Patent Publication Number: US-2020289620-A1

Title: Therapeutic agent preparations and methods for drug delivery into a lumen of the intestinal tract using a swallowable drug delivery device

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
     This application claims priority to, and the benefit of, U.S. Provisional Patent Application Ser. Nos. 62/818,053 filed on Mar. 13, 2019 and 62/820,174 filed on Mar. 18, 2019; both of which are incorporated by reference herein in their entirey for all purposes. 
     This application is also related to the followings U.S. patents and patent applications: U.S. Pat. Nos. 8,562,589, 8,721,620, 8,734,429, 8,759,284, 8,809,269, 9,149,617 and U.S. patent application Ser. No. 16/731,834 filed Dec. 31, 2019; 62/786,831, filed Dec. 31, 2018 and 62/812,118 filed Feb. 28, 2019 all of which are fully incorporated by reference herein for all purposes along with any paper cited herein. 
    
    
     BACKGROUND 
     Field of the Invention 
     Embodiments of the invention relate to swallowable drug delivery devices. More specifically, embodiments of the invention relate to swallowable drug delivery devices for delivering drugs to the small intestine. 
     While there has been an increasing development of new drugs in recent years for the treatment of a variety of diseases, many have limited application because they cannot be given orally. This is due to a number of reasons including: poor oral toleration with complications including gastric irritation and bleeding; breakdown/degradation of the drug compounds in the stomach; and poor, slow or erratic absorption of the drug. Conventional alternative drug delivery methods such as intravenous and intramuscular delivery have a number of drawbacks including pain and risk of infection from a needle stick, requirements for the use of sterile technique and the requirement and associated risks of maintaining an IV line in a patient for an extended period of time. While other drug delivery approaches have been employed such as implantable drug delivery pumps, these approaches require the semi-permanent implantation of a device and can still have many of the limitations of IV delivery. Thus, there is a need for an improved method for delivery of drugs and other therapeutic agents. Also, while there have been some attempts at the delivery of such drugs by oral delivery they suffer the drawback of only being able to deliver drugs during a fasted state limiting their practicality for many patients. 
     BRIEF SUMMARY 
     Embodiments of the invention provide devices, systems, kits and methods for delivering drugs and other therapeutic agents to various locations in the body. Many embodiments provide a swallowable device for delivering drugs and other therapeutic agents within the Gastrointestinal (GI) tract. Particular embodiments provide a swallowable device such as a capsule for delivering drugs and other therapeutic agents into the wall of the small intestine and/or surrounding tissue or other GI organ wall. Embodiments of the invention are particularly useful for the delivery of drugs and other therapeutic agents which are poorly absorbed, poorly tolerated and/or degraded within the GI tract. Further, embodiments of the invention can be used to deliver drugs and other therapeutic agents which were previously only capable of or preferably delivered by intravenous or other form of parenteral administration including various non-vascular injected forms of administration such as intramuscular or subcutaneous injection due to degradation within the GI tract and/or poor adsorption through the small intestine. In various embodiments, such therapeutic agents may include insulin (e.g., basal insulin, recombinant insulin) and various other bio therapeutic agents (also described as biologics) such as various immunoglobulins or antibodies including immunoglobulin G. Particular embodiment provides devices and methods for delivering such biologics with a bioavailability 70 or 80 percent or higher. As used herein the term “biotherapeutic agent” (also referred to as a biologic) refers to product that is produced from living organisms or contains components of living organisms. It may include one or more forms of insulin such as basal insulin, recombinant human insulin or one or more antibodies including for example, Immunoglobulin G (IgG). It may also include cells such as various immune cells (e.g., white blood cells, macrophages, T-cells etc. and the like) or a component or fragment of a cell such as platelets. 
     In one aspect of the invention, the invention provides a therapeutic agent preparation for delivery into the wall of a lumen of the gastro-intestinal tract (e.g., the stomach, small intestine, large intestine, etc.) or surrounding tissue (e.g., the peritoneal wall or cavity), where the preparation comprises a therapeutically effective dose of at least one therapeutic agent such as basal insulin or other form of insulin. The preparation has a shape and material consistency to be contained in or otherwise protected by a swallowable capsule or other swallowable device and delivered from the capsule into the intestinal wall to release the dose of therapeutic agent from within the intestinal wall or surrounding tissue such as the peritoneal wall or peritoneal cavity. In many embodiments, the preparation is configured to be contained in a swallowable capsule and operably coupled to one or more of an actuator, expandable member (e.g., a balloon) or other device having a first configuration and a second configuration. The preparation is contained within the capsule in the first configuration and advanced out of the capsule and into the intestinal wall in the second configuration to deliver the therapeutic agent into the intestinal wall. In variations, the preparation may configured to be partially be contained in the capsule or attached or otherwise disposed on the capsule surface. In these and related embodiments, release of the preparation can be achieved or otherwise facilitated by use of a dissolvable pH sensitive coating that degrades in the small intestine. 
     In other embodiments, the invention provides a method for delivering a therapeutic agent into the wall of a lumen in the GI tract (e.g., stomach, intestines, etc.) comprising swallowing a drug delivery device comprising a capsule, an actuator and an embodiment of the therapeutic agent preparation. The actuator is responsive to a condition in a particular location in the GI (e.g., pH) so as to actuate delivery of the therapeutic agent preparation into the wall of the small intestine. In specific embodiments, the actuator can comprise a release element or coating on the capsule which is degraded by a selected pH in the stomach, small intestine, large intestine. Once degraded, the element or coating initiates delivery of the therapeutic agent preparation by one or more delivery means such as the by expansion of one or more balloons that are operably coupled to tissue penetrating members that contain the therapeutic agent preparation and are configured to penetrate and be advanced into the intestinal wall upon expansion of the balloon. Once the tissue penetrating members are in the intestinal wall or surrounding tissue, they degrade to release the therapeutic agent into the bloodstream. Because embodiments of the invention deliver the therapeutic agent preparation directly into the wall of the GI tract (e.g. the small intestine, stomach, etc.) or surrounding tissue, the time period (described herein as T max ) for achieving the maximum concentration of the therapeutic agent in the bloodstream or other location in the body is shorter than a corresponding time period for achieving such a maximum concentration when the therapeutic agent is non-vascularly injected into the body such as by intramuscular or other subcutaneous injection. In various embodiments, the T max  achieved by insertion of the therapeutic preparation into the intestinal wall using one or more embodiments of the invention (such as an embodiment of the swallowable device) can be 80%, 50%, 30%, 20 or even 10% of T max  achieved through the use of a non-vascular injection of the therapeutic agent. 
     In related embodiments, the invention provides therapeutic preparations and associated methods for their delivery into the gastro-intestinal wall or surrounding tissue where one or more pharmacokinetic parameters of delivery can be achieved. Such parameters may include, for example, one or more of absolute bioavailability, relative bioavailability, T max , T 1/2  C max  and area under the curve. “Absolute bioavailability” which is expressed as percentage, is the amount of drug from a formulation that reaches the systemic circulation (as determined from an area under the curve (AUC) measurement) relative to that from an intravenous (IV) dose, where the IV dose is assumed to be 100% bioavailable. “Relative bioavailability”, also expressed as percentage, is the amount drug from a first formulation that reaches the systemic circulation (as determined from an AUC measurement) relative to that of another formulation of the same drug delivered by the same or a different route of administration. T max  is the time period for the therapeutic agent to reach its maximum concentration in the blood stream, C max , and T 1/2  being the time period required for the concentration of the therapeutic agent in the bloodstream (or other location in the body) to reach half its original C max  value after having reached C max . In particular embodiments, including those, for example, where the therapeutic preparation comprises an antibody such as IgG, the absolute bioavailability of therapeutic agent delivered by embodiments of the invention can be in the range from about 50 to 68.3% with a specific value of 60.7%. Still other values are contemplated as well. Also the T max  for delivery of antibodies, for example, IgG, can be about 24 hours while the T 1/4  can be in a range from about 40.7 to 128 hours, with a specific value of about 87.7 hours. 
     Also in related embodiments, the therapeutic preparation and associated methods for their delivery into the wall of the small intestine or surrounding tissue can be configured to produce plasma/blood concentration vs time profiles of the therapeutic agent having a selected shape with C max  or T max  as reference points. For example, the plasma concentration vs time profile may have a rising portion and falling portion with selected ratios of the time it takes to go from pre delivery concentration of therapeutic agent to a C max  level during the rising portion (known as rise time), to the time it takes during the falling portion to go from the C max  level back to the pre-delivery concentration (known as fall time). In various embodiments, the ratio of the rising portion to the falling portion can be in the range of about 1 to 20, 1 to 10 and 1 to 5. In specific embodiments of therapeutic preparations comprising antibodies such as IgG, the ratio of rise time to fall time in the profile can be about 1 to 9. Whereas for various types of insulin including recombinant human insulin, the ratio of rise time to fall time can be in a range of about 1 to 2 to 1 to 6, with specific embodiments of 1:4, 1:4.5 and 1:6. 
     In another aspect, the invention provides a swallowable device for delivering a drug or other therapeutic agent preparation into the wall of the small or large intestine or other organ of the gastro-intestinal tract such as the stomach. The device comprises a capsule sized to be swallowed and passed through the gastro-intestinal tract, a deployable aligner positioned within the capsule for aligning a longitudinal axis of the capsule with a longitudinal axis of the small intestine, a delivery mechanism for delivering the therapeutic agent into the intestinal wall and a deployment member for deploying at least one of the aligner or the delivery mechanism. The capsule wall is degradable by contact with liquids in the GI tract but also may include an outer coating or layer which only degrades in the higher pH&#39;s found in the small intestine, and serves to protect the underlying capsule wall from degradation within the stomach before the capsule reaches the small intestine at which point the drug delivery is initiated by degradation of the coating. In use, such materials allow for the targeted delivery of a therapeutic agent in a selected portion of the intestinal tract such as the small intestine. Suitable outer coatings can include various enteric coatings such as various co-polymers of methacrylic acid and ethyl acrylate. 
     Another embodiment of the capsule includes at least one guide tube, one or more tissue penetrating members positioned in the at least one guide tube, a delivery member and an actuating mechanism. The tissue penetrating member will typically comprise a hollow needle or other like structure and will have a lumen and a tissue penetrating end for penetrating a selectable depth into the intestinal wall. In various embodiments, the device can include a second and a third tissue penetrating member with additional numbers contemplated. Each tissue penetrating member can include the same or a different drug. In preferred embodiments having multiple tissue penetrating members, the tissue penetrating members can be symmetrically distributed around the perimeter of the capsule so as to anchor the capsule onto the intestinal wall during delivery of drug. In some embodiments, all or a portion of the tissue penetrating member (e.g., the tissue penetrating end) can be fabricated from the drug preparation itself. In these and related embodiments, the drug preparation can have a needle or dart-like structure (with or without barbs) configured to penetrate and be retained in the intestinal wall. 
     The tissue penetrating member can be fabricated from various biodegradable materials (e.g., polyethylene oxide (PEO), PLGA (polylactic-co-glycolic acid), maltose or other sugar) so as to degrade within the small intestine and thus provide a fail-safe mechanism for detaching the tissue penetrating member from the intestinal wall should this component become retained in the intestinal wall. Additionally, in these and related embodiments, selectable portions of the capsule can be fabricated from such biodegradable materials so as to allow the entire device to controllably degrade into smaller pieces. Such embodiments facilitate passage and excretion of the devices through the GI tract. In particular embodiments, the capsule can include seams of biodegradable material which controllably degrade to break the capsule into pieces of a selectable size and shape to facilitate passage through the GI tract. The seams can be pre-stressed, perforated or otherwise treated to accelerate degradation. The concept of using biodegradable seams to produce controlled degradation of a swallowable device in the GI tract can also be applied to other swallowable devices such as swallowable cameras to facilitate passage through the GI tract and reduce the likelihood of a device becoming stuck in the GI tract. 
     The delivery member is configured to advance the drug from the capsule through the tissue penetrating member lumen and into the intestinal wall, stomach wall or other luminal wall of the GI tract. Typically, at least a portion of the delivery member is advanceable within the tissue penetrating member lumen. In one or more embodiments, the delivery member can have a piston or like structure sized to fit within the delivery member lumen. The distal end of the delivery member (the end which is advanced into tissue) can have a plunger element which advances the drug within tissue penetrating member lumen and also forms a seal with the lumen. The plunger element can be integral or attached to the delivery member. Preferably, the delivery member is configured to travel a fixed distance within the needle lumen so as to deliver a fixed or metered dose of drug into the intestinal wall. This can be achieved by one or more of the selection of the diameter of the delivery member (e.g., the diameter can be distally tapered), the diameter of the tissue penetrating member (which can be narrowed at its distal end), use of a stop, and/or the actuating mechanism. For embodiments of the device having a tissue penetrating member fabricated from drug (e.g., a drug dart), the delivery member is adapted to advance the dart out of the capsule and into tissue. 
     The delivery member and tissue penetrating member can be configured for the delivery of liquid, semi-liquid or solid forms of drug or all three. Solid forms of drug can include both powder or pellet. Semi liquid can include a slurry or paste. The drug can be contained within a cavity of the capsule, or in the case of the liquid or semi-liquid, within an enclosed reservoir. In some embodiments, the capsule can include a first second, or a third drug (or more). Such drugs can be contained within the tissue penetrating member lumen (in the case of solids or powder) or in separate reservoirs within the capsule body. 
     The actuating mechanism can be coupled to at least one of the tissue penetrating member or the delivery member. The actuating mechanism is configured to advance the tissue penetrating member a selectable distance into the intestinal wall as well as advance the delivery member to deliver the drug and then withdraw the tissue penetrating member from the intestinal wall. In various embodiments, the actuating mechanism can comprise a preloaded spring mechanism which is configured to be released by the release element. Suitable springs can include both coil (including conical shaped springs) and leaf springs with other spring structures also contemplated. In particular embodiments, the spring can be cone shaped to reduce the length of the spring in the compressed state even to the point where the compressed length of the spring is about the thickness of several coils (e.g., two or three) or only one coil. 
     In particular embodiments the actuating mechanism comprises a spring, a first motion converter, and a second motion converter and a track member. The release element is coupled to the spring to retain the spring in a compressed state such that degradation of the release element releases the spring. The first motion converter is configured to convert motion of the spring to advance and withdraw the tissue penetrating element in and out of tissue. The second motion converter is configured to convert motion of the spring to advance the delivery member into the tissue penetrating member lumen. The motion converters are pushed by the spring and ride along a rod or other track member which serves to guide the path of the converters. They engage the tissue penetrating member and/or delivery member (directly or indirectly) to produce the desired motion. They are desirably configured to convert motion of the spring along its longitudinal axis into orthogonal motion of the tissue penetrating member and/or delivery member though conversion in other directions is also contemplated. The motion converters can have a wedge, trapezoidal or curved shape with other shapes also contemplated. In particular embodiments, the first motion converter can have a trapezoidal shape and include a slot which engages a pin on the tissue penetrating member that rides in the slot. The slot can have a trapezoidal shape that mirrors or otherwise corresponds to the overall shape of the converter and serves to push the tissue penetrating member during the upslope portion of the trapezoid and then pull it back during the down slope portion. In one variation, one or both of the motion converters can comprise a cam or cam like device which is turned by the spring and engages the tissue penetrating and/or delivery member. 
     In other variations, the actuating mechanism can also comprise an electro-mechanical device or mechanism such as a solenoid or a piezoelectric device. In one embodiment, the piezoelectric device can comprise a shaped piezoelectric element which has a non-deployed and deployed state. This element can be configured to go into the deployed state upon the application of a voltage and then return to the non-deployed state upon the removal of the voltage. This and related embodiments allow for a reciprocating motion of the actuating mechanism so as to both advance the tissue penetrating member and then withdraw it. 
     The release element is coupled to at least one of the actuating mechanism or a spring coupled to the actuating mechanism. In particular embodiments, the release element is coupled to a spring positioned within the capsule so as to retain the spring in a compressed state. Degradation of the release element releases the spring to actuate the actuation mechanism. In many embodiments, the release element comprises a material configured to degrade upon exposure to chemical conditions in the small 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 greater. However, it can also be configured to degrade in response to other conditions in the small intestine. In particular embodiments, the release element can be configured to degrade in response to particular chemical conditions in the fluids in the small intestine such as those which occur after ingestion of a meal (e.g., a meal high in fats or proteins). 
     Biodegradation of the release element from one or more conditions in the small intestine, stomach (or other location in the GI tract) can be achieved by selection of the materials for the release element, the amount of cross linking of those materials as well as the thickness and other dimensions of the release elements. Lesser amounts of cross linking and or thinner dimensions can increase the rate of degradation and vice versa. Suitable materials for the release element can comprise biodegradable materials such as various enteric materials which are configured to degrade upon exposure to the higher pH or other condition in the small intestine. The enteric materials can be copolymerized or otherwise mixed with one or more polymers to obtain a number of particular material properties in addition to biodegradation. Such properties can include without limitation stiffness, strength, flexibility and hardness. 
     In particular embodiments, the release element can comprise a film or plug that fits over or otherwise blocks the guide tube and retains the tissue penetrating member inside the guide tube. In these and related embodiments, the tissue penetrating member is coupled to a spring loaded actuating mechanism such that when the release element is degraded sufficiently, it releases the tissue penetrating member which then springs out of the guide tube to penetrate into the intestinal wall. In other embodiments, the release element can be shaped to function as a latch which holds the tissue penetrating element in place. In these and related embodiments, the release element can be located on the exterior or the interior of the capsule. In the interior embodiments, the capsule and guide tubes are configured to allow for the ingress of intestinal fluids into the capsule interior to allow for the degradation of the release element. 
     In some embodiments, the actuating mechanism can be actuated by means of a sensor, such as a pH or other chemical sensor which detects the presence of the capsule in the small intestine and sends a signal to the actuating mechanism (or to an electronic controller coupled to the actuating mechanism to actuate the mechanism). Embodiments of a pH sensor can comprise an electrode-based sensor or it can be a mechanically-based sensor such as a polymer which shrinks or expands upon exposure to the pH or other chemical conditions in the small intestine. In related embodiments, an expandable/contractible sensor can also comprise the actuating mechanism itself by using the mechanical motion from the expansion or contraction of the sensor. 
     According to another embodiment for detecting that the device is in the small intestine (or other location in the GI tract), the sensor can comprise a strain gauge or other pressure/force sensor for detecting the number of peristaltic contractions that the capsule is being subject to within a particular location in the intestinal tract. In these embodiments, the capsule is desirably sized to be gripped by the small intestine during a peristaltic contraction. Different locations within the GI tract have different number of peristaltic contractions. The small intestine has between 12 to 9 contractions per minute with the frequency decreasing down the length of the intestine. Thus, according to one or more embodiments detection of the number of peristaltic contractions can be used to not only determine if the capsule is in the small intestine but the relative location within the intestine as well. 
     As an alternative or supplement to internally activated drug delivery, in some embodiments, the user may externally activate the actuating mechanism to deliver drug by means of RF, magnetic or other wireless signaling means known in the art. In these and related embodiments, the user can use a handheld device (e.g., a hand held RF device) which not only includes signaling means, but also means for informing the user when the device is in the small intestine or other location in the GI tract. The later embodiment can be implemented by including an RF transmitter on the swallowable device to signal to the user when the device is in the small intestine or other location (e.g., by signaling an input from the sensor). The same handheld device can also be configured to alter the user when the actuating mechanism has been activated and the selected drug(s) delivered. In this way, the user is provided confirmation that the drug has been delivered. This allows the user to take other appropriate drugs/therapeutic agents as well as make other related decisions (e.g., for diabetics to eat a meal or not and what foods should be eaten). The handheld device can also be configured to send a signal to the swallowable device to over-ride the actuating mechanism and so prevent, delay or accelerate the delivery of drug. In use, such embodiments allow the user to intervene to prevent, delay or accelerate the delivery of drug based upon other symptoms and/or patient actions (e.g., eating a meal, deciding to go to sleep, exercise etc.). 
     The user may also externally activate the actuating mechanism at a selected time period after swallowing the capsule. The time period can be correlated to a typical transit time or range of transit times for food moving through the user&#39;s GI tract to a particular location in the tract such as the stomach, small intestine or large intestine. 
     Another aspect of the inventions provides therapeutic agent preparations for delivery into the wall of the small intestine or surrounding tissue using embodiments of the swallowable device described herein. The preparation comprises a therapeutically effective dose of at least one therapeutic agent, for example IgG or another antibody. Also, it may comprise a solid, liquid or combination of both and can include one or more pharmaceutical excipients. The preparation has a shape and material consistency to be contained in embodiments of the swallowable capsule, delivered from the capsule into the intestinal wall and degrade within the wall or surrounding tissue to release the dose of therapeutic agent. The preparation may also have a selectable surface area to volume ratio so as enhance or otherwise control the rate of degradation of the preparation in the wall of the small intestine or other body lumen. In various embodiments, the preparation can be configured to be coupled to an actuator such as a release element or actuation mechanism which has a first configuration in which the preparation is contained in the capsule and a second configuration in which the preparation is advanced out of the capsule and into the wall of the small intestine. The dose of the drug or other therapeutic agent in the preparation can be titrated downward from that which would be required for conventional oral delivery methods so that potential side effects from the drug can be reduced. 
     Typically, though not necessarily, the preparation will be shaped and otherwise configured to be contained in the lumen of a tissue penetrating member, such as a hollow needle which is configured to be advanced out of the capsule and into the wall of the small intestine. Also, The preparation itself may comprise a tissue penetrating member configured to be advanced into the wall of the small intestine or other lumen in the intestinal tract. The tip of tissue penetrating member may have a variety of shapes including have a symmetric or asymmetric taper or bevel. The later embodiments may be used to deflect or steer the tissue penetrating member into a particular tissue layer such as into the intestinal wall. 
     Another aspect of the invention provides methods for the delivery of drugs and the therapeutic agents into the walls of the GI tract using embodiments of the swallowable drug delivery devices. Such methods can be used for the delivery of therapeutically effective amounts of a variety of drugs and other therapeutic agents. These include a number of large molecule peptides and proteins which would otherwise require injection due to chemical breakdown in the stomach e.g., growth hormone, parathyroid hormone, insulin, interferons and other like compounds. Suitable drugs and other therapeutic agents which can be delivered by embodiments of invention include various chemotherapeutic agents (e.g., interferon), antibiotics, antivirals, insulin and related compounds, glucagon like peptides (e.g., GLP-1, exenatide), parathyroid hormones, growth hormones (e.g., IFG (Insulin-like growth factor) and other growth factors), anti-seizure agents, immune suppression agents and anti-parasitic agents such as various anti-malarial agents. The dosage of the particular drug can be titrated for the patient&#39;s weight, age, condition or other parameter. 
     In various method embodiments of the invention, embodiments of the drug swallowable drug delivery device can be used to deliver a plurality of drugs for the treatment of multiple conditions or for the treatment of a particular condition (e.g., a mixture of protease inhibitors for treatment HIV AIDS). In use, such embodiments allow a patient to forgo the necessity of having to take multiple medications for a particular condition or conditions. Also, they provide a means for facilitating that a regimen of two or more drugs is delivered and absorbed into the small intestine and thus, the blood stream at about the same time. Due to differences in chemical makeup, molecular weight, etc., drugs can be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves. Embodiments of the invention address this issue by injecting the desired drug mixtures at about the same time. This in turn, improves pharmacokinetics and thus, the efficacy of the selected mixture of drugs. 
     The following numbered clauses describe other examples, aspects, and embodiments of the inventions described herein: 
     1. A therapeutic preparation comprising a therapeutically effect amount of insulin, the preparation adapted for insertion into a wall of a patient&#39;s small intestine or surrounding tissue after oral ingestion, wherein upon insertion, the preparation degrades to releases insulin into the blood stream from the intestinal wall or surrounding tissue so as to yield a relative bioavailability in a range of about 72 to 129% compared to a subcutaneously injected dose of insulin. 
     2. The preparation of clause 1, wherein the relative bioavailability is in a range of about 104 to 129% compared to the subcutaneously injected dose of insulin. 
     3. The preparation of clause 1, wherein the surrounding tissue is the peritoneum or peritoneal cavity. 
     4. The preparation of clause 1, wherein the insulin is human recombinant insulin. 
     5. The preparation of clause 1, wherein the released insulin exhibits a T max  in a range of about 97 to 181 min. 
     6. The preparation of clause 5, wherein the released insulin exhibits a T max  of about 139 minutes. 
     7. The preparation of clause 1, wherein the preparation comprises about 19.3 to 19.9 RU of insulin. 
     8. The preparation of clause 1, wherein the preparation is adapted for insertion into the wall of the small intestine. 
     9. The preparation of clause 1, wherein at least a portion of the preparation is in solid form. 
     10. The preparation of clause 1, wherein the preparation is adapted to be orally delivered in a swallowable capsule. 
     11. The preparation of clause 10, wherein the preparation is adapted to be operably coupled to delivery means having a first configuration and a second configuration, the preparation being contained within the capsule in the first configuration and advanced out of the capsule and into the intestinal wall in the second configuration. 
     12. The preparation of clause 1, wherein the preparation comprises a biodegradable material which degrades within the intestinal wall to release insulin into the blood stream. 
     13. The preparation of clause 12, wherein the biodegradable material comprises PET, PLGA, a sugar or maltose. 
     14. The preparation of clause 1, wherein the preparation comprises at least one pharmaceutical excipient. 
     15. The preparation of clause 14, wherein the at least one pharmaceutical excipient comprises at least one of a binder, a preservative or a disintegrant. 
     16. The preparation of clause 1, wherein the preparation comprises a tissue penetrating member that is configured to penetrate and be inserted into a lumen wall of the GI tract. 
     17. The preparation of clause 16, wherein the tissue penetrating member comprises a biodegradable material which degrades within the intestinal wall to release the insulin into the blood stream. 
     18. The preparation of clause 16, wherein the insulin is contained in the tissue penetrating member in a shaped section. 
     19. The preparation of clause 18, wherein the shaped section has a cylinder or pellet shape. 
     20. The preparation of clause 16, wherein the lumen wall comprises a wall of the small intestine or a wall of the stomach. 
     21. A therapeutic preparation comprising a therapeutically effect amount of insulin, the preparation adapted for insertion into a patients intestinal wall or surrounding tissue after oral ingestion, wherein upon insertion, the preparation degrades to releases insulin into the blood stream from the intestinal wall or surrounding tissue so as to produce a glucose lowering effect comparable to an equivalent dose of subcutaneously injected insulin. 
     22. The preparation of clause 21, wherein the insulin is human recombinant insulin. 
     23. A therapeutic preparation comprising a therapeutically effect dose of insulin, the preparation adapted for insertion into a patient&#39;s intestinal wall or surrounding tissue after oral ingestion, wherein upon insertion, the preparation degrades to releases insulin into the blood stream from the intestinal wall or surrounding tissue so as to yield a plasma concentration of insulin in a range of about 381 to 527 pM/kg body weight/IU of insulin dose. 
     24. The preparation of clause 23, wherein the insulin is human recombinant insulin. 
     25. The preparation of clause 23, wherein the plasma concentration of insulin is about 459 pM/kg body weight/IU of insulin dose. 
     26. A therapeutic preparation comprising a therapeutically effect dose of insulin, the preparation adapted for insertion into an intestinal wall or surrounding tissue after oral ingestion, wherein upon insertion, the preparation degrades to releases insulin into the blood stream from the intestinal wall or surrounding tissue so as to maintain a patient&#39;s blood glucose within a euglycemic level upon the ingestion of a simple sugar. 
     27. The preparation of clause 26, wherein the euglycemic level is within the range of about 60-90 mg ml. 
     28. The preparation of clause 26, wherein the simple sugar is dextrose. 
     29. The preparation of clause 26, wherein the insulin is human recombinant insulin. 
     30. A therapeutic preparation comprising insulin, the preparation adapted for insertion into an intestinal wall or surrounding tissue of a patient after oral ingestion, wherein upon insertion, the preparation degrades to releases insulin into the patient&#39;s blood stream from the intestinal wall or surrounding tissue, the release exhibiting a plasma concentration profile having a rising portion and a falling portion, the rising portion reaching a C max  level of insulin from a pre-release level of insulin at least about 2 times faster than a time it takes in the falling portion to go from the C max  level of insulin to the prelease level of insulin. 
     31. The preparation of clause 30, wherein the rising portion reaches a C max  level of insulin from the prerelease level of insulin in a range of about 3 to 5 times faster than a time it takes in the falling portion go from the C max  of insulin to the prelease level of insulin. 
     32. The preparation of clause 30, wherein the rising portion reaches the C max  level of insulin from the prerelease level of insulin about 4.5 times faster than a time it takes in the falling portion go from the C max  of insulin to the prelease level of insulin. 
     33. The preparation of clause 30, wherein the surrounding tissue is the peritoneum or peritoneal cavity. 
     34. The preparation of clause 30, wherein the insulin is human recombinant insulin. 
     35. A method for delivering insulin to a patient, the method comprising: 
     providing a solid insulin dosage; and delivering the solid dosage insulin into an intestinal wall or surrounding tissue of the patient after oral ingestion, wherein the insulin is released into the patient&#39;s blood stream from the solid dosage insulin in the intestinal wall or surrounding tissue so as to produce a plasma concentration profile having a rising portion and a falling portion, the rising portion reaching a C max  level of insulin from a pre-release level of insulin at least about 2 times faster than a time it takes in the falling portion to go from the C max  of insulin it to the prelease level of insulin. 
     36. The method of clause 35, wherein the rising portion reaches the C max  level of insulin in a range of about 3 to 5 times faster than the time it takes in the falling portion go from the C max  of insulin it to the prelease level of insulin. 
     37. The method of clause 35, wherein the released insulin exhibits a T max  in a range of about 97 to 181 minutes. 
     38. The method of clause 35, wherein the released insulin exhibits a T max  of about 139 minutes. 
     39. The method of clause 35, wherein the surrounding tissue is the peritoneum or peritoneal cavity. 
     40. The method of clause 35, wherein the insulin is human recombinant insulin. 
     41. A method for delivering insulin to a patient, the method comprising: providing a solid insulin dosage; and delivering the solid dosage insulin into an intestinal wall or surrounding tissue of the patient after oral ingestion, wherein the insulin is released into the patient&#39;s blood stream from the solid dosage insulin in the intestinal wall or surrounding tissue so as so as to obtain an absolute bioavailability of insulin of at least about 60% and relative bioavailability in a range of about 72 to 129% compared to a subcutaneously injected dose of insulin. 
     42. The method of clause 41, wherein the surrounding tissue is the peritoneum or peritoneal cavity. 
     43. The method of clause 41, wherein the released insulin exhibits a T max  in a range of about 97 to 181 min. 
     44. The method of clause 43, wherein the released insulin exhibits a T max  of about 139 minutes. 
     45. The method of clause 41, wherein the insulin is human recombinant insulin. 
     46. A method for delivering a therapeutic agent into a wall of a lumen of the gastro-intestinal (GI) tract of a patient, the method comprising: swallowing a drug delivery device having an interior, an actuator having a first configuration and a second configuration and a therapeutic preparation operably coupled to the actuator, the therapeutic preparation comprising a therapeutically effective dose of at least one therapeutic agent, the preparation being contained within the device interior in the first configuration and advanced out of the interior and into the GI lumen wall in the second configuration by the application of force on the preparation so as to deliver the therapeutic agent into the lumen wall; and actuating the actuator responsive to a condition in the GI lumen to deliver the therapeutic agent from the device into the wall of the GI lumen, wherein a time period between exit of the device from the patients stomach and actuation of the actuator in the patient&#39;s small intestine is not appreciably affected by the presence of food contents in the patient&#39;s GI tract. 
     47. The method of clause 46, wherein the swallowable device comprises a swallowable capsule and the actuator is contained within the interior of the swallowable capsule 
     48. The method of clause 47, wherein the swallowable capsule has an oval shape. 
     49. The method of clause 46, wherein the actuator is operably coupled to an expandable member or expandable balloon and wherein actuation of the actuator causes expansion of the expandable member or expandable balloon. 
     50. The method of clause 46, wherein the condition in the small intestine is a selected pH. 
     51. The method of clause 50, wherein the selected pH is above about 7.1. 
     52. A method for delivering a therapeutic agent into a wall of a small intestine of a patient, the method comprising: swallowing a drug delivery device having an interior, an actuator having a first configuration and a second configuration and a therapeutic preparation operably coupled to the actuator, the therapeutic preparation comprising a therapeutically effective dose of at least one therapeutic agent, the preparation being contained within the device interior in the first configuration and advanced out of the interior and into the GI lumen wall in the second configuration by the application of force on the preparation so as to deliver the therapeutic agent into the lumen wall; and actuating the actuator responsive to a condition in the GI lumen to deliver the therapeutic agent from the device into the wall of the small intestine, wherein the patient does not have a perceptible sensitization when the actuator is actuated. 
     53. The method of clause 52, where the actuator is coupled to at expandable balloon or other expandable delivery means. 
     54. The method of clause 52, wherein the condition in the small intestine is a selected pH. 
     55. The method of clause 54, wherein the selected pH is above about 7.1. 
     Further details of these and other embodiments and aspects of the invention are described more fully below, with reference to the attached drawing figures. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1 a    is a lateral viewing showing an embodiment of a swallowable drug delivery device. 
         FIG. 1 b    is a lateral viewing showing an embodiment of a system including a swallowable drug delivery device. 
         FIG. 1 c    is a lateral viewing showing an embodiment of a kit including a swallowable drug delivery device and a set of instructions for use. 
         FIG. 1 d    is a lateral viewing showing an embodiment of a swallowable drug delivery device including a drug reservoir. 
         FIG. 2  is a lateral view illustrating an embodiment of the swallowable drug delivery device having a spring loaded actuation mechanism for advancing tissue penetrating members into tissue. 
         FIG. 3  is a lateral view illustrating an embodiment of the swallowable drug delivery device having a spring loaded actuation mechanism having a first motion converter. 
         FIG. 4  is a lateral view illustrating an embodiment of the swallowable drug delivery device having a spring loaded actuation mechanism having first and a second motion converter. 
         FIG. 5  is a perspective view illustrating engagement of the first and second motion converters with the tissue penetrating member and delivery members. 
         FIG. 6  is a cross sectional view illustrating an embodiment of the swallowable drug delivery device having a single tissue penetrating member and an actuating mechanism for advancing the tissue penetrating member. 
         FIG. 7 a    is a cross sectional view illustrating an embodiment of the swallowable drug delivery device having multiple tissue penetrating members and an actuating mechanism for advancing the tissue penetrating members. 
         FIG. 7 b    is a cross sectional view illustrating deployment of the tissue penetrating members of the embodiment of  FIG. 7 a    to deliver medication to a delivery site and anchor the device in the intestinal wall during delivery. 
         FIGS. 8 a -8 c    are side views illustrating positioning of the drug delivery device in the small intestine and deployment of the tissue penetrating members to deliver drug;  FIG. 8 a    shows the device in the small intestine prior to deployment of the tissue penetrating members with the release element in tact;  FIG. 8 b    shows the device in the small intestine with the release element degraded and the tissue penetrating elements deployed; and  FIG. 8 c    shows the device in the small intestine with the tissue penetrating elements retracted and the drug delivered. 
         FIG. 9 a    shows an embodiment of a swallowable drug delivery device including a capsule having bio-degradable seams positioned to produce controlled degradation of the capsule in the GI tract. 
         FIG. 9 b    shows the embodiment of  FIG. 9 a    after having been degraded in the GI tract into smaller pieces. 
         FIG. 10  shows an embodiment of a capsule having biodegradable seams including pores and/or perforations to accelerate biodegradation of the capsule. 
         FIG. 11  is a lateral viewing illustrating use of an embodiment of a swallowable drug delivery device including transit of device in the GI tract and operation of the device to deliver drug. 
         FIGS. 12 a  and 12 b    are lateral view illustrating an embodiment of a capsule for the swallowable drug delivery device including a cap and a body coated with pH sensitive biodegradable coatings,  FIG. 12 a    shows the capsule in an unassembled state and  FIG. 12 b    in an assembled state 
         FIGS. 13 a  and 13 b    illustrate embodiments of unfolded multi balloon assemblies containing a deployment balloon, an aligner balloon, a delivery balloon and assorted connecting tubes;  FIG. 13 a    shows an embodiment of the assembly for a single dome configuration of the deployment balloon; and  FIG. 13 b    shows an embodiment of the assembly for dual dome configuration of the deployment balloon; and. 
         FIG. 13 c    is a perspective views illustrating embodiments of a nested balloon configuration which can be used for one or more embodiments of the balloons described herein including the aligner balloon. 
         FIGS. 14 a -14 c    are lateral views illustrating embodiments of a multi compartment deployment balloon;  FIG. 14 a    shows the balloon in a non-inflated state with the separation valve closed;  FIG. 14 b    shows the balloon with valve open and mixing of the chemical reactants; and  FIG. 14 c    shows the balloon in an inflated state. 
         FIGS. 15 a -15 g    are lateral views illustrating a method for folding of the multiple balloon assembly, the folding configuration in each figure applies to both single and dual dome configurations of the deployment balloon, with the exception that  FIG. 15 c   , pertains to a folding step unique to dual dome configurations; and  FIG. 15 d   , pertains to the final folding step unique to dual dome configurations;  FIG. 15 e   , pertains to a folding step unique to single dome configurations; and  FIGS. 15 f  and 15 g    are orthogonal views pertaining to the final folding step unique to single dome configurations. 
         FIGS. 16 a  and 16 b    are orthogonal views illustrating embodiments of the final folded multi balloon assembly with the attached delivery assembly. 
         FIGS. 17 a  and 17 b    are orthogonal transparent views illustrating embodiments of the final folded multi balloon assembly inserted into the capsule. 
         FIG. 18 a    is a side view of an embodiment of the tissue penetrating member. 
         FIG. 18 b    is a bottom view of an embodiment of the tissue penetrating member illustrating placement of the tissue retaining features. 
         FIG. 18 c    is a side view of an embodiment of the tissue penetrating member having a trocar tip and inverted tapered shaft. 
         FIG. 18 d    is a side view of an embodiment of the tissue penetrating member having a separate drug containing section. 
         FIGS. 18 e  and 8 f    are side views showing the assembly of an embodiment of a tissue penetrating member having a shaped drug containing section.  FIG. 18 e    shows the tissue penetrating member and shaped drug section prior to assembly; and  FIG. 18 f    after assembly. 
         FIG. 19  provides assorted views of the components and steps used to assemble an embodiment of the delivery assembly. 
         FIGS. 20 a -20 i    provides assorted views illustrating a method of operation of swallowable device to deliver medication to the intestinal wall. 
         FIG. 21  is a graph of mean plasma concentration vs time, illustrating pharmacokinetic results and the shape of a plasma concentration vs time curve for delivery of IgG using embodiments of a swallowable device described herein, also referred to as the RaniPill. 
         FIG. 22  is a graph of mean plasma concentration vs time for delivery of IgG using the RaniPill (the Rani Group) as compared to intravenous (the IV Group) and subcutaneous injection (the SC Group) of the IgG. 
         FIG. 23  is a graph of plasma concentration vs time, for intravenous injection of IgG in the dogs used for the mean IV Group graph in  FIG. 22 . 
         FIG. 24  is a graph of plasma concentration vs time, for subcutaneous injection of IgG in the dogs used for the mean SC Group graph in  FIG. 22 . 
         FIG. 25  is a graph of plasma concentration vs time, for delivery of IgG using the RaniPill in the dogs used for the mean Rani Group graph in  FIG. 22 . 
         FIG. 26  is a graph of mean plasma concentration of insulin vs time for delivery of human recombinant insulin (HRI) using the RaniPill (the Rani Group) and via subcutaneous injection (the SC Group) 
         FIG. 27  is a graph of glucose (Dextrose) infusion rates vs time for the Euglycemic clamp experiments comparing HRI delivered in the Rani Group versus the SC Group. 
         FIG. 28  is a graph of mean insulin plasma concentration and glucose infusion rates vs time illustrating the interactions (e.g., Pharamakokinetic (PK) and Pharmacodynamic (PD)) between mean serum insulin concentrations and mean glucose (dextrose) infusion rates for HRI delivered in the Rani Group during the Euglycemic clamp experiments. 
         FIG. 29  is a graph of mean insulin plasma concentration and glucose infusion rates vs time illustrating the PK-PD interactions between mean serum insulin concentrations and mean glucose (dextrose) infusion rates for HRI delivered in the SC Group during the Euglycemic clamp experiments. 
     
