the electropulsation current to be between about 1 and 30 Hz.
- the capsule includes a self-expansible portion, and the first electrode is disposed on an outer surface of the self-expansible portion. In an embodiment, the capsule includes a second self-expansible portion, and the second electrode is disposed on an outer surface of the second self-expansible portion.
- the capsule includes a coating on an outer surface thereof, and the control component is adapted to initiate driving the elecfropulsation current in response to a change of state of the coating.
- apparatus including: a capsule adapted to travel through a gastrointestinal tract of a subject, the capsule including: first and second electrodes; a coating on an outer surface of the capsule; and a control component, adapted to drive an iontophoretic current that travels from the first electrode, through an endothelial layer of the gasfrointestinal tract, and to the second electrode, in response to a change of state of the coating.
- the capsule includes first and second self-expansible portions, at respective ends of the capsule, and the first and second electrodes are disposed on respective outer surfaces of the first and second self-expansible portions.
- a method for administration of a drug including: administering to a subject an ingestible capsule that includes a drag; detecting a disposition of the capsule within a gastrointestinal tract of the subject; and in response to detecting the disposition, driving the drag directly through an endothelial layer of the gastrointestinal tract.
- driving the drug includes iontophoretically driving the drug. In an embodiment, driving the drug includes applying an electropulsation current configured to facilitate the driving of the drug.
- driving the drag includes expanding a portion of the capsule in response to detecting the disposition.
- detecting the disposition includes causing an interaction between a coating on an outer surface of the capsule and fluid of the gastrointestinal fract.
- Embodiments of the present invention successfully address the shortcomings of the presently-known configurations by providing a typically ingestible, electrically or mechanically assisted, drag-delivery system, which acts as a medication carrier, and which utilizes electrically or mechanically induced means to enhance the absorption of the medication through the GI walls.
- Fig. 1 is a schematic illustration of the intestinal wall
- Fig. 2 is a schematic illustration of a device for electrically-assisted drag delivery, in accordance with some embodiments of the present invention
- FIGs. 3 A and 3B are schematic illustrations of ingestible, electrically-assisted drug- delivery systems, in accordance with embodiments of the present invention
- FIG. 4 is a schematic illustration of an ingestible, electrically-assisted drag-delivery system, having a plurality of elecfrodes, in accordance with an embodiment of the present invention
- Fig. 5 is a schematic illustration of another ingestible, electrically-assisted drag- delivery system, having a plurality of electrodes, in accordance with an embodiment of the present invention
- Figs. 6A and 6B are schematic illustrations of an ingestible, electrically-assisted drag-delivery system, having self-expansible portions, in accordance with embodiment of the present invention
- Fig. 7 is a schematic illustration of an ingestible, electrically-assisted drug-delivery system, having a plurality of electrodes, in accordance with an embodiment of the present invention
- Fig. 8 is a schematic illustration of an ingestible, electrically-assisted drug-delivery system, having a plurality of electrodes and self-expansible portions, in accordance with an embodiment of the present invention
- Fig. 9 is a schematic illustration of another ingestible, electrically-assisted drug- delivery system, having a plurality of electrodes and self-expansible portions, in accordance with an embodiment of the present invention
- Fig. 10 is a schematic illustration of an ingestible, electrically-assisted drag- delivery system, having a plurality of electrodes and self-expansible portions, when in the gastrointestinal tract, in accordance with an embodiment of the present invention
- Figs. 11A-11D are schematic illustrations of an ingestible, electrically-assisted drag-delivery system, wherein the drag-dispensing cavities are formed as self-expansible portions, in accordance with embodiments of the present invention
- Fig. 12 is a schematic illustration of an ingestible, electrically-assisted drug- delivery system, having a drug cavity with a biodegradable cap, in accordance with an embodiment of the present invention
- Fig. 13 is a schematic illustration of an ingestible, electrically-assisted drag- delivery system, wherein the drag is pressed into an integrated tablet with the system, in accordance with an embodiment of the present invention
- Figs. 14A and 14B are schematic illustrations of an ingestible, electrically-assisted drug-delivery system, adapted to form an osmosis pump in the gastrointestinal tract, in accordance with embodiments of the present invention
- Fig. 15 is a schematic illustration of an ingestible, electrically-assisted drug- delivery system, having a pH-dependent controlled drug release, in accordance with an embodiment of the present invention
- Fig. 16 is a schematic illustration of an ingestible, electrically-assisted drug- delivery system, having an electronically activated, pH-dependent controlled drug release, in accordance with an embodiment of the present invention
- Fig. 17 is a schematic illustration of an ingestible, electrically-assisted drag- delivery system, adapted for sonophoresis, in accordance with an embodiment of the present invention
- Fig. 18 is a schematic illustration of an ingestible, electrically-assisted drag- delivery system, adapted for ablation, in accordance with an embodiment of the present invention
- Fig. 19 is a schematic illustration of an ingestible, electrically-assisted drag- delivery system, adapted for telemetry communication, in accordance with an embodiment of the present invention
- Fig. 20 is a schematic illustration of an ingestible, electrically-assisted drag- delivery system, adapted to make a galvanic cell with the body, in accordance with an embodiment of the present invention
- Figs. 21A and 21B are schematic illustrations of a drag-delivery system comprising a capsule, in accordance with embodiments of the present invention
- Figs. 22A and 22B are schematic illustrations of a drag-delivery system comprising a gas generator, in accordance with an embodiment of the present invention
- Figs. 23A and 23B are schematic illustrations of a drug-delivery system comprising a gas generator having a power source, in accordance with an embodiment of the present invention
- Figs. 24A and 24B are schematic illustrations of a drag-delivery system comprising a gas generator having a hydrophilic membrane, in accordance with an embodiment of the present invention
- Figs. 25A and 25B are schematic illustrations of another drug-delivery system comprising a gas generator having a hydrophilic membrane, in accordance with an embodiment of the present invention
- Figs. 26A and 26B are schematic illustrations of yet another drag-delivery system comprising a gas generator having a hydrophilic membrane, in accordance with an embodiment of the present invention
- Figs. 27A and 27B are schematic illustrations of a drug-delivery system comprising a piston, in accordance with an embodiment of the present invention
- Figs. 28A, 28B, and 28C are schematic illustrations of a drug-delivery system comprising a drug stored in powder form, in accordance with an embodiment of the present invention
- Figs. 29A and 29B are schematic illustrations of a drug-delivery system comprising a needle, in accordance with an embodiment of the present invention.
- Fig. 30 is a schematic illustration of a drug-delivery system, in accordance with an embodiment of the present invention.
- Embodiments of the present invention comprise a typically ingestible, electrically- or mechanically-assisted, drag-delivery system. Specifically, these embodiments of the present invention act as a medication carrier, which utilizes electrically- or mechanically- induced means to enhance the absorption of the medication through the gastrointestinal (GI) tract walls.
- GI gastrointestinal
- Fig. 2 is a schematic diagram of an electrically- assisted, drug-delivery device 10, in accordance with some embodiments of the present invention.
- Device 10 is biologically inert and biologically compatible, and is typically adapted for ingestion.
- Device 10 comprises a power supply 12, a control component 14 in power communication with power supply 12, and at least one apparatus 17 for electrically-assisted drag fransport, which is in signal communication with confrol component 14 and in power communication with power supply 12.
- Control component 14 may be dedicated circuitry, a controller, or a microcomputer, as known in the art.
- apparatus 17 comprises a pulse generator 15 and at least two electrodes 16, designed for electrotransport. Alternatively, four or more electrodes 16 may be provided. Apparatus 17 may be designed, for example, as an electrotransport device, as described in any one, or a combination of, US Patent 5,674,196, to Donaldson et al., US Patent 5,961,482 to Chien et al., US Patent 5,983,131 to Weaver et al., US Patent 5,983,134 to Osfrow, and US Patent 6,477,410 to Henley et al, all of which are incorporated herein by reference.
- apparatus 17 is designed for performing sonophoresis, or for performing a combination of sonophoresis and electrotransport, and comprises at least one ultrasound transducer 22.
- Apparatus 17 may be designed, for example, as a sonophoresis device, as described in any one, or a combination of, US Patents 6,002,961, 6,018,678, and 6,002,961 to Mitragotri et al., US Patents 6,190,315 and 6,041,253 to Kost et al, US Patent 5,947,921 to Johnson et al., and US Patents 6,491,657 and 6,234,990 to Rowe et al., all of which are incorporated herein by reference.
- apparatus 17 is designed for performing ablation, or for performing a combination of ablation and electrotransport, ablation and sonophoresis, or ablation, electrotransport, and sonophoresis, and comprises at least one ablation apparatus 24.
- the ablation process may be, for example, any one of, or a combination of, laser ablation, cryogenic ablation, thermal ablation, microwave ablation, radiofrequency (RF) ablation, electrical ablation, and liquid jet ablation.
- Apparatus 17 may be designed, for example, as an ablation device, as described in any one, or a combination of, US patent 6,471,696, to Berube et al.
- device 10 further comprises at least one sensor 18.
- Sensor 18 may be, for example, a physical sensor, such as a temperature sensor or a pressure sensor.
- sensor 18 may be a chemical sensor, such as a pH sensor or a drag-concentration sensor.
- sensor 18 may be a biological sensor, such as a glucose sensor or a bacterial-count sensor.
- more than one sensor 18 is used. These may be of the same type or of different types.
- device 10 further comprises a telemetry system 20, operative, for example, by RF, infrared radiation, or by ultrasound, for providing communication with an extracorporeal station 21, for example, a remote control.
- extracorporeal station 21 comprises a computer system.
- telemetry system 20 comprises a power transducer (such as a coil), as is known in the art, adapted to receive electromagnetic radiation transmitted by extracorporeal station 21, and to transduce the radiation into a current for powering the operation of drug-delivery device 10.
- the power transducer may replace power supply 12, or supplement its operation.
- device 10 further comprises at least one electronic valve 26 for dispensing medication, for example, responsive to input from sensor 18.
- System 30 comprises device 10, enclosed within a biocompatible, biologically inert housing 32, formed for example, of stainless steel or silicone, or another biocompatible, inert material.
- Device 10 of the present embodiment typically comprises at least power supply 12, control component 14, pulse generator 15, and at least two elecfrostimulating electrodes 16, for providing elecfrofransport.
- housing 32 of device 10 defines an internal cavity in which components of device 10 are located.
- housing 32 defines no cavity; rather, it is formed as a cast, for example of silicone, wherein components of device 10 are imbedded.
- System 30 further comprises a drug 36, attached to device 10 and enclosed by a sheath 34, which encapsulates both device 10 and drug 36.
- sheath 34 encapsulates only drag 36.
- Drug 36 is held in drug-dispensing cavities 23, which typically are formed at two ends of system 30, or at one end.
- Sheath 34 typically comprises a biologically compatible, biologically inert polymeric material, such as cellulose acetate or ethyl cellulose, that allows diffusion of drag 36 to the GI tract.
- sheath 34 is formed of a mixture of water-soluble particles in a water- insoluble matrix, such as polyvinyl acetate, or acrylic acid copolymers, so that the water soluble particles dissolve in the GI tract, leaving micropores in matrix, and drug 36 diffuses through the micropores.
- sheath 34 is formed of biologically- degradable material, which degrades when in contact with water, or at a specific pH value, so as to release drag 36 to the GI fract, where drug 36 travels with device 10 until the drug is absorbed.
- the biologically-degradable material may comprise hydroxypropylcellulose or glycerol behenate.
- the electrotransport may include any one of, or a combination of, iontophoresis, elecfroosmosis, and elecfrophoresis, which enhance diffusion processes through the epithelial cells, and, for some applications, additionally electroporation, which physically punctures or opens biological barriers, along the tight junctions of the epithelial cell boundaries, enabling passage of large molecules through the epithelium.
- Appropriate electrostimulation parameters may include a DC voltage of up to 3 volts, or square pulses of up to 3 volts at a low frequency of 1 - 50 Hz. These parameters are typically appropriate for iontophoresis. Alternatively, the parameters may include an AC voltage of between 3 and 50 Volts, at a frequency of between 1 and 300 Hz. These parameters are typically appropriate for electroporation. Additionally, for some applications, the DC or low-frequency square-pulse voltage and the AC voltage are superimposed, in order to perform a combination of two or more electrotransport processes.
- pulses of other shapes and (or) duty cycles may similarly be used.
- the aforementioned parameters are provided as examples; in accordance with embodiments of the present invention, other parameters, which may be higher or lower, may be used.
- electrotransport parameters appropriate for the transport of drags across the epithelial cells of the GI tract are lower than parameters appropriate for transdermal drag fransport, as the GI tract lacks the stratum corneum barrier found in the skin.
- drag-delivery system 30 comprises a plurality of electrodes 16.
- system 30 comprises a single cathode 16A and two anodes 16B, or a single anode 16A and two cathodes 16B.
- system 30 comprises a plurality of anodes and cathodes 16.
- Figs. 6A and 6B illustrate ingestible, electrically-assisted, drag-delivery system 30 in respective resting and drag-delivery phases thereof, in accordance with an embodiment of the present invention.
- device 10 comprises self-expansible portions 33, enclosed in a biologically-inert and biocompatible elastic film 39, such as natural or synthetic thin rabber.
- elecfrodes 16 are painted on elastic film 39, for better contact between elecfrodes 16 and the GI walls.
- the self- expansible effect may be produced, for example, by a chemical reaction of a substance 35 (Fig. 6A), that produces a gas 37, such as CO2 (Fig. 6B).
- drag-dispensing cavities 23 may be located between self-expansible portions 33 and the main body of device 10.
- system 30 of the present embodiment is used to facilitate contact between electrodes 16 and the GI walls of the colon.
- device 10 comprises a central self-expansible portion 33 a, disposed between self-expansible portions 33 that have elecfrodes 16 thereon.
- self-expansible portion 33a is adapted to expand until it contacts the inner wall of the gasfrointestinal fract.
- self-expansible portion 33a is typically able to expand to at least the same diameter as self-expansible portions 33, and thereby inhibit current flow in the fluid of the lumen of the gastrointestinal tract, and (for constant voltage) facilitate higher current flow in the tissue of the gastrointestinal fract itself.
- similar central self-expansible portions 33a may be integrated into the embodiments of the invention described with reference to one or more of the other figures of the present patent application.
- Figs. 7, 8, and 9 illustrate ingestible, electrically-assisted, drug-delivery systems 30, in accordance with embodiments of the present invention.
- system 30 comprises a plurality of electrodes 16 and self-expansible forms.
- Fig. 10 illustrates ingestible, electrically-assisted, drug-delivery system 30, as it fravels in a GI fract 50, in accordance with an embodiment of the present invention.
- Both the self-expansible portions of system 30 and the plurality of electrodes 16 that cover its exterior are operative to facilitate sliding contact between walls of GI tract 50 and system
- Figs. 11A-11D illustrate ingestible, electrically-assisted, drug-delivery system 30, in accordance with embodiments of the present invention.
- a self- expansible drag matrix is used.
- drug 36 is enclosed by a swelling polymer 42, which may be biodegradable, such as hydroxypropylmethylcellulose-HPMC or POLYOXT (manufactured by The Dow Chemical Company), which expands when brought into contact with GI fluids.
- the drag is mixed with the swelling polymer, so as to swell with it.
- Fig. 12 illustrates ingestible, electrically-assisted, drag-delivery system 30, formed as a capsule 45, and containing drag 36, as micropellets 43, in accordance with an embodiment of the present invention.
- a biodegradable film 46 encapsulates micropellets
- Fig. 13 illustrates ingestible, electrically-assisted, drug-delivery system 30, in accordance with an embodiment of the present invention.
