Patent Description:
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. The prior art document <CIT> relates to a drug administration apparatus consisting of an ingestible capsule comprising a drug stored in powder form within the capsule, a sensor that changes in state in response to disposition of the capsule, a hydrophilic membrane, and a driving mechanism for driving the drug directly through an endothelial layer of the gastrointestinal tract in response to the change in state of the sensor. The hydrophilic membrane allows fluid from the gastrointestinal tract to enter into the capsule prior to activation of the driving mechanism.

<CIT> discloses a body-insertable apparatus for introducing into a subject to inject medical agent stored in a casing into a desired part in the subject. The body-insertable apparatus includes a fixing unit which fixes the casing to the desired part, and a projecting unit which projects, from the casing, an injection needle that is intended to inject the medical agent. The fixing unit and the projecting unit are driven by a driving source.

<CIT> discloses an in vivo sensing device which includes an immobilizer that may immobilize the device in an in vivo location. The immobilizer may be activated by for example a processor or in response to an in vivo condition or in response to a signal from an outside operator.

<CIT> discloses an introduction-into-subject system which is capable of making a puncture of a needle in a layer subjected to puncture. A capsule endoscope is disclosed, having a needle which can project from the surface of a casing and can be housed under the surface and the capsule endoscope has a permanent magnet. A magnetic field control part is intended to control a magnetic field generation part to generate a magnetic field which varies the direction of the permanent magnet on the basis of the magnetization direction of the permanent magnet at the capsule endoscope, the position of the needle at the capsule endoscope, and the direction of the tip of the needle.

<CIT> discloses a device that is used for the delivery of substances and for intracorporeal sampling through the ingestion of a capsule which is particularly intended for the intestine of a patient or animal. The capsule is disclosed as consisting of a body comprising an energy source, an emitter/receiver, a means of taking physical measurements in relation to the environment and position of the body, a module for delivering substances and/or a sampling module. All of these components are intended to be controlled by control means.

<CIT> discloses a device and method that is intended for releasing a therapeutic agent, wherein the device is for releasing a therapeutic agent brought into a position for therapy in the interior of a patient's body via a probe, comprising: a release, assigned to the probe and movable from a prestressing position into a destressing position, for releasing the therapeutic agent.

Examples of the disclosure provide devices, systems, kits and methods for delivering drugs and other therapeutic agents to various locations in the body. Many examples provide a swallowable device for delivering drugs and other therapeutic agents within the Gastrointestinal (GI) tract. Particular examples provide a swallowable device such as a capsule for delivering drugs and other therapeutic agents into the wall of the small intestine, large intestine or other GI organ wall. Examples of the invention are particularly useful for the delivery of drugs and other therapeutic agents which are poorly absorbed, poorly tolerated and/or chemically degraded (e.g. breakdown of the chemical structure of the molecule) within the GI tract (e.g. the digestive enzymes and acids in the stomach). Further, examples of the disclosure can be used to deliver drugs which were previously only capable of or preferably delivered by intravenous or other form of parenteral administration (e.g., intramuscular, etc). Additionally, examples of the disclosure are useful for achieving rapid release of a drug into the blood stream via oral delivery.

Examples of the disclosure provide devices, systems, kits and methods for delivering drugs and other therapeutic agents to various locations in the body. Many examples provide a swallowable device for delivering drugs and other therapeutic agents within the Gastrointestinal (GI) tract. Particular examples provide a swallowable device such as a capsule for delivering drugs and other therapeutic agents into the wall of the small intestine, large intestine or other GI organ wall. Examples of the disclosure are particularly useful for the delivery of drugs and other therapeutic agents which are poorly absorbed, poorly tolerated and/or chemically degraded (e.g. breakdown of the chemical structure of the molecule) within the GI tract/ Further, examples of the disclosure can be used to deliver drugs which were previously only capable of or preferably delivered by intravenous or other form of parenteral administration (e.g., intramuscular, etc).

According to the present invention there is provided an ingestible device comprising the features of claim <NUM>.

In one aspect of the invention, the actuator includes a release element comprising a material configured to degrade upon exposure to a selected pH in the gastrointestinal tract such that upon degradation, the preparation is advanced into the lumen wall. For example, the selected pH is greater than about <NUM>. In an alternative aspect, the actuator comprises a spring (<NUM>), the release element being coupled to the spring to retain the spring in a compressed state (<NUM>) and release the spring upon degradation of the release element.

In another aspect of the invention, the therapeutic agent preparation includes at least a first therapeutic agent and a second therapeutic agent.

In yet a further aspect of the invention, the therapeutic agent preparation comprises a therapeutically effective dose of insulin for the treatment of diabetes or a glucose regulation disorder.

In yet a further aspect of the invention, the therapeutic agent preparation comprises a therapeutically effective dose of an incretin for the treatment of diabetes or a glucose regulation disorder. For example, wherein the incretin comprises a glucagon like peptide-<NUM> (GLP-<NUM>), a GLP-<NUM> analogue, exenatide, liraglutide, albiglutide, taspoglutide or a gastric inhibitory polypeptide (GIP).

In yet a further aspect of the invention, the therapeutic agent preparation comprises a combination of therapeutic agents for the treatment of diabetes or a glucose regulation disorder, optionally, wherein the combination comprises a therapeutically effective dose of an incretin and a therapeutically effective dose of a biguanide. For example, the incretin comprises exenatide and the biguanide comprises metformin, or the dosages of the incretin and the biguanide are matched to produce an improved level of blood glucose control for an extended period.

In yet a further aspect of the invention, the therapeutic agent preparation comprises a therapeutically effective dose of growth hormone, a therapeutically effective dose of parathyroid hormone for the treatment of osteoporosis or a thyroid disorder, a therapeutically effective dose of a chemotherapeutic agent for the treatment of cancer, a therapeutically effective dose of antibiotic, a therapeutically effective dose of an antiviral compound, optionally wherein the antiviral compound comprises a protease inhibitor, or a therapeutically effective does of an anti-seizure compound, optionally wherein the anti-seizure compound comprises furosemide.

Further details of these and other embodiments and aspects of the invention are described more fully below, with reference to the attached drawing figures.

Embodiments of the invention provide devices 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 to the wall of the small intestine or other GI organ.

Referring now to <FIG>, embodiments of a device <NUM> for the delivery of medication <NUM> to a delivery site DS in the intestinal tract, comprises a capsule <NUM> including at least one aperture <NUM>, an expandable member <NUM>, guide tube <NUM>, and one or more tissue penetrating members <NUM> containing a medication <NUM>. The tissue penetrating member <NUM> can be formed at least in part from medication <NUM>, and/or contain a section or compartment <NUM> formed from or containing medication <NUM> that is integral with the tissue penetrating member <NUM> positioned or otherwise advanceable in the at least one guide tube, a delivery member <NUM>, an actuating mechanism <NUM> and release element <NUM>. Medication <NUM> also described herein as preparation <NUM>, typically comprises at least one drug or therapeutic agent <NUM> and may include one or more pharmaceutical excipients known in the art.

Device <NUM> including tissue penetrating member <NUM> can be configured for the delivery of liquid, semi-liquid or solid forms of medication <NUM> or all three. Solid forms of medication/preparation <NUM> can include both powder or pellet. Semi liquid can include a slurry or paste. Whatever the form, medication/preparation <NUM> 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 <NUM>. 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 <NUM> 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 <NUM> 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. 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 <NUM>:<NUM> to <NUM>:<NUM>, with specific embodiments of <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM> and <NUM>:<NUM>. Medication/preparation <NUM> will typically be pre-packed within a lumen <NUM> of tissue penetrating members <NUM>, but can also be contained at another location within an interior <NUM> of capsule <NUM>, or in the case of a liquid or semi-liquid, within an enclosed reservoir <NUM>. The medication can be pre-shaped to fit into the lumen or packed for example, in a powder form. Typically, the device <NUM> will be configured to deliver a single drug <NUM> as part of medication <NUM>. However in some embodiments, the device <NUM> can be configured for delivery of multiple drugs <NUM> including a first second, or a third drug which can be compounded into a single or multiple medications <NUM>. For embodiments having multiple medications/drugs, the medications can be contained in separate tissue penetrating members <NUM> or within separate compartments or reservoirs <NUM> within capsule <NUM>. In another embodiment, a first dose <NUM> of medication <NUM> containing a first drug <NUM> can be packed into the penetrating member(s) <NUM> and a second dose <NUM> of medication <NUM> (containing the same or a different drug <NUM>) can be coated onto the surface <NUM> of capsule as is shown in the embodiment of <FIG>. The drugs <NUM> in the two doses of medication <NUM> and <NUM> 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 <NUM> of medication <NUM> can have an enteric coating <NUM> to ensure that it is released in the small intestine and achieve a time release of the medication <NUM> as well. Enteric coating <NUM> can include one or more enteric coatings described herein or known in the art.