    
    
     DETAILED DESCRIPTION 
     Embodiments of the invention provide devices, systems and methods for delivering medications in to various locations in the body. As used herein, the term “medication” refers to a medicinal preparation in any form which can include drugs or other therapeutic agents as well as one or more pharmaceutical excipients. Many embodiments provide a swallowable device for delivering medication within the GI tract. Particular embodiments provide a swallowable device such as a capsule for delivering medications such as insulin or other glucose regulating agent for treating a glucose regulation disorder; or IgG or other antibody to the wall of the small intestine or other GI organ. As used herein, “GI tract” refers to the esophagus, stomach, small intestine, large intestine and anus, while “Intestinal tract” refers to the small and large intestine. Various embodiments of the invention can be configured and arranged for delivery of medication into the intestinal tract as well as the entire GI tract. In various embodiments, the delivery may be so configured so as to obtain one or more selectable pharmacokinetic parameters (e.g., T max , absolute bioavailability, relative bioavailability etc.) as well as a desired plasma drug concentration vs time profile as described in more detail below. As used herein, the terms “about” and “substantially” are intended to account for small differences. When used in conjunction with an event or circumstance, the terms can refer to instances in which the event or circumstance occurs precisely as well as instances in which the event or circumstance occurs to a close approximation. When used in conjunction with a numerical value (e.g., for a property, characteristic, dimension, pharmacokinetic parameter or other parameter) the terms can refer to a range of variation of less than or equal to ±10% of that numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%. means within 10% of a stated value for a, more preferably within 5% and still more preferably within 2%. 
     Referring now to  FIGS. 1-11 , an embodiment of a device  10  for the delivery of medication  100  to a delivery site DS in the gastro-intestinal tract such as the wall of the small intestine or surrounding tissue, comprises a capsule  20  including at least one guide tube  30 , one or more tissue penetrating members  40  positioned or otherwise advanceable in the at least one guide tube, a delivery member  50 , an actuating mechanism  60  and release element  70 . Medication  100 , also described herein as preparation  100 , typically comprises at least one drug or other therapeutic agent  101  and may include one or more pharmaceutical excipients known in the art. Collectively, one or more of delivery member  50  and mechanism  60  may comprise a means for delivery of medication  100  into a wall of the intestinal tract. Other delivery means contemplated herein include one or more expandable balloons (e.g., delivery balloon  172 ) or other expandable device/member described herein. 
     Device  10  can be configured for the delivery of liquid, semi-liquid or solid forms of medication  100  or all three. Solid forms of medication/preparation  100  can include one or more of powder, pellet or other shaped mass. Semi liquid forms can include a slurry or paste. Whatever the form, preparation  100  desirably has a shape and material consistency allowing the medication to be advanced out of the device, into the intestinal wall (or other luminal wall in the GI tract) and then degrade in the intestinal wall to release the drug or other therapeutic agent  101 . The material consistency can include one or more of the hardness, porosity and solubility of the preparation (in body fluids). The material consistency can be achieved by one or more of the following: i) the compaction force used to make the preparation; ii) the use of one or more pharmaceutical disintegrants known in the art; iii) use of other pharmaceutical excipients; iv) the particle size and distribution of the preparation (e.g., micronized particles); and v) use of micronizing and other particle formation methods known in the art. Suitable shapes for preparation  100  can include cylindrical, cubical, rectangular, conical, spherical, hemispherical and combinations thereof. Also, the shape can be selected so as to define a particular surface area and volume of preparation  100  and thus, the ratio between the two. The ratio of surface area to volume can in turn, be used to achieve a selected rate of degradation within the intestinal or other lumen wall within the GI tract. Larger ratios (e.g., larger amounts of surface area per unit volume) can be used to achieve faster rates of degradation and vice versa. In particular embodiments, the surface area to volume ratio can be in the range of about 1:1 to 100:1, with specific embodiments of 2:1, 5:1, 20:1, 25:1, 50:1 and 75:1. Preparation/medication  100  will typically be pre-packed within a lumen  44  of tissue penetrating members  40 , but can also be contained at another location within an interior  24  of capsule  20 , or in the case of a liquid or semi-liquid, within an enclosed reservoir  27 . The medication can be pre-shaped to fit into the lumen or packed for example, in a powder form. Typically, the device  10  will be configured to deliver a single drug  101  as part of medication  100 . However in some embodiments, the device  10  can be configured for delivery of multiple drugs  101  including a first second, or a third drug which can be compounded into a single or multiple medications  100 . For embodiments having multiple medications/drugs, the medications can be contained in separate tissue penetrating members  40  or within separate compartments or reservoirs  27  within capsule  20 . In another embodiment, a first dose  102  of medication  100  containing a first drug  101  can be packed into the penetrating member(s)  40  and a second dose  103  of medication  100  (containing the same or a different drug  101 ) can be coated onto the surface  25  of capsule as is shown in the embodiment of  FIG. 1 b   . The drugs  101  in the two doses of medication  102  and  103  can be the same or different. In this way, a bimodal pharmacokinetic release of the same or different drugs can be achieved. The second dose  103  of medication  100  can have an enteric coating  104  to ensure that it is released in the small intestine and achieve a time release of the medication  100  as well. Enteric coating  104  can include one or more enteric coatings described herein or known in the art. 
     A system  11  for delivery of medication  100  into the wall of the small intestine or other location within the GI tract, may comprise device  10 , containing one or more medications  100  for the treatment of a selected condition or conditions. In some embodiments, the system may include a hand held device  13 , described herein for communicating with device  10  as is shown in the embodiment of  FIG. 1 b   . System  11  may also be configured as a kit  14  including system  11  and a set of instructions for use  15  which are packaged in packaging  12  as is shown in the embodiment of  FIG. 1 c   . The instructions can indicate to the patient when to take the device  10  relative to one or more events such as the ingestion of a meal or a physiological measurement such as blood glucose, cholesterol, etc. In such embodiments, kit  14  can include multiple devices  10  containing a regimen of medications  100  for a selected period of administration, e.g., a day, week, or multiple weeks depending upon the condition to be treated. 
     Capsule  20  is sized to be swallowed and pass through the intestinal tract. The size can also be adjusted depending upon the amount of drug to be delivered as well as the patient&#39;s weight and adult vs. pediatric applications. Capsule  20  includes an interior volume  24  and an outer surface  25  having one or more apertures  26  sized for guide tubes  30 . In addition to the other components of device  10 , (e.g., the actuation mechanism etc.) the interior volume can include one or more compartments or reservoirs  27 . One or more portions of capsule  20  can be fabricated from various biocompatible polymers known in the art, including various biodegradable polymers which in a preferred embodiment can comprise PLGA (polylactic-co-glycolic acid). Other suitable biodegradable materials include various enteric materials described herein as well as lactide, glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone, trimethylene carbonate, caprolactone, blends and copolymers thereof. As is described in further detail herein, in various embodiments, capsule  20  can include seams  22  of bio-degradable material so as to controllably degrade into smaller pieces  23  which are more easily passed through the intestinal tract. Additionally, in various embodiments, the capsule can include various radio-opaque or echogenic materials for location of the device using fluoroscopy, ultrasound or other medical imaging modality. In specific embodiments, all or a portion of the capsule can include radio-opaque/echogenic markers  20   m  as is shown in the embodiment of  FIGS. 1 a  and 1 b   . In use, such materials not only allow for the location of device  10  in the GI tract, but also allow for the determination of transit times of the device through the GI tract. 
     In preferred embodiments, tissue penetrating members  40  are positioned within guide tubes  30  which serve to guide and support the advancement of members  40  into tissue such as the wall of the small intestine or other portion of the GI tract. The tissue penetrating members  40  will typically comprise a hollow needle or other like structure and will have a lumen  44  and a tissue penetrating end  45  for penetrating a selectable depth into the intestinal wall IW. Member  40  may also include a pin  41  for engagement with a motion converter  90  described herein. The depth of penetration can be controlled by the length of member  40 , the configuration of motion converter  90  described herein as well as the placement of a stop or flange  40   s  on member  40  which can, in an embodiment, correspond to pin  41  described herein. Medication  100  will typically be delivered into tissue through lumen  44 . In many embodiments, lumen  44  is pre-packed with the desired medication  100  which is advanced out of the lumen using delivery member  50  or other advancement means (e.g. by means of force applied to a collapsible embodiment of member  40 ). As an alternative, medication  100  can be advanced into lumen  44  from another location/compartment in capsule  20 . In some embodiments, all or a portion of the tissue penetrating member  40  can be fabricated from medication  100  itself. In these and related embodiments, the medication can have a needle or dart-like structure (with or without barbs) configured to penetrate and be retained in the intestinal wall, such as the wall of the small intestine. The dart can be sized and shaped depending upon the medication, dose and desired depth of penetration into the intestinal wall. Medication  100  can be formed into darts, pellets or other shapes using various compression molding methods known in the pharmaceutical arts. 
     In various embodiments, device  10  can include a second  42  and a third  43  tissue penetrating member  40  as is shown in the embodiments of  FIGS. 7 a  and 7 b   ., with additional numbers contemplated. Each tissue penetrating member  40  can be used to deliver the same or a different medication  100 . In preferred embodiments, the tissue penetrating members  40  can be substantially symmetrically distributed around the perimeter  21  of capsule  20  so as to anchor the capsule onto the intestinal wall IW during delivery of medications  100 . Anchoring capsule  20  in such a way reduces the likelihood that the capsule will be displaced or moved by peristaltic contractions occurring during delivery of the medication. In specific embodiments, the amount of anchoring force can be adjusted to the typical forces applied during peristaltic contraction of the small intestine. Anchoring can be further facilitated by configured some or all of tissue penetrating members  40  to have a curved or arcuate shape. 
     Delivery member  50  is configured to advance medication  100  through the tissue penetrating member lumen  44  and into the intestinal wall IW. Accordingly, at least a portion of the delivery member  50  is advanceable within the tissue penetrating member lumen  44  and thus member  50  has a size and shape (e.g., a piston like shape) configured to fit within the delivery member lumen  44 . 
     In some embodiments, the distal end  50   d  of the delivery member (the end which is advanced into tissue) can have a plunger element  51  which advances the medication within the tissue penetrating member lumen  44  and also forms a seal with the lumen. Plunger element  51  can be integral or attached to delivery member  50 . Preferably, delivery member  50  is configured to travel a fixed distance within the needle lumen  44  so as to deliver a fixed or metered dose of drug into the intestinal wall IW. This can be achieved by one or more of the selection of the diameter of the delivery member (e.g., the diameter can be distally tapered), the diameter of the tissue penetrating member (which can be narrowed at its distal end), use of a stop, and/or the actuating mechanism. However in some embodiments, the stroke or travel distance of member  50  can be adjusted in situ responsive to various factors such as one or more sensed conditions in the GI tract. In situ adjustment can be achieved through use of logic resource  29  (including controller  29   c ) coupled to an electro-mechanical embodiment of actuating mechanism  60 . This allows for a variable dose of medication and/or variation of the distance the medication is injected into the intestinal wall. 
     Actuating mechanism  60  can be coupled to at least one of the tissue penetrating member  40  or delivery member  50 . The actuating mechanism is configured to advance tissue penetrating member  40  a selectable distance into the intestinal wall IW as well as advance the delivery member to deliver medication  100  and then withdraw the tissue penetrating member from the intestinal wall. In various embodiments, actuating mechanism  60  can comprise a spring loaded mechanism which is configured to be released by release element  70 . Suitable springs  80  can include both coil (including conical shaped springs) and leaf springs with other spring structures also contemplated. In particular embodiments, spring  80  can be substantially cone-shaped to reduce the length of the spring in the compressed state even to the point where the compressed length of the spring is about the thickness of several coils (e.g., two or three) or only one coil. 
     In particular embodiments actuating mechanism  60  can comprise a spring  80 , a first motion converter  90 , and a second motion converter  94  and a track member  98  as is shown in the embodiments of  FIGS. 2, 4 and 8   a - 8   c . The release element  70  is coupled to spring  80  to retain the spring in a compressed state such that degradation of the release element releases the spring. Spring  80  may be coupled to release element  70  by a latch or other connecting element  81 . First motion converter  90  is configured to convert motion of spring  80  to advance and withdraw the tissue penetrating member  40  in and out of the intestinal wall or other tissue. The second motion converter  94  is configured to convert motion of the spring  80  to advance the delivery member  50  into the tissue penetrating member lumen  44 . Motion converters  90  and  94  are pushed by the spring and ride along a rod or other track member  98  which fits into a track member lumen  99  of converter  90 . The track member  98  serves to guide the path of the converters  90 . Converters  90  and  94  engage the tissue penetrating member  40  and/or delivery member  50  (directly or indirectly) to produce the desired motion. They have a shape and other characteristics configured to convert motion of the spring  80  along its longitudinal axis into orthogonal motion of the tissue penetrating member  40  and/or delivery member  50  though conversion in other directions is also contemplated. The motion converters can have a wedge, trapezoidal or curved shape with other shapes also contemplated. In particular embodiments, the first motion converter  90  can have a trapezoidal shape  90   t  and include a slot  93  which engages a pin  41  on the tissue penetrating member that rides in the slot as is shown in the embodiments of  FIGS. 2, 3 and 4 . Slot  93  can also have a trapezoidal shape  93   t  that mirrors or otherwise corresponds to the overall shape of converter  90 . Slot  93  serves to push the tissue penetrating member  40  during the upslope portion  91  of the trapezoid and then pull it back during the down slope portion  92 . In one variation, one or both of the motion converters  90  and  94  can comprise a cam or cam like device (not shown). The cam can be turned by spring  80  so as to engage the tissue penetrating and/or delivery members  40  and  50 . One or more components of mechanism  60  (as well as other components of device  10 ) including motion converters  90  and  94  can be fabricated using various MEMS-based methods known in the art so as to allow for selected amounts of miniaturization to fit within capsule  10 . Also as is described herein, they can be formed from various biodegradable materials known in the art. 
     In other variations, the actuating mechanism  60  can also comprise an electro-mechanical device/mechanism such as a solenoid or a piezoelectric device. In one embodiment, a piezoelectric device used in mechanism  60  can comprise a shaped piezoelectric element which has a non-deployed and deployed state. This element can be configured to go into the deployed state upon the application of a voltage and then return to the non-deployed state upon the removal of the voltage or other change in the voltage. This and related embodiments allow for a reciprocating motion of the actuating mechanism  60  so as to both advance the tissue penetrating member and then withdraw it. The voltage for the piezoelectric element can be obtained generated using a battery or a piezoelectric based energy converter which generates voltage by mechanical deformation such as that which occurs from compression of the capsule  20  by a peristaltic contraction of the small intestine around the capsule. Further description of piezoelectric based energy converters is found in U.S. patent application Ser. No. 12/556,524 which is fully incorporated by reference herein for all purposes. In one embodiment, deployment of tissue penetrating members  40  can in fact be triggered from a peristaltic contraction of the small intestine which provides the mechanical energy for generating voltage for the piezoelectric element. 
     Release element  70  will typically be coupled to the actuating mechanism  60  and/or a spring coupled to the actuating mechanism; however, other configurations are also contemplated. In preferred embodiments, release element  70  is coupled to a spring  80  positioned within capsule  20  so as to retain the spring in a compressed state  85  as shown in the embodiment of  FIG. 2 . Degradation of the release element  70  releases spring  80  to actuate actuation mechanism  60 . Accordingly, release element  70  can thus function as an actuator  70   a  (actuator  70  may also include spring  80  and other elements of mechanism  60 ). As is explained further below, release element  70 /actuator  70   a  has a first configuration where the therapeutic agent preparation  100  is contained within capsule  20  and a second configuration where the therapeutic agent preparation is advanced from the capsule into the wall of the small intestine or other luminal wall in the intestinal tract. 
     In many embodiments, release element  70  comprises a material configured to degrade upon exposure to chemical conditions in the small or large intestine such as pH. Typically, release element  70  is configured to degrade upon exposure to a selected pH in the small intestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6 8.0 or greater. The release element can also be configured to degrade within a particular range of pH such as, e.g., 7.0 to 7.5. In particular embodiments, the pH at which release element  70  degrades (defined herein as the degradation pH) can be selected for the particular drug to be delivered so as to release the drug at a location in small intestine which corresponds to the selected pH. Further, for embodiments of device  10  having multiple medications  100 , the device can include a first release element  70  (coupled to an actuating mechanism for delivering a first drug) configured to degrade at first pH and a second release element  70  (coupled to an actuating mechanism for delivering a second drug) configured to degrade at a second pH (with additional numbers of release elements contemplated for varying number of drugs). 
     Release element  70  can also be configured to degrade in response to other conditions in the small intestine (or other GI location). In particular embodiments, the release element  70  can be configured to degrade in response to particular chemical conditions in the fluids in the small intestine such as those which occur after ingestion of a meal (e.g., a meal containing fats, starches or proteins). In this way, the release of medication  100  can be substantially synchronized or otherwise timed with the digestion of a meal. 
     Various approaches are contemplated for biodegradation of release element  70 . In particular embodiments, biodegradation of release element  70  from one or more conditions in the small intestine (or other location in the GI tract) can be achieved by one or more of the following approaches: i) selection of the materials for the release element, ii) the amount of cross linking of those materials; and iii) the thickness and other dimensions of the release element. Lesser amounts of cross linking and or thinner dimensions can increase the rate of degradation and vice versa. Suitable materials for the release element can comprise biodegradable materials such as various enteric materials which are configured to degrade upon exposure to the higher pH in the intestines. Suitable enteric materials include, but are not limited to, the following: cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters as well as other enteric materials known in the art. The selected enteric materials can be copolymerized or otherwise combined with one or more other polymers to obtain a number of other particular material properties in addition to biodegradation. Such properties can include without limitation stiffness, strength, flexibility and hardness. 
     In alternative embodiments, the release element  70  can comprise a film or plug  70   p  that fits over or otherwise blocks guide tubes  30  and retains the tissue penetrating member  40  inside the guide tube. In these and related embodiments, tissue penetrating member  40  is coupled to a spring loaded actuating mechanism such that when the release element is degraded sufficiently, it releases the tissue penetrating member which then springs out of the guide tube to penetrate into the intestinal wall. In still other embodiments, release element  70  can be shaped to function as a latch which holds the tissue penetrating member  40  in place. In these and related embodiments, the release element can be located on the exterior or the interior of capsule  20 . In the latter case, capsule  20  and/or guide tubes  30  can be configured to allow for the ingress of intestinal fluids into the capsule interior to allow for the degradation of the release element. 
     In some embodiments, actuating mechanism  60  can be actuated by means of a sensor  67 , such as a pH sensor  68  or other chemical sensor which detects the presence of the capsule in the small intestine. Sensor  67  can then send a signal to actuating mechanism  60  or to an electronic controller  29   c  coupled to actuating mechanism  60  to actuate the mechanism. Embodiments of a pH sensor  68  can comprise an electrode-based sensor or it can be a mechanically-based sensor such as a polymer which shrinks or expands upon exposure to a selected pH or other chemical conditions in the small intestine. In related embodiments, an expandable/contractible sensor  67  can also comprise the actuating mechanism  60  itself by using the mechanical motion from the expansion or contraction of the sensor. 
     According to another embodiment for detecting that the device in the small intestine (or other location in the GI tract), sensor  67  can comprise pressure/force sensor such as strain gauge for detecting the number of peristaltic contractions that capsule  20  is being subject to within a particular location in the intestinal tract (in such embodiments capsule  20  is desirably sized to be gripped by the small intestine during a peristaltic contraction). Different locations within the GI tract have different number of peristaltic contractions. The small intestine has between 12 to 9 contractions per minute with the frequency decreasing down the length of the intestine. Thus, according to one or more embodiments, detection of the number of peristaltic contractions can be used to not only determine if capsule  20  is in the small intestine, but the relative location within the intestine as well. In use, these and related embodiments allow for release of medication  100  at a particular location in the small intestine. 
