WO2020257017A1 - Dispositif ingérable doté d'un composant capable de résider dans le tractus gastro-intestinal - Google Patents

Dispositif ingérable doté d'un composant capable de résider dans le tractus gastro-intestinal Download PDF

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Publication number
WO2020257017A1
WO2020257017A1 PCT/US2020/036920 US2020036920W WO2020257017A1 WO 2020257017 A1 WO2020257017 A1 WO 2020257017A1 US 2020036920 W US2020036920 W US 2020036920W WO 2020257017 A1 WO2020257017 A1 WO 2020257017A1
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WIPO (PCT)
Prior art keywords
sls
ingestible device
capsule
tract
biodegradable material
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PCT/US2020/036920
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English (en)
Inventor
Ryan Elliott JONES
Edgar D. Goluch
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Biora Therapeutics Inc
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Progenity Inc
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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6861—Capsules, e.g. for swallowing or implanting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6879—Means for maintaining contact with the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/06—Devices, other than using radiation, for detecting or locating foreign bodies ; Determining position of diagnostic devices within or on the body of the patient
    • A61B5/061—Determining position of a probe within the body employing means separate from the probe, e.g. sensing internal probe position employing impedance electrodes on the surface of the body
    • A61B5/064—Determining position of a probe within the body employing means separate from the probe, e.g. sensing internal probe position employing impedance electrodes on the surface of the body using markers
    • 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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14539—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or 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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or 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
    • A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4222—Evaluating particular parts, e.g. particular organs
    • A61B5/4255—Intestines, colon or appendix
    • 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
    • A61K9/4816—Wall or shell material
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug

Definitions

  • the disclosure relates generally to ingestible devices with a component capable of residing in the gastrointestinal (GI) tract, such as in the intestine, of a subject.
  • a component capable of residing in the gastrointestinal (GI) tract such as in the intestine, of a subject.
  • Such an ingestible device includes a capsule and a stent-like scaffold (“SLS”).
  • the capsule degrades at a desired location in the GI tract, such as the intestine, thereby allowing the SLS to expand and engage the walls of the intestine.
  • the SLS is sufficiently resistant to forces within the GI tract, such as peristaltic forces within the intestine, to allow the SLS to reside within the GI tract (e.g., the intestine) in a relatively stable manner and/or for a relatively long time.
  • the SLS may include one or more functional components as described herein.
  • the disclosure also relates to related components, systems and methods.
  • the GI tract generally provides a diagnostic and therapeutic medium for an individual’s body. However, non-invasive access to the GI tract remains challenging.
  • analytes and/or physiological conditions of the GI tract e.g., to diagnose and/or monitor a disease or a condition.
  • GI tract e.g., the intestine
  • therapeutic agents applied directly within the small intestine may not be contaminated or degraded in the stomach, thereby allowing a higher dose to be delivered at a specific location within the small intestine.
  • sustained release of a therapeutic agent systemically or topically in the intestine over days or weeks may lead to safer or more efficacious pharmacokinetic profiles.
  • a device or mechanism is used to carry the sensor or therapeutic agents to a desired location within the intestine and then automatically perform its function at the desired location.
  • Such a device or mechanism is desirably operated in a safe manner as the device or mechanism needs to enter the human body.
  • This disclosure provides an ingestible device that includes a capsule containing an SLS.
  • the ingestible device includes one or more functional components.
  • a subject ingests the ingestible device.
  • the ingestible device then passes through regions of the GI tract of the subject, eventually reaching a desired location (e.g., the intestine).
  • the capsule which is made of a biodegradable material such as an enteric material, then degrades to an extent that allows the SLS to expand into a shape or geometry that allows it to reside in a relatively stable fashion within the GI tract (e.g., within the intestine).
  • the SLS presses against the walls of the GI tract (e.g., the intestine) to slow transit of the SLS through, for example, the intestine.
  • the SLS may exist within the GI tract (e.g., the intestine) on the order of days, weeks or months (e.g., at least one day, at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least 10 weeks).
  • days, weeks or months e.g., at least one day, at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least 10 weeks.
