Classifications

• • 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
  • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
• • 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
  • 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
• • 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
• • 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
  • 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
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

• Embodiments of the invention provide devices, systems, kits and methods for delivering drugs and other therapeutic agents to various locations in the body.
• embodiments provide a swallowable device for delivering drugs and other therapeutic agents within the Gastrointestinal (GI) tract.
• a swallowable device such as a capsule for delivering drugs and other therapeutic agents into the wall of the small intestine and/or surrounding tissue 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.
• embodiments of the invention can be used to deliver drugs and other therapeutic agents 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 due to degradation within the GI tract and/or poor adsorption through the small intestine.
• such therapeutic agents may include insulin (e.g., basal insulin, recombinant insulin) and various other bio therapeutic agents (also described as biologies) such as various immunoglobulins or antibodies including immunoglobulin G.
• biotherapeutic agent also referred to as a biologic refers to product that is produced from living organisms or contains components of living organisms. It may include one or more forms of insulin such as basal insulin, recombinant human insulin or one or more antibodies including for example,
• Immunoglobulin G (IgG). It may also include cells such as various immune cells (e.g., white blood cells, macrophages, T-cells etc. and the like) or a component or fragment of a cell such as platelets.
• various immune cells e.g., white blood cells, macrophages, T-cells etc. and the like
• a component or fragment of a cell such as platelets.
• the invention provides a therapeutic agent preparation for delivery into the wall of a lumen of the gastro-intestinal tract (e.g., the stomach, small intestine, large intestine, etc.) or surrounding tissue (e.g., the peritoneal wall or cavity), where the preparation comprises a therapeutically effective dose of at least one therapeutic agent such as basal insulin or other form of insulin.
• the preparation has a shape and material consistency to be contained in or otherwise protected by 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 or surrounding tissue such as the peritoneal wall or peritoneal cavity.
• the preparation is configured to be contained in a swallowable capsule and operably coupled to one or more of an actuator, expandable member (e.g., a 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 preparation may configured to be partially be contained in the capsule or attached or otherwise disposed on the capsule surface. In these and related embodiments, release of the preparation can be achieved or otherwise facilitated by use of a dissolvable pH sensitive coating that degrades in the small intestine.
• the invention provides a method for delivering a therapeutic agent into the wall of a lumen in the GI tract (e.g., stomach, intestines, etc.) 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 a particular location in the GI (e.g., 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 stomach, small intestine, large intestine.
• tissue penetrating member e.g., the tissue penetrating end
• 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 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 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 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. They are desirably configured to convert motion of the spring along its longitudinal axis into orthogonal motion of the tissue penetrating member and/or delivery member though conversion in other directions is also contemplated.
• 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 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.
• Biodegradation of the release element from one or more conditions in the small intestine, stomach (or other location in the GI tract) 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 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/contractible 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 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 stomach, small intestine or large intestine.
• the preparation comprises a therapeutically effective dose of at least one therapeutic agent, for example IgG or another antibody. Also, 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 or surrounding tissue 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 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.
• the tip of tissue penetrating member may have a variety of shapes including have a symmetric or asymmetric taper or bevel. The later embodiments may be used to deflect or steer the tissue penetrating member into a particular tissue layer such as into the intestinal wall.
• 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 (Insulin-like growth factor) 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.
• PLGA a sugar or maltose
• tissue penetrating member comprises a biodegradable material which degrades within the intestinal wall to release the insulin into the blood stream.
• a therapeutic preparation comprising a therapeutically effect dose of insulin, the preparation adapted for insertion into an intestinal wall or surrounding tissue after oral ingestion, wherein upon insertion, the preparation degrades to releases insulin into the blood stream from the intestinal wall or surrounding tissue so as to maintain a patient’s blood glucose within a euglycemic level upon the ingestion of a simple sugar.
• a therapeutic preparation comprising insulin, the preparation adapted for insertion into an intestinal wall or surrounding tissue of a patient after oral ingestion, wherein upon insertion, the preparation degrades to releases insulin into the patient’s blood stream from the intestinal wall or surrounding tissue, the release exhibiting a plasma concentration profile having a rising portion and a falling portion, the rising portion reaching a Cmax level of insulin from a pre-release level of insulin at least about 2 times faster than a time it takes in the falling portion to go from the C max level of insulin to the prelease level of insulin.
