WO2017004623A1 - Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device - Google Patents

Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device Download PDF

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Publication number
WO2017004623A1
WO2017004623A1 PCT/US2016/041013 US2016041013W WO2017004623A1 WO 2017004623 A1 WO2017004623 A1 WO 2017004623A1 US 2016041013 W US2016041013 W US 2016041013W WO 2017004623 A1 WO2017004623 A1 WO 2017004623A1
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WO
WIPO (PCT)
Prior art keywords
preparation
patient
tissue penetrating
penetrating member
capsule
Prior art date
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PCT/US2016/041013
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English (en)
French (fr)
Inventor
Mir Imran
Original Assignee
Rani Therapeutics, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Rani Therapeutics, Llc filed Critical Rani Therapeutics, Llc
Priority to CN201680050621.8A priority Critical patent/CN108055826A/zh
Priority to CA2993215A priority patent/CA2993215C/en
Priority to EP16818960.3A priority patent/EP3316872A4/de
Priority to AU2016287843A priority patent/AU2016287843B2/en
Priority to JP2017567700A priority patent/JP2018519313A/ja
Publication of WO2017004623A1 publication Critical patent/WO2017004623A1/en

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2235—Secretins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Embodiments of the invention relate to swallowable drug delivery devices. More specifically, embodiments of the invention relate to swallowable drug delivery devices for delivering drugs to the small intestine.
  • Embodiments of the invention provide devices, systems, kits and methods for delivering drugs and other therapeutic agents to various locations in the body. Many embodiments provide a swallowable device for delivering drugs and other therapeutic agents within the Gastrointestinal (GI) tract. Particular embodiments provide a swallowable device such as a capsule for delivering drugs and other therapeutic agents into the wall of the small intestine or other GI organ wall. Embodiments of the invention are particularly useful for the delivery of drugs and other therapeutic agents which are poorly absorbed, poorly tolerated and/or degraded within the GI tract. Further, embodiments of the invention can be used to deliver drugs which were previously only capable of or preferably delivered by intravenous or other form of parenteral administration including various non-vascular injected forms of administration such as intramuscular or subcutaneous injection.
  • the invention provides a therapeutic agent preparation for delivery into a wall of the intestinal tract, where the preparation comprises a therapeutically effective dose of at least one therapeutic agent.
  • the preparation has a shape and material consistency to be contained in a swallowable capsule or other swallowable device and delivered from the capsule into the intestinal wall to release the dose of therapeutic agent from within the intestinal wall.
  • the invention provides a therapeutic agent preparation for delivery into a wall of the intestinal tract such as the wall of the small intestine, where the preparation comprises a therapeutically effective dose of at least one therapeutic agent.
  • the preparation is configured to be contained in a swallowable capsule and operably coupled to an actuator, expandable balloon or other device having a first configuration and a second configuration.
  • the preparation is contained within the capsule in the first configuration and advanced out of the capsule and into the intestinal wall in the second configuration to deliver the therapeutic agent into the intestinal wall.
  • the invention provides a method for delivering a therapeutic agent into the wall of the small intestine comprising swallowing a drug delivery device comprising a capsule, an actuator and an embodiment of the therapeutic agent preparation.
  • the actuator is responsive to a condition in the small intestine such as pH so as to actuate delivery of the therapeutic agent preparation into the wall of the small intestine.
  • the actuator can comprise a release element or coating on the capsule which is degraded by a selected pH in the small intestine.
  • the element or coating initiates delivery of the therapeutic agent preparation by one or more delivery means such as the by expansion of one or more balloons that are operably coupled to tissue penetrating members that contain the therapeutic agent preparation and are configured to penetrate and be advanced into the intestinal wall upon expansion of the balloon. Once the tissue penetrating members are in the intestinal wall, they degrade to release the therapeutic agent into the bloodstream. Because the therapeutic agent preparation is delivered directly into the wall of the small intestine, the time period (described herein as C max ) for achieving the maximum concentration of the therapeutic agent in the bloodstream or other location in the body is shorter than a corresponding time period for achieving such a maximum concentration when the therapeutic agent is non-vascularly injected into the body such as by intramuscular or subcutaneous injection. In various embodiments, the time period for achieving C max by insertion of the therapeutic preparation into the intestinal wall using one or more
  • embodiments of the invention can be 80%, 50%, 30%), 20 or even 10%> of the time period for achieving a C max through the use of a non-vascular injection of the therapeutic agent.
  • embodiments of the invention can be greater than a C max achieved by taking a convention oral form of the therapeutic agent (e.g., a pill) where the therapeutic agent is not inserted into the intestinal wall.
  • a convention oral form of the therapeutic agent e.g., a pill
  • the C ma x achieved by insertion of the therapeutic preparation into the intestinal wall using one or more embodiments of the invention can be 5, 10, 20, 30, 40, 50, 60, 70, 80 or even a 100 times greater than when the therapeutic agent is delivered in a pill or other oral form.
  • the composition can be configured to produce a long-term release of therapeutic agent with a selectable t1 ⁇ 2, that is the time period required for the concentration of the therapeutic agent in the bloodstream or other location in the body to reach half its original Cmax value after having reached C max .
  • the selectable t1 ⁇ 2 may be 6, or 9, or 12, or 15 or 18, or 24 hours.
  • the invention provides a swallowable device for delivering a drug or other therapeutic agent preparation into the wall of the small or large intestine or other organ of the gastro-intestinal tract organ.
  • the devise comprises a capsule sized to be swallowed and pass through the gastro-intestinal tract, a deployable aligner positioned within the capsule for aligning a longitudinal axis of the capsule with the a longitudinal axis of the small intestine, a delivery mechanism for delivering the therapeutic agent into the intestinal wall and a deployment member for deploying at least one of the aligner or the delivery mechanism.
  • the capsule wall is degradable by contact with liquids in the GI tract but also may include an outer coating or layer which only degrades in the higher pH's found in the small intestine, and serves to protect the underlying capsule wall from degradation within the stomach before the capsule reaches the small intestine at which point the drug delivery is initiated by degradation of the coating.
  • an outer coating or layer which only degrades in the higher pH's found in the small intestine, and serves to protect the underlying capsule wall from degradation within the stomach before the capsule reaches the small intestine at which point the drug delivery is initiated by degradation of the coating.
  • Suitable outer coatings can include various enteric coatings such as various co-polymers of Methacrylic Acid and Ethyl Acrylate.
  • tissue penetrating member will typically comprise a hollow needle or other like structure and will have a lumen and a tissue penetrating end for penetrating a selectable depth into the intestinal wall.
  • the device can include a second and a third tissue penetrating member with additional numbers contemplated.
  • Each tissue penetrating member can include the same or a different drug.
  • the tissue penetrating members can be symmetrically distributed around the perimeter of the capsule so as to anchor the capsule onto the intestinal wall during delivery of drug.
  • all or a portion of the tissue penetrating member can be fabricated from the drug preparation itself.
  • the drug preparation can have a needle or dart-like structure (with or without barbs) configured to penetrate and be retained in the intestinal wall.
  • the tissue penetrating member can be fabricated from various biodegradable materials (e.g., PGLA, Polyethylene, maltose or other sugar) so as to degrade within the small intestine and thus provide a fail-safe mechanism for detaching the tissue penetrating member from the intestinal wall should this component become retained in the intestinal wall.
  • biodegradable materials e.g., PGLA, Polyethylene, maltose or other sugar
  • selectable portions of the capsule can be fabricated from such biodegradable materials so as to allow the entire device to controllably degrade into smaller pieces. Such embodiments facilitate passage and excretion of the devices through GI tract.
  • the capsule can include seams of biodegradable material which controllably degrade to break the capsule into pieces of a selectable size and shape to facilitate passage through the GI tract.
  • the seams can be pre- stressed, perforated or otherwise treated to accelerate degradation.
  • the concept of using biodegradable seams to produce controlled degradation of a swallowable device in the GI tract can also be applied to other swallowable devices such as swallowable cameras to facilitate passage through the GI tract and reduce the likelihood of a device becoming stuck in the GI tract.
  • the delivery member is configured to advance the drug from the capsule through the tissue penetrating member lumen and into the intestinal wall. Typically, at least a portion of the delivery member is advanceable within the tissue penetrating member lumen.
  • the delivery member can have a piston or like structure sized to fit within the delivery member lumen.
  • the distal end of the delivery member (the end which is advanced into tissue) can have a plunger element which advances the drug within tissue penetrating member lumen and also forms a seal with the lumen.
  • the plunger element can be integral or attached to the delivery member.
  • the delivery member is configured to travel a fixed distance within the needle lumen so as to deliver a fixed or metered dose of drug into the intestinal wall.
  • the diameter of the delivery member e.g., the diameter can be distally tapered
  • the diameter of the tissue penetrating member which can be narrowed at its distal end
  • the delivery member is adapted to advance the dart out of the capsule and into tissue.
  • the delivery member and tissue penetrating member can be configured for the delivery of liquid, semi-liquid or solid forms of drug or all three.
  • Solid forms of drug can include both powder or pellet.
  • Semi liquid can include a slurry or paste.
  • the drug can be contained within a cavity of the capsule, or in the case of the liquid or semi-liquid, within an enclosed reservoir.
  • the capsule can include a first second, or a third drug (or more).
  • Such drugs can be contained within the tissue penetrating member lumen (in the case of solids or powder) or in separate reservoirs within the capsule body.
  • the actuating mechanism can be coupled to at least one of the tissue penetrating member or the delivery member.
  • the actuating mechanism is configured to advance the tissue penetrating member a selectable distance into the intestinal wall as well as advance the delivery member to deliver the drug and then withdraw the tissue penetrating member from the intestinal wall.
  • the actuating mechanism can comprise a preloaded spring mechanism which is configured to be released by the release element.
  • Suitable springs can include both coil (including conical shaped springs) and leaf springs with other spring structures also contemplated.
  • the spring can be cone shaped to reduce the length of the spring in the compressed state even to the point where the compressed length of the spring is about the thickness of several coils (e.g., two or three) or only one coil.
  • the actuating mechanism comprises a spring, a first motion converter, and a second motion converter and a track member.
  • the release element is coupled to the spring to retain the spring in a compressed state such that degradation of the release element releases the spring.
  • the first motion converter is configured to convert motion of the spring to advance and withdraw the tissue penetrating element in and out of tissue.
  • the second motion converter is configured to convert motion of the spring to advance the delivery member into the tissue penetrating member lumen.
  • the motion converters are pushed by the spring and ride along a rod or other track member which serves to guide the path of the converters. They engage the tissue penetrating member and/or delivery member (directly or indirectly) to produce the desired motion.
  • the motion converters can have a wedge, trapezoidal or curved shape with other shapes also contemplated.
  • the first motion converter can have a trapezoidal shape and include a slot which engages a pin on the tissue penetrating member that rides in the slot.
  • the slot can have a trapezoidal shape that mirrors or otherwise corresponds to the overall shape of the converter and serves to push the tissue penetrating member during the upslope portion of the trapezoid and then pull it back during the down slope portion.
  • one or both of the motion converters can comprise a cam or cam like device which is turned by the spring and engages the tissue penetrating and/or delivery member.
  • the actuating mechanism can also comprise an electromechanical device/mechanism such as a solenoid or a piezoelectric device.
  • the piezoelectric device can comprise a shaped piezoelectric element which has a non-deployed and deployed state. This element can be configured to go into the deployed state upon the application of a voltage and then return to the non-deployed state upon the removal of the voltage. This and related embodiments allow for a reciprocating motion of the actuating mechanism so as to both advance the tissue penetrating member and then withdraw it.
  • the release element is coupled to at least one of the actuating mechanism or a spring coupled to the actuating mechanism.
  • the release element is coupled to a spring positioned within the capsule so as to retain the spring in a compressed state. Degradation of the release element releases the spring to actuate the actuation mechanism.
  • the release element comprises a material configured to degrade upon exposure to chemical conditions in the small or large intestine such as pH.
  • the release element is configured to degrade upon exposure to a selected pH in the small intestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 8.0 or greater.
  • it can also be configured to degrade in response to other conditions in the small intestine.
  • the release element can be configured to degrade in response to particular chemical conditions in the fluids in the small intestine such as those which occur after ingestion of a meal (e.g., a meal high in fats or proteins).
  • Biodegradation of the release element from one or more conditions in the small intestine can be achieved by selection of the materials for the release element, the amount of cross linking of those materials as well as the thickness and other dimensions of the release elements. Lesser amounts of cross linking and or thinner dimensions can increase the rate of degradation and vice versa.
  • Suitable materials for the release element can comprise biodegradable materials such as various enteric materials which are configured to degrade upon exposure to the higher pH or other condition in the small intestine.
  • the enteric materials can be copolymerized or otherwise mixed with one or more polymers to obtain a number of particular material properties in addition to biodegradation. Such properties can include without limitation stiffness, strength, flexibility and hardness.
  • the release element can comprise a film or plug that fits over or otherwise blocks the guide tube and retains the tissue penetrating member inside the guide tube.
  • the tissue penetrating member is coupled to a spring loaded actuating mechanism such that when the release element is degraded sufficiently, it releases the tissue penetrating member which then springs out of the guide tube to penetrate into the intestinal wall.
  • the release element can be shaped to function as a latch which holds the tissue penetrating element in place.
  • the release element can be located on the exterior or the interior of the capsule. In the interior embodiments, the capsule and guide tubes are configured to allow for the ingress of intestinal fluids into the capsule interior to allow for the degradation of the release element.
  • the actuating mechanism can be actuated by means of a sensor, such as a pH or other chemical sensor which detects the presence of the capsule in the small intestine and sends a signal to the actuating mechanism (or to an electronic controller coupled to the actuating mechanism to actuate the mechanism).
  • a pH sensor can comprise an electrode-based sensor or it can be a mechanically-based sensor such as a polymer which shrinks or expands upon exposure to the pH or other chemical conditions in the small intestine.
  • an expandable/contractable sensor can also comprise the actuating mechanism itself by using the mechanical motion from the expansion or contraction of the sensor.
  • the sensor can comprise a strain gauge or other pressure/force sensor for detecting the number of peristaltic contractions that the capsule is being subject to within a particular location in the intestinal tract.
  • the capsule is desirably sized to be gripped by the small intestine during a peristaltic contraction. Different locations within the GI tract have different number of peristaltic contractions.
  • the small intestine has between 12 to 9 contractions per minute with the frequency decreasing down the length of the intestine.
  • detection of the number of peristaltic contractions can be used to not only determine if the capsule is in the small intestine but the relative location within the intestine as well.
  • the user may externally activate the actuating mechanism to deliver drug by means of RF, magnetic or other wireless signaling means known in the art.
  • the user can use a handheld device (e.g., a hand held RF device) which not only includes signaling means, but also means for informing the user when the device is in the small intestine or other location in the GI tract.
  • a handheld device e.g., a hand held RF device
  • the later embodiment can be implemented by including an RF transmitter on the swallowable device to signal to the user when the device is in the small intestine or other location (e.g., by signaling an input from the sensor).
  • the same handheld device can also be configured to alter the user when the actuating mechanism has been activated and the selected drug(s) delivered. In this way, the user is provided confirmation that the drug has been delivered. This allows the user to take other appropriate drugs/therapeutic agents as well as make other related decisions (e.g., for diabetics to eat a meal or not and what foods should be eaten).