- no film is used to contain drag 36. Rather, drag 36 is pressed onto a biocompatible solid bar 48, and slowly dissolves in the GI fract.
- Figs. 14A and 14B illustrate ingestible, electrically-assisted, drug-delivery system
- drag delivery occurs by osmosis.
- a water-soluble plug 29 (Fig. 14A) dissolves, an orifice 38 is opened (Fig. 14B).
- Fig. 14A dissolves, an orifice 38 is opened (Fig. 14B).
- Fig. 14B Uptake of water into drag-dispensing cavity 23 increases the osmotic pressure within the system.
- the build-up of the osmotic pressure gradient drives the drag through orifice 38 in a controlled manner.
- sheath 34 of drag 36 may be formed as cellulose acetate combined with polyethylene glycol (PEG). After ingestion the PEG dissolves, leaving the drug 36 coated with a semi-permeable membrane that controls the release of the drug by osmotic mechanism.
- PEG polyethylene glycol
- Osmognate additives such as NaCl
- added to the drag core, and/or perforation of the sheath 34 may contribute to better controlling the release patterns (osmognates are materials, usually salts, with high solubility and the ability to create high osmotic pressure, to attract water).
- Fig. 15 illustrates ingestible, electrically-assisted, drag-delivery system 30, in accordance with an embodiment of the present invention.
- drag release is pH-dependent.
- Drug 36 is enclosed by at least one film 46A, which dissolves at a specific pH value.
- the pH value is selected to be in the range commonly found in the small intestine, e.g., between about 4.7 and about 6.5, in order to release drug 36 into the small intestine, while substantially preventing the earlier release of the drug in the stomach.
- the pH is selected to be in the range commonly found in another portion of the GI fract, such as the large intestine. (See Table 1 of the Background Section for exemplary pH values.)
- the pH value is selected to be in the range commonly found in the stomach, e.g., between about 1.2 and about 3.5, such that film 46A dissolves in the stomach, releasing at least a portion 36A of drag 36.
- system 30 comprises a second film 46B, which dissolves at a pH characteristic of a more distal portion of the GI tract, such as the small intestine, releasing a second portion 36B of drug 36 therein.
- system 30 comprises a third film 46C, which dissolves at a pH characteristic of a still more distal portion of the GI tract, such as the large intestine (e.g., a pH value of between about 7.5 and about 8.0 for the large intestine), thereby releasing a third portion 36C of drug 36.
- a pH characteristic of a still more distal portion of the GI tract such as the large intestine (e.g., a pH value of between about 7.5 and about 8.0 for the large intestine)
- a pH value of drug 36 e.g., a pH value of between about 7.5 and about 8.0 for the large intestine
- specific drug portions, or even different drags 36A, 36B, and 36C may be targeted to different portions of the GI tract.
- the pH values are selected to release a first portion of drug 36 in the small intestine, and a second portion in the large intestine.
- Fig. 16 illustrates ingestible, electrically-assisted, drug-delivery system 30, in accordance with an embodiment of the present invention.
- drug release is pH-dependent.
- Drag 36 is enclosed by housing 32, in two or more drag- dispensing cavities, such as three drag-dispensing cavities 23A, 23B, and 23C, sealed respectively by three electronic valves 26A, 26B, and 26C, the operation of which is controlled by control component 14.
- a pH sensor 18 typically senses a specific pH value or range of values, and transmits the information to confrol component 14, which opens one or more of valves 26 A, 26B, and 26C, responsive to the sensing.
- device 10 comprises ultrasound transducer 22 for providing sonophoresis as a drag fransport mechanism. It will be appreciated that sonophoresis may be applied alone, or in combination with electrotransport, using elecfrodes 16.
- Fig. 18 illustrates ingestible, electrically-assisted, drag-delivery system 30, in accordance with an embodiment of the present invention.
- device 10 comprises ablation apparatus 24 for providing ablation, such as RF ablation, as a drag transport mechanism. It will be appreciated that ablation may be applied alone, or in combination with electrotransport, using elecfrodes 16.
- RF ablation parameters include frequencies of about 50 to about 150 kHz, and potentials of about 3 - 100 volts. These parameters are provided as examples; in accordance with embodiments of the present invention, other parameters, which may be higher or lower, may be used.
- ablation apparatus 24 performs microwave ablation, laser ablation, cryogenic ablation, thermal ablation, or liquid jet ablation.
- Fig. 19 illustrates ingestible, electrically-assisted, drag-delivery system 30, in accordance with an embodiment of the present invention.
- device 10 comprises telemetry system 20, for providing communication with an extracorporeal station 21 (Fig. 2).
- sensor 18 may transmit extracorporeal station 21 temperature values along the GI fract. These values may be used to inform a person using system 30 of a sudden, or localized temperature increase, suggestive of a problem.
- sensor 18 may comprise a pH sensor, and extracorporeal station 21 may be used to remotely confrol valves, such as valves 26A, 26B, and 26C of Fig. 16.
- Fig. 20 illustrates ingestible, electrically-assisted, drag-delivery system 30, in accordance with an embodiment of the present invention.
- power supply 12 of device 10 is constructed as a galvanic cell 60, comprising an anode 64, a cathode 66, and an orifice 68.
- GI fluids 62 enter galvanic cell 60 via orifice 68, and serve as the electrolyte for the cell.
- a controlled release dosage form may be designed, to reduce fluctuation in plasma drug concentration and to provide a more uniform therapeutic effect.
- Oral controUed-release forms are often designed to maintain therapeutic drug concentrations for at least 12 hours.
- Several controlled release mechanisms may be used, for example, as taught by Encyclopedia of Controlled Drug Delivery, volume 2, edited by Edith Mathiowitz, pp. 838-841. These are based on the use of specific substances, generally polymers, as a matrix or as a coating. These may be materials that degrade fast or slowly, depending on the desired effect.
- drug 36 is released in a controlled manner, using one or more of the following techniques: o
- the drug which may be solid, liquid or a suspension in liquid, may be encapsulated in a polymeric material, so that drag release is controlled by diffusion through the capsule walls.
- the drag particles may be coated with wax or poorly soluble material, or an insoluble material (e.g., polyvinyl chloride) mixed with a water- soluble, pore forming compound, so that drug release is controlled by the breakdown of the coating.
- the drug may be embedded in a slow-release matrix, which may be biodegradable or non-biodegradable, so that the drag release is controlled by diffusion through the matrix, erosion of the matrix, or both.
- the drug may be complexed with ion-exchange resins that slow down its release.
- the drag may be laminated, as a jellyroll, with a film, such as a polymeric material, which may be biodegradable or nonbiodegradable, so that the drug is released by diffusion, erosion or both.
- the drug may be dispersed in a hydrogel, or a substance that forms a hydrogel in the GI fract, so that the drag release is controlled by diffusion of the drag from the water-swollen hydrogel.
- Osmotic pressure may be used to release the drag in a controlled manner. Uptake of water into the dosage unit increases the osmotic pressure within the system. The build-up of the osmotic pressure gradient drives the drag through one or more orifices in the dosage form to release the drag in a controlled manner.
- the drag may be formed as micropellets, of a density that is lower than that of the GI fluid.
- the micropellets may float for a long time, before dissolution.
- the drug may contain a bioadhesive polymer that adheres to the surface of the epithelium, to extend the time of the drug in the GI tract.
- the drag may be chemically bonded to a polymer and released by hydrolysis.
- Macromolecular structures of the drag may be formed via ionic or covalent linkages, which confrol the drug release by hydrolysis, therrnodynamic dissociation or microbial degradation.
- the drag may be coated with a combination of a soluble and insoluble polymers. When the soluble particles dissolve, they form a microporous layer around the drag core, so that the drag may permeate slowly through the micropores. The rate of release depends on the porosity and thickness of the coating layer.
- the coating layer components can be varied to prolong release of the drag until the dosage unit is in the presence of a specific pH (e.g., for colon targeting).
- the drag may be laminated with a layer designed to dissolve at a specific pH value, for targeting a specific portion of the GI fract.
- the drag may be laminated with several layers, each designed to dissolve at a different specific pH value, for targeting different portions of the GI tract, for example, for targeting the colon.
- the drag may be designed for pH-independent controlled release, and produced by wet granulating an acidic or basic drag blend with a buffering agent and the appropriate excipients, wherein the granules are then coated with a film, which is permeable in GI fluid and compressed into tablets.
- GI fluid permeates the film coating, and the buffering agents adjust the pH value of the tablet so that the drug can dissolve and permeate out of the dosage form at a constant rate, independent of the pH level in the GI fract.
- the drug formulation may be sealed in the insoluble capsule body by means of a water-soluble plug and a hydrogel plug.
- the water-soluble plug dissolves in the gastric juice and exposes the hydrogel plug, which begins to swell.
- the hydrogel plug is ejected and the encapsulated drug formation is then released into the alimentary tract.
- other controlled release means known in the art are used.
- some or all portions of the capsule are configured to be biodegraded by bacteria in the patient's colon.
- drug release may take any of the following options: controlled release, delayed release, pulsatile release, chronotherapeutic release, immediate release, enterocoated release (activation starts at the small intestine, and the pH-dependent coating protects from the gastric acidic environment).
- the dosage forms may be chronotherapeutic (adaptation to the circadian rhythm) or colonic delivery type, based on multiple coatings system.
- the drug may be formed as a capsule of hard gelatin, as compressed powder, or as any other alternative known in the art, for example, hydroxypropyl methylcellulose (HPMC).
- Typical entities are: protease inhibitors, stabilizers, absorption enhancers, and PGP inhibitors, such as verapamil or quinidine. Additionally, various additives may be used with drug 36. These may include protease inhibitors, which shield against luminal brash, border peptidases, such as Trypsin inhibitor, Chemostatin, Bowman Birk Inhibitor, Aprotinin, SBTI, and polycarbophyl.
- absorption enhancers such as NSAIDs, decanoic acid, sodium salicylate, SLS, quaternary ammonium salts, Bile salts-na-cholate, octanoic acid, glycerides, saponins, and/or medium chain fatty acids may be used.
- An advantage of some embodiments of the present invention is the ability to circumvent this interaction, by using electrically assisted absorption, in place of chemical enhancers.
- stabilizers such as proteins, sugars, polyols, amino acids, inorganic salts, and/or surfactants, may be used.
- Suitable polymers for matrix formation for controlled or slowed release of oral drags include Acrylates, acrylic acid copolymers, Eudragit, RL/RS type, cellulose derivatives like ethyl cellulose, HPMC, carboxymethylcellulose, carbomers, cellulose acetate, PVA, gums, and any other pharmaceutically acceptable polymers.
- lipids may serve as matrix formers as well, for example, glycerol behenate, or glycerol monostearate.
- the matrix forming polymers may be filled into capsules or compressed into tablets.
- Suitable polymers for functional coatings of oral drugs for controlled or slowed drag release include Ethocel (ethyl cellulose), HPMC, Kollicoat (PVA, PVP combinations), CA esters, Eudragits, and enteric coating (pH-dependent) type polymers
- MCC lactose
- ca-phosphate may be used as well.
- coatings may be applied to both tablets and capsules. It will be appreciated that the type of coating will be determined according to the drag and the desired release profile, such as slow release, enteric (mainly for peptide type), chronotherapeutic, colonic, osmotic, etc.
- coating may be additional to matrix-based dosage forms, either for tablets or for capsules.
- Drag candidates for some embodiments of the present invention include peptides, proteins, macromolecules, hormones, polar compounds, and poorly soluble compounds.
- Drags that may be used as drug 36, in accordance with embodiments of the present invention, include Interleukin 2, TGF-Beta 3, heparin, erythropoietin, cyclosporin, anticancer drugs, viral and non viral vectors for gene delivery, TNF, somafropin, interferones, copaxone, recombinant proteins, immune system modulators, monoclonal antibodies (Herceptin), vaccines, filgastrin, somatostatin, insulins, LHRH antagonists and analogs (Decapeptide, Leuprolide, Goseralin, calcitonin, triptorelin, oxytocin, and sandostatin.
- Interleukin 2 TGF-Beta 3
- heparin erythropoietin
- cyclosporin anticancer drugs
- TNF somafropin
- interferones copaxone
- small molecule drags such as statins, immunosuppressants (e.g., sirolimus, tacrolimus), galantamine, celebrex, and other poorly soluble drags, or drags of low availability, may be used.
- statins e.g., statins, immunosuppressants (e.g., sirolimus, tacrolimus), galantamine, celebrex, and other poorly soluble drags, or drags of low availability
- immunosuppressants e.g., sirolimus, tacrolimus
- galantamine e.g., celebrex, and other poorly soluble drags, or drags of low availability
- These drugs may be Cox 2 inhibitors, CNS drugs, antibiotics, and any others that require improvement in their oral bioavailability.
- An electrically assisted, drug-delivery device 10 10.
- Active drag Insulin.
- Filler microcrystalline cellulose, lactose.
- Protease inhibitor chemostatin, trypsin inhibitor.
- the components are mixed and compressed into tablets.
- An enterocoat is applied to protect from gastric environment.
- Eudragit L may be used.
- Example 2 Similar to Example 1, but additionally including an absorption enhancer, such as decanoic acid.
- an absorption enhancer such as decanoic acid.
- Capsule for oral delivery of copaxone prepared as in Example 1.
- the components are dry-mixed and filled into capsules, which are coated with an enterocoat polymer like HPMCP.
- a tablet for controlled release of cyclosporin A tablet for controlled release of cyclosporin.
- Both device 10 and HPMC and the drug substance are mixed together, and compressed into tablets (See Fig. 13).
- the complete system 30 is then coated with ethyl cellulose, which together with the HPMC delays and confrols the drag release.
- Example 4 An osmotic device.
- the tablet of Example 4 may be coated with cellulose acetate combined with PEG. After ingestion the PEG dissolves, leaving the tablet coated with a semi-permeable membrane that confrols the release of the drag by an osmotic mechamsm.
- Osmognate additives such as NaCl
- NaCl are added to the drag core, and perforation of the coating may contribute to better controlling the release patterns.
- the electrically- assisted, drug-delivery system further comprises a visual imaging apparatus, for example, as described in US Patent 5,984,860 to Shan, US Patents 5,604,531 and 6,428,469 and US Patent Application 2001/0035902, all to Iddan et al, all of which are incorporated herein by reference
- the electrically- assisted, drug-delivery system further increases the dissolution rate of drugs that dissolve slowly. For example, sonophoresis which produces cavitation has an abrasive effect, and may be operative to enhance the dissolution of drugs of poor solubility.
- the electrically-assisted, drug-delivery system is ingestible. Typically, it is free to pass through the GI fract. Alternatively, it may be tethered to a portion of the patient's body, e.g., to a tooth or to a band placed around the patient's head. Alternatively, the electrically-assisted, drug- delivery system may be mounted on a catheter.
- Embodiments of the present invention are designed to achieve previously unmet efficiency and bioavailability of orally delivered protein and peptide drugs. It will be appreciated that the electrically-assisted improvement may be performed in addition to and synergistically with known drug enhancers and stabilizers.
- Fig. 21A is a schematic illustration of a drug-delivery system 100, comprising a capsule 102, in accordance with an embodiment of the present invention.
- Capsule 102 comprises a mechanism that is operative to be responsive to its environment, such as, for example, a pH-sensitive coating 104.
- Coating 104 is typically configured, using techniques known in the art, to dissolve upon entering a small intestine 120 of a patient.
- the environmentally-responsive mechanism comprises, for example, a sensor (such as an electronic sensor) a timer, a transmitter / receiver, or a camera.
- Capsule 102 typically comprises a drag 106, which is intended for delivery to the patient at a desired site or range of sites in small intestine 120.