A system <NUM> for delivery of medication <NUM> into the wall of the small intestine or other location within the GI tract, may comprise device <NUM>, containing one or more medications <NUM> for the treatment of a selected condition or conditions. In some embodiments, the system may include a hand held device <NUM>, described herein for communicating with device <NUM> as is shown in the embodiment of <FIG>. System <NUM> may also be configured as a kit <NUM> including system <NUM> and a set of instructions for use <NUM> which are packaged in packaging <NUM> as is shown in the embodiment of <FIG>. The instructions can indicate to the patient when to take the device <NUM> 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 examples , kit <NUM> can include multiple devices <NUM> containing a regimen of medications <NUM> for a selected period of administration, e.g., a day, week, or multiple weeks depending upon the condition to be treated.

Capsule <NUM> is sized to be swallowed and pass through the intestinal tract. The size can also be adjusted depending upon the amount of drug to be delivered as well as the patient's weight and adult vs. pediatric applications. Typically the capsule will have a tubular shape with curved ends similar to a vitamin. In these and related examples , capsule lengths <NUM> can be in the range of <NUM> to <NUM> (<NUM> to <NUM> inches) and diameters 20D in the range of <NUM> to <NUM> (<NUM> to <NUM> inches) with other dimensions contemplated. The capsule <NUM> includes a capsule wall 21w, having an exterior surface <NUM> and an interior surface <NUM> defining an interior space or volume 24v. The capsule wall 21w includes volume <NUM> and an outer surface <NUM> having one or more apertures <NUM> sized for the outward advancement of tissue penetrating members <NUM>. via guide tubes <NUM>. In addition to the other components of device <NUM>, (e.g., the expandable member, actuation mechanism etc.) the interior volume can include one or more compartments or reservoirs <NUM>.

One or more portions of capsule <NUM> can be fabricated from various biocompatible polymers known in the art, including various biodegradable polymers which in a preferred example can comprise PGLA (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.

Use of biodegradable materials for capsule <NUM>, including biodegradable enteric materials allows the capsule to degrade in whole or part to facilitate passage through the GI system after drug deliver. As is described in further detail herein, in various examples, capsule <NUM> can include seams <NUM> of bio-degradable material so as to controllably degrade into smaller pieces <NUM> which are more easily passed through the intestinal tract.

Additionally, in various examples , the capsule <NUM> can include various radio-opaque or echogenic materials for location of the device using fluoroscopy, ultrasound or other medical imaging modality. In specific examples , all or a portion of the capsule can include radio-opaque/echogenic markers <NUM> as is shown in the example of <FIG> and <FIG>. In use, such materials not only allow for the location of device <NUM> in the GI tract, but also allow for the determination of transit times of the device through the GI tract.

Expandable member <NUM> can comprise a variety of expandable devices shaped and sized to fit within capsule <NUM>, but will typically comprise an expandable balloon <NUM>. Other suitable expandable members include various shape memory devices, and/or chemically expandable polymer devices having an expanded shape and size corresponding to the interior volume 24v of the capsule <NUM>. For ease of discussion, expandable member <NUM> will now be referred to as balloon <NUM>, but other embodiments are equally applicable. Balloon <NUM> will typically be attached to an interior surface <NUM> of the capsule <NUM> in at least a partially non-expanded state. Means of attachment can include the use of various adhesive known in the medical device arts. The balloon can be packed inside capsule <NUM> in a furled or other compact configuration to conserve space within the interior portion of the capsule. Furling may be achieved by placement of separation valve <NUM> over a selected portion of the un-inflated balloon <NUM>. In a particular embodiments, furling can be facilitated by the use of a collar type separation valve <NUM> described herein that is placed around the un-inflated balloon to hold in a furled configuration. In another approach, furling can also be achieved by the use of one or more pre-formed creases 30c placed along the balloon in a lateral, spiral or other configuration. In preferred embodiments, tissue penetrating members <NUM> are positioned within guide tubes <NUM> which serve to guide and support the advancement of members <NUM> into tissue such as the wall of the small intestine or other portion of the GI tract. In other embodiments, tissue penetrating members <NUM> can be positioned in capsule <NUM> without guide tubes. The tissue penetrating members <NUM> will typically comprise a hollow needle or other like structure and will have a lumen <NUM> and a tissue penetrating end <NUM> for penetrating a selectable depth into the intestinal wall IW. Member <NUM> may also include a pin <NUM> for engagement with a motion converter <NUM> described herein. The depth of penetration can be controlled by the length of member <NUM>, the configuration of motion converter <NUM> described herein as well as the placement of a stop or flange <NUM> on member <NUM> which can, in an embodiment, correspond to pin <NUM> described herein. Medication <NUM> will typically be delivered into tissue through lumen <NUM>. In many embodiments, lumen <NUM> is pre-packed with the desired medication <NUM> which is advanced out of the lumen using delivery member <NUM> or other advancement means (e.g. by means of force applied to a collapsible embodiment of member <NUM>). As an alternative, medication <NUM> can be advanced into lumen <NUM> from another location/compartment in capsule <NUM>. In some embodiments, all or a portion of the tissue penetrating member <NUM> can be fabricated from medication <NUM> itself. In these and related examples , 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 <NUM> can be formed into darts, pellets or other shapes using various compression molding and other related methods known in the pharmaceutical arts.

Balloon <NUM> can comprise various polymers known in the medical device arts, but preferably comprises non-compliant polymers such as PET (Polyethylene Teraphalate) and other non compliant materials known in the art. It can be fabricated using various balloon blowing methods known in the balloon catheters arts (e.g., mold blowing) to have a shape <NUM> and size which corresponds approximately to the interior volume 24v of capsule <NUM>. Suitable shapes <NUM> for balloon <NUM> include various cylindrical shapes having tapered or curved end portions <NUM> (an example of such a shape including a hot dog). In some examples , the inflated size of balloon <NUM>, including its diameter 30D can be slightly larger than capsule <NUM> so as to cause the capsule to come apart from the force of inflation, (e.g., due to hoop stress). Desirably, the walls <NUM> of balloon <NUM> will be thin and can have a wall thickness <NUM> in the range of <NUM> to <NUM> (<NUM> to <NUM>") more preferably, in the range <NUM> to <NUM> (<NUM> to <NUM>"), with specific examples of <NUM>, <NUM> and <NUM> (<NUM>, <NUM>, and <NUM>").

In various examples , device <NUM> can include a second <NUM> and a third <NUM> tissue penetrating member <NUM> as is shown in the examples of <FIG> and <FIG>. , with additional numbers contemplated. Each tissue penetrating member <NUM> can be used to deliver the same or a different medication <NUM> as well as different doses of the same drug. In preferred examples , the tissue penetrating members <NUM> can be substantially symmetrically distributed around the perimeter <NUM> of capsule <NUM> so as to anchor the capsule onto the intestinal wall IW during delivery of medications <NUM>. Anchoring capsule <NUM> 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 examples , 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 <NUM> to have a curved or arcuate shape.