  • the handheld device can also be configured to send a signal to the swallowable device to over-ride the actuating mechanism and so prevent, delay or accelerate the delivery of drug. In use, such
  • embodiments allow the user to intervene to prevent, delay or accelerate the delivery of drug based upon other symptoms and/or patient actions (e.g., eating a meal, deciding to go to sleep, exercise etc.).
  • the user may also externally activate the actuating mechanism at a selected time period after swallowing the capsule.
  • the time period can be correlated to a typical transit time or range of transit times for food moving through the user's GI tract to a particular location in the tract such as the small intestine.
  • the preparation comprises a therapeutically effective dose of at least one therapeutic agent. It may comprise a solid, liquid or combination of both and can include one or more pharmaceutical excipients.
  • the preparation has a shape and material consistency to be contained in embodiments of the swallowable capsule, delivered from the capsule into the intestinal wall and degrade within the wall to release the dose of therapeutic agent.
  • the preparation may also have a selectable surface area to volume ratio so as enhance or otherwise control the rate of degradation of the preparation in the wall of the small intestine or other body lumen.
  • the preparation can be configured to be coupled to an actuator such as a release element or actuation mechanism which has a first configuration in which the preparation is contained in the capsule and a second configuration in which the preparation is advanced out of the capsule and into the wall of the small intestine.
  • an actuator such as a release element or actuation mechanism which has a first configuration in which the preparation is contained in the capsule and a second configuration in which the preparation is advanced out of the capsule and into the wall of the small intestine.
  • the dose of the drug or other therapeutic agent in the preparation can be titrated downward from that which would be required for conventional oral delivery methods so that potential side effects from the drug can be reduced.
  • the preparation will be shaped and otherwise configured to be contained in the lumen of a tissue penetrating member, such as a hollow needle which is configured to be advanced out of the capsule and into the wall of the small intestine.
  • a tissue penetrating member such as a hollow needle which is configured to be advanced out of the capsule and into the wall of the small intestine.
  • the preparation itself may comprise a tissue penetrating member configured to be advanced into the wall of the small intestine or other lumen in the intestinal tract.
  • Another aspect of the invention provides methods for the delivery of drugs and the therapeutic agents into the walls of the GI tract using embodiments of the swallowable drug delivery devices. Such methods can be used for the delivery of therapeutically effective amounts of a variety of drugs and other therapeutic agents. These include a number of large molecule peptides and proteins which would otherwise require injection due to chemical breakdown in the stomach e.g., growth hormone, parathyroid hormone, insulin, interferons and other like compounds.
  • Suitable drugs and other therapeutic agents which can be delivered by embodiments of invention include various chemotherapeutic agents (e.g., interferon), antibiotics, antivirals, insulin and related compounds, glucagon like peptides (e.g., GLP-1, exenatide), parathyroid hormones, growth hormones (e.g., IFG and other growth factors), anti-seizure agents, immune suppression agents and anti-parasitic agents such as various anti-malarial agents.
  • the dosage of the particular drug can be titrated for the patient's weight, age, condition or other parameter.
  • embodiments of the drug swallowable drug delivery device can be used to deliver a plurality of drugs for the treatment of multiple conditions or for the treatment of a particular condition (e.g., a mixture of protease inhibitors for treatment HIV AIDS).
  • a particular condition e.g., a mixture of protease inhibitors for treatment HIV AIDS.
  • such embodiments allow a patient to forgo the necessity of having to take multiple medications for a particular condition or conditions.
  • they provide a means for facilitating that a regimen of two or more drugs is delivered and absorbed into the small intestine and thus, the blood stream at about the same time. Due to differences in chemical makeup, molecular weight, etc., drugs can be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves.
  • Embodiments of the invention address this issue by injecting the desired drug mixtures at about the same time. This in turn, improves pharmacokinetics and thus, the efficacy of the selected mixture of drugs.
  • the invention provides therapeutic preparations comprising a plurality of glucose regulating compounds, including for example, insulin, GLP-1 and at least a third compound.
  • the third compound being selected to produce a synergistic effect in one or more of blood glucose reduction, blood glucose regulation, appetite control/ suppression or other therapeutic effect of the insulin and GLP-1.
  • Such synergistic effects in turn provide treatment for various conditions associated with diabetes (or other glucose regulating disorder) such as hyperglycemia, insulin resistance or hyperlipidemia.
  • the glucose regulating compounds may include those which lower blood glucose, also known as hypoglycemic compounds, and those which raise blood glucose.
  • They also include those which affect (e.g., reduce) glucose directly, and/or indirectly e.g., by causing the secretion of hormone which subsequently lower glucose levels, agonize or enhance the effect of glucose reducing hormones (as is the case for DDP4 inhibitors with incretins), reduce appetite (as is the case with, peptide YY) or all of the above.
  • the other glucose regulating compound can be selected from the group consisting of glucagon, peptide YY, GIP, metformin, peptide YY, Dipeptidyl peptidase-4 (DPP4), DPP4 inhibitors, sodium/glucose co-transporter 2 (SGLT2) inhibitors along with their analogues and derivatives.
  • the compounds can be contained in and/or formed as an embodiment of the tissue penetrating member that is configured to be advanced from the swallowable capsule configured to be inserted into the intestinal wall as is described herein. Once so inserted into the intestinal wall, the tissue penetrating member degrades to release the glucose regulating compounds into the blood stream as described herein for other therapeutic agents.
  • the tissue penetrating member is configured to concurrently release the plurality of glucose regulating compounds (e.g., by compounding and/or mixing all of the compounds in the same material used to formulate the tissue penetrating member).
  • the concurrent release of the compounds into the wall of the small intestine and, in turn the blood stream serves to promote and enhance the synergistic effects between two or more of the compounds (e.g., increased blood glucose control, appetite suppression, etc.).
  • the tissue penetrating member can be configured such that upon insertion the tissue penetrating member releases the glucose regulating compounds into the blood stream to achieve a C ma x in a shorter time period than a time period to achieve a C ma x for an extravascularly injected dose of at least one of the glucose regulating compounds with improvements in one or more other pharmacokinetic parameters described herein.
  • Another aspect of the invention provides a method for delivering a plurality of glucose regulating compounds to a patient in need thereof, comprising providing a solid therapeutic preparation comprising a plurality of glucose regulating compounds including at least insulin, GLP-1 and a third compound, the third compound configured to interact with the insulin or GLP-1 to enhance a therapeutic effect in the patient.
  • the preparation is shaped as a tissue penetrating member, which is configured to be carried by a swallowable capsule and penetrate and be inserted into an intestinal wall, wherein upon ingestion the capsule advances to the small intestine of the patient.
  • the solid therapeutic preparation is inserted into the wall of the small intestine by an application of mechanical force upon a surface of the tissue penetrating member from an expandable device operably coupled to the tissue penetrating member wherein upon insertion into the intestinal wall.
  • the tissue penetrating member remains to concurrently release the plurality of glucose regulating compounds into the blood stream from the intestinal wall by degradation of the of the tissue penetrating member.
  • the third compound interacts with the insulin or GLP-1 to produce an enhanced therapeutic effect for the patient in one or more of improved glucose control, reduction in blood glucose levels, reduction in period or magnitude of hyperglycemia or hypoglycemia, reduction in glycosylated hemoglobin levels, reduction in insulin resistance, alfa or beta cell preservation or reduction in hyperlipidemia.
  • the third compound can be selected from the group consisting of glucagon, GIP, Peptide YY, metformin, DPP4, DPP4 inhibitors and SGLT inhibitors
  • Fig. la is a lateral viewing showing an embodiment of a swallowable drug delivery device.
  • Fig. lb is a lateral viewing showing an embodiment of a system including a swallowable drug delivery device.
  • Fig. lc is a lateral viewing showing an embodiment of a kit including a swallowable drug delivery device and a set of instructions for use.
  • Fig. Id is a lateral viewing showing an embodiment of a swallowable drug delivery device including a drug reservoir.
  • FIG. 2 is a lateral view illustrating an embodiment of the swallowable drug delivery device having a spring loaded actuation mechanism for advancing tissue penetrating members into tissue.
  • Fig. 5 is a perspective view illustrating engagement of the first and second motion converters with the tissue penetrating member and delivery members.
  • Fig. 6 is a cross sectional view illustrating an embodiment of the swallowable drug delivery device having a single tissue penetrating member and an actuating mechanism for advancing the tissue penetrating member.
  • Fig. 7b is a cross sectional view illustrating deployment of the tissue penetrating members of the embodiment of Fig. 7a to deliver medication to a delivery site and anchor the device in the intestinal wall during delivery.
  • Figs. 8a-8c are side views illustrating positioning of the drug delivery device in the small intestine and deployment of the tissue penetrating members to deliver drug;
  • Fig. 8a shows the device in the small intestine prior to deployment of the tissue penetrating members with the release element in tact;
  • Fig. 8b shows the device in the small intestine with the release element degraded and the tissue penetrating elements deployed;
  • Fig. 8c shows the device in the small intestine with the tissue penetrating elements retracted and the drug delivered.
  • Fig. 9a shows an embodiment of a swallowable drug delivery device including a capsule having bio-degradable seams positioned to produce controlled degradation of the capsule in the GI tract.
  • Fig. 9b shows the embodiment of Fig. 9a after having been degraded in the GI tract into smaller pieces.
  • Fig. 10 shows an embodiment of a capsule having biodegradable seams including pores and/or perforations to accelerate biodegradation of the capsule.
  • Fig. 11 is a lateral viewing illustrating use of an embodiment of a swallowable drug delivery device including transit of device in the GI tract and operation of the device to deliver drug.
  • Figs. 12a and 12b are lateral view illustrating an embodiment of a capsule for the swallowable drug delivery device including a cap and a body coated with pH sensitive biodegradable coatings, Fig. 12a shows the capsule in an unassembled state and Fig. 12b in an assembled state
  • FIGs. 13a and 13b illustrate embodiments of unfolded multi balloon assemblies containing a deployment balloon, an aligner balloon, a delivery balloon and assorted connecting tubes;
  • Fig. 13a shows an embodiment of the assembly for a single dome configuration of the deployment balloon;
  • Fig. 13b shows an embodiment of the assembly for dual dome configuration of the deployment balloon; and.
  • Figs. 13c is a perspective views illustrating embodiments of a nested balloon configuration which can be used for one or more embodiments of the balloons described herein, including the aligner balloon.
  • Figs. 15a-15g are lateral views illustrating a method for folding of the multiple balloon assembly, the folding configuration in each figure applies to both single and dual dome configurations of the deployment balloon, with the exception that Fig. 15c, pertains to a folding step unique to dual dome configurations; and Fig. 15d, pertains to the final folding step unique to dual dome configurations; Fig. 15e, pertains to a folding step unique to single dome configurations; and Figs. 15f and 15g are orthogonal views pertaining to the final folding step unique to single dome configurations.
  • Figs. 16a and 16b are orthogonal views illustrating embodiments of the final folded multi balloon assembly with the attached delivery assembly.
  • Figs. 17a and 17b are orthogonal transparent views illustrating embodiments of the final folded multi balloon assembly inserted into the capsule.
  • Fig. 18b is a bottom view of an embodiment of the tissue penetrating member illustrating placement of the tissue retaining features.
  • Fig. 18c is a side view of an embodiment of the tissue penetrating member having a trocar tip and inverted tapered shaft.
  • Fig. 18d is a side view of an embodiment of the tissue penetrating member having a separate drug containing section.
  • Figs. 18e and 8f are side views showing assembly of an embodiment of a tissue penetrating member having a shaped drug containing section.
  • Fig. 18e shows the tissue penetrating member and shaped drug section prior to assembly; and Fig. 18f after assembly.
  • Fig. 19 provides assorted views of the components and steps used to assemble an embodiment of the delivery assembly.
  • Figs. 20a-20i provides assorted views illustrating a method of operation of swallowabe device to deliver medication to the intestinal wall.
  • Embodiments of the invention provide devices, systems and methods for delivering medications in to various locations in the body.
  • the term "medication” refers to a medicinal preparation in any form which can include drugs or other therapeutic agents as well as one or more pharmaceutical excipients.
  • Many embodiments provide a swallowable device for delivering medication within the GI tract.
  • Particular embodiments provide a swallowable device such as a capsule for delivering medications to the wall of the small intestine or other GI organ.
  • GI tract refers to the esophagus, stomach, small intestine, large intestine and anus
  • “Intestinal tract” refers to the small and large intestine.
  • Various embodiments of the invention can be configured and arranged for delivery of medication into the intestinal tract as well as the entire GI tract.
  • an embodiment of a device 10 for the delivery of medication 100 to a delivery site DS in the intestinal tract comprises a capsule 20 including at least one guide tube 30, one or more tissue penetrating members 40 positioned or otherwise advanceable in the at least one guide tube, a delivery member 50, an actuating mechanism 60 and release element 70.
  • Medication 100 also described herein as preparation 100, typically comprises at least one drug or other therapeutic agent 101 and may include one or more pharmaceutical excipients known in the art.
  • delivery member 50 and mechanism 60 may comprise a means for delivery of medication 100 into a wall of the intestinal tract.
  • Other delivery means contemplated herein include one or more expandable balloons (e.g., delivery balloon 172) or other expandable device/member described herein.
  • Device 10 can be configured for the delivery of liquid, semi-liquid or solid forms of medication 100 or all three.
  • Solid forms of medication/preparation 100 can include both powder or a pellet form.
  • Semi liquid forms can include a slurry or paste.
  • preparation 100 desirably has a shape and material consistency allowing the medication to be advanced out of the device, into the intestinal wall (or other luminal wall in the GI tract) and then degrade in the intestinal wall to release the drug or other therapeutic agent 101.
  • the material consistency can include one or more of the hardness, porosity and solubility of the preparation (in body fluids).
  • the material consistency can be achieved by one or more of the following: i) the compaction force used to make the preparation; ii) the use of one or more pharmaceutical disintegrants known in the art; iii) use of other pharmaceutical excipients; iv) the particle size and distribution of the preparation (e.g., micronized particles); and v) use of micronizing and other particle formation methods known in the art.
  • Suitable shapes for preparation 100 can include cylindrical, cubical, rectangular, conical, spherical,
  • the shape can be selected so as to define a particular surface area and volume of preparation 100 and thus, the ratio between the two.
  • the ratio of surface area to volume can in turn, be used to achieve a selected rate of degradation within the intestinal or other lumen wall within the GI tract. Larger ratios (e.g., larger amounts of surface area per unit volume) can be used to achieve faster rates of degradation and vice versa.
  • the surface area to volume ratio can be in the range of about 1 : 1 to 100: 1, with specific embodiments of 2: 1, 5: 1, 20: 1, 25: 1, 50: 1 and 75: 1.
  • Preparation/medication 100 will typically be pre-packed within a lumen 44 of tissue penetrating members 40, but can also be contained at another location within an interior 24 of capsule 20, or in the case of a liquid or semi-liquid, within an enclosed reservoir 27.
  • the medication can be pre-shaped to fit into the lumen or packed for example, in a powder form.
  • the device 10 will be configured to deliver a single drug 101 as part of medication 100.
  • the device 10 can be configured for delivery of multiple drugs 101 including a first second, or a third drug which can be compounded into a single or multiple medications 100.
