SWALLOWABLE DRUG DELIVERY DEVICE AND DRUG DELIVERY METHOD - Patent application

Abstract

To provide a swallowable drug delivery device.SOLUTION: The invention provides swallowable devices 10, preparations and methods for delivering drugs and other therapeutic agents within the GI tract. Some embodiments provide a swallowable device 10 such as a capsule 10 for delivering drugs into the intestinal wall or other GI lumen. The device 10 is sized to be swallowed and pass through the intestinal tract. The capsule 10 can include at least one guide tube, one or more tissue penetrating members positioned in the guide tube, a delivery member, an actuating mechanism, and a release element. The release element degrades upon exposure to various conditions in the intestine so as to release and actuate the actuating mechanism. The devices 10 are particularly useful for delivery of drugs which are poorly absorbed, tolerated and / or degraded within the GI tract.SELECTED DRAWING: Figure 1b

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is a joint venture between U.S. Patent Application Serial No. 61 / 339,941 (filed on March 3, 2010, Attorney Docket No. 028205-000300US) and U.S. Patent Application Serial No. 61 / 284,766 (filed on March 3, 2010, Attorney Docket No. 028205-000300US). No. 61 / 340,331 (entitled "Swallowable Drug Delivery Device and Method of Delivery," filed on March 15, 2010, Attorney Docket No. 028205-000400US), and U.S. Patent Application No. 61 / 395,304 (entitled "Swallowable Drug Delivery Device and Method of Delivery," filed on May 10, 2010, Attorney Docket No. 028205-000500US), all of which are incorporated herein by reference in their entirety for all purposes. This application is also related to U.S. Patent Application Serial No. ______ / ______, entitled "Swallowable Drug Delivery Device and Method of Delivery," filed December 23, 2010, Attorney Docket No. 028205-000510US, and U.S. Patent Application Serial No. ______ / ______, entitled "Therapeutic Agent Preparations for Delivery into a Lumen of the Intestinal Tract Using a Swallowable Drug Delivery Device," filed December 23, 2010, Attorney Docket No. 028205-000310US, all of which are incorporated by reference in their entirety.

[0002] FIELD OF THEINVENTION FIELD OF THE DISCLOSURE 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 drugs to the small intestine. [Background technology]

[0003] Increasingly, new drugs have been developed in recent years for the treatment of various diseases, but many cannot be administered orally, limiting their use. 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 absorption of drugs. Traditional alternative drug delivery methods, such as intravenous and intramuscular delivery, have several drawbacks, including pain and risk of infection from needle pricks, the requirement to use sterile technique, and the requirement and associated risks of maintaining an intravenous line in the patient for extended periods of time. Other drug delivery approaches, such as implantable drug delivery pumps, have been adopted, but these approaches require semi-permanent implantation of a device and may still have many of the limitations of intravenous delivery. Thus, 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, the following: (Item 1) 1. An ingestible device suitable for swallowing into a lumen of a patient's digestive tract, the lumen having a luminal wall, the device comprising: a capsule sized to pass through the intestinal tract; a therapeutic agent preparation disposable within the capsule, the preparation comprising at least one therapeutic agent, the therapeutic agent preparation chemically degrades or exerts adverse effects on the patient when released within the lumen of the gastrointestinal tract; an actuator coupled to the therapeutic agent preparation and having a first configuration and a second configuration, the preparation being retained within the capsule when the actuator is in the first configuration, the preparation being advanced from the capsule into the lumen wall by movement of the actuator from the first configuration to the second configuration, thereby inhibiting the deleterious effects or chemical degradation of the therapeutic agent within the lumen; A device comprising: (Item 2) 2. The device of claim 1, wherein a therapeutic dose of the therapeutic agent is contained within the capsule, and the actuator is configured to advance substantially all of the therapeutic dose of the therapeutic agent into the lumen wall to minimize the adverse effects. (Item 3) 2. The device of claim 1, wherein the actuator includes a release element comprising a material configured to degrade upon exposure to a selected pH in the gastrointestinal tract, whereby the adjustment is advanced into the lumen wall upon degradation. (Item 4) 4. The device of claim 3, wherein the selected pH is greater than about 7.4. (Item 5) Item 4. The device of item 3, wherein the actuator comprises a spring, the release element being coupled to the spring to hold the spring in compression and release the spring upon disassembly of the release element. (Item 6) 6. The device of claim 5, wherein the actuator comprises an actuation mechanism including a first motion converter and a second motion converter, a tissue penetrating member having a lumen in which the therapeutic agent preparation is disposed, a delivery member, and a track member, wherein the first motion converter is configured to convert motion of the spring to advance the tissue penetrating member into and retract it out of the lumen wall, and the second motion converter is configured to convert motion of the spring to advance the delivery member into the lumen of the tissue penetrating member, thereby advancing a therapeutic agent preparation from the lumen of the tissue penetrating member into the lumen wall, and the first and second motion converters advance along the track member. (Item 7) 7. The device of claim 6, wherein the tissue penetrating member comprises a biodegradable material configured to degrade and release the tissue penetrating member from the gastrointestinal wall. (Item 8) 7. The device of claim 6, wherein the tissue penetrating member comprises a needle. (Item 9) 7. The device of claim 6, wherein the delivery member comprises a plunger. (Item 10) 2. The device of claim 1, wherein the therapeutic agent preparation comprises a solid, pellet, powder, or liquid. (Item 11) 2. The device of claim 1, wherein the therapeutic agent preparation comprises a tissue penetrating member advanceable into the lumen wall. (Item 12) 2. The device of item 1, wherein the therapeutic agent preparation comprises at least a first therapeutic agent and a second therapeutic agent. (Item 13) 2. The device of claim 1, wherein the therapeutic drug preparation comprises a therapeutically effective dose of insulin for the treatment of diabetes or a glucose regulation disorder. (Item 14) 2. The device of claim 1, wherein the therapeutic drug preparation comprises a therapeutically effective dose of an incretin for the treatment of diabetes or a glucose regulation disorder. (Item 15) 15. The device of item 14, wherein the incretin comprises glucagon-like peptide-1 (GLP-1), a GLP-1 analog, exenatide, liraglutide, albiglutide, taspoglutide, or gastric inhibitory polypeptide (GIP). (Item 16) 2. The device of claim 1, wherein the therapeutic drug preparation comprises a combination of therapeutic drugs for the treatment of diabetes or a glucose regulation disorder. (Item 17) 17. The device of item 16, wherein the combination comprises a therapeutically effective dose of an incretin and a therapeutically effective dose of a biguanide. (Item 18) 18. The device of claim 17, wherein the incretin comprises exenatide and the biguanide comprises metformin. (Item 19) 18. The device of claim 17, wherein the dosages of the incretin and the biguanide are adapted to produce improved levels of glycemic control over an extended period of time. (Item 20) 2. The device of item 1, wherein the therapeutic drug preparation comprises a therapeutically effective dose of growth hormone. (Item 21) 2. The device of claim 1, wherein the therapeutic drug preparation comprises a therapeutically effective dose of parathyroid hormone for the treatment of osteoporosis or thyroid disease. (Item 22) 2. The device of item 1, wherein the therapeutic drug preparation comprises a therapeutically effective dose of a chemotherapeutic drug for the treatment of cancer. (Item 23) 2. The device of item 1, wherein the therapeutic drug preparation comprises a therapeutically effective dose of an antibiotic. (Item 24) 2. The device of claim 1, wherein the therapeutic drug preparation comprises a therapeutically effective dose of an antiviral compound. (Item 25) 26. The device of claim 24, wherein the antiviral compound comprises a protease inhibitor. 2. The device of item 1, wherein the therapeutic drug preparation comprises a therapeutically effective dose of an anti-seizure compound. (Item 27) 27. The device of claim 26, wherein the anti-seizure compound comprises furosemide. (Item 28) 1. A method for delivering a therapeutic agent into a wall of a patient's small intestine, the method comprising: Swallowing a drug delivery device comprising a therapeutic agent, a release element, and a tissue-penetrating member, the therapeutic agent chemically degrading or causing adverse effects to the patient if released within the lumen of the digestive tract; Releasing the release element within the small intestine in response to conditions within the small intestine; and delivering the therapeutic agent into a wall of the small intestine using the tissue penetrating member such that the adverse effects or chemical degradation of the therapeutic agent within the lumen is inhibited; A method comprising: (Item 29) 29. The method of claim 28, wherein the dose of the therapeutic agent in the capsule does not include an amount to compensate for chemical degradation and / or poor absorption of the therapeutic agent in the digestive tract. (Item 30) 29. The method of claim 28, wherein the dose of the therapeutic agent is reduced to an amount between about 10 and 50 percent compared to a standard oral dosage. (Item 31) 29. The method of claim 28, wherein the patient has a shortened section of the small intestine and the dose of the therapeutic agent in the capsule does not include a portion that compensates for underabsorption of the therapeutic agent in the small intestine. (Item 32) 29. The method of claim 28, wherein the adverse effect comprises one of stomach cramps, diarrhea, irritable bowel, or bleeding in the digestive tract. (Item 33) 29. The method of claim 28, wherein the adverse effect comprises a toxic effect on a non-target tissue. (Item 34) 29. The method of claim 28, wherein the therapeutic agent comprises a chemotherapeutic agent for the treatment of cancer, and the adverse effects comprise at least one of a toxic effect on non-target tissue or the development of resistance to the therapeutic agent by cancer tissue in the patient. (Item 35) 29. The method of claim 28, wherein the therapeutic agent comprises an antibiotic and the adverse effect comprises the development of bacterial resistance to the antibiotic. (Item 36) 29. The method of claim 28, wherein the therapeutic agent comprises an antiviral agent and the adverse effect comprises the development of viral resistance to the antiviral agent. (Item 37) 29. The method of claim 28, wherein the therapeutic agent comprises an anti-seizure compound and the adverse effect comprises a neuromuscular, cardiac, or gastrointestinal effect. (Item 38) 38. The method of claim 37, wherein the therapeutic agent comprises furosemide. (Item 39) 29. The method of claim 28, wherein the therapeutic agent comprises an antibody that is chemically degraded in the digestive tract and the agent is delivered into the wall of the small intestine with minimal or no loss in binding capacity or specificity to the target antigenic site. (Item 40) 29. The method of claim 28, wherein the therapeutic agent comprises a polypeptide that is chemically degraded in the gastrointestinal tract and the agent is delivered into the wall of the small intestine with minimal or no loss in binding capacity or specificity to the target binding site. (Item 41) 29. The method of claim 28, wherein the therapeutic agent comprises a cytokine or interferon that is chemically degraded in the digestive tract and the agent is delivered into the wall of the small intestine with minimal or no loss in immune stimulatory capacity. (Item 42) 29. The method of claim 28, wherein the therapeutic agent comprises a growth hormone that is chemically broken down in the digestive tract and the agent is delivered into the wall of the small intestine with minimal or no loss in growth stimulating effect. (Item 43) 29. The method of claim 28, wherein the therapeutic agent comprises a chemotherapy agent for the treatment of cancer that is chemically degraded in the digestive tract and that is delivered into the wall of the small intestine with minimal or no loss in cancer treatment effect. (Item 44) 29. The method of claim 28, wherein the therapeutic agent comprises a glucose regulating agent that is chemically degraded in the digestive tract and is delivered into the wall of the small intestine with minimal or no loss in glucose regulating capacity. (Item 45) 40. The method of claim 39, wherein the glucose regulating agent comprises an insulin compound. (Item 46) 40. The method of claim 39, wherein the glucose regulating agent comprises an incretin compound, a GLP-1 compound, or exenatide. (Item 47) 29. The method of claim 28, wherein the conditions in the small intestine are a pH of about 7.1 or greater. (Item 48) 49. The method of claim 28, wherein the release element degrades in response to chemical conditions in the small intestine. 49. The method of claim 48, wherein the condition is a selected pH. (Item 50) 29. The method of claim 28, wherein the release element comprises an enteric material. (Item 51) further comprising delivering a first therapeutic agent and a second therapeutic agent; 30. The method of claim 28, wherein the first therapeutic agent is delivered using a first tissue-penetrating member and the second therapeutic agent is delivered using a second tissue-penetrating member. (Item 52) 1. A swallowable device for delivering a drug into an intestinal wall, the device comprising: a capsule sized to pass through the intestinal tract; a tissue penetrating member disposed within the capsule and configured to contain the drug, the tissue penetrating member having a tissue penetrating end for penetrating the intestinal wall; a delivery member for delivering the drug from the tissue penetrating member into tissue; an actuation mechanism coupled to at least one of the tissue penetrating member or the delivery member, the actuation mechanism configured to advance the tissue penetrating member into the intestinal wall and advance the delivery member to deliver the drug; a release element operably coupled to the actuation mechanism, the release element comprising a material configured to degrade upon exposure to a selected pH in the intestine, such that upon degradation, the release element is actuated to release the tissue penetrating member and advance an advanceable member to deliver the drug into the intestinal wall; A device comprising: (Item 53) Item 53. The device of item 52, wherein the capsule includes at least one guide tube, and the tissue penetrating member is disposed within the at least one guide tube. (Item 54) 53. The device of claim 52, wherein the tissue penetrating member has a lumen for carrying the drug, and at least a portion of the delivery member is advanceable within the lumen of the tissue penetrating member. (Item 55) 53. The device of claim 52, wherein the selected pH is greater than about 7.4. (Item 56) 53. The device of claim 52, wherein at least a portion of the device comprises a biodegradable material configured to degrade in the intestinal tract, thereby allowing the device to pass atraumatically through the intestinal tract. (Item 57) Item 53. The device of item 52, wherein the tissue penetrating member comprises a biodegradable material configured to degrade, thereby releasing the tissue penetrating member from the intestinal wall. (Item 58) Item 53. The device of item 52, wherein the tissue penetrating member comprises a needle. (Item 59) Item 53. The device of item 52, wherein the advanceable member comprises a plunger. (Item 60) 1. A system for delivering a drug, comprising: A device according to item 52, a drug disposed within the capsule or the tissue penetrating member; A system comprising: (Item 61) 61. The system of claim 60, wherein the drug comprises a solid, pellet, or powder. (Item 62) 61. The system of claim 60, wherein the tissue penetrating member comprises the drug. (Item 63) 61. The system of item 60, wherein the drug comprises a chemotherapy drug, an interferon, an antibody, an antibiotic, a growth hormone, a parathyroid hormone, a glucose regulating drug, an insulin compound, an incretin hormone, a GLP-1 compound, or exenatide. (Item 64) 1. A method of drug delivery, the method comprising: Swallowing a drug delivery device comprising a capsule, a drug, an actuation mechanism, a release element, and a tissue-penetrating member; Releasing the release element within the small intestine in response to conditions within the small intestine; activating the actuation mechanism to deliver the drug into the wall of the small intestine using the tissue penetrating member; A method comprising: (Item 65) 65. The method of claim 64, wherein the drug comprises a chemotherapy drug, an interferon, an antibody, an antibiotic, a growth hormone, a parathyroid hormone, a glucose regulating drug, an insulin compound, an incretin hormone, a GLP-1 compound, or exenatide. (Item 66) Item 67. The method of item 64, wherein the release element degrades in response to chemical conditions in the small intestine. 65. The method of claim 64, wherein the release element comprises an enteric material. (Item 68) Item 65. The method of item 64, wherein the actuation mechanism comprises a spring, a cam, an electromechanical mechanism, a solenoid, or a piezoelectric material. (Item 69) 1. A swallowable device for inserting a therapeutic drug preparation into an intestinal wall of a patient's intestinal tract, the device comprising: a swallowable capsule sized to pass through the intestinal tract, the capsule having a capsule wall including an opening; at least a portion of the capsule wall covering the opening and protecting the capsule from degradation in the stomach and comprising a material or coating that degrades in response to the pH in the small intestine; a tissue penetrating member comprising a therapeutic agent preparation; means for advancing the tissue penetrating member from the capsule, through the opening, and into the intestinal wall of the patient in response to a selected pH in the small intestine. A device comprising: (Item 70) 70. The swallowable device of claim 69, wherein the means for advancing the tissue penetrating member comprises an expandable member that is expandable in response to pH within the small intestine. (Item 71) Item 71. The swallowable device of item 70, wherein the expandable member is a balloon. (Item 72) Item 71. The swallowable device of item 70, wherein the expandable member is expanded by a chemical reaction. (Item 73) Item 73. The swallowable device of item 72, wherein the expandable member includes a pH sensitive valve for initiating the chemical reaction in response to pH within the small intestine. (Item 74) Item 73. The swallowable device of item 72, wherein reactants for the chemical reaction are contained within the expandable member. (Item 75) Item 73. The swallowable device of item 72, wherein the expandable member comprises at least a first portion and a second portion, the portions being separated by a separating means, the first portion containing a liquid and the second portion containing a reactant, the reactant and liquid producing a gas that, when mixed, expands the expandable device. (Item 76) Item 76. The swallowable device of item 75, wherein the separating means comprises a valve that opens in response to forces from peristaltic contractions in the small intestine. (Item 77) 1. A swallowable device for delivering a therapeutic drug preparation into an intestinal wall of a patient's intestinal tract, the device comprising: a swallowable capsule sized to pass through the intestinal tract, the capsule having a capsule wall including an opening; an expandable member disposed within the capsule in at least a partially unexpanded state, the expandable member including a first portion and a second portion separated by a separation valve that degrades upon exposure to a selected pH in the intestine, the first portion including a liquid and the second portion including a reactant configured to react with the liquid to produce a gas that expands the expandable member, and upon degradation of the valve, the liquid from the first portion mixes with the reactant in the second portion to produce the gas that expands the expandable member; a tissue penetrating member formed at least in part from a therapeutic agent preparation, the tissue penetrating member including proximal and distal portions, the proximal portion being removably coupled to the expandable member, the tissue penetrating member including at least one retaining feature for retaining the tissue penetrating member within the intestinal wall, and upon expansion of the expandable member, the tissue penetrating member disengages from the expandable member by being advanced through the opening into the intestinal wall where it is retained by the at least one retaining feature; A device comprising: (Item 78) Item 78. The device of item 77, wherein at least a portion of the capsule includes a coating that seals the opening and that degrades in response to a selected pH in the small intestine, and upon opening of the opening, intestinal fluids enter the interior space of the capsule and contact the isolation valve. (Item 79) 80. The device of claim 78, wherein at least one of the coating or the isolation valve comprises PGLA. (Item 80) 80. The device of claim 78, wherein the intestine is the small intestine and the coating is configured to degrade in response to a selected pH in the small intestine. (Item 81) Item 81. The device of item 80, wherein the selected pH is greater than about 6.0. (Item 82) Item 78. The device of item 77, wherein the tissue penetrating element is configured to detach from the expandable member upon contraction of the expandable member. (Item 83) Item 78. The device of item 77, wherein the tissue penetrating element is configured to detach from the expandable member in response to forces exerted on the expandable member by peristaltic contractions of the intestine. (Item 84) Item 78. The device of item 77, wherein the expandable member has a wall thickness of less than about 0.001. (Item 85) Item 78. The device of item 77, wherein the expandable member comprises a polymer, a substantially inflexible polymer, polyethylene PET, or polyimide. (Item 86) Item 78. The device of item 77, wherein the expandable member includes a deflation valve that is degradable upon exposure to at least one of the liquid in the expandable member or the liquid in the intestine to deflate the expandable member after expansion, the deflation valve being configured to degrade at a selectable time period after expansion of the expandable member to allow the expandable member to advance the tissue penetrating member into the intestinal wall. (Item 87) Item 87. The device of item 86, wherein the deflation valve degrades at a slower rate than the isolation valve. (Item 88) Item 89. The device of item 86, further comprising a piercing element disposed on an interior surface of the capsule, the piercing element disposed and configured to pierce and contract the expandable member. Item 87. The device of item 86, wherein the capsule is configured to disintegrate into at least two pieces upon expansion of the expandable member. (Item 90) Item 87. The device of item 86, wherein the liquid comprises water. (Item 91) Item 87. The device of item 86, wherein the reactants include solid reactants. (Item 92) Item 87. The device of item 86, wherein the liquid comprises citric acid and the reactant comprises sodium bicarbonate. (Item 93) Item 87. The device of item 86, wherein the device includes at least two tissue penetrating members and corresponding openings disposed in opposing walls of the expandable member such that the at least two tissue penetrating members exit through openings disposed in opposing walls of the capsule. (Item 94) Item 87. The device of item 86, wherein the device includes at least three tissue penetrating members and corresponding openings. (Item 95) and an advancement member coupled to a surface of the expandable member and removably coupled to the proximal portion of the tissue penetrating member, the advancement member advancing the tissue penetrating member into tissue upon expansion of the expandable member; the advancement member includes an attachment feature that engages a mating feature on the proximal portion of the tissue penetrating member; Item 87. The device of item 86, wherein the attachment feature is a pin and the mating feature is a recess into which the pin inserts. (Item 96) Item 96. The device of item 95, further comprising a support member for supporting the advancing member during expansion of the expandable member, the support member including a first surface attached to a surface of the expandable member and an opposing surface attached to the advancing member surface, the opposing surface being attached to the advancing member surface, the opposing surface of the support member having a larger surface area than a surface of the advancing member so as to increase pressure applied to the advancing member from expansion of the expandable member, and upon expansion of the expandable member, the support member pushes the advancing member to advance the tissue penetrating member into tissue. (Item 97) Item 78. The device of item 77, wherein the tissue penetrating member is needle-shaped. (Item 98) 80. The device of claim 77, wherein the tissue penetrating member comprises a biodegradable polymer. (Item 99) 99. The device of claim 98, wherein the biodegradable polymer comprises PLGA. (Item 100) Item 99. The device of item 98, wherein less than about 5% of the therapeutic agent in the tissue penetrating member is thermally decomposed. (Item 101) Item 101. The device of item 100, wherein less than about 1% of the therapeutic agent in the tissue penetrating member is thermally decomposed. (Item 102) Item 78. The device of item 77, further comprising at least one reservoir for storing a therapeutic agent preparation, the reservoir being fluidly coupled to the tissue penetrating member, the tissue penetrating member comprising a hollow tissue penetrating member having a lumen, the reservoir being configured to be collapsible by expansion of the expandable member to release a therapeutic agent from the reservoir through the lumen and into the intestinal wall, and disposed within the capsule. (Item 103) 1. A swallowable device for delivering a therapeutic drug preparation into an intestinal wall of a patient's intestinal tract, the device comprising: a swallowable capsule sized to pass through the intestinal tract, the capsule having a capsule wall including an opening; an expandable member disposed within the capsule in at least a partially unexpanded state, the expandable member including a first portion and a second portion separated by a separation valve that degrades upon exposure to a selected pH in the intestine, the first portion including a liquid and the second portion including a reactant configured to react with the liquid to produce a gas that expands the expandable member, and upon degradation of the valve, the liquid from the first portion mixes with the reactant in the second portion to produce the gas that expands the expandable member; a tissue penetrating member having a lumen and proximal and distal portions, the proximal portion coupled to the expandable member such that upon expansion of the expandable member, the tissue penetrating member is advanced through an opening and into the intestinal wall; at least one reservoir for storing a therapeutic agent preparation, the reservoir being fluidly connected to the tissue penetrating member lumen, the reservoir being configured to be collapsible by expansion of the expandable member to release a therapeutic agent from the reservoir through the lumen and into the intestinal wall, the reservoir being disposed within the capsule; A device comprising: (Item 104) 104. The method of claim 103, wherein the therapeutic agent comprises a therapeutically effective dose of an incretin and a therapeutically effective dose of a biguanide. (Item 105) 105. The method of claim 104, wherein the dosages of the incretin and the biguanide are adapted to produce an improved level of glycemic control over an extended period of time. (Item 106) Item 106. The method of item 105, wherein the extended period is up to about one day. (Item 107) Item 106. The method of item 105, wherein the extended period is up to about one week. (Item 108) Item 104. The device of item 103, wherein the at least one reservoir comprises a first reservoir and a second reservoir. (Item 109) Item 104. The device of item 103, further comprising a manifold having channels all in fluid communication, a tissue penetrating member connector, and at least one reservoir connector, the tissue penetrating member connector coupled to the tissue penetrating member lumen, and the at least one reservoir connector coupled to the at least one reservoir. (Item 110) Item 110. The device of item 109, wherein the at least one reservoir comprises a first reservoir and a second reservoir, and the at least one reservoir connector comprises a first and a second reservoir connector, the first reservoir connector coupled to the first reservoir and the second reservoir connector coupled to the second reservoir. The embodiments of the present invention provide devices, systems, kits, and methods for delivering drugs and other therapeutic agents to various locations in the body. Many embodiments provide swallowable devices for delivering drugs and other therapeutic agents in the gastrointestinal (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 tract walls. The embodiments of the present invention are particularly useful for delivering drugs and other therapeutic agents that are poorly absorbed, poorly tolerated, and / or degraded (e.g., destruction of the chemical structure of the molecule) in the GI tract (e.g., digestive enzymes and acids in the stomach). Furthermore, the embodiments of the present invention can be used to deliver drugs that were previously only possible, or preferably delivered, by intravenous or other forms of parenteral administration (e.g., intramuscular, etc.). In addition, the embodiments of the present invention are useful for achieving rapid release of drugs into the bloodstream via oral delivery.