     As an alternative or supplement to internally activated drug delivery (e.g., using a release element and/or sensor), in some embodiments, the user may externally activate the actuating mechanism  60  to deliver medication  100  by means of RF, magnetic or other wireless signaling means known in the art. In these and related embodiments, the user can use a handheld communication device  13  (e.g., a hand held RF device such as a cell phone) as is shown in the embodiment of  FIG. 1 b   , to send a receive signals  17  from device  10 . In such embodiments, swallowable device may include a transmitter  28  such as an RF transceiver chip or other like communication device/circuitry. Handheld device  13  may not only includes signaling means, but also means for informing the user when device  10  is in the small intestine or other location in the GI tract. The later embodiment can be implemented through the use of logic resources  29  (e.g., a processor  29 ) coupled to transmitter  28  to signal to detect and singe to the user when the device is in the small intestine or other location (e.g., by signaling an input from the sensor). Logic resources  29  may include a controller  29   c  (either in hardware or software) to control one or more aspects of the process. The same handheld device can also be configured to alert the user when actuating mechanism  60  has been activated and the selected medication  100  delivered (e.g., using processor  29  and transmitter  28 ). In this way, the user is provided confirmation that medication  100  has been delivered. This allows the user to take other appropriate drugs/therapeutic agents as well as make other related decisions (e.g., for diabetics to eat a meal or not and what foods should be eaten). The handheld device can also be configured to send a signal to swallowable device  10  to over-ride actuating mechanism  60  and so prevent delay or accelerate the delivery of medication  100 . In use, such embodiments allow the user to intervene to prevent, delay or accelerate the delivery of medication, based upon other symptoms and/or patient actions (e.g., eating a meal, deciding to go to sleep, exercise etc.). The user may also externally activate actuating mechanism  60  at a selected time period after swallowing the capsule. The time period can be correlated to a typical transit time or range of transit times for food moving through the user&#39;s GI tract to a particular location in the tract such as the small intestine. 
     In particular embodiments, the capsule  20  can include seams  22  of biodegradable material which controllably degrade to break the capsule into capsule pieces  23  of a selectable size and shape to facilitate passage through the GI tract as is shown in the embodiment of  FIGS. 10 a  and 10 b   . Seams  22  can also include pores or other openings  22   p  for ingress of fluids into the seam to accelerate biodegradation as is shown in the embodiment of  FIG. 10 . Other means for accelerating biodegradation of seams  22  can include pre-stressing the seam and/or including perforations  22   f  in the seam as is also shown in the embodiment of  FIG. 10 . In still other embodiments, seam  22  can be constructed of materials and/or have a structure which is readily degraded by absorption of ultrasound energy, e.g. high frequency ultrasound (HIFU), allowing the capsule to be degraded into smaller pieces using externally or endoscopically (or other minimally invasive method) administered ultrasound. 
     Suitable materials for seams  22  can include one or more biodegradable materials described herein such as PLGA, glycolic acid etc. Seams  22  can be attached to capsule body  20  using various joining methods known in the polymer arts such as molding, hot melt junctions, etc. Additionally for embodiments of capsule  20  which are also fabricated from biodegradable materials, faster biodegradation of seam  22  can be achieved by one or more of the following: i) fabricating the seam from a faster biodegrading material, ii) pre-stressing the seam, or iii) perforating the seam. The concept of using biodegradable seams  22  to produce controlled degradation of a swallowable device in the GI tract can also be applied to other swallowable devices such as swallowable cameras (or other swallowable imaging device) to facilitate passage through the GI tract and reduce the likelihood of such a device becoming stuck in the GI tract. Accordingly, embodiments of biodegradable seam  22  can be adapted for swallowable imaging and other swallowable devices. 
     Another aspect of the invention provides methods for the delivery of drugs and other therapeutic agents (in the form of medication  100 ) into the walls of the GI tract using one or more embodiments of swallowable drug delivery device  10 . An exemplary embodiment of such a method will now be described. The described embodiment of drug delivery occurs in the small intestine SI. However, it should be appreciated that this is exemplary and that embodiments of the invention can be used for delivering drug in a number of locations in the GI tract including the stomach and the large intestine. For ease of discussion, the swallowable drug delivery device  10  will sometimes be referred to herein as a capsule. As described above, in various embodiments, device  10  may be packaged as a kit  11  within sealed packaging  12  that includes device  10  and a set of instructions for use  15 . If the patient is using a handheld device  13 , the patient may be instructed to enter data into device  13  either manually or via a bar code  18  (or other identifying indicia  18 ) located on the instructions  15  or packaging  12 . If a bar code is used, the patient would scan the bar code using a bar code reader  19  on device  13 . After opening packaging  12 , reading the instructions  15  and entering any required data, the patient swallows an embodiment of the swallowable drug delivery device  10 . Depending upon the drug, the patient may take the device  10  in conjunction with a meal (before, during or after) or a physiological measurement. Capsule  20  is sized to pass through the GI tract and travels through the patient&#39;s stomach S and into the small intestine SI through peristaltic action as embodied in device  10  as is shown in the embodiment of  FIG. 11 . Once in the small intestine, the release element  70  is degraded by the basic pH in the small intestine (or other chemical or physical condition unique to the small intestine) so as to actuate the actuating mechanism  60  and deliver medication  100  into the wall of the small intestine SI according to one or more embodiments of the invention. For embodiments including a hollow needle or other hollow tissue penetrating member  40 , medication delivery is effectuated by using the actuating mechanism  60  to advance the needle  40  a selected distance into the mucosa of the intestinal wall IS, and then the medication is injected through the needle lumen  40  by advancement of the delivery member  50 . The delivery member  50  is withdrawn and the needle  40  is then withdrawn back within the body of the capsule (e.g. by recoil of the spring) detaching from the intestinal wall. For embodiments of device  10  having multiple needles, a second or third needle  42 ,  43  can also be used to deliver additional doses of the same drug or separate drugs  101 . Needle advancement can be done substantially simultaneously or in sequence. In preferred embodiments that use multiple needles, needle advancement can be done substantially simultaneously so as to anchor device  10  in the small intestine during drug delivery. 
     After medication delivery, device  10  then passes through the intestinal tract including the large intestine LI and is ultimately excreted. For embodiments of the capsule  20  having biodegradable seams  22  or other biodegradable portions, the capsule is degraded in the intestinal tract into smaller pieces to facilitate passage through and excretion from the intestinal tract as is shown in the embodiments of  FIGS. 9 a  and 9 b   . In particular embodiments having biodegradable tissue penetrating needles/members  40 , should the needle get stuck in the intestinal wall, the needle biodegrades releasing the capsule  20  from the wall. 
     For embodiments of device  10  including a sensor  67 , actuation of mechanism  60  can be effectuated by the senor sending a signal to actuating mechanism  60  and/or a processor  29 /controller  29   c  coupled to the actuating mechanism. For embodiments of device  10  including external actuation capability, the user may externally activate actuating mechanism  60  at a selected time period after swallowing the capsule. The time period can be correlated to a typical transit time or range of transit times for food moving through the user&#39;s GI tract to a particular location in the tract such as the small intestine. 
     One or more embodiments of the above methods can be used for the delivery of preparations  100  containing therapeutically effective amounts of a variety of drugs and other therapeutic agents  101  to treat a variety of diseases and conditions. These include a number of large molecule peptides and proteins which would otherwise require injection due to chemical breakdown in the stomach. The dosage of the particular drug can be titrated for the patient&#39;s weight, age or other parameter. Also the dose of drug  101  to achieve a desired or therapeutic effect (e.g., insulin for blood glucose regulation) when delivered by one or more embodiments of the invention can be less than the amount required should the drug have been delivered by conventional oral delivery (e.g., a swallowable pill that is digested in the stomach and absorbed through the wall of the small intestine, stomach or other location in the GI tract). This is due to the fact that there is no degradation of the drug by acid 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 in the intestinal tract, e.g., large intestine, stomach, etc.). Depending upon the drug  101 , the dose  102  delivered in preparation  100  can be in the range from 100 to 5% of a dose delivered by conventional oral delivery (e.g., a pill) to achieve a desired therapeutic effect (e.g., blood glucose regulation, seizure regulation, etc.) with even lower amounts contemplated. The particular dose reduction can be titrated based upon the particular drug, the condition to be treated, and the patient&#39;s weight, age and condition. For some drugs (with known levels of degradation in the intestinal tract) a standard dose reduction can be employed (e.g., 10 to 20%). Larger amounts of dose reduction can be used for drugs which are more prone to degradation and poor absorption. In this way, the potential toxicity and other side effects (e.g., gastric cramping, irritable bowel, hemorrhage, etc.) of a particular drug or drugs delivered by device  10  can be reduced because the ingested dose is lowered. This in turn, improves patient compliance because the patient has reduction both in the severity and incidence of side effects. Additional benefits of embodiments employing dose reduction of drug  101  include a reduced likelihood for the patient to develop a tolerance to the drug (requiring higher doses) and, in the case of antibiotics, for the patient to develop resistant strains of bacteria. Also, other levels of dose reduction can be achieved for patients undergoing gastric bypass operations and other procedures in which sections of the small intestine have been removed or its working (e.g., digestive) length effectively shortened. 
     In addition to delivery of a single drug, embodiments of swallowable drug delivery device  10  and methods of their use can be used to deliver a plurality of drugs for the treatment of multiple conditions or for the treatment of a particular condition (e.g., protease inhibitors for treatment HIV AIDS). In use, such embodiments allow a patient to forgo the necessity of having to take multiple medications for a particular condition or conditions. Also, they provide a means for facilitating that a regimen of two or more drugs is delivered and absorbed into the small intestine and thus, the blood stream, at about the same time. Due to difference in chemical makeup, molecular weight, etc., drugs can be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves. Embodiments of the invention address this issue by injecting the desired drug mixtures at substantially the same time. This in turn, improves the pharmacokinetics and thus the efficacy of the selected mixture of drugs. Additionally, eliminating the need to take multiple drugs is particularly beneficial to patients who have one or more long term chronic conditions including those who have impaired cognitive or physical abilities. 
     In various applications, embodiments of the above methods can be used to deliver preparations  100  including drugs and therapeutic agents  101  to provide treatment for a number of medical conditions and diseases. The medical conditions and diseases which can be treated with embodiments of the invention can include without limitation: cancer, hormonal conditions (e.g., hypo/hyper thyroid, growth hormone conditions), osteoporosis, high blood pressure, elevated cholesterol and triglyceride, diabetes and other glucose regulation disorders, infection (local or septicemia), epilepsy and other seizure disorders, osteoporosis, coronary arrhythmias (both atrial and ventricular), coronary ischemia anemia or other like condition. Still other conditions and diseases are also contemplated. 
     In many embodiments, the treatment of the particular disease or condition can be performed without the need for injecting the drug or other therapeutic agent (or other non-oral form of delivery such as suppositories) but instead, relying solely on the therapeutic agent(s) that is delivered into the wall of the small intestine or other portion of the GI tract. Similarly, the patient need not take conventional oral forms of a drug or other therapeutic agent, but again rely solely on delivery into the wall of the small intestine using embodiments of the swallowable capsule. In other embodiments, the therapeutic agent(s) delivered into the wall of the small intestine (or other GI-tract organ wall) can be delivered in conjunction with an injected dose of the agent(s). For example, the patient may take a daily dose of therapeutic agent using the embodiments of the swallowable capsule, but only need take an injected dose every several days or when the patient&#39;s condition requires it (e.g., hyperglycemia). The same is true for therapeutic agents that are traditionally delivered in oral form (e.g., the patient can take the swallowable capsule and take the conventional oral form of the agent as needed). The dosages delivered in such embodiments (e.g., the swallowed and injected dose) can be titrated as needed (e.g., using standard dose response curve and other pharmacokinetic methods can be used to determine the appropriate dosages). Also, for embodiments using therapeutic agents that can be delivered by conventional oral means, the dose delivered using embodiments of the swallowable capsule can be titrated below the dosage normally given for oral delivery of the agent since there is little or no degradation of the agent within the stomach or other portion of the intestinal tract (herein again standard dose response curve and other pharmacokinetic methods can be applied). 
     Various groups of embodiments of preparation  100  containing one or more drugs or other therapeutic agents  101  for the treatment of various diseases and conditions will now be described with references to dosages. It should be appreciated that these embodiments, including the particular therapeutic agents and the respective dosages are exemplary and the preparation  100  can comprise a number of other therapeutic agents described herein (as well as those known in the art) that are configured for delivery into a luminal wall in the intestinal tract (e.g., the wall of the small intestine) or surrounding tissue (e.g., the peritoneal cavity) using various embodiments of device  10 . The dosages can be larger or smaller than those described and can be adjusted using one or more methods described herein or known in the art. In one group of embodiments, therapeutic agent preparation  100  can comprise a therapeutically effective dose of insulin for the treatment of diabetes and other glucose regulation disorders. The insulin can be human or synthetically derived as is known in the art. In one embodiment, preparation  100  can contain a therapeutically effective amount of insulin in the range of about 1-10 units (one unit being the biological equivalent of about 45.5 μg of pure crystalline insulin), with particular ranges of 2-4, 3-9, 4-9, 5-8 or 6-7. Larger ranges are also contemplated such as 1 to 25 units or 1-50 units. The amount of insulin in the preparation can be titrated based upon one or more of the following factors (herein, “glucose control titration factors”): i) the patient&#39;s condition (e.g., type 1 vs. type II diabetes; ii) the patients previous overall level of glycemic control; iii) the patient&#39;s weight; iv) the patient&#39;s age; v) the frequency of dosage (e.g., once vs. multiple times a day); vi) time of day (e.g., morning vs. evening); vii) particular meal (breakfast vs. dinner); vii) content/glycemic index of a particular meal (e.g., high fat/lipid and sugar content (e.g., foods causing a rapid rise in blood sugar) vs. low fat and sugar content; and viii) content of the patient&#39;s overall diet (e.g., amount of sugars and other carbohydrates, lipids and protein consumed daily). In use, various embodiments of the therapeutic preparation  100  comprising insulin or other therapeutic agent for the treatment of diabetes or other blood glucose disorder, to allow for improved control of blood glucose levels by delivering more precisely controlled dosages of insulin without requiring the patient to inject themselves. Also, the patient can swallow a device such as swallowable device  10 , or  110  (containing insulin and/or other therapeutic agent for the treatment of diabetes) at the same time as they take food such that insulin or other therapeutic is released into the blood stream from the small intestine at about the same time or close to the same time as glucose or other sugar in the food is released from the small intestine into the blood stream. This concurrent or otherwise time proximate release allows the insulin to act on various receptors (e.g., insulin receptors) to increase the uptake of glucose into muscle and other tissue just as blood glucose levels are starting to rise from absorption of sugars into the blood from the small intestine. 
     In another group of embodiments, therapeutic agent preparation  100  can comprise a therapeutically effective dose of one or more incretins for the treatment of diabetes and other glucose regulation disorders. Such incretins can include Glucagon like peptides 1 (GLP-1) and their analogues, and Gastric inhibitory peptide (GIP). Suitable GLP-1 analogues include exenatide, liraglutide, albiglutide and taspoglutide as well as their analogues, derivatives and other functional equivalents. In one embodiment preparation  100  can contain a therapeutically effective amount of exenatide in the range of about 1-10 μg, with particular ranges of 2-4, 4-6, 4-8 and 8-10 respectively. In another embodiment, preparation  100  can contain a therapeutically effective amount of liraglutide in the range of about 1-2 mg (milligrams), with particular ranges of 1.0 to 1.4, 1.2 to 1.6 and 1.2 to 1.8 mg respectively. One or more of the glucose control titration factors can be applied to titrate the dose ranges for exenatide, liraglutide or other GLP-1 analogue or incretin. 
     In yet another group of embodiments, therapeutic agent preparation  100  can comprise a combination of therapeutic agents for the treatment of diabetes and other glucose regulation disorders. Embodiments of such a combination can include for example, therapeutically effective doses of incretin and biguanide compounds. The incretin can comprise one or more GLP-1 analogues described herein, such as exenatide and the biguanide can comprise metformin (e.g., that available under the Trademark of GLUCOPHAGE® manufactured by Merck Sante S.A.S.) and its analogue, derivatives and other functional equivalents. In one embodiment, preparation  100  can comprise 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 a range of about 1 to 3 grams. Smaller and larger ranges are also contemplated with one or more of the glucose control titration factors used to titrate the respective dose of exenatide (or other incretin) and metformin or other biguanide. Additionally, the dosages of the exenatide or other incretin and metformin or other biguanide can be matched to improved level of glucose control for the patient (e.g., maintenance of blood glucose within normal physiological levels and/or a reduction in the incidence and severity of instances of hyperglycemia and/or hypoglycemia) for extended periods of time ranges from hours (e.g., 12) to a day to multiple days, with still longer periods contemplated. Matching of dosages can also be achieved by use of the glucose control regulation factors as well as monitoring of the patient&#39;s blood glucose for extended periods using glycosylated hemoglobin (known as hemoglobin A1c, HbA1c, A1C, or Hb1c) and other analytes and measurements correlative to long term average blood glucose levels. 
     Drug delivery compositions and components of known drug delivery systems may be employed and/or modified for use in some embodiments of the inventions described herein. For example, micro-needles and other microstructures used for delivery of drugs through the skin surface with drug patches may be modified and included within the capsules described herein and used to instead deliver a drug preparation into a lumen wall of the gastrointestinal tract such as the wall of the small intestine. Suitable polymer micro-needle structures may be commercially available from Corium of California, such as the MicroCor™ micro delivery system technology. Other components of the MicroCor™ patch delivery systems, including drug formulations or components, may also be incorporated into the capsules described herein. Alternatively, a variety of providers are commercially available to formulate combinations of polymers or other drug-delivery matrices with selected drugs and other drug preparation components so as to produce desired shapes (such as the releasable tissue-penetrating shapes described herein) having desirable drug release characteristics. Such providers may, for example, include Corium, SurModics of Minnesota, BioSensors International of Singapore, or the like. 
     One advantage and feature of various embodiments of the therapeutic compositions described herein is that the biologic drug payload (e.g., a therapeutic peptide or protein, e.g., IgG and other antibodies, basal and other types of insulin etc.) is protected from degradation and hydrolysis by the action of peptidases and proteases in the gastrointestinal (GI) tract. These enzymes are ubiquitous throughout living systems. The GI tract is especially rich in proteases whose function is to break down the complex proteins and peptides in one&#39;s diet into smaller segments and release amino acids which are then absorbed from the intestine. The compositions described herein are designed to protect the therapeutic peptide or protein from the actions of these GI proteases and to deliver the peptide or protein payload directly into the wall of the intestine. There are two features in various embodiments of the compositions described herein which serve to protect the protein or peptide payload from the actions of GI proteases. First, in certain embodiments, the capsule shell, which contains the deployment engine and machinery, does not dissolve until it reaches the duodenal and sub-duodenal intestinal segments, owing to the pH-sensitive coating on the outer surface of the capsule which prevents its dissolution in the low pH of the stomach. Second, in certain embodiments, hollow maltose (or other appropriate polymer) micro-spears contain the actual therapeutic peptide or protein; the maltose (or other polymer) micro-spears are designed to penetrate the intestine muscle as soon as the outer capsule shell dissolves; and the micro-spears themselves slowly dissolve in the intestinal muscle wall to release the drug payload. Thus, the peptide or protein payload is not exposed to the actions of the GI proteases and therefore does not undergo degradation via proteolysis in the GI tract. This feature, in turn, contributes to the high % bioavailability of the therapeutic peptide or protein. 
     As discussed above, embodiments described herein include therapeutic compositions comprising insulin, for the treatment of various disorders such as diabetes or other glucose regulation disorder. Such compositions result in the delivery of insulin with desirable pharmacokinetic properties. In this regard, pharmacokinetic metrics of note include C max , the peak plasma concentration of insulin after administration; T max , the time to reach C max ; and T 1/2 , the time required for the plasma concentration of insulin to reach half its C max  value after having reached C max . These metrics can be measured using standard pharmacokinetic measurement techniques known in the art. In one approach plasma samples may be taken at set time intervals (e.g., one minute, five minutes, ½ hour, 1 hour, etc.) beginning and then after administration of the therapeutic composition either by use of a swallowable device or by non-vascular injection (e.g., subcutaneous injection). The concentration of insulin in plasma can then be measured using one or more appropriate analytical methods such as GC-Mass Spec, LC-Mass Spec, HPLC or various ELISA (Enzyme-linked immunosorbent assays) which can be adapted for the particular drug. A concentration vs. time curve (also herein referred to as a concentration profile) can then be developed using the measurements from the plasma samples. The peak of the concentration curve corresponds to C max  and the time at which this occurs corresponds to T max . The time in the curve where the concentration reaches half its maximum value (i.e., C max ) after having reached C max  corresponds to t 1/2  this value is also known as the elimination half-life of therapeutic agent. The start time for determination of C max  can be based on the time at which the injection is made for the case on non-vascular injection and the point in time at which embodiments of the swallowable device advances one or more tissue penetrating members (containing the drug) into the small intestine or other location in the GI tract (e.g., the large intestine). In the latter case, this time can determined using one or means including a remote controlled embodiment of the swallowable device which deploys the tissue penetrating members into the intestine wall and/or into surrounding tissue in response to an external control signal (e.g., an RF signal) or for an embodiment of the swallowable device which sends an RF or other signal detectable outside the body when the tissue penetrating members have been deployed. Other means for detection of tissue penetrating member deployment into the small intestine are contemplated such as one more medical imaging modalities including for example, ultrasound or fluoroscopy. In any one of these studies, appropriate animal models can be used for example, dog, pig, rat etc. in order to model the human pharmacokinetic response. 