Balloon <NUM> also will typically include at least a first and a second portion or compartment <NUM> and <NUM> which are separated by a separation valve, delivery member, or other separation means which separates the contents of each compartment. In many embodiments, compartments <NUM> and <NUM> will have at least a small connecting section <NUM> between them which is where separation valve <NUM> will typically be placed. A liquid <NUM>, typically water, can be disposed within first compartment <NUM> and one or more reactants <NUM> disposed in second compartment <NUM> (which typically are solid though liquid may also be used) as is shown in the embodiment of <FIG>. When valve <NUM> opens (e.g., from degradation caused by fluids within the small intestine) liquid <NUM> enters compartment <NUM> (or vice versa or both), the reactant(s) <NUM> mix with the liquid and produce a gas <NUM> such as carbon dioxide which expands balloon <NUM> as is shown in the embodiments of <FIG>. Expansion of balloon <NUM> is configured to advance medication <NUM> through the tissue penetrating member <NUM> into the intestinal wall IW as will be explained more fully herein. Accordingly, at least a portion of the delivery member <NUM> is advanceable within the tissue penetrating member lumen <NUM> and thus member <NUM> has a size and shape (e.g., a piston like shape) configured to fit within the delivery member lumen <NUM> or other chamber or compartment within tissue penetrating member <NUM>.

Reactants <NUM> will typically include at least a first and a second reactant, <NUM> and <NUM> for example, an acid such as citric acid and a base such as sodium hydroxide. Additional numbers of reactants are also contemplated. For embodiments using citric acid and sodium hydroxide, the ratio's between the two reactants (citric acid to sodium hydroxide) can be in the range of <NUM>:<NUM> to <NUM>:<NUM>, with a specific ratio of <NUM>:<NUM>. Desirably, solid reactants <NUM> have little or no absorbed water. Accordingly, one or more of the reactants, such as sodium hydroxide can be pre-dried (e.g., by vacuum drying) before being placed within balloon <NUM>. Other reactants <NUM> including other acids, e.g., ascetic acid and bases are also contemplated. The amounts of particular reactants <NUM>, 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 some embodiments, the distal end 50d of the delivery member (the end which is advanced into tissue) can have a plunger element <NUM> which advances the medication within the tissue penetrating member lumen <NUM> and also forms a seal with the lumen. Plunger element <NUM> can be integral or attached to delivery member <NUM>. Preferably, delivery member <NUM> is configured to travel a fixed distance within the needle lumen <NUM> 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 <NUM> 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 <NUM> (including controller 29c) coupled to an electro-mechanical embodiment of actuating mechanism <NUM>. This allows for a variable dose of medication and/or variation of the distance the medication is injected into the intestinal wall.

Various embodiments of the invention provide a number of structures and configurations for a separation valve <NUM> or other separation means <NUM>. As is described below, in one or more embodiments, valve <NUM> may comprise a beam like structure, or collar type valve. Still other structures are considered. In one or more of these embodiments, valve <NUM> can include one or more pinching features <NUM> such as a ridge which engages a depression or other mating feature <NUM> on the internal surface <NUM> of capsule <NUM> as is shown in the embodiment of <FIG>. In use, pinching features <NUM> provide for the application of additional force on the balloon wall <NUM> beneath the pinching feature and redundancy to the seal. Valve <NUM> may include multiple pinching features <NUM> to create a seal under each feature.

Actuating mechanism <NUM> can be coupled to at least one of the tissue penetrating member <NUM> or delivery member <NUM>. The actuating mechanism is configured to advance tissue penetrating member <NUM> a selectable distance into the intestinal wall IW as well as advance the delivery member to deliver medication <NUM> and then withdraw the tissue penetrating member from the intestinal wall. In various embodiments, actuating mechanism <NUM> can comprise a spring loaded mechanism which is configured to be released by release element <NUM>. Suitable springs <NUM> can include both coil (including conical shaped springs) and leaf springs with other spring structures also contemplated. In particular embodiments, spring <NUM> 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.

Also in various embodiments, separation valve <NUM> can be configured to open in a number of ways and responsive to a number of conditions within the GI tract. In many embodiments, the separation valve <NUM> will be configured to open by having one or more portions degrade in response to the higher pH or other conditions found within the small intestine such that upon degradation, the valve opens. As an alternative or additional approach, separation valve <NUM> may also be configured to open in response to compressive forces applied by a peristaltic contraction within the small intestine. In still another approach, separation valve <NUM> may be a time-release valve configured to open after a certain period of time after a trigger event, e.g., an activation step initiated by the patient such as the pealing of a tab or pressing of a button.

In particular embodiments actuating mechanism <NUM> can comprise a spring <NUM>, a first motion converter <NUM>, and a second motion converter <NUM> and a track member <NUM> as is shown in the embodiments of <FIG>, <FIG> and <FIG>. The release element <NUM> is coupled to spring <NUM> to retain the spring in a compressed state such that degradation of the release element releases the spring. Spring <NUM> may be coupled to release element <NUM> by a latch or other connecting element <NUM>. First motion converter <NUM> is configured to convert motion of spring <NUM> to advance and withdraw the tissue penetrating member <NUM> in and out of the intestinal wall or other tissue. The second motion converter <NUM> is configured to convert motion of the spring <NUM> to advance the delivery member <NUM> into the tissue penetrating member lumen <NUM>. Motion converters <NUM> and <NUM> are pushed by the spring and ride along a rod or other track member <NUM> which fits into a track member lumen <NUM> of converter <NUM>. The track member <NUM> which serves to guide the path of the converters <NUM>. Converters <NUM> and <NUM> engage the tissue penetrating member <NUM> and/or delivery member <NUM> (directly or indirectly) to produce the desired motion. They have a shape and other characteristics configured to convert motion of the spring <NUM> along its longitudinal axis into orthogonal motion of the tissue penetrating member <NUM> and/or delivery member <NUM> 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 <NUM> can have a trapezoidal shape 90t and include a slot <NUM> which engages a pin <NUM> on the tissue penetrating member that rides in the slot as is shown in the embodiments of <FIG>, <FIG> and <FIG>. Slot <NUM> can also have a trapezoidal shape 93t that mirrors or otherwise corresponds to the overall shape of converter <NUM>. Slot <NUM> serves to push the tissue penetrating member <NUM> during the upslope portion <NUM> of the trapezoid and then pull it back during the down slope portion <NUM>. In one variation, one or both of the motion converters <NUM> and <NUM> can comprise a cam or cam like device (not shown). The cam can be turned by spring <NUM> so as to engage the tissue penetrating and/or delivery members <NUM> and <NUM>. One or more components of mechanism <NUM> (as well as other components of device <NUM>) including motion converters <NUM> and <NUM> 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 <NUM>. Also as is described herein, they can be formed from various biodegradable materials known in the art.

Examples of a degradable separation valve <NUM> can be positioned in a variety of locations on or within capsule <NUM> so as to exposed to and degraded by the intestinal fluids. While at least a portion of the valve may be exposed to the capsule exterior surface <NUM>, typically, the valve will be positioned within the capsule interior 224v where it is exposed to intestinal fluids which enter through the at least one aperture <NUM> or other opening. In these and related examples , at least a portion of the capsule exterior surface <NUM> including the portion containing the at least one aperture <NUM> is desirably coated with a protective layer or coating 220c, such as an enteric coating which also degrades in response to pH or other conditions within the small intestine. Typically, the entire capsule will be so coated, however in some embodiments only a portion over apertures <NUM> will be coated. Such coatings provide a protective seal <NUM> over the at least one aperture <NUM> so that digestive fluids do not enter the capsule interior 224v and start to degrade the separation valve <NUM> until the capsule has reached the small intestine. The examples of <FIG> illustrate the sequence of degradation of the coating, ingress of intestinal or other fluid F into the capsule interior and subsequent degradation of the separation valve. In use, examples of device <NUM> employing a degradable coating 220c over the aperture <NUM> and a degradable valve <NUM> provide a primary and secondary seal for assuring that balloon <NUM> does not prematurely expand and deploy its tissue penetrating members <NUM> until capsule <NUM> has reached the small intestine.