[0005] Embodiments of the present invention provide devices, systems, kits, and methods for delivering drugs and other therapeutic agents to various locations in the body. Many embodiments provide swallowable devices for delivering drugs and other therapeutic agents in the gastrointestinal (GI) tract. Certain embodiments provide swallowable devices, such as capsules, for delivering drugs and other therapeutic agents into the walls of the small intestine or other digestive tracts. Embodiments of the present invention are particularly useful for the delivery of drugs and other therapeutic agents that are poorly absorbed, poorly tolerated, and / or degraded in the GI tract. Additionally, embodiments of the present invention can be used to deliver drugs that were previously only possible, or preferably delivered, by intravenous or other forms of parenteral administration (e.g., intramuscular, etc.).

[0006] In one aspect, the present invention provides a swallowable device for delivering drugs and other therapeutic agents into the wall of the small or large intestine. The device comprises a capsule sized to be swallowed and passed through the intestinal tract. The capsule comprises an interior volume and can be manufactured from a variety of biocompatible polymers known in the art, including a variety of biodegradable polymers. The capsule can comprise at least one guide tube, one or more tissue penetrating members disposed within the at least one guide tube, a delivery member, and an actuation mechanism. Alternatively, the tissue penetrating members can be disposed within the capsule without a guide tube. The tissue penetrating members generally comprise a hollow needle or other similar structure, having a lumen or other compartment and a tissue penetrating end for penetrating at a selective depth into the intestinal wall. In various embodiments, the device can include a second and a third tissue penetrating member, with additional numbers being contemplated. Each tissue penetrating member can include the same or different drugs. In preferred embodiments having multiple tissue penetrating members, the tissue penetrating members can be distributed symmetrically around the capsule to anchor the capsule on the intestinal wall during delivery of the drug. In some embodiments, all or a portion of the tissue-piercing member (e.g., the tissue-piercing end) can be manufactured from the drug itself. In these and related embodiments, the drug can have a needle or dart-like structure (with or without barbs) configured to penetrate and be retained within the intestinal wall.

[0007] The tissue penetrating member can be made from various biodegradable materials (e.g., PGLA) to degrade in the small intestine, thus providing a fail-safe mechanism for detaching the tissue penetrating member from the intestinal wall if the component is retained therein. Additionally, in these and related embodiments, selectable portions of the capsule can be made from such biodegradable materials to allow the entire device to controllably degrade into smaller pieces. Such embodiments facilitate passage and excretion of the device through the digestive tract. In certain embodiments, the capsule can include seams of biodegradable materials that produce capsule fragments of selectable sizes and shapes and controllably degrade to facilitate passage through the digestive tract. The seams can be compressively stressed, perforated, or otherwise treated to accelerate degradation. The concept of using biodegradable seams to create controlled degradation of the swallowable device in the digestive tract can also be applied to other swallowable devices, such as swallowable cameras, to facilitate passage through the digestive tract and reduce the likelihood of the device becoming trapped therein.

[0008] The delivery member is configured to advance the drug from the capsule through the tissue-penetrating member lumen and into the intestinal wall. Typically, at least a portion of the delivery member is advanceable within the lumen of the tissue-penetrating member. The delivery member can have a piston or similar structure sized to fit within the lumen of the delivery member. The distal end of the delivery member (the end advanced into the tissue) can have a plunger element that advances the drug within the lumen of the tissue-penetrating member and forms a seal with the lumen. The plunger element can be integral with or attached to the delivery member. Preferably, the delivery member is configured to advance a fixed distance within the needle lumen to deliver a fixed or metered dose of drug into the intestinal wall. This can be achieved by one or more of the following: selection of the diameter of the delivery member (e.g., the diameter can be tapered distally), the diameter of the tissue-penetrating member (which can be narrowed at its distal end), the use of a stop, and / or an actuation mechanism. For embodiments of the device having tissue-penetrating members (eg, drug darts) made from a drug, the delivery member is adapted to advance the darts from outside the capsule and into the tissue.

[0009] The delivery member and tissue penetrating member can be configured for delivery of drugs in liquid, semi-liquid, or solid form, or all three. Drugs in solid form can include both powders or pellets. Semi-liquids can include slurries or pastes. Drugs can be contained within the cavity of the capsule, or in enclosed reservoirs if liquid or semi-liquid. In some embodiments, the capsule can contain a first, second, or third drug (or more). Such drugs can be contained within the lumen of the tissue penetrating member (if solid or powder) or in separate reservoirs within the capsule body.

[0010] The actuation mechanism can be coupled to at least one of the tissue-piercing member or the delivery member. The actuation mechanism is configured to advance the tissue-piercing member a selectable distance into the intestinal wall, as well as advance the delivery member to deliver the drug, and then retract the tissue-piercing member from the intestinal wall. For example, in some embodiments where the tissue-piercing member itself is a drug, the actuation mechanism is configured to leave the tissue-piercing member within the intestinal wall. In various embodiments, the actuation mechanism can include a pre-loaded spring mechanism configured to be released by a release element. Suitable springs can include both coils (including conical springs) and leaf springs, with other spring configurations also being contemplated. In certain embodiments, the spring can be conical to reduce the length of the spring in a compressed state to a point where the compressed length of the spring is approximately the thickness of a few coils (e.g., two or three) or only one coil.

[0011] In certain embodiments, the actuation mechanism comprises a spring, a first motion converter, a second motion converter, and a track member. A release element is coupled to the spring to hold the spring in a compressed state such that disassembly of the release element releases the spring. The first motion converter is configured to convert the motion of the spring to advance and retract the tissue penetrating element in tissue. The second motion converter is configured to convert the motion of the spring to advance the delivery member into the lumen of the tissue penetrating member. The motion converters are pushed by the spring and run along a rod or other track member that serves to guide the path of the converter. They engage (directly or indirectly) the tissue penetrating member and / or the delivery member to produce the desired motion. They are desirably configured to convert the motion of the spring along its longitudinal axis into an orthogonal motion of the tissue penetrating member and / or the delivery member, although conversion in other directions is also contemplated. The motion converters can have a wedge, trapezoid, or curved shape, and other shapes are also contemplated. In certain embodiments, the first motion converter can have a trapezoidal shape and include a slot that engages a pin on the tissue penetrating member that rides in the slot. The slot can have a trapezoidal shape that mirrors or otherwise corresponds to the overall shape of the converter and serves to push the tissue penetrating member in the upslope of the trapezoid and retract it in the downslope. In one variation, one or both of the motion converters can include a cam or cam-like device that is pivoted by a spring and engages the tissue penetrating and / or delivery member.

[0012] In other variations, the actuation mechanism may also comprise an electromechanical device / mechanism, such as a solenoid, or a piezoelectric device. In one embodiment, the piezoelectric device may comprise a shaped piezoelectric element having an undeployed and deployed state. The element may be configured to be in the deployed state upon application of a voltage and return to the undeployed state upon removal of the voltage. This and related embodiments allow for reciprocating motion of the actuation mechanism to advance and then retract the tissue penetrating member.

[0013] The release element is coupled to at least one of the actuation mechanism or a spring coupled to the actuation mechanism. In certain embodiments, the release element is coupled to a spring disposed within the capsule to hold the spring in a compressed state. Degradation of the release element releases the spring to actuate the actuation mechanism. In many embodiments, the release element comprises a material configured to degrade upon exposure to chemical conditions in the small intestine or large intestine, such as pH. Typically, the release element is configured to degrade upon exposure to a selected pH in the small intestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 8.0, or higher. However, it can also be configured to degrade in response to other conditions in the small intestine. In certain embodiments, the release element can be configured to degrade in response to certain chemical conditions in the fluid in the small intestine, such as those that occur after ingestion of a meal (e.g., a meal high in fat or protein).

[0014] Biodegradation of the release element from one or more conditions in the small intestine (or elsewhere in the digestive tract) can be achieved by selection of materials for the release element, the amount of crosslinking of those materials, and the thickness and other dimensions of the release element. A smaller amount of crosslinking and / or a thinner thickness can increase the rate of degradation, and vice versa. Suitable materials for the release element can include biodegradable materials, such as various enteric materials, that are configured to degrade upon exposure to higher pH or other conditions in the small intestine. The enteric materials can be copolymerized or otherwise mixed with one or more polymers to obtain certain material properties in addition to biodegradation. Such properties can include, without limitation, stiffness, strength, flexibility, and hardness.

[0015] In certain embodiments, the release element may comprise a film or plug that fits or otherwise blocks over the guide tube and holds the tissue penetrating member inside the guide tube and / or capsule. In these and related embodiments, the tissue penetrating member is coupled to a spring-loaded actuation mechanism such that when the release element is sufficiently disassembled, it releases the tissue penetrating member, which then pops out of the guide tube and penetrates the intestinal wall. In other embodiments, the release element may be shaped to function as a latch that holds the tissue penetrating element in place. In these and related embodiments, the release element may be located on the exterior or interior of the capsule. In an internal embodiment, the capsule and guide tube are configured to allow intestinal fluids to enter into the capsule interior to allow disassembly of the release element.

[0016] In some embodiments, the actuation mechanism can be actuated using a sensor, such as a pH or other chemical sensor, that detects the presence of the capsule in the small intestine and sends a signal to the actuation mechanism (or to an electronic controller coupled to the actuation mechanism to actuate the mechanism). pH sensor embodiments can comprise an electrode-based sensor, or can be a mechanically based sensor, such as a polymer that contracts or expands upon exposure to pH or other chemical conditions in the small intestine. In related embodiments, an expandable / contractible sensor can also comprise the actuation mechanism itself, by using mechanical motion from the expansion or contraction of the sensor.

[0017] According to another embodiment for detecting that the device is in the small intestine (or other location in the digestive tract), the sensor can include a strain gauge or other pressure / force sensor for detecting the number of peristaltic contractions the capsule is undergoing within a particular location in the digestive tract. In these embodiments, the capsule is desirably sized to be gripped by the small intestine during peristaltic contractions. Different locations in the digestive tract have different numbers of peristaltic contractions. The small intestine has between 12-9 contractions per minute, with the frequency decreasing down the entire length of the intestine. Thus, according to one or more embodiments, detection of the number of peristaltic contractions can be used to determine not only whether the capsule is in the small intestine, but also its relative location within the intestine.

[0018] As an alternative or supplement to internally activated drug delivery, in some embodiments, the user may externally activate the actuation mechanism to deliver the drug using RF, magnetic, or other wireless signaling means known in the art. In these and related embodiments, the user may use a handheld device (e.g., a handheld RF device) that includes not only the signaling means, but also means for informing the user when the device is in the small intestine or elsewhere in the digestive tract. Subsequent embodiments may be implemented by including an RF transmitter on the swallowable device to signal the user when the device is in the small intestine or elsewhere in the digestive tract (e.g., by signaling input from a sensor). The same handheld device may also be configured to alert the user when the actuation mechanism has been activated and the selected drug has been delivered. In this way, the user is provided with confirmation that the drug has been delivered. This allows the user to take other appropriate drugs / therapeutic agents as well as make other related decisions (e.g., a diabetic to eat or not eat a meal and what food to eat). The handheld device may also be configured to send a signal to the swallowable device to override the actuation mechanism and thus prevent, delay or accelerate delivery of the drug. In use, such embodiments allow the user to intervene to prevent, delay or accelerate delivery of the drug based on other symptoms and / or patient actions (e.g., eating a meal, deciding to go to sleep, exercising, etc.).

[0019] The user may also externally activate the actuation mechanism at a selected time period after swallowing the capsule, which may correlate to a typical transit time or range of transit times for food to travel through the user's digestive tract to a particular location in the tract, such as the small intestine.

[0020] Another aspect of the invention provides a method for delivering drugs into the wall of the digestive tract using embodiments of a swallowable drug delivery device. Such methods can be used to deliver therapeutically effective amounts of various drugs and other therapeutic agents. These include several macromolecular peptides and proteins, such as growth hormone, parathyroid hormone, insulin, interferon, and other similar compounds, that would otherwise require injection due to their chemical degradation in the stomach / digestive tract. Suitable drugs and other therapeutic agents that can be delivered by embodiments of the invention include various chemotherapy drugs (e.g., interferon), antibiotics, antiviral agents, insulin and related compounds, glucagon-like peptides (e.g., GLP-1, exenatide), parathyroid hormone, growth hormones (e.g., IFG and other growth factors), anti-seizure drugs, immunosuppressants, and antiparasitic agents such as various antimalarial agents. Dosages of particular drugs can be titrated for the patient's weight, age, or other parameters.

[0021] In various method embodiments, embodiments of the swallowable drug delivery device can be used to deliver multiple drugs 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 a patient to eliminate the need to have to take multiple medications for one or more specific conditions. They also provide a means to facilitate the delivery and absorption of two or more drug regimens into the small intestine and thus into 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 and thus reaching the target at different times. 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.

