Device for oral delivery of therapeutic compounds - Patent Application 20070122997

Abstract

To provide a swallowable device for delivering drugs and other therapeutic agents within a GI tract.SOLUTION: A swallowable device includes a capsule sized to pass through a GI tract, a therapeutic agent disposed in the capsule, an aligner, and a delivery mechanism advancing the therapeutic agent from the capsule inside the GI wall. The delivery mechanism is provided with an expandable member and a piston-cylinder assembly operably coupled to the expandable member. The piston-cylinder assembly is provided with a piston disposed slidably inside the cylinder and, when the swallowable device is swallowed, the piston-cylinder assembly is aligned relative to the GI wall via the aligner so that a long shaft of the piston-cylinder assembly is perpendicular to the surface of the GI wall. The expandable member advances the piston inside the cylinder and applies to the therapeutic agent a force to advance the therapeutic agent in the GI wall.SELECTED DRAWING: Figure 12A

Description

[Technical Field]

[0001] (Citation of Related Application) This application claims the benefit of U.S. Patent Application No. 13 / 837,025 (Attorney Docket No. 42197-715.501), filed March 15, 2013, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION Embodiments of the present invention relate to swallowable drug delivery devices. More particularly, embodiments of the present invention relate to swallowable drug delivery devices for delivering therapeutic agents to the small intestine. [Background technology]

[0003] In recent years, new drugs have been increasingly developed for the treatment of various diseases; however, many, including proteins, antibodies, and peptides, have limited application due to their inability to be administered orally. This is due to several reasons, including poor oral tolerance with complications including stomach discomfort and bleeding, destruction / degradation of drug compounds in the stomach, and poor, slow, or inconsistent drug absorption. Alternative conventional drug delivery methods, such as intravenous and intramuscular delivery, have several drawbacks, including the risk of needlestick pain and infection, the requirement to use sterile technique, and the need and associated risks of maintaining an intravenous line within the patient for extended periods of time. While other drug delivery approaches, such as implantable drug delivery pumps, have been adopted, these approaches require the semi-permanent implantation of a device and may still have many of the limitations of intravenous delivery. Therefore, there is a need for improved methods for the delivery of drugs and other therapeutic agents. Summary of the Invention [Means for solving the problem]

[0004] The present invention provides, for example: (Item 1) 1. A swallowable device for delivering a therapeutic agent formulation into the intestinal wall of a patient's intestinal tract, comprising: a swallowable capsule sized to pass through the intestinal tract, the capsule having a capsule wall that degrades, at least a portion of which degrades in response to exposure to a selected pH in the intestine, while protecting the capsule wall from degradation in the patient's stomach; at least one expandable member assembly disposed within the capsule, the expandable member assembly comprising a first compartment at least partially in an unexpanded state and a second compartment at least partially in an unexpanded state, the first and second compartments fluidly separated by a degradable valve that degrades in response to exposure to fluid within the intestinal tract; a liquid contained within one of the compartments; and a reactant contained in the other compartment, wherein when the valve disassembles, the liquid and the reactant mix, produce gas, and expand at least the second compartment; a delivery mechanism coupled to the second compartment, the delivery mechanism comprising at least one piston-cylinder assembly; at least one tissue penetrating member, a. a proximal portion removably coupled to the delivery mechanism; b. a distal portion of the tissue puncture; c. a therapeutic agent formulation for delivery into the intestinal wall; a tissue piercing member configured to be retained within the intestinal wall, Equipped with In response to expansion of the second compartment, the at least one tissue-piercing member is advanced by the delivery mechanism into the intestinal wall, where it is retained within the intestinal wall to deliver the therapeutic agent into the intestine. (Item 2) the at least one piston-cylinder assembly includes a piston slidably disposed inside a cylinder, the cylinder coupled to a wall of the second compartment, the piston exposing a proximal surface to an interior of the second compartment such that the piston is driven by gas produced in the second compartment; Item 10. The swallowable device of item 1, wherein the piston is configured to advance the tissue piercing member into the intestinal wall as the piston slides inside the cylinder. (Item 3) the piston-cylinder assembly further comprising a needle lumen coupled to the cylinder, the needle lumen providing access to an exterior of the second compartment; 3. The swallowable device of claim 2, wherein the tissue-piercing member is disposed inside the needle lumen and coupled to the piston by a piston rod, the piston rod being sized to be advanced through the needle lumen as the piston slides inside the cylinder. (Item 4) 3. The swallowable device of claim 2, wherein the piston-cylinder assembly further comprises a pressure-sensitive release that prevents the piston from sliding inside the cylinder until a predetermined pressure is reached inside the at least one expandable member. (Item 5) Item 5. The swallowable device of item 4, wherein the pressure-sensitive release portion comprises a tab, a latch, or an O-ring. (Item 6) Item 5. The swallowable device of item 4, wherein the pressure-sensitive release portion is configured to release at a pressure within a range of approximately 8 to 10 psi. (Item 7) 4. The swallowable device of claim 3, further comprising a means for aligning a piston-cylinder assembly, the means for aligning the piston-cylinder assembly being configured to align the piston-cylinder assembly when the second compartment expands such that a longitudinal axis of the piston-cylinder assembly is perpendicular to a surface of the intestinal wall and the tissue-piercing member is advanced perpendicularly into the intestinal wall. (Item 8) Item 8. The swallowable device of item 7, wherein the piston-cylinder assembly alignment means comprises a joint configured to apply a force to the piston-cylinder assembly, urging it into a vertical orientation. (Item 9) Item 4. The swallowable device of item 3, wherein the delivery mechanism comprises an array of piston-cylinder assemblies. (Item 10) 10. The swallowable device of claim 9, wherein the array of piston-cylinder assemblies share a common expansion manifold, the common expansion manifold configured to direct the gas to drive each piston in the array of piston-cylinder assemblies. (Item 11) Item 10. The device of item 1, wherein the degradable valve comprises an O-ring positioned over a dissolvable pinch valve, the pinch valve configured to dissolve upon contact with fluid in the small intestine. (Item 12) Item 3. The device of item 2, wherein the piston-cylinder assembly further comprises an O-ring disposed around the piston to maintain a seal between the piston and the cylinder. (Item 13) Item 10. The device of item 1, wherein the capsule comprises a first capsule portion and a second capsule portion, the first portion disintegrating at a first pH and the second portion disintegrating at a second pH. (Item 14) Item 14. The device of item 13, wherein the first capsule portion covers at least a portion of the degradable valve, and when the first capsule portion degrades, intestinal fluids can flow into the capsule and contact the degradable valve. (Item 15) Item 14. The device of item 13, wherein the first capsule portion degrades at a pH of about 5.5 or greater. (Item 16) Item 14. The device of item 13, wherein the second capsule portion degrades at a pH of about 6.5 or above. (Item 17) Item 14. The device of item 13, wherein the first capsule portion comprises a body and the second capsule portion comprises a cap that fits over the body. (Item 18) Item 1, wherein the pH-degradable portion of the capsule wall comprises a pH-sensitive coating. (Item 19) Item 10. The device of item 1, wherein the valve comprises a sugar. (Item 20) 20. The device of claim 19, wherein the sugar comprises maltose. (Item 21) Item 10. The device of item 1, wherein the reactants comprise at least a first and a second reactant. (Item 22) 22. The device of claim 21, wherein the first and second reactants comprise an acid and a base. (Item 23) 23. The device of claim 22, wherein the first reactant comprises potassium bicarbonate and the second reactant comprises citric acid. (Item 24) Item 10. The device of item 1, wherein the at least one tissue-piercing member comprises a sugar. (Item 25) 25. The device of claim 24, wherein the sugar comprises maltose. (Item 26) 2. The device of claim 1, wherein the therapeutic agent formulation comprises a shaped section disposed within the tissue-piercing member. (Item 27) 2. The device of claim 1, wherein the tissue-piercing member is formed at least in part from the therapeutic agent formulation. (Item 28) Item 10. The device of item 1, wherein the tissue-piercing member includes a retaining feature for retaining the tissue-piercing member within the intestinal wall. (Item 29) Item 10. The device of item 1, wherein the retaining features comprise barbs or hooks. (Item 30) 30. The device of claim 29, wherein the at least one tissue piercing member comprises a plurality of tissue piercing members. (Item 31) 2. The device of claim 1, wherein the intestine is the small intestine and the capsule wall is configured to degrade in response to a selected pH in the small intestine. (Item 32) Item 10. The device of item 1, wherein the expandable member assembly comprises a polymer, a substantially non-flexible polymer, polyethylene, PET, or polyimide. (Item 33) 1. A swallowable device for inserting a therapeutic agent formulation into an intestinal wall of a patient's intestinal tract, comprising: a swallowable capsule sized to pass through the intestinal tract, the capsule having a capsule wall, at least a portion of which disintegrates in response to exposure to a selected pH in the intestine while protecting the capsule wall from degradation in the stomach; at least one expandable member assembly disposed within the capsule, the assembly comprising a first compartment at least partially in an unexpanded state and a second compartment at least partially in an unexpanded state, the first and second compartments fluidly separated by a degradable valve that degrades in response to exposure to fluid within the intestinal tract; a liquid contained within one of the compartments; and a reactant contained in the other compartment, wherein when the valve disassembles, the liquid and the reactant mix, produce gas, and expand at least the second compartment; a delivery mechanism coupled to a wall of the second expandable compartment; and at least one tissue penetrating member, a.) a proximal portion removably coupled to the delivery mechanism; b.) a distal portion of the tissue puncture; c.) a therapeutic agent formulation for delivery into the intestinal wall; and a tissue piercing member configured to be retained within the intestinal wall, Equipped with In response to expansion of the second compartment, the at least one tissue-piercing member is advanced by the delivery mechanism into the intestinal wall where it is retained within the intestinal wall to deliver the therapeutic agent into the intestine; the delivery mechanism comprises a third compartment having a lower portion and an upper portion, the lower portion coupled to a wall of the second compartment having one or more tissue piercing members disposed thereon and directed toward the upper portion and the intestinal wall, the upper portion having one or more penetration needles disposed thereon and directed toward the lower portion; In response to expansion of the second compartment, the lower portion of the third compartment is driven relative to the upper portion of the third compartment, the one or more tissue piercing members are driven through the upper portion of the third compartment and into the intestinal wall, and the one or more penetration needles are driven through the lower portion of the third compartment, thereby penetrating the wall of the second compartment and contracting the expandable member assembly. (Item 34) Item 34. The swallowable device of item 33, wherein an upper portion of the third compartment comprises one or more openings configured to allow the one or more tissue piercing members to pass through and into the intestinal wall. (Item 35) Item 34. The swallowable device of item 33, wherein the one or more tissue piercing members are sufficiently long relative to the one or more penetration needles so that the expandable member assembly is not retracted until the tissue piercing members are inserted into the intestinal wall. (Item 36) Item 34. The swallowable device of item 33, wherein the bottom portion is fabricated from a material that does not allow penetration by the one or more penetration needles until a desired pressure is reached inside the second compartment. (Item 37) 1. A method for delivering a therapeutic agent formulation into the intestinal wall of the intestinal tract of a patient, comprising: providing a swallowable capsule sized to pass through the intestinal tract, the capsule having a capsule wall that at least a portion of which degrades in response to exposure to a selected pH in the intestine while protecting the capsule wall from degradation in the patient's stomach; the swallowable capsule also having at least one expandable member assembly disposed within the capsule, the expandable member assembly including a first compartment at least partially in an unexpanded state and a second compartment at least partially in an unexpanded state, the first and second compartments fluidly separated by a degradable valve that degrades in response to exposure to fluid in the intestinal tract; degrading the degradable valve with fluid in the intestinal tract, thereby allowing a liquid contained in one of the compartments to mix with a reactant contained in the other compartment; producing a gas using a reaction of the liquid and the reactant; inflating at least a second compartment of the expandable member assembly with a gas produced by the reaction of the liquid and the reactant; orienting a cylinder-piston assembly disposed inside the expandable member assembly, the cylinder-piston assembly including a piston slidably disposed inside a cylinder, an interface between the piston and the cylinder sealed with an O-ring, a cylinder coupled to a wall of the second compartment in communication with a needle lumen, and a needle lumen providing access to an exterior of the second compartment; the cylinder-piston assembly is oriented so that the needle lumen is perpendicular to the intestinal wall; using pressure from the gas to drive a piston inside the cylinder toward the exterior of the second compartment, thereby driving a tissue penetrating member disposed within the needle lumen into the intestinal wall using a piston rod coupled between the piston and the tissue penetrating member, the piston rod being sized to be slidable inside the needle lumen; the tissue-piercing member comprising at least the therapeutic agent formulation; A method comprising: Embodiments provide devices, systems, kits, and methods for delivering drugs and other therapeutic agents to various locations within the body. Many embodiments provide swallowable devices for delivering drugs and other therapeutic agents within the GI tract. Certain embodiments provide swallowable devices, such as capsules, for delivering drugs and other therapeutic agents into the walls of the small intestine, large intestine, or other digestive tracts. Embodiments of the present invention are particularly useful for delivering drugs and other therapeutic agents that are poorly absorbed, poorly tolerated, and / or degraded within the GI tract. Furthermore, embodiments of the present invention can be used to deliver drugs and other therapeutic agents, such as proteins, polypeptides, and antibodies, that were previously only possible or preferably delivered via intravenous or other forms of parenteral administration (e.g., intramuscular, etc.). Additionally, embodiments of the present invention are useful for achieving rapid release of drugs into the bloodstream via oral delivery.

[0005] In one aspect, a swallowable device is provided for delivering a drug or other therapeutic agent into the wall of the small or large intestine or other organ of the gastrointestinal tract. The device includes a capsule sized to be swallowed and passed through the gastrointestinal tract; a deployable aligner positioned within the capsule to align the longitudinal axis of the capsule with the 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 delivery mechanism. The capsule wall may include an outer coating or layer that is degradable by contact with fluids in the GI tract but that degrades only at a higher pH than found in the small intestine, and that serves to protect the underlying capsule wall from degradation in the stomach before the capsule reaches the small intestine, at which point drug delivery begins via degradation of the coating. In use, such materials enable targeted delivery of the therapeutic agent into selected portions of the intestinal tract, such as the small intestine. Suitable outer coatings include various enteric coatings, such as various copolymers of methacrylic acid and ethyl acrylate.

[0006] In many embodiments, the capsule is formed of two parts, such as a body and a cap, where the cap fits onto the body, e.g., by fitting over or under the body. One part, such as the cap, can be configured to degrade above a first pH (e.g., pH 5.5), and the second part can be configured to degrade above a second, higher pH (e.g., 6.5). This allows triggers and / or mechanisms in one part of the capsule to be activated before those in other parts of the capsule, because intestinal fluids will flow into those parts first, causing the lower pH coating to degrade and thus activate the trigger (e.g., a degradable valve) in response to such fluids. In use, such embodiments provide several advantages to the drug delivery process, including improved location specificity for drug delivery and improved reliability for such delivery. This is due to the fact that deployment of certain sub-mechanisms, such as the aligner, begins in the upper area of ​​the small intestine SI, allowing the capsule to be aligned within the intestine for optimal delivery, and while the capsule is still in the small intestine or other selected location, deployment / actuation of other mechanisms can allow sufficient time to achieve drug delivery into the intestinal wall.

[0007] In addition to having degradable cap and body sections, selectable portions of the capsule can be configured to allow the entire device to controllably disintegrate into smaller pieces. Such embodiments facilitate passage and evacuation of the device through the GI tract. In certain embodiments, the capsule can include a seam of biodegradable material that controllably disintegrates to produce capsule fragments of selectable sizes and shapes to facilitate passage through the GI tract. The seam can be pre-stressed, perforated, or otherwise treated to accelerate degradation. The seam can also be treated to allow the capsule to split into smaller pieces by the force applied from expansion of a balloon or other expandable member. In other embodiments, to effect capsule disintegration after deployment of the tissue-piercing member, the capsule can include two halves or other divided sections that mechanically fit together, e.g., by a snap fit, and are therefore easily separated by the force applied from balloon inflation.