- Drag 106 is typically stored within capsule 102 in a liquid state, although other embodiments of the present invention (some described herein) provide for drag 106 to be stored in another form, such as in solid-, powder-, and/or gel-form.
- Capsule 102 typically comprises a driving mechanism 108 located within the capsule (as described hereinbelow) or on an outer surface of the capsule (as described hereinabove).
- Driving mechanism 108 typically actively drives drug 106 through an orifice 110 of capsule 108 and actively drives the drag through the wall of small intestine 120.
- the orifice is shaped like a nozzle suitable for facilitating passage of a high pressure / high velocity stream. Such nozzles are known, for example, in the field of needleless drug injection.
- the active driving of drug 106 through the GI tract wall is accomplished by: (a) driving the drag through the wall by passage of the drag through tight junctions of the epithelial layer of the small intestine, and/or (b) driving the drag through the wall by penetrating the epithelial cells themselves.
- a therapeutically-significant portion of drug 106 is thereby passed into direct contact with the capillary supply of the GI tract (e.g., the small intestine), and therefrom into the systemic circulation. It is noted that this embodiment therefore typically allows entry into the bloodstream of drug molecules which would normally be largely excluded (e.g., due to size or chemical properties).
- orifice 110 may or may not be provided.
- drag 106 may be at least in part on an outer surface of capsule 102, or may exit the capsule through an opening larger than orifice 102.
- the dissolving of coating 104 triggers activation of driving mechanism 108, which, in turn, actively drives drag 106 through the wall of small intestine 120.
- coating 104 is configured to dissolve in a pH range of about 4.7 - 6.5.
- the coating may be configured to dissolve after about 5-90 minutes of exposure to a pH of about 5 or 6.
- coating 104 may comprise Eudragit or HPMCP, and is typically several tenths of a micron thick.
- Fig. 2 IB is a schematic illustration of drag-delivery system 100, in accordance with another embodiment of the present invention.
- coating 104 is applied at a first thickness over a first portion of capsule 102 (e.g., over driving mechanism 108), and at a second thickness over a second portion of capsule 102 (e.g., over orifice 110).
- no coating 104 (or, alternatively, only a small amount of coating 104) is applied to the second portion of capsule 102.
- different types of coatings are applied to different portions of capsule 102, e.g., in order to provide for the respective portions of the capsule to be exposed to the small intestine at different times.
- a sealing mechanism such as a plug 111, is placed within orifice 110, and is automatically removed therefrom upon activation of driving mechanism 108.
- driving mechanism 108 may generate pressure within capsule 102, which ejects plug 111 and facilitates rapid ejection of drug 106 through the wall of small intestine 120.
- plug 111 is not shown in all of the figures, it is to be appreciated that it may be integrated in any of the gas generation embodiments or other embodiments described herein, as appropriate.
- a sealing mechanism as described may be provided in combination with or separately from a variable-thickness coating 104. It is further noted that although the figures generally show a small space between the outer surface of capsule 102 and the surrounding small intestinal wall, this is for purposes of visual clarity only. In practice, the intestinal wall is typically in contact with the capsule throughout the capsule's peristaltically-driven passage through the GI tract.
- Fig. 22A is a schematic illustration of drag-delivery system 100, in accordance with an embodiment of the present invention.
- driving mechanism 108 comprises a gas generator 118 and a movable member, such as a membrane 122. Membrane 122 moves within capsule 102 in response to the generation of gas by generator 118.
- the movable member comprises a piston.
- a movable member is not provided, but instead gas generator 118 acts directly on drug 106.
- Fig. 22B is a schematic illustration of drag-delivery system 100, configured as in the embodiment of Fig. 22A, but in a drug-delivery phase thereof.
- the dissolving of coating 104 activates gas generator 118 to release a gas that deflects membrane 122. This deflection, in turn, applies pressure to drag 106, driving it out of orifice 110, through the epithelial layer of small intestine 120, and into contact with the capillary circulation of the small intestine.
- orifice 110 typically has a characteristic diameter between about 20 and 400 microns. As appropriate for a given application, the diameter may be between about 20-50 microns, 50-150 microns, or 150-400 microns.
- the pressure developed within the capsule typically increases by about 0.1 to 5 atmospheres, for example, about 0.5 to 1.5 atmospheres. For some applications, the pressure change occurs over a time period of less than about 1 minute (e.g., for gas-generating reactions between chemicals). For other applications (e.g., those utilizing electrolysis), the pressure change typically occurs over longer time periods, such as 1-20 minutes, or 20-60 minutes.
- gas generator 118 comprises a power source, such as a battery 128, having positive and negative poles thereof coupled to respective elecfrodes 130 and 132. (Alternatively, the positive and negative poles are reversed.)
- Elecfrode 130 is typically in contact with a liquid, such as a saline solution 140 contained within capsule 102.
- Solution 140 is typically in contact with or otherwise mechanically coupled to membrane 122.
- battery 128 may be placed within solution 140, it is typically in a separate compartment, with a barrier 138 protecting the battery from the solution.
- Electrode 132 is typically mounted to an external surface of capsule 102, within coating 104. Elecfrode 132 may protrude from the surface of the capsule (as shown), or, alternatively, may be flat mounted on the outer surface of the capsule.
- capsule 102 comprises an electrode having a first electrode contact
- electrode contacts 134 and 136 are embodied as opposite faces of a flat metallic surface which forms a portion of the casing of capsule 102.
- coating 104 typically has very low electrical conductivity, and can be generally considered to act as an electrical insulator. Thus, when coating 104 is still present (e.g., before ingestion, and while capsule 102 is in the patient's stomach), the current drain from battery 128 is minimal or essentially zero.
- electrode 132 and electrode contact 134 are electrically coupled via the ion-rich fluids naturally present in the small intestine.
- a current is thereby able to flow, powered by battery 128, from electrode 130 via solution 140 to electrode contact 136.
- the flow of the current through solution 140 is associated with electrolysis of the water, and generates a gas.
- the gas generated by this process deflects membrane 122 and forces drag 106 out of orifice 110, as described hereinabove.
- battery 128 comprises biocompatible / biodegradable components, such as zinc and manganese dioxide.
- capsule 102 instead of or in addition to battery 128, capsule 102 comprises a piezoelectric crystal coupled to a capacitor. The capacitor stores energy applied to capsule 102 during gastric contractions and during the initial stages of peristalsis in the small intestine.
- gas generator 118 comprises a hydrophilic membrane 150 and a substance 152 typically adjacent to the hydrophilic membrane.
- Hydrophilic membrane 150 is typically embedded in or otherwise coupled to the outer surface of capsule 102, on an opposite side of membrane 122 relative to that side of membrane 122 that faces drag 106.
- a suitable membrane may be obtained from Celgard, Inc. (Charlotte, NC).
- Substance 152 is typically disposed within capsule 102, and has the characteristic of rapidly releasing gas upon contact with the fluid of the GI tract.
- substance 152 comprises sodium bicarbonate.
- Hydrophilic membrane 150 is protected from the fluid of the GI tract by membrane 104 until capsule 102 arrives at a suitable region of the GI fract, such as a portion of the small intestine having a particular pH. At this point, membrane 104 dissolves, and hydrophilic membrane 150 allows passage of the GI tract fluid into the capsule, where it contacts substance 152. As shown in Fig. 24B, gas is released rapidly in response to the reaction of the GI fract fluid with substance 152. In turn, membrane 122 is deflected and drag 106 is ejected at high pressure and velocity through orifice 110 and through the wall of the small intestine.
- hydrophilic membrane 150 By virtue of the physical properties of hydrophilic membrane 150, the fluid which passes through hydrophilic membrane 150 to react with substance 152 also wets the hydrophilic membrane.
- the wetting of hydrophilic membrane 152 typically provides a partial or substantially-complete barrier to the release of gas through the hydrophilic membrane, and thereby facilitates the desired mechanical work performed by the generated gas on membrane 122 and drug 106.
- gas generator 118 comprises hydrophilic membrane 150, as described hereinabove, and two elecfrodes 160 and 162 typically but not necessarily embedded in the casing of capsule 102. Elecfrodes 160 and 162 typically comprise different metals, such as zinc and manganese dioxide, or zinc and silver oxide.
- a conductor 166 electrically couples electrode 160 to elecfrode 162. Typically, conductor 166 and elecfrodes 160 and 162 are encased within an insulator 164, and, in combination, constitute a galvanic cell.
- fluid from the GI fract enters capsule 102 via hydrophilic membrane 150.
- the fluid once inside the capsule, provides (a) a low resistance pathway for current flow between electrodes 160 and 162, and, in parallel, (b) the water source for electrolysis and corresponding rapid production of gas.
- the released gas deflects membrane 122 and drives drug 106 out of orifice 110 and through the intestinal wall.
- gas generator 118 comprises hydrophilic membrane 150 and one or more gas-releasing elements 180.
- gas-releasing elements 180 comprise elemental sodium or elemental calcium, which reacts with the acidic GI fract fluid passing through hydrophilic membrane 150 after the dissolving of coating 104. As shown in Fig. 26B, this reaction rapidly releases gas, and drives membrane 122 to push drug 106 through orifice 110 and through the epithelial layer of the small intestine.
- driving mechanism 108 comprises a piston 202 and a piston driver 200.
- piston driver 200 comprises a mechanical spring, as shown.
- piston driver 200 comprises a source of compressed air.
- capsule 202 is typically stored with piston driver 200 in the tense state.
- the piston driver is prevented from releasing its energy by a portion 204 of coating 104 that is disposed in a position within capsule 102 that inhibits motion of piston 202.
- portion 204 is an extension of coating 104, and comprises the same material as coating 104.
- portion 204 comprises a pH-sensitive adhesive that exhibits sufficiently- strong adhesive properties, prior to digestion, whereby it is able to hold piston 202 in place. After ingestion of the capsule and the dissolving of coating 104 in the small intestine, portion 204 is exposed to the acidic environment of the small intestine, and dissolves as well, thereby freeing piston 202. As shown in Fig. 27B, after portion 204 releases piston 202, piston driver 200 drives piston 202 to force drug 106 through orifice 110 and through the wall of the small intestine.
- Figs. 28A, 28B, and 28C are schematic illustrations of drag-delivery system 100 in respective resting, partially-activated, and drug-delivery phases thereof, in accordance with an embodiment of the present invention.
- capsule 102 comprises a drag 106a (such as drag 106), stored in powder form within capsule 102.
- a hydrophilic membrane 150 in addition to any uses it may have in activating driving mechanism 108 as described hereinabove, allows fluid from the GI fract to mix with drag 106a.
- capsule 102 is configured to facilitate this mixing prior to activation of driving mechanism 108.
- this pre- mixing of drag 106a with the GI fract fluid is brought about by setting a thickness LI of coating 104 to be lower in a region surrounding hydrophilic membrane 150 than a thickness L2 of coating 104 in a region surrounding driving mechanism 108.
- pH-sensitive coating 104 over hydrophilic membrane 150 essentially completely dissolves, allowing the GI fract fluid to enter the capsule and mix with drug 106a.
- the portion of coating 104 over driving mechanism 108 is smaller than as shown in Fig. 28A, but not yet sufficiently small to cause the activation of the driving mechanism.
- Figs. 29A and 29B are schematic illustrations of drag-delivery system 100 in respective resting and drag-delivery phases thereof, in accordance with an embodiment of the present invention.
- Fig. 29B shows an expanded view of the portion of system 100 shown in Fig. 29 A.
- capsule 102 comprises a hollow needle 220 located adjacent to orifice 110 and in communication with drag 106.
- one or more elastic elements 222 hold hollow needle 220 generally within capsule 102, such that the sharp tip of the needle does not extend past coating 104, and, typically, does not extend past the outer surface of the capsule.
- elastic elements 222 may comprise springs, spring-like mechanical elements, or compressed air.
- a substantial force is generated by drug 106 upon needle 220.
- This force surpasses the force generated by elastic elements 222, and thrusts hollow needle 220 out of the body of capsule 102 and through the wall of the small intestine.
- drag 106 passes through the channel in hollow needle 220, past the endothelial layer of the small intestine, and into contact with the underlying capillary bed.
- the high pressure subsequently declines (e.g., after several seconds to about a minute)
- the force provided by elastic elements 222 surpasses that generated by driving mechanism 108, and hollow needle 220 refracts within the body of capsule 102.
- needle 220 is not hollow, but instead provides a transient small hole in the wall of the small intestine through which drag 106 may pass.
- Fig. 30 is a schematic illustration of drug-delivery system 100, in accordance with another embodiment of the present invention.
- the functionality for activating driving mechanism 108 described hereinabove as being provided by coating 104, is supplemented or replaced by other activating functionalities.
- capsule 102 comprises a bio-sensor 240 that detects a biological or physiological parameter, and activates driving mechanism 108 responsive thereto.
- bio-sensor 240 may comprise one or more of the following: (a) an enzymatic sensor, selectively sensitive to an enzyme indicative of the capsule's presence in a given portion of the GI tract and/or sensitive to a pathological condition, such as inflammation or GI bleeding,
- a temperature sensor e.g., a sensor sensitive to elevated temperatures associated with inflammation
- a pH sensor e.g., a pH sensor sensitive to a particular pH in the range of about
- a timer typically comprising chemicals that react in a known manner to activate driving mechanism 108 at a predetermined time following an event such as the patient squeezing the capsule or the patient ingesting the capsule.
- capsule 102 comprises a camera 242, such as is produced by Given Imaging, Ltd. (Israel), which records an image of the GI fract for onboard analysis and, if appropriate, activation of driving mechanism 108 in response to the image.
- a camera 242 such as is produced by Given Imaging, Ltd. (Israel), which records an image of the GI fract for onboard analysis and, if appropriate, activation of driving mechanism 108 in response to the image.
- capsule 102 comprises a transmit / receive unit 244, adapted to transmit a signal responsive to an image recorded by the camera and/or responsive to a reading by bio-sensor 240.
- the transmitted data are typically analyzed in real-time, and a decision is made (e.g., by a physician or by a computer external to the patient) whether and when to administer drag 106.
- capsule 102 may be configured to control the quantity of drag 106 administered.
- drag 106 may be stored in several chambers within capsule
- the signal sent to the transmit/receive unit instructs the driving mechanism to deliver the drag from none, one, some, or all of the chambers.
- capsule is to be understood to refer to oral dosage forms generally, i.e., comprising capsules, tablets, and similar forms, for example, as shown in Figs. 3-20 with respect to drug-delivery system 30, or as shown in Figs. 21-30 with respect to capsule 102.