  • the SLS contains a radiopaque compound, such as bismuth oxychloride, to enhance the ability to image the SLS within the subject.
  • a radiopaque compound such as bismuth oxychloride
  • the SLS may include one or more functional components.
  • a functional component can be supported by (e.g., coated on and/or attach to) the SLS.
  • a functional component may be an integral part of the SLS.
  • a functional component may deliver (e.g., passively and/or actively) one or more therapeutic agents within the GI tract.
  • a functional component can deliver the therapeutic agent(s) locally and/or systemically.
  • the SLS is formed of one or more a biodegradable materials, such as a biodegradable polymer or the like, and the therapeutic agent is contained within the biodegradable material (e.g., by having been extruded with the biodegradable material during formation of the SLS) in a manner that allows a desired release profile of the therapeutic agent.
  • a functional component may help determine one or more conditions within the GI tract.
  • a functional component may include, for example, a thermal sensor, a pH sensor, a pressure sensor, an analyte sensor, or the like.
  • Such functional component may be used for diagnosis, prognosis, and/or monitoring of a patient.
  • the device is designed so that it can be swallowed voluntarily under medical supervision or in a home use environment with instruction provided ahead of subsequent ingestion.
  • Devices are intended for single subject, single use.
  • the disclosure provides an ingestible device that includes: a capsule that includes a first biodegradable material; and an expandable SLS contained within the capsule, wherein the SLS is configured to lodge within the GI tract of a subject.
  • the disclosure provides an ingestible device that includes: a capsule including a first biodegradable material; and an expandable SLS contained within the capsule.
  • the SLS is configured to lodge within the intestine of a subject.
  • the SLS can be configured to expand and lodge within the GI tract when removed from the capsule.
  • the SLS can be pre-tensioned.
  • the capsule can configured to biodegrade to allow release of the SLS.
  • the SLS can include a composite which includes a second biodegradable material and a dispensable substance.
  • the second biodegradable material can include a polymer, such as polydiaxanone.
  • the dispensable substance can include a therapeutic agent.
  • the composite material can further include a radiopaque material, such as a shape memory alloy, e.g., that includes nitinol and/or bismuth oxychloride.
  • the SLS can define a hyperbolic paraboloid.
  • the capsule can provide a restraining force on the SLS and maintains the SLS in a first configuration.
  • the SLS can be configured to adopt a second configuration when the restraining force of the capsule is removed, and the second configuration is different from the first configuration.
  • the capsule can remove the restraining force after the first biodegradable material is degraded.
  • the first biodegradable material can degrade when exposed to the GI tract of the subject, such as when exposed to the intestine of the subject.
  • the first biodegradable material can degrade when exposed to at least one condition selected from the group consisting of a temperature of the GI tract, a pH of the GI tract, a presence of an enzyme in the GI tract, and a time within the GI tract.
  • the ingestible device can further include a functional component.
  • the functional component can be an integral component of the SLS.
  • the functional component can include a dispensable substance.
  • the dispensable substance can include a therapeutic agent.
  • the therapeutic agent can include at least one member selected form the group consisting of a small molecule compound and a large molecule compound.
  • the functional component can include a sensor.
  • the capsule can be coated on the SLS.
  • the disclosure provides a method that includes: combining a therapeutic agent with a biodegradable material to provide a combination; forming the combination into a filament; and forming the filament into an SLS.
  • the SLS can be in the shape of a hyperbolic paraboloid.
  • the method can further include folding SLS into a smaller configuration smaller, and inserting the SLS into a capsule to provide an ingestible device.
  • the ingestible device can include an ingestible device as described herein.
  • the device is ingestible such that the SLS is self-placing within a desired location in the GI tract in a manner that is non-obstructive and semi permanent.
  • the SLS is drug eluting and can be formulated for dose release of small and large molecules, including peptides and oligonucleotides.
  • the SLS provides long term delivery of the drug.
  • a delivery method can be more convenient for the patient, e.g., because it can reduce the frequency with which the patient should take a pill.