[0008] The aligner will typically comprise an expandable balloon, known as an aligning balloon, which can be fabricated from a variety of polymers known in the medical device art. The aligning balloon serves to extend the length of the capsule when inflated, so that the capsule aligns in a parallel manner with the longitudinal axis of the small intestine. Furthermore, the aligning balloon can have an expanded shape and length such that, when inflated, the force imparted on the elongated capsule by peristaltic contractions of the intestine serves to align the capsule in a parallel manner with the longitudinal axis of the small intestine. A suitable shape can include an elongated hot dog shape. A suitable length can range from about 1 / 2 to 2 times the length of the capsule. In embodiments where the deployment engine includes the use of an expandable balloon and a chemical reactant, the aligning balloon is fluidly coupled to the deployment balloon such that expansion of the expandable balloon serves to expand the alignment balloon. In some embodiments, the alignment balloon can contain a chemical reactant that reacts upon mixing with water or other liquid from the expandable balloon. In addition to performing an alignment function, expansion of the alignment balloon can also serve to push out various components of the device contained within the capsule, such as a delivery mechanism. In use, such a configuration improves reliability for delivery of therapeutic agents, as it is not necessary to wait for a particular portion of the capsule covering the delivery mechanism to degrade before drug delivery can occur.

[0009] In many embodiments, the deployment member will comprise an expandable balloon, known as a deployment balloon, fluidly coupled to the aligner balloon using a connector tube and a pH-degradable valve that responds to the higher pH found in intestinal fluids. As used herein, the term "fluidically coupled," when applied to two or more elements, means that the two or more elements are connected such that fluid transfer is possible between the elements, e.g., by active pumping or passive flow. In the deployed state, the deployment balloon can have a dome shape corresponding to the shape of the end of the capsule. In many embodiments, the deployment balloon in combination with the aligner balloon can comprise a deployment engine, the deployment balloon containing liquid water, and the aligner balloon containing at least one chemical reactant that reacts in the presence of water to produce a gas, thereby expanding the aligner balloon. The reactants will typically have a ratio of about 1:2, but other ratios are also contemplated. They will include at least two reactants, for example, an acid, such as citric acid, and a base, such as sodium hydroxide or potassium hydroxide. Other reactants are also contemplated, including other acids, e.g., acetic acid, and bases. When the valve or other separating means is opened, the reactants mix in the liquid, producing a gas, such as carbon dioxide, that expands the aligner balloon or other expandable member.

[0010] In one alternative embodiment, the deployment balloon may actually comprise two balloons connected by a connecting tube or other connecting means having a pH-responsive degradable valve. Each of the two balloons may have a half-dome shape, allowing them to fit within the end portions of the capsule when in an expanded state. One balloon may contain a chemical reactant (e.g., sodium bicarbonate, citric acid, etc.) and other liquid water such that, upon degrading of the valve, the two components mix and form a gas (e.g., carbon dioxide), inflating both the balloon / compartment and, in turn, the alignment balloon. In these embodiments, the deployment engine comprises two deployment balloons. In yet another alternative embodiment, the deployment balloon may include at least first and second portions or compartments separated by a separation valve or other separating means. Water may be disposed in the first compartment and a chemical reactant may be disposed in the other compartment. When the valve or other separating means opens, the reactants mix in the liquid and produce a gas used to inflate the alignment balloon and the deployment balloon. In various embodiments using a chemical reactant, the chemical reactant alone can comprise the deployment engine in combination with the deployment balloon to deploy either or both the alignment balloon (or other aligner) or the delivery mechanism. Other forms of deployment engines are also contemplated, such as the use of expandable piezoelectric materials (which expand with the application of a voltage), springs, and other shape memory materials and various thermally expandable materials.

[0011] Various embodiments of the valve separating the alignment balloon from the deployment balloon can be configured to open in several ways and in response to several conditions. Typically, the valve is configured to open by having one or more moieties that degrade in response to the higher pH found in intestinal fluids and may be fabricated from various enteric materials known in the art, such as the various copolymers of methacrylic acid and co-ethyl acrylate described herein. In other embodiments, including those in which the deployment balloon contains a chemical reactant, the valve can be configured to open in response to a selected pressure so that gas from the deployment balloon can inflate the alignment balloon. Similarly, the same or related embodiments of such pressure-sensitive valves can be used to provide inflation of the delivery balloon in response to the generation of sufficient pressure within the alignment balloon so that a continuous inflation effect is achieved. In alternative or additional embodiments, the valve may also be configured to open in response to compressive forces applied by peristaltic contractions in the small intestine. In yet another approach, the valve may be a time-release valve configured to open after a period of time following a patient-initiated activation step, such as peeling a tab or pressing a button.

[0012] Embodiments of the delivery mechanism will typically include an expandable member, such as an expandable balloon (known as a delivery balloon) fluidly coupled to the alignment balloon, and a delivery assembly coupled to the wall of the delivery balloon. At least one tissue-piercing member (TPM) is coupled to the delivery device. In various embodiments, the delivery balloon can have an elongated shape with two relatively flat sides connected by an articulating accordion-like body. The flat sides can be configured to press against the intestinal wall upon expansion of the balloon to insert the TPM into the intestinal wall. The TPM can be positioned on one or both sides, allowing for insertion of the drug-containing TPM into both sides of the intestinal wall. The sides may have sufficient surface area to allow placement of several drug-containing tissue-piercing members on each side.

[0013] The TPM contains a drug or other therapeutic agent and is configured to be inserted into the intestinal wall by expansion of a delivery balloon or other expandable delivery means. The TPM typically comprises a shaft including a proximal portion that is detachably coupled to a delivery device, a tissue-piercing distal portion, and retaining features for retaining the tissue-piercing member within the intestinal wall. However, in some embodiments, the TPM need not include retaining features, but instead can have a shape or be otherwise configured to be retained within the intestinal wall without retaining features. TPMs are described in further detail below.

[0014] In many embodiments, the delivery mechanism device includes a delivery structure coupled to a delivery balloon or other expandable, deployable member. In one embodiment, the delivery structure has an open-box structure including side walls and a bottom wall that collectively define a cavity. The delivery balloon or other delivery member may include multiple support structures to position the TPM within multiple locations in the intestinal wall. In embodiments of a delivery balloon having an accordion-like shape, one or more support structures can be located on each side of the delivery balloon. The support structures can have a monolithic structure and may be fabricated using vacuum forming. The bottom wall is attached to the expandable member, for example, by adhesive. An advancement structure is positioned within the cavity and includes one or more tissue-piercing members removably coupled to the advancement structure. A protective, pierceable film is coupled to the side walls and covers the cavity. The protective film seals the tissue-piercing members inside the advancement structure and serves as a protective barrier for the TPM, protecting them from exposure to humidity and oxidation. In use, the film provides an additional level of protection to prevent the therapeutic agent from being degraded within the intestinal tract before being delivered into the intestinal wall. The film also serves to extend the shelf life of the therapeutic agent formulation by protecting the formulation from exposure to moisture and oxidation.

[0015] The TPM is formed, at least in part, from a therapeutic agent formulation comprising a drug or other therapeutic agent configured to dissolve or otherwise absorb within the intestinal wall so as to deliver the therapeutic agent formulation to the patient's bloodstream. The therapeutic agent formulation may also include one or more pharmaceutical excipients known in the art, e.g., disintegrants, binders, etc. The TPM is desirably configured to penetrate a selected distance into the intestinal wall so as to deliver the therapeutic agent to a particular tissue layer of the intestinal wall, e.g., the mucosal layer, the submucosa, etc. This can be achieved through the use of stops positioned on the TPM shaft and / or configured to cause the TPM shaft to bend or further shear once it has penetrated a selected distance into the intestinal wall.

[0016] Typically, the drug or other therapeutic agent delivered by the TPM will be mixed with a biodegradable polymer such as PGLA and / or a sugar such as maltose. In such embodiments, the TPM may comprise a substantially heterogeneous mixture of drug and biodegradable polymer. Alternatively, the piercing member may include a portion substantially formed from the biodegradable polymer and a separate section or compartment formed from or containing the drug or other therapeutic agent. For example, in one embodiment, the TPM may include an outer shell of biodegradable material with a hollow core mated with a slug (e.g., cylindrical) of therapeutic agent. The tip or tissue-piercing portion of the TPM may comprise a harder material, such as a sugar, to facilitate piercing the tissue. Once placed within the intestinal wall, the tissue-piercing member is broken down by interstitial fluids within the wall tissue, and the drug dissolves in those fluids and is absorbed into the bloodstream by capillaries in or around the intestinal wall tissue. The TPM will also typically include one or more tissue retention features, such as barbs or hooks, to retain the piercing member within the tissue of the intestinal wall after advancement. The retention features can be arranged in various patterns to enhance tissue retention, such as two or more barbs symmetrically distributed around the member shaft. However, the TPM can also be retained within the intestine through other means, such as a reverse taper or other shape. A reverse taper shape may also be combined with one or more retention features to further enhance retention.

[0017] The drug or other therapeutic agent may be in solid form and then formed into the shape of the tissue-piercing member using molding or other similar methods, or may be in solid or liquid form and then added to a biodegradable polymer in liquid form with the mixture and then formed into a TPM using molding or other forming methods known in the polymer art. Desirably, tissue-piercing member embodiments comprising a drug and a degradable polymer are formed (e.g., cured) at a temperature that does not result in any substantial thermal degradation of the 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. In certain embodiments, the amount of thermally degraded drug within the tissue-piercing member is desirably less than about 10% by weight, more preferably less than 5%, and even more preferably less than 1%. The thermal decomposition temperature for a particular drug is known or can be determined using methods known in the art, and this temperature can then be used to select and adjust a particular polymer processing method (e.g., molding, curing, solvent evaporation, etc.).

[0018] For various embodiments of the present invention in which one or more of the aligner, deployment member, and delivery member comprise an expandable balloon, the balloon can have material properties and dimensions (e.g., wall thickness) that allow it to be wrapped (or otherwise disposed within a capsule) to occupy a reduced / minimal space. Thus, various embodiments of expandable balloons used in accordance with the present invention can be thin-walled, e.g., less than about 0.001 inches, and can comprise various non-compliant polymers known in the art, such as PET, polyethylene, and polyimide.

[0019] One or more embodiments of the expandable balloon will also typically include a deflation valve, which serves to deflate the balloon after inflation. The deflation valve can comprise a biodegradable material configured to degrade upon exposure to fluids in the small intestine and / or liquids in one of the balloon's compartments to create an opening or channel for the escape of gas within the balloon. In certain embodiments, the deflation valve comprises a tubular valve attached to the end of the delivery balloon (opposite the end coupled to the aligner balloon). The tubular valve comprises a hollow tube having an end portion filled with a material, such as maltose, that degrades upon exposure to fluids, such as fluids in the small intestine. The positioning of the occlusion material within the tubular valve is configured to provide sufficient time for the delivery balloon to expand and deliver the tissue-piercing member into the intestinal wall before the occlusion material dissolves and opens the tubular valve. According to one or more embodiments, once the deflation valve opens, it deflates not only the delivery balloon, but also the aligner balloon and deployment balloon, as in many embodiments all three are fluidly connected. The opening of the deflation valve can be facilitated by placing it on the end of the delivery balloon and being pushed away from the capsule by inflation of the aligner balloon, so that it has good exposure to the fluids in the small intestine. Similar ductal deflation valves can also be positioned on one or both of the aligner balloon and the deployment balloon. In these latter two cases, the occlusive material in the ductal valve can be configured to degrade over a period of time, allowing sufficient time for inflation of the delivery balloon.

[0020] Additionally, as a further backup to ensure balloon deflation, one or more piercing elements can be attached to the inner surface of the capsule wall to be contacted and penetrated by the piercing elements upon full inflation of one or more balloons used in embodiments of the invention. In another alternative or additional embodiment of the means for deflation of the delivery balloon, one or more of the tissue piercing members can be coupled directly to the delivery balloon and configured to detach from the balloon upon detachment, rupturing the balloon wall in the process. In yet another alternative, one or more tissue piercing members attached on the delivery assembly and / or otherwise to the delivery balloon can be configured to pierce one or both of the delivery balloon and aligner balloon upon inflation of the delivery balloon.

[0021] Another aspect of the present invention provides a therapeutic agent formulation for delivery into the wall of the small intestine (or other wall of a lumen within the intestinal tract) using embodiments of the swallowable device described herein. The formulation comprises a therapeutically effective dose of at least one therapeutic agent (e.g., insulin, incretin, anti-seizure compound, NSAID, antibiotic, etc.). The formulation may comprise a solid, liquid, gel, or combination thereof, and may include one or more pharmaceutical excipients. The formulation has a shape and material consistency to be contained in a swallowable capsule that is delivered from the capsule into the lumen wall and degrades within the lumen wall to release a dose of the therapeutic agent. Typically, this shape and material consistency is achieved by placing or forming the formulation within one or more embodiments of a tissue-piercing member described herein. The formulation may also have a selectable surface area-to-volume ratio to enhance or otherwise control the degradation rate of the formulation within the wall of the small intestine or other body lumen. The dose of the drug or other therapeutic agent in the formulation can be titrated lower than that required for conventional oral delivery methods, which may reduce potential side effects from the drug.

[0022] One embodiment of the present invention is directed to a swallowable device for delivering a therapeutic agent into the intestinal wall of a patient's intestinal tract. The swallowable device includes a swallowable capsule sized to pass through the intestinal tract, the capsule having a capsule wall that degrades at least in part upon exposure to a selected pH in the intestine while protecting the capsule wall from degradation in the patient's stomach. The swallowable device also includes at least one expandable member assembly disposed within the capsule, the expandable member assembly including a first compartment and a second compartment separated by a degradable valve. The degradable valve typically includes an O-ring positioned over a dissolvable pinch valve. The dissolvable pinch valve typically includes a disk or volume of degradable valve material. The degradable valve material is typically configured to dissolve at a selected pH in the intestine. The force of the O-ring, combined with the presence of the degradable valve material, pinches the expandable member assembly, separating the first and second compartments. Dissolution or degradation of the degradable valve material in the intestine causes the expandable member assembly to cease pinching. The first compartment may initially be in at least a partially unexpanded state. The second compartment may initially be in at least a partially unexpanded state. The expandable member assembly may be a balloon. A compartment of the expandable member assembly may be part of the balloon. For purposes of this application, the terms "balloon" and "expandable member" may be used interchangeably. Typically, a liquid will be disposed in one of the compartments for the expandable member assembly, and a reactant will be disposed in the other compartment of the expandable member assembly. When the valve disintegrates, the liquid and reactant mix. The liquid itself may be a reactant. As described, in other embodiments, the liquid and reactant may include an acid and a base, such as citric acid and potassium bicarbonate. Upon mixing of the liquid and reactant, a chemical reaction occurs, producing a gas. The gas may be CO2 or another inert or otherwise biocompatible gas. The gas inflates at least the second compartment of the expandable member assembly. The gas may also inflates the other compartment of the expandable member assembly. The swallowable device further includes a delivery mechanism. The delivery mechanism is typically attached to the wall of the second compartment.The swallowable device also includes at least one tissue-piercing member. The tissue-piercing member includes at least a proximal portion detachably coupled to the delivery mechanism, a tissue-piercing distal portion, and a therapeutic compound for delivery into the patient's intestinal wall. The tissue-piercing member may be configured to be retained within the intestinal wall. The tissue-piercing member is typically also configured to degrade within the intestinal wall, thereby releasing the therapeutic compound. In response to expansion of the second compartment, the at least one tissue-piercing member is advanced by the delivery mechanism into the intestinal wall, where it is retained within the intestinal wall to deliver the therapeutic compound into the intestine. The delivery mechanism may include at least one piston-cylinder assembly. The at least one piston-cylinder assembly is typically disposed inside the second compartment of the expandable member assembly.

[0023] The piston-cylinder assembly typically includes a piston slidably disposed within the cylinder. The cylinder may be coupled to the wall of the expandable member assembly compartment. Typically, the cylinder is coupled to the wall of the second compartment of the expandable member assembly. An adhesive joint may be used to couple the cylinder to the wall of the expandable member assembly. The interface between the piston and the cylinder is typically sealed with a piston O-ring. The piston typically has a proximal surface exposed to the interior of the second compartment. Typically, the cylinder has a distal portion coupled to the wall of the second compartment such that the cylinder lumen communicates with the exterior of the second compartment and is sealed from the interior of the second compartment by the piston O-ring. The cylinder lumen may communicate with the exterior of the second compartment via a needle lumen, which is typically sized with a diameter less than that of the cylinder. The needle lumen provides access to the exterior of the second compartment. The piston is adapted to slide inside the cylinder toward the wall of the second compartment. The piston is configured to advance the tissue-piercing member into the intestinal wall as it slides inside the cylinder. In some embodiments, the tissue-piercing member is disposed inside the needle lumen and coupled to the piston via a piston rod sized to slide inside the needle lumen. The sliding motion of the piston advances the tissue-piercing member from the needle lumen, outside the expandable member assembly, and into the intestinal wall. Typically, gas produced by the mixture of liquid and reactant drives the piston through the cylinder.

[0024] The piston-cylinder assembly may further include a pressure-sensitive release or latch configured to prevent the piston from sliding inside the cylinder until a predetermined pressure is reached inside the second compartment (e.g., by generation of gas or other pressure-generating means).