     The embodiments described herein include therapeutic compositions comprising insulin for the treatment of diabetes or other glucose regulation disorder. Such compositions result in the delivery of insulin with desirable pharmacokinetic properties. In this regard, pharmacokinetic metrics of note include C max , the peak plasma concentration of a drug after administration; T max , the time to reach C max ; and t 1/2 , the time required for the plasma concentration of the drug to reach half its original value. 
     Thus, one embodiment provides a therapeutic composition comprising insulin, the composition adapted for insertion into a gastro-intestinal wall (e.g., the small intestine) after oral ingestion, wherein upon insertion, the composition releases insulin into the bloodstream from the intestinal wall to achieve a C max  faster than an extravascularly injected dose of insulin. In various embodiments, the therapeutic insulin composition has a T max  which is about 80%, or 50%, or 30%, or 20%, or 10% of a T max  for an extravascularly injected does of insulin. Such an extravascularly injected dose of insulin can be, for example, a subcutaneous injection or an intramuscular injection. In certain embodiments the C max  attained by delivering the therapeutic insulin composition by insertion into the intestinal wall (e.g., the wall of the small intestine) is substantially greater, such as 100, or 50, or 10, or 5 times greater, than the C max  attained when the composition is delivered orally without insertion into the intestinal wall. In some embodiments, the therapeutic insulin composition is configured to produce a long-term release of insulin, such as a long-term release of insulin with a selectable T 1/2 . For example, the selectable T 1/2  may be 6, or 9, or 12, or 15 or 18, or 24 hours. 
     The various embodiments described herein provide a therapeutic agent composition (also referred to herein as a preparation or composition) comprising insulin. The composition is adapted for insertion into an intestinal wall after oral ingestion, wherein upon insertion, the composition releases insulin into the bloodstream from the intestinal wall to achieve a C max  faster than an extravascularly injected dose of the therapeutic agent that is to say, achieving a C max  for the inserted form of therapeutic agent in a shorter time period (e.g., a smaller T max ) than that for a dose of the therapeutic agent that is injected extravascularly. Note, that the dose of therapeutic agent in the composition delivered into the intestinal wall and the dose delivered by extravascular injection, may, but need not, be comparable to achieve these results. In various embodiments, the composition is configured to achieve a T max  for the insulin (e.g., by release of the insulin into the bloodstream from the intestinal wall, e.g., that of the small intestine) which is about 80%, or 50%, or 30%, or 20%, or 10% of a T max  for an extravascularly injected dose of the insulin. Such an extravascularly injected dose of insulin can be, for example, a subcutaneous injection or an intramuscular injection. In certain embodiments, the C max  attained by delivering the therapeutic agent by insertion into the intestinal wall is substantially greater, such as 5, 10, 20, 30, 40, 50, 60, 70, 80 or even a 100 times greater, than the C max  attained when the therapeutic agent is delivered orally without insertion into the intestinal wall for example by a pill other convention oral form of the therapeutic agent or related compound. In some embodiments, the therapeutic insulin composition is configured to produce a long-term release of insulin. Also, the composition can be configured to produce a long-term release of insulin with a selectable t 1/2 . For example, the selectable t 1/2  may be 6, or 9, or 12, or 15 or 18, or 24 hours. 
     In some embodiments, the therapeutic agent composition may also include a therapeutically effective dose of an incretin for the treatment of diabetes or a glucose regulation disorder. Incretins which can be used include a glucagon-like peptide-1 (GLP-1), a GLP-1 analogue or a gastric inhibitory peptide (GIP). Exemplary GLP-1 analogues include exenatide, liraglutide, albiglutide and taspoglutide. Any appropriate dose of an incretin may be used; for example, exenatide may be used in a dose ranging from about 1 to 10 micrograms; or liraglutide may be used in a range from about 1 to 2 mg. 
     Various embodiments also provide an insulin composition adapted for insertion into an gastro-intestinal wall (e.g., the wall of the small intestine or stomach) after oral ingestion, wherein upon insertion, the composition releases the therapeutic agent into the blood stream from the intestinal wall to achieve a t 1/2  that is greater than a T 1/2  for an orally ingested dose of the therapeutic agent that is not inserted into the intestinal wall. For example, the t 1/2  of the dose inserted into the intestinal wall may be 100 or 50 or 10 or 5 times greater than the dose that is not inserted into the intestinal wall. 
     The insulin composition may be in solid form, such as a solid form composition configured to degrade in the intestinal wall, and the solid form composition may have, for example, a tissue penetrating feature such as a pointed tip. The insulin composition may comprise at least one biodegradable material and/or may comprise at least one pharmaceutical excipient, including a biodegradable polymer such as PLGA or a sugar such as maltose. 
     The insulin composition may be adapted to be orally delivered in a swallowable capsule. In certain embodiments such a swallowable capsule may be adapted to be operably coupled to a mechanism having a first configuration and a second configuration, the therapeutic insulin composition being contained within the capsule in the first configuration and advanced out of the capsule and into the intestinal wall in the second configuration. Such an operably coupled mechanism may comprise at least one of an expandable member, an expandable balloon, a valve, a tissue penetrating member, a valve coupled to an expandable balloon, or a tissue penetrating member coupled to an expandable balloon. 
     In some embodiments, the insulin composition may be configured to be delivered within a lumen or other cavity of a tissue penetrating member and/or the therapeutic composition may be shaped as a tissue penetrating member advanceable into the intestinal wall. The tissue penetrating member may be sized to be completely contained within the intestinal wall, and/or it may include a tissue penetrating feature for penetrating the intestinal wall, and/or it may include a retaining feature for retaining the tissue penetrating member within the intestinal wall. The retaining feature may comprise, for example, a barb. In some embodiments, the tissue penetrating member is configured to be advanced into the intestinal wall by the application of a force to a surface of the tissue penetrating member and, optionally, the tissue penetrating member has sufficient stiffness to be advanced completely into the intestinal wall and/or the surface of the penetrating member is configured to be operatively coupled to an expandable balloon which applies the force upon expansion and/or the tissue penetrating member is configured to detach from a structure applying the force when a direction of the force changes. 
     Various aspects of the invention also provide other embodiments of a swallowable delivery device for the delivery of medication  100  in addition to those described above. According to one or more such embodiments, the swallow delivery device can include one or more expandable balloons or other expandable devices for use in delivering one or more tissue penetrating members including medication  100  into the wall of an intestine, such as the small intestine. Referring now to  FIGS. 12-20 , another embodiment of a device  110  for the delivery of medication  100  to a delivery site DS in the gastro-intestinal (GI) tract, can comprise a capsule  120  to be swallowed and pass through the intestinal tract, a deployment member  130 , one or more tissue penetrating members  140  containing medication  100 , a deployable aligner  160  and a delivery mechanism  170 . In some embodiments, medication  100  (also referred to herein as preparation  100 ) may itself comprise tissue penetrating member  140 . The deployable aligner  160  is positioned within the capsule and configured to align the capsule with the intestine such as the small intestine. Typically, this will entail aligning a longitudinal axis of the capsule with a longitudinal axis of the intestine; however, other alignments are also contemplated. The delivery mechanism  170  is configured for delivering medication  100  into the intestinal wall and will typically include a delivery member  172  such as an expandable member. The deployment member  130  is configured for deploying at least one of the aligner  160  or the delivery mechanism  170 . As will be described further herein, all or a portion of the capsule wall is degradable by contact with liquids in the GI tract so as to allow those liquids to trigger the delivery of medication  100  by device  110 . As used herein, “GI tract” refers to the esophagus, stomach, small intestine, large intestine and anus, while “Intestinal tract” refers to the small and large intestine. Various embodiments of the invention can be configured and arranged for delivery of medication  100  into both the intestinal tract as well as the entire GI tract. 
     Device  110  including tissue penetrating member  140  can be configured for the delivery of liquid, semi-liquid or solid forms of medication  100  or combinations of all three. Whatever the form, medication  100  desirably has a material consistency allowing the medication to be advanced out of device  110 , into the intestinal wall (e.g. the small or large intestine) or other luminal wall in the GI tract and then degrade within the intestinal wall to release the drug or other therapeutic agent  101 . The material consistency of medication  100  can include one or more of the hardness, porosity and solubility of the preparation (in body fluids). The material consistency can be achieved by selection and use of one or more of the following: i) the compaction force used to make the preparation; ii) the use of one or more pharmaceutical disintegrants known in the art; iii) use of other pharmaceutical excipients; iv) the particle size and distribution of the preparation (e.g., micronized particles); and v) use of micronizing and other particle formation methods known in the art. 
     Capsule  120  is sized to be swallowed and pass through the intestinal tract. The size may be adjusted depending upon the amount of drug to be delivered as well as the patient&#39;s weight and adult vs. pediatric applications. Typically, the capsule will have a tubular shape with curved ends similar to a vitamin or capsule shape. In these and related embodiments, capsule lengths  120 L can be in the range of 0.5 to 2 inches and diameters  120 D in the range of 0.1 to 0.5 inches with other dimensions contemplated. The capsule  120  includes a capsule wall  121   w , having an exterior surface  125  and an interior surface  124  defining an interior space or volume  124   v . In some embodiments, the capsule wall  121   w  can include one or more apertures  126  sized for the outward advancement of tissue penetrating members  140 . In addition to the other components of device  110 , (e.g., the expandable member etc.) the interior volume can include one or more compartments or reservoirs  127 . 
     The capsule can be fabricated from various biodegradable gelatin materials known in the pharmaceutical arts, but can also include various enteric coatings  120   c , configured to protect the cap from degradation in the stomach (due to acids etc.), and then subsequently degrade in the in higher pH&#39;s found in the small intestine or other area of the intestinal tract. In various embodiments, the capsule  120  can be formed from multiple portions one or more of which may be biodegradable. In many embodiments, capsule  120  can be formed from two portions  120   p  such as a body portion  120   p ″ (herein body  120   p ″) and a cap portion  120   p ′ (herein cap  120   p ), where the cap fits onto the body, e.g., by sliding over or under the body (with other arrangements also contemplated). One portion such as the cap  120   p ′ can include a first coating  120   c ′ configured to degrade above a first pH (e.g., pH 5.5) and the second portion such as the body  120   p ″ can include a second coating  120   c ″ configured to degrade above a second higher pH (e.g. 6.5). Both the interior  124  and exterior  125  surfaces of capsule  120  are coated with coatings  120   c ′ and  120   c ″ so that that either portion of the capsule will be substantially preserved until it contacts fluid having the selected pH. For the case of body  120   p ″ this allows the structural integrity of the body  120   p ″ to be maintained so as to keep balloon  172  inside the body portion and not deployed until balloon  130  has expanded. Coatings  120   c ′ and  120   c ″ can include various methacrylate and ethyl acrylate based coatings such as those manufactured by Evonik Industries under the trade name EUDRAGIT. These and other dual coating configurations of the capsule  120  allows for mechanisms in one portion of capsule  120  to be actuated before those in the other portion of the capsule. This is due to the fact that intestinal fluids will first enter those portions where the lower pH coating has degraded thus actuating triggers which are responsive to such fluids (e.g., degradable valves). In use, such dual coating embodiments for capsule  120  provide for targeted drug delivery to a particular location in the small intestine (or other location in the GI tract), as well as improved reliability in the delivery process. This is due to the fact that deployment of a particular component, such as aligner  160 , can be configured to begin in the upper area of the small intestine (e.g., the duodenum) allowing the capsule to be aligned within the intestine for optimal delivery of the drug (e.g., into the intestinal wall) as well as providing sufficient time for deployment/actuation of other components to achieve drug delivery into the intestinal wall while the capsule is still in the small intestine or other selected location. 
     As is discussed above, one or more portions of capsule  120  can be fabricated from various biocompatible polymers known in the art, including various biodegradable polymers which in a preferred embodiment can comprise cellulose, gelatin materials PLGA (polylactic-co-glycolic acid). Other suitable biodegradable materials include various enteric materials described herein as well as lactide, glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone, trimethylene carbonate, caprolactone, blends and copolymers thereof. 
     In various embodiments, the wall  120   w  of the capsule is degradable by contact with liquids in the GI tract for example liquids in the small intestine. In preferred embodiments, the capsule wall is configured to remain intact during passage through the stomach, but then to be degraded in the small intestine. In one or more embodiments, this can be achieved by the use of an outer coating or layer  120   c  on the capsule wall  120   w , which only degrades in the higher pH&#39;s found in the small intestine and serves to protect the underlying capsule wall from degradation within the stomach before the capsule reaches the small intestine (at which point the drug delivery process is initiated by degradation of the coating as is described herein). In use, such coatings allow for the targeted delivery of a therapeutic agent in a selected portion of the intestinal tract such as the small intestine. 
     Similar to capsule  20 , in various embodiments, capsule  120  can include various radio-opaque, echogenic or other materials for location of the device using one or more medical imaging modalities such as fluoroscopy, ultrasound, MM, etc. 
     As is discussed further herein, in many embodiments, one or more of the deployment member  130 , delivery member  172  or deployable aligner  160 , may correspond to an expandable balloon that is shaped and sized to fit within capsule  120 . Accordingly, for ease of discussion, deployment member  130 , delivery member  172  and deployable aligner  160  will now be referred to as balloon  130 ,  160  and  172 ; however, it should be appreciated that other devices including various expandable devices are also contemplated for these elements and may include for example, various shape memory devices (e.g., an expandable basket made from shape memory biodegradable polymer spires), expandable piezo electric devices, and/or chemically expandable devices having an expanded shape and size corresponding to the interior volume  124   v  of the capsule  120 . 
     One or more of balloons  130 ,  160  and  172  can comprise various polymers known in the medical device arts. In preferred embodiments such polymers can comprise one or more types of polyethylene (PE) which may correspond to low density PE (LDPE), linear low density PE (LLDPE), medium density PE (MDPE) and high density PE (HDPE) and other forms of polyethylene known in the art. In one more embodiments using polyethylene, the material may be cross-linked using polymer irradiation methods known in the art so. In particular embodiments radiation-based cross-linking may be used as to control the inflated diameter and shape of the balloon by decreasing the compliance of the balloon material. The amount or radiation may be selected to achieve a particular amount of cross linking to in turn produce a particular amount of compliance for a given balloon, e.g., increased irradiation can be used to produce stiffer less compliant balloon material. Other suitable polymers can include PET (polyethylene teraphalate), silicone and polyurethane. In various embodiments balloons  130 ,  160  and  172  may also include various radio-opaque materials known in the art such as barium sulfate to allow the physician to ascertain the position and physical state of the balloon (e.g., un-inflated, inflated or punctures. Balloons  130 ,  160  and  172  can be fabricated using various balloon blowing methods known in the balloon catheters arts (e.g., mold blowing, free blowing, etc.) to have a shape and size which corresponds approximately to the interior volume  124   v  of capsule  120 . In various embodiments one or more of balloons  130 ,  160  and  172  and various connecting features (e.g., connecting tubes) can have a unitary construction being formed from a single mold. Embodiments employing such unitary construction provide the benefit of improved manufacturability and reliability since fewer joints must be made between one or more components of device  110 . 
     Suitable shapes for balloons  130 ,  160  and  172  include various cylindrical shapes having tapered or curved end portions (an example of such a shape including a hot dog). In some embodiments, the inflated size (e.g., diameter) of one or more of balloons  130 ,  160  and  172 , can be larger than capsule  120  so as to cause the capsule to come apart from the force of inflation, (e.g., due to hoop stress). In other related embodiments, the inflated size of one or more of balloons  130 ,  160  and  172  can be such that when inflated: i) the capsule  120  has sufficient contact with the walls of the small intestine so as to elicit a peristaltic contraction causing contraction of the small intestine around the capsule, and/or ii) the folds of the small intestine are effaced to allow. Both of these results allow for improved contact between the capsule/balloon surface and the intestinal wall so as deliver tissue penetrating members  40  over a selected area of the capsule and/or delivery balloon  172 . Desirably, the walls of balloons  130 ,  160  and  172  will be thin and can have a wall thickness in the range of 0.005 to 0.0001″ more preferably, in the range of 0.005 to 0.0001, with specific embodiments of 0.004, 0.003, 0.002, 0.001, and 0.0005). Additionally in various embodiments, one or more of balloon  130 ,  160  or  172  can have a nested balloon configuration having an inflation chamber  160 IC and extended finger  160 EF as is shown in the embodiments of  FIG. 13 c   . The connecting tubing  163 , connecting the inflation chamber  160 IC can be narrow to only allow the passage of gas  168 , while the connecting tubing  36  coupling the two halves of balloon  130  can be larger to allow the passage of water. 
     As indicated above, the aligner  160  will typically comprise an expandable balloon and for ease of discussion, will now be referred to as aligner balloon  160  or balloon  160 . Balloon  160  can be fabricated using materials and methods described above. It has an unexpanded and expanded state (also referred to as a deployed state). In its expanded or deployed state, balloon  160  extends the length of capsule  120  such that forces exerted by the peristaltic contractions of the small intestine SI on capsule  120  serve to align the longitudinal axis  120 LA of the capsule  120  in a parallel fashion with the longitudinal axis LAI of the small intestine SI. This in turn serves to align the shafts of tissue penetrating members  140  in a perpendicular fashion with the surface of the intestinal wall IW to enhance and optimize the penetration of tissue penetrating members  140  into the intestinal wall IW. In addition to serving to align capsule  120  in the small intestine, aligner  160  is also configured to push delivery mechanism  170  out of capsule  120  prior to inflation of delivery balloon  172  so that the delivery balloon and/or mechanism is not encumbered by the capsule. In use, this push out function of aligner  160  improves the reliability for delivery of the therapeutic agent since it is not necessary to wait for particular portions of the capsule (e.g., those overlying the delivery mechanism) to be degraded before drug delivery can occur. 
     Balloon  160  may be fluidically coupled to one or more components of device  110  including balloons  130  and  172  by means of polymer tube or other fluidic couplings  162  which may include a tube  163  for coupling balloons  160  and  130  and a tube  164  for coupling balloon  160  and balloon  172 . Tube  163  is configured to allow balloon  160  to be expanded/inflated by pressure from balloon  130  (e.g., pressure generated the mixture of chemical reactants within balloon  130 ) and/or otherwise allow the passage of liquid between balloons  130  and  160  to initiate a gas generating chemical reaction for inflation of one or both of balloons  130  and  160 . Tube  164  connects balloon  160  to  172  so as to allow for the inflation of balloon  172  by balloon  160 . In many embodiments, tube  164  includes or is coupled to a control valve  155  which is configured to open at a selected pressure so as to control the inflation of balloon  172  by balloon  160 . Tube  164  may thus comprise a proximal portion  164   p  connecting to the valve and a distal portion  164   d  leading from the valve. Typically, proximal and distal portions  164   p  and  164   d  will be connected to a valve housing  158  as is described below. 
     Valve  155  may comprise a triangular or other shaped section  156  of a material  157  which is placed within a the chamber  158   c  of a valve housing  158  (alternately, it may be placed directly within tubing  164 ). Section  157  is configured to mechanically degrade (e.g., tears, shears, delaminates, etc.) at a selected pressure so as to allow the passage of gas through tube  164  and/or valve chamber  158   c . Suitable materials  157  for valve  155  can include bees wax or other form of wax and various adhesives known in the medical arts which have a selectable sealing force/burst pressure. Valve fitting  158  will typically comprise a thin cylindrical compartment (made from biodegradable materials) in which section  156  of material  157  is placed (as is shown in the embodiment of  FIG. 13 b   ) so as to seal the walls of chamber  158   c  together or otherwise obstruct passage of fluid through the chamber. The release pressure of valve  155  can be controlled through selection of one or more of the size and shape of section  156  as well as the selection of material  157  (e.g., for properties such as adhesive strength, shear strength etc.). In use, control valve  155  allows for a sequenced inflation of balloon  160  and  172  such that balloon  160  is fully or otherwise substantially inflated before balloon  172  is inflated. This, in turn, allows balloon  160  to push balloon  172  along with the rest of delivery mechanism  170  out of capsule  120  (typically from body portion  120   p ′) before balloon  172  inflates so that deployment of tissue penetrating members  140  is not obstructed by capsule  120 . In use, such an approach improves the reliability of the penetration of tissue penetrating members  140  into intestinal wall IW both in terms of achieving a desired penetration depth and delivering greater numbers of the penetrating members  140  contained in capsule  120  since the advancement of the members into intestinal wall IW is not obstructed by capsule wall  120   w.    