  • the less-frequent dosing means that the drug can be administered in a facility or clinic, enhancing compliance and security, while also reducing the likelihood that the medication will be lost or stolen. This is achieved in a relatively straight-forward and lost cost manner via the ingestible devices disclosed herein.
  • the SLS includes one or more sensors for measuring and/or recording conditions and/or analytes in the GI tract.
  • the conditions may include pH, temperature, and/or pressure.
  • a sensor can determine the presence, absence, and/or amount of one or more analytes in the GI tract.
  • the data collected can be reported telemetrically or retrieved from the SLS, or parts thereof, after the subject passes the device.
  • a particular advantage of the device described herein is that it can be oriented within the intestine, preferably the small intestine (SI), in multiple ways without causing occlusion. That is, whatever the conformation in which the device is released by the dissolvable enteric capsule, it unfolds correctly and lodges in the GI tract.
  • the device need not be inserted in a particular configuration, as are endoscopic stents that must be placed along their long axis.
  • FIG. 1 illustrates an embodiment of an ingestible device.
  • FIG. 2 illustrates an embodiment of an ingestible device.
  • FIG. 3 illustrates an embodiment of an expanded/deployed SLS in the GI tract of a subject.
  • FIGs. 4A-4D illustrate an embodiment of stages of expansion of an SLS in a simulated GI tract.
  • FIGs. 5A-5C illustrate exemplary SLS expanded/deployed orientations.
  • FIG. 6 is a radiographic image from an in vivo implantation study.
  • An ingestible device includes a biodegrdable capsule (e.g., formed of an enteric material) that contains an SLS which is capable of residing in the GI tract (e.g., in the intestine) of a subject.
  • the SLS may include one or more functional components.
  • a functional component may deliver (e.g., passively and/or actively) one or more therapeutic agents within the GI tract.
  • a functional component can deliver the therapeutic agent(s) locally and/or systemically.
  • the SLS is formed of one or more biodegradable materials, such as a biodegradable polymer or the like, and the therapeutic agent is contained within the biodegradable material (e.g., by having been extruded with the biodegradable material during formation of the SLS) in a manner that allows a desired release profile of the therapeutic agent.
  • a functional component is a delivery mechanism for delivering one or more therapeutic agents.
  • Such a drug delivery mechanism may include, for example, one or more needles, spikes and/or cannulas for delivering drug into intestinal tissue.
  • the spikes are made of a biodegradable material and include one or more therapeutic agents.
  • a delivery mechanism may include a pump, such as, for example, a diaphragm pump, for actively pumping drug into intestinal tissue.
  • a delivery mechanisms is an osmotic pump.
  • a functional component may help determine one or more conditions within the GI tract.
  • a functional component may include, for example, a thermal sensor, a pH sensor, a pressure sensor, an analyte sensor, or the like.
  • Such functional component may be used for diagnosis, prognosis, and/or monitoring of a patient.
  • the ingestible device Upon oral ingestion, the ingestible device enters the GI tract.
  • the capsule degrades to an extent that the SLS expands/deploys within the GI tract (e.g., within the intestine).
  • the SLS engages the walls of the GI tract (e.g., the intestine).
  • the one or more functional components can be implemented as desired.
  • the SLS is shaped as a hyperbolic paraboloid (e.g., saddle-shaped). Without wishing to be bound by theory, it is believed that this geometry can helpsthe SLS reside in the GI tract (e.g., the intestine) for an extended period of time compared, for example, to a non-expanding capsule or device.
  • the SLS may exist within the GI tract (e.g., the intestine) on the order of days, weeks or months (e.g., at least one day, at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least 10 weeks).
  • FIG. 1 illustrates an embodiment of an ingestible device 100 including a biodegradable capsule 102 containing an SLS 104.
  • the capsule 102 is depicted as being transparent. More generally, how the capsule 102 can be transparent or non-transparent. In some embodiments, the capsule 102 is colored (e.g., dyed). Further, while the capsule 102 is depicted in FIG. 1 as having the form of a package, alternative embodiments are possible. As an example, the capsule 102 can be coated onto the SLS 104. Typically, the capsule 102 has a generally smooth exterior.
  • capsule 102 is biodegradable.