[0025] The swallowable device may further comprise a means for alignment configured to align the longitudinal axis of the balloon with the longitudinal axis of the intestine. Such a means for alignment may comprise a deployable aligner, such as those described elsewhere herein. The means for alignment may also be the shape of the swallowable device. The shape may be that of an elongated pill or hot dog, and the shape has an aspect ratio and size scale sufficient to necessarily align the longitudinal axis of the swallowable device with the longitudinal axis of the intestine as the swallowable device is advanced through the patient's intestinal tract.

[0026] The swallowable device may further include a means for aligning the piston-cylinder assembly configured to align the piston-cylinder assembly so that the longitudinal axis of the cylinder is oriented perpendicular to the surface of the intestinal wall so that the tissue-piercing member is advanced perpendicularly into the intestinal wall. In some embodiments, the longitudinal axis of the piston-cylinder assembly, defined by the longitudinal axis of the cylinder, is initially aligned with the longitudinal axis of the swallowable device. In response to expansion of the second section of the expandable member assembly, the piston-cylinder assembly is realigned so that the longitudinal axis of the piston-cylinder assembly is perpendicular to the longitudinal axis of the swallowable device. In this alignment, the longitudinal axis of the piston-cylinder assembly is also perpendicular to the intestinal wall. Such means for aligning the piston-cylinder assembly may include an aligner balloon described elsewhere herein. In some embodiments, such means for aligning the piston-cylinder assembly includes a pre-stressed portion of the wall of the second section of the expandable member assembly, to which the piston-cylinder assembly is bonded via an adhesive joint. Once the adhesive joint is created, the second section may be expanded, and the piston-cylinder assembly longitudinal axis may be aligned perpendicular to the wall of the second section. After the joint is created, the piston-cylinder assembly is urged into alignment with the longitudinal axis of the swallowable device, and the second section of the expandable member is contracted. In the contracted state, the piston-cylinder assembly lacks the degree of freedom of movement to align itself perpendicular to the longitudinal axis of the swallowable device. A pre-stressed state is thereby created such that when the second section is later expanded during use, the piston-cylinder assembly will inevitably realign itself perpendicular to the longitudinal axis of the swallowable device and the intestinal wall.

[0027] In some embodiments, the needle lumen providing access to the exterior of the second compartment of the expandable member assembly may have a coating or film that prevents a tissue-piercing member disposed therein from advancing out of the delivery mechanism until sufficient pressure is achieved inside the second compartment of the expandable member such that the piston provides sufficient force to advance the tissue-piercing member through the film or coating.

[0028] In some embodiments, the delivery mechanism includes an array of piston-cylinder assemblies configured to advance a tissue-piercing member into the intestinal wall. The array of piston-cylinder assemblies may share a common inflation manifold configured to direct gas to each piston in the array of piston-cylinder assemblies. The common manifold may have a central lumen communicating with each piston in the array. The central lumen of the common inflation manifold may be coupled to a dedicated inflation balloon, where a chemical reaction produces gas to pressurize the common inflation manifold, thereby driving each cylinder in the array to advance multiple tissue-piercing members. Each piston-cylinder assembly in the array may have an independent pressure release latch configured to prevent movement of the piston within the cylinder until a predetermined pressure is reached within the common inflation manifold. The pressure release latch may allow movement of the piston at different predetermined pressures to control the timing of advancement of the tissue-piercing members.

[0029] Embodiments of the swallowable device may further include a deflation valve assembly configured to deflate the expandable member assembly after delivery of the therapeutic agent. The deflation valve assembly may include an O-ring surrounding a dissolvable pinch valve. The pinch valve isolates an opening in the expandable member assembly that would allow gas trapped therein to escape. The dissolvable pinch valve is configured to dissolve in the intestinal tract at some point after delivery of the therapeutic agent. Upon dissolving the pinch valve, the opening in the expandable member assembly is no longer isolated and gas trapped within the expandable member assembly is free to escape, thereby deflating the expandable member assembly.

[0030] In some embodiments, the delivery mechanism comprises a delivery compartment coupled to a delivery balloon or an expandable member assembly. In the aforementioned embodiment, the delivery balloon corresponds to the second compartment of the expandable member assembly. It should be understood that this embodiment of the delivery mechanism may be combined with any of the embodiments of the swallowable device presented herein. It should be understood that the term "delivery balloon" is synonymous with any part thereof, such as the "expandable member assembly" or the "second compartment of the expandable member assembly." The delivery balloon is inflated by a chemical reaction that produces gas therein. The delivery compartment comprises an upper portion facing a lower portion. The upper portion typically abuts the intestinal wall. The lower portion is coupled to the delivery balloon and has one or more tissue-piercing members disposed thereon that are directed toward the upper portion of the delivery compartment. The upper portion of the delivery compartment has one or more penetration needles disposed thereon that are directed toward the lower portion of the delivery compartment. In response to inflation of the delivery balloon, pressure inside the delivery balloon urges the upper and lower portions of the delivery compartment toward each other. One or more tissue-piercing members are driven into the intestinal wall through the upper portion. The piercing members may have a distal portion containing a therapeutic agent formulation configured to break and remain within the intestinal wall. The upper portion of the delivery compartment may have one or more openings arranged to allow passage of the tissue-piercing members. The penetration needles penetrate the lower portion of the delivery compartment and the delivery balloon, thereby facilitating deflation of the delivery balloon. Typically, the one or more tissue-piercing members have a length longer than the piercing members. Preferably, the one or more tissue-piercing members are sufficiently long relative to the one or more piercing members so that the one or more tissue-piercing members are driven into the intestinal wall before the delivery balloon is inflated. The lower portion of the delivery compartment may be processed to allow penetration by the one or more piercing members only after a desired pressure is achieved in the delivery balloon. This may be done by processing the lower portion of the delivery compartment with a material of appropriate penetration resistance or by adjusting the thickness of the lower portion.

[0031] One aspect of the present invention relates to a method for delivering a therapeutic agent formulation into the intestinal wall of a patient's intestinal tract. The method includes providing a swallowable capsule sized to pass through the intestinal tract. The capsule has a capsule wall that degrades, at least in part, upon exposure to a selected pH in the intestine while protecting the capsule wall from degradation in the patient's stomach. The swallowable capsule may also have at least one expandable member assembly disposed within the capsule. The expandable member assembly includes a first compartment at least partially in an unexpanded state and a second compartment at least partially in an unexpanded state, the first and second compartments being fluidly separated by a degradable valve that degrades upon exposure to fluid in the intestinal tract. The method further includes using fluid in the intestinal tract to degrade the degradable valve, thereby allowing a liquid contained in one of the compartments to mix with a reactant contained in the other compartment. Gas is produced by the reaction of the liquid and the reactant. An exemplary reaction would involve the combination of citric acid (liquid) and potassium bicarbonate (reactant) to produce CO gas. The gas inflates at least the second compartment of the expandable member assembly. The method then further includes orienting a cylinder-piston assembly disposed inside the expandable member assembly, the cylinder-piston assembly including a piston slidably disposed inside the cylinder and an O-ring-sealed interface between the piston and the cylinder. The cylinder may be coupled to a wall of the second compartment and may communicate with the needle lumen. The needle lumen provides access to the exterior of the second compartment. The cylinder-piston assembly is oriented so that the needle lumen is perpendicular to the intestinal wall. The needle lumen communicating with the cylinder is typically aligned with the cylinder. The piston is driven inside the cylinder toward the exterior of the second compartment using pressure from the gas. This drives a tissue piercing member disposed within the needle lumen into the intestinal wall. Driving is achieved by coupling the piston to the tissue piercing member using a piston rod, the piston rod being sized to be slidable inside the needle lumen. The tissue piercing member includes at least a therapeutic agent formulation.

[0032] Another aspect of the present invention provides methods for the delivery of drugs and therapeutic agents into the wall of the GI tract using embodiments of a swallowable drug delivery device. Such methods can be used to deliver therapeutically effective amounts of a variety of drugs and other therapeutic agents. These include several large peptides and proteins that undergo chemical degradation in the stomach or otherwise require injection, such as growth hormone, parathyroid hormone, insulin, interferon (for the treatment of MS and other conditions), and other similar compounds. Suitable drugs and other therapeutic agents that can be delivered by embodiments of the present invention include various antibodies (e.g., HER2 antibodies), chemotherapeutic agents (e.g., interferon), insulin and related compounds for treating diabetes, glucagon-like peptides (e.g., GLP-1, exenatide), parathyroid hormone, growth hormones (e.g., IFG and other growth factors), immunosuppressants (e.g., cyclosporine, cortisone, etc.), vaccines, and antiparasitic agents such as various antimalarials. In a specific embodiment, embodiments of the swallowable capsule can be used to deliver therapeutically effective amounts of the monoclonal antibody adalimumab for the treatment of various autoimmune-related disorders, such as rheumatoid arthritis. The dosage of this or a particular therapeutic agent can be titrated to the patient's weight, age, condition, or other parameters.

[0033] In various method embodiments of the present invention, swallowable drug delivery device embodiments can be used to deliver multiple drugs for the treatment of multiple conditions or for the treatment of a specific condition (e.g., a mixture of protease inhibitors for the treatment of HIV AIDS). In use, such embodiments allow a patient to avoid having to take multiple drugs for one or more specific conditions. They also provide a means for facilitating the delivery and absorption of two or more drug regimens into the small intestine and, therefore, the bloodstream, at approximately the same time. Due to differences in chemical composition, molecular weight, etc., drugs can be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves. Embodiments of the present invention address this issue by injecting the desired drug mixture at approximately the same time. This, in turn, improves the pharmacokinetics and, therefore, the effectiveness of the selected mixture of drugs.

[0034] Further details of these and other embodiments and aspects of the present invention are described more fully below with reference to the accompanying drawings. [Brief explanation of the drawings]

[0035] [Figure 1A] FIG. 1A is a side view illustrating an embodiment of a swallowable drug delivery device. [Figure 1B] FIG. 1B is a side view illustrating an embodiment of a system including a swallowable drug delivery device. [Figure 1C] FIG. 1C is a side view illustrating an embodiment of a kit including a swallowable drug delivery device and a set of instructions for use. [Figure 1D] FIG. 1D is a side view illustrating an embodiment of a swallowable drug delivery device including a drug reservoir. [Figure 1E] FIG. 1E is a side view illustrating the use of an embodiment of a swallowable drug delivery device, including transport of the device within the GI tract, and operation of the device to deliver a drug. [Figure 2]2A and 2B are side views illustrating an embodiment of a capsule for a swallowable drug delivery device, including a cap and body coated with a pH-sensitive biodegradable coating, with FIG. 2A showing the capsule in an unassembled state and FIG. 2B showing the capsule in an assembled state. [Figure 3A] 3A and 3B illustrate embodiments of non-folded multi-balloon assemblies containing a deployment balloon, an aligner balloon, a delivery balloon, and assorted connecting tubing, with FIG. 3A showing an embodiment of the assembly for a single-dome configuration of the deployment balloon and FIG. 3B showing an embodiment of the assembly for a double-dome configuration of the deployment balloon. [Figure 3B] 3A and 3B illustrate embodiments of non-folded multi-balloon assemblies containing a deployment balloon, an aligner balloon, a delivery balloon, and assorted connecting tubing, with FIG. 3A showing an embodiment of the assembly for a single-dome configuration of the deployment balloon and FIG. 3B showing an embodiment of the assembly for a double-dome configuration of the deployment balloon. [Figure 3C] FIG. 3C is a perspective view illustrating an embodiment of a nested balloon configuration that may be used for one or more embodiments of the balloons described herein, including aligner balloons. [Figure 4A] 4A-4C are side views illustrating an embodiment of a multi-compartment deployment balloon, where FIG. 4A shows the balloon in an uninflated state with the isolation valves closed, FIG. 4B shows the balloon with the valves open and with mixing of chemical reactants, and FIG. 4C shows the balloon in an inflated state. [Figure 4B] 4A-4C are side views illustrating an embodiment of a multi-compartment deployment balloon, where FIG. 4A shows the balloon in an uninflated state with the isolation valves closed, FIG. 4B shows the balloon with the valves open and with mixing of chemical reactants, and FIG. 4C shows the balloon in an inflated state. [Figure 4C]4A-4C are side views illustrating an embodiment of a multi-compartment deployment balloon, where FIG. 4A shows the balloon in an uninflated state with the isolation valves closed, FIG. 4B shows the balloon with the valves open and with mixing of chemical reactants, and FIG. 4C shows the balloon in an inflated state. [Figure 5A] Figures 5A-5G are side views illustrating a method for folding multiple balloon assemblies, where the folding configurations in each figure apply to both single and double dome configurations of deployed balloons, with Figure 5C relating to a folding step unique to the double dome configuration, Figure 5D relating to a final folding step unique to the double dome configuration, Figure 5E relating to a folding step unique to the single dome configuration, and Figures 5F and 5G being orthogonal views relating to a final folding step unique to the single dome configuration. [Figure 5B] Figures 5A-5G are side views illustrating a method for folding multiple balloon assemblies, where the folding configurations in each figure apply to both single and double dome configurations of deployed balloons, with Figure 5C relating to a folding step unique to the double dome configuration, Figure 5D relating to a final folding step unique to the double dome configuration, Figure 5E relating to a folding step unique to the single dome configuration, and Figures 5F and 5G being orthogonal views relating to a final folding step unique to the single dome configuration. [Figure 5C] Figures 5A-5G are side views illustrating a method for folding multiple balloon assemblies, where the folding configurations in each figure apply to both single and double dome configurations of deployed balloons, with Figure 5C relating to a folding step unique to the double dome configuration, Figure 5D relating to a final folding step unique to the double dome configuration, Figure 5E relating to a folding step unique to the single dome configuration, and Figures 5F and 5G being orthogonal views relating to a final folding step unique to the single dome configuration. [Figure 5D]Figures 5A-5G are side views illustrating a method for folding multiple balloon assemblies, where the folding configurations in each figure apply to both single and double dome configurations of deployed balloons, with Figure 5C relating to a folding step unique to the double dome configuration, Figure 5D relating to a final folding step unique to the double dome configuration, Figure 5E relating to a folding step unique to the single dome configuration, and Figures 5F and 5G being orthogonal views relating to a final folding step unique to the single dome configuration. [Figure 5E] Figures 5A-5G are side views illustrating a method for folding multiple balloon assemblies, where the folding configurations in each figure apply to both single and double dome configurations of deployed balloons, with Figure 5C relating to a folding step unique to the double dome configuration, Figure 5D relating to a final folding step unique to the double dome configuration, Figure 5E relating to a folding step unique to the single dome configuration, and Figures 5F and 5G being orthogonal views relating to a final folding step unique to the single dome configuration. [Figure 5F] Figures 5A-5G are side views illustrating a method for folding multiple balloon assemblies, where the folding configurations in each figure apply to both single and double dome configurations of deployed balloons, with Figure 5C relating to a folding step unique to the double dome configuration, Figure 5D relating to a final folding step unique to the double dome configuration, Figure 5E relating to a folding step unique to the single dome configuration, and Figures 5F and 5G being orthogonal views relating to a final folding step unique to the single dome configuration. [Figure 5G] Figures 5A-5G are side views illustrating a method for folding multiple balloon assemblies, where the folding configurations in each figure apply to both single and double dome configurations of deployed balloons, with Figure 5C relating to a folding step unique to the double dome configuration, Figure 5D relating to a final folding step unique to the double dome configuration, Figure 5E relating to a folding step unique to the single dome configuration, and Figures 5F and 5G being orthogonal views relating to a final folding step unique to the single dome configuration. [Figure 6] 6A and 6B are orthogonal views illustrating an embodiment of a final folded multi-balloon assembly with a delivery assembly attached. [Figure 7] 7A and 7B are orthogonal transparent views illustrating an embodiment of the final folded multi-balloon assembly inserted into the capsule. [Figure 8A] FIG. 8A is a side view of an embodiment of a tissue-piercing member. [Figure 8B] FIG. 8B is a bottom view of an embodiment of a tissue penetrating member illustrating placement of a tissue retaining feature. [Figure 8C] FIG. 8C is a side view of an embodiment of a tissue penetrating member having a trocar tip and an inverted tapered shaft. [Figure 8D] FIG. 8D is a side view of an embodiment of a tissue-piercing member having a separate drug-containing section. [Figure 8E] Figures 8E and 8F are side views showing the assembly of an embodiment of a tissue-piercing member having a shaped drug-containing segment, Figure 8E showing the tissue-piercing member and shaped drug segment before assembly and Figure 8F showing the tissue-piercing member and shaped drug segment after assembly. [Figure 8F] Figures 8E and 8F are side views showing the assembly of an embodiment of a tissue-piercing member having a shaped drug-containing segment, Figure 8E showing the tissue-piercing member and shaped drug segment before assembly and Figure 8F showing the tissue-piercing member and shaped drug segment after assembly. [Figure 9] FIG. 9 provides a breakdown of the components and steps used to assemble an embodiment of the delivery assembly. [Figure 10A] 10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 10B] 10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 10C] 10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 10D] 10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 10E]10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 10F] 10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 10G] 10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 10H] 10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 10I] 10A-10I provide a schematic diagram illustrating the method of operation of a swallowable device for delivering medication to the intestinal wall. [Figure 11] Figure 11A shows an embodiment of a swallowable drug delivery device including a capsule with a biodegradable seam positioned to cause controlled degradation of the capsule in the GI tract, and Figure 11B shows the embodiment of Figure 11A after it has been degraded into smaller pieces in the GI tract. [Figure 12A] 12A-B show an embodiment of the capsule having a piston-cylinder assembly. [Figure 12B] 12A-B show an embodiment of the capsule having a piston-cylinder assembly. [Figure 12C] FIG. 12C shows an embodiment of a delivery mechanism having an array of piston-cylinder assemblies. [Figure 12D] FIG. 12D shows an embodiment of a capsule having a piston-cylinder assembly and a deflation valve. [Figure 13A] FIG. 13A shows an embodiment of a delivery mechanism having a delivery balloon and a delivery compartment. [Figure 13B] FIG. 13B depicts the balloon inflation pressure curve, including the penetration pressure at which the penetration needle penetrates the balloon. [Figure 14] FIG. 14 shows an embodiment of a capsule with biodegradable seams that includes pores and / or perforations to accelerate the biodegradation of the capsule. [Figure 15] 15A-15B show embodiments of a capsule having rupturable seams arranged in a radial or lateral pattern for rupturing the capsule upon inflation of an expandable balloon, with FIG. 15A showing the capsule before inflation and FIG. 15B showing the capsule broken into pieces by inflation of the balloon. [Figure 16] FIG. 16 shows an embodiment of a balloon-rupturable capsule fabricated from separate pieces joined by a seam that can be ruptured by inflation of an expandable balloon. DETAILED DESCRIPTION OF THE INVENTION