In other variations, the actuating mechanism <NUM> can also comprise an electro-mechanical device/mechanism such as a solenoid, or a piezoelectric device. In one examples, a piezoelectric device used in mechanism <NUM> 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 examples allow for a reciprocating motion of the actuating mechanism <NUM> 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 <NUM> by a peristaltic contraction of the small intestine around the capsule. Further description of piezoelectric based energy converters is found in <CIT>.

In one example , deployment of tissue penetrating members <NUM> 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.

According to one or more examples , separation valve <NUM> may comprise a beam-like structure <NUM> that is placed within capsule <NUM> to compress and seal the portion of the balloon <NUM> between the first and second compartments <NUM> and <NUM> as is shown in the example of <FIG>. Beam <NUM> is desirably constructed of one more degradable materials described herein, e.g., PGLA, cellulose, etc. which degrade in response to the fluids found within the small intestine. When beam <NUM> degrades, the compressive forces of the balloon are released and contents from the first and second compartments <NUM> and <NUM> mix causing balloon expansion as described herein. Beam <NUM> can be attached at one or both sides of the interior surface <NUM> of the capsule. Typically, the beam will be placed proximate a central portion <NUM> of balloon <NUM>, though other locations are also contemplated. In preferred examples , the beam <NUM> is positioned in radially oriented fashion with respect to balloon lateral axis 20la, attached to the radial sides 220rs of capsule interior surface <NUM> as is shown in the example of <FIG>. However, beam <NUM> may also be attached to the lateral ends 20le of the capsule interior surface. Preferably, in either of these two examples , beam <NUM> is attached to capsule interior surface <NUM> using an interference fit so that the beam can be snapped into place within the capsule using pick and place and other like methods known in the manufacturing arts. In specific examples , interior surface <NUM> can include notches 224n for placement of beam ends 258e to allow a snap or press fit of the beam <NUM> into the capsule <NUM>.

Release element <NUM> will typically be coupled to the actuating mechanism <NUM> and/or a spring coupled to the actuating mechanism; however other configurations are also contemplated. In preferred embodiments, release element <NUM> is coupled to a spring <NUM> positioned within capsule <NUM> so as to retain the spring in a compressed state <NUM> as shown in the embodiment of <FIG>. Degradation of the release element <NUM> releases spring <NUM> to actuate actuation mechanism <NUM>. Accordingly, release element <NUM> can thus function as an actuator 70a (actuator 70a may also include (singularly or coupled to release element <NUM>) spring <NUM> and other elements of mechanism <NUM>). As is explained further below, actuator 70a has a first configuration where the therapeutic agent preparation <NUM> is contained within capsule <NUM> 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 <NUM> comprises a material configured to degrade upon exposure to chemical conditions in the small or large intestine such as pH. Typically, release element <NUM> is configured to degrade upon exposure to a selected pH in the small intestine, e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM><NUM> or greater. The release element can also be configured to degrade within a particular range of pH such as, e.g., <NUM> to <NUM>. In particular embodiments, the pH at which release element <NUM> 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 <NUM> having multiple medications <NUM>, the device can include a first release element <NUM> (coupled to an actuating mechanism for delivering a first drug) configured to degrade at first pH and a second release element <NUM> (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).

According to another embodiment shown in <FIG>, the separation valve <NUM> can comprise a collar valve <NUM> including a connecting <NUM> of the expandable member <NUM> with an overlying constricting collar 255c made from biodegradable material. Collar 255c holds connection section <NUM> closed and releases it when the collar is degraded.

Release element <NUM> 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 <NUM> 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 <NUM> can be substantially synchronized or otherwise timed with the digestion of a meal. Such embodiments are particularly useful for the delivery of medication to control levels of blood sugar/glucose (e.g., insulin), serum cholesterol and serum triglycerides.

In addition to release valve <NUM>, the balloon or other expandable member <NUM> will also typically include a deflation valve <NUM> which serves to deflate balloon <NUM> after inflation. Deflation valve <NUM> 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 balloon. In one embodiment shown in <FIG>, the deflation valve <NUM> can comprise a biodegradable section <NUM> positioned on an end portion <NUM> of the balloon <NUM> so as to join opposing ends of the balloon wall <NUM> together. In this and related embodiments, when degradable section <NUM> degrades from exposure to the liquid, balloon wall <NUM> tears or otherwise comes apart providing for a high assurance of rapid deflation. Multiple degradable sections <NUM> can be placed at various locations within balloon wall <NUM> is shown in the embodiment of <FIG>, to provide an even higher degree of reliability in deflation. Desirably, sections <NUM> are only placed within the wall <NUM> of compartment <NUM>. For embodiments where the deflation valve <NUM> is degraded by fluids within the small intestine, degradation of the valve can be facilitated by configuring inflated balloon <NUM> to break apart capsule <NUM> into two or more pieces so that large sections of the balloon are directly exposed to degrading fluids within the small intestine. This can be achieved by fabricating capsule <NUM> from separate parts (e.g., two halves mechanically fit together) and/or through the use of seams <NUM> in the capsule wall as is described herein.

Various approaches are contemplated for biodegradation of release element <NUM>. In particular embodiments, biodegradation of release element <NUM> 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: 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 visa 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.

Additionally, as further backup for insured deflation, one or more puncture elements <NUM> can be attached to the inside surface <NUM> of the capsule wall such that when the balloon fully deflates it is contacts and is punctured by the puncture element. Puncture elements <NUM> can comprise short protrusions from surface <NUM> having a pointed tip <NUM>. In another alternative or additional embodiment of means for balloon deflation, one or more of the tissue penetrating members <NUM> can be directly coupled to balloon wall <NUM> and configured to tear away from the balloon when they detach, tearing the balloon wall in the process.

In alternative embodiments, the release element <NUM> can comprise a film or plug 70p that fits over or otherwise blocks guide tubes <NUM> and retains the tissue penetrating member <NUM> inside the guide tube (<FIG>). In these and related embodiments, tissue penetrating member <NUM> 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 <NUM> can be shaped to function as a latch which holds the tissue penetrating member <NUM> in place. In these and related embodiments, the release element can be located on the exterior or the interior of capsule <NUM>. In the latter case, capsule <NUM> and/or guide tubes <NUM> can be configured to allow for the ingress of intestinal fluids into the capsule interior to allow for the degradation of the release element.

Tissue penetrating member <NUM> can be fabricated from various drugs and other therapeutic agents <NUM> as well as one or more biodegradable polymers to provide desired structural properties to the penetrating member (e.g., column strength) and/or control the release of drug. Referring now to <FIG>, in many embodiments, the penetrating member <NUM> can be formed to have a shaft <NUM> and a needle tip <NUM> or other pointed tip <NUM> so as to readily penetrate tissue of the intestinal wall as shown in the embodiment of <FIG>. Tip <NUM> may comprise degradable materials (within the body of the tip or as a coating), such as sucrose which increase the hardness and tissue penetrating properties of the tip. Once placed in the intestinal wall, the penetrating member <NUM> is degraded by the interstitial fluids within the wall tissue, the drug dissolves in those fluids and is absorbed into the blood stream. Penetrating member <NUM> will also typically include one or more tissue retaining features <NUM> such as a barb or hook to retain the penetrating member within the tissue of the intestinal wall after advancement. Retaining remembers <NUM> can be arranged in various patterns 43p to enhance tissue retention such as two or more barbs symmetrically or otherwise distributed around and along member shaft <NUM> as is shown in the embodiments of <FIG>. Additionally, in many embodiments, penetrating member will also include a recess or other mating feature <NUM> for attachment to a coupling component which attaches the penetrating member to the balloon (such as advancement member 80a described below).

As described above, tissue penetrating member <NUM> can be fabricated from a number of drugs and other therapeutic agents <NUM>. The penetrating member may be fabricated entirely from drug <NUM> or may have other constituent components as well, e.g., various pharmaceutical excipients. Typically, the drug or other therapeutic agent <NUM> will be mixed in with a biodegradable polymer <NUM> such as PGLA, cellulose or other biodegradable material described herein or known in the art. In such embodiments, the penetrating member <NUM> may comprise a substantially heterogeneous mixture of drug <NUM> and biodegradable polymer <NUM>. Alternatively, the penetrating member may <NUM> include a <NUM> portion formed substantially from biodegradable material <NUM> and a separate section or compartment <NUM> that is formed from or contains drug <NUM> as shown in the embodiment of <FIG>.