  • capsule 102 is formed of an enteric material.
  • enteric refers to a material that permits transition through the stomach to the intestine before undergoing substantial biodegradation.
  • an enteric coating reduces (e.g., prevents) drugs from undergoing degradation by gastric fluid and enzymes.
  • an enteric material is selected from mixtures of fats and fatty acids; shellac and shellac derivatives; and cellulose acetate phthalates.
  • Enteric materials can be enteric polymers.“Enteric polymers” means polymers which remain insoluble in the stomach, but dissolve at the higher pH of the intestine (e.g., small intestine or large intestine), and are used to deliver drugs to the intestine.
  • Examples include Colorcon’s Opadry Enteric 91 series Polyvinyl Acetate Phthalate, Opadry Enteric 94 series Methacrylic Acid, Opadry Enteric 95 series Methacrylic Acid, Sureteric PVAP (Polyvinyl Acetate Phthalate), Nutrateric Ethylcellulose Evonik Acryl-EZE (Colorcon & Evonik collaboration - Eudragit L 100-55 Mixture
  • Methacrylic copolymers Evonik’ s Eudragit L 100-55 Methacrylic copolymers, Eudragit L 30 D-55 Methacrylic copolymers (30%), Eudragit L 100 Methacrylic copolymers, Eudragit L 12,5 Methacrylic copolymers (12.5%), Eudragit S 100 Methacrylic copolymers, Eudragit S 12,5 Methacrylic copolymers (12.5%), Eudragit FS 30 D Methacrylic copolymers (30%);
  • an enteric material dissolves in the small intestine and is suitable for small intestine release.
  • Enteric materials suitable for small intestine release are known to one of skill in the art. Examples of such materials include, but are not limited to, cellulose derivatives, e.g., cellulose acetate phthalate,
  • HPMCP hydroxypropylmethylcellulose phthalate
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • RLIOO e.g., HP-55
  • malic acid-propane 1,2-diol polyvinyl acetate phthalate
  • anionic polymers of methacrylic acid and methyl methacrylate hydroxypropylcellulose acetate phthalate
  • polyvinyl acetate phthalate polyvinyl acetate phthalate
  • methacrylate-methacrylic acid copolymers styrol
  • maleic acid copolymers shellac, and others.
  • enteric coating is a water emulsion of ethylacrylate methylacrylic acid copolymer, or hydroxypropyl methyl cellulose acetate succinate (HPMAS). (See, e.g., U.S. Pat. No. 5,591,433).
  • an enteric material dissolves in the large intestine and is suitable for colonic release.
  • Enteric materials suitable for large intestine (e.g., colonic) release are known to one of skill in the art.
  • degradation of the coating is microbially triggered, e.g., the bacteria in the colon enzymatically trigger degradation of the coating (see, e.g., Archana et al, Int. J. Pharm. Sci. Res. (2016) l(5):40-47; and Sethi et al, Int. J. Pharm. Sci. Res. (2012) 3(9):2989-3000).
  • the coating is a pH-dependent polymer that is insoluble at low pH but becomes increasingly soluble as pH increases.
  • the coating is a polymethacrylates with a pH-dependent dissolution threshold of about pH 6.0 to about 7.0.
  • suitable enteric coating materials include, but are not limited to, chitosan, alginates (e.g., as calcium salts), Eudragit® L (e.g., Eudragit® 100), Eudragit® S (e.g., Eudragit® S 100), Eudragit® L (e.g., Eudragit® L-30D), Eudragit® FS (e.g., Eudragit® FS 30D),
  • the enteric coating is a coating described in US 10,226,430; Sethi et al., Int. J. Pharm. Sci. Res. (2012) 3(9):2989-3000; or Archana et al, Int. J. Pharm. Sci. Res. (2016) l(5):40-47, each of which are herein incorporated by reference in their entireties.
  • an enteric material permits transition through the stomach and the small intestine before the dissolvable elements 116 of the device 100 are exposed to the colon are not pH-sensitive materials; rather, the materials for colon-specific drug delivery are biodegradable polymers.