[0036] Embodiments of the present invention provide devices, systems, and methods for delivering medication into various locations within the body. As used herein, the term "medication" refers to any form of pharmaceutical preparation, which may include a drug or other therapeutic agent and one or more pharmaceutical excipients. Many embodiments provide swallowable devices for delivering medication within the GI tract. Certain embodiments provide swallowable devices, such as capsules, for delivering medication to the wall of the small intestine or other digestive organs.

[0037] 1-9 , an embodiment of a device 10 for delivery of a medicament 100 to a delivery site DS in the gastrointestinal (GI) tract comprises a capsule 20 sized to be swallowed and passed through the intestinal tract, a deployment member 30, one or more tissue-piercing members 40 containing the medicament 100, a deployable aligner 60, and a delivery mechanism 70. The deployable aligner 60 is positioned within the capsule and configured to align the capsule with an intestine, such as the small intestine. Typically, this would involve aligning the longitudinal axis of the capsule with the longitudinal axis of the intestine; however, other alignments are also contemplated. The delivery mechanism 70 is configured to deliver the medicament 100 into the intestinal wall and would typically include a delivery member 72, such as an expandable member. The deployment member 30 is configured to deploy at least one of the aligner 60 or the delivery mechanism 70. As will be further described herein, all or a portion of the capsule wall is degradable by contact with fluid in the GI tract, allowing the fluid to trigger delivery of the medicament 100 by the device 10. As used herein, the "GI tract" refers to the esophagus, stomach, small intestine, large intestine, and anus, while the "intestinal tract" refers to the small intestine and large intestine. Various embodiments of the present invention can be configured and arranged for delivery of the medicament 100 into both the intestinal tract and the entire GI tract.

[0038] The device 10, including the tissue-piercing member 40, can be configured for delivery of a medicament 100 in liquid, semi-liquid, or solid form, or a combination of all three. Whatever form, the medicament 100 desirably has a material consistency that allows the medicament to be advanced from the device 10 into the intestinal wall (small or large intestine) or other luminal wall in the GI tract and then disintegrate within the intestinal wall, releasing the drug or other therapeutic agent 101. The material consistency of the medicament 100 can include one or more of the formulation's hardness, porosity, and solubility (in bodily fluids). Material consistency can be achieved by the selection and use of one or more of: i) the compression force used to create the formulation; ii) the use of one or more pharmaceutical disintegrants known in the art; iii) the use of other pharmaceutical excipients; iv) the formulation's particle size and distribution (e.g., micronized particles); and v) the use of micronization and other particle formation methods known in the art.

[0039] A system 11 for delivery of a pharmaceutical agent 100 into the wall of the small intestine or elsewhere in the intestinal or GI tract may include a device 10 containing one or more medications 100 for the treatment of a selected condition or conditions. In some embodiments, the system may include a handheld device 13 described herein for communicating with the device 10, as shown in the embodiment of FIG. 1B. In many embodiments, the system 11 may also be configured as a kit 14 including the system 11 and a set of instructions for use 15, packaged in packaging 12, as shown in the embodiment of FIG. 1C. The instructions may instruct the patient when to take the device 10 in relation to one or more events, such as food intake, or physiological measurements, such as blood glucose, cholesterol, etc. In such embodiments, the kit 14 may include multiple devices 10 containing a dosing regimen of medication 100 over a selected period of administration, e.g., daily, weekly, or multiple weeks, depending on the condition being treated (e.g., treatment of cancer with a course of interferon therapy, treatment of an autoimmune disease such as psoriasis, multiple sclerosis or arthritis with immunosuppressants).

[0040] The capsule 20 is sized to be swallowed and passed through the intestinal tract. Size can also be adjusted depending on the amount of medication to be delivered, as well as the patient's weight and adult versus pediatric application. Typically, the capsule has a tubular shape with curved ends similar to a vitamin. In these and related embodiments, the capsule length 20L can be in the range of 0.5 to 2 inches, and the diameter 20D can be in the range of 0.1 to 0.5 inches, although other dimensions are also contemplated. The capsule 20 includes a capsule wall 21w having an outer surface 25 and an inner surface 24 that define an interior space or volume 24v. In some embodiments, the capsule wall 21w can include one or more openings 26 sized for outward advancement of the tissue-piercing member 40. In addition to other components of the device 10 (e.g., an expandable member, etc.), the interior volume can include one or more compartments or reservoirs 27.

[0041] The capsule can be fabricated from various biodegradable gelatin materials known in the pharmaceutical arts, but can also include various enteric coatings 20c configured to protect the cap from degradation in the stomach (e.g., due to acid) and then subsequently degrade at the higher pH found in the small intestine or other areas of the intestinal tract. In various embodiments, the capsule 20 can be formed from multiple parts, one or more of which can be biodegradable. In many embodiments, the capsule 20 can be formed from two parts 20p, such as a body part 20p'' (herein, body 20p'') and a cap part 20p' (herein, cap 20p'), where the cap fits over the body, e.g., by sliding over or under the body (other arrangements are also contemplated). One portion, such as cap 20p', can include a first coating 20c' configured to degrade above a first pH (e.g., pH 5.5), and a second portion, such as body 20p'', can include a second coating 20c'' configured to degrade above a second, higher pH (e.g., 6.5). Both the interior 24 and exterior 25 surfaces of capsule 20 are coated with coatings 20c' and 20c'' such that either portion of the capsule will be substantially preserved until contacted with a fluid having a selected pH. In the case of body 20p'', this allows the structural integrity of body 20p'' to be maintained, keeping balloon 72 inside the body portion and preventing deployment until balloon 30 is expanded. Coatings 20c' and 20c'' can include various methacrylic acid and ethyl acrylate-based coatings, such as those manufactured by Evonik Industries under the trade name EUDRAGIT. These and other dual-coat configurations of capsule 20 allow mechanisms in one portion of capsule 20 to be activated before those in the other portion of the capsule. This is due to the fact that intestinal fluids enter those portions first, degrading the lower pH coating and therefore the activation trigger (e.g., a degradable valve) that responds to such fluids.In use, such dual-coating embodiments for capsule 20 provide targeted drug delivery to specific locations within the small intestine (or other locations within the GI tract) as well as improved reliability in the delivery process. This is due to the fact that deployment of certain components, such as aligner 60, can be configured to begin in an 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), and 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.

[0042] As previously mentioned, one or more portions of capsule 20 can be fabricated from a variety of biocompatible polymers known in the art, including various biodegradable polymers, and in preferred embodiments, can comprise cellulose, gelatin materials, and PGLA (polylactic-co-glycolic acid). Other suitable biodegradable materials include the various enteric materials described herein, as well as lactide, glycolide, lactic acid, glycolic acid, paradioxanone, caprolactone, trimethylene carbonate, caprolactone, blends and copolymers thereof.

[0043] The use of biodegradable materials for capsule 20, including biodegradable enteric materials, allows the capsule to degrade in whole or in part, facilitating transit through the GI system before, during, or after drug delivery. As described in further detail herein, in various embodiments, capsule 20 can include seams 22 of biodegradable material to controllably degrade into smaller pieces 23 that can be more easily passed through the intestinal tract.

[0044] In various embodiments, the capsule wall 20w is degradable by contact with fluids in the GI tract, e.g., fluids in the small intestine. In preferred embodiments, the capsule wall is configured to remain intact during passage through the stomach but then degrade in the small intestine. In one or more embodiments, this can be achieved by the use of an outer coating or layer 20c on the capsule wall 20w that degrades only at the higher pH found in the small intestine and serves to protect the underlying capsule wall from degradation in the stomach before the capsule reaches the small intestine (at which point the drug delivery process begins with the degradation of the coating, as described herein). In use, such a coating allows for targeted delivery of a therapeutic agent in a selected portion of the intestinal tract, such as the small intestine.

[0045] In various embodiments, capsule 20 can include various radiopaque, echogenic, or other materials to identify the location of the device using one or more medical imaging modalities, such as fluoroscopy, ultrasound, MRI, etc. In a specific embodiment, all or a portion of the capsule can include radiopaque / echogenic markers 20m, as shown in the embodiment of FIGS. 1a and 1b. Suitable materials for radiopaque markers 20m include barium sulfate, compounds, titanium dioxide, and compounds thereof. In use, such materials provide the location of device 10 within the GI tract as well as its deployment status (e.g., one distinctive marker positioned on cap 20p′ and another on body 20p″ can enable determination of whether deployment balloon 30 (discussed below) has been inflated but delivery balloon 72 has not). They can also be used to enable determination of the transit time of the device through the GI tract. Such information can be used to titrate medication dosages for particular patients and, in the case of insulin taken to treat diabetes, provide information regarding when a particular medication should be taken after an event, such as the ingestion of a meal. Markers 20m may also be positioned on the capsule 20 to allow the physician to determine whether the capsule is intact or ruptured.

[0046] As discussed further herein, in many embodiments, one or more of the deployment member 30, delivery member 72, or deployable aligner 60 may correspond to an expandable balloon that is shaped and sized to fit within the capsule 20. Thus, for ease of discussion, the deployment member 30, delivery member 72, and deployable aligner 60 will be referred to herein as balloons 30, 60, and 72. However, it should be understood that other devices, including various expandable devices, are also contemplated for these elements and may include, for example, various shape memory devices (e.g., expandable baskets made from cusps of shape memory biodegradable polymers), expandable piezoelectric devices, and / or chemically expandable devices having an expanded shape and size that corresponds to the interior volume 24v of the capsule 20.

[0047] One or more of balloons 30, 60, and 72 can comprise various polymers known in the medical device art. In preferred embodiments, 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), as well as other forms of polyethylene known in the art. In one or more embodiments using polyethylene, the material may be crosslinked using polymer irradiation methods known in the art. In certain embodiments, radiation-based crosslinking may be used to control the balloon's expanded diameter and shape by reducing the flexibility of the balloon material. The amount or radiation may be selected to achieve a specific amount of crosslinking and, therefore, a specific amount of flexibility for a given balloon; for example, increased radiation can be used to produce a stiffer, less flexible balloon material. Other suitable polymers include PET (polyethylene terephthalate), silicone, and polyurethane. In various embodiments, balloons 30, 60, and 72 may also comprise various radiopaque materials known in the art, such as barium sulfate, to allow a physician to verify the balloon's position and physical state (e.g., uninflated, inflated, or penetrated). Balloons 30, 60, and 72 can be fabricated using various balloon blowing methods (e.g., mold blowing, free blowing, etc.) known in the balloon catheter art to have a shape and size that approximately corresponds to the interior volume 24v of capsule 20. In various embodiments, one or more of balloons 30, 60, and 72 and various connecting features (e.g., connecting tubing) can have a unitary structure formed from a single mold. Embodiments employing such a unitary structure offer the advantages of improved manufacturability and reliability, as fewer joints must be made between one or more components of device 10.

[0048] Suitable shapes for balloons 30, 60, and 72 include various cylindrical shapes with tapered or curved end portions (an example of such a shape includes a hot dog). In some embodiments, the inflated size (e.g., diameter) of one or more of balloons 30, 60, and 72 can be larger than capsule 20 so as to separate the capsule from the forces of inflation (e.g., due to hoop stress). In other related embodiments, the inflated size of one or more of balloons 30, 60, and 72 can be such that, upon inflation, i) capsule 20 makes sufficient contact with the wall of the small intestine to induce peristaltic contractions and cause contraction of the small intestine around the capsule, and / or ii) small intestinal folds disappear. Both of these results allow for improved contact between the capsule / balloon surface and the intestinal wall to deliver tissue-piercing member 40 over selected areas of the capsule and / or delivery balloon 72. Desirably, the walls of balloons 30, 60, and 72 can be thin, having wall thicknesses in the range of 0.005 to 0.0001 inches, more preferably in the range of 0.005 to 0.0001 inches (specific embodiments are 0.004, 0.003, 0.002, 0.001, and 0.0005). Additionally, in various embodiments, one or more of balloons 30, 60, or 72 can have a nested balloon configuration, having inflation chambers 60IC and extending fingers 60EF, as shown in the embodiment of FIG. 3C. Connecting tubing 63 connecting inflation chambers 60IC can be narrow to allow only the passage of gas 68, while connecting tubing 36 joining the two halves of balloon 30 can be larger to allow the passage of water.

[0049] As mentioned above, the aligner 60 typically comprises an expandable balloon and, for ease of discussion, will be referred to herein as the aligner balloon 60 or balloon 60. The balloon 60 can be fabricated using the materials and methods described above. It has an unexpanded and an expanded state (also referred to as a deployed state). In its expanded or deployed state, the balloon 60 extends the length of the capsule 20 such that forces imparted by peristaltic contractions of the small intestine SI on the capsule 20 serve to align the longitudinal axis 201A of the capsule 20 in a parallel manner with the longitudinal axis LAI of the small intestine SI. This, in turn, serves to align the shaft of the tissue-piercing member 40 in a perpendicular manner with the surface of the intestinal wall IW, enhancing and optimizing penetration of the tissue-piercing member 40 into the intestinal wall IW. In addition to serving to align capsule 20 within the small intestine, aligner 60 is also configured to push delivery mechanism 70 out of capsule 20 prior to inflation of delivery balloon 72 so that the delivery balloon and / or mechanism are not obstructed by the capsule. In use, this pushing function of aligner 60 improves reliability for delivery of therapeutic agents because it is not necessary to wait for certain portions of the capsule (e.g., those covering the delivery mechanism) to degrade before agent delivery can occur.

[0050] Balloon 60 may be fluidly coupled to one or more components of device 10, including balloons 30 and 72, using polymer tubing or other fluid couplers 62, which may include tubing 63 for coupling balloons 60 and 30 and tubing 64 for coupling balloons 60 and 72. Tube 63 is configured to allow balloon 60 to be expanded / inflated by pressure from balloon 30 (e.g., pressure generated from a mixture of chemical reactants within balloon 30) and / or otherwise allow the passage of liquid between balloons 30 and 60 to initiate a gas-generating chemical reaction for inflation of one or both of balloons 30 and 60. Tube 64 connects balloon 60 to balloon 72 to allow inflation of balloon 72 by balloon 60. In many embodiments, tube 64 includes or is coupled to control valve 55, configured to open at a selected pressure to control inflation of balloon 72 by balloon 60. Tube 64 may thus comprise a proximal portion 64p that connects to the valve and a distal portion 64d that leads from the valve. Typically, the proximal and distal portions 64p and 64d will be connected to the valve housing 58, as described below.