• a method for delivering insulin to a patient comprising:
• the solid dosage insulin into an intestinal wall or surrounding tissue of the patient after oral ingestion, wherein the insulin is released into the patient’s blood stream from the solid dosage insulin in the intestinal wall or surrounding tissue so as to produce a plasma concentration profile having a rising portion and a falling portion, the rising portion reaching a C ma x level of insulin from a pre-release level of insulin at least about 2 times faster than a time it takes in the falling portion to go from the Cmax of insulin it to the prelease level of insulin.
• a method for delivering insulin to a patient comprising: providing a solid insulin dosage; and delivering the solid dosage insulin into an intestinal wall or surrounding tissue of the patient after oral ingestion, wherein the insulin is released into the patient’s blood stream from the solid dosage insulin in the intestinal wall or surrounding tissue so as so as to obtain an absolute bioavailability of insulin of at least about 60% and relative bioavailability in a range of about 72 to 129% compared to a subcutaneously injected dose of insulin.
• a method for delivering a therapeutic agent into a wall of a lumen of the gastro intestinal (GI) tract of a patient comprising: swallowing a drug delivery device having an interior, an actuator having a first configuration and a second configuration and a therapeutic preparation operably coupled to the actuator, the therapeutic preparation comprising a therapeutically effective dose of at least one therapeutic agent, the preparation being contained within the device interior in the first configuration and advanced out of the interior and into the GI lumen wall in the second configuration by the application of force on the preparation so as to deliver the therapeutic agent into the lumen wall; and actuating the actuator responsive to a condition in the GI lumen to deliver the therapeutic agent from the device into the wall of the GI lumen, wherein a time period between exit of the device from the patients stomach and actuation of the actuator in the patient’s small intestine is not appreciably affected by the presence of food contents in the patient’s GI tract.
• a method for delivering a therapeutic agent into a wall of a small intestine of a patient comprising: swallowing a drug delivery device having an interior, an actuator having a first configuration and a second configuration and a therapeutic preparation operably coupled to the actuator, the therapeutic preparation comprising a therapeutically effective dose of at least one therapeutic agent, the preparation being contained within the device interior in the first configuration and advanced out of the interior and into the GI lumen wall in the second configuration by the application of force on the preparation so as to deliver the therapeutic agent into the lumen wall; and actuating the actuator responsive to a condition in the GI lumen to deliver the therapeutic agent from the device into the wall of the small intestine, wherein the patient does not have a perceptible sensitization when the actuator is actuated.
• Fig. la is a lateral viewing showing an embodiment of 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. 3 is a lateral view illustrating an embodiment of the swallowable drug delivery device having a spring loaded actuation mechanism having a first motion converter.
• Fig. 4 is a lateral view illustrating an embodiment of the swallowable drug delivery device having a spring loaded actuation mechanism having first and a second motion converter.
• Fig. 5 is a perspective view illustrating engagement of the first and second motion converters with the tissue penetrating member and delivery members.
• Fig. 7a is a cross sectional view illustrating an embodiment of the swallowable drug delivery device having multiple tissue penetrating members and an actuating mechanism for advancing the tissue penetrating members.
• 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. 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
• Fig. 28 is a graph of mean insulin plasma concentration and glucose infusion rates vs time illustrating the interactions (e.g., Pharamakokinetic (PK) and Pharmacodynamic (PD)) between mean serum insulin concentrations and mean glucose (dextrose) infusion rates for HRI delivered in the Rani Group during the Euglycemic clamp experiments.
• PK Pharamakokinetic
• PD Pharmacodynamic
• 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. In various embodiments, the delivery may be so configured so as to obtain one or more selectable pharmacokinetic parameters (e.g., T max , absolute bioavailability, relative bioavailability etc.) as well as a desired plasma drug
• Medication 100 typically comprises at least one drug or other therapeutic agent 101 and may include one or more pharmaceutical excipients known in the art. Collectively, one or more of 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 one or more of powder, pellet or other shaped mass.
• 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, hemispherical and combinations thereof. Also, 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 PLGA (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.
• 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.
• all or a portion of the capsule can include radio-opaque/echogenic markers 20m as is shown in the embodiment of Figs la and lb.