  • the colon-specific degradation of these materials relies on the presence of microorganisms that reside only in the colon, more particularly, biodegradable enzymes produced by these microorganisms.
  • the microorganisms consist mainly of anaerobic bacteria, e.g., Bacteroides, Bifidobacteria, Enterobacteria, Eubacteria, Clostridia, Enterococci, and Ruminococcus, etc.
  • micro floras fulfill their energy needs by fermenting various types of substrates that have been left undigested in the small intestine, e.g., polysaccharides, di- and tri-saccharides, etc. These polymers are stable in the environments of the stomach and small intestine. On reaching the colon, the polymers undergo degradation by the enzyme or break down of the polymer backbone leads to a subsequent reduction in their molecular weight and thereby loss of the mechanical strength (Sethi et al, Int. J. Pharm. Sci. Res. (2012) 3(9):2989-3000; Pharmacology (2001) 53:895-900).
  • the SLS may include an attached functional component (e.g., one or more of sensors, drug-eluting materials, pumps, cannulas, spikes or the like) that is integrally formed.
  • an attached functional component e.g., one or more of sensors, drug-eluting materials, pumps, cannulas, spikes or the like.
  • the ingestible device 100 is generally cylindrical with a longitudinal axis.
  • FIG. 2 illustrates an embodiment of an ingestible device 200 in which the SLS 104 supports a separate functional component 106.
  • the SLS is designed to biodegrade over time, with the resulting portions being passed by the patient. In certain embodiments, the SLS is designed such that it remains intact when passed by the subject.
  • FIG. 3 shows an embodiment of an SLS 104 shaped as a hyperbolic paraboloid (e.g., saddle-shaped) having two opposite upper curves and two opposite lower curves.
  • the upper curves are symmetric with respect to one another, and both bend toward the same direction (e.g., towards one side of a plane intersecting the inflection points of the filament as it forms into curves in sequence).
  • the lower curves are also symmetric with respect to one another, and both bend toward to the opposite direction of the upper curves. Note that the“upper” and“lower” designation in this instance is arbitrary, due to the symmetry of the hyperbolic paraboloid design.
  • multiple parameters are considered for the design of an SLS that expands to a desired shape, lodges in the GI tract, remains in place for the desired time, and is later safely passed by a subject (with or without biodegradation).
  • These parameters include, for example, drug loading capacity, stability during peristalsis (the wave-like constriction and relaxation of the muscles of the GI tract that push the contents forward), ease of packaging and deployment, device complexity, likelihood of actuation, and ability to safely exit the body.
  • the SLS can has a cross-sectional diameter as appropriate.
  • the SLS can have a cross-section diameter between 0.25 and 5 mm.
  • the SLS has a varying cross-sectional thickness.
  • the overall dimensions of the SLS can vary substantially between its folded and expanded configurations.
  • the SLS at its smallest size in its folded configuration, can fit within a size 000 capsule (e.g., less than 22.2 mm in length and 9.55 mm in diameter) or size 00 capsule (e.g., less than 20.25 mm in length and 8.55 mm in diameter).
  • the SLS In its unfolded configuration, can stretch to the width of a hyperbolic paraboloid (e.g., as shown in FIG. 3).
  • a hyperbolic paraboloid e.g., as shown in FIG. 3
  • the human intestine is typically 25 mm to 35 mm in diameter, and the SLS can expand to encompass this measurement.
  • the SLS can simultaneously expand in two main axes, open and apply pressure in multiple directions to stretch across the full diameter of the GI tract (e.g., intestine). In some embodiments, the SLS can expand to a width of three centimeters or more (e.g., at least 3.5 centimeters).
  • a hyperbolic paraboloid design of the SLS has geometric symmetry that can reduce (e.g., minimize) movement when external lateral forces are applied. Ease of molding, packaging, and deployment are other positive characteristics. Such a design can be oriented within the GI tract in multiple ways without causing occlusion. Because the SLS is a hollow hyperbolic paraboloid, intestinal fluid can still pass through the hollow portion (e.g., center portion) of the SLS when it is deployed and lodged.
  • the SLS (or part of the SLS) is formed by a shape memory alloy that returns to an expanded state upon transition to body temperature.