[0051] Valve 55 may comprise a triangular or other shaped section 56 of material 57 mounted within chamber 58c of valve housing 58 (alternatively, it may be mounted directly within tubing 64). Section 57 is configured to mechanically degrade (e.g., tear, shear, peel, etc.) at a selected pressure to allow passage of gas through tubing 64 and / or valve chamber 58c. Suitable materials 57 for valve 55 may include beeswax or other forms of wax and various adhesives known in the medical arts, having selectable sealing force / burst pressure. Valve fitting 58 will typically comprise a thin cylindrical section (made from a biodegradable material) within which section 56 of material 57 is mounted to seal the walls of chamber 58c together or otherwise occlude passage of fluid through the chamber (as shown in the embodiment of FIG. 3B). The discharge pressure of valve 55 can be controlled through selection of one or more of the size and shape of section 56 and selection of material 57 (e.g., for properties such as adhesive strength, shear strength, etc.). In use, control valve 55 allows for sequenced inflation of balloons 60 and 72, such that balloon 60 is fully or otherwise substantially inflated before balloon 72 is inflated. This, in turn, allows balloon 60 to push balloon 72, along with the rest of delivery mechanism 70, out of capsule 20 (typically from body portion 20p′) before balloon 72 is inflated, such that deployment of tissue-piercing members 40 is not occluded by capsule 20. In use, such an approach improves the reliability of penetration of tissue-piercing members 40 into intestinal wall IW, both in terms of achieving the desired penetration depth and delivering a larger number of piercing members 40 contained within capsule 20, since advancement of the members into intestinal wall IW is not occluded by capsule wall 20w.

[0052] As previously mentioned, the inflated length 601 of the aligner balloon 60 is sufficient to align the capsule 20 with the lateral axis of the small intestine from peristaltic contractions of the intestine. Suitable inflated lengths 601 for the aligner 60 include a range of approximately ½ to 2 times the length 201 of the capsule 20 prior to inflation of the aligner 60. Suitable shapes for the aligner balloon 60 include various elongated shapes, such as a hot dog shape. In a specific embodiment, the balloon 60 can include a first section 60′ and a second section 60″, where expansion of the first section 60′ is configured to advance the delivery mechanism 70 from the capsule 20, and typically, expansion of the second section 60″ is used to inflate the delivery balloon 72. In these and related embodiments, the first and second segments 60′ and 60″ can be configured to have a telescoping expansion, with the first segment 60′ expanding first, pushing the mechanism 70 out of the capsule (typically from the body portion 20p′), and the second segment 60″ expanding, inflating the delivery member 72. This can be achieved by configuring the first segment 60′ to have a smaller diameter and volume than the second segment 60″, such that the first segment 60′ expands first (due to its smaller volume) and the second segment 60″ does not expand until the first segment 60′ is substantially expanded. In one embodiment, this can be facilitated by the use of control valve 55 (described above) connecting segments 60′ and 60″, which do not allow the passage of gas into segment 60″ until a minimum pressure is reached within segment 60′. In some embodiments, the aligner balloon can contain a chemical reactant that reacts upon mixing with water or other liquid from the expandable balloon.

[0053] In many embodiments, the deployment member 30 will comprise an expandable balloon, known as a deployment balloon 30. In various embodiments, the deployment balloon 30 is configured to facilitate the deployment / expansion of the aligner balloon 60 through the use of a gas, for example, the generation of gas 69 from a chemical. The gas may be generated by the reaction of solid chemical reactants 65, such as an acid 66 (e.g., citric acid) and a base 66 (e.g., potassium bicarbonate, sodium bicarbonate, and the like), which are then mixed with water or other aqueous liquid 68. The amounts of reactants are chosen using a stoichiometric method to produce a selected pressure within one or more of the balloons 30, 60, and 72. The reactants 65 and liquid can be stored separately within the balloons 30 and 60 and then combined in response to a triggering event, such as pH conditions within the small intestine. Reactant 65 and liquid 68 can be stored in either balloon; however, in a preferred embodiment, liquid 68 is stored in balloon 30 and reactant 65 is stored in balloon 60. To allow the passage of liquid 68 and initiate the reaction and / or resultant gas 69, balloon 30 may be coupled to aligner balloon 60 using connector tube 63, which typically also includes a separation means 50, such as a degradable valve 50 described below. For embodiments in which balloon 30 contains a liquid, tube 63 has a diameter sufficient to allow the passage of sufficient water from balloon 30 to balloon 60 and to produce the desired amount of gas to inflate inflated balloon 60 and inflated balloon 72. Also, when balloon 30 contains a liquid, one or both of balloon 30 and tube 63 are configured to allow the passage of liquid to balloon 60 by one or more of: i) compressive forces applied to balloon 30 by peristaltic contractions of the small intestine over exposed balloon 30; and ii) wicking of liquid through tube 63 by capillary action.

[0054] The tube 63 will typically include a degradable isolation valve or other isolation means 50 that separates the contents of the balloon 30 (e.g., water 58) from those of the balloon 60 (e.g., reactant 65) until the valve degrades. The valve 50 can be fabricated from a material, such as maltose, that is degradable by liquid water so that the valve opens in response to exposure to water, along with the various fluids in the digestive tract. It may also be made from a material, such as a methacrylate-based coating, that is degradable in response to the higher pH found in intestinal fluids. The valve is desirably positioned on the tube 63 in a location that protrudes above and / or is otherwise sufficiently exposed to the balloon 30 so that, once the cap 20p' degrades, the valve 50 is exposed to the intestinal fluids that flow into the capsule. In various embodiments, the valve 50 can be positioned at or even protrude above the surface of the balloon 30 so as to have clear exposure to the intestinal fluids once the cap 20p' degrades (as shown in the embodiment of FIGS. 6A and 6B). Various embodiments of the present invention provide several structures for the isolation valve 50, such as a beam-like structure (where the valve comprises a beam that presses against the tube 63 and / or the connecting section 36), or a collar-type structure (where the valve comprises a collar over the tube 63 and / or the connecting section 36). Still, other valve structures are also contemplated.

[0055] The balloon 30 has a deployed and undeployed state. In the deployed state, the deployment balloon 30 can have a dome shape 30d corresponding to the shape of the end of the capsule. Other shapes 30s for the deployment balloon 30, such as a spherical or tubular shape, are also contemplated. The reactants 65 will typically include at least two reactants 66 and 67, e.g., an acid such as citric acid and a base such as sodium bicarbonate, which may have a ratio of about 1:2. Other reactants 65, including other acids, e.g., acetic acid, and bases, e.g., sodium hydroxide, are also contemplated. When the valve or other separation means 50 is opened, the reactants mix in the liquid, producing a gas, such as carbon dioxide, which inflates the aligner balloon 60 or other expandable member.

[0056] In an alternative embodiment shown in FIG. 3B, the deployment balloon 30 may actually comprise first and second balloons 30′ and 30″ connected by a tube 36 or other connecting means 36 (e.g., connecting section). The connecting tube 36 will typically include an isolation valve 50 that is degradable by fluids such as those described above and / or fluids having a particular pH, such as the basic pH (e.g., 5.5 or 6.5) found in the small intestine. The two balloons 30′ and 30″ may each have a half-dome shape 30hs, allowing them to fit within the end portions of the capsule when in an expanded state. One balloon may contain a chemical reactant 65 (e.g., sodium bicarbonate, citric acid, etc.) and the other liquid water 68, such that, upon valve degradation, the two components mix, form a gas, and inflate one or both of the balloons 30′ and 30″, and thus the aligner balloon 60.

[0057] In yet another alternative embodiment, balloon 30 can comprise a multi-compartment balloon 30mc formed or otherwise constructed to have multiple compartments 30c. Typically, compartments 30c will include at least first and second compartments 34 and 35 separated by an isolation valve 50 or other isolation means 50, as shown in the embodiment of FIG. 4A. In many embodiments, compartments 34 and 35 will have at least a small connecting section 36 between them, where isolation valve 50 is typically located. A liquid 68, typically water, can be disposed in first compartment 34, as shown in the embodiment of FIG. 4A, and one or more reactants 65 (typically solid, although liquids may also be used) can be disposed in second compartment 35. When valve 50 opens (e.g., from degradation caused by fluid in the small intestine), liquid 68 flows into compartment 35 (or vice versa, or both), and reactant 65 mixes with the liquid, producing gas 69, such as carbon dioxide, which inflates balloon 30 and can in turn be used to inflate one or more of balloons 60 and 72.

[0058] Reactants 65 will typically include at least first and second reactants 66 and 67, e.g., an acid such as citric acid and a base such as sodium bicarbonate or potassium bicarbonate. As discussed herein, in various embodiments, they may be placed within one or more of balloon 30 (including compartments 34 and 35 or halves 30′ and 30″) and balloon 60. Additional reactants, including other combinations of acids and bases that produce inert gas by-products, are also contemplated. For embodiments using citric acid and sodium or carbonate, the ratio between the two reactants (citric acid to potassium bicarbonate) may be within the range of about 1:1 to about 1:4 (a specific ratio is about 1:3). Desirably, solid reactant 65 has little or no adsorbed water. Therefore, one or more of the reactants, such as sodium bicarbonate or potassium bicarbonate, may be pre-dried (e.g., by vacuum drying) before being placed within balloon 30. Other reactants 65 are also contemplated, including other acids, e.g., acetic acid, and bases. The amounts of specific reactants 65, including combinations of reactants, can be selected to produce specific pressures using known stoichiometric equations (e.g., PV = nRT) for specific chemical reactions and balloon inflation volumes and the ideal gas law. In certain embodiments, the amounts of reactants can be selected to: i) achieve a specific penetration depth into the intestinal wall; ii) produce a specific diameter for one or more of balloons 30, 60, and 72; and iii) produce a selected pressure for one or more of balloons 30, 60, and 72 to impart a selected amount of force against the intestinal wall IW. In certain embodiments, the amounts and ratios of reactants (e.g., citric acid and potassium bicarbonate) can be selected to achieve a pressure within the range of 10-15 psi within one or more of balloons 30, 60, and 72, although smaller and larger pressures are also contemplated. Again, the amounts and ratios of reactants to achieve these pressures can be determined using known stoichiometric equations.

[0059] Various embodiments of the present invention that use a chemical reactant 65 to generate gas 69 can include a deployment engine 80 for deploying one or both of the aligner balloon 60 and delivery mechanism 70, including a delivery balloon 72, either alone or in combination with a deployment balloon 30. The deployment engine 80 may also include embodiments that use two deployment balloons 30 and 30'' (a double-dome configuration as shown in FIG. 3B) or a multi-compartment balloon 30mc as shown in FIG. 4A. Other forms of deployment engine 80 are also contemplated by various embodiments of the present invention, such as the use of expandable piezoelectric materials (which expand with the application of a voltage), springs, and other shape-memory materials and various thermally expandable materials.

[0060] One or more of the expandable balloons 30, 60, and 72 will also typically include a deflation valve 59, which serves to deflate the balloon after inflation. The deflation valve 59 can comprise a biodegradable material configured to degrade in response to exposure to fluids in the small intestine and / or liquids in one of the balloon's compartments to create an opening or channel for the escape of gas within the particular balloon. Desirably, the deflation valve 59 is configured to degrade at a slower rate than the valve 50, allowing sufficient time for inflation of the balloons 30, 60, and 72 before the deflation valve degrades. In various embodiments of the compartmentalized balloon 30, the deflation valve 59 can correspond to a degradable segment 39 positioned on the balloon's end portion 31, as shown in the embodiment of FIG. 4A. In this and related embodiments, when the degradable segment 39 degrades from exposure to liquid, the balloon wall 32 ruptures or otherwise separates, providing a high degree of assurance of rapid deflation. Multiple degradable segments 39 can be located in various locations within the balloon wall 32.

[0061] In various embodiments of the balloon 72, the deflation valve 59 may correspond to a tubular valve 73 attached to the end 72e of the delivery balloon 72 (opposite the end coupled to the aligner balloon), as shown in the embodiment of FIG. 3B. The tubular valve 73 comprises a hollow tube 73t having a lumen that is occluded at a selected location 73l with a material 73m, such as maltose, that dissolves in response to exposure to fluid, such as fluid in the small intestine. The location 73l of the occluding material 73m within the tube 73t is selected to provide sufficient time for the delivery balloon 72 to expand and deliver the tissue-piercing member 40 into the intestinal wall IW before the occluding material dissolves and opens the valve 73. Typically, this will be close to the end 73e of the tube 73t, but not far enough to allow time for liquid to wick into the tube lumen before reaching the material 73m. According to one or more embodiments, once the deflation valve 73 opens, it serves to deflate not only the delivery balloon 72, but also the aligner balloon 60 and deployment balloon 30, since in many embodiments all three are fluidly connected (the aligner balloon is fluidly connected to the delivery balloon 72, and the deployment balloon 30 is fluidly connected to the aligner balloon 60). Opening of the deflation valve 73 can be facilitated by placing it on the end 72e of the delivery balloon 72 so that it is forced away from the capsule 20 by inflation of the aligner balloon 60, so that it has good exposure to fluids in the small intestine. A similar ductal deflation valve 73 can also be positioned on one or both of the aligner balloon 62 and deployment balloon 30. In these latter two cases, the occlusive material in the ductal valve can be configured to degrade over a period of time to allow sufficient time for inflation of the delivery balloon 72 and advancement of the tissue-piercing member 40 into the intestinal wall.

[0062] Additionally, as a further backup for guaranteed deflation, one or more piercing elements 82 (shown in FIG. 2A ) can be attached to the inner surface 24 of the capsule to be contacted and penetrated by the piercing elements 82 when the balloon (e.g., balloons 30, 60, 72) is fully inflated. The piercing elements 82 can comprise short protrusions from the surface 24 having pointed tips. In another alternative or additional embodiment of the means for balloon deflation, one or more of the tissue piercing members 40 can be directly coupled to the wall 72w of the balloon 72 and configured to tear away from the balloon, rupturing the balloon wall in the process when removed.

[0063] A discussion of tissue-piercing member 40 will now be presented. Tissue-piercing member 40 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 materials that can be used to form the primary structural components of tissue-piercing member 40, including shaft 44 and tip 45, discussed below. The latter materials can be selected to provide the piercing member with desired structural and material properties (e.g., column strength for insertion into the intestinal wall, or porosity and hydrophilicity for controlled drug release). Referring now to FIGS. 8A-8F, in many embodiments, piercing member 40 can be formed with a shaft 44 and a needle tip 45 or other pointed tip 45 to easily pierce tissue in the intestinal wall, as shown in the embodiment of FIG. 8A. In a preferred embodiment, tip 45 has a trocar shape, as shown in the embodiment of FIG. 8C. The tip 45 may comprise various degradable materials (either within the body of the tip or as a coating), such as sucrose, maltose, or other sugars that increase the tip's hardness and tissue-piercing properties. Once placed within the intestinal wall, the piercing member 40 is degraded by the interstitial fluids within the wall tissue, allowing the drug or other therapeutic agent 101 to dissolve in those fluids and be absorbed into the bloodstream. One or more of the size, shape, and chemical composition of the tissue-piercing member 40 can be selected to allow dissolution and absorption of the drug 101 within seconds, minutes, or even hours. The dissolution rate 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 carboxymethylcellulose. The choice of disintegrant can be specifically tailored to the environment within the small intestinal wall, e.g., blood flow, average number of peristaltic contractions, etc.

[0064] The tissue-piercing member 40 will also typically include one or more tissue retention features 43, such as barbs or hooks, to retain the penetrating member within the tissue of the intestinal wall IW after advancement. The retention features 43 can be arranged in various patterns 43p to enhance tissue retention, such as two or more barbs symmetrically or otherwise distributed around and along the member shaft 44, as shown in the embodiment of Figures 8A and 8B. Additionally, in many embodiments, the penetrating member will also include recesses or other mating features 46 for attaching a coupling component onto the delivery mechanism 70.

[0065] The tissue-piercing member 40 is desirably configured to be removably coupled to the platform 75 (or other component of the delivery mechanism 70) such that the piercing member is detached from the balloon after advancement of the tissue-piercing member 40 into the intestinal wall. Detachability can be implemented by various means, including: i) a fit or engagement between the opening 74 in the platform 75 and the member shaft 44; ii) the configuration and placement of tissue retention features 43 on the piercing member 40; and iii) the depth of penetration of the shaft 44 into the intestinal wall. Using one or more of these factors, the piercing member 40 is configured to be detached as a result of balloon deflation (the retention features 43 hold the piercing member 40 in the tissue as the balloon deflates or otherwise retracts from the intestinal wall) and / or forces imparted on the capsule 20 by peristaltic contractions of the small intestine.