  • the medications can be contained in separate tissue penetrating members 40 or within separate compartments or reservoirs 27 within capsule 20.
  • a first dose 102 of medication 100 containing a first drug 101 can be packed into the penetrating member(s) 40 and a second dose 103 of medication 100 (containing the same or a different drug 101) can be coated onto the surface 25 of capsule as is shown in the embodiment of Fig. lb.
  • the drugs 101 in the two doses of medication 102 and 103 can be the same or different. In this way, a bimodal pharmacokinetic release of the same or different drugs can be achieved.
  • the second dose 103 of medication 100 can have an enteric coating 104 to ensure that it is released in the small intestine and achieve a time release of the medication 100 as well.
  • Enteric coating 104 can include one or more enteric coatings described herein or known in the art.
  • a system 11 for delivery of medication 100 into the wall of the small intestine or other location within the GI tract may comprise device 10, containing one or more medications 100 for the treatment of a selected condition or conditions.
  • the system may include a hand held device 13, described herein for communicating with device 10 as is shown in the embodiment of Fig. lb.
  • System 11 may also be configured as a kit 14 including system 11 and a set of instructions for use 15 which are packaged in packaging 12 as is shown in the embodiment of Fig. lc.
  • the instructions can indicate to the patient when to take the device 10 relative to one or more events such as the ingestion of a meal or a physiological measurement such as blood glucose, cholesterol, etc.
  • kit 14 can include multiple devices 10 containing a regimen of medications 100 for a selected period of administration, e.g., a day, week, or multiple weeks depending upon the condition to be treated.
  • Capsule 20 is sized to be swallowed and pass through the intestinal tract. The size can also be adjusted depending upon the amount of drug to be delivered as well as the patient's weight and adult vs. pediatric applications.
  • Capsule 20 includes an interior volume 24 and an outer surface 25 having one or more apertures 26 sized for guide tubes 30.
  • the interior volume can include one or more compartments or reservoirs 27.
  • One or more portions of capsule 20 can be fabricated from various biocompatible polymers known in the art, including various biodegradable polymers which in a preferred embodiment can comprise PGLA (polylactic-co-glycolic acid).
  • capsule 20 can include seams 22 of bio-degradable material so as to controllably degrade into smaller pieces 23 which are more easily passed through the intestinal tract.
  • the capsule can include various radio-opaque or echogenic materials for location of the device using fluoroscopy, ultrasound or other medical imaging modality.
  • tissue penetrating members 40 are positioned within guide tubes 30 which serve to guide and support the advancement of members 40 into tissue such as the wall of the small intestine or other portion of the GI tract.
  • the tissue penetrating members 40 will typically comprise a hollow needle or other like structure and will have a lumen 44 and a tissue penetrating end 45 for penetrating a selectable depth into the intestinal wall IW.
  • Member 40 may also include a pin 41 for engagement with a motion converter 90 described herein.
  • the depth of penetration can be controlled by the length of member 40, the configuration of motion converter 90 described herein as well as the placement of a stop or flange 40s on member 40 which can, in an embodiment, correspond to pin 41 described herein.
  • Medication 100 will typically be delivered into tissue through lumen 44.
  • lumen 44 is pre-packed with the desired medication 100 which is advanced out of the lumen using delivery member 50 or other advancement means (e.g. by means of force applied to a collapsible embodiment of member 40).
  • medication 100 can be advanced into lumen 44 from another location/compartment in capsule 20.
  • all or a portion of the tissue penetrating member 40 can be fabricated from medication 100 itself.
  • the medication can have a needle or dart-like structure (with or without barbs) configured to penetrate and be retained in the intestinal wall, such as the wall of the small intestine.
  • the dart can be sized and shaped depending upon the medication, dose and desired depth of penetration into the intestinal wall.
  • Medication 100 can be formed into darts, pellets or other shapes using various compression molding methods known in the pharmaceutical arts.
  • device 10 can include a second 42 and a third 43 tissue penetrating member 40 as is shown in the embodiments of Figs. 7a and 7b., with additional numbers contemplated.
  • Each tissue penetrating member 40 can be used to deliver the same or a different medication 100.
  • the tissue penetrating members 40 can be substantially symmetrically distributed around the perimeter 21 of capsule 20 so as to anchor the capsule onto the intestinal wall IW during delivery of medications 100.
  • Delivery member 50 is configured to advance medication 100 through the tissue penetrating member lumen 44 and into the intestinal wall IW. Accordingly, at least a portion of the delivery member 50 is advanceable within the tissue penetrating member lumen 44 and thus member 50 has a size and shape (e.g., a piston like shape) configured to fit within the delivery member lumen 44.
  • a size and shape e.g., a piston like shape
  • the distal end 50d of the delivery member (the end which is advanced into tissue) can have a plunger element 51 which advances the medication within the tissue penetrating member lumen 44 and also forms a seal with the lumen.
  • Plunger element 51 can be integral or attached to delivery member 50.
  • delivery member 50 is configured to travel a fixed distance within the needle lumen 44 so as to deliver a fixed or metered dose of drug into the intestinal wall TvV. This can be achieved by one or more of the selection of the diameter of the delivery member (e.g., the diameter can be distally tapered), the diameter of the tissue penetrating member (which can be narrowed at its distal end), use of a stop, and/or the actuating mechanism.
  • the stroke or travel distance of member 50 can be adjusted in situ responsive to various factors such as one or more sensed conditions in the GI tract. In situ adjustment can be achieved through use of logic resource 29 (including controller 29c) coupled to an electro-mechanical embodiment of actuating mechanism 60. This allows for a variable dose of medication and/or variation of the distance the medication is injected into the intestinal wall.
  • actuating mechanism 60 can comprise a spring 80, a first motion converter 90, and a second motion converter 94 and a track member 98 as is shown in the embodiments of Figs. 2, 4 and 8a-8c.
  • the release element 70 is coupled to spring 80 to retain the spring in a compressed state such that degradation of the release element releases the spring.
  • Spring 80 may be coupled to release element 70 by a latch or other connecting element 81.
  • First motion converter 90 is configured to convert motion of spring 80 to advance and withdraw the tissue penetrating member 40 in and out of the intestinal wall or other tissue.
  • the second motion converter 94 is configured to convert motion of the spring 80 to advance the delivery member 50 into the tissue penetrating member lumen 44.
  • Motion converters 90 and 94 are pushed by the spring and ride along a rod or other track member 98 which fits into a track member lumen 99 of converter 90.
  • the track member 98 serves to guide the path of the converters 90.
  • Converters 90 and 94 engage the tissue penetrating member 40 and/or delivery member 50 (directly or indirectly) to produce the desired motion. They have a shape and other characteristics configured to convert motion of the spring 80 along its longitudinal axis into orthogonal motion of the tissue penetrating member 40 and/or delivery member 50 though conversion in other directions is also contemplated.
  • the motion converters can have a wedge, trapezoidal or curved shape with other shapes also
  • the first motion converter 90 can have a trapezoidal shape 90t and include a slot 93 which engages a pin 41 on the tissue penetrating member that rides in the slot as is shown in the embodiments of Figs. 2, 3 and 4.
  • Slot 93 can also have a trapezoidal shape 93t that mirrors or otherwise corresponds to the overall shape of converter 90. Slot 93 serves to push the tissue penetrating member 40 during the upslope portion 91 of the trapezoid and then pull it back during the down slope portion 92.
  • one or both of the motion converters 90 and 94 can comprise a cam or cam like device (not shown).
  • the cam can be turned by spring 80 so as to engage the tissue penetrating and/or delivery members 40 and 50.
  • One or more components of mechanism 60 (as well as other components of device 10) including motion converters 90 and 94 can be fabricated using various MEMS-based methods known in the art so as to allow for selected amounts of miniaturization to fit within capsule 10. Also as is described herein, they can be formed from various biodegradable materials known in the art.
  • the actuating mechanism 60 can also comprise an electromechanical device/mechanism such as a solenoid or a piezoelectric device.
  • a piezoelectric device used in mechanism 60 can comprise a shaped
  • piezoelectric element which has a non-deployed and deployed state.
  • This element can be configured to go into the deployed state upon the application of a voltage and then return to the non-deployed state upon the removal of the voltage or other change in the voltage.
  • This and related embodiments allow for a reciprocating motion of the actuating mechanism 60 so as to both advance the tissue penetrating member and then withdraw it.
  • the voltage for the piezoelectric element can be obtained generated using a battery or a piezoelectric based energy converter which generates voltage by mechanical deformation such as that which occurs from compression of the capsule 20 by a peristaltic contraction of the small intestine around the capsule. Further description of piezoelectric based energy converters is found in U.S. Patent Application Serial No.
  • tissue penetrating members 40 can in fact be triggered from a peristaltic contraction of the small intestine which provides the mechanical energy for generating voltage for the piezoelectric element.
  • Release element 70 will typically be coupled to the actuating mechanism 60 and/or a spring coupled to the actuating mechanism; however, other configurations are also contemplated.
  • release element 70 is coupled to a spring 80 positioned within capsule 20 so as to retain the spring in a compressed state 85 as shown in the embodiment of Fig. 2. Degradation of the release element 70 releases spring 80 to actuate actuation mechanism 60. Accordingly, release element 70 can thus function as an actuator 70a (actuator 70 may also include spring 80 and other elements of mechanism 60).
  • release element 70/actuator 70a has a first configuration where the therapeutic agent preparation 100 is contained within capsule 20 and a second configuration where the therapeutic agent preparation is advanced from the capsule into the wall of the small intestine or other luminal wall in the intestinal tract.
  • release element 70 comprises a material configured to degrade upon exposure to chemical conditions in the small or large intestine such as pH.
  • release element 70 is configured to degrade upon exposure to a selected pH in the small intestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6 8.0 or greater.
  • the release element can also be configured to degrade within a particular range of pH such as, e.g., 7.0 to 7.5.
  • the pH at which release element 70 degrades (defined herein as the degradation pH) can be selected for the particular drug to be delivered so as to release the drug at a location in small intestine which corresponds to the selected pH.
  • the device can include a first release element 70 (coupled to an actuating mechanism for delivering a first drug) configured to degrade at first pH and a second release element 70 (coupled to an actuating mechanism for delivering a second drug) configured to degrade at a second pH (with additional numbers of release elements contemplated for varying number of drugs).
  • Release element 70 can also be configured to degrade in response to other conditions in the small intestine (or other GI location).
  • the release element 70 can be configured to degrade in response to particular chemical conditions in the fluids in the small intestine such as those which occur after ingestion of a meal (e.g., a meal containing fats, starches or proteins). In this way, the release of medication 100 can be substantially synchronized or otherwise timed with the digestion of a meal.
  • biodegradation of release element 70 from one or more conditions in the small intestine can be achieved by one or more of the following approaches: i) selection of the materials for the release element, ii) the amount of cross linking of those materials; and iii) the thickness and other dimensions of the release element. Lesser amounts of cross linking and or thinner dimensions can increase the rate of degradation and vice versa.
  • Suitable materials for the release element can comprise biodegradable materials such as various enteric materials which are configured to degrade upon exposure to the higher pH in the intestines. Suitable enteric materials include, but are not limited to, the following: cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,
  • enteric materials can be copolymerized or otherwise combined with one or more other polymers to obtain a number of other particular material properties in addition to biodegradation. Such properties can include without limitation stiffness, strength, flexibility and hardness.
  • the release element 70 can comprise a film or plug 70p that fits over or otherwise blocks guide tubes 30 and retains the tissue penetrating member 40 inside the guide tube.
  • tissue penetrating member 40 is coupled to a spring loaded actuating mechanism such that when the release element is degraded sufficiently, it releases the tissue penetrating member which then springs out of the guide tube to penetrate into the intestinal wall.
  • release element 70 can be shaped to function as a latch which holds the tissue penetrating member 40 in place.
  • the release element can be located on the exterior or the interior of capsule 20. In the latter case, capsule 20 and/or guide tubes 30 can be configured to allow for the ingress of intestinal fluids into the capsule interior to allow for the degradation of the release element.
  • actuating mechanism 60 can be actuated by means of a sensor 67, such as a pH sensor 68 or other chemical sensor which detects the presence of the capsule in the small intestine. Sensor 67 can then send a signal to actuating mechanism 60 or to an electronic controller 29c coupled to actuating mechanism 60 to actuate the mechanism.
  • a pH sensor 68 can comprise an electrode-based sensor or it can be a mechanically-based sensor such as a polymer which shrinks or expands upon exposure to a selected pH or other chemical conditions in the small intestine.
  • an expandable/contractible sensor 67 can also comprise the actuating mechanism 60 itself by using the mechanical motion from the expansion or contraction of the sensor.
  • sensor 67 can comprise pressure/force sensor such as strain gauge for detecting the number of peristaltic contractions that capsule 20 is being subject to within a particular location in the intestinal tract (in such embodiments capsule 20 is desirably sized to be gripped by the small intestine during a peristaltic contraction). Different locations within the GI tract have different number of peristaltic contractions.
  • the small intestine has between 12 to 9 contractions per minute with the frequency decreasing down the length of the intestine.
  • detection of the number of peristaltic contractions can be used to not only determine if capsule 20 is in the small intestine, but the relative location within the intestine as well. In use, these and related embodiments allow for release of medication 100 at a particular location in the small intestine.
  • the user may externally activate the actuating mechanism 60 to deliver medication 100 by means of RF, magnetic or other wireless signaling means known in the art.
  • the user can use a handheld communication device 13 (e.g., a hand held RF device such as a cell phone) as is shown in the embodiment of Fig, lb, to send a receive signals 17 from device 10.
  • swallowable device may include a transmitter 28 such as an RF transceiver chip or other like communication device/circuitry.
  • Handheld device 13 may not only includes signaling means, but also means for informing the user when device 10 is in the small intestine or other location in the GI tract.
  • the later embodiment can be implemented through the use of logic resources 29 (e.g., a processor 29) coupled to transmitter 28 to signal to detect and singe to the user when the device is in the small intestine or other location (e.g., by signaling an input from the sensor).
  • Logic resources 29 may include a controller 29c (either in hardware or software) to control one or more aspects of the process.
  • the same handheld device can also be configured to alert the user when actuating mechanism 60 has been activated and the selected medication 100 delivered (e.g., using processor 29 and transmitter 28). In this way, the user is provided confirmation that medication 100 has been delivered.
  • the handheld device can also be configured to send a signal to swallowable device 10 to over-ride actuating mechanism 60 and so prevent delay or accelerate the delivery of medication 100.
  • actuating mechanism 60 allows the user to intervene to prevent, delay or accelerate the delivery of medication, based upon other symptoms and/or patient actions (e.g., eating a meal, deciding to go to sleep, exercise etc.).
  • the user may also externally activate actuating mechanism 60 at a selected time period after swallowing the capsule. The time period can be correlated to a typical transit time or range of transit times for food moving through the user's GI tract to a particular location in the tract such as the small intestine.
  • the capsule 20 can include seams 22 of biodegradable material which controllably degrade to break the capsule into capsule pieces 23 of a selectable size and shape to facilitate passage through the GI tract as is shown in the embodiment of Figs. 10a and 10b.
  • Seams 22 can also include pores or other openings 22p for ingress of fluids into the seam to accelerate biodegradation as is shown in the embodiment of Fig. 10.