Tissue penetrating member <NUM> can be fabricated using one or more polymer and pharmaceutical fabrication techniques known in the art. For example, drug <NUM> (with or without biodegradable material <NUM>) can be in solid form and then formed into the shape of the tissue penetrating member <NUM> using molding, compaction or other like method with one or more binding agents added. Alternatively, drug <NUM> and/or drug preparation <NUM> may be in solid or liquid form and then added to the biodegradable polymer <NUM> in liquid form with the mixture then formed into the penetrating member <NUM> using molding or other forming method known in the polymer arts.

Desirably, embodiments of the tissue penetrating member <NUM> comprising a drug or other therapeutic agent <NUM> and degradable polymer <NUM> 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 <NUM>% by weight and more preferably, less than <NUM>% and still more preferably less than <NUM>%. 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.

Tissue penetrating member <NUM> is desirably configured to be detachably coupled (directly or indirectly) to the balloon or other expandable member <NUM> so that after advancement of the tissue penetrating member <NUM> into the intestinal wall, the penetrating member detaches from the balloon. Detachability can be implemented by a variety of means including: i) the configuration and strength of the joint between penetrating member <NUM> and advancement member 380a (or other intermediary component(s) coupling member <NUM> to balloon <NUM>); <NUM>) the configuration and placement of tissue retaining features <NUM> on penetrating member <NUM>; and iii) the depth of penetration of shaft <NUM> into the intestinal wall. Using one or more of these factors, penetrating member <NUM> be configured to detach as a result of balloon deflation (where the retaining features <NUM> hold the penetrating member in tissue as the balloon deflates or otherwise pulls back away from the intestinal wall) and/or the forces exerted on capsule <NUM> by a peristaltic contraction of the small intestine.

Tissue penetrating member <NUM> can be directly or indirectly coupled to balloon <NUM>. Referring now to <FIG> and <FIG>, indirect coupling can be implemented using one or more coupling components <NUM> such as an advancement member 380a. Accordingly, in particular embodiments, the tissue penetrating member <NUM> may be coupled to balloon <NUM> by an advancement member 380a comprising a rigid structure attached to the balloon surface <NUM> which detachably engages the penetrating member <NUM>. The advancement member 380a engages the penetrating member <NUM> by means of an attachment feature <NUM> such as a pin or other protrusion <NUM> (integral or attached to member 380a) which fits into a recess or other mating feature <NUM> of the penetrating member as is shown in the embodiment of <FIG>. The pin <NUM> and recess <NUM> can be configured to detach from the force of balloon deflation and/or force applied to capsule <NUM> by peristaltic contraction. In many embodiment, advancement member 380a can have a larger horizontal surface area <NUM> than the surface area <NUM> of penetrating member <NUM> so as to function as a force concentration element <NUM> as is shown in the embodiment of <FIG>. In use force concentration element <NUM> functions to increase the force per unit area applied to the penetrating member from expansion of balloon <NUM> or other expandable member.

In some embodiments, the advancement member 480a can be coupled to the balloon <NUM> via a support member <NUM> as is shown in the embodiments of <FIG> and <FIG>. Support member <NUM> may correspond to a platform <NUM> having one surface <NUM> attached to the balloon surface <NUM> and the other surface <NUM> attached to the advancement member 480a (one or both of these attachments can be an adhesive attachment) as is shown in the embodiment of <FIG>. Platform <NUM> is desirably rigid, can have a plate-like structure and can be sized to allow for attachment and advancement of multiple advancement members 480a and tissue penetrating members <NUM> at the same time as is shown in the embodiment of <FIG>. For example, in particular embodiments, three, four or five groups of advancement and tissue penetrating members can be attached to platform <NUM>, with additional numbers contemplated. In such embodiments, the platform may include a recess <NUM> for positioning of isolation valve <NUM>.

Also, platforms <NUM> can be placed on either side of balloon <NUM> to allow for bilateral deployment of tissue penetrating members <NUM> into intestinal wall IW as is shown in the embodiment of <FIG> and <FIG>. In addition to delivering more drug, bilateral deployment serves to anchor capsule <NUM> on both sides of the intestinal wall IW during deployment of penetrating members <NUM>, thus reducing the likelihood of the capsule from being dislodged during deployment (e.g., due to peristaltic contraction). In these and related embodiments tissue penetrating members <NUM> can be directly coupled to platform <NUM> without necessarily using advancement members 480a. Desirably, both advancement members <NUM> and platform <NUM> are constructed from biodegradable materials such as PGLA, which can be cross linked and/or copolymerized with to have increased rigidity to support the advancement of penetrating members <NUM> into tissue.

As an additional or alternative embodiment to the use of advancement member 480a and/or platform <NUM>, tissue penetrating members <NUM> may be directly coupled to the balloon <NUM>, e.g., by an adhesive where the adhesive force is less than the necessary to pull penetrating member out of tissue once it is deployed into the intestinal wall. In these and related embodiments, the tissue penetrating members <NUM> may also be configured to tear the balloon wall <NUM> when they detach from the balloon and thus provide a means for balloon deflation.

In various embodiments, penetrating members <NUM> can carry the same or a different drug <NUM> or other therapeutic agent. The former configuration allows for the delivery of greater amounts of a particular drug <NUM>, 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 various embodiments, depending upon the drug and associated drug regimen (e.g., dose and times per day, etc), tissue penetrating members <NUM> can be placed and distributed in a number of locations and patterns on the balloon surface. As described above for the embodiments of <FIG> and <FIG>, tissue penetrating members <NUM> can be placed on opposite sides of balloon surface <NUM> so that balloon inflation can place tissue penetrating members <NUM> on opposite sides of the intestinal wall IW. Referring now to <FIG>, in other embodiments, tissue penetrating members <NUM> can be symmetrically or otherwise distributed around substantially the entire perimeter 430p of the balloon <NUM> or other expandable member <NUM> as is shown in the embodiments of <FIG>. In use, such embodiments not only anchor capsule <NUM> into the intestinal wall IW (as described above for bidirectional deployment) but also place tissue penetrating members <NUM> in a distributed pattern 440p around the circumference of the intestinal wall IW. Embodiments of the invention utilizing such a distributed delivery of drug into the intestinal wall can achieve the following: i) allow for additional amounts of a particular drug to be delivered; and ii) provide for faster absorption of the drug into the blood stream due to a more even distribution of the drug within the intestinal wall (e.g., due to placement of the tissue penetrating members within a larger volume of intestinal vascular for mass transfer and absorption into the blood).

As described herein, many embodiments of device <NUM> include a drug carrying tissue penetrating member <NUM> as a means for delivering drug or other therapeutic agent <NUM> into the intestinal wall. Referring now to <FIG> and <FIG>, as an alternative or additional means for delivering drug into the intestinal wall, in various embodiments, device <NUM> can also be configured to inject drug <NUM> into the intestinal wall by means of hollow tissue penetrating members <NUM> coupled to one or more drug reservoirs <NUM>. Hollow tissue penetrating members <NUM> include at least one lumen <NUM>. Reservoirs <NUM> are desirably compressible by expansion of the balloon or other expandable member <NUM> and can thus comprise various biodegradable elastic polymers. The reservoirs <NUM> can contain drug or other therapeutic agent <NUM> in liquid or powder form. For liquid form, the drug will be dissolved in an aqueous drug solution <NUM>. In these and related embodiments, reservoirs <NUM> are fluidically coupled to hollow tissue penetrating members <NUM> such that inflation of balloon <NUM> compresses the reservoirs <NUM> so as to force the drug solution <NUM> through tissue penetrating member lumen <NUM> and into the intestinal wall as is shown in <FIG> and <FIG>. In these and related embodiments apertures <NUM>, can include a guide tube <NUM>, which is horizontally aligned with the tip <NUM> of penetrating member <NUM> and configured to guide the advancement of penetrating member <NUM> out of capsule <NUM> and into the intestinal wall. Multiple reservoirs <NUM> are contemplated including two, three, four or more. In particular embodiments, two reservoirs <NUM> can be coupled to a hollow tissue penetrating member with the reservoirs placed about <NUM> degrees apart with respect to penetrating member shaft <NUM>. Typically, the reservoirs <NUM> will be fluidically coupled to the hollow penetrating member <NUM> by means of a manifold <NUM>. Suitable manifolds <NUM> include a t-shaped manifold 590t having connectors <NUM> on either of its lateral ends <NUM> for connection to reservoirs <NUM> and a central connector <NUM> for connection to hollow tissue penetrating member <NUM> and a central lumen or channel <NUM> going to all connectors <NUM> (<FIG>). Other shapes and manifold configurations are also contemplated, for example, Y-shaped (connecting two reservoirs to tissue penetrating member <NUM>).