[0066] In a specific embodiment, detachability and retention of the tissue-piercing member 40 within the intestinal wall IW can be enhanced by configuring the tissue-piercing member shaft 44 to have an inverted taper 44t, as shown in the embodiment of FIG. 8C . The taper 44t on the shaft 44 is configured such that application of a peristaltic contractile force from the intestinal wall onto the shaft results in the shaft being urged inward (e.g., squeezed inward). This is due to the shaft taper 44t converting a laterally applied peristaltic force PF into an orthogonal force OF that acts to urge the shaft inward into the intestinal wall. In use, such an inverted taper shaft configuration serves to retain the tissue-piercing member 40 within the intestinal wall so that it does not become detached from the platform 75 (or other component of the delivery mechanism 70) in response to deflation of the balloon 72. Inverted tapers may also be used for embodiments of the tissue-piercing member 40 having any number of tip shapes 45, in addition to trocar tips. In additional embodiments, the tissue piercing member 40 having an inverted tapered shaft may also include one or more retention features 43 to further enhance retention of the tissue piercing member within the intestinal wall IW once inserted.

[0067] As mentioned above, in various embodiments, the tissue-piercing members 40 can be fabricated from several drugs and other therapeutic agents 101. Also, according to one or more embodiments, the tissue-piercing members may be fabricated entirely from the drug 101 or may have other component components as well, such as various pharmaceutical excipients (e.g., binders, preservatives, disintegrants, etc.), polymers that provide desired mechanical properties, etc. Furthermore, in various embodiments, one or more tissue-piercing members 40 may carry the same or different drug 101 (or other therapeutic agent) as other tissue-piercing members. The former configuration allows for the delivery of a greater amount of a particular drug 101, while the latter allows for two or more different drugs to be delivered into the intestinal wall at approximately the same time, facilitating drug treatment regimens that require substantially simultaneous delivery of multiple drugs. In embodiments in which the device 10 has multiple delivery assemblies 78 (e.g., two, one on each side of the balloon 72), the first assembly 78' can carry a tissue-piercing member having a first agent 101, and the second assembly 78'' can carry a tissue-piercing member having a second agent 101.

[0068] Typically, the drug or other therapeutic agent 101 carried by the tissue-piercing member 40 is mixed with a biodegradable material 105 to form the tissue-piercing member 40. The material 105 may include one or more biodegradable polymers, such as PGLA, cellulose, and a sugar, such as maltose, or other biodegradable materials described herein or known in the art. In such embodiments, the piercing member 40 may comprise a substantially heterogeneous mixture of the drug 101 and the biodegradable material 105. Alternatively, the tissue-piercing member 40 may include a portion 41 formed substantially from the biodegradable material 105 and a separate section 42 formed from or containing the drug 101, as shown in the embodiment of FIG. 8D . In one or more embodiments, the section 42 may correspond to a pellet, slug, cylinder, or other shaped section 42s of the drug 101. The shaped sections 42s may be preformed as separate sections and then inserted into the cavity 42c in the tissue-piercing member 40, as shown in the embodiment of Figures 8E and 8F. Alternatively, the sections 42s may be formed by the addition of a drug formulation 100 to the cavity 42c. In embodiments where the drug formulation 100 is added to the cavity 42c, the formulation may be added as a powder, liquid, or gel that is poured or injected into the cavity 42c. The shaped sections 42s may be formed from a drug formulation that is itself the drug 101 or that contains the drug 101 and one or more binders, preservatives, disintegrants, and other excipients. Suitable binders include polyethylene glycol (PEG) and other binders known in the art. In various embodiments, the PEG or other binder may be in the range of about 10-50% by weight of the section 42s, with a preferred embodiment being about 30% by weight. Other binders may include PLGA, cyclodextrin, cellulose, methylcellulose, maltose, dextrin, sucrose, PGA.

[0069] In various embodiments, the weight of the tissue-piercing member 40 can range from about 10 to 15 mg, with larger and smaller weights also being contemplated. For embodiments of the tissue-piercing member 40 fabricated from maltose, the weight can range from about 11 to 14 mg. In various embodiments, depending on the agent 101 and the desired delivered dose, the weight percent of the agent in the member 40 can range from about 0.1 to about 15%. The weight percent of the agent 101 in the member 40 can be adjusted depending on the desired dose and to provide structural and stoichiometric stability to the agent and to achieve the desired elution profile of the agent. Table 1 lists doses and weight percent ranges for several agents that can be delivered by the tissue-piercing member 40. [Table 1]

[0070] Tissue-piercing member 40 can be manufactured using one or more polymers and pharmaceutical manufacturing techniques known in the art. For example, agent 101 (with or without biodegradable material 105) can be in solid form and then formed into the shape of tissue-piercing member 40 using molding, compression, or other similar methods, and one or more binders are added. Alternatively, agent 101 and / or drug formulation 100 can be in solid or liquid form and then added to biodegradable polymer 105 in liquid form with the mixture and then formed into piercing member 40 using molding or other forming methods known in the polymer arts.

[0071] Desirably, embodiments of tissue-piercing member 40 including drug or other therapeutic agent 101 and degradable material 105 are formed at a temperature that does not result in substantial thermal decomposition of any of the drug (or other therapeutic agent), 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. In certain embodiments, the amount of thermally decomposed drug or other therapeutic agent within the tissue-piercing member is desirably less than about 10% by weight, more preferably less than about 5%, and even more preferably less than 1%. The thermal decomposition temperature for a particular drug is known or can be determined using methods known in the art, and this temperature can then be used to select and adjust a particular polymer processing method (e.g., molding, curing, solvent evaporation method, etc.) to minimize the temperature and associated level of thermal decomposition of the drug.

[0072] A description of a delivery mechanism 70 is now provided. Typically, the mechanism will include a delivery assembly 78 (containing a tissue-piercing member 40) attached to a delivery balloon 72, as shown in the embodiment of FIGS. 6A and 6B. Inflation of the delivery balloon provides a mechanical force to engage the delivery assembly 72 outward from the capsule into the intestinal wall IW to insert the tissue-piercing member 40 into the wall. In various embodiments, the delivery balloon 72 can have an elongated shape with two relatively flat sides 72f connected by an articulating accordion-like body 72b. The flat sides 72f can be configured to press against the intestinal wall (IW) to insert the tissue-piercing member (TPM) 40 into the intestinal wall upon expansion of the balloon 72. The TPM 40 (either by itself or as part of a delivery assembly 78 described below) can be positioned on one or both sides 72f of the balloon 70, allowing for insertion of the drug-containing TPM 40 on both sides of the intestinal wall. The faces 72f of the balloon 72 may have sufficient surface area for placement of several drug-containing TPMs 40 on each face.

[0073] 9, a description of assembly of a delivery assembly 78 will now be provided. In a first step 300, one or more tissue-piercing members 40 can be removably coupled to a biodegradable advancement structure 75, which may correspond to a support platform 75 (also known as a platform 75). In a preferred embodiment, the platform 75 includes one or more openings 74 for insertion of the members 40, as shown in step 300. The openings 74 are sized to allow insertion and retention of the members 40 within the platform 75, while allowing their removal from the platform 75 upon their puncture into the intestinal wall prior to expansion of the balloon 72. The support platform 75 can then be positioned within a carrier structure 76, as shown in step 301. The carrier structure 76 may correspond to a well structure 76 having side walls 76s and a bottom wall 76b defining a cavity or opening 76c. Platform 75 is desirably attached to the inner surface of bottom wall 76b using adhesive or other joining methods known in the art. Well structure 76 can comprise a variety of polymeric materials and may be formed using vacuum forming techniques known in the polymer processing arts. In many embodiments, opening 76o can be covered with a protective film 77, as shown in step 302. Protective film 77 has properties selected to act as a barrier to protect tissue-piercing member 40 from humidity and oxidation while still allowing tissue-piercing member 40 to pierce the film, as described below. Film 77 can desirably comprise a variety of water- and / or oxygen-impermeable polymers configured to be biodegradable in the small intestine and / or pass inertly through the digestive tract. It may also have a multi-layer structure, with specific layers selected to be impermeable to certain substances, such as oxygen, water vapor, etc. In use, embodiments employing protective film 77 serve to extend the shelf life of therapeutic agent 101 within tissue-piercing member 40 and, therefore, the shelf life of device 10.Collectively, the tissue-piercing member 40, well structure 76, and film 77 attached to the support platform 75 can comprise a delivery assembly 78. The delivery assembly 78, having one or more drugs or therapeutic agents 101 contained within the tissue-piercing member 40 or other drug delivery means, can be pre-fabricated, stored, and then subsequently used at a later time for the manufacture of the device 10. The shelf life of the assembly 78 can be further enhanced by filling the cavity 76c of the sealed assembly 78 with an inert gas, such as nitrogen.

[0074] 6A and 6B, assembly 78 can be positioned on one or both sides 72f of balloon 72. In a preferred embodiment, assembly 78 is positioned on both sides 72f (as shown in FIG. 6A) to provide a substantially equal distribution of force to both sides of intestinal wall IW upon expansion of balloon 72. Assembly 78 may be attached to side 72f using adhesive or other joining methods known in the polymer arts. Upon expansion of balloon 72, TPM 40 punctures through film 77 and enters intestinal wall IW, retained there by retention element 43 and / or other retention features of the tissue puncture (e.g., inverted tapered shaft 44t) for removal from platform 75 upon deflation of balloon 72.

[0075] In various embodiments, one or more of balloons 30, 60, and 72 can be folded, rolled up, or packed inside capsule 20 in other desired configurations to conserve space within capsule interior volume 24v. Folding can be performed using preformed folds or other folding features or methods known in the medical balloon arts. In certain embodiments, balloons 30, 60, and 72 can be folded into selected orientations to achieve one or more of: i) space conservation, ii) production of a particular inflated balloon desired orientation, and iii) facilitating a desired sequence of balloon inflation. The embodiments shown in FIGS. 5A-5F illustrate folding methods and various folding arrangements. However, it should be understood that the folding arrangements and resulting balloon orientations are exemplary, and others may also be used. In this and related embodiments, folding can be performed manually, by automated machinery, or a combination of both. Additionally, in many embodiments, folding can be facilitated by using a single multi-balloon assembly 7 (herein, assembly 7) including balloons 30, 60, and 70, valve chamber 58, and sorting and connecting tubing 62, as shown in the embodiment of FIGS. 3A and 3B. FIG. 3A illustrates an embodiment of assembly 7 having a single-dome structure for balloon 30, while FIG. 3B illustrates an embodiment of assembly 7 having a dual-balloon / dome configuration for balloon 30. Assembly 7 can be fabricated using thin polymer films that are vacuum-formed to 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 inches (specific embodiments are 0.005 inches). In preferred embodiments, the assembly is fabricated to have a one-piece structure, eliminating the need to join one or more components of the assembly (e.g., balloons 30, 60, etc.).However, it is also contemplated that assembly 7 may be fabricated from multiple parts (e.g., halves) or components (e.g., balloons) and then joined together using various joining methods known in the polymer / medical device arts.

[0076] 5A-5F, 6A-B, and 7A-7B, in a first folding step 210, balloon 60 is folded over valve fitting 58, with balloon 72 being flipped onto the other side of valve fitting 58 in the process (see FIG. 5A). Then, in step 211, balloon 72 is folded perpendicular to the folded combination of balloon 60 and valve 58 (see FIG. 5B). Then, in step 212 for a double-dome embodiment of balloon 30, the two halves 30′ and 30″ of balloon 30 are folded over each other to expose valve 50 (see FIG. 5C; in the case of a single-dome embodiment of balloon 30, they are folded over on themselves (see FIG. 5E)). A final folding step 213 may be performed, whereby folding balloon 30 is folded 180° on the opposite side of valve fitting 58 and balloon 60, resulting in final folded assembly 8 for the double-dome configuration shown in FIG. 5E and final folded assembly 8' for the single-dome configuration shown in FIGS. 5E and 5F. One or more delivery assemblies 78 are then attached to assembly 8 (typically two on face 72f of balloon 72) in step 214, resulting in final assembly 9 (shown in the embodiment of FIGS. 6A and 6B), which is then inserted into capsule 20. After insertion step 215, the final assembled version of device 10 with assembly 9 inserted is shown in FIGS. 7A and 7B.

[0077] 10A-10I, a description of a method of using device 10 to deliver medication 101 to a site within the GI tract wall, such as the small intestine or large intestine, is provided. It should be understood that the steps and their order are exemplary, and other steps and orders are also contemplated. After device 10 enters the small intestine SI, cap coating 20c' is degraded by the basic pH in the upper small intestine, causing degradation of cap 20p', as shown in step 400 in FIG. 10B. Valve 50 is then exposed to fluid within the small intestine, which begins to degrade the valve, as shown in step 401 in FIG. 10C. Then, in step 402, balloon 30 expands (due to the generation of gas 69), as shown in FIG. 10D. Then, in step 403, segment 60' of balloon 60 begins to expand, as shown in FIG. 10E, beginning to push assembly 78 out of the capsule body. Then, in step 404, segments 60′ and 60″ of balloon 60 are fully inflated, as shown in FIG. 10F, to push assembly 78 completely out of the capsule body and extend capsule length 201 to serve to align capsule lateral axis 20AL with small intestine lateral axis LAI. During this time, valve 55 begins to fail from the pressure buildup within balloon 60 (due to the fact that the balloon is fully inflated and gas 69 has nowhere to go). Then, in step 405, valve 55 fully opens, as shown in FIG. 10G, to inflate balloon 72, which then pushes the now fully exposed assembly 78 (completely pushed out of body 20p″) radially outward into the intestinal wall IW. Then, in step 406, balloon 72 continues to expand, as shown in FIG. 10H, now advancing the tissue-piercing member into the intestinal wall IW. Then, in step 407, balloon 72 (along with balloons 60 and 30) is deflated and pulled back, leaving the tissue-piercing member retained within the intestinal wall IW. Body portion 20p" of the capsule, along with the other biodegradable portions of device 10, also completely degrades (due to the degradation of coating 20c"). Any portions that do not degrade are carried distally through the small intestine by peristaltic contractions from digestion and are eventually expelled.

[0078] 1B , as an alternative or supplement to the use of pH-sensitive degradable coatings and valves for inflation of one or more of balloons 30, 60, and 72 (and deployment of medicament 100), in various embodiments, the balloons may expand in response to a sensor 97, such as a pH sensor 98 or other chemical sensor that detects the presence of a capsule in the small intestine. Sensor 97 can then send a signal to a controllable embodiment of isolation valve 50 or an electronic controller 29c coupled to controllable isolation valve 50, causing it to open and thus expand balloon 30, as described herein. Embodiments of pH sensor 98 can comprise an electrode-based sensor or can be a mechanically-based sensor, such as a polymer, that contracts or expands in response to exposure to selected pH or other chemical conditions in the small intestine. In related embodiments, expandable / contractable pH sensor 98 can also comprise isolation valve 50 itself by configuring the sensor to expand or contract about connectors 63 and / or 36 to open channels between balloons 30 and 60 and / or compartments 34 and 35.

[0079] According to another embodiment for detecting when device 10 is within the small intestine (or elsewhere in the GI tract), sensor 97 can include a pressure / force sensor, such as a strain gauge, for detecting the number of peristaltic contractions undergone by capsule 20 within a particular location within the intestinal tract (in such an embodiment, capsule 20 is desirably sized to be gripped by the small intestine during peristaltic contractions). Different locations within the GI tract have different numbers of peristaltic contractions. For example, the small intestine has between 12 and 9 contractions per minute, with the frequency decreasing down the entire length of the intestine. Thus, according to one or more embodiments, detecting the number of peristaltic contractions can be used to determine not only whether capsule 20 is within the small intestine, but also its relative location within the intestine. During use, these and related embodiments enable release of drug 100 at a particular location within the small intestine.