  • Other means for accelerating biodegradation of seams 22 can include pre-stressing the seam and/or including perforations 22f in the seam as is also shown in the embodiment of Fig. 10.
  • seam 22 can be constructed of materials and/or have a structure which is readily degraded by absorption of ultrasound energy, e.g. high frequency ultrasound (HTFU), allowing the capsule to be degraded into smaller pieces using externally or endoscopically (or other minimally invasive method) administered ultrasound.
  • ultrasound energy e.g. high frequency ultrasound (HTFU)
  • HTFU high frequency ultrasound
  • Suitable materials for seams 22 can include one or more biodegradable materials described herein such as PGLA, glycolic acid etc. Seams 22 can be attached to capsule body 20 using various joining methods known in the polymer arts such as molding, hot melt junctions, etc. Additionally for embodiments of capsule 20 which are also fabricated from biodegradable materials, faster biodegradation of seam 22 can be achieved by one or more of the following: i) fabricating the seam from a faster biodegrading material, ii) pre-stressing the seam, or iii) perforating the seam.
  • biodegradable seams 22 can also be applied to other swallowable devices such as swallowable cameras (or other swallowable imaging device) to facilitate passage through the GI tract and reduce the likelihood of such a device becoming stuck in the GI tract. Accordingly, embodiments of biodegradable seam 22 can be adapted for swallowable imaging and other swallowable devices.
  • Another aspect of the invention provides methods for the delivery of drugs and other therapeutic agents (in the form of medication 100) into the walls of the GI tract using one or more embodiments of swallowable drug delivery device 10.
  • An exemplary embodiment of such a method will now be described.
  • the described embodiment of drug delivery occurs in the small intestine SI.
  • this is exemplary and that embodiments of the invention can be used for delivering drug in a number of locations in the GI tract including the stomach and the large intestine.
  • the swallowable drug delivery device 10 will sometimes be referred to herein as a capsule.
  • device 10 may be packaged as a kit 11 within sealed packaging 12 that includes device 10 and a set of instructions for use 15.
  • the patient may instructed to enter data into device 13 either manually or via a bar code 18 (or other identifying indicia 18) located on the instructions 15 or packaging 12. If a bar code is used, the patient would scan the bar code using a bar code reader 19 on device 13. After opening packaging 12, reading the
  • Capsule 20 is sized to pass through the GI tract and travels through the patient's stomach S and into the small intestine SI through peristaltic action as is shown in the embodiment of Fig. 11.
  • the release element 70 is degraded by the basic pH in the small intestine (or other chemical or physical condition unique to the small intestine) so as to actuate the actuating mechanism 60 and deliver medication 100 into the wall of the small intestine SI according to one or more embodiments of the invention.
  • medication delivery is effectuated by using the actuating mechanism 60 to advance the needle 40 a selected distance into the mucosa of the intestinal wall IS, and then the medication is injected through the needle lumen 40 by advancement of the delivery member 50.
  • the delivery member 50 is withdrawn and the needle 40 is then withdrawn back within the body of the capsule (e.g. by recoil of the spring) detaching from the intestinal wall.
  • a second or third needle 42, 43 can also be used to deliver additional doses of the same drug or separate drugs 101. Needle advancement can be done substantially simultaneously or in sequence. In preferred embodiments that use multiple needles, needle advancement can be done substantially simultaneously so as to anchor device 10 in the small intestine during drug delivery.
  • device 10 After medication delivery, device 10 then passes through the intestinal tract including the large intestine LI and is ultimately excreted.
  • the capsule 20 having biodegradable seams 22 or other biodegradable portions, the capsule is degraded in the intestinal tract into smaller pieces to facilitate passage through and excretion from the intestinal tract as is shown in the embodiments of Figs. 9a and 9b.
  • the needle biodegrades releasing the capsule 20 from the wall.
  • actuation of mechanism 60 can be effectuated by the senor sending a signal to actuating mechanism 60 and/or a processor 29/controller 29c coupled to the actuating mechanism.
  • the user may externally activate actuating mechanism 60 at a selected time period after swallowing the capsule. The time period can be correlated to a typical transit time or range of transit times for food moving through the user's GI tract to a particular location in the tract such as the small intestine.
  • One or more embodiments of the above methods can be used for the delivery of preparations 100 containing therapeutically effective amounts of a variety of drugs and other therapeutic agents 101 to treat a variety of diseases and conditions. These include a number of large molecule peptides and proteins which would otherwise require injection due to chemical breakdown in the stomach.
  • the dosage of the particular drug can be titrated for the patient's weight, age or other parameter.
  • the dose of drug 101 to achieve a desired or therapeutic effect e.g., insulin for blood glucose regulation
  • the dose of drug 101 to achieve a desired or therapeutic effect when delivered by one or more embodiments of the invention can be less than the amount required should the drug have been delivered by conventional oral delivery (e.g., a swallowable pill that is digested in the stomach and absorbed through the wall of the small intestine).
  • the dose 102 delivered in preparation 100 can be in the range from 100 to 5% of a dose delivered by conventional oral delivery (e.g., a pill) to achieve a desired therapeutic effect (e.g., blood glucose regulation, seizure regulation, etc.) with even lower amounts contemplated.
  • the particular dose reduction can be titrated based upon the particular drug, the condition to be treated, and the patient's weight, age and condition.
  • a standard dose reduction can be employed (e.g., 10 to 20%). Larger amounts of dose reduction can be used for drugs which are more prone to degradation and poor absorption. In this way, the potential toxicity and other side effects (e.g., gastric cramping, irritable bowel, hemorrhage, etc.) of a particular drug or drugs delivered by device 10 can be reduced because the ingested dose is lowered. This in turn, improves patient compliance because the patient has reduction both in the severity and incidence of side effects.
  • Additional benefits of embodiments employing dose reduction of drug 101 include a reduced likelihood for the patient to develop a tolerance to the drug (requiring higher doses) and, in the case of antibiotics, for the patient to develop resistant strains of bacteria. Also, other levels of dose reduction can be achieved for patients undergoing gastric bypass operations and other procedures in which sections of the small intestine have been removed or its working (e.g., digestive) length effectively shortened.
  • embodiments of swallowable drug delivery device 10 and methods of their use can be used to deliver a plurality of drugs for the treatment of multiple conditions or for the treatment of a particular condition (e.g., protease inhibitors for treatment HIV AIDS).
  • a particular condition e.g., protease inhibitors for treatment HIV AIDS.
  • such embodiments allow a patient to forgo the necessity of having to take multiple medications for a particular condition or conditions.
  • they provide a means for facilitating that a regimen of two or more drugs is delivered and absorbed into the small intestine and thus, the blood stream, at about the same time. Due to difference in chemical makeup, molecular weight, etc., drugs can be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves.
  • Embodiments of the invention address this issue by injecting the desired drug mixtures at substantially the same time. This in turn, improves the pharmacokinetics and thus the efficacy of the selected mixture of drugs. Additionally, eliminating the need to take multiple drugs is particularly beneficial to patients who have one or more long term chronic conditions including those who have impaired cognitive or physical abilities.
  • embodiments of the above methods can be used to deliver preparations 100 including drugs and therapeutic agents 101 to provide treatment for a number of medical conditions and diseases.
  • the medical conditions and diseases which can be treated with embodiments of the invention can include without limitation: cancer, hormonal conditions (e.g., hypo/hyper thyroid, growth hormone conditions), osteoporosis, high blood pressure, elevated cholesterol and triglyceride, diabetes and other glucose regulation disorders, infection (local or septicemia), epilepsy and other seizure disorders, osteoporosis, coronary arrhythmia's (both atrial and ventricular), coronary ischemia anemia or other like condition. Still other conditions and diseases are also contemplated.
  • the treatment of the particular disease or condition can be performed without the need for injecting the drug or other therapeutic agent (or other non- oral form of delivery such as suppositories) but instead, relying solely on the therapeutic agent(s) that is delivered into the wall of the small intestine or other portion of the GI tract.
  • the patient need not take conventional oral forms of a drug or other therapeutic agent, but again rely solely on delivery into the wall of the small intestine using embodiments of the swallowable capsule.
  • the therapeutic agent(s) delivered into the wall of the small intestine can be delivered in conjunction with an injected dose of the agent(s).
  • the patient may take a daily dose of therapeutic agent using the embodiments of the swallowable capsule, but only need take an injected dose every several days or when the patient's condition requires it (e.g., hyperglycemia).
  • therapeutic agents that are traditionally delivered in oral form (e.g., the patient can take the swallowable capsule and take the conventional oral form of the agent as needed).
  • the dosages delivered in such embodiments e.g., the swallowed and injected dose
  • can be titrated as needed e.g., using standard dose response curve and other pharmacokinetic methods can be used to determine the appropriate dosages).
  • the dose delivered using therapeutic agents that can be delivered by conventional oral means the dose delivered using
  • embodiments of the swallowable capsule can be titrated below the dosage normally given for oral delivery of the agent since there is little or no degradation of the agent within the stomach or other portion of the intestinal tract (herein again standard dose response curve and other pharmacokinetic methods can be applied).
  • preparation 100 containing one or more drugs or other therapeutic agents 101 for the treatment of various diseases and conditions will now be described with references to dosages. It should be appreciated that these embodiments, including the particular therapeutic agents and the respective dosages are exemplary and the preparation 100 can comprise a number of other therapeutic agents described herein (as well as those known in the art) that are configured for delivery into a luminal wall in the intestinal tract (e.g., the small intestinal wall) using various embodiments of device 10. The dosages can be larger or smaller than those described and can be adjusted using one or more methods described herein or known in the art.
  • therapeutic agent preparation 100 can comprise a therapeutically effective dose of insulin for the treatment of diabetes and other glucose regulation disorders.
  • the insulin can be human or synthetically derived as is known in the art.
  • preparation 100 can contain a therapeutically effective amount of insulin in the range of about 1-10 units (one unit being the biological equivalent of about 45.5 ⁇ g of pure crystalline insulin), with particular ranges of 2-4, 3-9, 4-9, 5-8 or 6-7. Larger ranges are also contemplated such as 1 to 25 units or 1-50 units.
  • the amount of insulin in the preparation can be titrated based upon one or more of the following factors (herein, "glucose control titration factors”): i) the patient's condition (e.g., type 1 vs. type II diabetes; ii) the patient's previous overall level of glycemic control; iii) the patient's weight; iv) the patient's age; v) the frequency of dosage (e.g., once vs. multiple times a day); vi) time of day (e.g., morning vs. evening); vii) particular meal (breakfast vs.
  • the patient's condition e.g., type 1 vs. type II diabetes
  • iii) the patient's previous overall level of glycemic control e.g., the patient's weight; iv) the patient's age
  • the frequency of dosage e.g., once vs. multiple times a day
  • time of day e.g.
  • composition/glycemic index of a particular meal e.g., high fat/lipid and sugar content (e.g., foods causing a rapid rise in blood sugar) vs. low fat and sugar content
  • content of the patient's overall diet e.g., amount of sugars and other carbohydrates, lipids and protein consumed daily.
  • various embodiments of the therapeutic preparation 100 comprising insulin or other therapeutic agent for the treatment of diabetes or other blood glucose disorder, to allow for improved control of blood glucose levels by delivering more precisely controlled dosages of insulin without requiring the patient to inject themselves.
  • the patient can swallow a device such as swallowable device 10, or 110 (containing insulin and/or other therapeutic agent for the treatment of diabetes) at the same time as they take food such that insulin or other therapeutic is released into the blood stream from the small intestine at about the same time or close to the same time as glucose or other sugar in the food is released from the small intestine into the blood stream would raise blood glucose levels.
  • a device such as swallowable device 10, or 110 (containing insulin and/or other therapeutic agent for the treatment of diabetes) at the same time as they take food such that insulin or other therapeutic is released into the blood stream from the small intestine at about the same time or close to the same time as glucose or other sugar in the food is released from the small intestine into the blood stream would raise blood glucose levels.
  • This concurrent or otherwise time proximate release allows the insulin to act on various receptors (e.g., insulin receptors) to increase the uptake of glucose into muscle and other tissue just as blood glucose levels are starting to rise from absorption of sugars into the blood from the small intestine.
  • compositions comprising insulin for the treatment of various disorders such as diabetes or other glucose regulation disorder.
  • Such compositions result in the delivery of insulin with various desirable pharmacokinetic properties.
  • pharmacokinetic metrics of note include C ma x, the peak plasma concentration of insulin after administration; t max , the time to reach C ma x; and t 1 ⁇ 2 , the time required for the plasma concentration of insulin to reach half its Cmax value after having reached Cmax- These metrics can be measured using standard pharmacokinetic measurement techniques known in the art.
  • plasma samples may be taken at set time intervals (e.g., one minute, five minutes, 1 ⁇ 2 hour, 1 hour, etc.) beginning and then after administration of the therapeutic composition either by use of a swallowable device or by non-vascular injection.
  • concentration of insulin in plasma can then be measured using one or more appropriate analytical methods such as GC-Mass Spec, LC-Mass Spec, HPLC or various ELISA (Enzyme-linked immunosorbent assays) which can be adapted for the particular drug.
  • a concentration vs. time curve (also herein referred to as a concentration profile) can then be developed using the measurements from the plasma samples.
  • the peak of the concentration curve corresponds to C ma x and the time at which this occurs corresponds to t max .
  • the time in the curve where the concentration reaches half its maximum value (i.e., Cmax) after having reached C max corresponds to t 1 ⁇ 2 this value is also known as the elimination half-life of therapeutic agent.
  • the start time for determination of Cmax can be based on the time at which the injection is made for the case on non-vascular injection and the point in time at which embodiments of the swallowable device advances one or more tissue penetrating members (containing the drug) into the small intestine or other location in the GI tract (e.g., the large intestine).
  • this time can determined using one or more means including a remote controlled embodiment of the swallowable device which deploys the tissue penetrating members into the intestine wall in response to an external control signal (e.g., an RF signal) or for an embodiment of the swallowable device which sends an RF or other signal detectable outside the body when the tissue penetrating members have been deployed.
  • an external control signal e.g., an RF signal
  • Other means for detection of tissue penetrating member deployment into the small intestine are contemplated such as one more medical imaging modalities including for example, ultrasound or fluoroscopy.
  • appropriate animal models can be used for example, dog, pig, rat etc. in order to model the human pharmacokinetic response.
  • one or more embodiments of the invention provide a therapeutic composition comprising insulin, the composition adapted for insertion into an intestinal wall after oral ingestion, wherein upon insertion, the composition releases insulin into the bloodstream from the intestinal wall to achieve a C ma x faster than an extravascularly injected dose of insulin.
  • the therapeutic insulin composition has a tmax which is about 80%, or 50%, or 30%, or 20%, or 10% of a tmax for an extravascularly injected does of insulin.
  • Such an extravascularly injected dose of insulin can be, for example, a subcutaneous injection or an intramuscular injection.
  • the Cmax attained by delivering the therapeutic insulin composition by insertion into the intestinal wall is substantially greater, such as 100, or 50, or 10, or 5 times greater, than the Cmax attained when the composition is delivered orally without insertion into the intestinal wall.
  • the therapeutic insulin composition is configured to produce a long-term release of insulin, such as a long-term release of insulin with a selectable t 1 ⁇ 2 .
  • the selectable t 1 ⁇ 2 may be 6, or 9, or 12, or 15 or 18, or 24 hours.