     As is describe above, the inflated length  1601  of the aligner balloon  160  is sufficient to have the capsule  120  become aligned with the lateral axis of the small intestine from peristaltic contractions of the intestine. Suitable inflated lengths  1601  for aligner  160  can include a range between about ½ to two times the length  1201  of the capsule  120  before inflation of aligner  160 . Suitable shapes for aligner balloon  160  can include various elongated shapes such as a hotdog like shape. In specific embodiments, balloon  160  can include a first section  160 ′ and a second section  160 ″, where expansion of first section  160 ′ is configured to advance delivery mechanism  170  out of capsule  120  (typically out of and second section  160 ″ is used to inflate delivery balloon  172 . In these and related embodiments, first and second sections  160 ′ and  160 ″ can be configured to have a telescope-style inflation where first section  160 ′ inflates first to push mechanism  170  out of the capsule (typically from body portion  120   p ′) and second section  160 ″ inflates to inflate delivery member  172 . This can be achieved by configuring first section  160 ′ to have smaller diameter and volume than second section  160 ″ such that first section  160 ′ inflates first (because of its smaller volume) and with second section  160 ″ not inflating until first section  60 ′ has substantially inflated. In one embodiment, this can be facilitated by use of a control valve  155  (described above) connecting sections  160 ′ and  160 ″ which does not allow passage of gas into section  160 ″ until a minimum pressure has been reached in section  160 ′. In some embodiments, the aligner balloon can contain the chemical reactants which react upon mixture with water or other liquid from the deploying balloon. 
     In many embodiments, the deployment member  130  will comprise an expandable balloon, known as the deployment balloon  130 . In various embodiments, deployment balloon  30  is configured to facilitate deployment/expansion of aligner balloon  160  by use of a gas, for example, generation of a gas  169  from a chemical. The gas may be generated by the reaction of solid chemical reactants  165 , such as an acid  166  (e.g., citric acid) and a base  166  (e.g., potassium bicarbonate, sodium bicarbonate and the like) which are then mixed with water or other aqueous liquid  168 . The amount of reactants can be chosen using stoichiometric methods to produce a selected pressure in one or more of balloons  130 ,  160  and  72 . The reactants  165  and liquids can be stored separately in balloon  130  and  160  and then brought together in response to a trigger event, such as the pH conditions in the small intestine. The reactants  165  and liquids  168  can be stored in either balloon, however in preferred embodiments, liquid  168  is stored in balloon  130  and reactants  165  in balloon  160 . To allow for passage of the liquid  168  to start the reaction and/or the resulting gas  169 , balloon  130  may be coupled to aligner balloon  160  by means of a connector tube  163  which also typically includes a separation means  150  such as a degradable valve  150  described below. For embodiments where balloon  130  contains the liquid, tube  163  has sufficient diameter to allow for the passage of sufficient water from balloon  130  to balloon  60  to produce the desired amount of gas to inflate balloon  160  as well inflate balloon  172 . Also when balloon  130  contains the liquid, one or both of balloon  30  and tube  63  are configured to allow for the passage of liquid to balloon  160  by one or more of the following: i) the compressive forced applied to balloon  130  by peristaltic contractions of the small intestine on the exposed balloon  130 ; and ii) wicking of liquid through tube  163  by capillary action. 
     Tube  163  will typically include a degradable separation valve or other separation means  150  which separates the contents of balloon  130 , (e.g., water  158 ) from those of balloon  160  (e.g., reactants  165 ) until the valve degrades. Valve  150  can be fabricated from a material such as maltose, which is degradable by liquid water so that the valve opens upon exposure to water along with the various liquids in the digestive tract. It may also be made from materials that are degradable responsive to the higher pH&#39;s found in the intestinal fluids such as methacrylate based coatings. The valve is desirably positioned at location on tube  163  which protrudes above balloon  130  and/or is otherwise sufficient exposed such that when cap  120   p ′ degrades the valve  150  is exposed to the intestinal liquids which enter the capsule. In various embodiments, valve  150  can be positioned to lie on the surface of balloon  130  or even protrude above it (as is shown in the embodiments of  FIGS. 16 a  and 16 b   ), so that is has clear exposure to intestinal fluids once cap  120   p ′ degrades. Various embodiments of the invention provide a number of structures for a separation valve  150 , for example, a beam like structure (where the valve comprises a beam that presses down on tube  163  and/or connecting section  136 ), or collar type structure (where the valve comprise a collar lying over tube  163  and/or connecting section  136 ). Still other valve structures are also contemplated. 
     Balloon  130  has a deployed and a non-deployed state. In the deployed state, the deployment balloon  130  can have a dome shape  130   d  which corresponds to the shape of an end of the capsule. Other shapes  130   s  for the deployed balloon  130  are also contemplated, such as spherical, tube-shape, etc. The reactants  165  will typically include at least two reactants  166  and  167 , for example, an acid such as citric acid and a base such as sodium bicarbonate. Other reactants  165  including other acids, e.g., ascetic acid and bases, e.g., sodium hydroxide are also contemplated. When the valve or other separation means  150  opens, the reactants mix in the liquid and produce a gas such as carbon dioxide which expands the aligner balloon  160  or other expandable member. 
     In an alternative embodiment shown in  FIG. 13 b   , the deployment balloon  130  can actually comprise a first and second balloon  130 ′ and  130 ″ connected by a tube  36  or other connection means  136  (e.g., a connecting section). Connecting tube  136  will typically include a separation valve  150  that is degradable by a liquid as described above and/or a liquid having a particular pH such as basic pH found in the small intestine (e.g., 5.5 or 6.5). The two balloons  130 ′ and  130 ″ can each have a half dome shape  130   hs  allowing them to fit into the end portion of the capsule when in the expanded state. One balloon can contain the chemical reactant(s)  165  (e.g., sodium bicarbonate, citric acid, etc.) the other the liquid water  168 , so that when the valve is degraded the two components mix to form a gas which inflates one or both balloons  130 ′ and  130 ″ and in turn, the aligner balloon  160 . 
     In yet another alternative embodiment, balloon  130  can comprise a multi-compartment balloon  130   mc , that is formed or other constructed to have multiple compartments  130   c . Typically, compartments  130   c  will include at least a first and a second compartment  134  and  135  which are separated by a separation valve  150  or other separation means  150  as is shown in the embodiment of  FIG. 14 a   . In many embodiments, compartments  134  and  135  will have at least a small connecting section  136  between them which is where separation valve  150  will typically be placed. A liquid  168 , typically water, can be disposed within first compartment  134  and one or more reactants  165  disposed in second compartment  135  (which typically are solid though liquid may also be used) as is shown in the embodiment of  FIG. 14 a   . When valve  150  opens (e.g., from degradation caused by fluids within the small intestine) liquid  168  enters compartment  135  (or vice versa or both), the reactant(s)  165  mix with the liquid and produce a gas  169  such as carbon dioxide which expands balloon  130  which in turn can be used to expand one or more of balloons  160  and  172 . 
     Reactants  165  will typically include at least a first and a second reactant,  166  and  167  for example, an acid such as citric acid and a base such as sodium bi-carbonate or potassium bi-carbonate. As discussed herein, in various embodiments they may be placed in one or more of balloon  130  (including compartments  134  and  135  or halves  130 ′ and  130 ″) and balloon  160 . Additional reactants, including other combinations of acids and bases which produce an inert gas by product are also contemplated. For embodiments using citric acid and sodium or potassium bicarbonate, the ratios between the two reactants (e.g., citric acid to potassium bicarbonate) can be in the range of about 1:1 to about 1:4, with a specific ratio of about 1:3. Desirably, solid reactants  165  have little or no absorbed water. Accordingly, one or more of the reactants, such as sodium bicarbonate or potassium bicarbonate can be pre-dried (e.g., by vacuum drying) before being placed within balloon  130 . Other reactants  165  including other acids, e.g., ascetic acid and bases are also contemplated. The amounts of particular reactants  165 , including combinations of reactants can be selected to produce particular pressures using known stoichiometric equations for the particular chemical reactions as well as the inflated volume of the balloon and the ideal gas law (e.g., PV=nRT). In particular embodiments, the amounts of reactants can be selected to produce a pressure selected one or more of balloons  130 ,  160  and  172  to: i) achieve a particular penetration depth into the intestinal wall; and produce a particular diameter for one or more of balloons  130 ,  160  and  172 ; and iii) exert a selected amount of force against intestinal wall IW. In particular embodiments, the amount and ratios of the reactants (e.g., citric acid and potassium bicarbonate) can be selected to achieve pressures in one more of the balloons  130 ,  160  and  172  in the range of 10 to 15 psi, with smaller and larger pressures contemplated. Again the amounts and ratios of the reactants to achieve these pressures can be determined using known stoichiometric equations. 
     In various embodiments of the invention using chemical reactants  165  to generate gas  169 , the chemical reactants alone or in combination with the deployment balloon  130  can comprise a deployment engine for 180 deploying one or both of the aligner balloon  160  and delivery mechanism  170  including delivery balloon  172 . Deployment engine  180  may also include embodiments using two deployment balloons  130  and  130 ″ (a dual dome configuration as shown in  FIG. 13 b   ), or a multi compartment balloon  130   mc  as shown in  FIG. 14 a   . Other forms of a deployment engine  180  are also contemplated by various embodiments of the invention such as use of expandable piezo-electric materials (that expand by application of a voltage), springs and other shape memory materials and various thermally expandable materials. 
     One or more of the expandable balloons  130 ,  160  and  172  will also typically include a deflation valve  159  which serves to deflate the balloon after inflation. Deflation valve  159  can comprise biodegradable materials which are configured to degrade upon exposure to the fluids in the small intestine and/or liquid in one of the compartments of the balloon so as to create an opening or channel for escape of gas within a particular balloon. Desirably, deflation valves  159  are configured to degrade at a slower rate than valve  150  to allow sufficient time for inflation of balloons,  130 ,  160  and  172  before the deflation valve degrades. In various embodiments, of a compartmentalized balloon  130 , deflation valve  159  can correspond to a degradable section  139  positioned on an end portion  131  of the balloon as is shown in the embodiment of  FIG. 14 a   . In this and related embodiments, when degradable section  139  degrades from exposure to the liquid, balloon wall  132  tears or otherwise comes apart providing for a high assurance of rapid deflation. Multiple degradable sections  139  can be placed at various locations within balloon wall  132 . 
     In various embodiments of balloon  172 , deflation valve  159  can correspond to a tube valve  173  attached to the end  172   e  of the delivery balloon  172  (opposite to the end which is coupled to the aligner balloon) as is shown in the embodiment of  FIG. 13 b   . The tube valve  173  comprises a hollow tube  173   t  having a lumen that is obstructed at a selected location  1731  with a material  173   m  such as maltose that degrades upon exposure to fluid such as the fluid in the small intestine. The location  1731  of the obstructing material  173   m  in tube  173   t  is selected to provide sufficient time for the delivery balloon  172  to inflate and deliver the tissue penetrating members  40  into the intestinal wall IW before the obstructing material dissolves to open valve  173 . Typically, this will be close to the end  173   e  of the tube  173   t , but not quite so as to allow time for liquid to have to wick into the tube lumen before it reaches material  173   m . According to one or more embodiments, once the deflation valve  173  opens, it not only serves to deflate the delivery balloon  172  but also the aligner balloon  160  and deployment balloon  130  since in many embodiments, all three are fluidically connected (aligner balloon being fluidically connected to delivery balloon  172  and the deployment balloon  130  being i connected to aligner balloon  160 ). Opening of the deflation valve  173  can be facilitated by placing it on the end  172   e  of the delivery balloon  172  that is forced out of capsule  120  by inflation of the aligner balloon  160  so that the deflation valve has good exposure to liquids in the small intestine. Similar tube deflation valves  173  can also be positioned on one or both of aligner balloon  162  and the deployment balloon  130 . In these later two cases, the obstructing material in the tube valve can be configured to degrade over a time period to allow sufficient time for inflation of delivery balloon  172  and advancement of tissue penetrating members  140  into the intestinal wall. 
     Additionally, as further backup for insured deflation, one or more puncture elements  182  can be attached to the inside surface  124  of the capsule such that when a balloon (e.g., balloon  130 ,  160 ,  172 ) fully inflates it contacts and is punctured by the puncture element  182 . Puncture elements  182  can comprise short protrusions from surface  124  having a pointed tip. In another alternative or additional embodiment of means for balloon deflation, one or more of the tissue penetrating members  140  can be directly coupled to the wall of  172   w  of balloon  172  and configured to tear away from the balloon when they detach, tearing the balloon wall in the process. 
     A discussion will now be presented of tissue penetrating members  140 . Tissue penetrating member  140  can be fabricated from various drugs and other therapeutic agents  101 , one or more pharmaceutical excipients (e.g., disintegrants, stabilizers, etc.) and one or more biodegradable polymers. The later materials can be chosen to confer desired structural and material properties to the penetrating member (for example, column strength for insertion into the intestinal wall, or porosity and hydrophilicity for control the release of drug). Referring now to  FIGS. 18 a -18 f   , in many embodiments, the penetrating member  140  can be formed to have a shaft  144  and a needle tip  145  or other pointed tip  145  so as to readily penetrate tissue of the intestinal wall as shown in the embodiment of  FIG. 18 a   . In preferred embodiments, tip  145  has a trocar shape as is shown in the embodiment of  FIG. 18 c   . Tip  145  may comprise various degradable materials (within the body of the tip or as a coating), such as sucrose or other sugar which increase the hardness and tissue penetrating properties of the tip. Once placed in the intestinal wall, the penetrating member  140  is degraded by the interstitial fluids within the wall tissue so that the drug or other therapeutic agent  101  dissolves in those fluids and is absorbed into the blood stream. One or more of the size, shape and chemical composition of tissue penetrating member  140  can be selected to allow for dissolution and absorption of drug  101  in a matter of seconds, minutes or even hours. In particular embodiments, rates of dissolution can be controlled through the use of various disintegrants known in the pharmaceutical arts. Examples of disintegrants include, but are not limited to, various starches such as sodium starch glycolate and various cross linked polymers such as carboxymethyl cellulose. The choice of disintegrants can be specifically adjusted for the environment within the wall of the small intestine. 
     Tissue penetrating member  140  will also typically include one or more tissue retaining features  143  such as a barb or hook to retain the penetrating member within the tissue of the intestinal wall IW or surrounding tissue (e.g., the peritoneal wall) after advancement. Retaining features  143  can be arranged in various patterns  143   p  to enhance tissue retention such as two or more barbs symmetrically or otherwise distributed around and along member shaft  144  as is shown in the embodiments of  FIGS. 18 a  and 18 b   . Additionally, in many embodiments, penetrating member will also include a recess or other mating feature  146  for attachment to a coupling component on delivery mechanism  170 . 
     Tissue penetrating member  140  is desirably configured to be detachably coupled to platform  175  (or other component of delivery mechanism  170 ), so that after advancement of the tissue penetrating member  140  into the intestinal wall, the penetrating member detaches from the balloon. Detachability can be implemented by a variety of means including: i) the snugness or fit between the opening  174  in platform  175  and the member shaft  144 ); ii) the configuration and placement of tissue retaining features  143  on penetrating member  140 ; and iii) the depth of penetration of shaft  144  into the intestinal wall. Using one or more of these factors, penetrating member  140  be configured to detach as a result of balloon deflation (where the retaining features  143  hold the penetrating member  140  in tissue as the balloon deflates or otherwise pulls back away from the intestinal wall) and/or the forces exerted on capsule  120  by a peristaltic contraction of the small intestine. 
     In a specific embodiment, the detachability and retention of tissue penetrating member  140  in the intestinal wall IW or surrounding tissue (e.g., the peritoneal wall) can be enhanced by configuring the tissue penetrating member shaft  144  to have an inverse taper  144   t  as is shown in the embodiment of  FIG. 18 c   . The taper  144   t  on the shaft  144  is configured such that the application of peristaltic contractile forces from the intestinal wall on the shaft result in the shaft being forced inward (e.g., squeezed inward). This is due to the conversion by shaft taper  144   t  of the laterally applied peristaltic force PF to an orthogonal force OF acting to force the shaft inward into the intestinal wall. In use, such inverse tapered shaft configurations serve to retain tissue penetrating member  140  within the intestinal wall so as to detach from platform  175  (or other component of delivery mechanism  170 ) upon deflation of balloon  172 . In additional embodiments, tissue penetrating members  140  having an inverse tapered shaft may also include one or more retaining features  143  to further enhance the retention of the tissue penetrating member within intestinal wall IW once inserted. 
     As described above, in various embodiments, tissue penetrating member  140  can be fabricated from a number of drugs and other therapeutic agents  101  including various antibodies such as IgG. Also according to one or more embodiments, the tissue penetrating member may be fabricated entirely from drug/therapeutic agent  101  or may have other constituent components as well, e.g., various pharmaceutical excipients (e.g., binders, preservatives, disintegrants, etc.), polymers conferring desired mechanical properties, etc. Further, in various embodiments one or more tissue penetrating members  140  can carry the same or a different drug  101  (or other therapeutic agent) from other tissue penetrating members. The former configuration allows for the delivery of greater amounts of a particular drug  101 , while the later, allows two or more different drugs to be delivered into the intestinal wall at about the same time to facilitate drug treatment regimens requiring substantial concurrent delivery of multiple drugs. In embodiments of device  110 , having multiple delivery assemblies  178  (e.g., two, one on each face of balloon  172 ), a first assembly  178 ′ can carry tissue penetrating members having a first drug  101  and a second assembly  178 ″ can carry tissue penetrating members having a second drug  101 . 
     Typically, the drug or other therapeutic agent  101  carried by the tissue penetrating member  140  will be mixed in with a biodegradable material  105  to form tissue penetrating member  140 . Material  105  may include one or more biodegradable polymers such as PLGA, cellulose, as well as sugars such as maltose or other biodegradable material described herein or known in the art. In such embodiments, the penetrating member  140  may comprise a substantially heterogeneous mixture of drug  101  and biodegradable material  105 . Alternatively, the tissue penetrating member  140  may include a portion  141  formed substantially from biodegradable material  105  and a separate section  142  that is formed from or contains drug  101  as shown in the embodiment of  FIG. 18 d   . In one or more embodiments, section  142  may correspond to a pellet, slug, cylinder or other shaped section  142   s  of drug  101 . Shaped section  142   s  may be pre-formed as a separate section which is then inserted into a cavity  142   c  in tissue penetrating member  140  as is shown in the embodiments of  FIGS. 18 e  and 18 f    Alternatively, section  142   s  may be formed by adding of drug preparation  100  to cavity  142   c . In embodiments, where drug preparation  100  is added to cavity  142   c , preparation may be added in as a powder, liquid, or gel which is poured or injected into cavity  142   c . Shaped section  142   s  may be formed of drug  101  by itself or a drug preparation containing drug  101  and one or more binders, preservatives, disintegrates and other excipients. Suitable binders include polyethylene glycol (PEG) and other binders known in the art. In various embodiments, the PEG or other binder may comprise in the range of about 10 to 90% weight percent of the section  142   s , with a preferred embodiment for insulin preparations of about 25-90 weight percent. Other excipients which may be used for binders may include, PLA, PLGA, Cyclodextrin, Cellulose, Methyl Cellulose, maltose, Dextrin, Sucrose and PGA. Further information on the weight percent of excipients in section  142  may be found in Table 1. For ease of discussion, section  142  is referred to as a pellet in the table, but the data in the table is also applicable to other embodiments of section  142  described herein. 
     In various embodiments, the weight of tissue penetrating member  140  can range between about 10 to 15 mg, with larger and smaller weights contemplated. For embodiments of tissue penetrating member  140  fabricated from maltose, the weight can range from about 11 to 14 mg. In various embodiments, depending upon the drug  101  and the desired delivered dose, the weight percent of drug in member  140  can range from about 0.1 to about 15%. In exemplary embodiments these weight per cents correspond to embodiments of members  140  fabricated from maltose or PLGA, however they are also applicable to any of the biodegradable materials  105  used in the fabrication of members  140 . The weight percent of drug or other therapeutic agent  101  in member  140  can be adjusted depending upon the desired dose as well as to provide for structural and stoichiometric stability of the drug and also to achieve a desired concentration profile of the drug in the blood or other tissue of the body. Various stability tests and models (e.g., using the Arrhenius equation) known in the art and/or known rates of drug chemical degradation may be used to make specific adjustments in the weight percent range. Table 1 lists the dose and weight percent range for insulin and number of other drugs which may be delivered by tissue penetrating member  140 . In some cases the table lists ranges as well a single value for the dose. It should be appreciated that these values are exemplary and other values recited herein including the claims are also considered. Further, embodiments of the invention also consider variations around these values including for example, ±1, ±5, ±10, ±25, and even larger variations. Such variations are considered to fall within the scope of an embodiment claiming a particular value or range of values. The table also lists the weight percentage of drug in in section  142  for various drugs and other therapeutic agents, where again for ease of discussion, section  142  is referred to as a pellet. Again, embodiments of the invention consider the variations described above. 
     