• radio-opaque/echogenic markers 20m as is shown in the embodiment of Figs la and lb.
• such materials not only allow for the location of device 10 in the GI tract, but also allow for the determination of transit times of the device through the GI tract.
• 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. Anchoring capsule 20 in such a way reduces the likelihood that the capsule will be displaced or moved by peristaltic contractions occurring during delivery of the medication.
• the amount of anchoring force can be adjusted to the typical forces applied during peristaltic contraction of the small intestine.
• Anchoring can be further facilitated by configured some or all of tissue penetrating members 40 to have a curved or arcuate 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 IW. 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.
• 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 contemplated.
• 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.
• 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. 12/556,524 which is fully incorporated by reference herein for all purposes. In one embodiment,
• 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).
• biodegradation of release element 70 from one or more conditions in the small intestine (or other location in the GI tract) 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, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters as well as other enteric materials known in the art.
• the selected 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.
• 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 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.
• Embodiments of 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.
• 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 (HIFU), 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 (HIFU)
• HIFU high frequency ultrasound
• Suitable materials for seams 22 can include one or more biodegradable materials described herein such as PLGA, 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.
• the swallowable drug delivery device 10 will sometimes be referred to herein as a capsule.
• 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.
• 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.
• 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.
• 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.
• 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 (or other Gl-tract organ wall) can be delivered in conjunction with an injected dose of the agent(s).
• 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 pg 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 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.
• 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.
• 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.
• the dosages of the 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.
• glycosylated hemoglobin known as hemoglobin Ale, HbAlc, AIC, or Hblc
• MicroCorTM patch delivery systems including drug formulations or components, may also be incorporated into the capsules described herein.
• 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., a therapeutic peptide or protein, e.g., IgG and other antibodies, basal and other types of insulin etc.
• a therapeutic peptide or protein e.g., IgG and other antibodies, basal and other types of insulin etc.
• GI gastrointestinal
• proteases and proteases are ubiquitous throughout living systems.
• the GI tract is especially rich in proteases whose function is to break down the complex proteins and peptides in one’s diet into smaller segments and release amino acids which are then absorbed from the intestine.
• 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 Cmax and the time at which this occurs corresponds to Tmax.
• 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.
• tissue penetrating member deployment into the small intestine are contemplated such as one more medical imaging modalities including for example, ultrasound or fluoroscopy.
• 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.
• compositions comprising insulin for the treatment of diabetes or other glucose regulation disorder.
• Such compositions result in the delivery of insulin with desirable pharmacokinetic properties.
• pharmacokinetic metrics of note include Cmax, the peak plasma concentration of a drug after administration; Tmax, the time to reach Cmax; and t 1 ⁇ 2 , the time required for the plasma
• the composition is configured to achieve a T max 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 max 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 substantially greater, such as 5, 10,
• 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 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 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 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.
• 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
• 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).
• 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.
• Other 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 expanded/inflated by pressure from balloon 130 (e.g., pressure generated the mixture of chemical reactants within balloon 130) and/or otherwise allow the passage of liquid between balloons 130 and 160 to initiate a gas generating chemical reaction for inflation of one or both of balloons 130 and 160.
• 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 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.
• 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) wicking of liquid through tube 163 by capillary action.
• 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.
• balloon 130 can comprise a multi-compartment balloon 130mc, that is formed or other constructed to have multiple compartments 130c.
• 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 134 and 135 will have at least a small connecting section 136 between them which is where separation valve 150 will typically be placed.
• a liquid 168 typically water, can be disposed within first compartment 134 and one or more reactants 165 disposed in second compartment 135 (which typically are solid though liquid may also be used) as is shown in the embodiment of Fig. 14a.
• valve 150 opens (e.g., from degradation caused by fluids within the small intestine) liquid 168 enters
• 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.
• PV ideal gas law
• 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 fluidically connected (aligner balloon being fluidically connected to delivery balloon 172 and the deployment balloon 130 being i connected to aligner balloon 160).
• 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.
• 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.
• 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.
• 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.
• Example 1 provides pharmacokinetic data and other results illustrating the achievement of one or more of the above parameters using embodiments of the therapeutic preparations containing IgG which were delivered to canines using embodiments of the swallowable capsule described herein.