  • the composition is adapted for insertion into an intestinal wall after oral ingestion, wherein upon insertion, the composition releases insulin into the bloodstream from the intestinal wall to achieve a C max faster than an extravascularly injected dose of the therapeutic agent that is to say, achieving a C max for the inserted form of therapeutic agent in a shorter time period (e.g., a smaller t max ) than that for a dose of the therapeutic agent that is injected extravascularly
  • a shorter time period e.g., a smaller t max
  • the dose of therapeutic agent in the composition delivered into the intestinal wall and the dose delivered by extravascular injection may, but need not, be comparable to achieve these results.
  • the composition is configured to achieve a t ma x for the insulin (e.g., by release of the insulin into the bloodstream from the intestinal wall, e.g., that of the small intestine) which is about 80%, or 50%, or 30%, or 20%, or 10% of a t max for an extravascularly injected dose of the insulin.
  • a t ma x for the insulin e.g., by release of the insulin into the bloodstream from the intestinal wall, e.g., that of the small intestine
  • a t max for an extravascularly injected dose of the insulin can be, for example, a subcutaneous injection or an intramuscular injection.
  • the Cmax attained by delivering the therapeutic agent by insertion into the intestinal wall is
  • the insulin compositions adapted for insertion into the wall of the small intestine can be configured to release the insulin into the blood stream from the intestinal wall to achieve a t 1 ⁇ 2 that is greater than a t 1 ⁇ 2 for an orally ingested dose of the therapeutic agent that is not inserted into the intestinal wall.
  • the t 1 ⁇ 2 of the dose inserted into the intestinal wall may be 100 or 50 or 10 or 5 times greater than the dose that is not inserted into the intestinal wall.
  • the insulin compositions adapted for insertion into the wall of the small intestine may also be configured to produce a long-term release of insulin with a selectable t 1 ⁇ 2 .
  • the selectable t 1 ⁇ 2 may be 6, or 9, or 12, or 15 or 18, 24 or 48 hours.
  • the insulin composition may be in solid form, such as a solid form composition configured to degrade in the intestinal wall, and the solid form composition may have, for example, a tissue penetrating feature such as a pointed tip.
  • the insulin composition may comprise at least one biodegradable material and/or may comprise at least one
  • the insulin composition may be adapted to be orally delivered in a swallowable capsule.
  • a swallowable capsule may be adapted to be operably coupled to a mechanism having a first configuration and a second configuration, the therapeutic insulin composition being contained within the capsule in the first configuration and advanced out of the capsule and into the intestinal wall in the second configuration.
  • Such an operably coupled mechanism may comprise at least one of an expandable member, an expandable balloon, a valve, a tissue penetrating member, a valve coupled to an expandable balloon, or a tissue penetrating member coupled to an expandable balloon.
  • the insulin composition may be configured to be delivered within a lumen or other cavity of a tissue penetrating member and/or the therapeutic composition may be shaped as a tissue penetrating member advanceable into the intestinal wall.
  • the tissue penetrating member may be sized to be completely contained within the intestinal wall, and/or it may include a tissue penetrating feature for penetrating the intestinal wall, and/or it may include a retaining feature for retaining the tissue penetrating member within the intestinal wall.
  • the retaining feature may comprise, for example, a barb.
  • the tissue penetrating member is configured to be advanced into the intestinal wall by the application of a force (e.g.
  • the force can be applied by means of an expandable balloon or other expandable member or structure operatively coupled to the tissue penetrating member with the tissue penetrating member configured to detach or otherwise disengage from the expandable structure when a direction or magnitude of force applied by the expandable structure changes (e.g., when the balloon or other expandable member completes its expansion and starts to shrink or otherwise contract).
  • the tissue penetrating member has sufficient stiffness and/or column strength to be advanced completely into the intestinal wall.
  • the column strength of the tissue penetrating member can range from about 1 to about 20 lbs, 7 to 201bs, 8 to 12 lbs, with individual embodiments of 7, 8, 9, 10 and 11 lbs.
  • therapeutic agent preparation 100 can comprise a therapeutically effective dose of one or more incretins for the treatment of diabetes and other glucose regulation disorders.
  • incretins can include Glucacon like peptides 1 (e.g., GLP- 1) and their analogues, and Gastric inhibitory peptide (GIP).
  • GLP-1 analogues include exenatide, liraglutide, albiglutide and taspoglutide as well as their analogues, derivatives and other functional equivalents.
  • preparation 100 can contain a therapeutically effective amount of exenatide in the range of about 1-10 ⁇ g, with particular ranges of 2-4, 4-6, 4-8 and 8-10 ⁇ g respectively.
  • preparation 100 can contain a therapeutically effective amount of liraglutide in the range of about 1-2 mg (milligrams), with particular ranges of 1.0 to 1.4, 1.2 to 1.6 and 1.2 to 1.8 mg respectively.
  • glucose control titration factors can be applied to titrate the dose ranges for exenatide, liraglutide or other GLP-1 analogue or incretin.
  • Therapeutic Agent Preparations Comprising Combinations of Incretins and Biguanide
  • therapeutic agent preparation 100 can comprise a combination of therapeutic agents for the treatment of diabetes and other glucose regulation disorders.
  • Embodiments of such a combination can include for example, therapeutically effective doses of incretin and biguanide compounds.
  • An example biguanide can include metformin in a dose of 200 to lOOOmg, and a preferred does of 200 tO 500 mg.
  • the incretin can comprise one or more GLP-1 analogues described herein, such as exenatide and the biguanide can comprise metformin (e.g., that available under the Trademark of GLUCOPHAGE ® manufactured by Merck Sante S.A.S.) and its analogue, derivatives and other functional equivalents.
  • preparation 100 can comprise a combination of a therapeutically effective amount of exenatide in the range of about 1-10 ⁇ g and a therapeutically effective amount of metformin in a range of about 1 to 3 grams.
  • the glucose control titration factors used to titrate the respective dose of exenatide (or other incretin) and metformin or other biguanide can be matched to improved level of glucose control for the patient (e.g., maintenance of blood glucose within normal physiological levels and/or a reduction in the incidence and severity of instances of hyperglycemia and/or hypoglycemia) for extended periods of time ranges from hours (e.g., 12) to a day to multiple days, with still longer periods contemplated.
  • Matching of dosages can also be achieved by use of the glucose control regulation factors as well as monitoring of the patient's blood glucose for extended periods using glycosylated hemoglobin (known as hemoglobin Ale, HbAlc, AIC, or Hblc) and other analytes and measurements correlative to long term average blood glucose levels.
  • Therapeutic Preparations Comprising Combinations of Glucose Regulating Compounds
  • therapeutic agent preparation 100 can comprise a combination of between two to three glucose regulating compounds such as those compounds shown in tables 1 and 2 (an “x" in the table indicates that the particular glucose regulating compound is included, a "-" indicates that it is not).
  • Such compounds can be selected to produce a synergistic effect (e.g. an enhancement) in one or more of blood glucose reduction, blood glucose regulation, appetite control/suppression or other therapeutic effect.
  • Such synergistic effects in turn provide treatment for various conditions associated with diabetes such as hyperglycemia, insulin resistance or hyperlipidemia.
  • the compounds shown in Table 1 can be contained in and/or formed as an embodiment of the tissue penetrating member that is configured to be advanced from the swallowable capsule configured to be inserted into the intestinal wall as is described herein. Once so inserted into the intestinal wall, the tissue penetrating member degrades to release the glucose regulating compounds into the blood stream as described herein for other therapeutic agents.
  • the tissue penetrating member is configured to concurrently release the plurality of glucose regulating compounds (e.g., by compounding and/or mixing all of the compounds in the same material used to formulate the tissue penetrating member). The concurrent release of the aforementioned compounds into the wall of the small intestine and, in turn the blood stream, serves to promote and enhance the synergistic effects between two or more of the compounds (e.g., increased blood glucose control, appetite suppression, etc.).
  • the compounds shown in Table 2 can be orally delivered in the form of a dissolvable pill contained in an embodiment of the swallowable capsule but in these embodiments are released into the lumen of the small intestine where the swallowable capsule dissolves but not into the wall of the small intestine.
  • the various pharamacokinetic parameters achieved by delivering insulin using embodiments of the swallowable capsule are equally obtainable for each of the respective glucose regulating compounds listed above in tables 1 and 2, either alone or in combination using embodiments of the swallowable capsule to deliver the compounds into the wall of the small intestine or other wall of the intestinal tract.
  • Table 1 Combination of Compounds Which May Be Delivered by Embodiments of the
  • the combination of glucose regulating compounds may comprise a plurality of compounds including, for example, insulin, GLP-1 and at least one other compound.
  • the glucose regulating compounds may include those which lower blood glucose also known as hypoglycemic compounds and those which raise blood glucose. They also include those which affect (e.g., reduce) glucose directly, and/or indirectly e.g., by causing the secretion of hormone which subsequently lower glucose levels, agonize or enhance the effect of glucose reducing hormones (as is the case for DDP4 inhibitors with incretins), reduce appetite (as is the case with, peptide YY) or all of the above.
  • the other glucose regulating compound can be selected from the group consisting of glucagon, peptide YY, GIP, metformin, peptide YY, Dipeptidyl peptidase-4 (DPP4), DPP4 inhibitors, sodium/glucose co-transporter 2 (SGLT2) inhibitors along with their analogues and derivatives.
  • DPP4 Dipeptidyl peptidase-4
  • SGLT2 sodium/glucose co-transporter 2
  • Peptide YY also known as peptide tyrosine tyrosine or pancreatic peptide YY3-36 is a peptide in the incretin class of molecules that is encoded by the PPY gene. It is a short (36-amino acid) peptide released by L-cells (being co-released with GLP-1) in the ileum and colon in response to feeding (and is co released with GLP-1). In the blood, gut, and other elements of periphery of the body, PYY acts to reduce appetite and when administered in conjunction with GLP-1, augment the appetite suppressing effects of that incretin.
  • the dose of PPY delivered by embodiments of the swallowable capsule can be in a range from 200 to 600 ⁇ g, with a preferred range of about 400 to 500 ⁇ g.
  • Such doses being sufficient to produce a reduction in the patient's appetite and/or enhance (e.g. by an amount of 25, 50, 75 or 100%) the appetite suppressing effect of GLP-1 when the PPY is co-administered with GLP-1.
  • embodiments of the therapeutic preparation comprising insulin, GLP-1 and Peptide YY serve to not only regulate glucose homeostasis in the diabetic patient but also to produce weight loss in the patient from the synergistic appetite suppressing effect of GLP-1 and the PPY.
  • the latter effect also serving to reduce insulin resistance in diabetics thus produce a long term improvement in glucose control/homeostasis in the diabetic patient.
  • such combinations are particularly useful and novel in that they provide in a single pill an approach for treating the different pathophysiologies of diabetes by treating one or more of glucose regulation dysfunction, obesity (through appetite suppression) and insulin resistance.
  • the patient would have to take three separate injections all close in time. This is presently not done for type II diabetes treatment due to a number of reasons including patient compliance, adverse reactions at the injections sites, logistic (three separate liquid doses need to be formulated, stored and carried by the patient).
  • the single pill oral delivery approach contemplated by embodiments of the invention also provides benefits in that the therapeutics agents are released in a more physiologically natural fashion vs injected forms of the drugs. This results in the
  • the sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the SLC5 A2 (solute carrier family 5 (sodium/glucose cotransporter)) gene.
  • SLC5 A2 solute carrier family 5 (sodium/glucose cotransporter)
  • SGLT2 inhibitors also known as gliflozins cause a reduction in blood glucose levels. Specifically, they block glucose reabsorption in the kidney, thereby, disposing excess glucose in the urine and in turn, reducing blood glucose levels. The latter effect serves to improve insulin resistance in the patient by reducing the blood glucose burden.
  • SGLT2 inhibitors have potential use for the treatment of type II diabetes to improve glycemic control.
  • Example SGLT2 Inhibitors include canagliflozin and dapagliflozin.
  • Canagliflozin has been shown to enhance glycemic control as well as reduce body weight and systolic and diastolic blood pressure. Specifically clinical trials, canagliflozin have been shown to produce consistent dose-dependent decreases in HbAlc levels of 0.77% to 1.16% (from initial levels of 7.8% to 8.1%) when administered either as monotherapy, in combination with metformin, in combination with metformin and a sulfonylurea, in combination with metformin and pioglitazone, or in combination with insulin.
  • the dose of canagliflozin delivered by embodiments of the swallowable capsule or other oral delivery means described herein can be in a range from aboutlOO to 300 mg, with a preferred range of about 400 to 500 ⁇ g.
  • a suitable SGLT2 inhibitor includes
  • dapagliflozinm Its dose can be in a range of 5 to lOmg with a preferred range of 7 to 9mg.
  • Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine which lowers blood glucose. As such when used over extended time periods, dapagliflozin also produces reductions in HbAlc levels, in particular cases this can be as much as 0.6 percentage points.
  • SGLT2 sodium-glucose transport proteins
  • Embodiments of the invention which deliver one or more of the above SGLT2 inhibitors in combination with GLP-1 are particularly useful in that these two compounds work synergistically to both improve insulin resistance and the efficacy of the delivered insulin, (delivering the compounds together in one pill with the ability for long term release further enhances these effects). These combined effects in turn not only greatly improve glucose homeostasis but also serve to slow, halt or even reverse the progression of diabetes or other related glucose control disorder. Also, embodiments which deliver insulin together with SGLT2 inhibitors are particularly useful for the treatment of diabetes in that these two compounds act synergistically to reduce blood glucose more than each could alone and thus in turn reduce HbAlc levels.
  • the dose of the particular SGLT2 inhibitor e.g., canagliflozin, dapagliflozinm, etc.
  • the dose of insulin can titrated in the therapeutic agent combination 100 to produce a selected decrease in HbAlc levels e.g., decrease by 0.2 to 1. 2% with a specific range of 0.77% to 1.16% etc.
  • Dipeptidyl peptidase-4 (DDPP4) Inhibitors are a class of oral antidiabetic agents that block the effect of the DPP-4 enzymes which degrade incretins such as GLP-1. The net result being the half-life of incretins (both natural and delivered) in circulation is increased thereby augmenting anti-diabetic effects of the incretins.
  • Example DDPP4 Inhibitors include sitagliptin, with a dose range of about 20 to 100 mg, and saxagliptin, with a dose range of about 5 to 10 mg dose.
  • DDPP4 inhibitors serve to the prolong the duration of action of the otherwise short lived incretin peptides (e.g. natural GLP-1 has a half -life of about two minutes).
  • This effect produces a long lived glucose regulating effect of the GLP-1 eliminate and/or reduces the need of meal time insulin injection.
  • This effect in turn reduces the burden on insulin secreting cells in the pancreas (e.g., pancreatic beta cell) which in turn, contributes to slowing the progression of diabetic disease by preserving the function of pancreatic beta cells.
  • GIP Gastric Inhibitory Peptides
  • GIP Gastric inhibitory polypeptide
  • GIP also known as the glucose-dependent insulinotropic peptide
  • GIP is a member of the secretin family of hormones.
  • GIP is derived from a 153-amino acid pro-protein encoded by the GIP gene and circulates as a biologically active 42-amino acid peptide. It is synthesized by K cells, which are found in the mucosa of the duodenum and the jejunum of the gastrointestinal tract. GIP reduces blood glucose levels by inducing insulin secretion.