- drag means any natural or synthetic chemical that may be administered as an aid in the diagnosis, treatment, cure, mitigation, or prevention of disease or other abnormal conditions, or to improve health. Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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CA002514392A CA2514392A1 (en) | 2003-01-29 | 2004-01-29 | Active drug delivery in the gastrointestinal tract |
EP04706261A EP1594477A4 (en) | 2003-01-29 | 2004-01-29 | Active drug delivery in the gastrointestinal tract |
JP2006502626A JP2006517827A (en) | 2003-01-29 | 2004-01-29 | Delivery of active drugs in the gastrointestinal tract |
AU2004208580A AU2004208580A1 (en) | 2003-01-29 | 2004-01-29 | Active drug delivery in the gastrointestinal tract |
Applications Claiming Priority (2)
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US44317303P | 2003-01-29 | 2003-01-29 | |
US60/443,173 | 2003-01-29 |
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WO2004066903A2 true WO2004066903A2 (en) | 2004-08-12 |
WO2004066903A3 WO2004066903A3 (en) | 2005-05-12 |
WO2004066903B1 WO2004066903B1 (en) | 2005-07-21 |
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PCT/IL2004/000093 WO2004066903A2 (en) | 2003-01-29 | 2004-01-29 | Active drug delivery in the gastrointestinal tract |
Country Status (9)
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US (1) | US20040253304A1 (en) |
EP (1) | EP1594477A4 (en) |
JP (1) | JP2006517827A (en) |
KR (1) | KR20050098277A (en) |
CN (1) | CN1774239A (en) |
AU (1) | AU2004208580A1 (en) |
CA (1) | CA2514392A1 (en) |
RU (1) | RU2334506C2 (en) |
WO (1) | WO2004066903A2 (en) |
Cited By (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006028281A1 (en) * | 2004-09-08 | 2006-03-16 | Olympus Corporation | Capsule type medical device |
GB2418144A (en) * | 2004-09-17 | 2006-03-22 | Psimedica Ltd | Medical device for delivery of beneficial substance |
WO2006056944A1 (en) * | 2004-11-29 | 2006-06-01 | Koninklijke Philips Electronics N.V. | Electronically controlled pill |
WO2007069696A1 (en) | 2005-12-16 | 2007-06-21 | Olympus Corporation | Device to be introduced into subject’s body and method of jetting liquid drug |
WO2007072297A2 (en) | 2005-12-22 | 2007-06-28 | Koninklijke Philips Electronics N.V. | Device for controlled release of chemical molecules |
EP1884259A1 (en) * | 2005-05-27 | 2008-02-06 | Olympus Corporation | Device for introduction into subject |
WO2008038246A3 (en) * | 2006-09-29 | 2008-10-09 | Koninkl Philips Electronics Nv | Miniaturized threshold sensor |
EP1981581A2 (en) * | 2006-02-11 | 2008-10-22 | Genetronics, Inc. | Device and method for single-needle in vivo electroporation |
US7512442B2 (en) | 2000-12-11 | 2009-03-31 | Metacure N.V. | Acute and chronic electrical signal therapy for obesity |
WO2010004490A2 (en) | 2008-07-07 | 2010-01-14 | Koninklijke Philips Electronics N.V. | Electronic pill comprising a medicine reservoir |
WO2011008534A1 (en) * | 2009-06-30 | 2011-01-20 | Boston Scientific Scimed, Inc. | Implantable self-powered biodegradable medical device to treat or prevent reperfusion injury |
US8442841B2 (en) | 2005-10-20 | 2013-05-14 | Matacure N.V. | Patient selection method for assisting weight loss |
US8934975B2 (en) | 2010-02-01 | 2015-01-13 | Metacure Limited | Gastrointestinal electrical therapy |
WO2015059569A1 (en) * | 2013-09-26 | 2015-04-30 | Medimetrics Personalized Drug Delivery, B.V. | Delivery capsule with threshold release |
US9067011B2 (en) | 2008-06-19 | 2015-06-30 | MEDIMETRICS Personalized Drug Delivery B.V. | Device for delivery of powder like medication in a humid environment |
US9327076B2 (en) | 2004-08-27 | 2016-05-03 | Medimetrics Personalized Drug Delivery | Electronically and remotely controlled pill and system for delivering at least one medicament |
US9492396B2 (en) | 2014-07-15 | 2016-11-15 | Yossi Gross | Enhanced drug delivery pill |
EP2254464B1 (en) * | 2008-02-18 | 2017-01-04 | Medimetrics Personalized Drug Delivery B.V. | Administration of drugs to a patient |
US9597179B2 (en) | 2011-07-25 | 2017-03-21 | Rainbow Medical Ltd. | Sinus stent |
US9603550B2 (en) | 2008-07-08 | 2017-03-28 | Proteus Digital Health, Inc. | State characterization based on multi-variate data fusion techniques |
US9649066B2 (en) | 2005-04-28 | 2017-05-16 | Proteus Digital Health, Inc. | Communication system with partial power source |
US9756874B2 (en) | 2011-07-11 | 2017-09-12 | Proteus Digital Health, Inc. | Masticable ingestible product and communication system therefor |
US9770591B2 (en) | 2015-12-29 | 2017-09-26 | Rainbow Medical Ltd. | Disc therapy |
US9796576B2 (en) | 2013-08-30 | 2017-10-24 | Proteus Digital Health, Inc. | Container with electronically controlled interlock |
US9821158B2 (en) | 2005-02-17 | 2017-11-21 | Metacure Limited | Non-immediate effects of therapy |
US9883819B2 (en) | 2009-01-06 | 2018-02-06 | Proteus Digital Health, Inc. | Ingestion-related biofeedback and personalized medical therapy method and system |
US9941931B2 (en) | 2009-11-04 | 2018-04-10 | Proteus Digital Health, Inc. | System for supply chain management |
US9950156B2 (en) | 2016-09-13 | 2018-04-24 | Rainbow Medical Ltd. | Disc therapy |
US9962107B2 (en) | 2005-04-28 | 2018-05-08 | Proteus Digital Health, Inc. | Communication system with enhanced partial power source and method of manufacturing same |
WO2018112264A1 (en) * | 2016-12-14 | 2018-06-21 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with a chemokine/chemokine receptor inhibitor |
WO2018112245A1 (en) * | 2016-12-14 | 2018-06-21 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with a jak inhibitor and devices |
WO2018112215A1 (en) * | 2016-12-14 | 2018-06-21 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with an integrin inhibitor |
US10084880B2 (en) | 2013-11-04 | 2018-09-25 | Proteus Digital Health, Inc. | Social media networking based on physiologic information |
WO2018183934A1 (en) * | 2017-03-30 | 2018-10-04 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with a chst15 inhibitor |
WO2018183931A1 (en) * | 2017-03-30 | 2018-10-04 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with il-10 or an il-10 agonist |
US10175376B2 (en) | 2013-03-15 | 2019-01-08 | Proteus Digital Health, Inc. | Metal detector apparatus, system, and method |
US10187121B2 (en) | 2016-07-22 | 2019-01-22 | Proteus Digital Health, Inc. | Electromagnetic sensing and detection of ingestible event markers |
US10207093B2 (en) | 2010-04-07 | 2019-02-19 | Proteus Digital Health, Inc. | Miniature ingestible device |
WO2019036382A1 (en) * | 2017-08-15 | 2019-02-21 | Progenity Inc. | Treatment of inflammatory disease using ingestible device to release immune modulator |
US10223905B2 (en) | 2011-07-21 | 2019-03-05 | Proteus Digital Health, Inc. | Mobile device and system for detection and communication of information received from an ingestible device |
US10238604B2 (en) | 2006-10-25 | 2019-03-26 | Proteus Digital Health, Inc. | Controlled activation ingestible identifier |
WO2019118778A1 (en) * | 2017-12-14 | 2019-06-20 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a s1p modulator |
EP2544668B1 (en) * | 2009-12-24 | 2019-07-10 | Rani Therapeutics, LLC | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10398161B2 (en) | 2014-01-21 | 2019-09-03 | Proteus Digital Heal Th, Inc. | Masticable ingestible product and communication system therefor |
WO2019178071A1 (en) * | 2018-03-13 | 2019-09-19 | Progenity, Inc. | Ingestible device with relatively large payload volume |
US10441194B2 (en) | 2007-02-01 | 2019-10-15 | Proteus Digital Heal Th, Inc. | Ingestible event marker systems |
WO2019246313A1 (en) * | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a tnf inhibitor |
WO2019246273A1 (en) * | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a jak or other kinase inhibitor |
WO2019246312A1 (en) * | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immunomodulator |
WO2019246317A1 (en) * | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease or condition in a tissue originating from the endoderm |
US10518085B2 (en) | 2015-12-29 | 2019-12-31 | Rainbow Medical Ltd. | Disc therapy |
US10517506B2 (en) | 2007-05-24 | 2019-12-31 | Proteus Digital Health, Inc. | Low profile antenna for in body device |
US10529044B2 (en) | 2010-05-19 | 2020-01-07 | Proteus Digital Health, Inc. | Tracking and delivery confirmation of pharmaceutical products |
US10588544B2 (en) | 2009-04-28 | 2020-03-17 | Proteus Digital Health, Inc. | Highly reliable ingestible event markers and methods for using the same |
US10632251B2 (en) | 2010-12-23 | 2020-04-28 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
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US10675248B2 (en) | 2018-08-14 | 2020-06-09 | Alma Therapeutics Ltd. | Expandable pill |
WO2020106704A3 (en) * | 2018-11-19 | 2020-07-02 | Progenity, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
US10752681B2 (en) | 2010-12-23 | 2020-08-25 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
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Families Citing this family (232)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US8150519B2 (en) | 2002-04-08 | 2012-04-03 | Ardian, Inc. | Methods and apparatus for bilateral renal neuromodulation |
US7617005B2 (en) | 2002-04-08 | 2009-11-10 | Ardian, Inc. | Methods and apparatus for thermally-induced renal neuromodulation |
US9636174B2 (en) | 2002-04-08 | 2017-05-02 | Medtronic Ardian Luxembourg S.A.R.L. | Methods for therapeutic renal neuromodulation |
US20080213331A1 (en) | 2002-04-08 | 2008-09-04 | Ardian, Inc. | Methods and devices for renal nerve blocking |
US20050058701A1 (en) * | 2003-01-29 | 2005-03-17 | Yossi Gross | Active drug delivery in the gastrointestinal tract |
JP3993546B2 (en) * | 2003-09-08 | 2007-10-17 | オリンパス株式会社 | In-subject introduction apparatus and wireless in-subject information acquisition system |
DE202004021947U1 (en) | 2003-09-12 | 2013-05-13 | Vessix Vascular, Inc. | Selectable eccentric remodeling and / or ablation of atherosclerotic material |
JP2008501466A (en) * | 2004-06-07 | 2008-01-24 | ギブン イメージング リミテッド | Aspiration biopsy method, system and apparatus |
US9713730B2 (en) | 2004-09-10 | 2017-07-25 | Boston Scientific Scimed, Inc. | Apparatus and method for treatment of in-stent restenosis |
US8396548B2 (en) | 2008-11-14 | 2013-03-12 | Vessix Vascular, Inc. | Selective drug delivery in a lumen |
US8364228B2 (en) * | 2004-12-09 | 2013-01-29 | Flexible Medical Systems, Llc | Appartus and method for continuous real-time trace biomolecular sampling, analysis, and delivery |
EP1819304B1 (en) | 2004-12-09 | 2023-01-25 | Twelve, Inc. | Aortic valve repair |
US20080188837A1 (en) * | 2004-12-14 | 2008-08-07 | Ziv Belsky | Local Delivery of Drugs or Substances Using Electronic Permeability Increase |
US8852083B2 (en) * | 2005-02-04 | 2014-10-07 | Uti Limited Partnership | Self-stabilized encapsulated imaging system |
US20060240096A1 (en) * | 2005-04-22 | 2006-10-26 | Kugler Chad J | Devices and methods for treating the gastrointestinal system |
US8912908B2 (en) | 2005-04-28 | 2014-12-16 | Proteus Digital Health, Inc. | Communication system with remote activation |
US8730031B2 (en) | 2005-04-28 | 2014-05-20 | Proteus Digital Health, Inc. | Communication system using an implantable device |
US9198608B2 (en) | 2005-04-28 | 2015-12-01 | Proteus Digital Health, Inc. | Communication system incorporated in a container |
US8836513B2 (en) * | 2006-04-28 | 2014-09-16 | Proteus Digital Health, Inc. | Communication system incorporated in an ingestible product |
US20070003612A1 (en) * | 2005-06-30 | 2007-01-04 | Microsoft Corporation | Capsule |
US9047746B1 (en) * | 2005-07-20 | 2015-06-02 | Neil Euliano | Electronic medication compliance monitoring system and associated methods |
US8547248B2 (en) | 2005-09-01 | 2013-10-01 | Proteus Digital Health, Inc. | Implantable zero-wire communications system |
US8333874B2 (en) * | 2005-12-09 | 2012-12-18 | Flexible Medical Systems, Llc | Flexible apparatus and method for monitoring and delivery |
US20070282252A1 (en) * | 2006-02-24 | 2007-12-06 | Stukanov Igor I | Method for oral delivery of a healing substance to a target place in gastrointestinal tract of human or animals |
US8019435B2 (en) | 2006-05-02 | 2011-09-13 | Boston Scientific Scimed, Inc. | Control of arterial smooth muscle tone |
EP2056902A1 (en) * | 2006-08-21 | 2009-05-13 | Koninklijke Philips Electronics N.V. | Drug delivery device with piezoelectric actuator |
ATE535057T1 (en) | 2006-10-17 | 2011-12-15 | Proteus Biomedical Inc | LOW VOLTAGE OSCILLATOR FOR MEDICAL FACILITIES |
EP2076194B1 (en) | 2006-10-18 | 2013-04-24 | Vessix Vascular, Inc. | System for inducing desirable temperature effects on body tissue |
JP5312337B2 (en) | 2006-10-18 | 2013-10-09 | べシックス・バスキュラー・インコーポレイテッド | Regulated RF energy and electrical tissue characterization for selective treatment of target tissues |
ES2560006T3 (en) | 2006-10-18 | 2016-02-17 | Vessix Vascular, Inc. | Induction of desirable temperature effects on body tissue |
WO2008053396A2 (en) * | 2006-10-31 | 2008-05-08 | Koninklijke Philips Electronics N.V. | Design of swallowable multi-nozzle, dosing device for releasing medicines in the gastrointesinal tract |
WO2008063626A2 (en) | 2006-11-20 | 2008-05-29 | Proteus Biomedical, Inc. | Active signal processing personal health signal receivers |
US9878094B2 (en) * | 2006-11-21 | 2018-01-30 | Stoco 10 GmbH | Medicament delivery device, capsule and in vivo medicine delivery or diagnostic system |
RU2009123434A (en) * | 2006-11-21 | 2010-12-27 | Конинклейке Филипс Электроникс Н.В. (Nl) | GASTRONIC ELECTRONIC CAPSULE AND DIAGNOSTIC OR DELIVERY SYSTEM OF THE MEDICINE INSIDE THE LIVING ORGANISM |
EP2121107B1 (en) | 2006-12-18 | 2012-10-31 | Eatlittle Inc. | Device for delivery of a substance |
EP2124725A1 (en) | 2007-03-09 | 2009-12-02 | Proteus Biomedical, Inc. | In-body device having a multi-directional transmitter |