In some embodiments, balloon <NUM> or other expandable member <NUM> can be expanded responsive to a sensor <NUM>, such as a pH sensor <NUM> or other chemical sensor which detects the presence of the capsule in the small intestine. Sensor <NUM> (<FIG>) can then send a signal to a controllable embodiment of isolation valve <NUM> or to an electronic controller 29c coupled to a controllable isolation valve <NUM> to open and thus expand balloon <NUM> as is described herein. Embodiments of a pH sensor <NUM> 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/contractable sensor <NUM> can also comprise the actuating mechanism <NUM> itself by using the mechanical motion from the expansion or contraction of the sensor.

Referring now to <FIG> and <FIG>, in related embodiments, an expandable/contractible pH sensor <NUM> can also comprise the isolation valve <NUM> itself, by configuring the sensor to expand or contract so as to open a channel between balloon compartments <NUM> and <NUM>. According to one embodiment for such an approach, a pH sensor <NUM> may be integrated into a collar valve <NUM> where sensor <NUM> comprises all or a portion of a collar 655c that is placed over connecting portion <NUM> of balloon <NUM> (<FIG>). In this embodiment, sensor <NUM> would be an expandable sensor 668e, configured to expand upon exposure to the pH conditions in the small intestine (e.g., a pH above <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, etc) so as to either have the collar come off or significantly loosen collar 655c enough to allow contents of compartments <NUM> and <NUM> to mix. According to another embodiment shown in <FIG>, a pH sensor <NUM> could be integrated into a beam valve <NUM> described herein, where the beam is under compressive load by being snap fit against the capsule interior surface <NUM>. The beam applies a portion of this compressive load onto balloon connecting section <NUM> so as to maintain the seal between compartments <NUM> and <NUM>. In this case, sensor <NUM> would be a contractible sensor 668c configured to open valve <NUM> by contracting upon exposure to higher pH in the intestine, so that the beam shortens sufficiently so that it falls out of place against capsule surface <NUM> or other wise no longer applies a compressive load sufficient to maintain a seal over balloon connecting section <NUM>.

According to another embodiment for detecting when the device is in the small intestine (or other location in the GI tract), sensor <NUM> can comprise pressure/force sensor such as strain gauge for detecting the number of peristaltic contractions that capsule <NUM> is being subject to within a particular location in the intestinal tract (in such embodiments capsule <NUM> 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 <NUM> to <NUM> 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 <NUM> 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 <NUM> 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 send a signal to expand balloon <NUM> or other expandable member <NUM> to activate the actuating mechanism <NUM> to deliver medication <NUM> by means of RF, magnetic or other wireless signaling means known in the art. In various embodiments, including those with reference to <FIG>, external activation can be achieved by use of a controllable isolation valve <NUM> for example, a radio frequency (RF) controlled miniature solenoid valve or other electro-mechanical control valve (not shown). In other embodiments, a controllable isolation valve <NUM> may correspond to a miniature magnetically valve such as a magnetically controlled miniature reed switch (not shown). Such electromechanical or magnetic-based valves can be fabricated using MEMS and other micro-manufacturing methods. In these and related embodiments, the user can use a handheld communication device <NUM> (e.g., a hand held RF device such as a cell phone) as is shown in the embodiment of <FIG>, to send a receive signals <NUM> from device <NUM>. In such embodiments, swallowable device may include a transmitter <NUM> such as an RF transceiver chip or other like communication device/circuitry. Handheld device <NUM> may not only includes signaling means, but also means for informing the user when device <NUM> is in the small intestine or other location in the GI tract. The later embodiment can be implemented through the use of logic resources <NUM> (e.g., a processor <NUM>) coupled to transmitter <NUM> 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 <NUM> may include a controller 29c (either in hardware or software) to control one or more aspects of the process. The same handheld device can also be configured to alert the user when balloon <NUM> or actuating mechanism <NUM> has been expanded or activated (respectively) and the selected medication <NUM> delivered (e.g., using processor <NUM> and transmitter <NUM>). In this way, the user is provided confirmation that medication <NUM> 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 <NUM> to over-ride isolation valve <NUM> or actuating mechanism <NUM> and so prevent delay or accelerate the delivery of medication <NUM>. 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 expand balloon <NUM> or activate actuating mechanism <NUM> at a selected time period after swallowing the capsule. The time period can be correlated to a typical transit time or range of transit times for food moving through the user's GI tract to a particular location in the tract such as the small intestine.

Referring now to <FIG> and <FIG>, in various embodiments, the capsule <NUM> can include seams <NUM> of biodegradable material which controllably degrade to produce capsule pieces <NUM> of a selectable size and shape to facilitate passage through the GI tract as is shown in the embodiment of <FIG>, <FIG>, for example. Seams <NUM> can also include pores or other openings 722p for ingress of fluids into the seam to accelerate biodegradation as is shown in the embodiment of <FIG>. Other means for accelerating biodegradation of seams <NUM> can include pre-stressing the seam and/or including perforations 722f in the seam (<FIG>). In still other embodiments, seam <NUM> 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.

Referring now to <FIG> and <FIG>, in many embodiments seams <NUM> can also be configured and arranged so as to allow capsule <NUM> to be broken into smaller pieces by the inflation of balloon <NUM> or other expandable member <NUM>. In particular embodiments, seams <NUM> can be oriented with respect to capsule radial perimeter <NUM>, including having a radial pattern 722rp so as to have the capsule break into halves or other fractional pieces along its perimeter. Seams <NUM> may also be longitudinally-oriented with respect to capsule lateral access 7201a to have the capsule break up into lengthwise pieces.

As alternative or additional approach for breaking up capsule <NUM> by balloon inflation (or expansion of other expandable member <NUM>), capsule <NUM> can be fabricated from two or more separate joinable pieces 723j (e.g., radial halves) that are joined at a joint 722j formed by seams <NUM> (which function as an adhesive joint) as shown in the embodiment of <FIG>. Alternatively, joinable pieces 723j may be merely joined by a mechanical fit such as a snap or press fit.

Suitable materials for seams <NUM> can include one or more biodegradable materials described herein such as PGLA, glycolic acid etc. Seams <NUM> can be attached to capsule body <NUM> using various joining methods known in the polymer arts such as molding, hot melt junctions, etc. Additionally for embodiments of capsule <NUM> which are also fabricated from biodegradable materials, faster biodegradation of seam <NUM> 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 <NUM> 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 <NUM> can be adapted for swallowable imaging and other swallowable devices.

In still other embodiments, seam <NUM> 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.