[0022] Embodiments of the present invention provide devices, systems, kits, and methods for delivering drugs and other therapeutic agents to various locations in the body. Many embodiments provide swallowable devices for delivering drugs and other therapeutic agents in the digestive tract. Certain embodiments provide swallowable devices, such as capsules, for delivering drugs and other therapeutic agents into the walls of the small intestine or other digestive organs. Embodiments of the present invention are particularly useful for delivering drugs and other therapeutic agents that are poorly absorbed, poorly tolerated, and / or chemically degraded (e.g., destruction of the molecule's chemical structure) in the digestive tract (e.g., by digestive enzymes and acids in the stomach). Additionally, embodiments of the present invention can be used to deliver drugs that were previously only possible, or preferably delivered, by intravenous or other forms of parenteral administration (e.g., intramuscular, etc.).

[0023] The present invention provides a swallowable device for delivering drugs and other therapeutic agents into the wall of the small or large intestine. The device comprises a capsule sized to be swallowed and passed through the intestinal tract. The capsule comprises an interior volume and can be made from a variety of biocompatible polymers known in the art, including a variety of biodegradable polymers. The capsule comprises at least one guide tube, one or more tissue penetrating members disposed within the at least one guide tube, a delivery member, and an actuation mechanism. The tissue penetrating members generally comprise a hollow needle or other similar structure, having a lumen and a tissue penetrating end for penetrating at a selective depth into the intestinal wall. In various embodiments, the device can include a second and a third tissue penetrating member, with additional numbers being contemplated. Each tissue penetrating member can include the same or a different drug. In preferred embodiments having multiple tissue penetrating members, the tissue penetrating members can be distributed symmetrically around the capsule to anchor the capsule on the intestinal wall during delivery of the drug. In some embodiments, all or a portion of the tissue penetrating member (e.g., the tissue penetrating end) can be made from the drug itself. In these and related embodiments, the drug can have needle or dart-like structures (with or without barbs) configured to penetrate and be retained within the intestinal wall.

[0024] The tissue penetrating member can be made from various biodegradable materials (e.g., PGLA) to degrade in the small intestine, thus providing a fail-safe mechanism for detaching the tissue penetrating member from the intestinal wall if the component is retained therein. Additionally, in these and related embodiments, selectable portions of the capsule can be made from such biodegradable materials to allow the entire device to controllably degrade into smaller pieces. Such embodiments facilitate passage and excretion of the device through the digestive tract. In certain embodiments, the capsule can include seams of biodegradable materials that produce capsule fragments of selectable sizes and shapes and controllably degrade to facilitate passage through the digestive tract. The seams can be compressively stressed, perforated, or otherwise treated to accelerate degradation. The concept of using biodegradable seams to create controlled degradation of the swallowable device in the digestive tract can also be applied to other swallowable devices, such as swallowable cameras, to facilitate passage through the digestive tract and reduce the likelihood of the device becoming trapped therein.

[0025] The delivery member is configured to advance the drug from the capsule through the tissue-penetrating member lumen and into an intestinal wall, such as the wall of the small intestine. Typically, at least a portion of the delivery member is advanceable within the lumen of the tissue-penetrating member. The delivery member can have a piston or similar structure sized to fit within the lumen of the delivery member. The distal end of the delivery member (the end advanced into the tissue) can have a plunger element that advances the drug within the lumen of the tissue-penetrating member and forms a seal with the lumen. The plunger element can be integral with or attached to the delivery member. Preferably, the delivery member is configured to advance a fixed distance within the needle lumen to deliver a fixed or metered dose of drug into the intestinal wall. This can be accomplished by one or more of the following: selection of the diameter of the delivery member (e.g., the diameter can be tapered distally), the diameter of the tissue-penetrating member (which can be narrowed at its distal end), the use of a stop, and / or an actuation mechanism. For embodiments of the device having tissue-penetrating members (eg, drug darts) made from a drug, the delivery member is adapted to advance the darts from outside the capsule and into the tissue.

[0026] The delivery member and tissue-piercing member can be configured for delivery of drugs (or other therapeutic agents) in liquid, semi-liquid, or solid form, or all three. Drugs in solid form can include both powders or pellets. Semi-liquids can include slurries or pastes. Drugs can be contained within the cavity of the capsule, or in enclosed reservoirs if liquid or semi-liquid. In some embodiments, the capsule can contain a first, second, or third drug (or more). Such drugs can be contained within the lumen of the tissue-piercing member (if solid or powder) or in separate reservoirs within the capsule body.

[0027] The actuation mechanism can be coupled to at least one of the tissue-penetrating member or the delivery member. The actuation mechanism is configured to advance the tissue-penetrating member a selectable distance into the intestinal wall, as well as advance the delivery member to deliver the drug, and then retract the tissue-penetrating member from the intestinal wall. In various embodiments, the actuation mechanism can include a pre-loaded spring mechanism configured to be released by a release element. Suitable springs can include both coils (including conical springs) and leaf springs, with other spring configurations also being contemplated. In certain embodiments, the spring can be conical to reduce the length of the spring in a compressed state to a point where the compressed length of the spring is approximately the thickness of a few coils (e.g., two or three) or only one coil.

[0028] In certain embodiments, the actuation mechanism comprises a spring, a first motion converter, a second motion converter, and a track member. A release element is coupled to the spring to hold the spring in a compressed state such that disassembly of the release element releases the spring. The first motion converter is configured to convert the motion of the spring to advance and retract the tissue penetrating element in tissue. The second motion converter is configured to convert the motion of the spring to advance the delivery member into the lumen of the tissue penetrating member. The motion converters are pushed by the spring and run along a rod or other track member that serves to guide the path of the converter. They engage (directly or indirectly) the tissue penetrating member and / or the delivery member to produce the desired motion. They are desirably configured to convert the motion of the spring along its longitudinal axis into an orthogonal motion of the tissue penetrating member and / or the delivery member, although conversion in other directions is also contemplated. The motion converters can have a wedge, trapezoid, or curved shape, and other shapes are also contemplated. In certain embodiments, the first motion converter can have a trapezoidal shape and include a slot that engages a pin on the advancing tissue penetrating member that rides in the slot. The slot can have a trapezoidal shape that mirrors or otherwise corresponds to the overall shape of the converter and serves to push the tissue penetrating member in the upslope of the trapezoid and retract it in the downslope. In one variation, one or both of the motion converters can include a cam or cam-like device that is pivoted by a spring and engages the tissue penetrating and / or delivery member.

[0029] In other variations, the actuation mechanism may also comprise an electromechanical device / mechanism, such as a solenoid, or a piezoelectric device. In one embodiment, the piezoelectric device may comprise a shaped piezoelectric element having an undeployed and deployed state. The element may be configured to be in the deployed state upon application of a voltage and return to the undeployed state upon removal of the voltage. This and related embodiments allow for reciprocating motion of the actuation mechanism to advance and then retract the tissue penetrating member.

[0030] The release element is coupled to at least one of the actuation mechanism or a spring coupled to the actuation mechanism. In certain embodiments, the release element is coupled to a spring disposed within the capsule to hold the spring in a compressed state. Degradation of the release element releases the spring to actuate the actuation mechanism. In many embodiments, the release element comprises a material configured to degrade upon exposure to chemical conditions in the small intestine or large intestine, such as pH. Typically, the release element is configured to degrade upon exposure to a selected pH in the small intestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 8.0, or higher. However, it can also be configured to degrade in response to other conditions in the small intestine. In certain embodiments, the release element can be configured to degrade in response to certain chemical conditions in the fluid in the small intestine, such as those that occur after ingestion of a meal (e.g., a meal high in fat or protein).

[0031] Biodegradation of the release element from one or more conditions in the small intestine (or elsewhere in the digestive tract) can be achieved by selection of materials for the release element, the amount of crosslinking of those materials, and the thickness and other dimensions of the release element. A smaller amount of crosslinking and / or a thinner thickness can increase the rate of degradation, and vice versa. Suitable materials for the release element can include biodegradable materials, such as various enteric materials, that are configured to degrade upon exposure to higher pH or other conditions in the small intestine. The enteric materials can be copolymerized or otherwise mixed with one or more polymers to obtain certain material properties in addition to biodegradation. Such properties can include, without limitation, stiffness, strength, flexibility, and hardness.

[0032] In certain embodiments, the release element may comprise a film or plug that fits or otherwise blocks over the guide tube and holds the tissue penetrating member inside the guide tube. In these and related embodiments, the tissue penetrating member is coupled to a spring-loaded actuation mechanism such that when the release element is sufficiently disassembled, it releases the tissue penetrating member, which then pops out of the guide tube and penetrates the intestinal wall. In other embodiments, the release element may be shaped to function as a latch that holds the tissue penetrating element in place. In these and related embodiments, the release element may be located on the exterior or interior of the capsule. In an internal embodiment, the capsule and guide tube are configured to allow ingress of interstitial fluid into the capsule interior to allow disassembly of the release element.

[0033] In some embodiments, the actuation mechanism can be actuated using a sensor, such as a pH or other chemical sensor, that detects the presence of the capsule in the small intestine and sends a signal to the actuation mechanism (or to an electronic controller coupled to the actuation mechanism to actuate the mechanism). pH sensor embodiments can comprise an electrode-based sensor, or can be a mechanically based sensor, such as a polymer that contracts or expands upon exposure to pH or other chemical conditions in the small intestine. In related embodiments, an expandable / contractible sensor can also comprise the actuation mechanism itself, by using mechanical motion from the expansion or contraction of the sensor.

[0034] According to another embodiment for detecting that the device is in the small intestine (or other location in the digestive tract), the sensor can include a strain gauge or other pressure / force sensor for detecting the number of peristaltic contractions the capsule is undergoing in a particular location in the intestinal tract. In these embodiments, the capsule is desirably sized to be gripped by the small intestine during peristaltic contractions. Different locations in the digestive tract have different numbers of peristaltic contractions. 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, detection of the number of peristaltic contractions can be used to determine not only whether the capsule is in the small intestine, but also its relative location in the intestine.

[0035] As an alternative or supplement to internally activated drug delivery, in some embodiments, the user may externally activate the actuation mechanism to deliver the drug using RF, magnetic, or other wireless signaling means known in the art. In these and related embodiments, the user may use a handheld device (e.g., a handheld RF device) that includes not only the signaling means, but also means for informing the user when the device is in the small intestine or elsewhere in the digestive tract. Subsequent embodiments may be implemented by including an RF transmitter on the swallowable device to signal the user when the device is in the small intestine or elsewhere in the digestive tract (e.g., by signaling input from a sensor). The same handheld device may also be configured to alert the user when the actuation mechanism has been activated and the selected drug has been delivered. In this way, the user is provided with confirmation that the drug has been delivered. This allows the user to select other appropriate drugs / treatments. The handheld device may be configured to send a signal to the swallowable device to override the actuation mechanism and thus prevent, delay or accelerate delivery of the drug. In use, such embodiments enable the user to intervene to prevent, delay or accelerate delivery of the drug based on other symptoms and / or patient actions (e.g., eating a meal, deciding to go to sleep, exercising, etc.).

[0036] The user may also externally activate the actuation mechanism at a selected time period after swallowing the capsule, which may correlate to a general transit time or range of transit times for food to travel through the user's digestive tract to a particular location in the tract, such as the small intestine.

[0037] Another aspect of the invention provides a therapeutic agent preparation for delivery into the wall of the small intestine (or other luminal wall of the intestinal tract) using embodiments of a swallowable device described herein. The preparation includes a therapeutically effective dose of at least one therapeutic agent (e.g., insulin, anti-seizure compounds, NSAIDs, antibiotics, etc.). It may include a solid, liquid, or a combination of both, and may include one or more pharmaceutical excipients. The preparation has a shape and material consistency to be contained in an embodiment of a swallowable capsule that is delivered from the capsule into the luminal wall, and degrades within the luminal wall to release a dose of the therapeutic agent. The preparation may also have a selectable surface area to volume ratio to enhance or otherwise control the rate of degradation of the preparation within the wall of the small intestine or other body lumen. In various embodiments, the preparation can be configured to be coupled to an actuator, such as a release element (and / or other component coupled to the release element), having a first configuration in which the preparation is contained in the capsule and a second configuration in which the preparation is advanced from outside the capsule into the wall of the small intestine. The dose of the drug or other therapeutic agent in the preparation can be titrated downward from that required for conventional oral delivery methods so that potential side effects from the drug can be reduced.

[0038] Typically, but not necessarily, the preparation is shaped or otherwise configured to be contained within the lumen of a tissue-piercing member, such as a hollow needle, configured to be advanced from outside the capsule into the wall of the small intestine. The preparation itself may comprise a tissue-piercing member configured to be advanced into the wall of the small intestine or other lumen of the intestinal tract.

[0039] Another aspect of the present invention provides a method for delivering drugs and therapeutic agents into the wall of the digestive tract using embodiments of a swallowable drug delivery device. Such methods can be used to deliver therapeutically effective amounts of various drugs and other therapeutic agents. These include several macromolecular peptides and proteins that would otherwise require injection and / or intravenous infusion due to chemical degradation by digestive fluids in the lumen of the stomach and small intestine. Such compounds that can be delivered using various embodiments of the present invention include, without limitation, growth hormones, parathyroid hormones, insulin compounds, antibodies and other globulin proteins (e.g., gamma globulins), interferons and other cytokines, glucagon-like peptides (e.g., GLP-1, exenatide) and other incretins, parathyroid hormones, growth hormones (e.g., IFG and other growth factors), chemotherapeutic drugs (doxorubicin), and other similar compounds. Other drugs and other therapeutic agents that can be delivered by embodiments of the present invention include any number of oral delivery agents, antibiotics (vancomycin, penicillin, erythromycin, etc.), antivirals (protease inhibitors, anti-seizure compounds (furosemide, dilatin), NSIADs (ibuprofen), immunosuppressants, and antiparasitic agents such as various antimalarials. Many of these compounds can include various therapeutic agents that, when taken by standard oral delivery methods, cause adverse effects in the intestinal tract and elsewhere, such as cramping, bleeding, diarrhea, and irritable bowel. Various embodiments of the present invention provide for drugs or other therapeutic agents to be infused directly into the small intestine, whereby these effects can be largely avoided, and the dosage of the compound can be adjusted accordingly (e.g., increased in many cases). In various embodiments, the dosage of a particular drug can be titrated to these considerations as well as the patient's weight, age, and condition being treated.

[0040] In various method embodiments, 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 eliminate the need to have to take multiple medications for one or more specific conditions. They also provide a means to facilitate the delivery and absorption of two or more drug regimens into the small intestine and thus 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 into the intestinal wall at approximately the same time. This in turn improves the pharmacokinetics and therefore the effectiveness of the selected mixture of drugs.

[0041] Further details of these and other embodiments and aspects of the invention are described more fully below with reference to the accompanying drawings.

[0042] The present invention provides 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 in the gastrointestinal (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 tract walls. The present invention is particularly useful for the delivery of drugs and other therapeutic agents that are poorly absorbed, poorly tolerated, and / or degraded. Furthermore, the present invention can be used to deliver drugs that were previously only possible, or preferably delivered, by intravenous or other forms of parenteral administration (e.g., intramuscular, etc.). In addition, the present invention is useful for achieving rapid release of drugs into the bloodstream via oral delivery.

[0043] In one aspect, the present invention provides a swallowable device for delivering drugs and other therapeutic agents into the walls of the small or large intestine or other intestinal organs. The device includes a capsule sized to be swallowed and passed through the intestinal tract, an expandable member disposed within the capsule, and a tissue penetrating member advanceable into the intestinal wall by expansion of the expandable member. The capsule includes an interior volume and at least one opening through which the tissue penetrating member can be advanced into the intestinal wall. The tissue penetrating member is formed at least in part from a drug or other therapeutic agent. The capsule can be manufactured from a variety of non-toxic materials, including a variety of biodegradable polymers. The capsule may also have an enteric or other coating to protect the capsule from stomach acid while allowing for biodegradation in the small intestine to allow the device to deliver drugs and other therapeutic agents into the wall of the small intestine in response to pH or other conditions in the small intestine.

[0044] A balloon or other expandable member is disposed within the capsule interior volume and coupled to the tissue penetrating member. The balloon is typically attached to the inner wall of the capsule in an at least partially undeployed state and may comprise a variety of non-compliant polymers known in the art, such as PET, polyethylene, and polyimide. Desirably, the balloon is thin-walled, e.g., less than about 0.001 inches. The balloon also typically comprises at least a first and a second portion or compartment, separated by an isolation valve or other isolation means. A liquid, typically water, may be disposed within the first compartment, and at least one reactant, which may be liquid but is typically a solid, may be disposed within the second compartment. The reactants typically comprise at least a reactant, e.g., an acid, such as citric acid, and a base, such as sodium hydroxide, which may have a ratio of about 1:2. Other reactants are contemplated, including other acids, e.g., acetic acid, and bases. When the valve or other separation means is opened, the reactants mix in the liquid and produce a gas, such as carbon dioxide, that expands the balloon and advances the tissue penetrating member into the intestinal wall, as described more fully herein. In addition to advancing the tissue penetrating member into the tissue, the device can also be configured to crack the inflated balloon or otherwise separate the capsule into one or more pieces for easier passage through the intestinal tract.

[0045] The isolation valve can be configured to open in a number of ways and in response to a number of conditions. Typically, the isolation valve is configured to open by disintegrating one or more portions in response to a higher pH or other condition found in the small intestine such that the valve opens upon disintegration. Also typically, the isolation valve is located in the central portion of the balloon, although other locations are contemplated. In certain embodiments, the isolation valve can have a beam-like structure that is located within the capsule to compress the portion of the balloon between the first and second compartments. The beam can be attached to the inner surface of the capsule at one or both ends. In a preferred embodiment, the beam is attached to the radial side of the capsule, preferably using an interference fit, so that the beam can be snapped into place using pick-and-place and other similar methods known in the manufacturing art. As the beam disintegrates, the compressive force is released. These and other embodiments of the valve can include one or more pinching features, such as ridges, that engage with indentations or other mating features on the inner surface of the capsule to apply additional force to the balloon wall below the pinching feature and add redundancy to the seal. In another embodiment, the isolation valve can include a neck of an expandable member over which is placed a clamping collar made of a biodegradable material that holds the valve closed and releases the valve upon disassembly.

[0046] The isolation valve can be located at various locations on or within the capsule so that it is exposed to and degraded by intestinal fluids. While at least a portion of the valve may be exposed to the capsule surface, typically the valve is located within the capsule interior where it is exposed to intestinal fluids entering through at least one aperture or opening. In these and related embodiments, at least a portion of the capsule surface, including the portion containing the at least one aperture, is desirably coated with a protective layer, such as an enteric coating, that also degrades in response to pH or other conditions in the small intestine. Such a coating provides a protective seal over the at least one aperture so that digestive fluids do not enter the capsule interior and begin to degrade the isolation valve until the capsule reaches the small intestine. During use, embodiments employing a degradable coating / seal and a degradable valve over the aperture provide a primary and secondary means of ensuring that the balloon does not inflate to deploy its tissue penetrating member until the capsule reaches the small intestine.

[0047] As an alternative or additional embodiment, 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 sustained 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.