US9270025B2 (en) | 2007-03-09 | 2016-02-23 | Proteus Digital Health, Inc. | In-body device having deployable antenna |
US20080268037A1 (en) * | 2007-04-24 | 2008-10-30 | Igor Igorevich Stukanov | Autonomous method for oral delivery of a healing substance to a target place in gastrointestinal tract of humans or animals |
ES2928197T3 (en) | 2007-09-25 | 2022-11-16 | Otsuka Pharma Co Ltd | Intracorporeal device with virtual dipole signal amplification |
EP3235491B1 (en) | 2008-03-05 | 2020-11-04 | Proteus Digital Health, Inc. | Multi-mode communication ingestible event markers and systems |
WO2009122323A1 (en) | 2008-03-31 | 2009-10-08 | Koninklijke Philips Electronics N.V. | Method of preparing a swallowable capsule comprising a sensor |
US8961498B2 (en) * | 2008-06-25 | 2015-02-24 | Medimetrics Personalized Drug Delivery | Electronic pill comprising a plurality of medicine reservoirs |
US8287902B2 (en) | 2008-07-23 | 2012-10-16 | Rainbow Medical Ltd. | Enhanced-diffusion capsule |
CN102176862B (en) | 2008-08-13 | 2014-10-22 | 普罗透斯数字保健公司 | Ingestible circuitry |
CN101721194B (en) * | 2008-10-14 | 2011-11-09 | 鸿富锦精密工业(深圳)有限公司 | Capsule endoscope and method for manufacturing lenses thereof |
KR101192690B1 (en) | 2008-11-13 | 2012-10-19 | 프로테우스 디지털 헬스, 인코포레이티드 | Ingestible therapy activator system, therapeutic device and method |
CA2743992A1 (en) | 2008-11-17 | 2010-05-20 | Minnow Medical, Inc. | Selective accumulation of energy with or without knowledge of tissue topography |
AU2009324536A1 (en) | 2008-12-11 | 2011-07-14 | Proteus Digital Health, Inc. | Evaluation of gastrointestinal function using portable electroviscerography systems and methods of using the same |
US9439566B2 (en) | 2008-12-15 | 2016-09-13 | Proteus Digital Health, Inc. | Re-wearable wireless device |
TWI503101B (en) | 2008-12-15 | 2015-10-11 | Proteus Digital Health Inc | Body-associated receiver and method |
US9659423B2 (en) | 2008-12-15 | 2017-05-23 | Proteus Digital Health, Inc. | Personal authentication apparatus system and method |
CN102365084B (en) | 2009-01-06 | 2014-04-30 | 普罗秋斯数字健康公司 | Pharmaceutical dosages delivery system |
WO2010111403A2 (en) | 2009-03-25 | 2010-09-30 | Proteus Biomedical, Inc. | Probablistic pharmacokinetic and pharmacodynamic modeling |
US8414559B2 (en) | 2009-05-07 | 2013-04-09 | Rainbow Medical Ltd. | Gastroretentive duodenal pill |
EP2432458A4 (en) | 2009-05-12 | 2014-02-12 | Proteus Digital Health Inc | Ingestible event markers comprising an ingestible component |
US20100298697A1 (en) * | 2009-05-19 | 2010-11-25 | Medtronic, Inc. | Method and devices for improved efficiency of rna delivery to cells |
US8207138B2 (en) * | 2009-05-19 | 2012-06-26 | Medtronic, Inc. | Methods and devices for improved efficiency of RNA delivery to cells |
US20100331760A1 (en) * | 2009-06-30 | 2010-12-30 | Boston Scientific Scimed, Inc. | Biodegradable implant for treating or preventing reperfusion injury |
AU2010279575B2 (en) | 2009-08-03 | 2016-05-05 | Incube Labs, Llc | Swallowable capsule and method for stimulating incretin production within the intestinal tract |
CN102811762B (en) * | 2009-08-12 | 2014-08-27 | 皇家飞利浦电子股份有限公司 | Medicine Reservoir For Drug Delivery Device |
EP2467707A4 (en) | 2009-08-21 | 2014-12-17 | Proteus Digital Health Inc | Apparatus and method for measuring biochemical parameters |
WO2011024159A2 (en) | 2009-08-24 | 2011-03-03 | Refael Hof | Phase-change and shape-change materials |
US9014799B2 (en) * | 2009-10-08 | 2015-04-21 | Palo Alto Research Center Incorporated | Transmucosal drug delivery device and method including electrically-actuated permeation enhancement |
UA109424C2 (en) | 2009-12-02 | 2015-08-25 | PHARMACEUTICAL PRODUCT, PHARMACEUTICAL TABLE WITH ELECTRONIC MARKER AND METHOD OF MANUFACTURING PHARMACEUTICAL TABLETS | |
CN102088281B (en) * | 2009-12-04 | 2013-05-29 | 北京华清益康科技有限责任公司 | Electric switching device based on body fluid PH value in alimentary canal |
JP2013515576A (en) * | 2009-12-24 | 2013-05-09 | インキューブ ラブズ, エルエルシー | Swallowable drug delivery device and drug delivery method |
WO2011092936A1 (en) * | 2010-01-27 | 2011-08-04 | オリンパス株式会社 | Power supply system and medical capsule device mounted with same |
WO2011094606A2 (en) | 2010-02-01 | 2011-08-04 | Proteus Biomedical, Inc. | Data gathering system |
CA2795229A1 (en) | 2010-04-09 | 2011-10-13 | Vessix Vascular, Inc. | Power generating and control apparatus for the treatment of tissue |
US9192790B2 (en) | 2010-04-14 | 2015-11-24 | Boston Scientific Scimed, Inc. | Focused ultrasonic renal denervation |
US8473067B2 (en) | 2010-06-11 | 2013-06-25 | Boston Scientific Scimed, Inc. | Renal denervation and stimulation employing wireless vascular energy transfer arrangement |
US9084609B2 (en) | 2010-07-30 | 2015-07-21 | Boston Scientific Scime, Inc. | Spiral balloon catheter for renal nerve ablation |
US9408661B2 (en) | 2010-07-30 | 2016-08-09 | Patrick A. Haverkost | RF electrodes on multiple flexible wires for renal nerve ablation |
US9155589B2 (en) | 2010-07-30 | 2015-10-13 | Boston Scientific Scimed, Inc. | Sequential activation RF electrode set for renal nerve ablation |
US9463062B2 (en) | 2010-07-30 | 2016-10-11 | Boston Scientific Scimed, Inc. | Cooled conductive balloon RF catheter for renal nerve ablation |
US9358365B2 (en) | 2010-07-30 | 2016-06-07 | Boston Scientific Scimed, Inc. | Precision electrode movement control for renal nerve ablation |
WO2012046166A1 (en) * | 2010-10-06 | 2012-04-12 | Koninklijke Philips Electronics N.V. | Electronic pill for delivery of powder medication |
JP5734614B2 (en) * | 2010-10-08 | 2015-06-17 | オリンパス株式会社 | Biological information acquisition device |
JP2012081016A (en) * | 2010-10-08 | 2012-04-26 | Olympus Corp | Biological information acquisition device |
US8974451B2 (en) | 2010-10-25 | 2015-03-10 | Boston Scientific Scimed, Inc. | Renal nerve ablation using conductive fluid jet and RF energy |
US9220558B2 (en) | 2010-10-27 | 2015-12-29 | Boston Scientific Scimed, Inc. | RF renal denervation catheter with multiple independent electrodes |
US9028485B2 (en) | 2010-11-15 | 2015-05-12 | Boston Scientific Scimed, Inc. | Self-expanding cooling electrode for renal nerve ablation |
US9089350B2 (en) | 2010-11-16 | 2015-07-28 | Boston Scientific Scimed, Inc. | Renal denervation catheter with RF electrode and integral contrast dye injection arrangement |
US9668811B2 (en) | 2010-11-16 | 2017-06-06 | Boston Scientific Scimed, Inc. | Minimally invasive access for renal nerve ablation |
US9326751B2 (en) | 2010-11-17 | 2016-05-03 | Boston Scientific Scimed, Inc. | Catheter guidance of external energy for renal denervation |
US9060761B2 (en) | 2010-11-18 | 2015-06-23 | Boston Scientific Scime, Inc. | Catheter-focused magnetic field induced renal nerve ablation |
US9023034B2 (en) | 2010-11-22 | 2015-05-05 | Boston Scientific Scimed, Inc. | Renal ablation electrode with force-activatable conduction apparatus |
US9192435B2 (en) | 2010-11-22 | 2015-11-24 | Boston Scientific Scimed, Inc. | Renal denervation catheter with cooled RF electrode |
US9877673B2 (en) | 2010-12-10 | 2018-01-30 | Clinitech, Llc | Transdermal sampling and analysis device |
US9451913B2 (en) | 2010-12-10 | 2016-09-27 | Touchtek Labs, Llc | Transdermal sampling and analysis device |
US20120157993A1 (en) | 2010-12-15 | 2012-06-21 | Jenson Mark L | Bipolar Off-Wall Electrode Device for Renal Nerve Ablation |
US9149617B2 (en) | 2010-12-23 | 2015-10-06 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
US8764733B2 (en) | 2010-12-23 | 2014-07-01 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8809271B2 (en) | 2010-12-23 | 2014-08-19 | Rani Therapeutics, Llc | Therapeutic agent preparations comprising liraglutide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8846040B2 (en) | 2010-12-23 | 2014-09-30 | Rani Therapeutics, Llc | Therapeutic agent preparations comprising etanercept for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
WO2012100095A1 (en) | 2011-01-19 | 2012-07-26 | Boston Scientific Scimed, Inc. | Guide-compatible large-electrode catheter for renal nerve ablation with reduced arterial injury |
US9439599B2 (en) | 2011-03-11 | 2016-09-13 | Proteus Digital Health, Inc. | Wearable personal body associated device with various physical configurations |
CN103517731B (en) | 2011-04-08 | 2016-08-31 | 柯惠有限合伙公司 | For removing iontophoresis formula drug delivery system and the method for renal sympathetic nerve and iontophoresis formula drug delivery |
WO2012148969A2 (en) | 2011-04-25 | 2012-11-01 | Brian Kelly | Apparatus and methods related to constrained deployment of cryogenic balloons for limited cryogenic ablation of vessel walls |
WO2012158648A1 (en) * | 2011-05-13 | 2012-11-22 | Massachusetts Institute Of Technology | Method and apparatus for delivering a substance |
CN103987422B (en) * | 2011-06-29 | 2017-02-15 | 拉尼医疗有限公司 | Device, system and methods for the oral delivery of therapeutic compounds |
WO2013003824A1 (en) * | 2011-06-29 | 2013-01-03 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
AU2012283908B2 (en) | 2011-07-20 | 2017-02-16 | Boston Scientific Scimed, Inc. | Percutaneous devices and methods to visualize, target and ablate nerves |
JP6106669B2 (en) | 2011-07-22 | 2017-04-05 | ボストン サイエンティフィック サイムド,インコーポレイテッドBoston Scientific Scimed,Inc. | A neuromodulation system having a neuromodulation element that can be placed in a helical guide |
WO2013055826A1 (en) | 2011-10-10 | 2013-04-18 | Boston Scientific Scimed, Inc. | Medical devices including ablation electrodes |
EP2765940B1 (en) | 2011-10-11 | 2015-08-26 | Boston Scientific Scimed, Inc. | Off-wall electrode device for nerve modulation |
US9420955B2 (en) | 2011-10-11 | 2016-08-23 | Boston Scientific Scimed, Inc. | Intravascular temperature monitoring system and method |
US9364284B2 (en) | 2011-10-12 | 2016-06-14 | Boston Scientific Scimed, Inc. | Method of making an off-wall spacer cage |
US9079000B2 (en) | 2011-10-18 | 2015-07-14 | Boston Scientific Scimed, Inc. | Integrated crossing balloon catheter |
US9162046B2 (en) | 2011-10-18 | 2015-10-20 | Boston Scientific Scimed, Inc. | Deflectable medical devices |
CN104023662B (en) | 2011-11-08 | 2018-02-09 | 波士顿科学西美德公司 | Hole portion renal nerve melts |
US9235683B2 (en) | 2011-11-09 | 2016-01-12 | Proteus Digital Health, Inc. | Apparatus, system, and method for managing adherence to a regimen |
US9119600B2 (en) | 2011-11-15 | 2015-09-01 | Boston Scientific Scimed, Inc. | Device and methods for renal nerve modulation monitoring |
US9119632B2 (en) | 2011-11-21 | 2015-09-01 | Boston Scientific Scimed, Inc. | Deflectable renal nerve ablation catheter |
US9968284B2 (en) | 2011-12-02 | 2018-05-15 | Clinitech, Llc | Anti-interferent barrier layers for non-invasive transdermal sampling and analysis device |
CN104271028B (en) * | 2011-12-15 | 2017-11-17 | 基文影像公司 | Determine the intestines and stomach of patient with the system of the type of the bleeding profile of time |
US9265969B2 (en) | 2011-12-21 | 2016-02-23 | Cardiac Pacemakers, Inc. | Methods for modulating cell function |
CN104254291B (en) | 2011-12-23 | 2018-02-13 | 维西克斯血管公司 | The method and apparatus for the tissue rebuild near the tissue or body passageway of body passage |
US9433760B2 (en) | 2011-12-28 | 2016-09-06 | Boston Scientific Scimed, Inc. | Device and methods for nerve modulation using a novel ablation catheter with polymeric ablative elements |
US9050106B2 (en) | 2011-12-29 | 2015-06-09 | Boston Scientific Scimed, Inc. | Off-wall electrode device and methods for nerve modulation |
US10660703B2 (en) | 2012-05-08 | 2020-05-26 | Boston Scientific Scimed, Inc. | Renal nerve modulation devices |
ES2967970T3 (en) | 2012-07-23 | 2024-05-06 | Otsuka Pharma Co Ltd | Techniques for manufacturing ingestible event markers comprising an ingestible component |
CN104540465A (en) | 2012-08-24 | 2015-04-22 | 波士顿科学西美德公司 | Intravascular catheter with a balloon comprising separate microporous regions |
CN104780859B (en) | 2012-09-17 | 2017-07-25 | 波士顿科学西美德公司 | Self-positioning electrode system and method for renal regulation |
US10549127B2 (en) | 2012-09-21 | 2020-02-04 | Boston Scientific Scimed, Inc. | Self-cooling ultrasound ablation catheter |
US10398464B2 (en) | 2012-09-21 | 2019-09-03 | Boston Scientific Scimed, Inc. | System for nerve modulation and innocuous thermal gradient nerve block |
EP2906135A2 (en) | 2012-10-10 | 2015-08-19 | Boston Scientific Scimed, Inc. | Renal nerve modulation devices and methods |
MY168018A (en) | 2012-10-18 | 2018-10-11 | Proteus Biomedical Inc | Apparatus, system , and method to adaptively optimize power dissipation and broadcast power in a power source for a communication device |
CN102920418B (en) * | 2012-10-24 | 2014-07-30 | 刘思德 | Self-stable patency capsule of alimentary canal |
WO2014163987A1 (en) | 2013-03-11 | 2014-10-09 | Boston Scientific Scimed, Inc. | Medical devices for modulating nerves |
US9693821B2 (en) | 2013-03-11 | 2017-07-04 | Boston Scientific Scimed, Inc. | Medical devices for modulating nerves |
US9808311B2 (en) | 2013-03-13 | 2017-11-07 | Boston Scientific Scimed, Inc. | Deflectable medical devices |
EP2968071B1 (en) * | 2013-03-15 | 2021-08-04 | Rani Therapeutics, LLC | Device for oral delivery of therapeutic compounds |
US9297845B2 (en) | 2013-03-15 | 2016-03-29 | Boston Scientific Scimed, Inc. | Medical devices and methods for treatment of hypertension that utilize impedance compensation |
EP2967734B1 (en) | 2013-03-15 | 2019-05-15 | Boston Scientific Scimed, Inc. | Methods and apparatuses for remodeling tissue of or adjacent to a body passage |
JP6498177B2 (en) | 2013-03-15 | 2019-04-10 | プロテウス デジタル ヘルス, インコーポレイテッド | Identity authentication system and method |
US10265122B2 (en) | 2013-03-15 | 2019-04-23 | Boston Scientific Scimed, Inc. | Nerve ablation devices and related methods of use |
CN105473091B (en) | 2013-06-21 | 2020-01-21 | 波士顿科学国际有限公司 | Renal denervation balloon catheter with co-movable electrode supports |