Further are disclosed, not claimed, methods for the delivery of drugs and other therapeutic agents (in the form of medication <NUM>) into the walls of the GI tract using one or more embodiments of swallowable drug delivery device <NUM>. An example of such a method will now be described. The described example of drug delivery occurs in the small intestine SI. However, it should be appreciated that this is exemplary and that methods 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 <NUM> will sometimes be referred to herein as a capsule. As described above, in various embodiments device <NUM> may be packaged as a kit <NUM> within sealed packaging <NUM> that includes device <NUM> and a set of instructions for use <NUM>. If the patient is using a handheld device <NUM>, the patient may instructed to enter data into device <NUM> either manually or via a bar code <NUM> (or other identifying indicia <NUM>) located on the instructions <NUM> or packaging <NUM>. If a bar code is used, the patient would scan the bar code using a bar code reader <NUM> on device <NUM>. After opening packaging <NUM>, reading the instructions <NUM> and entering any required data, the patient swallows an embodiment of the swallowable drug delivery device <NUM>. Depending upon the drug, the patient may take the device <NUM> in conjunction with a meal (before, during or after) or a physiological measurement such as a blood glucose measurement. Capsule <NUM> is sized to pass through the GI tract and travels through the patient's stomach S and into the small intestine SI through peristaltic action as is shown in the embodiment of <FIG>. Once the capsule <NUM> is in the small intestine, the release element <NUM> is degraded by the basic pH in the small intestine (or other chemical or physical condition unique to the small intestine) so as expand balloon <NUM> or other expandable member <NUM>, actuate the actuating mechanism <NUM> and deliver medication <NUM> into the wall of the small intestine SI. In case a hollow needle or other hollow tissue penetrating member <NUM> is used, medication delivery is effectuated by using balloon <NUM> the actuating mechanism <NUM> to advance the needle <NUM> a selected distance into the mucosa of the intestinal wall IS, and then the medication is injected through the needle lumen by advancement of the delivery member <NUM>. The delivery member <NUM> is withdrawn and the needle <NUM> is then withdrawn back within the body of the capsule (e.g. by recoil) detaching from the intestinal wall. For embodiments of device <NUM> having multiple needles, a second or third needle <NUM>, <NUM> can also be used to deliver additional doses of the same drug or separate drugs <NUM>. Needle advancement can be done substantially simultaneously or in sequence. When using multiple needles, needle advancement can be done substantially simultaneously so as to anchor device <NUM> in the small intestine during drug delivery.

After medication delivery, device <NUM> then passes through the intestinal tract including the large intestine LI and is ultimately excreted. When using a tearable capsule, the capsule may immediately be broken into smaller pieces by inflation of balloon <NUM>. For embodiments of the capsule <NUM> having biodegradable seams <NUM> 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 <FIG>. When using biodegradable tissue penetrating needles/members <NUM>, should the needle get stuck in the intestinal wall, the needle biodegrades releasing the capsule <NUM> from the wall.

For embodiments of device <NUM> including a sensor <NUM>, can be effectuated by the senor sending a signal to a controllable embodiment of isolation valve <NUM> or actuating mechanism <NUM> and/or a processor <NUM>/controller 29c coupled to the isolation valve <NUM> or actuating mechanism. For embodiments of device <NUM> including external actuation capability, the user may externally expand balloon <NUM> or activate actuating mechanism <NUM> at a selected time period after swallowing the capsule. The time period can be correlated to a typical transit time or range of transit times for food moving through the user's GI tract to a particular location in the tract such as the small intestine.

One or more of the above methods can be used for the delivery of preparations <NUM> containing therapeutically effective amounts of a variety of drugs and other therapeutic agents <NUM> to treat a variety of diseases and conditions. These include a number of large molecule peptides and proteins which would otherwise require injection and/or IV infusion due to chemical breakdown or other degradation of the compound by the digestive fluids in the stomach and/or the lumen of the small intestine. Such compounds which can be delivered can include without limitation, parathyroid hormones, growth hormones (e.g., IFG and other growth factors), insulin compounds, antibodies and other gamma globulin proteins (e.g., gamma globulin) interferons and other cytokines, glucagon like peptides e.g., (GLP-<NUM>, exenatide) and other incretins, chemotherapeutic agents (doxorubicin) and other like compounds. These and other compounds can be delivered into the wall of the small intestine and subsequently absorbed into the blood stream with minimal or no loss of activity of the compound, e.g., in the case of an antibody, minimal or no loss in affinity and/or specificity to a target antigen; in the case of an interferon or other cytokine, minimal or no loss in an immune stimulating effect, in the case of insulin or GLP-<NUM>, minimal or no loss in glucose regulating ability; in the case of growth hormone, minimal or no loss in growth stimulating effect; in the case of a chemotherapeutic agent for the treatment of cancer, minimal or no loss in cancer treatment effect (e.g., a tumor necrosis, and/or reduced cell division); and in the case of any polypeptide, minimal or no loss in affinity and/or specificity to a target binding site. Suitable drugs and other therapeutic agents which can be delivered by embodiments of the invention include any number of orally delivered agents, antibiotics (vancomycin, penicillin, erythromycin, etc.), antivirals (protease inhibitors, anti-seizure compounds (fluosemide, dilatin), non-steroidal anti-inflamatory drugs (NSAIDS) such as ibuprofen), various chemotherapeutic agents (e.g., interferon), antibiotics, antivirals, insulin and related compounds, glucagon like peptides (e.g., GLP-<NUM>, exenatide), parathyroid hormones, growth hormones (e.g., IFG and other growth factors), anti-seizure agents (e.g., furosimide), anti-migraine medication (sumatriptan), immune suppression agents (e.g., cyclosporine) and anti- parasitic agents such as various anti- malarial agents. The dosage of the particular drug can be titrated for the patient's weight, age or other parameter. It is also possible to allow dosages of drug other therapeutic agent <NUM> to be advantageously adjusted for other factors as well. For example, for drugs that would otherwise be partially degraded or poorly absorbed in the GI tract, the amount or dose of drug <NUM> to achieve a desired or therapeutic effect (e.g., insulin for blood glucose regulation, furosimide for anti-seizure) 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). This is due to the fact that there is little or 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 <NUM>, the dose <NUM> delivered in preparation <NUM> can be in the range from <NUM> to <NUM>% of a dose delivered by conventional oral delivery means (e.g., a formulated pill) to achieve a desired therapeutic effect (e.g., blood glucose regulation, seizure regulation, etc.) with even lower amounts contemplated. The particular dose reduction can be titrated based upon the particular drug, the condition to be treated, and the patient's weight, age and condition. For some drugs (with known levels of degradation in the intestinal tract) a standard dose reduction can be employed (e.g., <NUM> to <NUM>%). Larger amounts of dose reduction can be used for drugs which are more prone to degradation in the GI tract and poor absorption. In this way, the potential toxicity (particularly to non target tissue sites) and other other deleterious side effects (e.g., gastric cramping, diarrhea, irritable bowel, hemorrhage, etc.) of a particular drug or drugs delivered by device <NUM> can be reduced because the ingested dose is lowered and all or nearly all of the drug is delivered into the wall of the small intestine. This in turn, improves patient compliance because the patient has a reduction both in the severity and incidence of deleterious effects. Additional benefits of dose reduction of drug <NUM> that include a reduced likelihood for the patient to develop a tolerance to the drug (requiring higher doses) and, in the case of antibiotics or antivirals, for the patient to develop resistant strains of bacteria or viruses (e.g., resistance to the use of vancomycin by bacteria or to a protease inhibitor by the Aids virus). For the case of a chemotherapeutic agent for the treatment of cancer, the deleterious effect can comprise the development of resistance to the chemotherapeutic agent by cancer cells as well as toxicity to non-target tissue. For the case of an anti-seizure medication such as dilatin, the deleterious effects can include various neuromuscular conditions such as tremor, nystagmus, slurred speech, dizziness, memory and concentration problems as well conditions such as rash and bone loss. For anti-seizure and/or diuretics such as furesomide such deleterious effects can include various neuromuscular, vascular, gastro intestinal effects such as dizziness, low blood pressure, dehydration, nausea, loss of electrolytes, tinnitus and rash. Also, other levels of dose reduction can be achieved for patients who have undergone gastric bypass surgery and other procedures in which sections of the small intestine have been removed or its working (e.g., digestive) length otherwise effectively shortened. Levels of dose reduction can be achieved in the range of <NUM> to <NUM>% or even greater and the patient need only take one dose of the drug versus multiple doses because of poor absorption issues. The dose of a particular orally delivered drug <NUM> can be increased because the various deleterious effects in the GI system (e.g., cramping, bleeding, etc.) are avoided since the drug or other therapeutic agent is injected directly into the wall of the small intestine. This increased dosage in turn allows for one or more of the following: fewer doses, faster treatment, faster obtainment of a therapeutic effective level of the drug in the blood stream , better control of blood concentrations and other pharmacokinetic parameters. The dosage of a particular drug can increased in the range of <NUM> to <NUM>% or higher. The amount of the increase can again be titrated based on the patient's, weight, age, condition and individual tolerance to the drug (which can be determined e.g., by using various biomarkers of tolerance and/or toxicity).