[0048] In addition to the release valve, the balloon or other expandable member also typically includes a deflation valve that serves to deflate the expandable member after inflation. The deflation valve may include a biodegradable material configured to degrade upon exposure to fluids in the small intestine and / or liquids in one of the compartments of the balloon to create an opening or channel for leakage of gas within the balloon. In one embodiment, the deflation valve may include a biodegradable section located at an end portion of the balloon to join opposite ends of the balloon wall together. In these and related embodiments, as the degradable section degrades upon exposure to liquid, the balloon wall tears or otherwise breaks, providing a high degree of assurance of rapid deflation. To provide an even higher degree of reliability in deflation, multiple degradable sections may desirably be located within the solid reactant portion of the balloon. For embodiments in which the deflation valve is degraded by fluids in the small intestine, the degradation of the valve may be facilitated by configuring the inflated balloon to break the capsule into two or more pieces such that a majority of the balloon is directly exposed to the degradative liquids in the small intestine. This can be accomplished by manufacturing the capsule from separate pieces (e.g., two halves that are mechanically fitted together) and / or through the use of seams as described herein.

[0049] Additionally, as a further aid in guaranteed deflation, one or more piercing elements can be attached to the inner surface of the capsule wall such that they contact and are pierced by the piercing elements when the balloon is fully deflated. In another alternative or additional embodiment of the means for deflation, one or more of the tissue penetrating members can be directly coupled to the balloon and configured to pull away from the balloon when they are disengaged, rupturing the balloon in the process.

[0050] The tissue penetrating member in this aspect of the invention can be made from a variety of drugs and other therapeutic agents. Typically, the drug or other therapeutic agent is mixed with a biodegradable polymer such as PGLA. In such an embodiment, the penetrating member can include a substantially heterogeneous mixture of drug and biodegradable polymer. Alternatively, the penetrating member may include a portion substantially formed from biodegradable material and a separate section or compartment formed from or containing a drug. The penetrating member can be formed with a shaft and a needle tip or other sharp distal tip to easily penetrate the tissue of the intestinal wall. Once positioned in the intestinal wall, the tissue penetrating member is degraded by the interstitial fluids in the wall tissue and the drug dissolves in these fluids and is absorbed into the bloodstream. The penetrating member also typically includes one or more tissue retention features, such as barbs or hooks, to retain the penetrating member in 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 distributed symmetrically around the member shaft. The drug may be in a solid form and then formed into the shape of the tissue-penetrating member using molding or other similar methods, or may be in a solid or liquid form and then added to a biodegradable polymer in liquid form, and then the mixture is formed into the penetrating member using molding or other forming methods known in the polymer art. Desirably, the tissue-penetrating member embodiment including the drug and the degradable polymer is formed (e.g., cured) at a temperature that does not result in substantial thermal decomposition of any 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 decomposed drug in the tissue-penetrating 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 the particular polymer processing method (e.g., molding, curing, solvent evaporation, etc.).

[0051] The tissue penetrating member is desirably releasably coupled (directly or indirectly) to the balloon or other expandable member such that the tissue penetrating member disengages from the balloon following advancement of the tissue penetrating member into the intestinal wall. The penetrating member can be configured to disengage as a result of forces exerted on the capsule by balloon deflation (when the retaining features retain the penetrating member in the tissue) and / or peristaltic contractions of the small intestine. Typically, the tissue penetrating member is indirectly coupled to the balloon by an advancement member comprising a rigid structure attached to the balloon surface that releasably engages the penetrating member. The advancement member engages the penetrating member using attachment features such as pins that fit into recesses or other mating features of the penetrating member. The pins and recesses can be configured to disengage due to the force of balloon deflation and / or forces applied to the capsule by peristaltic contractions. The rigid advancement member can have a larger horizontal surface area than the penetrating member to act as a force concentrating element that increases the force per unit area applied to the penetrating member from balloon expansion. In some embodiments, the advancement member can be coupled to the balloon via a platform, also described herein as a support member, having one surface attached to the balloon surface and the other surface attached to the advancement member. The support member can be sized to allow for the attachment and advancement of multiple advancement and tissue penetrating members. In addition, the support member can have a larger surface area than the advancement member / tissue penetrating member to have a force concentration function similar to that described above for the advancement member. As an additional or alternative embodiment, the tissue penetrating member can be directly coupled to the balloon, for example, by adhesive. In these and related embodiments, the tissue penetrating member can be configured to breach the balloon wall when disengaged, thus providing a means for balloon deflation.

[0052] Multiple tissue-piercing members can be coupled to the balloon or other expandable member and may have several arrangements. In specific embodiments, the capsule can include two, three, or four piercing members, with additional numbers being contemplated. The piercing members can carry the same or different drugs. The former provide for the delivery of larger amounts of a particular drug, while the latter allow two or more drugs to be delivered into the intestinal wall at approximately the same time. The tissue-piercing members can be positioned and distributed in several locations and patterns on the balloon surface. In certain embodiments, the piercing members can be positioned on opposite sides of the balloon (e.g., 180 degrees apart around the circumference of the balloon) so that balloon inflation can place the tissue-piercing members on opposite sides of the intestinal wall lumen. In preferred embodiments having multiple tissue-piercing members, the tissue-piercing members can be symmetrically distributed around the capsule to anchor the capsule on the intestinal wall during delivery of the drug, as well as to place the tissue-piercing members in multiple locations within the intestinal wall. This not only allows additional amounts of drug to be delivered, but also provides a more even distribution of the drug within the intestinal wall and more rapid absorption into the bloodstream.

[0053] As an additional or alternative embodiment to the use of a drug-carrying tissue-piercing member, various embodiments of the device can also include a drug reservoir disposed in a capsule that is compressible by the expansion of a balloon or other expandable member. The reservoir contains a drug or other therapeutic agent in liquid or powder form. For liquid form, the drug is dissolved in an aqueous drug solution. In these and related embodiments, the reservoir is fluidly coupled to the advanceable hollow tissue-piercing member such that the expansion of the balloon compresses the reservoir to force the drug solution through the tissue-piercing member and into the intestinal wall. Multiple reservoirs are contemplated, including two, three, four, or more. In certain embodiments, two reservoirs can be coupled to the tissue-piercing member, the reservoirs being positioned approximately 180 degrees apart relative to the longitudinal axis of the penetrating member. Typically, the reservoir is fluidly coupled to the hollow penetrating member using a manifold. A suitable manifold includes a t-shaped manifold having connectors for the reservoirs on either of its outer ends, a central connector for the hollow tissue penetrating members, and a central lumen or channel running to all of the connectors. Other shapes and manifold configurations are also contemplated.

[0054] In another aspect, the present invention provides a swallowable device for delivering a drug or other therapeutic agent into the wall of the small or large intestine, comprising a capsule sized to be swallowed and passed through the intestinal tract, the capsule comprising at least one guide tube, one or more tissue penetrating members disposed within the at least one guide tube, a delivery member, and an actuation mechanism. In these and related embodiments, the tissue penetrating members generally comprise hollow needles or other similar structures, having a lumen and a tissue penetrating end for penetrating a selectable depth into the intestinal wall. In various embodiments, the device can include a second and a third tissue penetrating member, with additional numbers being contemplated. Each tissue penetrating member can include the same or a different drug. In preferred embodiments having multiple tissue penetrating members, the tissue penetrating members can be distributed symmetrically around the capsule to anchor the capsule on the intestinal wall during delivery of the drug. In some embodiments, the tissue penetrating members (e.g., the tissue penetrating end) can be manufactured in whole or in part from the drug itself. In these and related embodiments, the drug can have needle or dart-like structures (with or without barbs) configured to penetrate and be retained within the intestinal wall.

[0055] The tissue penetrating member embodiments of this aspect of the invention can be manufactured from various biodegradable materials (e.g., PGLA) to degrade in the small intestine, thus providing a fail-safe mechanism for detaching the tissue penetrating member from the intestinal wall if the component is retained therein. Additionally, in these and related embodiments, selectable portions of the capsule can be manufactured from such biodegradable materials to allow the entire device to controllably degrade into smaller pieces. Such embodiments facilitate passage and evacuation of the device through the digestive tract. In certain embodiments, the capsule can include seams of biodegradable materials that produce capsule fragments of selectable sizes and shapes and controllably degrade to facilitate passage through the digestive tract. The seams can be compressively stressed, perforated, or otherwise treated to accelerate degradation. The seams can also be so treated to allow the capsule to break down into smaller pieces by the forces applied from the expansion of a balloon or other expandable member. In other embodiments for producing capsule disintegration after deployment of the tissue penetrating member, the capsule can comprise two halves or other separate sections that are mechanically fitted together, for example by a snap fit, and thus separated by the force applied from balloon inflation.

[0056] The delivery member is configured to advance the drug from the capsule through the tissue-penetrating member lumen and into the intestinal wall. Typically, at least a portion of the delivery member is advanceable within the lumen of the tissue-penetrating member. The delivery member can have a piston or similar structure sized to fit within the lumen of the delivery member. The distal end of the delivery member (the end advanced into the tissue) can have a plunger element that advances the drug within the lumen of the tissue-penetrating member and forms a seal with the lumen. The plunger element can be integral with or attached to the delivery member. Preferably, the delivery member is configured to advance a fixed distance within the needle lumen to deliver a fixed or metered dose of drug into the intestinal wall. This can be achieved by one or more of the following: selection of the diameter of the delivery member (e.g., the diameter can be tapered distally), the diameter of the tissue-penetrating member (which can be narrowed at its distal end), the use of a stop, and / or an actuation mechanism. For embodiments of the device having a tissue-piercing member (eg, a drug dart) made from a drug, the delivery member is adapted to advance the tissue-piercing member from outside the capsule and into the tissue.

[0057] The delivery member and tissue penetrating member can be configured for delivery of drugs in liquid, semi-liquid, or solid form, or all three. Drugs in solid form can include both powders or pellets. Semi-liquids can include slurries or pastes. Drugs can be contained within the cavity of the capsule, or in enclosed reservoirs if liquid or semi-liquid. In some embodiments, the capsule can contain a first, second, or third drug (or more). Such drugs can be contained within the lumen of the tissue penetrating member (if solid or powder) or in separate reservoirs within the capsule body.

[0058] The actuation mechanism can be coupled to at least one of the tissue-penetrating member or the delivery member. The actuation mechanism is configured to advance the tissue-penetrating member a selectable distance into the intestinal wall, as well as advance the delivery member to deliver the drug, and then retract the tissue-penetrating member from the intestinal wall. In various embodiments, the actuation mechanism can include a pre-loaded spring mechanism configured to be released by a release element. Suitable springs can include both coils (including conical springs) and leaf springs, with other spring configurations also being contemplated. In certain embodiments, the spring can be conical to reduce the length of the spring in a compressed state to a point where the compressed length of the spring is approximately the thickness of a few coils (e.g., two or three) or only one coil.

[0059] In certain embodiments, the actuation mechanism comprises a spring, a first motion converter, a second motion converter, and a track member. A release element is coupled to the spring to hold the spring in a compressed state such that disassembly of the release element releases the spring. The first motion converter is configured to convert the motion of the spring to advance and retract the tissue penetrating element in tissue. The second motion converter is configured to convert the motion of the spring to advance the delivery member into the lumen of the tissue penetrating member. The motion converters are pushed by the spring and run along a rod or other track member that serves to guide the path of the converter. They engage (directly or indirectly) the tissue penetrating member and / or the delivery member to produce the desired motion. They are desirably configured to convert the motion of the spring along its longitudinal axis into an orthogonal motion of the tissue penetrating member and / or the delivery member, although conversion in other directions is also contemplated. The motion converters can have a wedge, trapezoid, or curved shape, and other shapes are also contemplated. In certain embodiments, the first motion converter may have a trapezoidal shape and may include a slot that engages a pin on the tissue penetrating member that rides in the slot. The slot may have a trapezoidal shape that mirrors or otherwise corresponds to the overall shape of the converter and serves to push the tissue penetrating member in the upslope of the trapezoid and then retract in the downslope. In one variation, one or both of the motion converters may include a cam or cam-like device that is pivoted by a spring and engages the tissue penetrating and / or delivery member.

[0060] In other variations, the actuation mechanism may also comprise an electromechanical device / mechanism, such as a solenoid, or a piezoelectric device. In one embodiment, the piezoelectric device may comprise a shaped piezoelectric element having an undeployed and deployed state. The element may be configured to be in the deployed state upon application of a voltage and return to the undeployed state upon removal of the voltage. This and related embodiments allow for reciprocating motion of the actuation mechanism to advance and then retract the tissue penetrating member.

[0061] The release element is coupled to at least one of the actuation mechanism or a spring coupled to the actuation mechanism. In certain embodiments, the release element is coupled to a spring disposed within the capsule to hold the spring in a compressed state. Degradation of the release element releases the spring to actuate the actuation mechanism. In many embodiments, the release element comprises a material configured to degrade upon exposure to chemical conditions in the small intestine or large intestine, such as pH. Typically, the release element is configured to degrade upon exposure to a selected pH in the small intestine, e.g., 6.0, 6.3, 6.5, 6.7, 7.0, 7.1, 7.2, 7.3, 7.4, 8.0, or higher. However, it can also be configured to degrade in response to other conditions in the small intestine, e.g., the presence of various enzymes. In certain embodiments, the release element can be configured to degrade in response to certain chemical conditions in the fluid in the small intestine, such as those that occur after ingestion of a meal (e.g., a meal high in fat or protein).

[0062] Biodegradation of the release element from one or more conditions in the small intestine (or elsewhere in the digestive tract) can be achieved by selection of materials for the release element, the amount of crosslinking of those materials, and the thickness and other dimensions of the release element. A smaller amount of crosslinking and / or a thinner thickness can increase the rate of degradation, and vice versa. Suitable materials for the release element can include biodegradable materials, such as various enteric materials, that are configured to degrade upon exposure to higher pH or other conditions in the small intestine. The enteric materials can be copolymerized or otherwise mixed with one or more polymers to obtain certain material properties in addition to biodegradation. Such properties can include, without limitation, stiffness, strength, flexibility, and hardness.

[0063] In certain embodiments, the release element may comprise a film or plug that fits or otherwise blocks over the guide tube and holds the tissue penetrating member inside the guide tube. In these and related embodiments, the tissue penetrating member is coupled to a spring-loaded actuation mechanism such that when the release element is sufficiently disassembled, it releases the tissue penetrating member, which then pops out of the guide tube and penetrates the intestinal wall. In other embodiments, the release element may be shaped to function as a latch that holds the tissue penetrating element in place. In these and related embodiments, the release element may be located on the exterior or interior of the capsule. In an internal embodiment, the capsule and guide tube are configured to allow intestinal fluids to enter into the capsule interior to allow disassembly of the release element.

[0064] In some embodiments, the actuation mechanism can be actuated using a sensor, such as a pH or other chemical sensor, that detects the presence of the capsule in the small intestine and sends a signal to the actuation mechanism (or to an electronic controller coupled to the actuation mechanism to actuate the mechanism). pH sensor embodiments can comprise an electrode-based sensor, or can be a mechanically based sensor, such as a polymer that contracts or expands upon exposure to pH or other chemical conditions in the small intestine. In related embodiments, an expandable / contractible sensor can also comprise the actuation mechanism itself, by using mechanical motion from the expansion or contraction of the sensor.

[0065] According to another embodiment for detecting that the swallowable device is in the small intestine (or other location in the digestive tract), the sensor can include a strain gauge or other pressure / force sensor for detecting the number of peristaltic contractions the capsule is undergoing in a particular location in the intestinal tract. In these embodiments, the capsule is desirably sized to be gripped by the small intestine during peristaltic contractions. Different locations in the digestive tract have different numbers of peristaltic contractions. 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, detection of the number of peristaltic contractions can be used to determine not only whether the capsule is in the small intestine, but also its relative location in the intestine.

[0066] As an alternative or supplement to internally activated drug delivery, in another aspect of the invention, the user may externally activate the actuation mechanism to deliver the drug using RF, magnetic, or other wireless signaling means known in the art. In these and related embodiments, the user may use a handheld device (e.g., a handheld RF device) that includes not only the signaling means, but also means for informing the user when the device is in the small intestine or elsewhere in the digestive tract. Subsequent embodiments may be implemented by including an RF transmitter on the swallowable device to signal the user when the device is in the small intestine or elsewhere in the digestive tract (e.g., by signaling an input from a sensor). The same handheld device may also be configured to alert the user when the actuation mechanism has been activated and the selected drug has been delivered. In this way, the user is provided with confirmation that the drug has been delivered. This allows the user to select other appropriate drugs / therapeutic agents. The handheld device may be configured to send a signal to the swallowable device to override the actuation mechanism and thus prevent, delay or accelerate delivery of the drug. In use, such embodiments enable a user to intervene to prevent, delay or accelerate delivery of the drug based on other symptoms and / or patient actions (e.g., eating a meal, deciding to go to sleep, exercising, etc.).

[0067] The user may also externally activate the actuation mechanism at a selected time period after swallowing the capsule, which may correlate to a typical transit time or range of transit times for food to travel through the user's digestive tract to a particular location in the tract, such as the small intestine.

[0068] Another aspect of the invention provides a therapeutic agent preparation for delivering a drug into the wall of the small intestine (e.g., other wall of the intestinal lumen) using embodiments of a swallowable device described herein. The preparation includes a therapeutically effective dose of at least one therapeutic agent (e.g., insulin, anti-seizure compounds, NSAIDs, antibiotics, etc.). It may include a solid, liquid, or a combination of both, and may include one or more pharmaceutical excipients. The preparation has a shape and material consistency to be contained in an embodiment of 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. The preparation may also have a selectable surface area to volume ratio to enhance or otherwise control the rate of degradation of the preparation within the wall of the small intestine or other body lumen. In various embodiments, the preparation can be configured to be coupled to an actuator, such as a release element (and / or other component coupled to the release element), having a first configuration in which the preparation is contained in the capsule and a second configuration in which the preparation is advanced from outside the capsule into the wall of the small intestine. The dose of the drug or other therapeutic agent in the preparation can be titrated downward from that required for conventional oral delivery methods so that potential side effects from the drug can be reduced.

[0069] Typically, but not necessarily, the preparation is shaped or otherwise configured to be contained within the lumen of a tissue-piercing member, such as a hollow needle, that is configured to be advanced from outside the capsule into the wall of the small intestine, and, as described herein, in various embodiments, the preparation itself may comprise a tissue-piercing member that is shaped and configured to be advanced into the wall of the small intestine or other lumen of the intestinal tract.

[0070] Another aspect of the invention provides a method for delivering drugs and therapeutic agents into the wall of the digestive tract using embodiments of a swallowable drug delivery device. Such methods can be used to deliver therapeutically effective amounts of various drugs and other therapeutic agents. These include several macromolecular peptides and proteins that would otherwise require injection due to chemical degradation in the stomach. Examples include growth hormone, parathyroid hormone, insulin, interferon, and other similar compounds. Suitable drugs and other therapeutic agents that can be delivered by embodiments of the invention include various chemotherapeutic drugs (e.g., interferon), antibiotics, antiviral agents, insulin and related compounds, glucagon-like peptides (e.g., GLP-1, exenatide), parathyroid hormone, growth hormones (e.g., IFG and growth factors), anti-seizure drugs, immunosuppressants, and antiparasitic agents such as various antimalarial agents. The dosage of a particular drug can be titrated for the patient's weight, age, symptoms, or other parameters.