EP3010436A1 (en) | 2013-06-21 | 2016-04-27 | Boston Scientific Scimed, Inc. | Medical devices for renal nerve ablation having rotatable shafts |
US9707036B2 (en) | 2013-06-25 | 2017-07-18 | Boston Scientific Scimed, Inc. | Devices and methods for nerve modulation using localized indifferent electrodes |
AU2014284558B2 (en) | 2013-07-01 | 2017-08-17 | Boston Scientific Scimed, Inc. | Medical devices for renal nerve ablation |
CN105377170A (en) | 2013-07-11 | 2016-03-02 | 波士顿科学国际有限公司 | Medical device with stretchable electrode assemblies |
US10660698B2 (en) | 2013-07-11 | 2020-05-26 | Boston Scientific Scimed, Inc. | Devices and methods for nerve modulation |
WO2015010074A1 (en) | 2013-07-19 | 2015-01-22 | Boston Scientific Scimed, Inc. | Spiral bipolar electrode renal denervation balloon |
EP3024406B1 (en) | 2013-07-22 | 2019-06-19 | Boston Scientific Scimed, Inc. | Medical devices for renal nerve ablation |
US10695124B2 (en) | 2013-07-22 | 2020-06-30 | Boston Scientific Scimed, Inc. | Renal nerve ablation catheter having twist balloon |
EP3035879A1 (en) | 2013-08-22 | 2016-06-29 | Boston Scientific Scimed, Inc. | Flexible circuit having improved adhesion to a renal nerve modulation balloon |
US9895194B2 (en) | 2013-09-04 | 2018-02-20 | Boston Scientific Scimed, Inc. | Radio frequency (RF) balloon catheter having flushing and cooling capability |
CN105530885B (en) | 2013-09-13 | 2020-09-22 | 波士顿科学国际有限公司 | Ablation balloon with vapor deposited covering |
EP3047618B1 (en) | 2013-09-20 | 2023-11-08 | Otsuka Pharmaceutical Co., Ltd. | Methods, devices and systems for receiving and decoding a signal in the presence of noise using slices and warping |
WO2015044722A1 (en) | 2013-09-24 | 2015-04-02 | Proteus Digital Health, Inc. | Method and apparatus for use with received electromagnetic signal at a frequency not known exactly in advance |
WO2015057521A1 (en) | 2013-10-14 | 2015-04-23 | Boston Scientific Scimed, Inc. | High resolution cardiac mapping electrode array catheter |
US11246654B2 (en) | 2013-10-14 | 2022-02-15 | Boston Scientific Scimed, Inc. | Flexible renal nerve ablation devices and related methods of use and manufacture |
US9770606B2 (en) | 2013-10-15 | 2017-09-26 | Boston Scientific Scimed, Inc. | Ultrasound ablation catheter with cooling infusion and centering basket |
US9962223B2 (en) | 2013-10-15 | 2018-05-08 | Boston Scientific Scimed, Inc. | Medical device balloon |
US10945786B2 (en) | 2013-10-18 | 2021-03-16 | Boston Scientific Scimed, Inc. | Balloon catheters with flexible conducting wires and related methods of use and manufacture |
JP2016534842A (en) | 2013-10-25 | 2016-11-10 | ボストン サイエンティフィック サイムド,インコーポレイテッドBoston Scientific Scimed,Inc. | Embedded thermocouples in denervation flex circuits |
US10521561B1 (en) | 2013-12-17 | 2019-12-31 | Etectrx, Inc. | Electronic compliance system and associated methods |
EP3091922B1 (en) | 2014-01-06 | 2018-10-17 | Boston Scientific Scimed, Inc. | Tear resistant flex circuit assembly |
EP3424453A1 (en) | 2014-02-04 | 2019-01-09 | Boston Scientific Scimed, Inc. | Alternative placement of thermal sensors on bipolar electrode |
US11000679B2 (en) | 2014-02-04 | 2021-05-11 | Boston Scientific Scimed, Inc. | Balloon protection and rewrapping devices and related methods of use |
US10709490B2 (en) | 2014-05-07 | 2020-07-14 | Medtronic Ardian Luxembourg S.A.R.L. | Catheter assemblies comprising a direct heating element for renal neuromodulation and associated systems and methods |
US11548940B2 (en) | 2014-05-15 | 2023-01-10 | Rani Therapeutics, Llc | Anti-interleukin antibody preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
GB201410507D0 (en) * | 2014-06-12 | 2014-07-30 | Univ Bath | Drug delivery enhancement agents |
EP3193728B1 (en) * | 2014-09-17 | 2020-07-01 | Mars, Incorporated | Sampling device |
US10835152B2 (en) | 2014-09-25 | 2020-11-17 | Progenity, Inc. | Electromechanical pill device with localization capabilities |
CN104287685B (en) * | 2014-10-08 | 2016-03-02 | 南京航空航天大学 | Parked and the pose adjusting device of elastic rod guide type capsule endoscope robot and method |
CN114209830B (en) | 2014-11-25 | 2023-12-22 | 纽菲斯有限公司 | phase change nanoparticles |
WO2016089413A1 (en) * | 2014-12-04 | 2016-06-09 | Capso Vision, Inc. | Capsule coating for image capture control |
CA2983337A1 (en) | 2015-05-01 | 2016-11-10 | Incube Labs, Llc | Pharmaceutical compositions and methods for fabrication of solid masses comprising polypeptides and/or proteins |
WO2016193964A1 (en) * | 2015-05-31 | 2016-12-08 | Check-Cap Ltd. | Drug delivery capsule |
EP3108810A1 (en) * | 2015-06-23 | 2016-12-28 | Valtronic Technologies (Holding) SA | Ingestible device for measuring glucose concentration |
US11660436B1 (en) | 2015-08-04 | 2023-05-30 | Verily Life Sciences Llc | Device, system, and formulation for oral delivery of functionalized particles |
FR3043333B1 (en) * | 2015-11-06 | 2017-12-22 | Seb Sa | DEVICE FOR APPLYING A PRODUCT TO BE DISTRIBUTED ON THE SKIN OF AN IONTOPHORESIS USER COMPRISING MEANS FOR MEASURING ABSENCE OF PRODUCT AND CORRESPONDING METHOD |
CN105361848B (en) * | 2015-11-24 | 2017-11-24 | 陈玉玲 | Dispenser gastroscope |
CN108125669B (en) * | 2015-11-24 | 2020-07-28 | 米琛 | Gastroscope with control end |
AU2017230737B2 (en) | 2016-03-09 | 2022-07-14 | Incube Labs, Llc | Methods and articles for delivering viable cells into solid tissue |
US10314514B2 (en) * | 2016-05-29 | 2019-06-11 | Ankon Medical Technologies (Shanghai) Co., Ltd. | System and method for using a capsule device |
GB2554354B (en) | 2016-09-21 | 2021-06-02 | Vibrant Ltd | Systems for adaptive treatment of disorders in the gastrointestinal tract |
US11504024B2 (en) | 2018-03-30 | 2022-11-22 | Vibrant Ltd. | Gastrointestinal treatment system including a vibrating capsule, and method of use thereof |
EP3551046B1 (en) | 2016-12-07 | 2023-07-19 | Biora Therapeutics, Inc. | Gastrointestinal tract detection methods, devices and systems |
WO2018112223A1 (en) * | 2016-12-14 | 2018-06-21 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with a tlr modulator |
CA3046093A1 (en) * | 2016-12-14 | 2018-06-21 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with an il-1 inhibitor |
US10905378B1 (en) | 2017-01-30 | 2021-02-02 | Vibrant Ltd | Method for treating gastroparesis using a vibrating ingestible capsule |
US10888277B1 (en) | 2017-01-30 | 2021-01-12 | Vibrant Ltd | Method for treating diarrhea and reducing Bristol stool scores using a vibrating ingestible capsule |
WO2018183711A2 (en) | 2017-03-31 | 2018-10-04 | Progenity Inc. | Localization systems and methods for an ingestible device |
CA3063426A1 (en) | 2017-05-17 | 2018-11-22 | Massachusetts Institute Of Technology | Tissue anchoring articles |
US11541015B2 (en) | 2017-05-17 | 2023-01-03 | Massachusetts Institute Of Technology | Self-righting systems, methods, and related components |
CN107041727A (en) * | 2017-05-26 | 2017-08-15 | 杭州师范大学 | A kind of intelligent radio capsule and its control method |
JP7183194B2 (en) * | 2017-06-12 | 2022-12-05 | ラニ セラピューティクス, エルエルシー | Swallowable Capsules, Systems, and Methods for Measuring Gastric Emptying Parameters |
KR20190052241A (en) * | 2017-11-08 | 2019-05-16 | 서울바이오시스 주식회사 | Sterilizing device |
EP3720425B1 (en) | 2017-12-06 | 2024-04-17 | James Phillip Jones | Sampling capsule system |
US11116561B2 (en) | 2018-01-24 | 2021-09-14 | Medtronic Ardian Luxembourg S.A.R.L. | Devices, agents, and associated methods for selective modulation of renal nerves |
US10537720B2 (en) * | 2018-04-09 | 2020-01-21 | Vibrant Ltd. | Method of enhancing absorption of ingested medicaments for treatment of parkinsonism |
US11638678B1 (en) | 2018-04-09 | 2023-05-02 | Vibrant Ltd. | Vibrating capsule system and treatment method |
US11510590B1 (en) | 2018-05-07 | 2022-11-29 | Vibrant Ltd. | Methods and systems for treating gastrointestinal disorders |
EP3793667A1 (en) | 2018-05-17 | 2021-03-24 | Massachusetts Institute of Technology | Systems for electrical stimulation |
AU2019269638A1 (en) | 2018-05-17 | 2020-11-19 | Massachusetts Institute Of Technology | Quick release capsules |
US20210213263A1 (en) * | 2018-08-23 | 2021-07-15 | Baywind Bioventures | Capsule device for delivery of active agent to gastrointestinal tract |
US20200093740A1 (en) * | 2018-09-25 | 2020-03-26 | Incube Labs, Llc | Ingestible device with expandable enclosure |
WO2020101737A1 (en) * | 2018-11-15 | 2020-05-22 | Massachusetts Institute Of Technology | Actuating components and related methods |
CN109464742A (en) * | 2018-12-29 | 2019-03-15 | 上海安翰医疗技术有限公司 | Gastrointestinal tract position-sensing switch and preparation method thereof and alimentary canal site-specific drug release capsule |
JP7311917B2 (en) * | 2019-01-03 | 2023-07-20 | ヴァイブラント リミテッド | A device for delivering an ingestible agent into a user's gastrointestinal tract |
GB201900780D0 (en) | 2019-01-21 | 2019-03-06 | Vibrant Ltd | Device and method for delivering a flowable ingestible medicament into the gastrointestinal tract of a user |
CN113993560B (en) | 2019-02-01 | 2024-05-07 | 麻省理工学院 | System and method for liquid injection |
GB201901470D0 (en) | 2019-02-04 | 2019-03-27 | Vibrant Ltd | Vibrating capsule for gastrointestinal treatment, and method of use thereof |
EP3930693A4 (en) * | 2019-03-01 | 2023-01-11 | Rani Therapeutics, LLC | Devices, systems, and methods for delivering therapeutic agents into a stomach wall |
US11633129B2 (en) | 2019-04-05 | 2023-04-25 | Cambridge Medical Technologies LLC | Non-invasive transdermal sampling and analysis device incorporating redox cofactors |
WO2020214689A1 (en) * | 2019-04-15 | 2020-10-22 | Verily Life Sciences Llc | Ingestible capsules for sampling intestinal contents |
US11375931B2 (en) | 2019-08-08 | 2022-07-05 | Cambridge Medical Technologies LLC | Non-invasive transdermal sampling and analysis device incorporating an electrochemical bioassay |
US11541216B2 (en) | 2019-11-21 | 2023-01-03 | Massachusetts Institute Of Technology | Methods for manufacturing tissue interfacing components |
CN115666704A (en) | 2019-12-13 | 2023-01-31 | 比奥拉治疗股份有限公司 | Ingestible device for delivery of therapeutic agents to the gastrointestinal tract |
EP4087488A4 (en) * | 2020-01-06 | 2024-01-10 | Check-Cap Ltd. | Radiation capsule for bowel disease imaging and localize drug delivery |
KR102535610B1 (en) * | 2020-03-05 | 2023-05-26 | 서울대학교산학협력단 | Biodegradable fully-implantable iontophoretic drug delivery system |
CN111493946A (en) * | 2020-04-27 | 2020-08-07 | 上海长海医院 | Biological nano robot for treating aortic dissection |
EP4171715A4 (en) * | 2020-06-29 | 2024-07-24 | Governing Council Univ Toronto | Magnetically actuated capsule |
US20220039686A1 (en) * | 2020-08-10 | 2022-02-10 | Massachusetts Institute Of Technology | Drug delivery device |
WO2022069605A1 (en) * | 2020-09-30 | 2022-04-07 | Novo Nordisk A/S | A swallowable capsule device |
DK4037666T3 (en) | 2020-12-08 | 2024-06-24 | Ruminant Biotech Corp Ltd | IMPROVEMENT OF DEVICES AND METHODS FOR ADMINISTERING SUBSTANCES TO ANIMALS |
US20240149031A1 (en) * | 2021-03-05 | 2024-05-09 | Bitherapeutics Inc. | Oral drug delivery device |
WO2023280416A1 (en) | 2021-07-09 | 2023-01-12 | Novo Nordisk A/S | Capsule administering assembly |
WO2023129980A2 (en) * | 2021-12-30 | 2023-07-06 | Massachusetts Institute Of Technology | Ingestible chemical energy harvesting system with extended lifetime |
WO2023158778A1 (en) * | 2022-02-21 | 2023-08-24 | Rani Therapeutics, Llc | Ingestible devices for delivering a fluid preparation into a gastrointestinal tract |
IT202200008993A1 (en) * | 2022-05-03 | 2023-11-03 | Fondazione St Italiano Tecnologia | Degradable device for the passive and traceable release of a substance |
WO2024137754A1 (en) * | 2022-12-20 | 2024-06-27 | Celero Systems, Inc. | Ingestible electronically triggered drug delivery system |
CN117137609B (en) * | 2023-08-25 | 2024-04-05 | 上海交通大学医学院附属瑞金医院 | Cryoablation device with ablation record and saccule positioning functions |
Family Cites Families (79)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH337989A (en) * | 1957-04-09 | 1959-04-30 | Perrenoud Jean Pierre Dr | Capsule |
US3057344A (en) * | 1957-05-21 | 1962-10-09 | Abella Carlos Alberto | Capsule for the study of the digestive tract and method of using the same |
US3315660A (en) * | 1963-08-08 | 1967-04-25 | Carlos A Abella | Capsule for insertion in the digestive track |
US3485235A (en) * | 1967-12-04 | 1969-12-23 | Ronald Felson | Capsule for the study and treatment of the digestive tract |
US3528429A (en) * | 1968-10-21 | 1970-09-15 | Charles B Beal | Method and device for orally admitting an elongated flexible element in the alimentary canal |
US3659600A (en) * | 1970-02-24 | 1972-05-02 | Estin Hans H | Magnetically operated capsule for administering drugs |
US4239040A (en) * | 1976-10-19 | 1980-12-16 | Kabushiki Kaisha Daini Seikosha | Capsule for medical use |
DE2928477C3 (en) * | 1979-07-14 | 1982-04-15 | Battelle-Institut E.V., 6000 Frankfurt | Device for the release of substances at defined locations in the digestive tract |
JPS57163309A (en) * | 1981-04-01 | 1982-10-07 | Olympus Optical Co Ltd | Capsule apparatus for medical use |
US5961482A (en) * | 1986-07-25 | 1999-10-05 | Rutgers, The State University Of New Jersey | Iontotherapeutic device and process and iontotherapeutic unit dose |
US4869248A (en) * | 1987-04-17 | 1989-09-26 | Narula Onkar S | Method and apparatus for localized thermal ablation |
WO1989006555A1 (en) * | 1988-01-21 | 1989-07-27 | Massachusetts Institute Of Technology | Transport of molecules across tissue using electroporation |
US4844076A (en) * | 1988-08-26 | 1989-07-04 | The Johns Hopkins University | Ingestible size continuously transmitting temperature monitoring pill |
US5474785A (en) * | 1990-01-24 | 1995-12-12 | Alza Corporation | Delivery system comprising means for controlling internal pressure |