• the therapeutic preparation comprises an antibody such as IgG
• the absolute bioavailability of therapeutic agent delivered by embodiments of the invention can be in the range of about 50 to 68.3% with a specific value of 60.7%. Still other values are contemplated as well.
• the T max for delivery of antibodies, for example, IgG can be about 24 hours while the T 1 ⁇ 2 can be in range from about 40.7 to 128 hours, with a specific value of about 87.7 hours.
• Example 1 In Vivo Canine Study of the Delivery of IgG using Embodiments of a Swallowable Capsule
• the Experimental Group i.e., the Rani Group
• samples were collected up to Day 10.
• the PK parameters were estimated by non-compartmental methods from serum samples. Nominal elapsed time from dosing was used to estimate individual PK parameters.
• Serum concentration levels of IgG following IV administration reached Cmax by 3.3 ⁇ 1 hours with a mean concentration of 5339 ⁇ 179 ng/mL.
• IgG serum concentrations in the SC Group for the two animals had a Cmax of 1246 ng/mL at 120 hours and a Cmax of 1510 ng/mL at 72 hours and an average T1/2 of 49.9 hours.
• the mean AUCiast and AUCinf were found to be 274200 ⁇ 21570 and 298300 ⁇ 46130 ng*hr/mL, respectively.
• the mean bioavailability of IgG delivered subcutaneously was calculated to be 50.9%.
• Rani Group i.e., the RaniPill Group
• RHI recombinant human insulin
• PK pharmacokinetic
• PD pharmacodynamic
• Tables 8 and 9 The values in the table are expressed as means ⁇ SEM.
• the C max serum concentrations were 342 ⁇ 50 pM and 516 ⁇ 109 pM for the SC and Rani Groups respectively.
• the AUCs were comparable at 81 ⁇ 10 and 83 ⁇ 18 nmol/L/min for the SC and Rani Groups respectively.
• the T- max for the Rani Group was 139 ⁇ 42 min as compared to 227 ⁇ 24 min for the SC Group. Serum HRI concentration levels in animals of the SC and Rani Group were plotted against time and are shown in Fig. 26.
• Glucose (dextrose) Infusion Rates are shown in Fig. 27.
• the AUC for glucose infusion curves for both the RaniPill and SC Groups were comparable showing that the bioactivity of insulin delivered via the RaniPill is preserved similar to the SC route.
• the relationship between the PK-PD data during the euglcyemic clamp experiments for the Rani Group and SC Group are presented in Figs. 28 and 29 respectively.
• a pilot IRB (Investigational Review Board) study was performed in 10 fasting and 10 postprandial healthy human volunteers to examine the tolerability and safety of an embodiment of the swallowable capsule (the RaniPill Capsule) administered with without a microneedle or drug payload but did have a balloon based deployment mechanism described herein.
• the device was designed to align and deploy in the small intestine as described herein. It also contained a radio-opaque material allowing i) location of the capsule position in the patient’s GI tract; and ii) when the balloon/device deployed. Serial radiographic imaging was used to determine the residence time of the capsule in the stomach and the deployment time within the small intestine.
• the Gastric residence time and deployment time data are shown below in Tables 10 and 11 respectively.
• the mean gastric residence time of the capsule was 217 ⁇ 36 min in the postprandial state and 100 ⁇ 79 min in the fasting state, though the intestinal deployment times were closely similar (100 ⁇ 40 vs. 97 ⁇ 30 min) in both groups. No subject perceived the transit, deployment or excretion of the capsule and all subjects excreted the capsule remnants uneventfully, which was confirmed radiographically within 72-96 hours after capsule ingestion.
• capsule deployment including capsule deployment or activation times were not appreciably affected by the presence of food in the GI tract including one or both of the stomach and small intestine.
• appreciably affected means less than about a 20% difference in deployment/activation times, more preferably, less than about 10 % and still more preferably less than about 5 %.
• patients do not have a perceptible sensation of the capsule passing into, through or existing the GI tract including when the capsule is actuated and deploys in the small intestine (actuation and deployment including the expansion of one more balloons or other expandable device).
• Subject ID GET (min) Subject ID GET (min)
• Subject ID IDT (min) Subject ID IDT (min)

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• 2020
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