       
         
           
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                 % Weight of Drug 
               
               
                 Drug 
                 Dose Via Capsule** 
                 in the needle 
               
               
                   
               
             
            
               
                 Insulin 
                 4-9 units, 5-30 
                 2-15% 
               
               
                   
                 units, 1-50 Units 
               
               
                 Exenatide 
                 1-10 ug, 1-20 ug, 
                 &lt;1%, 0.1-1% 
               
               
                   
                 10 ug 
               
               
                 Liraglutide 
                 0.1-1 mg, 0.5-2 
                  3-6% 
               
               
                   
                 mg, 0.6 mg 
               
            
           
           
               
               
               
               
            
               
                 Pramlintide 
                 15-120 
                 ug 
                 0.1-1%  
               
            
           
           
               
               
               
            
               
                 Growth Hormone 
                 0.2-1 mg, 0.1-4 mg 
                 2-10% 
               
               
                 Somatostatin and Analogs 
                 50-600 ug, 10-100 ug 
                 0.3-8%  
               
               
                 GnRH and Analogs 
                 0.3-1.5 mg, 0.1-2 mg 
                 2-15% 
               
            
           
           
               
               
               
               
            
               
                 Vasopressin 
                 2-10 
                 units 
                 &lt;1%, 0.1-1% 
               
            
           
           
               
               
               
            
               
                 PTH and Analogues 
                 0.1 to 10 ug, 
                  1-2% 
               
               
                   
                 10-30 ug, 20 ug 
               
               
                 Interferons and analogs 
               
            
           
           
               
               
               
               
            
               
                 1. For Multiple Sclerosis 
                 0.03-0.25 
                 mg 
                 0.1-3%  
               
               
                 2. For Hep B and Hep C 
                 6-20 
                 ug 
                 0.05-0.2%    
               
            
           
           
               
               
               
            
               
                 Adalimumab 
                 1-5 mg, 2-4 mg 
                 8-12% 
               
               
                 Infliximab 
                 1-10, 5 mg 
                 8-12% 
               
               
                 Etanercept 
                 1-5 mg, 3 mg 
                 8-12% 
               
               
                 Natalizumab 
                 1-5 mg, 3 mg 
                 8-12% 
               
               
                   
               
            
           
         
       
     