In addition to delivery of a single drug, embodiments of swallowable drug delivery device <NUM> 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). This 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. It is possible to 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, the above methods can be used to deliver preparations <NUM> including drugs and therapeutic agents <NUM> to provide treatment for a number of medical conditions and diseases. The medical conditions and diseases which can be treated can include without limitation: cancer, hormonal conditions (e.g., hypo/hyper thyroid, growth hormone conditions), osteoporosis, high blood pressure, elevated cholesterol and triglyceride, diabetes and other glucose regulation disorders, infection (local or septicemia), epilepsy and other seizure disorders, osteoporosis, coronary arrhythmia's (both atrial and ventricular), coronary ischemia anemia or other like condition. Still other conditions and diseases are also contemplated.

The treatment of the particular disease or condition can be performed without the need for injecting the drug or other therapeutic agent (or other non-oral form of delivery such as suppositories) but instead, relying solely on the therapeutic agent(s) that is delivered into the wall of the small intestine or other portion of the GI tract. For example, diabetes or another glucose regulation disorder can be treated (e.g., by controlling blood glucose levels) solely through the use of insulin that is delivered into the wall of the small intestine without the need for the patient to ever inject insulin. 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 instances, the therapeutic agent(s) delivered into the wall of the small intestine can be delivered in conjunction with an injected dose of the agent(s). For example, the patient may take a daily dose of insulin or compound for blood glucose regulation using the embodiments of the swallowable capsule, but only need take an injected dose every several days or when the patient's condition requires it (e.g., hyperglycemia). 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
(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, when 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 <NUM> containing one or more drugs or other therapeutic agents <NUM> 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 <NUM> can comprise a number of other therapeutic agents described herein (as well as those known in the art) that are configured for delivery into a luminal wall in the intestinal tract (e.g., the small intestinal wall) using various embodiments of device <NUM>. 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 <NUM> 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 <NUM> can contain a therapeutically effective amount of insulin in the range of about <NUM>-<NUM> units (one unit being the biological equivalent of about <NUM>µg of pure crystalline insulin), with particular ranges of <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM> or <NUM>-<NUM>. The amount of insulin in the preparation can be titrated based upon one or more of the following factors (herein, then 'glucose control titration factors"): i) the patient's condition (e.g., type <NUM> vs. type II diabetes; ii) the patients previous overall level of glycemic control; iii) the patient's weight; iv) the patient's age; v) the frequency of dosage (e.g., once vs. multiple times a day); vi) time of day (e.g., morning vs. evening); vii) particular meal (breakfast vs. dinner); viii) content/glycemic index of a particular meal (e.g., meals having a high fat/lipid and sugar content (which tend to cause a rapid rise in blood sugar and thus have a higher glycemic index) vs. low fat and sugar content that do not (and thus have a lower glycemic index)); and ix) content of the patient's overall diet (e.g., amount of sugars and other carbohydrates, lipids and protein consumed daily).

In another group of embodiments, therapeutic agent preparation <NUM> 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 Glucacon like peptides <NUM> (GLP-<NUM>) and their analogues, and Gastric inhibitory peptide (GIP). Suitable GLP-<NUM> analogues include exenatide, liraglutide, albiglutide and taspoglutide as well as their analogues, derivatives and other functional equivalents. In one embodiment preparation <NUM> can contain a therapeutically effective amount of exenatide in the range of about <NUM>-<NUM>µg, with particular ranges of <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM> and <NUM>-<NUM>µg respectively. In another embodiment, preparation <NUM> can contain a therapeutically effective amount of liraglutide in the range of about <NUM>-<NUM> (milligrams), with particular ranges of <NUM> to <NUM>, <NUM> to <NUM> and <NUM> to <NUM> respectively. One or more of the glucose control titration factors can be applied to titrate the dose ranges for exenatide, liraglutide or other GLP-<NUM> analogue or incretin.

In yet another group of embodiments, therapeutic agent preparation <NUM> can comprise a combination of therapeutic agents for the treatment of diabetes and other glucose regulation disorders. Embodiments of such a combination can include therapeutically effective doses of incretin and biguanide compounds. The incretin can comprise one or more GLP-<NUM> analogues described herein, such as exenatide and the biguanide can comprise metformin (e.g., that available under the Trademark of GLUCOPHAGE® manufactured by Merck Santé S. ) and its analogues, derivatives and other functional equivalents. In one embodiment, preparation <NUM> can comprise a combination of a therapeutically effective amount of exenatide in the range of about <NUM>-<NUM>µg and a therapeutically effective amount of metformin in a range of about <NUM> to <NUM> 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 improve the 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 ranging from hours (e.g., <NUM>) to a day to multiple days, with still longer periods contemplated. Matching of dosages can also be achieved by use of the glucose control regulation factors as well as monitoring of the patient's blood glucose levels 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.

In still yet another group of embodiments, therapeutic agent preparation <NUM> can comprise a therapeutically effective dose of growth hormone for the treatment of one or more growth disorders, as well as wound healing. In one embodiment, preparation <NUM> can contain a therapeutically effective amount of growth hormone in the range of about <NUM>-<NUM>, with particular ranges of <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM> and <NUM>-<NUM>, with still larger ranges contemplated. The particular dose can be titrated based on one or more of the following: i) the particular condition to be treated and its severity (e.g., stunted growth, vs. wound healing); ii) the patient's weight; iii) the patient's age; and iv) the frequency of dosage (e.g., daily vs. twice daily).

In still yet another group of embodiments, therapeutic agent preparation <NUM> can comprise a therapeutically effective dose of parathyroid hormone for the treatment osteoporosis or a thyroid disorder. In one embodiment, preparation <NUM> can contain a therapeutically effective amount of parathyroid hormone in the range of about <NUM>-<NUM>µg, with particular ranges of <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM> and <NUM>-<NUM>µg, with still larger ranges contemplated. The particular dose can be titrated based on one or more of the following: i) the particular condition to be treated and its severity (e.g., the degree of osteoporosis as determined by bone density measurements); ii) the patient's weight; iii) the patient's age; and iv) the frequency of dosage (e.g., daily vs. twice daily).

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.

Claim 1:
An ingestible device (<NUM>) suitable for swallowing into a lumen of an intestinal tract of a patient, the lumen having a lumen wall, the device comprising:
a capsule (<NUM>) sized to pass through the intestinal tract;
a therapeutic agent preparation (<NUM>) disposed within the capsule, the preparation comprising at least one therapeutic agent (<NUM>), wherein the therapeutic agent preparation would chemically degrade or impose a deleterious effect on the patient if released within the lumen of the intestinal tract, wherein the therapeutic agent preparation further comprises a tissue penetrating member (<NUM>) including a hollow needle that is advanceable into the lumen wall, wherein the hollow needle is formed from a biodegradable material so as to degrade within the lumen wall; and
an actuator (70a) coupled to the therapeutic agent preparation and having a first configuration and a second configuration, the preparation being retained within the capsule when the actuator is in the first configuration, wherein the preparation is advanced from the capsule and into the lumen wall by movement of the actuator from the first configuration to the second configuration such that the deleterious effect or chemical degradation of the therapeutic agent in the lumen is inhibited, wherein a therapeutic dose of the therapeutic agent is included in the capsule, and wherein the actuator is configured to advance substantially all of the therapeutic dose of the therapeutic agent into the lumen wall by way of the hollow needle so as to minimize the deleterious effect.