[0071] In various method embodiments, 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 eliminate the need to have to take multiple medications for one or more specific conditions. They also provide a means to facilitate two or more drug regimens being delivered and absorbed into the small intestine and thus 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.

[0072] In one embodiment, the ingestible device is suitable for swallowing into a lumen of the patient's digestive tract. The lumen has a wall. The device comprises a capsule sized to pass through the intestinal tract. A therapeutic agent preparation is disposable within the capsule. The preparation includes at least one therapeutic agent, the therapeutic agent preparation chemically degrades or causes adverse effects to the patient if released within the lumen of the digestive tract. An actuator is coupled to the therapeutic agent preparation and has a first configuration and a second configuration. The preparation, which is held within the capsule when the actuator is in the first configuration, is advanced from the capsule into the lumen by movement of the actuator from the first configuration to the second configuration such that adverse effects or chemical degradation of the therapeutic agent within the lumen is inhibited.

[0073] In another embodiment, a method for delivering a therapeutic agent into a wall of a patient's small intestine includes swallowing a drug delivery capsule device including a therapeutic agent, a release element, and a tissue-penetrating member. The therapeutic agent, if released within the lumen of the gastrointestinal tract, will chemically degrade or cause adverse effects to the patient. The release element is released within the small intestine in response to conditions within the small intestine, and the therapeutic agent is delivered into the wall of the small intestine using the tissue-penetrating member such that adverse effects or degradation of the therapeutic agent within the lumen is inhibited.

[0074] In yet another embodiment, a swallowable device for inserting a therapeutic agent preparation into the intestinal wall of a patient's intestinal tract comprises a swallowable capsule sized to pass through the intestinal tract. The capsule has a capsule wall including an opening. At least a portion of the capsule wall comprises a material or coating overlying the opening, protecting the capsule from degradation in the stomach and disintegrating in response to a pH in the small intestine. A tissue penetrating member comprises the therapeutic agent preparation and means for advancing the tissue penetrating member from the capsule through the opening and into the intestinal wall of the patient in response to a selected pH in the small intestine.

[0075] In another embodiment, a swallowable device for delivering a therapeutic agent preparation into an intestinal wall of a patient's intestinal tract comprises a swallowable capsule sized to pass through the intestinal tract. The capsule has a capsule wall including an opening. An expandable member is disposed within the capsule in an at least partially unexpanded state. The expandable member includes a first portion and a second portion separated by a separation valve that degrades upon exposure to a selected pH in the intestine. The first portion includes a liquid and the second portion includes a reactant configured to react with the liquid upon degradation of the valve to produce a gas that expands the expandable member. The liquid from the first portion mixes with the reactant in the second portion to produce a gas that expands the expandable member. The tissue penetrating member is formed at least in part from the therapeutic agent preparation, the tissue penetrating member including a proximal and a distal portion. The proximal portion is removably coupled to the expandable member. The tissue penetrating member includes at least one retention feature for retaining the tissue penetrating member within the intestinal wall. Upon expansion of the expandable member, the tissue penetrating member is advanced through the opening into the intestinal wall where it is retained by the at least one retaining feature such that it disengages from the expandable member.

[0076] In yet another embodiment, a swallowable device for delivering a therapeutic agent preparation into an intestinal wall of a patient's intestinal tract comprises a swallowable capsule sized to pass through the intestinal tract. The capsule has a capsule wall including an opening. An expandable member is disposed within the capsule in an at least partially unexpanded state. The expandable member includes a first portion and a second portion separated by a separation valve that disintegrates upon exposure to a selected pH in the intestine. The first portion includes a liquid and the second portion includes a reactant configured to react with the liquid to produce a gas that expands the expandable member upon disintegration of the valve, and the liquid from the first portion mixes with the reactant in the second portion to produce the gas that expands the expandable member. The tissue penetrating member has a lumen and proximal and distal portions. The proximal portion is coupled to the expandable member such that upon expansion of the expandable member, the tissue penetrating member is advanced through the opening into the intestinal wall. At least one reservoir stores a therapeutic agent preparation. The reservoir is fluidly coupled to the tissue penetrating member. The reservoir is configured to be collapsible by expansion of the expandable member and disposed within the capsule to release the therapeutic agent from the reservoir through the lumen and into the intestinal wall.

[0077] In another embodiment, a swallowable device for delivering a drug into the intestinal wall comprises a capsule sized to pass through the intestinal tract. A tissue penetrating member is disposed within the capsule and contains a drug. The tissue penetrating member has a tissue penetrating end for penetrating the intestinal wall. A delivery member delivers the drug from the tissue penetrating member into the tissue. An actuation mechanism is coupled to at least one of the tissue penetrating member or the delivery member. The actuation mechanism is configured to advance the tissue penetrating member into the intestinal wall and advance the delivery member to deliver the drug. A release element is operably coupled to the actuation mechanism, the release element comprising a material configured to degrade upon exposure to a selected pH in the intestine such that upon degradation, the actuation mechanism is actuated to release the tissue penetrating member and advance the advanceable member to deliver the drug into the intestinal wall.

[0078] In yet another embodiment, a method of drug delivery includes swallowing a drug delivery device comprising a capsule, a drug, an actuation mechanism, a release element, and a tissue-penetrating member, wherein the release element is released within the small intestine in response to conditions within the small intestine, and the actuation mechanism is actuated to deliver the drug into a wall of the small intestine using the tissue-penetrating member.

[0079] Further details of these and other embodiments and aspects of the invention are described more fully below with reference to the accompanying drawings. [Brief description of the drawings]

[0080] [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. [Diagram 2] FIG. 2 is a side view illustrating an embodiment of a swallowable drug delivery device having a spring-loaded actuation mechanism for advancing a tissue-piercing member into tissue. [Diagram 3] FIG. 3 is a side view illustrating an embodiment of a swallowable drug delivery device having a spring-loaded actuation mechanism with a first motion transducer. [Figure 4] FIG. 4 is a side view illustrating an embodiment of a swallowable drug delivery device having a spring-loaded actuation mechanism with first and second motion transducers. [Diagram 5] FIG. 5 is a perspective view illustrating engagement of the first and second motion converters with the tissue penetrating member and the delivery member. [Figure 6]FIG. 6 is a cross-sectional view illustrating an embodiment of a swallowable drug delivery device having a single tissue-piercing member and an actuation mechanism for advancing the tissue-piercing member. [Figure 7a] FIG. 7a is a cross-sectional view illustrating an embodiment of a swallowable drug delivery device having multiple tissue-penetrating members and an actuation mechanism for advancing the tissue-penetrating members. [Figure 7b] FIG. 7b is a cross-sectional view illustrating deployment of the tissue penetrating member of the embodiment of FIG. 7a to deliver agent to a delivery site and anchor the device within the intestinal wall during delivery. [Figure 8a] 8a-8c are side views illustrating placement of a drug delivery device in the small intestine and deployment of a tissue penetrating member to deliver drug, where FIG. 8a shows the device in the small intestine before deployment of the tissue penetrating member with the release element intact, FIG. 8b shows the device in the small intestine with the release element degraded and the tissue penetrating element deployed, and FIG. 8c shows the device in the small intestine with the tissue penetrating element retracted and the drug delivered. [Figure 8b] 8a-8c are side views illustrating placement of a drug delivery device in the small intestine and deployment of a tissue penetrating member to deliver drug, where FIG. 8a shows the device in the small intestine before deployment of the tissue penetrating member with the release element intact, FIG. 8b shows the device in the small intestine with the release element degraded and the tissue penetrating element deployed, and FIG. 8c shows the device in the small intestine with the tissue penetrating element retracted and the drug delivered. [Figure 8c] 8a-8c are side views illustrating placement of a drug delivery device in the small intestine and deployment of a tissue penetrating member to deliver drug, where FIG. 8a shows the device in the small intestine before deployment of the tissue penetrating member with the release element intact, FIG. 8b shows the device in the small intestine with the release element degraded and the tissue penetrating element deployed, and FIG. 8c shows the device in the small intestine with the tissue penetrating element retracted and the drug delivered. [Figure 9]Figure 9a shows an embodiment of a swallowable drug delivery device including a capsule with biodegradable seams positioned to cause controlled degradation of the capsule in the digestive tract, and Figure 9b shows the embodiment of Figure 9a after it has been degraded into smaller pieces in the digestive tract. [Figure 10] FIG. 10 shows an embodiment of a capsule with a biodegradable seam that includes pores and / or perforations to accelerate the biodegradation of the capsule. [Figure 11] FIG. 11 is a side view illustrating the use of an embodiment of a swallowable drug delivery device, including transportation of the device through the digestive tract and manipulation of the device to deliver a drug. [Figure 12] FIG. 12 is a cross-sectional view illustrating an embodiment of a swallowable drug device having an expandable member, such as an expandable balloon. [Figure 13] FIG. 13 is a side view illustrating an embodiment of an expandable balloon in an inflated state inside an embodiment of a swallowable capsule. [Figure 14a] 14a-14c are side views illustrating inflation of an expandable balloon with chemical reactants, where FIG. 14a shows the balloon in an uninflated state with the isolation valve closed, FIG. 14b shows the balloon with the valve open and mixing of the chemical reactants, and FIG. 14c shows the balloon in an inflated state. [Figure 14b] 14a-14c are side views illustrating inflation of an expandable balloon with chemical reactants, where FIG. 14a shows the balloon in an uninflated state with the isolation valve closed, FIG. 14b shows the balloon with the valve open and mixing of the chemical reactants, and FIG. 14c shows the balloon in an inflated state. [Figure 14c] 14a-14c are side views illustrating inflation of an expandable balloon with chemical reactants, where FIG. 14a shows the balloon in an uninflated state with the isolation valve closed, FIG. 14b shows the balloon with the valve open and mixing of the chemical reactants, and FIG. 14c shows the balloon in an inflated state. [Figure 15] FIG. 15 shows an embodiment of an isolation valve having a pinching feature. [Figure 16a]16a-16c are side views illustrating the use of a swallowable drug delivery device having a biodegradable coated capsule and a biodegradable isolation valve to initiate balloon expansion in the small intestine, with Fig. 16a showing the balloon in an uninflated state with the capsule coating intact and the isolation valve closed, Fig. 16b showing the degraded capsule coating and the resulting intestinal fluids entering the capsule interior to contact the isolation valve, and Fig. 16c showing the decomposition and opening of the isolation valve due to contact with the intestinal fluids. [Figure 16b] 16a-16c are side views illustrating the use of a swallowable drug delivery device having a biodegradable coated capsule and a biodegradable isolation valve to initiate balloon expansion in the small intestine, with Fig. 16a showing the balloon in an uninflated state with the capsule coating intact and the isolation valve closed, Fig. 16b showing the degraded capsule coating and the resulting intestinal fluids entering the capsule interior to contact the isolation valve, and Fig. 16c showing the decomposition and opening of the isolation valve due to contact with the intestinal fluids. [Figure 16c] 16a-16c are side views illustrating the use of a swallowable drug delivery device having a biodegradable coated capsule and a biodegradable isolation valve to initiate balloon expansion in the small intestine, with Fig. 16a showing the balloon in an uninflated state with the capsule coating intact and the isolation valve closed, Fig. 16b showing the degraded capsule coating and the resulting intestinal fluids entering the capsule interior to contact the isolation valve, and Fig. 16c showing the decomposition and opening of the isolation valve due to contact with the intestinal fluids. [Figure 17] Figure 17a shows a cross-sectional view of an embodiment of an isolation valve having a beam-like structure, and Figure 17b shows a top view of the embodiment of Figure 17a. [Figure 18] FIG. 18 shows an embodiment of an isolation valve comprising a collar valve. [Figure 19a] 19a and 19b show an embodiment of an expandable balloon having a deflation valve with a biodegradable section of the balloon wall. [Figure 19b] 19a and 19b show an embodiment of an expandable balloon having a deflation valve with a biodegradable section of the balloon wall. [Figure 20-1] Figures 20a and 20b are side and bottom views of an embodiment of a tissue penetrating member illustrating the placement of tissue retaining features. [Figure 20-2] FIG. 20c is a side view of an embodiment of a tissue penetrating member having a separate drug-containing section. [Figure 21] Figure 21a is a side view and Figure 21b is a bottom view illustrating the use of an advancement member to couple a tissue penetrating member to an expandable balloon, respectively, and illustrates an embodiment of an advancement member having a larger surface area than the tissue penetrating member to act as a force concentrating element. [Figure 22a] FIG. 22a is a side view illustrating the use of an advancement member and a base platform to couple one or more tissue penetrating members to an expandable balloon. [Figure 22b] FIG. 22b is a side view showing an embodiment of a platform having multiple advancement members and tissue penetrating members. [Figure 23a] Figures 23a and 23b are side views illustrating the use of an embodiment of a swallowable device having a platform and tissue-penetrating member positioned on opposite sides of a balloon to achieve bilateral deployment of the tissue-penetrating member, with Figure 23a showing the balloon in an uninflated state and Figure 23b showing an inflated balloon with the penetrating member deployed. [Figure 23b] Figures 23a and 23b are side views illustrating the use of an embodiment of a swallowable device having a platform and tissue-penetrating member positioned on opposite sides of a balloon to achieve bilateral deployment of the tissue-penetrating member, with Figure 23a showing the balloon in an uninflated state and Figure 23b showing an inflated balloon with the penetrating member deployed. [Figure 24] Figures 24a and 24b are cross-sectional views illustrating the use of an embodiment of a swallowable device having tissue-penetrating members distributed around the entire circumference of the balloon, with Figure 24a showing the balloon in an uninflated state and Figure 24b showing the inflated balloon and the penetrating members arranged in a distributed pattern within the intestinal wall. [Figure 25a]25a and 25b are side views illustrating the use of an embodiment of a swallowable device having a drug reservoir that is compressible by inflation of an inflatable balloon, with FIG. 25 showing the balloon in an uninflated state and FIG. 25b showing the inflated balloon with drug being injected from the reservoir into the intestinal wall. [Figure 25b] 25a and 25b are side views illustrating the use of an embodiment of a swallowable device having a drug reservoir that is compressible by inflation of an inflatable balloon, with FIG. 25 showing the balloon in an uninflated state and FIG. 25b showing the inflated balloon with drug being injected from the reservoir into the intestinal wall. [Figure 26] FIG. 26 is a side view illustrating an embodiment of a manifold for connecting two or more drug reservoirs to a hollow tissue penetrating member. [Figure 27] 27a and 27b show an embodiment of a collar-type isolation valve that incorporates the use of an expandable pH sensor for valve opening, with FIG. 27a showing the valve in a closed position and FIG. 27b showing the valve in an open position. [Figure 28] 28a-28b are cross-sectional views of an embodiment of a beam-shaped isolation valve incorporating the use of a collapsible pH sensor for valve opening, with FIG. 28a showing the valve in a closed position and FIG. 28b showing the valve in an open position. [Figure 29] 29a-29b show embodiments of a capsule having rupturable seams arranged in a radial or lateral pattern for rupture of the capsule by inflation of an expandable balloon, with FIG. 29a showing the capsule before expansion and FIG. 29b showing the capsule broken into pieces by balloon expansion. [Diagram 30] FIG. 30 shows an embodiment of a balloon-rupturable capsule made from separate pieces joined by seams that can be ruptured by the inflation of an expandable balloon. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0081] 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 medical preparation that may include a drug or other therapeutic agent and one or more pharmaceutical excipients. Many embodiments provide swallowable devices for delivering medication within the gastrointestinal tract. Certain embodiments provide swallowable devices, such as capsules, for delivering medication to the wall of the small intestine or other digestive tract.

[0082] 1-11, an embodiment of a device 10 for delivery of a drug 100 to a delivery site DS in the intestinal tract comprises a capsule 20 including at least one opening 26, an expandable member 30, a guide tube 30, and one or more tissue-penetrating members 40 containing the drug 100. The tissue-penetrating members 40 can be formed at least in part from the drug 100 and / or can contain a section or compartment 42 formed from or containing the drug 100 that is located in or otherwise integral with the advanceable tissue-penetrating members 40 within at least one guide tube, a delivery member 50, an actuation mechanism 60, and a release element 70. The drug 100, also referred to herein as a preparation 100, generally includes at least one drug or therapeutic agent 101 and may include one or more pharmaceutical excipients known in the art.

[0083] The device 10 including the tissue penetrating member 40 can be configured for delivery of a drug 100 in liquid, semi-liquid, or solid form, or all three. A drug / preparation 100 in solid form can include both powders or pellets. A semi-liquid can include a slurry or paste. Whatever the form, the drug / preparation 100 desirably has a shape and material consistency that allows the drug to be advanced from outside the device into the intestinal wall (e.g., other luminal wall of the digestive tract), and then degrades within the intestinal wall to release the drug or other therapeutic agent 101. The material consistency can include one or more of the hardness, porosity, and solubility (in bodily fluids) of the preparation. The consistency of the material can be achieved by one or more of: i) the compression force used to make the preparation; ii) the use of one or more pharmaceutical disintegrants known in the art; iii) the use of other pharmaceutical excipients; iv) the particle size and distribution of the preparation (e.g., micronized particles); and v) micronization and other particle formation methods known in the art. Suitable shapes for the preparation 100 can include cylindrical, cubic, rectangular, conical, spherical, hemispherical, and combinations thereof. The shape can also be selected to define a particular surface area and volume of the drug 100, and thus the ratio between the two. The surface area to volume ratio can then be used to achieve a selected degradation rate within the intestinal or other lumen wall. To achieve a faster degradation rate, a larger ratio (e.g., a larger surface area per unit volume) can be used, and vice versa. In certain embodiments, the surface area to volume ratio may range from about 1:1 to 100:1, with specific embodiments of 2:1, 5:1, 20:1, 25:1, 50:1, and 75:1. The agent / preparation 100 is typically pre-packaged within the lumen 44 of the tissue penetrating member 40, but may also be contained elsewhere within the interior 24 of the capsule 20, or within the enclosed reservoir 27 if liquid or semi-liquid. The agent may be pre-formed to fit within the lumen or packed in, for example, powder form. Typically, the device 10 is configured to deliver a single drug 101 as part of the agent 100.However, in some embodiments, the device 10 can be configured for delivery of multiple drugs 101, including first, second, or third drugs that can be combined into a single or multiple drugs 100. For embodiments with multiple drugs / drugs, the drugs can be contained in separate tissue penetrating members 40 or in separate compartments or reservoirs 27 within the capsule 20. In another embodiment, a first dose 102 of drug 100 containing a first drug 101 can be packed into the penetrating member 40, and a second dose 103 of drug 100 (containing the same or a different drug 101) can be coated on the surface 25 of the capsule, as shown in the embodiment of FIG. 1a. The drugs 101 in the two doses of drug 102 and 103 can be the same or different. In this way, a bimodal pharmacokinetic release of the same or different drugs can be achieved. The second dose 103 of drug 100 can have an enteric coating 104 to ensure that it is released in the small intestine and also achieve a sustained release of drug 100. The enteric coating 104 can include one or more enteric coatings described herein or known in the art.