     Tissue penetrating member  140  can be fabricated using one or more polymer and pharmaceutical fabrication techniques known in the art. For example, drug  101  (with or without biodegradable material  105 ) can be in solid form and then formed into the shape of the tissue penetrating member  140  using molding, compaction or other like method with one or more binding agents added. Alternatively, drug  101  and/or drug preparation  100  may be in solid or liquid form and then added to the biodegradable material  105  in liquid form with the mixture then formed into the penetrating member  140  using molding or other forming method known in the polymer arts. 
     Desirably, embodiments of the tissue penetrating member  140  comprising a drug or other therapeutic agent  101  and degradable material  105  are formed at temperatures which do not produce any substantial thermal degradation of drug including drugs such as various peptides and proteins. This can be achieved through the use of room-temperature curing polymers and room temperature molding and solvent evaporation techniques known in the art. In particular embodiments, the amount of thermally degraded drug or other therapeutic agent within the tissue penetrating member is desirably less than about 10% by weight and more preferably, less than 5% and still more preferably less than 1%. The thermal degradation temperature(s) for a particular drug are either known or can be determined using methods known in the art and then this temperature can be used to select and adjust the particular polymer processing methods (e.g., molding, curing. solvent evaporation methods etc.) to minimize the temperatures and associated level of drug thermal degradation. 
     A description will be provided of delivery mechanism  170 . Typically, the mechanism will comprise a delivery assembly  178  (containing tissue penetrating members  140 ) that is attached to delivery balloon  172  as is shown in the embodiment of  FIGS. 16 a  and 16 b   . Inflation of the delivery balloon provides a mechanical force for engaging delivery assembly  172  outwards from the capsule and into the intestinal wall IW so as to insert tissue penetrating members  140  into the wall. In various embodiments, the delivery balloon  172  can have an elongated shape with two relatively flat faces  172   f  connected by an articulated accordion-like body  172   b . The flat faces  172   f  can be configured to press against the intestinal wall (IW) upon expansion of the balloon  172  so as to insert the tissue penetrating members (TPMs)  140  into the intestinal wall. TPMs  140  (either by themselves or as part of a delivery assembly  178  described below) can be positioned on one or both faces  172   f  of balloon  172  to allow insertion of drug containing TPMs  40  on opposite sides of the intestinal wall. The faces  172   f  of balloon  172  may have sufficient surface area to allow for placement of a number of drug containing TPMs  140  on each face. 
     Referring now to  FIG. 19 , a description will now be provided of the assembly of delivery assembly  178 . In a first step  300 , one or more tissue penetrating members  140  can be detachably coupled to a biodegradable advancement structure  175  which may correspond to a support platform  175  (also known as platform  175 ). In preferred embodiments, platform  175  includes one or more openings  174  for insertion of members  140  as shown in step  300 . Openings  174  are sized to allow for insertion and retention of members  140  in platform  175  prior to expansion of balloon  172  while allowing for their detachment from the platform upon their penetration into the intestinal wall. Support platform  175  can then be positioned within a carrying structure  176  as shown in step  301 . Carrying structure  176  may correspond to a well structure  176  having side walls  176   s  and a bottom wall  176   b  which define a cavity or opening  176   c . Platform  175  is desirably attached to inside surface of bottom wall  176   b  using adhesive or other joining methods known in the art. Well structure  176  can comprise various polymer materials and may be formed using vacuum forming techniques known in the polymer processing arts. In many embodiments, opening  176   o  can be covered with a protective film  177  as shown in step  302 . Protective film  177  has properties selected to function as a barrier to protect tissue penetrating members  140  from humidity and oxidation while still allowing tissue penetrating members  140  to penetrate the film as is described below. Film  177  can comprise various water and/or oxygen impermeable polymers which are desirably configured to be biodegradable in the small intestine and/or to pass inertly through the digestive tract. It may also have a multi-ply construction with particular layers selected for impermeability to a given substance, e.g., oxygen, water vapor etc. In use, embodiments employing protective film  177  serve to increase the shelf life of therapeutic agent  101  in tissue penetrating members  140 , and in turn, the shelf life of device  110 . Collectively, support platform  175  attached tissue penetrating members  140 , well structure  176 , and film  177  can comprise a delivery assembly  178 . Delivery assemblies  178  having one or more drugs or therapeutic agents  101  contained within tissue penetrating member  40  or other drug delivery means can be pre-manufactured, stored and subsequently used for the manufacture of device  110  at a later date. The shelf life of assembly  178  can be further enhanced by filling cavity  176   c  of the sealed assembly  178  with an inert gas such as nitrogen. 
     Referring back to  FIGS. 16 a  and 16 b   , assemblies  178  can be positioned on one or both faces  172   f  of balloon  172 . In preferred embodiments, assemblies  178  are positioned on both faces  172   f  (as shown in  FIG. 16 a   ) so as to provide a substantially equal distribution of force to opposite sides of the intestinal wall IW upon expansion of balloon  172 . The assemblies  178  may be attached to faces  172   f  using adhesives or other joining methods known in the polymer arts. Upon expansion of balloon  172 , TPMs  140  penetrate through film  177 , enter the intestinal wall IW and are retained there by retaining elements  143  and/or other retaining features of TPM  140  (e.g., an inverse tapered shaft  144   t ) such that they detach from platform  175  upon deflation of balloon  172 . 
     In various embodiments, one or more of balloons  130 ,  160  and  172  can be packed inside capsule  120  in a folded, furled or other desired configuration to conserve space within the interior volume  124   v  of the capsule. Folding can be done using preformed creases or other folding feature or method known in the medical balloon arts. In particular embodiments, balloon  130 ,  160  and  172  can be folded in selected orientations to achieve one or more of the following: i) conserve space, ii) produce a desired orientation of a particular inflated balloon; and iii) facilitate a desired sequence of balloon inflations. The embodiments shown in  FIGS. 15 a -15 f    illustrate an embodiment of a method of folding and various folding arrangements. However, it should be appreciated that this folding arrangement and the resulting balloon orientations are exemplary and others may also be used. In this and related embodiments, folding can be done manually, by automated machine or a combination of both. Also in many embodiments, folding can be facilitated by using a single multi-balloon assembly  7  (herein assembly  7 ) comprising balloons  130 ,  160 ,  170 ; valve chamber  158  and assorted connecting tubings  162  as is shown in the embodiments of  FIGS. 13 a  and 13 b   .  FIG. 13 a    shows an embodiment of assembly  7  having a single dome construction for balloon  130 , while  FIG. 13 b    shows the embodiment of assembly  7  having dual balloon/dome configuration for balloon  130 . Assembly  7  can be fabricated using a thin polymer film which is vacuum-formed into the desired shape using various vacuum forming and other related methods known in the polymer processing arts. Suitable polymer films include polyethylene films having a thickness in the range of about 0.003 to about 0.010″, with a specific embodiment of 0.005″. In preferred embodiments, the assembly is fabricated to have a unitary construction so as to eliminate the need for joining one or more components of the assembly (e.g., balloons  130 , 160 , etc.). However, it is also contemplated for assembly  7  to be fabricated from multiple portions (e.g., halves), or components (e.g., balloons) which are then joined using various joining methods known in the polymer/medical device arts. 
     Referring now to  FIGS. 15 a -15 f , 16 a -16 b  and 17 a -17 b   , in a first folding step  210 , balloon  160  is folded over onto valve fitting  158  with balloon  172  being flipped over to the opposite side of valve fitting  158  in the process (see  FIG. 15 a   ). Then in step  211 , balloon  172  is folded at a right angle to the folded combination of balloon  160  and valve  158  (see  FIG. 15 b   ). Then, in step  212  for dual dome embodiments of balloon  130 , the two halves  130 ′ and  130 ″ of balloon  130  are folded onto each other, leaving valve  150  exposed (see  FIG. 15 c   , for single dome embodiments of balloon  130 , is folded over onto itself see  FIG. 15 e   ). A final folding step  213  can be done whereby folded balloon  130  is folded over 180° to the opposite side of valve fitting  158  and balloon  160  to yield a final folded assembly  8  for dual dome configurations shown in the  FIG. 15 e    and a final folded assembly  8 ′ for single dome configurations shown in  FIGS. 15 e  and 15 f   . One or more delivery assemblies  178  are then be attached to assembly  8  in step  214  (typically two the faces  72   f  of balloon  72 ) to yield a final assembly  9  (shown in the embodiments of  FIGS. 16 a  and 16 b   ) which is then inserted into capsule  120 . After an insertion step  215 , the final assembled version of device  110  with inserted assembly  9  is shown  FIGS. 17 a    and  17   b.    
     Referring now to  FIGS. 20 a -20 i   , a description will be provided of a method of using device  110  to deliver medication  101  to a site in the GI tract such as the wall of the small or large intestine. It should be appreciated that the steps and their order is exemplary and other steps and orders also contemplated. After device  110  enters the small intestine SI, the cap coating  120   c ′ is degraded by the basic pH in the upper small intestine causing degradation of cap  120   p ′ as shown in step  400  in  FIG. 20 b   . Valve  150  is then exposed to fluids in the small intestine causing the valve to begin degrade as is shown in step  401  in  FIG. 20 c   . Then, in step  402 , balloon  130  expands (due to generation of gas  169 ) as shown in  FIG. 20 d   . Then, in step  403 , section  160 ′ of balloon  160  begins to expand to start to push assembly  178  out of the capsule body as shown in  FIG. 20 e   . Then, in step  404 , sections  160 ′ and  160 ″ of balloon  160  become fully inflated to completely push assembly  178  out of the capsule body extending the capsule length  1201  so as to serve to align capsule lateral axis  120 AL with the lateral axis of the small intestine LAI as shown in  FIG. 20 f   . During this time, valve  155  is beginning to fail from the increased pressure in balloon  60  (due to the fact that the balloon has fully inflated and there is no other place for gas  169  to go). Then, in step  405 , valve  155  has completely opened, inflating balloon  172  which then pushes the now completely exposed assembly  178  (having been pushed completely out of body  120   p ″) radially outward into the intestinal wall IW as shown in  FIG. 20 g   . Then, in step  406 , balloon  172  continues to expand to now advance tissue penetrating members into the intestinal wall IW as shown in  FIG. 20 h   . Then, in step  407 , balloon  172 , (along with balloons  160  and  130 ) has deflated pulling back and leaving tissue penetrating members retained in the intestinal wall IW. Also, the body portion  120   p ″ of the capsule has completely degraded (due to degradation of coating  120   c ″) along with other biodegradable portions of device  110 . Any portion not degraded is carried distally through the small intestine by peristaltic contraction from digestion and is ultimately excreted. 
     Pharmacokinetic Features and Parameters of the Invention 
     Referring now to  FIGS. 21-29 , a discussion of various pharmacokinetic parameters and features associated with methods and other embodiments of the invention will now be presented. Specifically, various embodiments of the invention provide therapeutic preparations and associated methods for delivery of therapeutic agents into various lumen walls of the GI tract including the stomach wall, intestinal wall (e.g., the small intestine) or surrounding tissue (e.g., the peritoneum) where one or more pharmacokinetic parameters of delivery can be achieved. Such parameters may include, without limitation, one or more of absolute bioavailability, relative bioavailability, T max , T 1/2 , C max  and area under the curve or AUC as is known in the pharmacokinetic/pharmaceutical arts. “Absolute bioavailability” is the amount of drug from a formulation that reaches the systemic circulation relative to an intravenous (IV) dose, where the IV dose is assumed to be 100% bioavailable. “Relative bioavailability” is the amount of drug from a formulation that reaches the systemic circulation relative to an intravenous (IV) dose, T max  is the time period for the therapeutic agent to reach its maximum concentration in the blood stream, C max , and T 1/2  is the time period required for the concentration of the therapeutic agent in the bloodstream (or other location in the body) to reach half its original C max  value after having reached C max . 
     Example 1, including  FIGS. 21-25 , provides pharmacokinetic data and other results illustrating the achievement of one or more of the above parameters using embodiments of the therapeutic preparations containing IgG which were delivered to canines using embodiments of the swallowable capsule described herein. As shown in Example 1, in various embodiments where the therapeutic preparation comprises an antibody such as IgG, the absolute bioavailability of therapeutic agent delivered by embodiments of the invention can be in the range of about 50 to 68.3% with a specific value of 60.7%. Still other values are contemplated as well. Also the T max  for delivery of antibodies, for example, IgG, can be about 24 hours while the T ¼ can be in range from about 40.7 to 128 hours, with a specific value of about 87.7 hours. 
     Referring now to  FIG. 21 , in various embodiments, the therapeutic preparations and associated methods for their delivery into the wall of the small intestine or surrounding tissue can be configured to produce plasma/blood concentration vs time profiles  200  of the therapeutic agent having a selected shape  203  with C max    205  or T max    206  or other pharmacokinetic value as reference points  207 . For example, as illustrated in  FIG. 21 , the plasma concentration vs time profile  200  may have a rising portion  210  and a falling portion  220  with a selected ratio of the time lengths of the rising portion  210  to the falling portion  220 . In specific embodiments this is the ratio of the time  208  it takes to go from a pre delivery concentration  204  of therapeutic agent to a C max  level  205  (this time corresponding to T max  time  206 ), during the rising portion (also described as rise time  208 ), to the time  209  (also described as fall time  209 ) it takes during the falling portion  210  to go from the C max  level  205  back to the pre-delivery concentration  204 . In various embodiments, the ratio of the rise time  208  to the fall time  209  can be in the range of about 1 to 20, 1 to 10 and 1 to 5. In specific embodiments of therapeutic preparations comprising antibodies such as IgG, the ratio of rise time to fall time in the profile  200  can be about 1 to 9 as illustrated in  FIGS. 21 and 22 . Still other ratios are contemplated. Whereas for various types of insulin including recombinant human insulin, the ratio of rise time to fall time can be in a range of about 1 to 2 to 1 to 6, with specific embodiments of 1:4, 1:4.5 and 1:6. 
     Example 3 including Tables 8 and 9 and  FIGS. 26-29  provides pharmacokinetic and pharmacodynamic data and other results illustrating the achievement of one or more of the above parameters using therapeutic preparations comprising recombinant human insulin (RHI) that were interjejunally delivered to porcine (pigs) using embodiments of the swallowable capsule described herein. As described in the Example 3 and as shown in the figures, in embodiments where the therapeutic preparation comprises recombinant human insulin (RHI), the T max  for intrajejunal delivery of RHI by embodiments of the swallowable capsules (the Rani Group) is about 139±42 minutes, compared to 227±24 minutes for subcutaneous injection (the SC Group) while the mean peak serum concentrations (C max ) of RHI were 516±109 pM. 8 and 342±50 pM in the Rani and SC Groups respectively. When accounting for the average weight of the animals and the average units of insulin delivered this works to 458 pM/kg weight/IU of delivered insulin dose. Further, when accounting for the out for all standard errors in the respective units of this value the range of values for this metric works out to 381 to 527 pM/kg weight/IU of delivered insulin dose. The areas under the insulin concentration curves achieved using the euglyemic clamp method described herein were 81±10 and 83±18 nM/min for the Rani and SC Groups respectively. This resulted in a relative bioavailabilities in the range of 72 to 129% (mean value of 104%) for insulin interjejunally delivered by embodiments of the swallowable capsule relative to doses delivered by subcutaneous injection. Likewise, the area under the blood glucose infusion curves using the euglyemic clamp method were 85±4 and 106±10 g/min 2  for the Rani and SC Groups respectively. The comparability of these AUC values illustrates that the blood glucose lowering effect of the insulin intrajejunally delivered by embodiments of the invention (the Rani Group) was comparable to that achieved by insulin delivered via subcutaneous injection. Further, the eugylemic clamp experiments demonstrated the ability of embodiments of the swallowable capsule to interjejunally deliver insulin in manner which maintain blood glucose levels within a range of 60-90 mg/ml 
     Example 4 including tables 10-11 provides results from a pilot IRB (investigational review board) study that was performed in 10 fasting and 10 postprandial healthy human volunteers to examine the tolerability and safety of an embodiment of the swallowable capsule (the RaniPill Capsule) administered with without a microneedle or drug payload but which did have a balloon based deployment mechanism described herein. The capsule was designed to align and deploy in the small intestine as described herein e.g. one or more balloons in the mechanism expanded and deployed in the small intestine. It also contained a radio-opaque material allowing: i) location of the capsule position in the patient&#39;s GI tract; and when ii) the capsule deployed within the small intestine including when the expandable balloon within the capsule was expanded and deployed within the small intestine. This later time, defined herein as capsule deployment time, or deployment time (also described as capsule activation time or activation time) is the time between from when the capsule left the stomach and subsequently deployed in the small intestine. Serial radiographic imaging was used to determine the residence time of the capsule in the stomach and the deployment time within the small intestine. The Gastric residence time and deployment times date are shown in tables 10-11. The mean gastric residence time of the capsule was 217±36 minutes in the postprandial state and 100±79 min in the fasting state. The intestinal deployment times of the capsule were closely similar (100±40 vs. 97±30 min) in both groups. The results surprisingly showed that capsule deployment including capsule deployment times were not appreciably affected by the presence of food in the GI tract including one or both of the patient&#39;s stomach and small intestine. As used herein, with respect to capsule deployment or activation times, appreciably affected means less than about a 20% difference in deployment/activation times, more preferably, less than about 10% and still more preferably less than about 5%. 
     The results also showed that no subject perceived the transit, deployment or excretion of the capsule and all subjects excreted the capsule remnants uneventfully, which was confirmed radiographically within 72-96 hours after capsule ingestion. In particular, no subject perceived when the capsule&#39;s balloon-based deployment mechanism expanded and deployed in the small intestine. 
     CONCLUSION 
     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 forms disclosed. Many modifications, variations and refinements will be apparent to practitioners skilled in the art. For example, embodiments of the device can be sized and otherwise adapted for various pediatric and neonatal applications as well as various veterinary applications. Also those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific devices and methods described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the appended claims below. 
     Elements, characteristics, or acts from one embodiment can be readily recombined or substituted with one or more elements, characteristics or acts from other embodiments to form numerous additional embodiments within the scope of the invention. Moreover, elements that are shown or described as being combined with other elements, can, in various embodiments, exist as standalone elements. Further still, embodiments of the invention also contemplate the exclusion or negative recitation of an element, feature, chemical, therapeutic agent, characteristic, value or step wherever said element, feature, chemical, therapeutic agent, characteristic, value, step or the like is positively recited. Hence, the scope of the present invention is not limited to the specifics of the described embodiments, but is instead limited solely by the appended claims. 
     EXAMPLES 
     Various embodiments of the invention are further illustrated with reference to the following examples. It should be appreciated that these examples are presented for purposes of illustration only and that the invention is not to be limited to the information or the details therein. 
     Example 1: In Vivo Canine Study of the Delivery of IgG Using Embodiments of a Swallowable Capsule 
     Objective: The objective of study was to demonstrate oral delivery of bio-therapeutic molecules via embodiments and/or variations of a swallowable capsule described herein (also described as the RaniPill™ or RANIPILL) in awake dogs and to assess their absolute bioavailability. Human immunoglobulin G (IgG) was used as representative for this class of molecules. 
     Materials 
     Purified human IgG was obtained from Alpha Diagnostic International Inc. (ADI Inc.), TX, USA (Cat #20007-1-100), and used for the preparation of the test articles in this study. IgG microtablets were prepared from dry powder formulated batches containing 90% (w/w) purified human IgG and 10% (w/w) excipients. IgG batches were analyzed and qualified based on acceptance criteria for physical characteristics and protein recovery as assessed by ELISA. 
     RaniPill™ capsules were manufactured and qualified by multiple performance tests of the payload chamber, to assess the pressure and speed at which the needle is deployed. In addition, testing was done to determine the peak chemical reaction pressure to establish adequate gas pressure to ensure needle delivery. These tests verify deployment reliability of the devices. The capsule lot used in the current study passed all qualification testing. All test articles and their corresponding ID numbers used in this study are listed in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Test Article Information 
               
            
           
           
               
               
               
            
               
                   
                 Test Article Type 
                 ID Number 
               
               
                   
                   
               
               
                   
                 RaniPill ™ containing 
                 Capsule Lot# 29NOV17C 
               
               
                   
                 IgG Microtablet 
                 IgG Batch 44 
               
               
                   
                 SC-IgG Microtablets 
                 IgG Batch 46 
               
               
                   
                 Pure Human IgG 
                 ADI Inc. Cat# 20007-1-100 
               
               
                   
                   
                 Lot# XE0908-P 
               
               
                   
                   
               
            
           
         
       
     
     Study Protocol 
     The study was conducted initially with the Test Group (i.e., the Rani Group) in which animals received IgG delivered by embodiments of the RaniPill with blood samples collected over a 10-day period. Based on this initial experience, two additional groups IV (intravenous administration of IgG) and SC (subcutaneous administration of IgG) were subsequently added with a protocol duration extension. The specific protocol for each group is described in more detail below. 
     Rani Group: One RaniPill™ capsule (2.4 mg IgG/microtablet) was administered orally; N=3. This was the initial group to be dosed and blood samples were collected over 10 days. Subsequent drug level analysis indicated that the study duration may have been too short as serum IgG concentrations had not fully recovered to baseline levels in all animals. Therefore, for the next 2 groups, the protocol for collecting blood samples was extended to 14 days. 
     SC Group: One IgG microtablet (2.4 mg IgG/microtablet) was dissolved in 1 mL sterile water for injection and administered subcutaneously (SC); N=2 
     IV Group: Pure human IgG lyophilized powder (2.4 mg IgG) was dissolved in 1 mL sterile water for injection, administered intravenously (IV); N=3 
     Details of subjects and test materials used for each group are summarized in Tables 3-5. The total IgG dose administered to each animal in the SC and Rani Groups was calculated based on microtablet weight and percentage of IgG in the microtablet. Pure human IgG and microtablets were dissolved for approximately 30 minutes prior to dosing. The Rani Group received one capsule orally and was monitored fluoroscopically to confirm successful transit into the small intestine and time of device deployment. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Animal and Test Material Data for Rani Group 
               