  • the SLS can be formed by a pre-tensioned structure that expands upon degradation of the capsule.
  • the material of the SLS as well as its saddle-shaped configuration can result in a degree of flexibility such that the SLS presses against the wall of the GI tract (e.g., intestinal wall) with a force insufficient to cause tissue damage.
  • the material forming the SLS can degrade, but at a slower rate than the material of the capsule (e.g., enteric material).
  • enteric materials include a methyl acrylate-methacrylic acid copolymers, a cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate, a methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate, zein, ethylcellulose, a medium chain triglyceride, oleic acid, sodium alginate and stearic acid.
  • the expandable SLS can re-collapse or break into pieces after or while in use (e.g., while dispensing the therapeutic agent), and in some cases can completely dissolve over time.
  • Biological variability can affect the transit time of a drug dosage in the GI tract of a patient and between patients. Factors such as age, diseased state, fed-unfed state, pH variation, gut flora composition, magnitude of peristalsis contractions, intestinal folds, length and diameter are common examples of causes for the variability. More importantly, design challenges stem from nonlinear and variable mechanical and physiological response of the GI tract and from a limited
  • the SLS deploys after the pyloric valve, such that the expanded SLS takes up residence in the small intestine.
  • the SLS deploys in the distal small intestine, and the expanded SLS takes up residence at or near the ileum.
  • the expanded SLS may slowly move distally through the ileum due to peristalsis without, for example, passing through the ileocecal valve until it re-collapses or breaks into pieces.
  • the biomechanical response of the GI tract to stress typically includes the coefficient of friction between the mucosa of the bowel and anything swallowed.
  • the capsule is formed of gelatin. In certain embodiments, the capsule is formed of gelatin.
  • the capsule is formed of an enteric material that desirably does not disintegrate in the stomach.
  • the enteric material can be chosen such that it responds to a feature of the GI tract, such as, for example, temperature, pH, or presence of an enzyme.
  • the enteric material dissolves with time.
  • Acryl- EZE ® delayed release enteric material can be used (a ready -to-use enteric material manufactured by Colorcon). Additional examples of enteric materials are discussed above.
  • the ingestible device is self-delivering and self-localizing. After the ingestible device is swallowed by the subject, it moves through the GI tract of the subject, and the enteric capsule actuates delivery of the SLS at the intended location along the GI tract. Degradation of the enteric material allows the SLS folded within the capsule to expand. The stent-like attributes due to the saddle shape of the SLS cause it to mechanically lodge against the walls of the GI tract, while not occluding the GI tract. The device is self-deploying and its expanded shape secures it in place, even with peristalsis, or slows transit of the expanded SLS and does not allow it to pass through the ileocecal valve.
  • a drug embedded in the SLS is delivered over time (e.g., several days or weeks). Routine tests (e.g., blood tests, fecal tests) can confirm that the drug is being delivered correctly during this time period.
  • the SLS includes a functional component including one or more of a bio-composite of polymer, drug, additives, and radiopaque material (e.g., a shape memory alloy), packaged inside the capsule.
  • a bio-composite of polymer e.g., polyethylene glycol dimethacrylate copolymer
  • drug e.g., a drug, additives, and radiopaque material
  • radiopaque material e.g., a shape memory alloy
  • the degradation properties of the polymeric SLS and time to extrusion from the GI tract dictate the eventual drug loading and PK characteristics.
  • the polymer porosity which is tied to the degradation time, can determine the rate at which the drug is delivered.
  • Biodegradable polymer as a carrier for the drug includes consideration of many properties such as melting point, radiopacity, degradation path, FDA precedence, and physical properties such as tensile modulus of elasticity (GPa), tensile strength (MPa), elongation at break (%), and degradation time (months).
  • GPa tensile modulus of elasticity
  • MPa tensile strength
  • elongation at break %
  • degradation time months
  • the molecular weight and crosslinking formulation for the material is the molecular weight and crosslinking formulation for the material.