[0084] A system 11 for delivering a drug 100 into the wall of the small intestine or elsewhere in the digestive tract may comprise a device 10 containing one or more drugs 100 for the treatment of one or more selected conditions. In some embodiments, the system may include a handheld device 13 as described herein for communicating with the device 10, as shown in the embodiment of FIG. 1b. The system 11 may also be configured as a kit 14 including the system 11 packaged in a package 12 and a set of instructions 15 for use, as shown in the embodiment of FIG. 1c. The instructions may indicate to the patient when to take the device 10 relative to one or more events, such as food intake, or physiological measurements, such as blood glucose, cholesterol, etc. In such an embodiment, the kit 14 may include multiple devices 10 containing a dosing regimen of the drug 100 over a period of administration selected depending on the condition to be treated, e.g., daily, weekly, or multiple weeks.

[0085] The capsule 20 is sized to be swallowed and passed through the intestinal tract. The size can also be adjusted depending on the amount of drug to be delivered, as well as the patient's weight and adult versus pediatric application. Generally, the capsule has a tubular shape with curved ends similar to vitamins. In these and related embodiments, the capsule length 20L can be within a range of 0.5 to 2 inches and the diameter 20D can be within a range of 0.1 to 0.5 inches, with other dimensions being contemplated. The capsule 20 includes a capsule wall 21w having an exterior surface 25 and an interior surface 24 that define an interior space or volume 24v. The capsule wall 21w includes the volume 24 and the exterior surface 25 having one or more openings 26 sized for outward advancement of the tissue penetrating member 40 through the guide tube 30. In addition to other components of the device 10 (e.g., expandable member, actuation mechanism, etc.), the interior volume can include one or more compartments or reservoirs 27.

[0086] One or more portions of capsule 20 can be made from a variety of biocompatible biopolymers known in the art, including various biodegradable polymers that can include PGLA (polylactic-co-glycolic acid) in a preferred embodiment. 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, and copolymers thereof.

[0087] The use of biodegradable materials for capsule 20, including biodegradable enteric materials, allows the capsule to degrade in whole or in part to facilitate passage through the gastrointestinal system following drug delivery. As further described 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.

[0088] Additionally, in various embodiments, the capsule 20 can include various radiopaque or echogenic materials to aid in the location of the device using fluoroscopy, ultrasound, or other medical imaging modalities. In specific embodiments, all or a portion of the capsule can include radiopaque / echogenic markers 20m, as shown in the embodiment of Figures 1a and 1b. In use, such materials not only allow for the location of the device 10 within the GI tract, but also allow for the determination of the transit time of the device through the GI tract.

[0089] The expandable member 30 can comprise a variety of expandable devices that are shaped and sized to fit within the capsule 20, but typically comprises an expandable balloon 30. Other suitable expandable members include a variety of shape memory devices, and / or chemically expandable polymeric devices that have an expanded shape and size that corresponds to the interior volume 24v of the capsule 20. For ease of discussion, the expandable member 30 is referred to herein as a balloon 30, but other embodiments are equally applicable. The balloon 30 is typically attached to the interior surface 24 of the capsule 20 in an at least partially unexpanded state. Means of attachment can include the use of various adhesives known in the medical device art. The balloon can be packed inside the capsule 20 in a rolled or other compact configuration to retain space inside the capsule. Rolling can be accomplished by placement of an isolation valve 50 covering selected portions of the non-inflated balloon 30. In certain embodiments, rolling can be facilitated by the use of a collar-type isolation valve 55, as described herein, that is placed around the non-inflated balloon to keep it in a rolled configuration. In another approach, rolling can also be accomplished by the use of one or more folds 30c disposed along the balloon in a lateral, helical, or other configuration. In a preferred embodiment, the tissue-penetrating member 40 is disposed within a guide tube 30 that serves to guide and support the advancement of the member 40 into tissue, such as the wall of the small intestine or other portions of the digestive tract. In other embodiments, the tissue-penetrating member 40 can be disposed within the capsule 20 without a guide tube. The tissue-penetrating member 40 generally comprises a hollow needle or other similar structure, having a tissue-penetrating end 45 for penetrating a selectable depth into the lumen 44 and the intestinal wall IW. The member 40 may also include a pin 41 for engaging a motion transducer 90 as described herein. The depth of penetration can be controlled by the length of the member 40, the configuration of the motion transducer 90 as described herein, and the placement of stops or flanges 40s on the member 40, which in embodiments can correspond to the pins 41 as described herein. The drug 100 is generally delivered into the tissue through the lumen 44.In many embodiments, the lumen 44 is pre-loaded with the desired drug 100 that is advanced out of the lumen using the delivery member 50 or other advancement member (e.g., using a force applied to a collapsible embodiment of the member 40). Alternatively, the drug 100 can be advanced into the lumen 44 from another location / compartment within the capsule 20. In some embodiments, all or a portion of the tissue-piercing member 40 can be manufactured from the drug 100 itself. In these and related embodiments, the drug can have a needle or dart-like structure (with or without barbs) configured to penetrate and be retained in an intestinal wall, such as the wall of the small intestine. The darts can be sized and shaped depending on the drug, the dose, and the desired depth of penetration into the intestinal wall. The drug 100 can be formed into darts, pellets, or other shapes using a variety of compression molding and other related methods known in the pharmaceutical arts.

[0090] The balloon 30 can comprise various polymers known in the medical device art, but preferably comprises a non-compliant polymer such as PET (polyethylene terephthalate) and other non-compliant materials known in the art. It can be manufactured using various balloon blowing methods (e.g., mold blowing) known in the balloon catheter art to have a shape 30s and size that approximately corresponds to the interior volume 24v of the capsule 20. Suitable shapes 30s for the balloon 30 include various cylindrical shapes with tapered or curved end portions 31 (examples of such shapes include hot dogs). In some embodiments, the inflated size of the balloon 30, including its diameter 30D, can be slightly larger than the capsule 20 so that the force of the expansion (e.g., due to hoop stress) causes the capsule to break down. Desirably, the wall 32 of the balloon 30 can be thin and have a wall thickness 33 in the range of 0.005 to 0.0001", more preferably in the range of 0.001 to 0.0001", with specific embodiments of 0.002, 0.001, and 0.0005. In various embodiments, the device 10 can include second 42 and third 43 tissue penetrating members 40, as shown in the embodiment of FIGS. 7a and 7b, with additional numbers being contemplated. Each tissue penetrating member 40 can be used to deliver the same or different drugs 100, and different doses of the same drug. In a preferred embodiment, the tissue-piercing members 40 can be substantially symmetrically distributed around the circumference 21 of the capsule 20 to anchor the capsule on the intestinal wall IW during delivery of the drug 100. Anchoring the capsule 20 in such a manner reduces the likelihood that the capsule will be displaced or moved by peristaltic contractions occurring during delivery of the drug. In a specific embodiment, the amount of anchoring force can be adapted to typical forces applied during peristaltic contractions of the small intestine. Anchoring can be further promoted by a portion or the entire tissue-piercing member 40 being configured to have a curved or arcuate shape.

[0091] The balloon 230 also typically includes at least first and second portions or compartments 234 and 235 separated by an isolation valve, a delivery member, and other separation means for separating the contents of each compartment. In many embodiments, the compartments 234 and 235 have at least a small connecting section 236 between them where an isolation valve 250 is typically located. As shown in the embodiment of FIG. 14a, a liquid 239, typically water, can be placed in the first compartment 234, and one or more reactants 260 (typically solid, although liquids may also be used) can be placed in the second compartment 235. When the valve 250 opens (e.g., due to decomposition caused by fluid in the small intestine), the liquid 239 enters the compartment 235 (or vice versa, or both), and the reactants 260 mix with the liquid and produce a gas 263, such as carbon dioxide, that expands the balloon 230, as shown in the embodiment of FIGS. 14b-14c. Expansion of balloon 230 is configured to advance medication 100 through tissue penetrating member 240 and into the intestinal wall IW, as described more fully herein. Accordingly, at least a portion of delivery member 250 is advanceable within tissue penetrating member lumen 244, such that member 250 has a size and shape (e.g., a piston-like shape) configured to fit within delivery member lumen 244 or other chamber or compartment within tissue penetrating member 240.

[0092] The reactants 260 generally include at least first and second reactants 261 and 262, e.g., an acid, such as citric acid, and a base, such as sodium hydroxide. Additional numbers of reactants are also contemplated. For embodiments using citric acid and sodium hydroxide, the ratio between the two reactants (citric acid to sodium hydroxide) can be in the range of 1:1 to 1:4, with a specific ratio of 1:2. Desirably, the solid reactants 260 have little or no adsorbed water. Thus, one or more of the reactants, such as sodium hydroxide, can be pre-dried (e.g., by vacuum drying) before being placed in the balloon 230. Other reactants 260, including other acids, e.g., acetic acid, and bases, are also contemplated. The amounts of a particular reactant 260, including combinations of reactants, can be selected to produce a particular pressure using known stoichiometric equations for a particular chemical reaction and the expansion volume of the balloon and the ideal gas law (e.g., PV=nRT).

[0093] In some embodiments, the distal end 50d of the delivery member (the end advanced into the tissue) can have a plunger element 51 that advances the drug within the tissue-penetrating member lumen 44 and forms a seal with the lumen. The plunger element 51 can be integral with the delivery member 50 or attached to the delivery member. Preferably, the delivery member 50 is configured to advance a fixed distance within the needle lumen 44 to deliver a fixed or metered dose of drug into the intestinal wall IW. This can be accomplished by one or more of the following: selection of the diameter of the delivery member (e.g., the diameter can be tapered distally), the diameter of the tissue-penetrating member (which can be narrow at its distal end), the use of stops, and / or the actuation mechanism. However, in some embodiments, the stroke or travel distance of the member 50 can be adjusted in situ in response to various factors, such as one or more sensed conditions within the GI tract. The in situ adjustment can be achieved through the use of logic resources 29 (including controller 29c) coupled to an electromechanical embodiment of the actuation mechanism 60. This allows for variable doses of drug and / or variation in the distance the drug is injected into the intestinal wall.

[0094] Various embodiments of the present invention provide several structures and configurations for the isolation valve 250 or other isolation means 250. As described below, in one or more embodiments, the valve 250 may comprise a beam-like structure, or a collar-type valve. Still other structures are contemplated. In one or more of these embodiments, the valve 250 may include one or more pinching features 251, such as a ridge that engages with a recess or other mating feature 252 on the inner surface 224 of the capsule 220, as shown in the embodiment of FIG. 15. In use, the pinching feature 251 provides additional force application to the balloon wall 232 below the pinching feature, providing redundancy in the seal. The valve 250 may include multiple pinching features 251 to create a seal below each feature.

[0095] The actuation mechanism 60 can be coupled to at least one of the tissue-piercing member 40 or the delivery member 50. The actuation mechanism is configured to advance the tissue-piercing member 40 a selectable distance into the intestinal wall IW and advance the delivery member to deliver the agent 100 and then retract the tissue-piercing member from the intestinal wall. In various embodiments, the actuation mechanism 60 can include a pre-loaded spring mechanism configured to be released by a release element 70. Suitable springs 80 can include both coils (including conical springs) and leaf springs, with other spring configurations also being contemplated. In certain embodiments, the spring 80 can be substantially conical to reduce the length of the spring in a compressed state to a point where the compressed length of the spring is approximately the thickness of a few coils (e.g., two or three) or only one coil.

[0096] Also, in various embodiments, the isolation valve 250 can be configured to open in response to some condition in the digestive tract in some manner. In many embodiments, the isolation valve 250 is configured to open by disintegrating one or more portions in response to a higher pH or other condition found in the small intestine such that the valve opens upon disintegration. As an alternative or additional approach, the isolation valve 250 may also be configured to open in response to compressive forces applied by peristaltic contractions in the small intestine. In yet another approach, the isolation valve 250 may be a sustained release valve configured to open after a period of time following a trigger event, e.g., an activation step initiated by the patient, such as the peeling of a tab or the pressing of a button.

[0097] In certain embodiments, the actuation mechanism 60 can include a spring 80, a first motion converter 90, a second motion converter 94, and a track member 98, as shown in the embodiment of Figs. 2, 4, and 8a-8c. A release element 70 is coupled to the spring 80 to hold the spring in a compressed state such that disassembly of the release element releases the spring. The spring 80 may be coupled to the release element 70 by a latch or other connecting element 81. The first motion converter 90 is configured to translate the motion of the spring 80 to advance and retract the tissue-piercing element 40 in and from tissue. The second motion converter 94 is configured to translate the motion of the spring 80 to advance the delivery member 50 into the lumen 44 of the tissue-piercing member. The motion converters 90 and 94 are pushed by the spring and travel along a rod or other track member 98 that fits into a track member lumen 99 of the converter 90. The track member 98 serves to guide the path of the converter 90. The motion converters 90 and 94 engage (directly or indirectly) the tissue-piercing member 40 and / or the delivery member 50 to produce the desired motion. They are configured to convert the motion of the spring 80 along its longitudinal axis into an orthogonal motion of the tissue-piercing member 40 and / or the delivery member 50, although conversion in other directions is also contemplated. The motion converters can have a wedge, trapezoid, or curved shape, and other shapes are also contemplated. In certain embodiments, the first motion converter 90 can have a trapezoidal shape 90t and include a slot that engages a pin 41 on the tissue-piercing member that rides in the slot, as shown in the embodiment of FIGS. 2, 3, and 4. The slot 93 can also have a trapezoidal shape 93t that closely resembles or otherwise corresponds to the overall shape of the converter 90. The slot 93 serves to push the tissue-piercing member 40 at the upslope portion 91 of the trapezoid and retract it at the downslope portion 92. In one variation, one or both of the motion converters 90 and 94 may include a cam or cam-like device (not shown). The cam may be pivoted by the spring 80 to engage the tissue penetrating and / or delivery members 40 and 50.One or more components of mechanism 60, including motion transducers 90 and 94 (as well as other components of device 10), can be manufactured using a variety of MEMS-based methods known in the art to allow a selected amount of miniaturization to fit within capsule 10. Also, as described herein, they can be formed from a variety of biodegradable materials known in the art.

[0098] Embodiments of the degradable isolation valve 250 can be located at various locations on or within the capsule 220 to be exposed to and degraded by intestinal fluids. While at least a portion of the valve may be exposed to the capsule exterior 225, typically the valve is located within the capsule interior 224v where it is exposed to intestinal fluids entering through at least one opening 226 or aperture. In these and related embodiments, at least a portion of the capsule exterior 225, including the portion containing the at least one opening 226, is desirably coated with a protective layer or coating 220c, such as an enteric coating, which also degrades in response to pH or other conditions in the small intestine. Typically the entire capsule is so coated, however, in some embodiments, only the portion covering the opening 226 is coated. Such a coating provides a protective seal 226s over the at least one opening 226 such that digestive fluids do not enter the capsule interior 224v and begin to degrade the isolation valve 250 until the capsule reaches the small intestine. 16a-16c illustrate the sequence of degradation of the coating, ingress of intestinal fluids or other fluids F into the capsule interior, and subsequent degradation of the isolation valve. In use, an embodiment of device 210 employing a degradable coating 220c covering opening 226 and a degradable valve 250 provides primary and secondary seals to ensure that balloon 230 does not prematurely inflate and deploy its tissue-piercing member 240 until capsule 220 reaches the small intestine.

[0099] In other variations, the actuation mechanism 60 may also comprise an electromechanical device / mechanism, such as a solenoid, or a piezoelectric device. In one embodiment, the piezoelectric device used in the mechanism 60 may comprise a shaped piezoelectric element having an undeployed and deployed state. The element may be configured to be in a deployed state upon application of a voltage and return to the undeployed state upon removal of the voltage. This and related embodiments allow for reciprocating motion of the actuation mechanism 60 to advance the tissue penetrating member and then retract it. The voltage to the piezoelectric element may be generated and obtained using a battery or a piezoelectric-based energy converter that generates a voltage from mechanical deformation, such as that resulting from compression of the capsule 20 by peristaltic contractions of the small intestine around the capsule. Further description of piezoelectric-based energy converters may be found in U.S. Patent Application Serial No. 12 / 556,524, which is incorporated herein by reference in its entirety for all purposes. In one embodiment, the deployment of the tissue penetrating member 40 may actually be induced from peristaltic contractions of the small intestine, which provides the mechanical energy to generate the voltage to the piezoelectric element.

[0100] According to one or more embodiments, the isolation valve 250 may comprise a beam-like structure 258 disposed within the capsule 220 to compress and seal a portion of the balloon 236 between the first compartment 234 and the second compartment 235, as shown in the embodiment of Figs. 17a and 17b. The beam 258 is desirably constructed of one or more degradable materials described herein, e.g., PGLA, cellulose, etc., that degrade in response to fluids found in the small intestine. As the beam 258 degrades, the compressive force of the balloon is released, allowing the contents from the first and second compartments 234 and 235 to mix, causing balloon expansion as described herein. The beam 258 may be attached to the capsule's inner surface 224 at one or both ends. Typically, the beam is disposed proximate to the central portion 236 of the balloon 230, although other locations are contemplated. In a preferred embodiment, the beams 258 are attached to the radial sides 220rs of the capsule inner surface 224 and are positioned in a radially oriented manner relative to the balloon transverse axis 201a, as shown in the embodiment of Figures 17a and 17b. However, the beams 258 may also be attached to the outer ends 201e of the capsule inner surface. Preferably, in either of these two embodiments, the beams 258 are attached to the capsule inner surface 224 such that the beams can be snapped into place within the capsule using pick-and-place and other similar methods known in the manufacturing art. In a specific embodiment, the inner surface 224 can include notches 224n for placement of the beam ends 258e to allow for a snap or press fit of the beams 258 into the capsule 220.

[0101] The release element 70 is typically coupled to the actuation mechanism 60 and / or a spring coupled to the actuation mechanism, although other configurations are contemplated. In a preferred embodiment, the release element 70 is coupled to a spring 80 located within the capsule 20 to hold the spring in a compressed state 85, as shown in the embodiment of FIG. 2. Disassembly of the release element 70 releases the spring 80 to actuate the actuation mechanism 60. Thus, the release element 70 can function as an actuator 70a (the actuator 70a may also include the spring 80 and other elements of the mechanism 60 (alone or coupled to the release element 70)). As described further below, the actuator 70a has a first configuration in which the therapeutic agent preparation 100 is contained within the capsule 20 and a second configuration in which the therapeutic agent preparation is advanced from the capsule into the wall of the small intestine or other luminal wall of the intestinal tract.