            
           
           
               
               
               
            
               
                 Animal ID # 
                 Animal Body Weight (kg) 
                 IgG Dose Administered (mg) 
               
               
                   
               
               
                 3107567 
                 8.1 
                 2.33 
               
               
                 3112404 
                 7.8 
                 2.30 
               
               
                 3281133 
                 8.9 
                 2.38 
               
               
                 Mean ± SD 
                 8.1 ± 0.04 
                 2.34 ± 0.04 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Animal and Test Material Data for SC Group 
               
            
           
           
               
               
               
            
               
                 Animal ID # 
                 Animal Body Weight (kg) 
                 IgG Dose Administered (mg) 
               
               
                   
               
               
                 3048242 
                 8.4 
                 2.39 
               
               
                 3283632 
                 8.4 
                 2.34 
               
               
                 Mean ± SD 
                 8.4 ± 0.0 
                 2.37 ± 0.04 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Animal and Test Material Data for IV Group 
               
            
           
           
               
               
               
            
               
                 Animal ID # 
                 Animal Body Weight (kg) 
                 IgG Dose Administered (mg) 
               
               
                   
               
               
                 2507154 
                 8.7 
                 2.39 
               
               
                 2928974 
                 9.6 
                 2.40 
               
               
                 3133223 
                 8.4 
                 2.39 
               
               
                 Mean ± SD 
                 8.3 ± 0.6 
                 2.40 ± 0.003 
               
               
                   
               
            
           
         
       
     
     Results 
     Serum IgG concentration levels in animals of the control (IV and SC) and experimental (Rani) group were plotted against time and are shown in  FIGS. 22-25 ,  FIG. 23  showing the results for IV delivery,  FIG. 24  for SC delivery,  FIG. 25  for delivery using embodiments of the RaniPill, and  FIG. 22  showing the mean concentration vs time plots for all three groups. From these PK (pharmacokinetic) profiles, pharmacokinetic parameters were calculated to determine the maximal concentration (C max ) of IgG, the time to reach C max  (known as T max ), terminal elimination half-life (T 1/2 ), and the weight normalized area under the curve (AUClast) representing the total drug exposure over time to the last time point taken, as well as the weight normalized area under the curve from extrapolated to infinity (AUCinf), and the bioavailability (% F) for each dose group. 
     The Experimental Group (i.e., the Rani Group) was first dosed and samples collected up to Day 10. However, upon analyzing the data, it was found that measurable IgG serum concentrations were still detectable in all three animals. Based on these results, samples were collected up to day 14 for the subsequent IV and SC Groups. To compare the dosing cohorts, the PK parameters were estimated by non-compartmental methods from serum samples. Nominal elapsed time from dosing was used to estimate individual PK parameters. 
     Serum concentration levels of IgG following IV administration reached C max  by 3.3±1 hours with a mean concentration of 5339±179 ng/mL. Measurable levels were detected through Day 14 with an average AUC last  of 500800±108000 ng*hr/mL. Extrapolated to infinity, the AUCinf showed a similar value, 513400±111700 ng*hr/mL, indicating the sample collection captured the majority of exposure. The mean clearance (CL) was relatively low 0.009±0.002 mL/min/kg and the volume of distribution (Vz) was also low at 0.04±0.01 L/kg. The mean terminal elimination half-life was 51.5±3.3 hours. 
     IgG serum concentrations in the SC Group for the two animals had a C max  of 1246 ng/mL at 120 hours and a C max  of 1510 ng/mL at 72 hours and an average T 1/2  of 49.9 hours. The mean AUC last  and AUCinf were found to be 274200±21570 and 298300±46130 ng*hr/mL, respectively. The mean bioavailability of IgG delivered subcutaneously was calculated to be 50.9%. 
     All animals in the experimental Group (i.e., the Rani Group) showed measurable levels of IgG throughout the course of the ten day study as is shown in  FIG. 25 . The mean maximal concentration (e.g., C max ) of IgG following oral administration of an embodiment of capsule  10  reached 2491±425 ng/mL at 24±0 hours, which thus corresponded to the T max  for the Rani Group. The average AUClast and AUCinf were calculated to be 327400±38820 and 409700±101800 ng*hr/mL. The T 1/2  for the Rani Group ranged from 40.7 to 128 hours with a mean value of 87.7 hours. This large range in T 1/2  may indicate that the actual terminal elimination half-life was not reached in this group. From the extrapolated AUCinf values (AUCext), the percentage extrapolated ranged from 4.55% to 29.1% and exceeded 20% for 2 of 3 animals. Because of this variability, the bioavailability (% F) was estimated using AUClast for the Rani Group and AUCinf value for IV administration. The % F values (i.e., absolute bioavailability) ranged from 50.0% to 68.3% with a mean of 60.7%. 
     Example 2: In Vivo Canine Safety Studies Using Embodiments of the Swallowable Capsule 
     In vivo safety studies were conducted in 23 awake, adult beagles, who each received between 2 and IX capsules (the Rani Capsule) using similar protocols as described above. All capsules passed uneventfully and painlessly through the gastrointestinal tract and were excreted within 96 h. The mean gastric residence time of the capsules was 93 min, and mean subsequent intestinal deployment time was 28 min. 
     Example 3: In Vivo Porcine Study of the Delivery of Human Recombinant Insulin Using Embodiments of a Swallowable Capsule Vs. Subcutaneous Injection 
     An observational, pilot study was performed in 17 juvenile anesthetized pigs using to compare plasma concentrations and pharmacokinetics for human recombinant insulin (HRI) delivered by embodiments of the swallowable capsule (the RaniPill) and subcutaneous injection using a 60-80 mg/dl euglycemic glucose clamp approach. The swallowable capsules herein defined as RaniPill capsules were delivered endoscopic intrajejunal endoscopic approach. The methodology and results are described below 
     Test Material/Groups 
     RaniPill™ capsules were manufactured containing recombinant human insulin microtablets at a dose of 20 IU which was sealed inside a PEO needle. Recombinant human insulin was obtained from the Manufacturer Imgenex (Cat # MIR-232-250). One IU of insulin is equivalent to 0.0347 mg (28 IU/mg). Tables 6 and 7 summarize the information on animal body weight, test article identification and dose data for Rani and SC Groups. 
     Insulin was delivered to two groups of animals as follows: 
     Rani Group (i.e., the RaniPill Group): intrajejunal placement of RaniPill™ capsule containing recombinant Insulin microtablet (N=8). 
     SC Group: SC administration of microneedle containing Insulin microtablet (N=9). 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Test article and Animal details for RaniPill Group. 
               
            
           
           
               
               
               
               
            
               
                   
                 Animal 
                 RaniPill 
                   
               
               
                 Animal ID # 
                 Body Weight (kg) 
                 Capsule ID 
                 Dose (IU) 
               
               
                   
               
               
                 14085 
                 18.0 
                 E23 
                 19.5 
               
               
                 14109 
                 14.3 
                 H45 
                 18.3 
               
               
                 14110 
                 13.2 
                 H43 
                 19.3 
               
               
                 14115 
                 16.3 
                 J68 
                 18.4 
               
               
                 14116 
                 15.0 
                 J44 
                 20.2 
               
               
                 14123 
                 19.0 
                 L29 
                 20.0 
               
               
                 14124 
                 22.3 
                 L2 
                 20.9 
               
               
                 14125 
                 21.4 
                 L38 
                 20.1 
               
               
                 Mean ± SEM 
                 17.4 ± 1.2 
                   
                 19.6 ± 0.3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Test article and Animal details for SC Group. 
               
            
           
           
               
               
               
               
            
               
                   
                 Animal 
                   
                   
               
               
                 Animal ID # 
                 Body Weight (kg) 
                 Microtablet ID 
                 Dose (IU) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 14007 
                 17.1 
                 6A 
                 (#10) 
                 18.4 
               
               
                 14008 
                 17.3 
                 6A 
                 (#1) 
                 17.8 
               
               
                 14033 
                 18.5 
                 7 
                 (#12) 
                 20.7 
               
               
                 14030 
                 15.2 
                 7 
                 (#27) 
                 20.5 
               
               
                 14034 
                 15.2 
                 7 
                 (#22) 
                 20.0 
               
               
                 14037 
                 15.9 
                 7 
                 (#20) 
                 19.8 
               
               
                 14057 
                 19.0 
                 7 
                 (#61) 
                 20.7 
               
               
                 14055 
                 17.5 
                 7 
                 (#36) 
                 20.4 
               
               
                 14058 
                 17.1 
                 7 
                 (#46) 
                 20.1 
               
               
                 Mean ± SEM 
                 17.0 ± 0.4 
                   
                   
                 19.8 ± 0.3 
               
               
                   
               
            
           
         
       
     
     Animals Preparation and Study Samples. 
     All study procedures described were approved by the Institutional Animal Care and Use Committee of Biosurg Inc., and were in compliance with the standard operating procedures of the testing facility. Female domestic swines weighing between 12 and 22 kg were anesthetized by an intramuscular injection of tiletamine and zolazepam (Telazol®), intubated and maintained under anesthesia with a mixture of isoflurane and oxygen delivered under intermittent positive pressure by a mechanical, animal ventilator. The Rani Group, in which 0.68±0.1 mg of RHI were delivered into the jejunal wall, included 8 pigs weighing 17.4±1.2 kg. The 9 pigs in the Control Group, which received 0.69±0.1 mg of RHI subcutaneously, weighed 17.0±0.4 kg. All animals underwent midline, abdominal laparotomies. In a TEST group of 8 pigs (mean weight=17.4±1.2 kg), 20 IU of recombinant human insulin (RHI) was-injected into the jejunal wall by inserting an embodiment of the swallowable capsule into the proximal jejunum via a 1-cm enterotomy and then allowing the capsule to be actuated by the pH conditions in the small jejunum so as to inject a drug needle (e.g., tissue penetrating member) containing RHI into the jenunal wall. A Control Group of 9 pigs (17.0±0.4 kg) received 20 IU of RHI which was injected subcutaneously (the SC Group). In both study groups, blood samples were collected at 10-min intervals, between −20 and +420 min after RHI administration for measurements of blood concentrations of glucose, using a handheld glucometer (as described below), and serum insulin, using an ELISA method (described below). 
     Euglycemic Clamp Method 
     The euglycemic clamp method was used to keep the animals&#39; blood glucose concentration between 60 and 80 mg/dl by titrating a 50% dextrose solution infused through a peripheral venous cannula while monitoring the arterial concentration at 10-min intervals, using a handheld OneTouch Ultra® 2 glucometer (LifeScan, Inc., Milpitas, Calif.—a Johnson &amp; Johnson Company). The euglycemic clamp is a widely used method for measuring insulin sensitivity in vivo (DeFronzo et al., Am J Physiol. 1979 September; 237(3):E214-23; Bergman et al., Diabetes Metab. 1989 Rev., 5: 411-429)). 
     Quantification of Human Insulin and Blood Glucose 
     Blood was collected at −20, −10 and 0 min before the Rani Group injection or subcutaneous injection (SC) of RHI, and every 10 min for 420 min thereafter. The samples were allowed to clot for 30 min at room temperature before their centrifugation at 3,000 rpm for 10-15 min at 4° C. Serum aliquots were then processed for measurements of RHI concentration, using a Human Insulin ELISA Kit and standard operating procedure recommended by the manufacturer (Alpha 
     The quantification of Human Insulin in serum samples was done using an Enzyme Linked Immunosorbent Assay (ELISA) method using a Human Insulin ELISA kit from Alpha Diagnostics International (catalog #0030N, lot # A4262cb). The SOP suggested by the kit manufacturer was used. The assay detection range was 6.25 to 100 μIU/ml. Blood glucose measurements were done using a handheld glucometer (OneTouch Ultra II). 
     Blood Sampling and Processing and Data Management 
     Diagnostic International Inc., San Antonio, Tex.). The detection of the assay ranged between 6.25 and 100 μIU/ml. In both study groups the following data and parameters were measured and compared: a) the serum concentrations and the areas under the curves (AUC) of insulin and glucose (dextrose concentrations, between RHI delivery and 420 min later, b) the peak serum concentrations (C max ) of RHI, and c) the mean time to peak serum concentration (T max ) of RHI. 
     Statistical Analysis 
     The study measurements made in the Rani Group versus the Subcutaneous Injection (SC) Group, presented as means±SEM, were compared, using Student&#39;s t-test and Microsoft Excel software. 
     Results 
     The pharmacokinetic (PK) and pharmacodynamic (PD) data and parameters from the HRI animal studies are summarized in Tables 8 and 9 and illustrated in  FIGS. 26-29 . The values in the table are expressed as means±SEM. The C max  serum concentrations were 342±50 pM and 516±109 pM for the SC and Rani Groups respectively. The AUCs were comparable at 81±10 and 83±18 nmol/L/min for the SC and Rani Groups respectively. The T-max for the Rani Group was 139±42 min as compared to 227±24 min for the SC Group. Serum HRI concentration levels in animals of the SC and Rani Group were plotted against time and are shown in  FIG. 26 . Glucose (dextrose) Infusion Rates (PD) are shown in  FIG. 27 . The AUC for glucose infusion curves for both the RaniPill and SC Groups were comparable showing that the bioactivity of insulin delivered via the RaniPill is preserved similar to the SC route. The relationship between the PK-PD data during the euglcyemic clamp experiments for the Rani Group and SC Group are presented in  FIGS. 28 and 29  respectively. 
     
       
         
           
               
            
               
                   
               
               
                 The Table 8 Serum Insulin Plasma Concentrations and 
               
               
                 Glucose infusion rate data from the Euglycemic clamp 
               
               
                 experiments for the RaniPill and SC Groups. 
               
            
           
           
               
               
               
            
               
                   
                 A. RaniPill n = 8 
                 B. SC n = 9 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Glucose 
                   
                 Glucose 
               
               
                 Time of 
                 Serum 
                 infusion 
                 Serum 
                 infusion 
               
               
                 measurement 
                 insulin 
                 rate 
                 insulin 
                 rate 
               
               
                 (min) 
                 (pM) 
                 (ml/h) 
                 (pM) 
                 (ml/h) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 10 
                  60.0 ± 23.2 
                  5.4 ± 1.3 
                 45.5 ± 4.5 
                  8.2 ± 1.3 
               
               
                 30 
                 217.4 ± 95.9 
                  9.4 ± 1.9 
                 50.4 ± 5.6 
                  7.2 ± 1.2 
               
               
                 60 
                 379.3 ± 98.8 
                 18.4 ± 1.5 
                 63.0 ± 9.4 
                  9.1 ± 2.0 
               
               
                 120 
                 297.1 ± 92.8 
                 28.3 ± 3.3 
                 210.8 ± 45.2 
                 28.6 ± 4.3 
               
               
                 180 
                 244.0 ± 60.5 
                 30.9 ± 2.7 
                 269.5 ± 54.5 
                 38.6 ± 5.1 
               
               
                 240 
                 128.4 ± 28.0 
                 29.0 ± 2.1 
                 270.2 ± 37.6 
                 41.0 ± 4.2 
               
               
                 300 
                 141.0 ± 25.1 
                 24.9 ± 3.2 
                 231.0 ± 32.2 
                 38.9 ± 3.7 
               
               
                 360 
                 106.8 ± 24.3 
                 23.4 ± 3.1 
                 190.6 ± 29.2 
                 37.9 ± 3.6 
               
               
                 410 
                  91.7 ± 20.0 
                 21.0 ± 3.2 
                 154.2 ± 37.9 
                 31.3 ± 2.5 
               
               
                   
               
               
                 Values are means ± SEM 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 PK and PD Parameters for RaniPill and SC Groups 
               
            
           
           
               
               
               
            
               
                 Parameter 
                 SC (N = 9) 
                 RaniPill (N = 8) 
               
               
                   
               
               
                 C max  (pM) 
                 342 ± 50 
                 517 ± 109 
               
               
                 T max  (min) 
                 227 ± 24 
                 139 ± 42  
               
               
                 PK: AUC for Serum Insulin 
                  81 ± 10 
                 83 ± 18 
               
               
                 (nM · min) 
               
               
                 PD: AUC for Glucose Infusion 
                 106 ± 10 
                 85 ± 4  
               
               
                 Rate (g/min 2 ) 
               
               
                   
               
            
           
         
       
     
     Conclusions 
     1) The bioactivity of RHI was preserved after its delivery into the jejunal wall, 2) the jejunal wall route provided a more rapid physiologic uptake of insulin compared with the subcutaneous route, and 3) the pharmacokinetic and pharmacodynamic profile of RHI after its jejunal wall delivery indicates that drugs such as basal insulin, currently administered parenterally, can be successfully delivered into the proximal intestinal wall via embodiments of the swallowable capsule described herein. 
     Example 4, Human Studies 
     A pilot IRB (Investigational Review Board) study was performed in 10 fasting and 10 postprandial healthy human volunteers to examine the tolerability and safety of an embodiment of the swallowable capsule (the RaniPill Capsule) administered with without a microneedle or drug payload but did have a balloon based deployment mechanism described herein. The device was designed to align and deploy in the small intestine as described herein. It also contained a radio-opaque material allowing i) location of the capsule position in the patient&#39;s GI tract; and ii) when the balloon/device deployed. Serial radiographic imaging was used to determine the residence time of the capsule in the stomach and the deployment time within the small intestine. The Gastric residence time and deployment time data are shown below in Tables 10 and 11 respectively. The mean gastric residence time of the capsule was 217±36 min in the postprandial state and 100±79 min in the fasting state, though the intestinal deployment times were closely similar (100±40 vs. 97±30 min) in both groups. No subject perceived the transit, deployment or excretion of the capsule and all subjects excreted the capsule remnants uneventfully, which was confirmed radiographically within 72-96 hours after capsule ingestion. The results showed that capsule deployment including capsule deployment or activation times (e.g., the time between after the capsule left the stomach and deployed in the small intestine) were not appreciably affected by the presence of food in the GI tract including one or both of the stomach and small intestine. As used herein, with respect to deployment/activation times, appreciably affected means less than about a 20% difference in deployment/activation times, more preferably, less than about 10% and still more preferably less than about 5%. They also showed that patients do not have a perceptible sensation of the capsule passing into, through or existing the GI tract including when the capsule is actuated and deploys in the small intestine (actuation and deployment including the expansion of one more balloons or other expandable device). 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Gastric Emptying Times of the RaniPill Capsule 
               
               
                 in Fasting vs Postprandial Subjects 
               
            
           
           
               
               
               
            
               
                 Fasting Group 
                 PostPrandial Group 
                   
               
            
           
           
               
               
               
               
            
               
                 Subject ID 
                 GET (min) 
                 Subject ID 
                 GET (min) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 001-001 
                 140 
                 001-021 
                 270 
               
               
                 001-004 
                 40 
                 001-024 
                 210 
               
               
                 001-007 
                 200 
                 001-035 
                 210 
               
               
                 001-010 
                 120 
                 001-033 
                 210 
               
               
                 001-003 
                 40 
                 001-038 
                 210 
               
               
                 001-009 
                 240 
                 001-022 
                 150 
               
               
                 001-011 
                 40 
                 001-025 
                 270 
               
               
                 001-013 
                 140 
                 001-026 
                 210 
               
               
                 001-002 
                 20 
                 001-029 
                 &gt;300 
               
               
                 001-008 
                 20 
                 001-032 
                 210 
               
               
                 Average ± SD 
                 100 ± 79 
                 Average ± SD 
                 217 ± 36 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Internal Deployment Times of the RaniPill 
               
               
                 Capsule in Fasting vs Postprandial Subjects 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Subject ID 
                 IDT (min) 
                 Subject ID 
                 IDT (min) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 001-001 
                 75 
                 001-021 
                 90 
               
               
                   
                 001-004 
                 90 
                 001-024 
                 60 
               
               
                   
                 001-007 
                 135 
                 001-035 
                 90 
               
               
                   
                 001-010 
                 105 
                 001-033 
                 180 
               
               
                   
                 001-003 
                 135 
                 001-038 
                 60 
               
               
                   
                 001-009 
                 NA 
                 001-022 
                 120 
               
               
                   
                 001-011 
                 75 
                 001-025 
                 120 
               
               
                   
                 001-013 
                 120 
                 001-026 
                 90 
               
               
                   
                 001-002 
                 120 
                 001-029 
                 NA 
               
               
                   
                 001-008 
                 45 
                 001-032 
                 120 
               
               
                   
                 Average ± SD 
                 97 ± 30 
                 Average ± SD 
                 100 ± 40