  • the dose of GIP delivered by embodiments of the swallowable capsule can be in a range from about 50 to about 250 ⁇ g.
  • embodiments of therapeutic preparations comprising GIP, insulin and GLP- 1 serve to restore the normal physiological levels of these hormones (these levels being comprised in diabetics), thereby restoring normal glucose disposal and, in turn, glucose homeostasis.
  • Normal glucose disposal being the ability of the body to prevent sustained hyperglycemia after a meal by the rapid metabolism and/or storage of circulating blood glucose levels.
  • Glucagon is a peptide hormone, produced by alpha cells of the pancreas and belongs to a family of hormones known as the secretin family. It acts to increase the concentration of glucose in the bloodstream. Its effect is opposite that of insulin. The pancreas releases glucagon when the concentration of glucose in the bloodstream falls too low. Glucagon causes the liver to convert stored glycogen into glucose, which is then released into the bloodstream raising blood glucose levels. While having opposite effects, glucagon and insulin work in concert to maintain glucose levels within normal physiologic levels (e.g. euglycemic levels). The diabetic patient has various complication with glucagon and/or glucagon metabolism.
  • the diabetic patient's tissue/cells have resistance to one or both of glucagon and insulin, resulting in the loss of their synergetic effect in controlling glucose and in turn, a loss in maintaining glucose homeostasis. Further in diabetics, glucagon resistance has been linked to hyperlipidemia and other adverse effects on the patient's energy homeostasis.
  • Hyperlipidemia in turn, can result in a number of adverse effects to the patient including one or more of increased insulin resistance, cardiovascular disease and metabolic syndrome
  • embodiments of therapeutic preparation comprising insulin, GLP-1 and glucagon can be configured to produce multiple beneficial effects in the diabetic patient including: i) restoring insulin resistance by the action of GLp-1; ii) reduce the burden on the beta cells of the pancreas by providing basal levels of insulin; iii) reduce the burden on alfa cells of the pancreas by providing basal levels of glucagon; iv) prevent or reduce sustained excursions in blood glucose levels (e.g., both hyperglycemia and hypoglycemia) which may result following a meal and/or an extra- vascularly injected dose of insulin.; v) reduces hyperlipidemia..
  • the dose can of glucagon or its analogues delivered by embodiments of the invention can be in a range from about 0.5 to about 2mg.
  • Drug delivery compositions and components of known drug delivery systems may be employed and/or modified for use in some embodiments of the inventions described herein.
  • micro-needles and other microstructures used for delivery of drugs through the skin surface with drug patches may be modified and included within the capsules described herein and used to instead deliver a drug preparation into a lumen wall of the gastrointestinal tract such as the wall of the small intestine.
  • Suitable polymer micro-needle structures may be commercially available from Corium of California, such as the MicroCorTM micro delivery system technology.
  • Other components of the MicroCorTM patch delivery systems, including drug formulations or components, may also be incorporated into the capsules described herein.
  • a variety of providers are commercially available to formulate combinations of polymers or other drug-delivery matrices with selected drugs and other drug preparation components so as to produce desired shapes (such as the releasable tissue-penetrating shapes described herein) having desirable drug release characteristics.
  • Such providers may, for example, include Corium, SurModics of Minnesota, BioSensors International of Singapore, or the like.
  • the biologic drug payload e.g., the therapeutic peptide or protein, e.g., insulin, GLP-1 and a third glucose regulating compound such as PPY, GIP, Glucagon, etc.
  • the biologic drug payload e.g., the therapeutic peptide or protein, e.g., insulin, GLP-1 and a third glucose regulating compound such as PPY, GIP, Glucagon, etc.
  • GI gastrointestinal
  • compositions described herein are designed to protect the therapeutic peptide or protein from the actions of these GI proteases and to deliver the peptide or protein payload directly into the wall of the intestine.
  • the capsule shell which contains the deployment engine and machinery, does not dissolve until it reaches the duodenal and sub-duodenal intestinal segments, owing to the pH-sensitive coating on the outer surface of the capsule which prevents its dissolution in the low pH of the stomach.
  • the tissue penetrating members which contain the actual therapeutic peptide or protein; the tissue penetrating members are designed to penetrate the intestine muscle as soon as the outer capsule shell dissolves; and the micro-spears themselves slowly dissolve in the intestinal muscle wall to release the drug payload.
  • the peptide or protein payload is not exposed to the actions of the GI proteases and therefore does not undergo degradation via proteolysis in the GI tract. This feature, in turn, contributes to the high % bioavailabilty of the therapeutic peptide or protein.
  • the swallow delivery device can include one or more expandable balloons or other expandable devices for use in delivering one or more tissue penetrating members including medication 100 into the wall of an intestine, such as the small intestine.
  • a device 110 for the delivery of medication 100 to a delivery site DS in the gastro-intestinal (GI) tract can comprise a capsule 120 sized to be swallowed and pass through the intestinal tract, a deployment member 130, one or more tissue penetrating members 140 containing medication 100, a deployable aligner 160 and a delivery mechanism 170.
  • medication 100 also referred to herein as preparation 100
  • the deployable aligner 160 is positioned within the capsule and configured to align the capsule with the intestine such as the small intestine.
  • the delivery mechanism 170 is configured for delivering medication 100 into the intestinal wall and will typically include a delivery member 172 such as an expandable member.
  • the deployment member 130 is configured for deploying at least one of the aligner 160 or the delivery mechanism 170.
  • all or a portion of the capsule wall is degradable by contact with liquids in the GI tract so as to allow those liquids to trigger the delivery of medication 100 by device 110.
  • GI tract refers to the esophagus, stomach, small intestine, large intestine and anus
  • Intestinal tract refers to the small and large intestine.
  • Various embodiments of the invention can be configured and arranged for delivery of medication 100 into both the intestinal tract as well as the entire GI tract.
  • Device 110 including tissue penetrating member 140 can be configured for the delivery of liquid, semi-liquid or solid forms of medication 100 or combinations of all three.
  • medication 100 desirably has a material consistency allowing the medication to be advanced out of device 110, into the intestinal wall (e.g., the small or large intestine) or other luminal wall in the GI tract and then degrade within the intestinal wall to release the drug or other therapeutic agent 101.
  • the material consistency of medication 100 can include one or more of the hardness, porosity and solubility of the preparation (in body fluids).
  • the material consistency can be achieved by selection and use of one or more of the following: i) the compaction force used to make the preparation; ii) the use of one or more pharmaceutical disintegrants known in the art; iii) use of other pharmaceutical excipients; iv) the particle size and distribution of the preparation (e.g., micronized particles); and v) use of micronizing and other particle formation methods known in the art.
  • Capsule 120 is sized to be swallowed and pass through the intestinal tract. The size can also be adjusted depending upon the amount of drug to be delivered as well as the patient's weight and adult vs. pediatric applications. Typically, the capsule will have a tubular shape with curved ends similar to a vitamin. In these and related embodiments, capsule lengths 120L can be in the range of 0.5 to 2 inches and diameters 120D in the range of 0.1 to 0.5 inches with other dimensions contemplated.
  • the capsule 120 includes a capsule wall 121w, having an exterior surface 125 and an interior surface 124 defining an interior space or volume 124v.
  • the capsule wall 121w can include one or more apertures 126 sized for the outward advancement of tissue penetrating members 140.
  • the interior volume can include one or more compartments or reservoirs 127.
  • Capsule 120 can be fabricated from various biodegradable materials known in the pharmaceutical arts such as various gelatins.
  • the capsule may also include various enteric coatings 120c, configured to protect the cap from degradation in the stomach (due to acids etc.), and then subsequently degrade in the in higher pH's found in the small intestine or other area of the intestinal tract.
  • the capsule 120 can be formed from multiple portions one or more of which may be biodegradable.
  • capsule 120 can be formed from two portions 120p such as a body portion 120p" (herein body 120p") and a cap portion 120p' (herein cap 120p), where the cap fits onto the body, e.g., by sliding over or under the body (with other arrangements also
  • One portion such as the cap 120p' can include a first coating 120c 'configured to degrade above a first pH (e.g., pH 5.5) and the second portion such as the body 120p" can include a second coating 120c" configured to degrade above a second higher pH (e.g.6.5).
  • first pH e.g., pH 5.5
  • second portion such as the body 120p"
  • Both the interior 124 and exterior 125 surfaces of capsule 120 are coated with coatings 120c' and 120c" so that that either portion of the capsule will be substantially preserved until it contacts fluid having the selected pH.
  • body 120p this allows the structural integrity of the body 120p" to be maintained so as to keep balloon 172 inside the body portion and not deployed until balloon 130 has expanded.
  • Coatings 120c' and 120c" can include various methacrylate and ethyl acrylate based coatings such as those manufactured by Evonik Industries under the trade name EUDRAGIT. These and other dual coating configurations of the capsule 120 allows for mechanisms in one portion of capsule 120 to be actuated before those in the other portion of the capsule. This is due to the fact that intestinal fluids will first enter those portions where the lower pH coating has degraded thus actuating triggers which are responsive to such fluids (e.g., degradable valves). In use, such dual coating embodiments for capsule 120 provide for targeted drug delivery to a particular location in the small intestine (or other location in the GI tract), as well as improved reliability in the delivery process.
  • aligner 160 can be configured to begin in the upper area of the small intestine (e.g., the duodenum) allowing the capsule to be aligned within the intestine for optimal delivery of the drug (e.g., into the intestinal wall) as well as providing sufficient time for deployment/actuation of other components to achieve drug delivery into the intestinal wall while the capsule is still in the small intestine or other selected location.
  • a particular component such as aligner 160
  • one or more portions of capsule 120 can be fabricated from various biocompatible polymers known in the art, including various biodegradable polymers which in a preferred embodiment can comprise cellulose, gelatin materials PGLA (polylactic- co-glycolic acid).
  • suitable biodegradable materials include various enteric materials described herein as well as lactide, glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone, trimethylene carbonate, caprolactone, blends and copolymers thereof.
  • the wall 120w of the capsule is degradable by contact with liquids in the GI tract for example liquids in the small intestine.
  • the capsule wall is configured to remain intact during passage through the stomach, but then to be degraded in the small intestine. In one or more embodiments, this can be achieved by the use of an outer coating or layer 120c on the capsule wall 120w, which only degrades in the higher pH's found in the small intestine and serves to protect the underlying capsule wall from degradation within the stomach before the capsule reaches the small intestine (at which point the drug delivery process is initiated by degradation of the coating as is described herein).
  • capsule 120 can include various radio-opaque, echogenic or other materials for location of the device using one or more medical imaging modalities such as fluoroscopy, ultrasound, MRI, etc.
  • one or more of the deployment member 130, delivery member 172 or deployable aligner 160 may correspond to an expandable balloon that is shaped and sized to fit within capsule 120. Accordingly, for ease of discussion, deployment member 130, delivery member 172 and deployable aligner 160 will now be referred to as balloon 130, 160 and 172; however, it should be appreciated that other devices including various expandable devices are also contemplated for these elements and may include for example, various shape memory devices (e.g., an expandable basket made from shape memory biodegradable polymer spires), expandable piezo electric devices, and/or chemically expandable devices having an expanded shape and size corresponding to the interior volume 124v of the capsule 120.
  • shape memory devices e.g., an expandable basket made from shape memory biodegradable polymer spires
  • expandable piezo electric devices e.g., a piezo electric devices having an expanded shape and size corresponding to the interior volume 124v of the capsule 120.
  • balloons 130, 160 and 172 can comprise various polymers known in the medical device arts.
  • such polymers can comprise one or more types of polyethylene (PE) which may correspond to low density PE(LDPE), linear low density PE (LLDPE), medium density PE (MDPE) and high density PE (HDPE) and other forms of polyethylene known in the art.
  • PE polyethylene
  • the material may be cross-linked using polymer irradiation methods known in the art so.
  • radiation-based cross-linking may be used as to control the inflated diameter and shape of the balloon by decreasing the compliance of the balloon material.
  • the amount or radiation may be selected to achieve a particular amount of cross linking to in turn produce a particular amount of compliance for a given balloon, e.g., increased irradiation can be used to produce stiffer less compliant balloon material.
  • suitable polymers can include PET (polyethylene teraphalate), silicone and polyurethane.
  • balloons 130, 160 and 172 may also include various radio-opaque materials known in the art such as barium sulfate to allow the physician to ascertain the position and physical state of the balloon (e.g., un-inflated, inflated or punctures.
  • Balloons 130, 160 and 172 can be fabricated using various balloon blowing methods known in the balloon catheters arts (e.g., mold blowing, free blowing, etc.) to have a shape and size which corresponds approximately to the interior volume 124v of capsule 120.
  • one or more of balloons 130, 160 and 172 and various connecting features can have a unitary construction being formed from a single mold. Embodiments employing such unitary construction provide the benefit of improved manufacturability and reliability since fewer joints must be made between one or more components of device 110.
  • Suitable shapes for balloons 130, 160 and 172 include various cylindrical shapes having tapered or curved end portions (an example of such a shape including a hot dog).
  • the inflated size (e.g., diameter) of one or more of balloons 130, 160 and 172 can be larger than capsule 120 so as to cause the capsule to come apart from the force of inflation, (e.g., due to hoop stress).
  • the inflated size of one or more of balloons 130, 160 and 172 can be such that when inflated: i) the capsule 120 has sufficient contact with the walls of the small intestine so as to elicit a peristaltic contraction causing contraction of the small intestine around the capsule, and/or ii) the folds of the small intestine are effaced to allow. Both of these results allow for improved contact between the capsule/balloon surface and the intestinal wall so as deliver tissue penetrating members 40 over a selected area of the capsule and/or delivery balloon 172.
  • the walls of balloons 130, 160 and 172 will be thin and can have a wall thickness in the range of 0.005 to 0.0001" more preferably, in the range of 0.005 to 0.0001, with specific embodiments of 0.004, 0.003, 0.002, 0.001, and 0.0005).
  • one or more of balloon 130, 160 or 172 can have a nested balloon configuration having an inflation chamber 160IC and extended finger 160EF as is shown in the embodiments of Fig. 13c.
  • the connecting tubing 163, connecting the inflation chamber 160IC can be narrow to only allow the passage of gas 168, while the connecting tubing 36 coupling the two halves of balloon 130 can be larger to allow the passage of water.
  • the aligner 160 will typically comprise an expandable balloon and for ease of discussion, will now be referred to as aligner balloon 160 or balloon 160.
  • Balloon 160 can be fabricated using materials and methods described above. It has an unexpanded and expanded state (also referred to as a deployed state). In its expanded or deployed state, balloon 160 extends the length of capsule 120 such that forces exerted by the peristaltic contractions of the small intestine SI on capsule 120 serve to align the longitudinal axis 120LA of the capsule 120 in a parallel fashion with the longitudinal axis LAI of the small intestine SI.
  • aligner 160 is also configured to push delivery mechanism 170 out of capsule 120 prior to inflation of delivery balloon 172 so that the delivery balloon and/or mechanism is not encumbered by the capsule. In use, this push out function of aligner 160 improves the reliability for delivery of the therapeutic agent since it is not necessary to wait for particular portions of the capsule (e.g., those overlying the delivery mechanism) to be degraded before drug delivery can occur.