[0102] In many embodiments, the release element 70 comprises a material configured to degrade upon exposure to chemical conditions, such as pH, in the small intestine or large intestine. Typically, the release element 70 is configured to degrade upon exposure to a selected pH in the small intestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 8.0, or higher. The release element can also be configured to degrade within a particular range of pH, e.g., 7.0 to 7.5. In certain embodiments, the pH at which the release element 70 degrades (defined herein as the degradation pH) can be selected for a particular drug to be delivered to release the drug at a location in the small intestine corresponding to the selected pH. Further, for embodiments of device 10 having multiple drugs 100, the device may include a first release element 70 (coupled to an actuation mechanism for delivering a first drug) configured to degrade at a first pH and a second release element 70 (coupled to an actuation mechanism for delivering a second drug) configured to degrade at a second pH (additional numbers of release elements are contemplated for different numbers of drugs).

[0103] 18, the isolation valve 250 can comprise a collar valve 255 that includes the connection portion 236 of the expandable member 230 over which is covered a retracting collar 255c made of a biodegradable material. The collar 255c holds the connection section 236 closed and releases it when the collar is degraded.

[0104] The release element 70 may also be configured to degrade in response to other conditions in the small intestine (or other gastrointestinal locations). In certain embodiments, the release element 70 may be configured to degrade in response to particular chemical conditions in fluids in the small intestine, such as those that occur after ingestion of a meal (e.g., a meal containing fat, starch, or protein). In this manner, release of the agent 100 may be substantially synchronized or otherwise timed with ingestion of a meal. Such embodiments are particularly useful for delivery of agents that control blood sugar / glucose (e.g., insulin), serum cholesterol, and serum triglyceride levels.

[0105] In addition to the release valve 250, the balloon or other expandable member 230 also typically includes a deflation valve 270 that serves to deflate the balloon 230 after inflation. The deflation valve 270 may include a biodegradable material configured to degrade upon exposure to fluids in the small intestine and / or liquids in one of the compartments of the balloon to create an opening or channel for escape of gas within the balloon. In one embodiment, as shown in FIG. 19a, the deflation valve 270 may include a biodegradable section 271 located at the end portion 231 of the balloon 230 to join opposite ends of the balloon wall 232 together. In these and related embodiments, as the degradable section 271 degrades upon exposure to liquid, the balloon wall 232 tears or otherwise breaks, providing a high degree of assurance of rapid deflation. To provide an even higher degree of reliability in deflation, multiple degradable sections 271 may be positioned at various locations within the balloon wall 232, as shown in the embodiment of FIG. 19b. Desirably, the section 271 is positioned only within the wall 232 of the compartment 235. For embodiments in which deflation valve 270 is to be degraded by fluids in the small intestine, degradation of the valve can be facilitated by configuring inflation balloon 230 to degrade capsule 220 into two or more pieces such that a majority of the balloon is directly exposed to the degradative fluids in the small intestine. This can be accomplished by manufacturing capsule 220 from separate pieces (e.g., two halves that are mechanically fitted together) and / or through the use of capsule wall seams 222 as described herein.

[0106] Various approaches are contemplated for the biodegradation of the release element 70. In certain embodiments, biodegradation of the release element 70 from one or more conditions in the small intestine (or elsewhere in the digestive tract) can be achieved by i) the selection of materials for the release element, ii) the amount of crosslinking of those materials, and iii) the thickness and other dimensions of the release element. A lesser amount of crosslinking and / or a thinner thickness can increase the rate of degradation, and vice versa. Suitable materials for the release element can include biodegradable materials, such as various enteric materials, that are configured to degrade upon exposure to the higher pH in the intestine. Suitable enteric materials include, without limitation, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, as well as other enteric materials known in the art. The enteric materials can be copolymerized or otherwise mixed with one or more other polymers to obtain some other specific material properties in addition to biodegradation. Such properties can include, without limitation, stiffness, strength, flexibility, and hardness.

[0107] Additionally, as a further aid in guaranteed deflation, one or more piercing elements 72 can be attached to the inner surface 24 of the capsule wall such that they contact and are pierced by the piercing elements when the balloon is fully deflated. The piercing elements 72 can comprise short projections from the surface 24 having sharp tips 73. In another alternative or additional embodiment of the means for balloon deflation, one or more of the tissue penetrating members 40 can be directly coupled to the balloon wall 32 and configured to pull away from the balloon when disengaged, rupturing the balloon in the process.

[0108] In alternative embodiments, the release element 70 may comprise a film or plug 70p that fits or otherwise blocks over the guide tube 30 and holds the tissue penetrating member 40 inside the guide tube (FIG. 1c). In these and related embodiments, the tissue penetrating member 40 is coupled to a spring-loaded actuation mechanism such that when the release element is sufficiently disassembled, it releases the tissue penetrating member, which then pops out of the guide tube and penetrates the intestinal wall. In still other embodiments, the release element 70 may be shaped to function as a latch that holds the tissue penetrating element 40 in place. In these and related embodiments, the release element may be located on the exterior or interior of the capsule 20. In the latter case, the capsule 20 and guide tube 30 may be configured to allow intestinal fluids to enter into the capsule interior to allow disassembly of the release element.

[0109] The tissue penetrating member 40 can be fabricated from a variety of drugs and other therapeutic agents 101 and one or more biodegradable polymers to provide the penetrating member with desired structural properties (e.g., column strength) and / or control the release of the drug. Referring now to Figures 20a-20c, in many embodiments, the penetrating member 40 can be formed with a shaft 44 and a needle tip 45 or other sharp tip 45 to easily penetrate the tissue of the intestinal wall, as shown in the embodiment of Figure 20a. The tip 45 may include a degradable material, such as sucrose (within the body of the tip or as a coating), which increases the hardness and tissue penetrating properties of the tip. Once positioned within the intestinal wall, the penetrating member 40 is degraded by the interstitial fluids within the wall tissue, and the drug dissolves in these fluids and is absorbed into the bloodstream. The penetrating member 40 also typically includes one or more tissue retention features 43, such as barbs or hooks, to retain the penetrating member within the tissue of the intestinal wall after advancement. The retention members 43 can be arranged in various patterns 43p to enhance tissue retention, such as two or more barbs symmetrically or otherwise distributed around the circumference of the member shaft 44, as shown in the embodiment of Figures 20a and 20b. Additionally, in many embodiments, the penetrating member also includes recesses or other mating features 46 for attachment to a linking component (such as advancement member 80a, described below) that attaches the penetrating member to the balloon.

[0110] As described above, the tissue penetrating member 340 can be made from a number of drugs and other therapeutic agents 3101. The penetrating member may be made entirely from the drug 3101 or may also have other components, such as various pharmaceutical excipients. Typically, the drug or other therapeutic agent 3101 is mixed with a biodegradable polymer 3105, such as PGLA, cellulose, or other biodegradable materials described herein or known in the art. In such embodiments, the penetrating member 340 may include a substantially heterogeneous mixture of the drug 3101 and the biodegradable polymer 3105. Alternatively, the penetrating member 340 may include a portion 341 formed substantially from the biodegradable material 3105 and a separate section or compartment 342 formed from or containing the drug 3101, as shown in the embodiment of FIG. 20c.

[0111] The tissue penetrating member 340 can be manufactured using one or more polymers and pharmaceutical manufacturing techniques known in the art. For example, the drug 3101 (with or without the biodegradable material 3105) can be in a solid form and then formed into the shape of the tissue penetrating member 340 using molding, compression, or other similar methods, and one or more binders are added. Alternatively, the drug 3101 and / or drug preparation 3100 can be in a solid or liquid form and then added to the biodegradable polymer 3105 in liquid form and then formed into the penetrating member 340 using molding or other forming methods known in the polymer art.

[0112] Desirably, embodiments of the tissue-penetrating member 340 including the drug or other therapeutic agent 3101 and the degradable polymer 3105 are formed at a temperature that does not result in substantial thermal degradation of any of the drug, including drugs such as various peptides and proteins. This can be accomplished through the use of room temperature curing polymers and room temperature molding and solvent evaporation techniques that are known in the art. In certain embodiments, the amount of thermally decomposed drug or other therapeutic agent within the tissue-penetrating 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 the particular polymer processing method (e.g., molding, curing, solvent evaporation, etc.) to minimize the temperature and associated level of thermal decomposition of the drug.

[0113] The tissue penetrating member 340 is desirably configured to be releasably coupled (directly or indirectly) to the balloon or other expandable member 330 such that the tissue penetrating member 340 becomes detached from the balloon following advancement of the tissue penetrating member 340 into the intestinal wall. Removability can be implemented by a variety of means, including i) the configuration and strength of the joint between the penetrating member 340 and the advancement member 380a (or other intermediate component connecting the member 340 to the balloon 330), 2) the configuration and arrangement of the tissue retaining features 343 on the penetrating member 340, and iii) the depth of penetration of the shaft 344 into the intestinal wall. The penetrating member 340 can be configured to become detached as a result of forces exerted on the capsule 320 by balloon deflation (wherein the retaining features 343 retain the penetrating member in tissue as the balloon deflates or otherwise retracts from the intestinal wall) and / or peristaltic contractions of the small intestine.

[0114] The tissue penetrating member 340 can be directly or indirectly coupled to the balloon 330. Referring now to FIGS. 21a-21b and 22, an indirect coupling can be implemented using one or more coupling components 380, such as an advancement member 380a. Thus, in certain embodiments, the tissue penetrating member 340 may be coupled to the balloon 330 by an advancement member 380a, which comprises a rigid structure attached to the balloon surface 338 that releasably engages the penetrating member 340. The advancement member 380a engages the penetrating member 340 using an attachment feature 381, such as a pin or other protrusion 382 (integral with or attached to the member 380a) that fits into a recess or other mating feature 346 of the penetrating member, as shown in the embodiment of FIG. 21a. The pin 382 and recess 346 can be configured to disengage due to forces applied to the capsule 320 by the force of balloon deflation and / or peristaltic contraction. In many embodiments, the advancement member 380a can have a horizontal surface area 383 that is greater than the surface area 347 of the penetrating member 340 so as to function as a force concentrating element 384, as shown in the embodiment of FIG. 21b. In use, the force concentrating element 384 functions to increase the force per unit area applied to the penetrating member from the expansion of the balloon 330 or other expandable member.

[0115] In some embodiments, the advancement member 480a can be coupled to the balloon 430 via a support member 486, as shown in the embodiment of Figures 22a and 22b. The support member 486 can correspond to a platform 486 having one surface 487 that is attached to the balloon surface 438 and another surface 488 that is attached to the advancement member 480a (one or both of these attachments can be adhesive attachments), as shown in the embodiment of Figure 22a. The platform 486 is desirably rigid and can have a plate-like structure and can be sized to allow for the attachment and advancement of multiple advancement members 480a and tissue penetrating members 440 simultaneously, as shown in the embodiment of Figure 22b. For example, in certain embodiments, groups of three, four, or five of the advancement and tissue penetrating members can be attached to the platform 486, with additional numbers being contemplated. In such embodiments, the platform can include a recess 489 for seating the isolation valve 450.

[0116] Also, the platform 486 can be disposed on either side of the balloon 430 to allow for bilateral deployment of the tissue penetrating member 440 into the intestinal wall IW, as shown in the embodiment of Figures 23a and 23b. In addition to delivering more drug, bilateral deployment serves to anchor the capsule 420 to either side of the intestinal wall IW during deployment of the penetrating member 440, thus reducing the likelihood of the capsule becoming dislodged during deployment (e.g., by peristaltic contractions). In these and related embodiments, the tissue penetrating member 440 can be directly coupled to the platform 486, without necessarily using the advancement member 480a. Desirably, both the advancement member 480 and the platform 486 are constructed from a biodegradable material, such as PGLA, that can be cross-linked and / or copolymerized to have increased stiffness that aids in the advancement of the penetrating member 440 into tissue.

[0117] As an additional or alternative embodiment to the use of advancement member 480a and / or platform 468, tissue penetrating member 440 may be coupled directly to balloon 430, for example, by an adhesive where the adhesive force, once deployed into the intestinal wall, is less than the force required to withdraw the penetrating member from the tissue. In these and related embodiments, tissue penetrating member 440 may also be configured to breach balloon wall 432 upon detachment from the balloon, thus providing a means for balloon deflation.

[0118] In various embodiments, the penetrating members 440 can carry the same or different drugs 4101 or other therapeutic agents, the former configuration allowing for the delivery of greater amounts of a particular drug 4101, while the latter allows for two or more drugs to be delivered near simultaneously into the intestinal wall to facilitate drug treatment regimens requiring substantially simultaneous delivery of multiple drugs.

[0119] In various embodiments, depending on the drug and associated drug administration regimen (e.g., dose and number of times per day, etc.), the tissue-piercing members 440 can be positioned and distributed in a number of locations and patterns on the balloon surface. As described above for the embodiment of Figures 23a and 23b, the tissue-piercing members 440 can be positioned on opposite sides of the balloon surface 438 such that balloon inflation can position the tissue-piercing members 440 on opposing sides of the intestinal wall IW. Now referring to Figures 24a-24b, in other embodiments, the tissue-piercing members 440 can be distributed symmetrically or otherwise around substantially the entire circumference 430p of the balloon 430 or other expandable member 430, as shown in the embodiment of Figures 24a and 24b. In use, such an embodiment not only anchors the capsule 420 into the intestinal wall IW (as described above for bilateral deployment), but also positions the tissue-piercing members 440 in a distribution pattern 440p around the circumference of the intestinal wall IW. Embodiments of the present invention utilizing such distributed delivery of drugs into the intestinal wall can achieve the following: i) allow additional amounts of a particular drug to be delivered, and ii) provide more rapid absorption of the drug into the bloodstream due to more even distribution of the drug within the intestinal wall (e.g., due to placement of a greater amount of tissue-penetrating members within the intestinal vasculature for mass transfer and absorption into the blood).

[0120] As described herein, many embodiments of the device 510 include a drug-carrying tissue-piercing member 540 as a means for delivering a drug or other therapeutic agent 5101 into the intestinal wall. Now referring to Figs. 25a-25b and 26, as an alternative or additional means for delivering a drug into the intestinal wall, in various embodiments the device 510 can also be configured to inject the drug 5101 into the intestinal wall using a hollow tissue-piercing member 548 coupled to one or more drug reservoirs 527. The hollow tissue-piercing member 548 includes at least one lumen 549. The reservoirs 527 are desirably compressible by expansion of a balloon or other expandable member 530, and thus can include various biodegradable elastomeric polymers. The reservoirs 527 can contain the drug or other therapeutic agent 5101 in liquid or powder form. For the liquid form, the drug is dissolved in an aqueous drug solution 5104. In these and related embodiments, the reservoir 527 is fluidly coupled to the hollow tissue penetrating member 548 such that expansion of the balloon 530 compresses the reservoir 527 to force the medical solution 5104 through the tissue penetrating member lumen 549 and into the intestinal wall, as shown in Figures 25a and 25b. In these and related embodiments, the opening 526 is horizontally aligned with the tip 544 of the penetrating member 548 and can include a guide tube 526g configured to guide advancement of the penetrating member 548 from outside the capsule 520 into the intestinal wall. Multiple reservoirs 527 are contemplated, including two, three, four, or more. In certain embodiments, two reservoirs 527 can be coupled to the hollow tissue penetrating member, the reservoirs being positioned approximately 180 degrees apart relative to the penetrating member shaft 544. Typically, the reservoir 527 is fluidly coupled to the hollow penetrating member 548 using a manifold 590. A suitable manifold 590 includes a T-shaped manifold 590t having connectors 592 on either of its outer ends 593 for connection to the reservoirs 527, a central connector 594 for connection to the hollow tissue-piercing member 547, and a central lumen or channel 595 running to all of the connectors (FIG. 16).Other shapes and manifold configurations are also contemplated, such as, for example, a Y-shape (connecting two reservoirs to tissue-piercing member 548).

[0121] In some embodiments, the balloon 30 or other expandable member 30 can expand in response to a sensor 67, such as a pH sensor 68 or other chemical sensor, that detects the presence of the capsule in the small intestine. The sensor 67 (FIG. 1b) can then send a signal to a controllable embodiment of the isolation valve 50, or to an electronic controller 29c coupled to the controllable isolation valve 50, to open and thus expand the balloon 30 as described herein. An embodiment of the pH sensor 68 can comprise an electrode-based sensor, or can be a mechanically based sensor, such as a polymer, that contracts or expands upon exposure to a selected pH or other chemical condition in the small intestine. In related embodiments, the expandable / contractible sensor 67 can also comprise the actuation mechanism 60 itself, by using mechanical motion from the expansion or contraction of the sensor.

[0122] 27a-27b and 28a-28b, in a related embodiment, the expandable / contractable pH sensor 668 can also comprise the isolation valve 650 itself by configuring the sensor to expand or contract to open the channel between the balloon sections 634 and 635. According to one embodiment for such an approach, the pH sensor 668 may be incorporated into the collar valve 655, the sensor 668 comprising all or a portion of the collar 655c disposed over the connecting portion 636 of the balloon 630 (FIGS. 27a and 27b). In this embodiment, the sensor 668 is an expandable sensor 668e configured to expand upon exposure to pH conditions within the small intestine (e.g., a pH greater than 6.0, 6.5, 7.0, 7.1, 7.2, etc.) to disengage the collar or to significantly relax the collar 655c to allow the contents of the sections 634 and 635 to mix. According to another embodiment shown in Figures 28a and 28b, a pH sensor 668 can be incorporated into the beam valve 658 described herein, where the beam is subjected to a compressive load by being snap-fitted against the capsule inner surface 624. The beam applies a portion of this compressive load on the balloon connection section 636 to maintain a seal between the compartments 634 and 635. In this case, the sensor 668 is a contractible sensor 668c configured to open the valve 650 by contracting upon exposure to a higher pH in the intestine, such that the beam shortens sufficiently to move out of position against the capsule surface 624 or otherwise no longer applies a sufficient compressive load to maintain a seal over the balloon connection section 636.

[0123] According to another embodiment for detecting when the device is in the small intestine (or other location in the digestive tract), the sensor 67 may comprise a pressure / force sensor, such as a strain gauge, for detecting the number of peristaltic contractions that the capsule 20 is undergoing within a particular location in the digestive tract (in such an embodiment, the capsule 20 is desirably sized to be gripped by the small intestine during peristaltic contractions). Different locations in the digestive tract have different numbers of peristaltic contractions. 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 the capsule 20 is in the small intestine, but also its relative location within the intestine. During use, these and related embodiments allow for the release of the drug 100 at a particular location in the small intestine.