  • the monomer of the material e.g., caprolactone in PCL
  • PCL defines the general chemical properties; however, the final material sourced from different vendors can vary significantly in molecular weight, extent of cross linking/polymerization, and additives.
  • a comparison of PCL is shown in Table 2, from Purac/Corbion, Lactel/Durect, and Filaments. ca reveals significant variability in physical properties. Samples of PCL were obtained from Lactel/Durect and Filaments Co. for analysis. Further optimization of the polymer material will be required to refine the chemical and physical properties, particularly after the material is compounded with a particular drug.
  • the drug can be compounded into the polymer prior to molding it into a filament. 35-40% mass of the total weight of the polymer can be compounded into the SLS. For example, as the daily dose for tofacitinib is 10-20 mg, a 2-week dosage of 150 mg requires a polymer mass of 375 mg. Since the weight of the saddle prototypes described herein range from 400-430 mg, drug compounding is feasible.
  • the drug or therapeutic agent compounded into the polymer of the SLS can include small molecules and large molecules including biologic drugs, proteins including fusion proteins, peptides including cyclic peptides, cells including stem cells, and nucleic acids such as inhibitory nucleic acids, antisense nucleic acids, siRNA, and ribozymes.
  • Example 1 Deployment test
  • the deployment test was carried out to determine whether the SLS deploys into the correct hyperbolic paraboloid (saddle) geometry and proper orientation upon dissolution of the gelatin capsule 102.
  • a circular ring was made by melting a 5.5 -inch-long (1.75 mm circular cross- sectional area) PCL filament at 55°C.
  • the ring was manually packaged into a 000 capsule.
  • the capsule was then placed inside a 28 mm collagen casing and the casing containing the capsule was then placed in a shallow tube filled with warm water. Water at a temperature of 37°C was filled inside the casing and capsule dissolution and device deployment were captured on video. The experiment was performed at least six times.
  • FIGs. 4A-4D illustrate various stages of the deployment process.
  • the device In FIG. 4A, the device is in its folded configuration. Upon dissolution of the gelatin capsule, the device expanded (the middle panels) until its final configuration where the upper and lower arms are pressed against the inside of the collagen casing (the final panel).
  • This deployment test determined the time for which the encapsulated device retains its shape memory.
  • the device deployed as a saddle for all time points that were tested. An average angle of 100° ⁇ 15° was observed.
  • peristaltic motion on devices was examined by simulating each concept, as modeled in 3D software, housed inside of an intestinal tract, approximated as a flexible sheath, and subjected to peristalsis, modeled as the propagation of annular contracting waveforms by means of displacement control functions on the sheath elements. Through an iterative process, the model was refined and improved to approximate the observations made on comparable benchtop studies.
  • FIGS. 5A-C shows exemplary model results.
  • FIG. 5A shows a coil geometry. As can be seen, the coil was determined to undesirably compress or bunch at low friction values.
  • FIG. 5B shows the saddle-shaped geometry from the side and FIG. 5C from the end (e.g., along the GI axis) in a simulation run prior to fabrication of saddle devices.
  • FIG. 5C shows the two ends or arms of the saddle meeting at the center of the tube during compression.
  • the results informed the fabrication of the actual devices, which were made shorter than what was tested in simulation.
  • the contact points move from the sides of the device to the ends, alleviating the excessive compression of the device under compression from the GI.
  • An immobilization test in vitro was carried out to determine the distance that the device will travel during its time in the GI.
  • a 23-28 mm diameter collagen casing was filled with water at 37°C and cushioned on the outside by water to simulate the GI.
  • a mechanical peristalsis simulator was displaced across the length of the collagen casing producing a‘Pac-man’ pattern of contractions.
  • the polymer (polydiaxanone) articles were wrapped with 0.002” radiopaque tungsten wire in two places, which were reinforced with epoxy, to enable X-ray or fluoroscopy-based monitoring of the device location during the study.
  • the test article formulations did not have any active ingredients.
  • These test articles were delivered encapsulated in 000 enterically coated gelatin capsules that were coated with petroleum jelly to make the capsules easier to position inside the small intestine.