  • Balloon 160 may be fluidically coupled to one or more components of device 110 including balloons 130 and 172 by means of polymer tube or other fluidic couplings 162 which may include a tube 163 for coupling balloons 160 and 130 and a tube 164 for coupling balloon 160 and balloon 172.
  • Tube 163 is configured to allow balloon 160 to be
  • Tube 164 connects balloon 160 to 172 so as to allow for the inflation of balloon 172 by balloon 160.
  • tube 164 includes or is coupled to a control valve 155 which is configured to open at a selected pressure so as to control the inflation of balloon 172 by balloon 160.
  • Tube 164 may thus comprise a proximal portion 164p connecting to the valve and a distal portion 164d leading from the valve.
  • proximal and distal portions 164p and 164d will be connected to a valve housing 158 as is described below.
  • Valve 155 may comprise a triangular or other shaped section 156 of a material 157 which is placed within a the chamber 158c of a valve housing 158 (alternately, it may be placed directly within tubing 164). Section 157 is configured to mechanically degrade (e.g., tears, shears, delaminates, etc.) at a selected pressure so as to allow the passage of gas through tube 164 and/or valve chamber 158c. Suitable materials 157 for valve 155 can include bees wax or other form of wax and various adhesives known in the medical arts which have a selectable sealing force/burst pressure.
  • Valve fitting 158 will typically comprise a thin cylindrical compartment (made from biodegradable materials) in which section 156 of material 157 is placed (as is shown in the embodiment of Fig. 13b) so as to seal the walls of chamber 158c together or otherwise obstruct passage of fluid through the chamber.
  • the release pressure of valve 155 can be controlled through selection of one or more of the size and shape of section 156 as well as the selection of material 157 (e.g., for properties such as adhesive strength, shear strength etc.).
  • control valve 155 allows for a sequenced inflation of balloon 160 and 172 such that balloon 160 is fully or otherwise substantially inflated before balloon 172 is inflated.
  • the inflated length 1601 of the aligner balloon 160 is sufficient to have the capsule 120 become aligned with the lateral axis of the small intestine from peristaltic contractions of the intestine.
  • Suitable inflated lengths 1601 for aligner 160 can include a range between about 1 ⁇ 2 to two times the length 1201 of the capsule 120 before inflation of aligner 160.
  • Suitable shapes for aligner balloon 160 can include various elongated shapes such as a hotdog like shape.
  • balloon 160 can include a first section 160' and a second section 160", where expansion of first section 160' is configured to advance delivery mechanism 170 out of capsule 120 (typically out of and second section 160" is used to inflate delivery balloon 172.
  • first and second sections 160' and 160" can be configured to have a telescope- style inflation where first section 160' inflates first to push mechanism 170 out of the capsule (typically from body portion 120p') and second section 160" inflates to inflate delivery member 172.
  • This can be achieve by configuring first section 160' to have smaller diameter and volume than second section 160" such that first section 160' inflates first (because of its smaller volume) and with second section 160" not inflating until first section 60' has substantially inflated.
  • this can be facilitated by use of a control valve 155 (described above) connecting sections 160' and 160" which does not allow passage of gas into section 160" until a minimum pressure has been reached in section 160' .
  • the aligner balloon can contain the chemical reactants which react upon mixture with water or other liquid from the deploying balloon.
  • the deployment member 130 will comprise an expandable balloon, known as the deployment balloon 130.
  • deployment balloon 30 is configured to facilitate deployment/expansion of aligner balloon 160 by use of a gas, for example, generation of a gas 169 from a chemical.
  • the gas may be generated by the reaction of solid chemical reactants 165, such as an acid 166 (e.g., citric acid) and a base 166 (e.g., potassium bicarbonate, sodium bicarbonate and the like) which are then mixed with water or other aqueous liquid 168.
  • an acid 166 e.g., citric acid
  • a base 166 e.g., potassium bicarbonate, sodium bicarbonate and the like
  • the amount of reactants can be chosen using
  • the reactants 165 and liquids can be stored separately in balloon 130 and 160 and then brought together in response to a trigger event, such as the pH conditions in the small intestine.
  • the reactants 165 and liquids 168 can be stored in either balloon, however in preferred embodiments, liquid 168 is stored in balloon 130 and reactants 165 in balloon 160.
  • balloon 130 may be coupled to aligner balloon 160 by means of a connector tube 163 which also typically includes a separation means 150 such as a degradable valve 150 described below.
  • tube 163 has sufficient diameter to allow for the passage of sufficient water from balloon 130 to balloon 60 to produce the desired amount of gas to inflate balloon 160 as well inflate balloon 172.
  • balloon 30 and tube 63 are configured to allow for the passage of liquid to balloon 160 by one or more of the following: i) the compressive forced applied to balloon 130 by peristaltic contractions of the small intestine on the exposed balloon 130; and ii) wi eking of liquid through tube 163 by capillary action.
  • Tube 163 will typically include a degradable separation valve or other separation means 150 which separates the contents of balloon 130, (e.g., water 158) from those of balloon 160 (e.g., reactants 165) until the valve degrades.
  • Valve 150 can be fabricated from a material such as maltose, which is degradable by liquid water so that the valve opens upon exposure to water along with the various liquids in the digestive tract. It may also be made from materials that are degradable responsive to the higher pH's found in the intestinal fluids such as methacrylate based coatings.
  • valve 150 is desirably positioned at location on tube 163 which protrudes above balloon 130 and/or is otherwise sufficient exposed such that when cap 120p' degrades the valve 150 is exposed to the intestinal liquids which enter the capsule.
  • valve 150 can be positioned to lie on the surface of balloon 130 or even protrude above it (as is shown in the embodiments of Figs. 16a and 16b), so that is has clear exposure to intestinal fluids once cap 120p' degrades.
  • a separation valve 150 for example, a beam like structure (where the valve comprises a beam that presses down on tube 163 and/or connecting section 136), or collar type structure (where the valve comprise a collar lying over tube 163 and/or connecting section 136). Still other valve structures are also contemplated.
  • Balloon 130 has a deployed and a non-deployed state.
  • the deployment balloonl30 can have a dome shape 130d which corresponds to the shape of an end of the capsule.
  • Other shapes 130s for the deployed balloon 130 are also contemplated, such as spherical, tube-shape, etc.
  • the reactants 165 will typically include at least two reactants 166 and 167, for example, an acid such as citric acid and a base such as sodium bicarbonate.
  • Other reactants 165 including other acids, e.g., ascetic acid and bases, e.g., sodium hydroxide are also contemplated.
  • the valve or other separation means 150 opens, the reactants mix in the liquid and produce a gas such as carbon dioxide which expands the aligner balloon 160 or other expandable member.
  • the deployment balloon 130 can actually comprise a first and second balloon 130' and 130" connected by a tube 36 or other connection means 136 (e.g., a connecting section).
  • Connecting tube 136 will typically include a separation valve 150 that is degradable by a liquid as described above and/or a liquid having a particular pH such as basic pH found in the small intestine (e.g., 5.5 or 6.5).
  • the two balloons 130' and 130" can each have a half dome shape 130hs allowing them to fit into the end portion of the capsule when in the expanded state.
  • One balloon can contain the chemical reactant(s) 165 (e.g., sodium bicarbonate, citric acid, etc.) the other the liquid water 168, so that when the valve is degraded the two components mix to form a gas which inflates one or both balloons 130' and 130" and in turn, the aligner balloon 160.
  • the chemical reactant(s) 165 e.g., sodium bicarbonate, citric acid, etc.
  • balloon 130 can comprise a multicompartment balloon 130mc, that is formed or other constructed to have multiple
  • compartments 130c will include at least a first and a second compartment 134 and 135 which are separated by a separation valve 150 or other separation means 150 as is shown in the embodiment of Fig. 14a.
  • compartments 130c will include at least a first and a second compartment 134 and 135 which are separated by a separation valve 150 or other separation means 150 as is shown in the embodiment of Fig. 14a.
  • compartments 130c will include at least a first and a second compartment 134 and 135 which are separated by a separation valve 150 or other separation means 150 as is shown in the embodiment of Fig. 14a.
  • a liquid 168 typically water, can be disposed within first compartment 134 and one or more reactants 165 disposed in second compartment
  • valve 150 opens (e.g., from degradation caused by fluids within the small intestine) liquid 168 enters compartment 135 (or vice versa or both), the reactant(s) 165 mix with the liquid and produce a gas 169 such as carbon dioxide which expands balloon 130 which in turn can be used to expand one or more of balloons 160 and 172.
  • a gas 169 such as carbon dioxide which expands balloon 130 which in turn can be used to expand one or more of balloons 160 and 172.
  • Reactants 165 will typically include at least a first and a second reactant, 166 and 167 for example, an acid such as citric acid and a base such as sodium bi-carbonate or potassium bi-carbonate. As discussed herein, in various embodiments they may be placed in one or more of balloon 130 (including compartments 134 and 135 or halves 130' and 130") and balloon 160. Additional reactants, including other combinations of acids and bases which produce an inert gas by product are also contemplated. For embodiments using citric acid and sodium or potassium bicarbonate, the ratio's between the two reactants (e.g., citric acid to potassium bicarbonate) can be in the range of about 1 : 1 to about 1 :4, with a specific ratio of about 1 :3. Desirably, solid reactants 165 have little or no absorbed water.
  • one or more of the reactants such as sodium bicarbonate or potassium bicarbonate can be pre-dried (e.g., by vacuum drying) before being placed within balloon 130.
  • Other reactants 165 including other acids, e.g., ascetic acid and bases are also contemplated.
  • the amounts of reactants can be selected to produce a pressure selected one or more of balloons 130, 160 and 172 to: i) achieve a particular penetration depth into the intestinal wall; and produce a particular diameter for one or more of balloons 130, 160 and 172; and iii) exert a selected amount of force against intestinal wall IW.
  • the amount and ratios of the reactants e.g., citric acid and potassium bicarbonate
  • the amounts and ratio's of the reactants to achieve these pressures can be determined using known stoichiometric equations.
  • the chemical reactants alone or in combination with the deployment balloon 130 can comprise a deployment engine for 180 deploying one or both of the aligner balloon 160 and delivery mechanism 170 including delivery balloon 172.
  • Deployment engine 180 may also include embodiments using two deployment balloons 130 and 130" (a dual dome
  • a deployment engine 180 is also contemplated by various embodiments of the invention such as use of expandable piezo-electric materials (that expand by
  • One or more of the expandable balloons 130, 160 and 172 will also typically include a deflation valve 159 which serves to deflate the balloon after inflation.
  • Deflation valve 159 can comprise biodegradable materials which are configured to degrade upon exposure to the fluids in the small intestine and/or liquid in one of the compartments of the balloon so as to create an opening or channel for escape of gas within a particular balloon.
  • deflation valves 159 are configured to degrade at a slower rate than valve 150 to allow sufficient time for inflation of balloons, 130, 160 and 172 before the deflation valve degrades.
  • deflation valve 159 can correspond to a degradable section 139 positioned on an end portion 131 of the balloon as is shown in the embodiment of Fig. 14a.
  • degradable section 139 when degradable section 139 degrades from exposure to the liquid, balloon wall 132 tears or otherwise comes apart providing for a high assurance of rapid deflation.
  • Multiple degradable sections 139 can be placed at various locations within balloon wall 132.
  • deflation valve 159 can correspond to a tube valve 173 attached to the end 172e of the delivery balloon 172 (opposite to the end which is coupled to the aligner balloon) as is shown in the embodiment of Fig. 13b.
  • the tube valve 173 comprises a hollow tube 173t having a lumen that is obstructed at a selected location 1731 with a material 173m such as maltose that degrades upon exposure to fluid such as the fluid in the small intestine.
  • the location 1731 of the obstructing material 173m in tube 173t is selected to provide sufficient time for the delivery balloon 172 to inflate and deliver the tissue penetrating members 40 into the intestinal wall IW before the obstructing material dissolves to open valve 173. Typically, this will be close to the end 173e of the tube 173t, but not quite so as to allow time for liquid to have to wick into the tube lumen before it reaches material 173m.
  • the deflation valve 173 once the deflation valve 173 opens, it not only serves to deflate the delivery balloon 172 but also the aligner balloon 160 and deployment balloon 130 since in many embodiments, all three are fludicially connected (aligner balloon being fludically connected to delivery balloon 172 and the deployment balloon 130 being fludically connected to aligner balloon 160). Opening of the deflation valve 173 can be facilitated by placing it on the end 172e of the delivery balloon 172 that is forced out of capsule 120 by inflation of the aligner balloon 160 so that the deflation valve has good exposure to liquids in the small intestine. Similar tube deflation valves 173 can also be positioned on one or both of aligner balloon 162 and the deployment balloon 130. In these later two cases, the obstructing material in the tube valve can be configured to degrade over a time period to allow sufficient time for inflation of delivery balloon 172 and advancement of tissue penetrating members 140 into the intestinal wall.
  • one or more puncture elements 182 can be attached to the inside surface 124 of the capsule such that when a balloon (e.g., balloon 130, 160, 172) fully inflates it contacts and is punctured by the puncture element 182. Puncture elements 182 can comprise short protrusions from surface 124 having a pointed tip.
  • one or more of the tissue penetrating members 140 can be directly coupled to the wall of 172w of balloon 172 and configured to tear away from the balloon when they detach, tearing the balloon wall in the process.
  • tissue penetrating member 140 can be fabricated from various drugs and other therapeutic agents 101, one or more pharmaceutical excipients (e.g., disintegrants, stabilizers, etc.) and one or more biodegradable polymers.
  • pharmaceutical excipients e.g., disintegrants, stabilizers, etc.
  • the penetrating member 140 can be formed to have a shaft 144 and a needle tip 145 or other pointed tip 145 so as to readily penetrate tissue of the intestinal wall as shown in the embodiment of Fig. 18a.
  • tip 145 has a trocar shape as is shown in the embodiment of Fig. 18c.
  • Tip 145 may comprise various degradable materials (within the body of the tip or as a coating), such as sucrose or other sugar which increase the hardness and tissue penetrating properties of the tip.
  • tissue penetrating member 140 can be selected to allow for dissolution and absorption of drug 101 in a matter of seconds, minutes or even hours. Rates of dissolution can be controlled through the use of various disintegrants known in the pharmaceutical arts. Examples of disintegrants include, but are not limited to, various starches such as sodium starch glycolate and various cross linked polymers such as carboxymethyl cellulose. The choice of disintegrants can be specifically adjusted for the environment within the wall of the small intestine.
  • Tissue penetrating member 140 will also typically include one or more tissue retaining features 143 such as a barb or hook to retain the penetrating member within the tissue of the intestinal wall IW after advancement.
  • Retaining features 143 can be arranged in various patterns 143p to enhance tissue retention such as two or more barbs symmetrically or otherwise distributed around and along member shaft 144 as is shown in the embodiments of Figs. 18a and 18b.
  • penetrating member will also include a recess or other mating feature 146 for attachment to a coupling component on delivery mechanism 170.
  • Tissue penetrating member 140 is desirably configured to be detachably coupled to platform 175 (or other component of delivery mechanism 170), so that after advancement of the tissue penetrating member 140 into the intestinal wall, the penetrating member detaches from the balloon.