US5167626A (en) * | 1990-10-02 | 1992-12-01 | Glaxo Inc. | Medical capsule device actuated by radio-frequency (RF) signal |
US5170801A (en) * | 1990-10-02 | 1992-12-15 | Glaxo Inc. | Medical capsule device actuated by radio-frequency (rf) signal |
US5158537A (en) * | 1990-10-29 | 1992-10-27 | Alza Corporation | Iontophoretic delivery device and method of hydrating same |
US5217449A (en) * | 1990-12-11 | 1993-06-08 | Miyarisan Kabushiki Kaisha | Medical capsule and apparatus for activating the same |
US5279607A (en) * | 1991-05-30 | 1994-01-18 | The State University Of New York | Telemetry capsule and process |
US5395366A (en) * | 1991-05-30 | 1995-03-07 | The State University Of New York | Sampling capsule and process |
US5318557A (en) * | 1992-07-13 | 1994-06-07 | Elan Medical Technologies Limited | Medication administering device |
US6315772B1 (en) * | 1993-09-24 | 2001-11-13 | Transmedica International, Inc. | Laser assisted pharmaceutical delivery and fluid removal |
US5993434A (en) * | 1993-04-01 | 1999-11-30 | Genetronics, Inc. | Method of treatment using electroporation mediated delivery of drugs and genes |
US5814599A (en) * | 1995-08-04 | 1998-09-29 | Massachusetts Insitiute Of Technology | Transdermal delivery of encapsulated drugs |
IL108352A (en) * | 1994-01-17 | 2000-02-29 | Given Imaging Ltd | In vivo video camera system |
IL108775A (en) * | 1994-02-25 | 2003-09-17 | Univ Ramot | Method for efficient incorporation of molecules into cells |
US5464395A (en) * | 1994-04-05 | 1995-11-07 | Faxon; David P. | Catheter for delivering therapeutic and/or diagnostic agents to the tissue surrounding a bodily passageway |
IE70735B1 (en) * | 1994-08-15 | 1996-12-11 | Elan Med Tech | Orally administrable delivery device |
US5551953A (en) * | 1994-10-31 | 1996-09-03 | Alza Corporation | Electrotransport system with remote telemetry link |
US5697896A (en) * | 1994-12-08 | 1997-12-16 | Alza Corporation | Electrotransport delivery device |
US5778882A (en) * | 1995-02-24 | 1998-07-14 | Brigham And Women's Hospital | Health monitoring system |
US5983134A (en) * | 1995-04-23 | 1999-11-09 | Electromagnetic Bracing Systems Inc. | Electrophoretic cuff apparatus drug delivery system |
US5735817A (en) * | 1995-05-19 | 1998-04-07 | Shantha; T. R. | Apparatus for transsphenoidal stimulation of the pituitary gland and adjoining brain structures |
US5947921A (en) * | 1995-12-18 | 1999-09-07 | Massachusetts Institute Of Technology | Chemical and physical enhancers and ultrasound for transdermal drug delivery |
US6002961A (en) * | 1995-07-25 | 1999-12-14 | Massachusetts Institute Of Technology | Transdermal protein delivery using low-frequency sonophoresis |
US6041253A (en) * | 1995-12-18 | 2000-03-21 | Massachusetts Institute Of Technology | Effect of electric field and ultrasound for transdermal drug delivery |
US5983131A (en) * | 1995-08-11 | 1999-11-09 | Massachusetts Institute Of Technology | Apparatus and method for electroporation of tissue |
DE19532676C1 (en) * | 1995-09-05 | 1997-05-07 | Inst Physikalische Hochtech Ev | Arrangement for determining the position of a marker in a cavity within the organism of a living being |
US5674196A (en) * | 1996-01-05 | 1997-10-07 | Donaldson; John | Device for introducing medical fluid into the human ear |
RU2075980C1 (en) * | 1996-01-18 | 1997-03-27 | Акционерное общество открытого типа "Завод "Компонент" | Electrostimulator of gastrointestinal tract |
US5957538A (en) * | 1996-03-27 | 1999-09-28 | Sullivan; John L. | Combination belly and rear dump trailer |
US6175763B1 (en) * | 1996-03-29 | 2001-01-16 | Alza Corporation | Electrotransport drug delivery device having tactile signaling means |
AU2716297A (en) * | 1996-04-01 | 1997-10-22 | Kobosev, Valerii Javanovich | Electrical gastro-intestinal tract stimulator |
US6718201B1 (en) * | 1996-06-07 | 2004-04-06 | Alza Corporation | Electrotransport agent delivery method and apparatus |
JP2002515786A (en) * | 1996-06-28 | 2002-05-28 | ソントラ メディカル,エル.ピー. | Ultrasound enhancement of transdermal delivery |
US6024717A (en) * | 1996-10-24 | 2000-02-15 | Vibrx, Inc. | Apparatus and method for sonically enhanced drug delivery |
US6091872A (en) * | 1996-10-29 | 2000-07-18 | Katoot; Mohammad W. | Optical fiber imaging system |
US6246904B1 (en) * | 1996-12-17 | 2001-06-12 | Alza Corporation | Electrotransport drug delivery reservoirs containing inert fillers |
DE19717023C2 (en) * | 1997-04-23 | 2003-02-06 | Micronas Gmbh | Device for treating malignant, tumorous tissue areas |
US6775569B2 (en) * | 1997-11-05 | 2004-08-10 | Hisamitsu Pharmaceutical Co., Inc. | Electroporation device for in vivo delivery of therapeutic agents |
IL122602A0 (en) * | 1997-12-15 | 1998-08-16 | Tally Eitan Zeev Pearl And Co | Energy management of a video capsule |
ES2281940T3 (en) * | 1997-12-17 | 2007-10-01 | Alza Corporation | IONTOPHORESIS WITH PROGRAMMED ADJUSTMENT OF THE ELECTRICAL POWER. |
JP2002500075A (en) * | 1998-01-08 | 2002-01-08 | ソントラ メディカル, インコーポレイテッド | Transdermal transport enhanced by ultrasound transmission |
JPH11239621A (en) * | 1998-02-25 | 1999-09-07 | Hisamitsu Pharmaceut Co Inc | Iontophoresis device |
US5984860A (en) * | 1998-03-25 | 1999-11-16 | Shan; Yansong | Pass-through duodenal enteroscopic device |
US6350470B1 (en) * | 1998-04-29 | 2002-02-26 | Cima Labs Inc. | Effervescent drug delivery system for oral administration |
US6322532B1 (en) * | 1998-06-24 | 2001-11-27 | 3M Innovative Properties Company | Sonophoresis method and apparatus |
US6369039B1 (en) * | 1998-06-30 | 2002-04-09 | Scimed Life Sytems, Inc. | High efficiency local drug delivery |
CA2337129A1 (en) * | 1998-07-13 | 2000-01-20 | Genetronics, Inc. | Method and apparatus for electrically assisted topical delivery of agents for cosmetic applications |
US6148232A (en) * | 1998-11-09 | 2000-11-14 | Elecsys Ltd. | Transdermal drug delivery and analyte extraction |
US5983135A (en) * | 1998-12-24 | 1999-11-09 | Avrahami; Zohar | Transdermal delivery of fine powders |
US6464687B1 (en) * | 1999-03-09 | 2002-10-15 | Ball Semiconductor, Inc. | Implantable drug delivery system |
US6477410B1 (en) * | 2000-05-31 | 2002-11-05 | Biophoretic Therapeutic Systems, Llc | Electrokinetic delivery of medicaments |
CA2370349C (en) * | 1999-04-16 | 2013-01-29 | Johnson & Johnson Consumer Companies, Inc. | Electrotransport delivery system comprising internal sensors |
US7171263B2 (en) * | 1999-06-04 | 2007-01-30 | Impulse Dynamics Nv | Drug delivery device |
CN100402105C (en) * | 1999-06-08 | 2008-07-16 | 奥尔蒂治疗学公司 | Apparatus and method for microporation of biological membranes using thin film tissue interface devices |
US6344027B1 (en) * | 1999-12-08 | 2002-02-05 | Scimed Life Systems, Inc. | Needle-less injection apparatus and method |
GB9930000D0 (en) * | 1999-12-21 | 2000-02-09 | Phaeton Research Ltd | An ingestible device |
KR20030025222A (en) * | 2000-03-08 | 2003-03-28 | 기븐 이미징 리미티드 | A device and system for in vivo imaging |
US6471696B1 (en) * | 2000-04-12 | 2002-10-29 | Afx, Inc. | Microwave ablation instrument with a directional radiation pattern |
US6572740B2 (en) * | 2000-04-13 | 2003-06-03 | Elan Pharma International Limited | Electrolytic cell |
US6853858B2 (en) * | 2000-05-08 | 2005-02-08 | Brainsgate, Ltd. | Administration of anti-inflammatory drugs into the central nervous system |
US6327426B1 (en) * | 2000-10-26 | 2001-12-04 | Ceramatec, Inc. | Apparatus and method for delivering a beneficial agent |
US6929636B1 (en) * | 2000-11-08 | 2005-08-16 | Hewlett-Packard Development Company, L.P. | Internal drug dispenser capsule medical device |
US6409698B1 (en) * | 2000-11-27 | 2002-06-25 | John N. Robinson | Perforate electrodiffusion pump |
US7160258B2 (en) * | 2001-06-26 | 2007-01-09 | Entrack, Inc. | Capsule and method for treating or diagnosing the intestinal tract |
RU2203697C2 (en) * | 2001-08-14 | 2003-05-10 | Государственное учреждение системы высшего и послевузовского профессионального образования "Сибирский государственный медицинский университет" | Device for performing organ and tissue electrostimulation |
US20030125788A1 (en) * | 2001-11-09 | 2003-07-03 | Long Gary L. | Self-propelled, intraluminal device with electrode configuration and method of use |
US20030093031A1 (en) * | 2001-11-09 | 2003-05-15 | Long Gary L. | Self-propelled, intraluminal device with medical agent applicator and method of use |
-
2004
- 2004-01-29 AU AU2004208580A patent/AU2004208580A1/en not_active Abandoned
- 2004-01-29 CN CNA2004800085220A patent/CN1774239A/en active Pending
- 2004-01-29 RU RU2005127045/14A patent/RU2334506C2/en not_active IP Right Cessation
- 2004-01-29 EP EP04706261A patent/EP1594477A4/en not_active Withdrawn
- 2004-01-29 CA CA002514392A patent/CA2514392A1/en not_active Abandoned
- 2004-01-29 WO PCT/IL2004/000093 patent/WO2004066903A2/en active Application Filing
- 2004-01-29 KR KR1020057014043A patent/KR20050098277A/en not_active Application Discontinuation
- 2004-01-29 US US10/767,663 patent/US20040253304A1/en not_active Abandoned
- 2004-01-29 JP JP2006502626A patent/JP2006517827A/en active Pending
Non-Patent Citations (1)
Title |
---|
See references of EP1594477A4 * |
Cited By (147)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7512442B2 (en) | 2000-12-11 | 2009-03-31 | Metacure N.V. | Acute and chronic electrical signal therapy for obesity |
US9327076B2 (en) | 2004-08-27 | 2016-05-03 | Medimetrics Personalized Drug Delivery | Electronically and remotely controlled pill and system for delivering at least one medicament |
KR101048916B1 (en) | 2004-09-08 | 2011-07-12 | 올림푸스 가부시키가이샤 | Capsule Type Medical Device |
WO2006028281A1 (en) * | 2004-09-08 | 2006-03-16 | Olympus Corporation | Capsule type medical device |
US8257257B2 (en) | 2004-09-08 | 2012-09-04 | Olympus Corporation | Capsule type medical device |
GB2418144A (en) * | 2004-09-17 | 2006-03-22 | Psimedica Ltd | Medical device for delivery of beneficial substance |
WO2006056944A1 (en) * | 2004-11-29 | 2006-06-01 | Koninklijke Philips Electronics N.V. | Electronically controlled pill |
JP2008521794A (en) * | 2004-11-29 | 2008-06-26 | コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ | Electronically controlled tablets and systems having at least one sensor for delivering at least one drug |
US9821158B2 (en) | 2005-02-17 | 2017-11-21 | Metacure Limited | Non-immediate effects of therapy |
US9962107B2 (en) | 2005-04-28 | 2018-05-08 | Proteus Digital Health, Inc. | Communication system with enhanced partial power source and method of manufacturing same |
US9681842B2 (en) | 2005-04-28 | 2017-06-20 | Proteus Digital Health, Inc. | Pharma-informatics system |
US10610128B2 (en) | 2005-04-28 | 2020-04-07 | Proteus Digital Health, Inc. | Pharma-informatics system |
US10542909B2 (en) | 2005-04-28 | 2020-01-28 | Proteus Digital Health, Inc. | Communication system with partial power source |
US10517507B2 (en) | 2005-04-28 | 2019-12-31 | Proteus Digital Health, Inc. | Communication system with enhanced partial power source and method of manufacturing same |
US11476952B2 (en) | 2005-04-28 | 2022-10-18 | Otsuka Pharmaceutical Co., Ltd. | Pharma-informatics system |
US9649066B2 (en) | 2005-04-28 | 2017-05-16 | Proteus Digital Health, Inc. | Communication system with partial power source |
EP1884259A1 (en) * | 2005-05-27 | 2008-02-06 | Olympus Corporation | Device for introduction into subject |
JPWO2006126653A1 (en) * | 2005-05-27 | 2008-12-25 | オリンパス株式会社 | Intra-subject introduction device |
EP1884259A4 (en) * | 2005-05-27 | 2011-03-30 | Olympus Corp | Device for introduction into subject |
JP5148274B2 (en) * | 2005-05-27 | 2013-02-20 | オリンパス株式会社 | Intra-subject introduction device |
US8021357B2 (en) | 2005-05-27 | 2011-09-20 | Olympus Corporation | Body-insertable apparatus |
US8442841B2 (en) | 2005-10-20 | 2013-05-14 | Matacure N.V. | Patient selection method for assisting weight loss |
EP1980290A1 (en) * | 2005-12-16 | 2008-10-15 | Olympus Corporation | Device to be introduced into subject s body and method of jetting liquid drug |
WO2007069696A1 (en) | 2005-12-16 | 2007-06-21 | Olympus Corporation | Device to be introduced into subject’s body and method of jetting liquid drug |
EP1980290A4 (en) * | 2005-12-16 | 2009-12-09 | Olympus Corp | Device to be introduced into subject s body and method of jetting liquid drug |
US8579883B2 (en) | 2005-12-16 | 2013-11-12 | Olympus Corporation | Body-insertable apparatus and medical agent discharge method |
CN101330940B (en) * | 2005-12-16 | 2012-07-11 | 奥林巴斯株式会社 | Device to be introduced into subject's body and method of jetting liquid drug |
WO2007072297A3 (en) * | 2005-12-22 | 2007-09-20 | Koninkl Philips Electronics Nv | Device for controlled release of chemical molecules |
US8062287B2 (en) | 2005-12-22 | 2011-11-22 | Koninklijke Philips Electronics N V | Device for controlled release of chemical molecules |
WO2007072297A2 (en) | 2005-12-22 | 2007-06-28 | Koninklijke Philips Electronics N.V. | Device for controlled release of chemical molecules |
US10369359B2 (en) | 2006-02-11 | 2019-08-06 | Genetronics, Inc. | Device and method for single-needle in vivo electroporation |
NO340500B1 (en) * | 2006-02-11 | 2017-05-02 | Genetronics Inc | Device and method for in vivo single needle electroporation |
EP1981581A2 (en) * | 2006-02-11 | 2008-10-22 | Genetronics, Inc. | Device and method for single-needle in vivo electroporation |
EP1981581A4 (en) * | 2006-02-11 | 2011-05-25 | Genetronics Inc | Device and method for single-needle in vivo electroporation |
US11331479B2 (en) | 2006-02-11 | 2022-05-17 | Inovio Pharmaceuticals, Inc. | Device and method for single-needle in vivo electroporation |
US11928614B2 (en) | 2006-05-02 | 2024-03-12 | Otsuka Pharmaceutical Co., Ltd. | Patient customized therapeutic regimens |
US9227011B2 (en) | 2006-09-29 | 2016-01-05 | MEDIMETRICS Personalized Drug Delivery B.V. | Miniaturized threshold sensor |
WO2008038246A3 (en) * | 2006-09-29 | 2008-10-09 | Koninkl Philips Electronics Nv | Miniaturized threshold sensor |