  • the nitinol and polydiaxanone had the same geometry and stiffness, with the only differentiator being that the polydiaxanone device was designed to soften after 6-8 weeks so that it can be excreted.
  • a 3D printed PTFE inert capsule having the dimensions of a 000 capsule was used as a control.
  • the control capsule had 0.002” tungsten wire sealed inside and was expected to pass through the intestine during peristalsis.
  • radiographic images were taken for up to 11 consecutive days to track the movement of the test devices along the gastrointestinal tract of each study animal. Additionally, feces from each study animal was collected daily to ensure that both the test devices and positive controls could be retrieved in a timely manner once they had been passed.
  • Radiographic (fluoroscopy, C-Arm) images were taken post-operatively on Study Day 1. Due to anesthetic complications, only a lateral view was taken for study animal 1502 post-operatively. Both ventral dorsal and lateral views were taken for study animal 1501 post-operatively. As shown in the example radiographic image of FIG. 6, all devices were visible in the images.
  • test device in animal 1501 was still visible in images taken on Day 8. The reason was thought to be the fact that liquid diet had been given in an effort to slow the transit through the GI of the devices. Feed was changed to standard solid diet and the study was extended for animal 1501 until Day 11 (radiographic images were taken once a day for Study Days 9-11). On Day 11, animal 1501’s test device could not be visualized in the morning fluoroscopy imaging; the test device was found and recovered from the animal’s feces immediately after fluoroscopy imaging that morning. Since all positive controls and test devices had been retrieved from study animal feces by Study Day 11, no additional radiographic images were taken after this time.
  • Gross necropsy with an emphasis on the small intestine and tissue surrounding the implantation site was performed on both study animals by a veterinary surgeon on Study Day 14.
  • Gross lesions (partial strangulation of jejunum secondary to adhesion formation at the enterotomy site) were found in the small intestine of study animal 1501. The partial strangulation of a 60 cm distal segment of jejunum resulted in poor motility and ingesta accumulation with resultant enlargement and thickening of the mucosa. The veterinarian performing the necropsy felt it was unlikely these lesions were associated with the implant.
  • Gross necropsy of study animal 1502 yielded no significant findings.
  • both test devices remain in the pig gastrointestinal tract for up to 8 days with no significant clinical observations or complications resultant of their surgical implantation.
  • the positive controls were passed prior to the test devices, which may suggest that the geometric shape of the test devices allows them to move more slowly through the gastrointestinal tract despite forward propulsive movements imposed on them by peristalsis.
  • the polymer test device was passed 3 days earlier than the nitinol test device, which suggests that the nitinol prototype may be a strong candidate for future study if an ideal timeframe of 14-28 days for continuous slow drug release is desired.
  • the SLS can also include a mechanism for being localizing in the GI tract.
  • a mechanism for being localizing in the GI tract is disclosed, for example, in published U.S. Patent Applications U.S. 2018-0279908 and U.S. US 2017-0296092 Al, each of which describes ingestible device localization systems and methods.
  • the mechanism for localizing the SLS is separate from the SLS and does not reside in the GI tract after the SLS deploys.
  • an SLS can include a mechanism for recording and/or transmitting data.

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Abstract

L'invention concerne un dispositif ingérable qui comprend une capsule contenant un SLS. La capsule se dégrade à un emplacement souhaité dans le tractus gastro-intestinal, tel que l'intestin, ce qui permet au SLS de se dilater et d'entrer en prise avec les parois de l'intestin. Lors d'une telle expansion/mise en prise, le SLS est suffisamment résistant à des forces présentes à l'intérieur du tractus gastro-intestinal, telles que des forces péristaltiques présentes à l'intérieur de l'intestin, pour résider à l'intérieur du tractus gastro-intestinal de manière relativement stable et/ou pendant une durée relativement longue. Le SLS peut comprendre un ou plusieurs composants fonctionnels tels que décrits ici. L'invention concerne également des composants, des systèmes et des procédés apparentés.
PCT/US2020/036920 2019-06-18 2020-06-10 Dispositif ingérable doté d'un composant capable de résider dans le tractus gastro-intestinal Ceased WO2020257017A1 (fr)

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