  • Detachability can be implemented by a variety of means including: i) the snugness or fit between the opening 174 in platform 175 and the member shaft 144); ii) the configuration and placement of tissue retaining features 143 on penetrating member 140; and iii) the depth of penetration of shaft 144 into the intestinal wall.
  • penetrating member 140 be configured to detach as a result of balloon deflation (where the retaining features 143 hold the penetrating member 140 in tissue as the balloon deflates or otherwise pulls back away from the intestinal wall) and/or the forces exerted on capsule 120 by a peristaltic contraction of the small intestine.
  • the detachability and retention of tissue penetrating member 140 in the intestinal wall IW can be enhanced by configuring the tissue penetrating member shaft 144 to have an inverse taper 144t as is shown in the embodiment of Fig.18c.
  • the taper 144t on the shaft 144 is configured such that the application of peristaltic contractile forces from the intestinal wall on the shaft result in the shaft being forced inward (e.g., squeezed inward). This is due to the conversion by shaft taper 144t of the laterally applied peristaltic force PF to an orthogonal force OF acting to force the shaft inward into the intestinal wall.
  • tissue penetrating members 140 having an inverse tapered shaft may also include one or more retaining features 143 to further enhance the retention of the tissue penetrating member within intestinal wall TvV once inserted.
  • tissue penetrating member 140 can be fabricated from a number of drugs and other therapeutic agents 101.
  • the tissue penetrating member may be fabricated entirely from drug 101 or may have other constituent components as well, e.g., various pharmaceutical excipients (e.g., binders, preservatives, disintegrants, etc.), polymers conferring desired mechanical properties, etc.
  • one or more tissue penetrating members 140 can carry the same or a different drug 101 (or other therapeutic agent) from other tissue penetrating members.
  • a first assembly 178' can carry tissue penetrating members having a first drug 101 and a second assembly 178" can carry tissue penetrating members having a second drug 101.
  • the drug or other therapeutic agent 101 carried by the tissue penetrating member 140 will be mixed in with a biodegradable material 105 to form tissue penetrating member 140.
  • Material 105 may include one or more biodegradable polymers such as PGLA, cellulose, as well as sugars such as maltose or other biodegradable material described herein or known in the art.
  • the penetrating member 140 may comprise a substantially heterogeneous mixture of drug 101 and biodegradable material 105.
  • the tissue penetrating member 140 may include a portion 141 formed substantially from biodegradable material 105 and a separate section 142 that is formed from or contains drug 101 as shown in the embodiment of Fig. l8d.
  • section 142 may correspond to a pellet, slug, cylinder or other shaped section 142s of drug 101. Shaped section 142s may be pre-formed as a separate section which is then inserted into a cavity 142c in tissue penetrating member 140 as is shown in the embodiments of Figs. 18e and 18f.
  • section 142s may be formed by adding of drug preparation 100 to cavity 142c.
  • preparation may be added in as a powder, liquid, or gel which is poured or injected into cavity 142c.
  • Shaped section 142s may be formed of drug 101 by itself or a drug preparation containing drug 101 and one or more binders, preservatives, disintegrates and other excipients.
  • Suitable binders include polyethylene glycol (PEG) and other binders known in the art.
  • the PEG or other binder may comprise in the range of about 10 to 90% weight percent of the section 142s, with a preferred embodiment for insulin preparations of about 25-90 weight percent.
  • excipients which may be used for binders may include, PLA, PLGA, Cyclodextrin, Cellulose, Methyl Cellulose, Maltose, Dextrin, Sucrose and PGA. Further information on the weight per cent of excipients in section 142 may be found in Table 3. For ease of discussion, section 142 is referred to as a pellet in the table, but the data in the table is also applicable to other embodiments of section 142 described herein.
  • the weight of tissue penetrating member 140 can range between about 10 to about 15 mg, with larger and smaller weights contemplated.
  • the weight can range from about 11 to 14 mg.
  • the weight percent of drug in member 140 can range from about 0.1 to about 15%. In exemplary embodiments these weight per cents correspond to embodiments of members 140 fabricated from maltose or PGLA, however they are also applicable to any of the biodegradable materials 105 used in the fabrication of members 140.
  • the weight percent of drug or other therapeutic agent 101 in member 140 can be adjusted depending upon the desired dose as well as to provide for structural and stoichiometric stability of the drug and also to achieve a desired concentration profile of the drug in the blood or other tissue of the body.
  • Various stability tests and models) known in the art e.g., using the Arrhenius equation and/or known rates of drug chemical degradation may be used to make specific adjustments in the weight per cent range.
  • Table 3 lists the dose and weight per cent range for insulin and a number of other drugs which may be delivered by tissue penetrating member 140. In some cases the tables lists ranges as well a single value for the dose, It should be appreciated that these values are exemplary and other values recited herein including the claims are also considered.
  • embodiments of the invention also consider variations around these values including for example, ⁇ 1, ⁇ 5, ⁇ 10, ⁇ 25, and even larger variations. Such variation are considered to fall within the scope of an embodiment claiming a particular value or range of values.
  • the table also lists the weight percentage of drug in in section 142 for various drugs and other therapeutic agents, where again for ease of discussion, section 142 is referred to as a pellet. Again, embodiments of the invention consider the variations described above.
  • Tissue penetrating member 140 can be fabricated using one or more polymer and pharmaceutical fabrication techniques known in the art.
  • drug 101 (with or without biodegradable material 105) can be in solid form and then formed into the shape of the tissue penetrating member 140 using molding, compaction or other like method with one or more binding agents added.
  • drug 101 and/or drug preparation 100 may be in solid or liquid form and then added to the biodegradable material 105 in liquid form with the mixture then formed into the penetrating member 140 using molding or other forming method known in the polymer arts.
  • embodiments of the tissue penetrating member 140 comprising a drug or other therapeutic agent 101 and degradable material 105 are formed at temperatures which do not produce any substantial thermal degradation of drug including drugs such as various peptides and proteins. This can be achieved through the use of room-temperature curing polymers and room temperature molding and solvent evaporation techniques known in the art.
  • the amount of thermally degraded drug or other therapeutic agent within the tissue penetrating member is desirably less than about 10% by weight and more preferably, less than 5% and still more preferably less than 1%.
  • the thermal degradation temperature(s) for a particular drug are either known or can be determined using methods known in the art and then this temperature can be used to select and adjust the particular polymer processing methods (e.g., molding, curing, solvent evaporation methods etc.) to minimize the temperatures and associated level of drug thermal degradation.
  • delivery mechanism 170 will comprise a delivery assembly 178 (containing tissue penetrating members 140) that is attached to delivery balloon 172 as is shown in the embodiment of Figs. 16a and 16b. Inflation of the delivery balloon provides a mechanical force for engaging delivery assembly 172 outwards from the capsule and into the intestinal wall IW so as to insert tissue penetrating members 140 into the wall.
  • the delivery balloon 172 can have an elongated shape with two relatively flat faces 172f connected by an articulated accordion -like body 172b.
  • the flat faces 172f can be configured to press against the intestinal wall (IW) upon expansion of the balloon 172 so as to insert the tissue penetrating members (TPMs) 140 into the intestinal wall.
  • TPMs 140 can be positioned on one or both faces 172f of balloon 172 to allow insertion of drug containing TPMs 40 on opposite sides of the intestinal wall.
  • the faces 172f of balloon 172 may have sufficient surface area to allow for placement of a number of drug containing TPMs 140 on each face.
  • one or more tissue penetrating members 140 can be detachably coupled to a biodegradable advancement structure 175 which may correspond to a support platform 175 (also known as platform 175).
  • platform 175 includes one or more openings 174 for insertion of members 140 as shown in step 300. Openings 174 are sized to allow for insertion and retention of members 140 in platform 175 prior to expansion of balloon 172 while allowing for their detachment from the platform upon their penetration into the intestinal wall.
  • Support platforml75 can then be positioned within a carrying structure 176 as shown in step 301.
  • Carrying structure 176 may correspond to a well structure 176 having side walls 176s and a bottom wall 176b which define a cavity or opening 176c.
  • Platform 175 is desirably attached to inside surface of bottom wall 176b using adhesive or other joining methods known in the art.
  • Well structure 176 can comprise various polymer materials and may be formed using vacuum forming techniques known in the polymer processing arts.
  • opening 176o can be covered with a protective film 177 as shown in step 302.
  • Protective film 177 has properties selected to function as a barrier to protect tissue penetrating members 140 from humidity and oxidation while still allowing tissue penetrating members 140 to penetrate the film as is described below.
  • Film 177 can comprise various water and/or oxygen impermeable polymers which are desirably configured to be biodegradable in the small intestine and/or to pass inertly through the digestive tract. It may also have a multi-ply construction with particular layers selected for impermeability to a given substance, e.g., oxygen, water vapor etc. In use, embodiments employing protective film 177 serve to increase the shelf life of therapeutic agent 101 in tissue penetrating members 140, and in turn, the shelf life of device 110.
  • support platform 175 attached tissue penetrating members 140, well structure 176, and film 177 can comprise a delivery assembly 178.
  • Delivery assemblies 178 having one or more drugs or therapeutic agents 101 contained within tissue penetrating member 40 or other drug delivery means can be pre-manufactured, stored and subsequently used for the manufacture of device 110 at a later date.
  • the shelf life of assembly 178 can be further enhanced by filling cavity 176c of the sealed assembly 178 with an inert gas such as nitrogen.
  • assemblies 178 can be positioned on one or both faces 172f of balloon 172. In preferred embodiments, assemblies 178 are positioned on both faces 172f (as shown in Fig.
  • TPMs 140 Upon expansion of balloon 172, TPMs 140 penetrate through film 177, enter the intestinal wall IW and are retained there by retaining elements 143 and/or other retaining features of TPM 140 (e.g., an inverse tapered shaft 144t) such that they detach from platform 175 upon deflation of balloon 172.
  • retaining elements 143 and/or other retaining features of TPM 140 e.g., an inverse tapered shaft 144t
  • one or more of balloons 130, 160 and 172 can be packed inside capsule 120 in a folded, furled or other desired configuration to conserve space within the interior volume 124v of the capsule. Folding can be done using preformed creases or other folding feature or method known in the medical balloon arts. In particular
  • balloon 130, 160 and 172 can be folded in selected orientations to achieve one or more of the following: i) conserve space, ii) produce a desired orientation of a particular inflated balloon; and iii) facilitate a desired sequence of balloon inflations.
  • the embodiments shown in Figs. 15a-15f illustrate an embodiment of a method of folding and various folding arrangements. However, it should be appreciated that this folding arrangement and the resulting balloon orientations are exemplary and others may also be used. In this and related embodiments, folding can be done manually, by automated machine or a combination of both.
  • a single multi-balloon assembly 7 comprising balloons 130, 160, 170; valve chamber 158 and assorted connecting tubings 162 as is shown in the embodiments of Figs. 13a and 13b.
  • Fig. 13a shows an embodiment of assembly 7 having a single dome construction for balloon 130
  • Fig. 13b shows the embodiment of assembly 7 having dual balloon/dome configuration for balloon 130.
  • Assembly 7 can be fabricated using a thin polymer film which is vacuum- formed into the desired shape using various vacuum forming and other related methods known in the polymer processing arts. Suitable polymer films include polyethylene films having a thickness in the range of about 0.003 to about 0.010", with a specific embodiment of 0.005".
  • the assembly is fabricated to have a unitary construction so as to eliminate the need for joining one or more components of the assembly (e.g., balloons 130,160, etc.).
  • assembly 7 it is also contemplated for assembly 7 to be fabricated from multiple portions (e.g., halves), or components (e.g., balloons) which are then joined using various joining methods known in the polymer/medical device arts.
  • step 211 balloon 172 is folded at a right angle to the folded combination of balloon 160 and valve 158 (see Fig. 15b).
  • step 212 for dual dome embodiments of balloon 130 the two halves 130' and 130" of balloon 130 are folded onto each other, leaving valve 150 exposed (see Fig. 15c, for single dome embodiments of balloon 130, is folded over onto itself see Fig. 15e).
  • a final folding step 213 can be done whereby folded balloon 130 is folded over 180° to the opposite side of valve fitting 158 and balloon 160 to yield a final folded assembly 8 for dual dome configurations shown in the Fig. 15e and a final folded assembly 8' for single dome configurations shown in Figs. 15e and 15f.
  • One or more delivery assemblies 178 are then be attached to assembly 8 in step 214 (typically two the faces 72f of balloon 72) to yield a final assembly 9 (shown in the embodiments of Figs. 16a and 16b) which is then inserted into capsule 120. After an insertion step 215, the final assembled version of device 110 with inserted assembly 9 is shown Figs. 17a and 17b.
  • the cap coating 120c' is degraded by the basic pH in the upper small intestine causing degradation of cap 120p'as shown in step 400 in Fig. 20b.
  • Valve 150 is then exposed to fluids in the small intestine causing the valve to begin degrade as is shown in step 401 in Fig. 20c. Then, in step
  • step 402 balloon 130 expands (due to generation of gas 169) as shown in Fig. 20d. Then, in step
  • section 160' of balloon 160 begins to expand to start to push assembly 178 out of the capsule body as shown in Fig. 20e. Then, in step 404, sections 160' and 160" of balloon 160 become fully inflated to completely push assembly 178 out of the capsule body extending the capsule length 1201 so as to serve to align capsule lateral axis 120AL with the lateral axis of the small intestine LAI as shown in Fig. 20f. During this time, valve 155 is beginning to fail from the increased pressure in balloon 60 (due to the fact that the balloon has fully inflated and there is no other place for gas 169 to go).
  • step 405 valve 155 has completely opened, inflating balloon 172 which then pushes the now completely exposed assembly 178 (having been pushed completely out of body 120p") radially outward into the intestinal wall IW as shown in Fig. 20g.
  • step 406 balloon 172 continues to expand to now advance tissue penetrating members into the intestinal wall IW as shown in Fig. 20h.
  • step 407 balloon 172, (along with balloons 160 and 130) has deflated pulling back and leaving tissue penetrating members retained in the intestinal wall IW.
  • the body portion 120p"of the capsule has completely degraded (due to degradation of coating 120c") along with other biodegradable portions of device 110. Any portion not degraded is carried distally through the small intestine by peristaltic contraction from digestion and is ultimately excreted.
  • embodiments of the swallowable device can be sized and otherwise adapted for various pediatric and neonatal applications as well as various veterinary applications.
  • dosages of therapeutic agents delivered by embodiments of the swallowable device can be titrated and/or otherwise adjusted for pediatric and neonatal applications.
  • those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific devices and methods described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the appended claims below.

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CN201680050621.8A CN108055826A (zh) 2015-07-02 2016-07-05 用于使用可吞服药物递送装置递送到肠道内腔中的治疗药剂制剂
CA2993215A CA2993215C (en) 2015-07-02 2016-07-05 Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
EP16818960.3A EP3316872A4 (de) 2015-07-02 2016-07-05 Zubereitung von therapeutischen wirkstoffen zur freisetzung in ein lumen des darmtraktes mit einer einnehmbaren wirkstofffreisetzungsvorrichtung
AU2016287843A AU2016287843B2 (en) 2015-07-02 2016-07-05 Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
JP2017567700A JP2018519313A (ja) 2015-07-02 2016-07-05 嚥下可能な薬物送達デバイスを使用する腸管の管腔中への送達のための治療剤製剤

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