[0080] Still referring to FIG. 1B , as an alternative or complement to internal activation of drug delivery in device 10 (e.g., using a pH-sensitive coating and / or sensor), in some embodiments, a user may externally send a signal to inflate one or more of balloons 30, 60, and 72 and deliver drug 100 to the intestinal wall. The signal may be sent using RF, magnetic, or other wireless signaling means known in the art. In various embodiments, external activation can be achieved through the use of a controllable isolation valve 50, such as an RF-controlled miniature solenoid valve or other electromechanical control valve (not shown). In other embodiments, the controllable isolation valve 50 may correspond to a miniature magnetic valve, such as a magnetically controlled miniature reed switch (not shown). Such electromechanical or magnetic-based valves can be fabricated using MEMS and other microfabrication methods. In these and related embodiments, a user can use a handheld communication device 13 (e.g., a handheld RF device such as a mobile phone) to transmit a received signal 17 from device 10, as shown in the embodiment of FIG. 1B . In such an embodiment, the swallowable device may include a transmitter 28, such as an RF transceiver chip or other similar communication device / circuit. The handheld device 13 may include not only the signaling means, but also a means for notifying the user when the device 10 is in the small intestine or elsewhere in the GI tract. The latter embodiment can be implemented through the use of logic resources 29 (e.g., processor 29) coupled to the transmitter 28 to detect and signal the user when the device is in the small intestine or elsewhere (e.g., by signaling input from a sensor). The logic resources 29 may include a controller 29c (in either hardware or software) for controlling one or more aspects of the process. The same handheld device can also be configured to alert the user when the balloon 30 (and balloons 52 and 60) has been expanded and the selected medication 100 has been delivered (e.g., using the processor 29 and transmitter 28).In this way, the user is provided with confirmation that medication 100 has been delivered. This allows the user to take other appropriate medications / therapeutics and make other related decisions (e.g., if diabetic, whether to eat a meal, and what food to eat). The handheld device can also be configured to send a signal to swallowable device 10 to override isolation valve 50 and thus prevent, delay, or accelerate delivery of medication 100. In use, such an embodiment allows the user to intervene to prevent, delay, or accelerate delivery of medication based on other symptoms and / or patient behavior (e.g., eating a meal, deciding to go to sleep, exercising, etc.). The user may also externally expand balloon 30 or expandable member 30 for a selected time period after swallowing the capsule. The time period may correlate to a typical transit time or range of transit times for food to travel through the user's GI tract to a particular location in a tract such as the small intestine.

[0081] 11A-11B and 16, in various embodiments, capsule 20 can include a seam 22 comprising a biodegradable material that controllably degrades to produce capsule fragments 23 of selectable sizes and shapes to facilitate passage through the GI tract, as shown in the embodiment of Figures 11A and 11B. Seam 22 can also include pores or other openings 22p for fluid ingress into the seam to accelerate biodegradation, as shown in the embodiment of Figure 16. Other means for accelerating biodegradation of seam 22 can include prestressing the seam and / or perforations 22f within the seam, as also shown in the embodiment of Figure 16.

[0082] 12A-12C , in other embodiments of the swallowable drug delivery device 10, the device 10 may include one or more piston-cylinder assemblies (PCAs) 250 for delivering one or more needles or other tissue-piercing members (TPMs) 40 into the intestinal wall. Accordingly, in these and related embodiments, the piston-cylinder assemblies (PCAs) comprise the delivery mechanism 70. Typically, the piston-cylinder assemblies (PCAs) 250 will be positioned substantially inside a balloon, such as balloon 260. However, they may be positioned partially or even completely outside balloon 260 or other balloons described herein. In some embodiments, the balloon 260 comprises multiple sections. As shown in FIG. 12A , the balloon 260 comprises two sections, a first section comprising a first compartment 265 and a second section comprising a second compartment 266, separated by a release valve assembly 290. One portion contains a solid reactant 810, such as potassium bicarbonate, and the other portion contains a liquid reactant 811, such as citric acid, which reacts with the solid reactant to produce a gas 299, such as CO. Valve assembly 290 includes an O-ring 270 positioned over a dissolvable pinch valve 292, which pinches and maintains a seal between two portions 265 and 266 of balloon 260. The dissolvable valve is fabricated from maltose or other material that dissolves upon contact with fluid in the small intestine. When this occurs, fluid from one portion of the balloon mixes with the reactant in the other, generating gas 299 and inflating balloon 260.

[0083] Typically, the PCA 250 is positioned within the portion / compartment of the balloon 260 containing the solid reactant (second compartment 266) and sized accordingly. In one or more dimensional embodiments, the balloon can have a vertical height of approximately 12-16 mm (a preferred embodiment is 14 mm), while the inner diameter of the balloon 260 can range from 18-22 mm (a preferred embodiment is 20 mm). Other dimensions are also contemplated. In various embodiments, all or part of the PCA 250 is fabricated from a material, which may be a dissolvable material such as maltose or methylcellulose. It can also be fabricated from ABS and other polymers that are inert within the GI tract. In a specific embodiment, the outer upper portion of the piston can be made from silicone, which is mounted on an inner structure, such as a base structure, which may be made from ABS.

[0084] As shown in FIG. 12A , when uninflated, the PCA 250 is positioned laterally (horizontally) (with respect to the balloon's longitudinal axis) within the balloon 260; however, once the balloon 260 is inflated, the PCA 250 reorients itself to a vertical position, as shown in FIG. 12B . This reorientation can be achieved using adhesive or other fittings 269 that attach the PCA 250 to the balloon wall 261 via a conformational / shape change and that can be configured to impart a force to the PCA 250, urging it into a vertical orientation once the balloon 260 is inflated (i.e., the fittings are made when the PCA 250 is in a vertical position, and then the PCA is placed in a horizontal position). The fittings 269 may comprise various elastic materials known in the art, including silicone. The PCA comprises a piston 252 and a piston rod 253 positioned inside a cylinder 251 (known as a piston-cylinder). The needle or TPM 40 sits above the piston rod 253 within a needle lumen 230 that is continuous with the piston cylinder. The needle lumen can also include a coating 231 (referred to herein as a needle lumen coating), which can comprise a foil or polymer film. The diameter ratio between the piston and the piston rod can be selected to provide a desired pressure-focusing effect (e.g., 2:1, 3:1, etc.) from a reduced surface area. An O-ring 271 is positioned between the piston 252 and the piston cylinder 251 to maintain a seal between the piston 252 and the wall of the piston cylinder 251. A pressure-sensitive release 235 is also positioned inside the cylinder 251 to hold the piston 252 in place until a desired pressure (also referred to as a pressure threshold) builds up inside the balloon 260 (e.g., 5 psi to 20 psi, more preferably 8 to 10 psi). The release 235 can correspond to a tab, latch, or O-ring. In use, this release serves to ensure that sufficient pressure exists within the balloon to drive the needle 40 into the small intestinal wall (IW) to the desired depth.

[0085] As the valve separating the two portions (265 and 266) of the balloon 260 dissolves and the balloon begins to expand, the PCA 250 reorients itself from a horizontal to a vertical orientation, as previously described. Then, when the pressure within the balloon 260 exceeds the release pressure of the release tab, the piston rod advances against the needle (or other TPM), forcing the needle 40 out of the needle lumen 230 and into the wall of the small intestine. Once the needle has passed through the needle lumen and into the intestinal wall, the balloon 260 then deflates through the now-open needle lumen. After needle deployment, the PCA 250 either dissolves or passes harmlessly through the GI tract.

[0086] In one or more embodiments, the delivery mechanism 70 can comprise an array 350 of PCAs (multiple needle PCAs), which can be configured for delivery of multiple needles 40 (or other TPMs), as shown in FIG. 12C. In these and related embodiments, the PCAs can include a common inflation manifold 357 coupled at one end to multiple needle lumens 330 via a central lumen 358 and at the other end to a balloon 359. Various embodiments of the multi-needle PCAs 350 can be configured to deliver from two to six or more needles. Each needle may contain the same or a different drug or other therapeutic agent.

[0087] As previously mentioned, deflation of the delivery balloon 260 occurs through the needle lumen once the needle is delivered into the tissue, without the need for additional means for balloon deflation. Referring now to FIG. 12D , in an alternative embodiment, the delivery balloon 260 may also include a separate deflation valve assembly 280, in addition to the needle lumen 230, which serves as a backup or secondary means for deflation. As shown in FIG. 12D , the deflation valve assembly includes an O-ring 272 positioned over a dissolvable pinch valve 281 that clamps the open end of the delivery balloon 260. The valve includes a dissolvable body portion made from maltose or other similar material as a release valve and an outer coating, such as methylcellulose. The outer coating 283 is configured to take substantially longer to dissolve than the dissolvable valve in the release valve assembly, so that the deflation valve is not activated for 10 minutes (preferably 20 minutes) or more after the release valve is activated. This ensures that the deflation valve is not activated until the needle is fully advanced into the intestinal wall.

[0088] 13A-13B , in one or more embodiments of the swallowable device, a delivery balloon 460 can include an assembly configured to control the pressure at which needles are advanced from the balloon into the intestinal wall and ensure that the balloon deflates upon penetration. The assembly can include a lower portion 463 to which one or more TPMs (also referred to herein as pharmaceutical needles) 40 are attached, and an upper portion 464 to which one or more penetration needles (piercing members) 450 are attached. The upper portion can include an opening 430 or aperture through which the pharmaceutical needles are advanced from the assembly into the intestinal wall. The upper and lower portions 464 and 463 can be joined by a sidewall 465. The sidewall 465 can be collapsible to bring the portions 464 and 463 together. The sidewall 465 can be sufficiently rigid to keep the upper and lower portions 464 and 463 apart while the balloon 460 is uninflated. However, the sidewall 465 collapses under the balloon pressure. The sidewall may be weakly bonded to the balloon 460 using a frangible adhesive 470 so that the sidewall conforms to the balloon until the balloon 460 is inflated. In response to inflation of the balloon 460, the sidewall 465 separates from the balloon 460. The lower portion 463 may also be bonded to the balloon, but with a stronger adhesive 469, the entire assembly is positioned between the balloon and the intestinal wall IW, as shown in FIG. 13A.

[0089] Upon inflation of the delivery balloon 460, the penetration needle 450 is configured to puncture and penetrate the lower portion 463 of the delivery assembly and the delivery balloon 460 to rupture the delivery balloon. Preferably, the pharmaceutical needle 40 has a length 401 that is sufficiently longer than the length of the penetration needle 4501 so that the pharmaceutical needle 40 is already partway out of the assembly and into the intestinal wall before the penetration needle 450 contacts the lower portion 463 and the balloon 460. According to one or more embodiments, the pharmaceutical needle is 25-300% longer than the penetration needle, with specific embodiments being 50, 75, 100, 150, 200, and 250%.

[0090] According to one or more embodiments, the lower portion 463 is fabricated from a material that is impenetrable by a penetrating needle until a desired pressure is reached (e.g., 4-20 psi, more preferably 8-12 psi). This, in turn, prevents the pharmaceutical needle from being fully advanced into the intestinal wall until the desired pressure is reached. Once the penetrating needles 450 puncture the lower portion 463, they simultaneously penetrate the inflated balloon 460, allowing the pharmaceutical needle 40 to be fully advanced while ensuring deflation. These and related embodiments provide the advantages of both controlling the pressure of the pharmaceutical needle 40 and ensuring the balloon is deflated.

[0091] FIG. 13B shows the balloon inflation pressure (BIP) 702 and the penetration needle pressure (PNP) 701, i.e., the pressure used to advance the penetration needle and puncture the balloon 460 and lower portion 463, as time progresses. The PNP rises and peaks as the penetration needle begins to puncture the lower portion 463. Once puncture of the lower portion 463 and balloon 460 is complete, the PNP drops to zero. After the drug needle 40 is fully inserted into the intestinal wall, gas inside the balloon 460 is allowed to escape through the opening 430, and the BIP drops to zero as the balloon 460 deflates. In various embodiments, the entire assembly can be fabricated from various biocompatible or inert polymers known in the art. The pressure at which the lower portion 463 is punctured can be controlled by one or more of the thickness and material for the lower portion 463. In various embodiments, the lower portion 463 can be fabricated from a polymer film, including various inert (ABS) and / or biodegradable polymer films (eg, methylcellulose) known in the art.

[0092] According to one or more embodiments, the drug needle or other tissue-piercing member 40 can be fabricated from a methylcellulose polymer. Such methylcellulose polymers can include hydroxymethylcellulose, carboxymethylcellulose, and various polymers thereof. Advantages of using such methylcellulose polymers for fabricating drug needles (or other tissue-piercing members) compared to maltose-based drug needles include little or no sensitivity to humidity during storage, reduced wall thickness, smaller needle size with the same drug payload capacity, and the ability to process the needle after fabrication, including grinding, sharpening, polishing, and other related processes. In one or more embodiments, the methylcellulose-based drug needle may have a wall thickness in the range of 0.05 to 0.15 mm (with a specific embodiment being 0.1 mm). Additionally, in one or more embodiments, the methylcellulose-based drug needle can carry 25 to 150% or more of the drug compared to a maltose-based drug needle of the same size. In a specific embodiment of a drug needle having an outer diameter of 1.5 mm, the methylcellulose needle can load 100% or more of the drug compared to a maltose-based needle.

[0093] 15A-15B and 16, in many embodiments, seam 22 can also be configured and arranged to allow capsule 20 to break into smaller pieces by inflation of balloon 30 or other expandable member 30. In certain embodiments, seam 22 can be oriented relative to the radial perimeter 21 of the capsule, including having a radial pattern 22rp, to break the capsule into halves or other separate pieces along its perimeter. Seam 22 can also be oriented longitudinally relative to the lateral access 201a of the capsule to break the capsule into longitudinal pieces.

[0094] As an alternative or additional approach to disassembling capsule 20 by balloon inflation (or expansion of other expandable member 30), capsule 20 can be fabricated from two or more separate joinable pieces 23j (e.g., radial halves) joined at joints 22j formed by seams 22 (which function as adhesive joints), as shown in the embodiment of Figure 16. Alternatively, joinable pieces 23j may only be joined by a mechanical fit, such as a snap or press fit.

[0095] Suitable materials for seam 22 can include one or more biodegradable materials described herein, such as PGLA, glycolic acid, etc. Seam 22 can be attached to capsule 20 using various bonding methods known in the polymer arts, such as molding, thermo-fusion bonding, etc. Additionally, for capsule 20 embodiments also fabricated from biodegradable materials, faster biodegradation of seam 22 can be achieved by one or more of: i) fabricating the seam from a faster-degrading material; ii) pre-stressing the seam; or iii) perforating the seam. The concept of using a biodegradable seam 22 to create controlled degradation of a swallowable device within the GI tract can also be applied to other swallowable devices, such as a swallowable camera (or other swallowable imaging device), to facilitate passage through the GI tract and reduce the likelihood of the device becoming trapped therein. Thus, embodiments of biodegradable seam 22 can be adapted for swallowable imaging and other swallowable devices.

[0096] In still other embodiments, seam 22 can be constructed of a material and / or have a structure that is readily broken down by absorption of ultrasound energy, e.g., high frequency ultrasound (HIFU), allowing the capsule to be broken down into smaller pieces using ultrasound administered externally or endoscopically (or other minimally invasive methods).

[0097] Another aspect of the present invention provides methods for delivering drugs and other therapeutic agents (in the form of medicaments 100) into the wall of the GI tract using one or more embodiments of a 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. However, it should be understood that this is exemplary and that embodiments of the present invention can be used to deliver drugs to several locations in the GI tract, including the stomach and large intestine. For ease of discussion, the swallowable drug delivery device 10 is sometimes referred to herein as a capsule. As explained above, in various embodiments, the device 10 may be packaged as a kit 14 in a sealed package 12 that includes the device 10 and a set of instructions for use 15. If the patient is using a handheld device 13, the patient may be instructed to enter data into the device 13 manually or via a barcode 18 (or other identifying indicia 18) located on the instructions 15 or package 12. If a barcode is used, the patient scans the barcode using a barcode reader 19 on the device 13. After opening packaging 12, reading instructions 15, and entering any necessary data, the patient swallows an embodiment of swallowable drug delivery device 10. Depending on the drug, the patient may take device 10 with a meal (before, during, or after a meal) or in conjunction with a physiological measurement, such as a blood glucose measurement. Capsule 20 is sized to pass through the GI tract and, as shown in the embodiment of FIG. 1E, progresses through the patient's stomach S and into the small intestine SI through peristaltic action. Once capsule 10 is inside the small intestine, coatings 20c' and 20c'' are degraded by the basic pH of the small intestine (or other chemical or physical conditions specific to the small intestine), in accordance with one or more embodiments of the present invention, causing balloons 30, 60, and 72 to expand or deliver drug 100 into the wall of the small intestine SI.

[0098] After drug delivery, device 10 then passes through the intestinal tract, including the large intestine LI, and is ultimately expelled. For embodiments having a rupturable capsule, the capsule may be instantly degraded into smaller pieces by inflation of balloon 30. For embodiments of capsule 20 having biodegradable seams 22 or other biodegradable portions, the capsule degrades into smaller pieces within the intestinal tract to facilitate passage through and evacuation from the intestinal tract. In certain embodiments having biodegradable tissue-piercing needles / members 40, if the needles become trapped within the intestinal wall, the needles biodegrade to release capsule 20 from the wall.