US11357730B2 (en) | 2006-10-25 | 2022-06-14 | Otsuka Pharmaceutical Co., Ltd. | Controlled activation ingestible identifier |
US10238604B2 (en) | 2006-10-25 | 2019-03-26 | Proteus Digital Health, Inc. | Controlled activation ingestible identifier |
US10441194B2 (en) | 2007-02-01 | 2019-10-15 | Proteus Digital Heal Th, Inc. | Ingestible event marker systems |
US11464423B2 (en) | 2007-02-14 | 2022-10-11 | Otsuka Pharmaceutical Co., Ltd. | In-body power source having high surface area electrode |
US10517506B2 (en) | 2007-05-24 | 2019-12-31 | Proteus Digital Health, Inc. | Low profile antenna for in body device |
US11612321B2 (en) | 2007-11-27 | 2023-03-28 | Otsuka Pharmaceutical Co., Ltd. | Transbody communication systems employing communication channels |
EP2254464B1 (en) * | 2008-02-18 | 2017-01-04 | Medimetrics Personalized Drug Delivery B.V. | Administration of drugs to a patient |
US9067011B2 (en) | 2008-06-19 | 2015-06-30 | MEDIMETRICS Personalized Drug Delivery B.V. | Device for delivery of powder like medication in a humid environment |
US8911425B2 (en) | 2008-07-07 | 2014-12-16 | Medimetrics Personalized Drug Delivery | Electronic pill comprising a medicine reservoir |
WO2010004490A2 (en) | 2008-07-07 | 2010-01-14 | Koninklijke Philips Electronics N.V. | Electronic pill comprising a medicine reservoir |
CN102088955A (en) * | 2008-07-07 | 2011-06-08 | 皇家飞利浦电子股份有限公司 | Electronic pill comprising a medicine reservoir |
CN107049928A (en) * | 2008-07-07 | 2017-08-18 | 皇家飞利浦电子股份有限公司 | Electronic pill including medicine storage |
WO2010004490A3 (en) * | 2008-07-07 | 2010-06-17 | Koninklijke Philips Electronics N.V. | Electronic pill comprising a medicine reservoir |
US11217342B2 (en) | 2008-07-08 | 2022-01-04 | Otsuka Pharmaceutical Co., Ltd. | Ingestible event marker data framework |
US10682071B2 (en) | 2008-07-08 | 2020-06-16 | Proteus Digital Health, Inc. | State characterization based on multi-variate data fusion techniques |
US9603550B2 (en) | 2008-07-08 | 2017-03-28 | Proteus Digital Health, Inc. | State characterization based on multi-variate data fusion techniques |
US9883819B2 (en) | 2009-01-06 | 2018-02-06 | Proteus Digital Health, Inc. | Ingestion-related biofeedback and personalized medical therapy method and system |
US10588544B2 (en) | 2009-04-28 | 2020-03-17 | Proteus Digital Health, Inc. | Highly reliable ingestible event markers and methods for using the same |
WO2011008534A1 (en) * | 2009-06-30 | 2011-01-20 | Boston Scientific Scimed, Inc. | Implantable self-powered biodegradable medical device to treat or prevent reperfusion injury |
US8386031B2 (en) | 2009-06-30 | 2013-02-26 | Boston Scientific Scimed, Inc. | Implantable self-powered biodegradable medical device to treat or prevent reperfusion injury |
US9941931B2 (en) | 2009-11-04 | 2018-04-10 | Proteus Digital Health, Inc. | System for supply chain management |
US10305544B2 (en) | 2009-11-04 | 2019-05-28 | Proteus Digital Health, Inc. | System for supply chain management |
US11253686B2 (en) | 2009-12-24 | 2022-02-22 | Rani Therapeutics, Llc | Swallowable drug delivery device and methods of drug delivery |
EP3603624A1 (en) * | 2009-12-24 | 2020-02-05 | Rani Therapeutics, LLC | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11376405B2 (en) | 2009-12-24 | 2022-07-05 | Rani Therapeutics, Llc | Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US11338118B2 (en) | 2009-12-24 | 2022-05-24 | Rani Therapeutics, Llc | Swallowable drug delivery device and methods of drug delivery |
US10987499B2 (en) | 2009-12-24 | 2021-04-27 | Rani Therapeutics, Llc | Swallowable drug delivery device and method of delivery |
EP2544668B1 (en) * | 2009-12-24 | 2019-07-10 | Rani Therapeutics, LLC | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8934975B2 (en) | 2010-02-01 | 2015-01-13 | Metacure Limited | Gastrointestinal electrical therapy |
US10207093B2 (en) | 2010-04-07 | 2019-02-19 | Proteus Digital Health, Inc. | Miniature ingestible device |
US11173290B2 (en) | 2010-04-07 | 2021-11-16 | Otsuka Pharmaceutical Co., Ltd. | Miniature ingestible device |
US10529044B2 (en) | 2010-05-19 | 2020-01-07 | Proteus Digital Health, Inc. | Tracking and delivery confirmation of pharmaceutical products |
US11504511B2 (en) | 2010-11-22 | 2022-11-22 | Otsuka Pharmaceutical Co., Ltd. | Ingestible device with pharmaceutical product |
US11684761B2 (en) | 2010-12-23 | 2023-06-27 | Rani Therapeutics, Llc | Preparation comprising exanatide for delivery into a lumen of the intestinal tract |
US10639272B2 (en) | 2010-12-23 | 2020-05-05 | Rani Therapeutics, Llc | Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US10980749B2 (en) | 2010-12-23 | 2021-04-20 | Rani Therapeutics, Llc | Therapeutic preparation comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11844867B2 (en) | 2010-12-23 | 2023-12-19 | Rani Therapeutics, Llc | Method of delivering insulin into a lumen of the intestinal tract using a swallowable drug delivery device |
US10967050B2 (en) | 2010-12-23 | 2021-04-06 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11555068B2 (en) | 2010-12-23 | 2023-01-17 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10953077B2 (en) | 2010-12-23 | 2021-03-23 | Rani Therapeutics, Llc | Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device |
US11638690B2 (en) | 2010-12-23 | 2023-05-02 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11654182B2 (en) | 2010-12-23 | 2023-05-23 | Rani Therapeutics, Llc | Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device |
US10926073B2 (en) | 2010-12-23 | 2021-02-23 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11771879B2 (en) | 2010-12-23 | 2023-10-03 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11806504B2 (en) | 2010-12-23 | 2023-11-07 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
US11813314B2 (en) | 2010-12-23 | 2023-11-14 | Rani Therapeutics, Llc | Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device |
US10632251B2 (en) | 2010-12-23 | 2020-04-28 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
US11304895B2 (en) | 2010-12-23 | 2022-04-19 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11419812B2 (en) | 2010-12-23 | 2022-08-23 | Rani Therapeutics, Llc | Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US10888517B2 (en) | 2010-12-23 | 2021-01-12 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11814427B2 (en) | 2010-12-23 | 2023-11-14 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10874840B2 (en) | 2010-12-23 | 2020-12-29 | Rani Therapeutics, Llc | Preparation comprising exanatide for delivery into a lumen of the intestinal tract |
US10752681B2 (en) | 2010-12-23 | 2020-08-25 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11229684B2 (en) | 2010-12-23 | 2022-01-25 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10864254B2 (en) | 2010-12-23 | 2020-12-15 | Rani Therapeutics, Llc | Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device |
US9756874B2 (en) | 2011-07-11 | 2017-09-12 | Proteus Digital Health, Inc. | Masticable ingestible product and communication system therefor |
US11229378B2 (en) | 2011-07-11 | 2022-01-25 | Otsuka Pharmaceutical Co., Ltd. | Communication system with enhanced partial power source and method of manufacturing same |
US10223905B2 (en) | 2011-07-21 | 2019-03-05 | Proteus Digital Health, Inc. | Mobile device and system for detection and communication of information received from an ingestible device |
US9597179B2 (en) | 2011-07-25 | 2017-03-21 | Rainbow Medical Ltd. | Sinus stent |
US11149123B2 (en) | 2013-01-29 | 2021-10-19 | Otsuka Pharmaceutical Co., Ltd. | Highly-swellable polymeric films and compositions comprising the same |
US11744481B2 (en) | 2013-03-15 | 2023-09-05 | Otsuka Pharmaceutical Co., Ltd. | System, apparatus and methods for data collection and assessing outcomes |
US10175376B2 (en) | 2013-03-15 | 2019-01-08 | Proteus Digital Health, Inc. | Metal detector apparatus, system, and method |
US9796576B2 (en) | 2013-08-30 | 2017-10-24 | Proteus Digital Health, Inc. | Container with electronically controlled interlock |
US10421658B2 (en) | 2013-08-30 | 2019-09-24 | Proteus Digital Health, Inc. | Container with electronically controlled interlock |
CN105916541A (en) * | 2013-09-26 | 2016-08-31 | 医学量度个性化药物输送有限公司 | Delivery capsule with threshold release |
WO2015059569A1 (en) * | 2013-09-26 | 2015-04-30 | Medimetrics Personalized Drug Delivery, B.V. | Delivery capsule with threshold release |
CN111097097A (en) * | 2013-09-26 | 2020-05-05 | 宝珍那提公司 | Delivery capsule with threshold release means |
EP3750590A1 (en) * | 2013-09-26 | 2020-12-16 | Progenity Inc. | Delivery capsule with threshold release |
US10084880B2 (en) | 2013-11-04 | 2018-09-25 | Proteus Digital Health, Inc. | Social media networking based on physiologic information |
US11950615B2 (en) | 2014-01-21 | 2024-04-09 | Otsuka Pharmaceutical Co., Ltd. | Masticable ingestible product and communication system therefor |
US10398161B2 (en) | 2014-01-21 | 2019-09-03 | Proteus Digital Heal Th, Inc. | Masticable ingestible product and communication system therefor |
US9492396B2 (en) | 2014-07-15 | 2016-11-15 | Yossi Gross | Enhanced drug delivery pill |
US11051543B2 (en) | 2015-07-21 | 2021-07-06 | Otsuka Pharmaceutical Co. Ltd. | Alginate on adhesive bilayer laminate film |
US11129981B2 (en) | 2015-12-29 | 2021-09-28 | Rainbow Medical Ltd. | Disc therapy |
US9770591B2 (en) | 2015-12-29 | 2017-09-26 | Rainbow Medical Ltd. | Disc therapy |
US10518085B2 (en) | 2015-12-29 | 2019-12-31 | Rainbow Medical Ltd. | Disc therapy |
US10797758B2 (en) | 2016-07-22 | 2020-10-06 | Proteus Digital Health, Inc. | Electromagnetic sensing and detection of ingestible event markers |
US10187121B2 (en) | 2016-07-22 | 2019-01-22 | Proteus Digital Health, Inc. | Electromagnetic sensing and detection of ingestible event markers |
IL297016B1 (en) * | 2016-09-09 | 2023-09-01 | Biora Therapeutics Inc | Electromechanical ingestible device for delivery of a dispensable substance |
US11793420B2 (en) | 2016-09-09 | 2023-10-24 | Biora Therapeutics, Inc. | Ingestible device for delivery of a dispensable substance |
EP4091538A1 (en) * | 2016-09-09 | 2022-11-23 | Biora Therapeutics, Inc. | Electromechanical ingestible device for delivery of a dispensable substance |
US11097098B2 (en) | 2016-09-13 | 2021-08-24 | Rainbow Medical Ltd. | Disc therapy |
US9950156B2 (en) | 2016-09-13 | 2018-04-24 | Rainbow Medical Ltd. | Disc therapy |
US11253700B2 (en) | 2016-09-13 | 2022-02-22 | Rainbow Medical Ltd. | Electrode for disc therapy |
US11793419B2 (en) | 2016-10-26 | 2023-10-24 | Otsuka Pharmaceutical Co., Ltd. | Methods for manufacturing capsules with ingestible event markers |
US11529071B2 (en) | 2016-10-26 | 2022-12-20 | Otsuka Pharmaceutical Co., Ltd. | Methods for manufacturing capsules with ingestible event markers |
US11597762B2 (en) | 2016-12-14 | 2023-03-07 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with an IL-12/IL-23 inhibitor released using an ingestible device |
WO2018112245A1 (en) * | 2016-12-14 | 2018-06-21 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with a jak inhibitor and devices |
WO2018112264A1 (en) * | 2016-12-14 | 2018-06-21 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with a chemokine/chemokine receptor inhibitor |
WO2018112215A1 (en) * | 2016-12-14 | 2018-06-21 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with an integrin inhibitor |
US10980739B2 (en) | 2016-12-14 | 2021-04-20 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a chemokine/chemokine receptor inhibitor |
US11033490B2 (en) | 2016-12-14 | 2021-06-15 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a JAK inhibitor and devices |
US11596670B2 (en) | 2017-03-30 | 2023-03-07 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with IL-10 or an IL-10 agonist |
WO2018183931A1 (en) * | 2017-03-30 | 2018-10-04 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with il-10 or an il-10 agonist |
WO2018183934A1 (en) * | 2017-03-30 | 2018-10-04 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with a chst15 inhibitor |
WO2019036382A1 (en) * | 2017-08-15 | 2019-02-21 | Progenity Inc. | Treatment of inflammatory disease using ingestible device to release immune modulator |
WO2019118778A1 (en) * | 2017-12-14 | 2019-06-20 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a s1p modulator |
US11241562B2 (en) | 2018-03-13 | 2022-02-08 | Progenity, Inc. | Ingestible device with relatively large payload volume |
WO2019178071A1 (en) * | 2018-03-13 | 2019-09-19 | Progenity, Inc. | Ingestible device with relatively large payload volume |
WO2019246312A1 (en) * | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immunomodulator |
WO2019246317A1 (en) * | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease or condition in a tissue originating from the endoderm |
WO2019246313A1 (en) * | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a tnf inhibitor |
WO2019246273A1 (en) * | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a jak or other kinase inhibitor |
US10675248B2 (en) | 2018-08-14 | 2020-06-09 | Alma Therapeutics Ltd. | Expandable pill |
WO2020106704A3 (en) * | 2018-11-19 | 2020-07-02 | Progenity, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
US11439802B2 (en) | 2018-11-19 | 2022-09-13 | Biora Therapeutics, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
US11007356B2 (en) | 2018-11-19 | 2021-05-18 | Progenity, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
US11123197B2 (en) | 2019-09-03 | 2021-09-21 | Rainbow Medical Ltd. | Hydropneumatic artificial intervertebral disc |
WO2022069604A1 (en) * | 2020-09-30 | 2022-04-07 | Novo Nordisk A/S | Lumen insertable capsule |
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WO2004066903A3 (en) | 2005-05-12 |
US20040253304A1 (en) | 2004-12-16 |
KR20050098277A (en) | 2005-10-11 |
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AU2004208580A1 (en) | 2004-08-12 |
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