[0124] As an alternative or supplement to internally activated drug delivery (e.g., using a release element and / or a sensor), in some embodiments, a user may externally send a signal to expand the balloon 30 or other expandable member 30 to activate the actuation mechanism 60 to deliver the drug 100 using RF, magnetic, or other wireless signaling means known in the art. In various embodiments, including by reference to FIG. 1b, external activation can be achieved through the use of a controllable isolation valve 50, such as a radio frequency (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, the user may use a handheld communication device 13 (e.g., a handheld RF device such as a mobile phone) as shown in the embodiment of FIG. 1b to transmit a receiving signal 17 from the device 10. 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 a signaling means, but also a means for informing the user when the device 10 is in the small intestine or elsewhere in the digestive tract. The latter embodiment may be implemented through the use of logic resources 29 (e.g., processor 29) coupled to the transmitter 28 to detect when the device is in the small intestine or elsewhere in the digestive tract (e.g., by signaling input from a sensor) and signal the user. The logic resources 29 may include a controller 29c (either hardware or software) to control one or more aspects of the process. The same handheld device may also be configured to alert the user when the balloon 30 or actuation mechanism 60 (respectively) has been expanded or activated and the selected medication 100 has been delivered (e.g., using the processor 29 and transmitter 28). In this manner, the user is provided with confirmation that the medication 100 has been delivered.This allows the user to take other appropriate medications / therapeutic agents as well as make other related decisions (e.g., whether a diabetic should or should not eat a meal and what food to eat). The handheld device may also be configured to send a signal to the swallowable device 10 to override the isolation valve 50 or the actuation mechanism 60, thus preventing, delaying or accelerating delivery of the medication 100. Such an embodiment in use allows the user to intervene to prevent, delay or accelerate delivery of the medication based on other symptoms and / or patient actions (e.g., deciding to eat a meal, go to sleep, exercise, etc.). The user may also externally expand the balloon 30 or activate the actuation mechanism 60 at 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 digestive tract to a particular location in a tract such as the small intestine.

[0125] 29a-29b and 30, in various embodiments, the capsule 720 can include a seam 722 of a biodegradable material that can controllably degrade to produce capsule fragments 723 of selectable sizes and shapes to facilitate passage through the digestive tract, as shown, for example, in the embodiment of Figs. 11, 29a, and 29b. The seam 722 can also include pores or other openings 722p for fluid ingress into the seam to accelerate biodegradation, as shown in the embodiment of Fig. 10. Other means for accelerating biodegradation of the seam 722 can include applying compressive stress to the seam and / or including perforations 722f in the seam (Fig. 10). In still other embodiments, the seam 722 can be constructed of a material and / or have a structure that is readily degraded by absorption of ultrasonic energy, e.g., high frequency ultrasound (HIFU), thereby allowing the capsule to be broken down into smaller fragments using ultrasound administered externally or by endoscope (or other minimally invasive method).

[0126] Now referring to 29a-29b and 30, in many embodiments, the seams 722 can also be configured and arranged to allow the capsule 720 to break into smaller pieces by inflation of the balloon 730 or other expandable member 730. In certain embodiments, the seams 722 can be oriented relative to the radial perimeter 721 of the capsule, including having a radial pattern 722rp to break the capsule into halves or other minute pieces along its circumference. The seams 722 can also be oriented longitudinally relative to the side access 7201a of the capsule to break the capsule into longitudinal pieces.

[0127] As an alternative or additional approach to dismantling the capsule 720 by balloon inflation (or expansion of other expandable member 730), the capsule 720 can be fabricated from two or more separate joinable pieces 723j (e.g., radial halves) that are joined at a joint 722j formed by a seam 722 (which acts as an adhesive joint), as shown in the embodiment of Figure 30. Alternatively, the joinable pieces 723j may only be joined by a mechanical fit, such as a snap or press fit.

[0128] Suitable materials for the seam 722 may include one or more biodegradable materials described herein, such as PGLA, glycolic acid, etc. The seam 722 may be attached to the capsule body 720 using various bonding methods known in the polymer arts, such as molding, thermo-fusion bonding, etc. Additionally, for capsule 720 embodiments that are also made from biodegradable materials, faster biodegradation of the seam 722 may be achieved by one or more of: i) making the seam from a faster degrading material, ii) subjecting the seam to compressive stress, or iii) perforating the seam. The concept of using a biodegradable seam 722 to produce controlled degradation of a swallowable device in the digestive tract may also be applied to other swallowable devices, such as a swallowable camera (or other swallowable imaging device), to facilitate passage through the digestive tract and reduce the likelihood of the device becoming trapped therein. Thus, embodiments of the biodegradable seam 722 may be adapted for swallowable imaging and other swallowable devices.

[0129] In still other embodiments, seam 722 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).

[0130] Another aspect of the present invention provides a method for delivering drugs and other therapeutic agents (in the form of a drug 100) into the wall of the digestive tract using one or more embodiments of the 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 digestive tract, including the stomach and large intestine. For ease of discussion, the swallowable drug delivery device 10 may also be referred to herein as a capsule. As explained above, in various embodiments, the device 10 may be packaged as a kit 11 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 bar code 18 (or other identifying indicia 18) located on the instructions 15 or package 12. If a bar code is used, the patient scans the bar code using a bar code reader 19 on the device 13. After opening the packaging 12, reading the instructions 15 and inputting the required data, the patient swallows the embodiment of the swallowable drug delivery device 10. Depending on the drug, the patient may take the device 10 with a meal (pre-, during, or after a meal) or in conjunction with a physiological measurement such as a blood glucose measurement. The capsule 20 is sized to pass through the digestive tract and, as shown in the embodiment of FIG. 11, progresses through the patient's stomach S and into the small intestine SI via peristaltic action. Once the capsule 10 is in the small intestine, the release element 70 is degraded by the base pH in the small intestine (or other chemical or physical conditions specific to the small intestine) to expand the balloon 30 or other expandable member 30, actuate the actuation mechanism 60, and deliver the drug 100 into the wall of the small intestine SI, in accordance with one or more embodiments of the present invention. For embodiments including a hollow needle or other hollow tissue-penetrating member 40, drug delivery is accomplished by using the balloon 30 of the actuation mechanism 60 to advance the needle 40 a selected distance into the mucosa of the intestinal wall IS, and the drug is then injected through the needle lumen by advancement of the delivery member 50.The delivery member 50 is withdrawn and the needle 40 is then retracted (e.g., by recoil) into the body of the capsule and out of the intestinal wall. For embodiments of the device 10 having multiple needles, a second or third needle 42, 43 may also be used to deliver additional doses of the same or a separate drug 101. Needle advancement may occur substantially simultaneously or sequentially. In preferred embodiments using multiple needles, needle advancement may occur substantially simultaneously to anchor the device 10 in the small intestine during drug delivery.

[0131] After drug delivery, the device 10 then passes through the intestinal tract, including the large intestine LI, and is eventually expelled. For embodiments having a rupturable capsule, the capsule may be instantly degraded into smaller pieces by inflation of the balloon 30. For embodiments of the capsule 20 having a biodegradable seam 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, as shown in the embodiment of Figures 9a and 9b. In certain embodiments having a biodegradable tissue-piercing needle / member 40, if the needle becomes trapped within the intestinal wall, the needle biodegrades to release the capsule 20 from the wall.

[0132] For embodiments of device 10 including sensor 67, this may be accomplished by the sensor sending a signal to the isolation valve 50 or actuation mechanism 60, and / or a controlled embodiment of the processor 29 / controller 29c coupled to the isolation valve 50 or actuation mechanism 60. For embodiments of device 10 including external actuation capability, the user may externally expand the balloon 30 or activate the actuation mechanism 60 at 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 digestive tract to a particular location in a tract such as the small intestine.

[0133] One or more embodiments of the above methods can be used to deliver 100 containing therapeutically effective amounts of various drugs and other therapeutic agents 101 to treat various diseases and conditions. These include several macromolecular peptides and proteins that would otherwise require injection and / or intravenous infusion due to chemical or other degradation of the compound by digestive fluids in the lumen of the stomach and / or small intestine. Such compounds that can be delivered using various embodiments of the present invention include, without limitation, parathyroid hormone, growth hormones (e.g., IFG and other growth factors), insulin compounds, antibodies and other gamma globulin proteins (e.g., gamma globulins), interferons and other cytokines, glucagon-like peptides (e.g., GLP-1, exenatide) and other incretins, chemotherapeutic drugs (doxorubicin) and other similar compounds. Embodiments of the invention allow these and other compounds to be delivered into the wall of the small intestine and subsequently absorbed into the bloodstream with minimal or no loss of the compound's activity, e.g., in the case of antibodies, with minimal or no loss of affinity and / or specificity for the target antigen, in the case of interferons or cytokines, with minimal or no loss of immune stimulatory effect, in the case of insulin or GLP-1, with minimal or no loss of glucose regulating ability, in the case of growth hormones, with minimal or no loss of growth stimulatory effect, in the case of chemotherapeutic drugs for the treatment of cancer, with minimal or no loss of cancer therapeutic effect (e.g., tumor necrosis and / or reduced cell division), and in the case of polypeptides, with minimal or no loss of affinity and / or specificity for the target binding site.Suitable drugs and other therapeutic agents that may be delivered by embodiments of the present invention include any number of orally delivered drugs, antibiotics (vancomycin, penicillin, erythromycin, etc.), antivirals (protease inhibitors, anti-seizure compounds (furosemide, dilatin), nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen), various chemotherapeutic drugs (e.g., interferons), 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), anti-seizure drugs (e.g., furosemide), anti-migraine drugs (sumatriptan), immunosuppressants (e.g., cyclosporine), and antiparasitic drugs such as various antimalarials. Dosages of particular drugs may be titrated for a patient's weight, age, or other parameters. Embodiments of the present invention also allow dosages of drugs and other therapeutic agents 101 to be advantageously adjusted for other factors as well. For example, for drugs that are otherwise partially degraded or poorly absorbed in the digestive tract, the amount or dose of drug 101 to achieve the desired or therapeutic effect (e.g., insulin for blood glucose regulation, or furosemide for anti-seizures) may be less than would be required 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 fact that there is little or no degradation of the drug by the acids and other digestive fluids in the stomach, 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 intestinal tract, e.g., colon, stomach, etc.). Depending on the drug 101, the dose 102 delivered in the preparation 100 may be within 100 to 5% of the dose delivered by traditional oral delivery means (e.g., prescription tablets) to achieve the desired therapeutic effect (e.g., blood glucose regulation, seizure regulation, etc.), with even lesser amounts being contemplated. The particular dose reduction can be titrated based on the particular drug, the condition being treated, and the patient's weight, age, and condition. For some drugs, where the level of degradation in the intestinal tract is known, standard dose reductions can be employed (eg, 10-20%).Larger dose reductions can be used for drugs that are more degraded and less absorbed in the digestive tract. In this way, potential toxicity (especially to non-target tissue sites) and other adverse side effects of the particular drug or drugs delivered by device 10 can be reduced because the ingested dose is lowered and the drug is delivered entirely or nearly entirely into the wall of the small intestine. This in turn improves patient compliance, as the patient experiences a reduction in both severity and incidence of adverse effects. Additional benefits of embodiments employing dose reductions of drug 101 include a reduction in the likelihood that the patient will develop resistance to the drug (requiring higher doses) and, in the case of antibiotics or antivirals, that the patient will develop resistant bacteria or virus strains (e.g., resistance to the use of amcomycin by bacteria, or resistance to protease inhibitors by the AIDS virus). For the case of chemotherapy drugs for the treatment of cancer, adverse effects can include resistance to the chemotherapy drug by cancer cells as well as the development of toxicity to non-target tissues. For anti-seizure drugs such as Dilatorin, adverse effects can include a variety of neuromuscular symptoms such as tremors, nystagmus, slurred speech, dizziness, memory and concentration problems, as well as symptoms such as rashes and bone loss. For anti-seizure drugs such as Furosemide and / or diuretics, such adverse effects can include a variety of neuromuscular, vascular, and gastrointestinal effects such as dizziness, hypotension, dehydration, nausea, electrolyte loss, tinnitus, and rashes. Other levels of dose reduction can also be achieved in patients who have undergone gastric bypass surgery and other procedures in which a segment of the small intestine has been removed or its working (e.g., digestive) length has otherwise been effectively shortened. In these and related embodiments, levels of dose reduction can be achieved within the range of 25 to 50% or more, and patients need only take a single dose of the drug versus multiple doses due to poor absorption issues. In yet other embodiments, the dose of a particular orally delivered drug 101 can be increased because the drug or other therapeutic agent is injected directly into the wall of the small intestine, thus avoiding various adverse effects in the gastrointestinal system (e.g., cramps, bleeding, etc.).This increased dosage in turn allows for one or more of: smaller doses, faster treatment, faster acquisition of therapeutically effective levels of drug in the bloodstream, and better control of blood concentrations and other pharmacokinetic parameters. In various embodiments, the dosage of a particular drug can be increased within the range of 5-100% or higher. The amount of increase can again be titrated based on the patient's weight, age, symptoms, and individual tolerance to the drug (which can be determined, for example, by using various biomarkers of tolerance and / or toxicity).

[0134] In addition to delivery of a single drug, embodiments of the swallowable drug delivery device 10 and their methods of use can be used to deliver multiple drugs 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 a patient to eliminate the need to have to take multiple medications for one or more specific conditions. They also provide a means to facilitate the delivery and absorption of two or more drug regimens into the small intestine and thus into 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. Additionally, eliminating the need to take multiple drugs is particularly beneficial for patients with one or more long-term chronic conditions, including patients with reduced cognitive or physical abilities.

[0135] In various approaches, the above method embodiments can be used to deliver preparations 100 including drugs and therapeutic agents 101 to provide treatment for a number of medical conditions and diseases. Medical conditions and diseases that can be treated using embodiments of the present invention include, without limitation, 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 (regional 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.

[0136] In many embodiments, it is not necessary to inject drugs or other therapeutic agents (or deliver other parenteral forms such as suppositories), but instead rely solely on therapeutic agents delivered into the wall of the small intestine or other parts of the digestive tract to treat a particular disease or condition. For example, diabetes or another glucose regulation disorder can 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 does 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 can be delivered in conjunction with an injection dose of the drug. For example, the patient may use a swallowable capsule embodiment to take a daily dose of insulin or 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 is true for therapeutic agents that are traditionally delivered in oral form (e.g., the patient can take a swallowable capsule and 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 necessary (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 to or below the doses normally given for oral delivery of the drug, since there is little or no degradation of the drug within the stomach or other parts of the intestinal tract (again, standard dose-response curves and other pharmacokinetic methods can be applied).

[0137] Now referring to dosages, various groups of embodiments of the preparation 100 containing one or more drugs or other therapeutic agents 101 for the treatment of various diseases and conditions are described. It should be understood that these embodiments, including the specific therapeutic agents and respective dosages, are exemplary and the preparation 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 intestine wall) using various embodiments of the device 10. Dosages can be larger or smaller than those described and can be adjusted using one or more methods described herein or known in the art. In one group of embodiments, the therapeutic agent preparation 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, the preparation 100 can contain a therapeutically effective amount of insulin in the range of about 1-10 units (one unit is about 45.5 μg bioequivalent 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) frequency of administration (e.g., once per day vs. multiple times per day), vi) time of day (e.g., morning vs. evening), vii) a particular meal (breakfast vs. dinner), viii) the content / glycemic index of a particular meal (e.g., a meal with high fat / lipid and sugar content (which causes 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 patient's overall dietary content (e.g., the amount of sugars and other carbohydrates, lipids and proteins consumed daily).

[0138] In another group of embodiments, the therapeutic drug preparation 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 analogs thereof, and gastric inhibitory peptide (GIP). Suitable GLP-1 analogs include exenatide, liraglutide, albiglutide, and taspoglutide, as well as analogs, derivatives, and other functional equivalents thereof. In one embodiment, the preparation 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 preparation 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 analogues, or incretins.

[0139] In yet another group of embodiments, the therapeutic drug preparation 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., those available under the trademark GLUCOPHAGE® from Merck Santoe SAS), and analogs, derivatives, and other functional equivalents thereof. In one embodiment, the preparation 100 can include a combination of 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, with one or more of the glucose control titration factors being used to titrate the respective doses of exenatide (or other incretin) and metformin or other biguanide. In addition, the dosage of exenatide or other incretin and metformin or other biguanide can be tailored to improve the 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 of time, ranging from a few hours (e.g., 12) to one day to multiple days, with longer periods being contemplated. Dosage tailoring can also be achieved through the use of glucose control regulators and monitoring the patient's blood glucose levels over extended periods of time using glycosylated hemoglobin (known as hemoglobin A1c, HbA1c, A1C, or Hb1c) and other analytes and measurements that correlate to long-term average blood glucose levels.

[0140] In yet another group of embodiments, the therapeutic drug preparation 100 can include a therapeutically effective dose of growth hormone for the treatment of one or more growth disorders as well as wound healing. In one embodiment, the preparation 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, and even larger ranges are contemplated. The specific dose can be titrated based on one or more of i) the specific condition being treated and its severity (e.g., stunted growth vs. wound healing), ii) the patient's weight, iii) the patient's age, and iv) the frequency of administration (e.g., daily vs. once a day).

[0141] In yet another group of embodiments, the therapeutic drug preparation 100 can include a therapeutically effective dose of parathyroid hormone for the treatment of osteoporosis or thyroid disease. In one embodiment, the preparation 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 specific condition being treated and its severity (e.g., the degree of osteoporosis as determined by bone density measurement), ii) the patient's weight, iii) the patient's age, and iv) the frequency of administration (e.g., daily vs. once a day).

[0142] The foregoing description of various embodiments of the 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. Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific devices and methods described herein. Such equivalents are considered to be within the scope of the invention and are the subject of the following appended claims.

[0143] Elements, features, or acts from one embodiment can be easily recombined or substituted with one or more elements, features, or advantages from other embodiments to form numerous additional embodiments within the scope of the present 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 present invention is not limited to the specific embodiments described, but instead is limited only by the appended claims.

Claims

1. a capsule sized to pass through the digestive tract; a drug substance disposed within the capsule; a tissue penetrating member disposed within the capsule and configured to contain the drug, the tissue penetrating member comprising a hollow needle having a tissue penetrating end for penetrating a wall of the gastrointestinal tract; a delivery member for delivering the agent from the tissue penetrating member into tissue; an actuation mechanism including a spring coupled to the tissue penetrating member and the delivery member and configured to advance the tissue penetrating member into the wall and advance the delivery member to deliver the agent; a degradable release element coupled to the spring of the actuation mechanism and configured to hold the spring in a compressed state until degraded and configured to degrade upon exposure to conditions of the gastrointestinal tract, whereupon the spring of the actuation mechanism is released from the compressed state and the actuation mechanism causes the tissue penetrating member to penetrate the wall and advances the delivery member to deliver the agent into the wall; A swallowable device comprising:

2. The swallowable device of claim 1, wherein the release element comprises a material configured to degrade when exposed to a selected pH in the small intestine.

3. The swallowable device of claim 1 , wherein the delivery member and the tissue penetrating member are configured to deliver the agent in a liquid or semi-liquid form.

4. The swallowable device of claim 1 , wherein the delivery member comprises a piston or plunger element.

5. The swallowable device of claim 3 , wherein the capsule comprises a reservoir containing the medication.

6. The swallowable device of claim 1 , wherein the actuation mechanism is further configured to retract the hollow needle from the wall.

7. The swallowable device of claim 1 , wherein the actuation mechanism and the tissue-penetrating member are configured to deliver the agent in a solid form.

8. The swallowable device of claim 7 , wherein the tissue penetrating member comprises a biodegradable material.

9. The swallowable device of claim 7 , wherein the tissue penetrating member is formed at least in part from the drug.

10. The swallowable device of claim 1 , wherein the medication comprises a chemotherapy drug, an interferon, an antibody, an antibiotic, a growth hormone, a parathyroid hormone, a glucose regulating drug, an insulin compound, an incretin hormone, a GLP-1 compound, or exenatide.

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