[0099] For embodiments of device 10 that include sensor 97, expansion of balloon 30 or other expandable member 30 can be effected by the sensor sending a signal to isolation valve 50 and / or a controlled embodiment of processor 29 / controller 29c coupled to isolation valve 50. For embodiments of device 10 that include external actuation capabilities, a user may externally expand balloon 30 (as well as balloons 52 and 60) for a selected time period after swallowing a capsule. The time period can correlate to a typical transit time (e.g., 30 minutes) or range of transit times (e.g., 10 minutes to 2 hours) for food to travel through a user's GI tract to a particular location in a tract such as the small intestine.

[0100] One or more embodiments of the aforementioned methods can be used to deliver formulations 100 containing therapeutically effective amounts of various drugs and other therapeutic agents 101 to treat various diseases and conditions. These include several large peptides and proteins that would otherwise require injection due to chemical degradation in the stomach, such as growth hormone, parathyroid hormone, insulin, interferon, and other similar compounds. Suitable drugs and other therapeutic agents that can be delivered by embodiments of the present invention include various chemotherapeutic agents (e.g., interferon), antibiotics, antivirals, insulin and related compounds, glucagon-like peptides (e.g., GLP-1, exenatide), parathyroid hormone, growth hormones (e.g., IFG and other growth factors), antiseizure medications (e.g., furosemide), antimigraine medications (sumatriptan), immunosuppressants (e.g., cyclosporine), and antiparasitic agents such as various antimalarials. Dosages of particular drugs can be titrated to the patient's weight, age, or other parameters. Additionally, a smaller amount of drug 101 (e.g., insulin for blood glucose regulation or furosemide for seizure control) to achieve a desired or therapeutic effect may be required than if the drug were delivered by traditional oral delivery (e.g., a swallowable tablet that is digested in the stomach and absorbed through the wall of the small intestine). This is due to the lack of degradation of the drug by stomach acid and other digestive fluids and the fact that all, as opposed to only a portion, of the drug is delivered into the wall of the small intestine (or other lumen of the gastrointestinal tract, e.g., colon, stomach, etc.). Depending on the drug 101, the dose 102 delivered in formulation 100 may range from 100% to 5% of the dose delivered by traditional oral delivery means to achieve the desired therapeutic effect (e.g., blood glucose regulation, seizure control, etc.), with even smaller amounts being contemplated. Specific dose reductions can be titrated based on the specific drug, the condition being treated, and the patient's weight, age, and condition. For some drugs (with known levels of intestinal degradation), standard dose reductions (e.g., 10% to 20%) can be employed. Larger dose reductions can be used for drugs that are more degraded and less absorbed.In this manner, the lowered ingested dose can reduce potential toxicity and other side effects (e.g., stomach cramps, irritable bowel, bleeding, etc.) of one or more particular drugs delivered by device 10. This, in turn, improves patient compliance, as the patient experiences a reduction in both the severity and incidence of adverse effects. Additional benefits of embodiments employing dose reduction of drug 101 include a reduced likelihood that the patient will develop resistance to the drug (requiring higher doses) and, in the case of antibiotics, that the patient will develop resistant bacteria. Other levels of dose reduction can also be achieved in patients who have undergone gastric bypass surgery and other procedures in which a section of the small intestine has been removed or its working (e.g., digestive) length has otherwise been effectively shortened.

[0101] In addition to delivering a single medication, embodiments of the swallowable medication delivery device 10 and their methods of use can be used to deliver multiple medications for the treatment of multiple conditions or for the treatment of a specific condition (e.g., protease inhibitors for the treatment of HIV AIDS). In use, such embodiments allow patients to eliminate the need to take multiple medications for one or more specific conditions. They also provide a means for facilitating the delivery and absorption of two or more medication regimens into the small intestine and, therefore, the bloodstream, at approximately the same time. Due to differences in chemical composition, molecular weight, etc., medications can be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves. Embodiments of the present invention address this issue by injecting the desired medication mixture at approximately the same time. This, in turn, improves the pharmacokinetics and, therefore, the effectiveness of the selected mixture of medications. Additionally, eliminating the need to take multiple medications is particularly beneficial for patients with one or more long-term chronic conditions, including those with impaired cognition or physical abilities.

[0102] In various approaches, the above-described method embodiments can be used to deliver formulations 100 containing drugs and therapeutic agents 101 to provide treatment for a number of conditions and diseases. Conditions and diseases that can be treated using embodiments of the present invention include, but are not limited to, cancer, hormonal conditions (e.g., hypo / hyperthyroidism, growth hormone conditions), osteoporosis, high blood pressure, high cholesterol and triglycerides, diabetes and other glucose regulation disorders, infections (local or septic), epilepsy and other seizure disorders, osteoporosis, coronary arrhythmias (both atrial and ventricular), coronary ischemia anemia, or other similar conditions. Still other conditions and diseases are contemplated.

[0103] In many embodiments, treatment of a particular disease or condition may be achieved without the need to inject a drug or other therapeutic agent (or other parenteral form of delivery, such as a suppository), but instead rely solely on the therapeutic agent being delivered into the wall of the small intestine or other portions of the GI tract. For example, diabetes or another glucose regulation disorder may be treated (e.g., by controlling blood glucose levels) solely through the use of insulin delivered into the wall of the small intestine, without the patient even needing to inject insulin. Similarly, the patient may not need to take a traditional oral form of a drug or other therapeutic agent, but again rely solely on delivery into the wall of the small intestine using a swallowable capsule embodiment. In other embodiments, the therapeutic agent delivered into the wall of the small intestine may be delivered in conjunction with an injection dose of the drug. For example, a patient may use a swallowable capsule embodiment to take a daily dose of insulin or a compound for blood sugar regulation, but only need to take an injection dose every few days or when the patient's symptoms require it (e.g., hyperglycemia). The same applies to therapeutic agents that are traditionally delivered in oral form (e.g., the patient may take a swallowable capsule and then take a traditional oral form of the drug as needed). Doses delivered in such embodiments (e.g., swallowed and injected doses) can be titrated as needed (e.g., standard dose-response curves can be used, and other pharmacokinetic methods can be used to determine appropriate doses). Also, for embodiments using therapeutic agents that can be delivered by conventional oral means, doses delivered using swallowable capsule embodiments can be titrated below doses typically given for oral delivery of the agent, since there is little or no degradation of the agent in the stomach or other parts of the intestinal tract (again, standard dose-response curves and other pharmacokinetic methods can be applied).

[0104] Various groups of embodiments of formulation 100 containing one or more drugs or other therapeutic agents 101 for the treatment of various diseases and conditions will now be described with reference to dosage amounts. These embodiments, including the specific therapeutic agents and their respective dosage amounts, are exemplary, and it should be understood that formulation 100 can include several other therapeutic agents described herein (as well as those known in the art) configured for delivery into the luminal wall of the intestinal tract (e.g., the small intestinal wall) using various embodiments of device 10. Dosage amounts may be higher or lower than those described and can be adjusted using one or more methods described herein or known in the art. In one group of embodiments, therapeutic agent formulation 100 can include a therapeutically effective dose of insulin for the treatment of diabetes and other glucose regulation disorders. The insulin can be of human or synthetic origin, as known in the art. In one embodiment, formulation 100 can contain a therapeutically effective amount of insulin in the range of about 1-10 units (1 unit is the bioequivalent of about 45.5 μg of pure crystalline insulin), with specific ranges of 2-4, 3-9, 4-9, 5-8, or 6-7. The amount of insulin in the formulation can be titrated based on one or more of the following factors (herein "glucose control titration factors"): i) the patient's condition (e.g., type 1 vs. type 2 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 the dose (e.g., once per day vs. multiple times per day), vi) the time of day (e.g., morning vs. evening), vii) the particular meal (breakfast vs. dinner), viii) the content / glycemic index of the particular meal (e.g., a meal with a high fat / lipid and sugar content (which tends to cause a rapid rise in blood glucose and therefore has a higher glycemic index) vs. a low fat and sugar content that does not cause a rapid rise (and therefore has a lower glycemic index), and ix) the content of the patient's overall diet (e.g., the amount of sugars and other carbohydrates, lipids, and protein consumed daily).

[0105] In another group of embodiments, the therapeutic agent formulation 100 can include a therapeutically effective dose of one or more incretins for the treatment of diabetes and other glucose regulation disorders. Such incretins can include glucagon-like peptide 1 (GLP-1) and its analogs, and gastric inhibitory peptide (GIP). Suitable GLP-1 analogs include exenatide, liraglutide, albiglutide, and taspoglutide, as well as their analogs, derivatives, and other functional equivalents. In one embodiment, the formulation 100 can contain a therapeutically effective amount of exenatide in the range of about 1-10 μg, with specific ranges of 2-4, 4-6, 4-8, and 8-10 μg, respectively. In another embodiment, the formulation 100 can contain a therapeutically effective amount of liraglutide in the range of about 1-2 mg (milligrams), with specific ranges of 1.0 to 1.4, 1.2 to 1.6, and 1.2 to 1.8 mg, respectively. One or more of the glucose control titration factors can be applied to titrate the dose range of exenatide, liraglutide, or other GLP-1 analogue, or incretin.

[0106] In yet another group of embodiments, the therapeutic drug formulation 100 can include a combination of therapeutic drugs for the treatment of diabetes and other glucose regulation disorders. Such combination embodiments can include therapeutically effective doses of an incretin and a biguanide compound. The incretin can include one or more GLP-1 analogs described herein, such as exenatide, and the biguanide can include metformin (e.g., available under the trademark GLUCOPHAGE from Merck Sante S.AS), as well as analogs, derivatives, and other functional equivalents thereof. In one embodiment, the formulation 100 can include a therapeutically effective amount of exenatide in the range of about 1-10 μg and a therapeutically effective amount of metformin in the range of about 1-3 grams. Smaller and larger ranges are also contemplated, and one or more of the glucose control titration factors can be used to titrate the respective doses of exenatide (or other incretin) and metformin or other biguanide. Additionally, dosages of exenatide or other incretin and metformin or other biguanide can be matched to improve a patient's level of glucose control (e.g., maintaining blood glucose within normal physiological levels and / or reducing the incidence and severity of hyperglycemic and / or hypoglycemic episodes) over extended periods ranging from several hours (e.g., 12) to one day to multiple days, with longer time periods being contemplated. Dosage matching can also be achieved through the use of glucose control regulators and monitoring a patient's blood glucose levels over an extended period using glycosylated hemoglobin (also known as hemoglobin A1c, HbA1c, A1c, or Hb1c) and other analytes and measurements that correlate to long-term average blood glucose levels.

[0107] In yet another group of embodiments, the therapeutic agent formulation 100 can include a therapeutically effective dose of growth hormone for the treatment of one or more growth abnormalities and wound healing. In one embodiment, the formulation 100 can contain a therapeutically effective amount of growth hormone in the range of about 0.1-4 mg, with specific ranges of 0.1-1, 1-4, 1-2, and 2-4 being contemplated, and even larger ranges being considered. The specific dose can be titrated based on one or more of: i) the specific condition being treated and its severity (e.g., impaired growth vs. wound healing), ii) the patient's weight, iii) the patient's age, and iv) the frequency of administration (e.g., daily vs. twice daily).

[0108] In yet another group of embodiments, the therapeutic agent formulation 100 can include a therapeutically effective dose of parathyroid hormone for the treatment of osteoporosis or thyroid disease. In one embodiment, the formulation 100 can contain a therapeutically effective amount of parathyroid hormone in the range of about 1-40 μg, with specific ranges of 10-20, 20-30, 30-40, and 10-40 μg, and even larger ranges are contemplated. The specific dose can be titrated based on one or more of: i) the particular condition being treated and its severity (e.g., the degree of osteoporosis as determined by bone densitometry), ii) the patient's weight, iii) the patient's age, and iv) the frequency of administration (e.g., daily vs. twice daily).

[0109] The foregoing description of various embodiments of the present invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Many modifications, variations, and improvements will be apparent to those skilled in the art. For example, device embodiments can be sized and otherwise adapted for various pediatric and neonatal applications, as well as various veterinary applications. Moreover, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many 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 following appended claims.

[0110] Elements, features, or acts from one embodiment can be readily recombined or substituted with one or more elements, features, or acts from other embodiments to form numerous additional embodiments within the scope of the invention. Also, elements shown or described as being combined with other elements can exist as stand-alone elements in various embodiments. Thus, the scope of the invention is not limited to the specific embodiments described, but instead is limited only by the appended claims.

Claims

1. 1. A swallowable device for delivering a therapeutic agent formulation to the intestinal wall of a patient, said swallowable device comprising: a capsule sized to pass through the gastrointestinal (GI) tract; the therapeutic agent formulation disposed within the capsule; a delivery mechanism for advancing the therapeutic agent formulation from the capsule into the intestinal wall; The delivery mechanism comprises: an expandable member having a longitudinal axis configured to align with a longitudinal axis of the intestinal wall upon expansion; a piston-cylinder assembly operably coupled to the expandable member, the piston-cylinder assembly including a piston slidably disposed inside a cylinder; configured to apply a force to the piston-cylinder assembly via a joint or pre-stressed portion attached to a wall of the expandable member when the expandable member expands, the force urging the longitudinal axis of the piston-cylinder assembly into a perpendicular orientation with the longitudinal axis of the expandable member aligned with the longitudinal axis of the intestinal wall such that the longitudinal axis of the piston-cylinder assembly is perpendicular to a surface of the intestinal wall; an internal pressure generated by expansion of the expandable member is applied to the piston, and when the internal pressure reaches a predetermined pressure, the internal pressure within the expandable member advances the piston within the cylinder, thereby advancing the therapeutic agent formulation into the intestinal wall.

2. 10. The swallowable device of claim 1, wherein the therapeutic agent formulation is formed as a tissue-piercing member disposed within the capsule and configured to be advanced into the intestinal wall by the piston-cylinder assembly.

3. 2. The swallowable device of claim 1, wherein the therapeutic agent formulation is disposed within a cavity of a tissue-piercing member, the tissue-piercing member being disposed within the capsule and configured to be advanced into the intestinal wall by the piston-cylinder assembly.

4. 4. The swallowable device of claim 1, wherein the expandable member comprises a first compartment and a second compartment separated by a releasable valve that opens in response to exposure to fluid in the GI tract.

5. 5. The swallowable device of claim 4, wherein the expandable member, in response to release of the releasable valve, orients the longitudinal axis of the piston-cylinder assembly to be in the perpendicular orientation relative to the longitudinal axis of the expandable member.

6. 5. The swallowable device of claim 4, wherein the expandable member further comprises a first reactant contained in one of the first compartment and the second compartment and a second reactant contained in the other of the first compartment and the second compartment, and wherein when the releasable valve is released, the first reactant and the second reactant mix to produce a gas.

7. The swallowable device of claim 6 , wherein the first reactant and the second reactant comprise an acid and a base.

8. 7. The swallowable device of claim 6, wherein the first reactant comprises potassium bicarbonate and the second reactant comprises citric acid.

9. The swallowable device of claim 1 , wherein the piston-cylinder assembly comprises a pressure-sensitive release that prevents the piston from advancing through the cylinder until the expandable member exerts a threshold force.

10. The swallowable device of claim 9 , wherein the pressure sensitive release comprises a tab, a latch, or an O-ring.

11. 10. The swallowable device of claim 1, wherein the capsule comprises a capsule wall at least a portion of which degrades upon exposure to a selected pH in the intestine while protecting the capsule wall from degradation in the patient's stomach.

12. The swallowable device of claim 1 , wherein the piston-cylinder assembly is at least partially disposed in the expandable member.

13. 10. The swallowable device of claim 1, wherein advancing the therapeutic agent formulation through the intestinal wall comprises advancing the therapeutic agent formulation through a mucosal or submucosal layer of the intestinal wall.

14. 10. The swallowable device of claim 1, wherein the piston-cylinder assembly further comprises a piston rod, the piston operably coupled to the expandable member, and the piston rod operably coupled to the therapeutic agent formulation to apply a force to advance the therapeutic agent formulation.

15. 2. The swallowable device of claim 1, wherein the expandable member comprises the joint configured to apply the force to the piston-cylinder assembly, urging the piston-cylinder assembly into the perpendicular orientation relative to the longitudinal axis of the expandable member.

16. 2. The swallowable device of claim 1, wherein the expandable member comprises a pre-stressed portion configured to apply the force to the piston-cylinder assembly, biasing the piston-cylinder assembly into the perpendicular orientation relative to the longitudinal axis of the expandable member.

17. 10. The swallowable device of claim 1, wherein the therapeutic agent formulation comprises a growth hormone, a parathyroid hormone, an antibody, a chemotherapeutic agent, insulin, one or more glucagon-like peptides, an immunosuppressant, a vaccine, or an antiparasitic agent.

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