Coagulation factor preparation for delivery to intestinal tissue using a swallowable drug delivery device

Abstract

To provide devices, preparations and methods for delivering therapeutic agents (TAs) such as clotting factors (CFs, e.g., Factor 8) within the GI tract.SOLUTION: Many embodiments provide a swallowable device, e.g., a capsule for delivering TAs into an intestinal wall (IW). Embodiments also provide TA preparations configured to be contained in the capsule and advanced from the capsule into the IW and / or a surrounding tissue (ST) and degrade to release the TA into a bloodstream to produce a therapeutic effect (e.g., improved clotting). The preparation can be operably coupled to delivery means having a first configuration in which the preparation is contained in the capsule, and a second configuration in which the preparation is advanced out of the capsule into the IW or ST (e.g., a peritoneal cavity). Embodiments are particularly useful for delivery of such CFs for treatment of clotting disorders (e.g., hemophilia) where the CFs are poorly absorbed and / or degraded within a GI tract.SELECTED DRAWING: Figure 11-3

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 582,857, filed on November 7, 2017, which is hereby incorporated by reference in its entirety for all purposes.

[0002] This application incorporates by reference the following patent applications, the entire contents of each of which are hereby incorporated by reference for all purposes: U.S. Patent Application No. 15 / 260,260, filed September 8, 2016, titled "PCSK9 Antibody Preparations For Delivery Into A Lumen Of The Intestinal Tract Using A Swallowable Drug Delivery Device"; U.S. Provisional Patent Application No. 61 / 571,642, filed June 30, 2011, titled "Therapeutic Agent Preparations for Delivery Into a Lumen of The Intestinal Tract Using a Swallowable Drug Delivery Device"; U.S. Provisional Patent Application No. 61 / 571,641, filed June 29, 2011, titled "Device, System and Method for the Oral Delivery of Therapeutic Compounds"; U.S. Patent Application No. 12 / 978,233, filed December 23, 2010, titled "Swallowable Drug Delivery Device and Methods of Drug Delivery"; U.S. Patent Application No. 12 / 978,164, filed December 23, 2010, titled "Therapeutic Agent Preparations for Delivery Into a Lumen of The Intestinal Tract Using a Swallowable Drug Delivery Device"; U.S. Patent Application No. 12 / 978,301, filed December 23, 2010, titled "Swallowable Drug Delivery Device and Method of Delivery"; U.S. Patent Application No. 13 / 532,589, filed June 25, 2012, titled "Device, System And Methods For The Oral Delivery Of Therapeutic Compounds".U.S. Patent No. 8,809,269, titled "Therapeutic Agent Preparations Comprising Insulin for Delivery into a Lumen of the Intestinal Tract using a Swallowable Drug Delivery Device"; U.S. Patent Application No. 61 / 993,907, titled "Pharmaceutical Compositions And Methods For Fabrication Of Solid Masses Comprising Polypeptides And / Or Proteins", filed on May 15, 2014; U.S. Patent Application No. 62 / 156,105, titled "Pharmaceutical Compounds And Methods For Fabrication Of Solid Masses Comprising Polypeptides And / Or Proteins", filed on May 1, 2015; U.S. Patent Application No. 62 / 159,134, titled "Anti-Interleukin Antibody Preparations For Delivery Into A Lumen Of The Intestinal Tract Using A Swallowable Drug Delivery Device", filed on May 8, 2015; U.S. Patent Application No. 62 / 215,586, titled "PCSK9 Antibody Preparations For Delivery Into A Lumen Of The Intestinal Tract Using A Swallowable Drug Delivery Device", filed on September 8, 2015.

[0003] Background Field of the Invention. Embodiments of the present invention relate to orally deliverable drug and other therapeutic agent formulations, and to swallowable drug delivery devices for delivering such formulations to the small intestine. More particularly, embodiments of the present invention relate to orally deliverable drug formulations for the treatment of coagulation disorders. Even more particularly, embodiments of the present invention relate to orally deliverable solid drug formulations for the treatment of hemophilia and von Willebrand disease, which include coagulation proteins as Factor VII, Factor VIII, Factor IX, and Factor X. BACKGROUND OF THE INVENTION

[0004] Over the past decade, the development of new drugs for treating a variety of diseases, including for example a variety of coagulation disorders, has continued to increase. Unfortunately, many have limited indications because they cannot be administered orally. This is due to multiple reasons including poor oral tolerance with complications including gastric irritation and bleeding, cleavage / degradation of drug compounds in the stomach, and poor, slow, or unstable absorption of the drug. Conventional alternative drug delivery methods such as intravenous and intramuscular delivery have multiple drawbacks including the risk of pain and needle-stick infections, the need to use aseptic techniques, and the need for the patient to maintain an IV line over a long period of time and the associated risks. Other drug delivery approaches such as implantable drug delivery pumps are used, but these approaches require semi-permanent implantation of the device and may still have many of the limitations of IV delivery. Thus, there is a need for improved and / or alternative methods for delivering drugs and other therapeutic agents.

[0005] In the human population, there are several hereditary bleeding disorders that can be lethal if left untreated. These include hemophilia A and B, the most common ones, which are caused by a decrease in the levels of coagulation factors in the patient's peripheral blood. They also include factor VII deficiency, factor X deficiency, also known as Stuart-Prower factor deficiency, and von Willebrand disease, which is caused by a deficiency of von Willebrand factor that binds to factor VIII. Hemophilia A is the most common form of hemophilia and is caused by a deficiency of factor VIII (FVIII). Hemophilia B is caused by a decrease in the synthesis of factor IX (FIX) or the synthesis of a defective FIX with reduced activity. Current forms of hemophilia treatment require replacing the missing or defective coagulation factors with recombinant or plasma-derived coagulation factors such as FVIII or FIX. Typically, these factors are usually administered by intravenous injection.

[0006] However, current forms of hemophilia treatment have several problems and drawbacks. In particular, many patients can produce antibodies against the replacement coagulation factors, impairing their effectiveness and leading to serious complications as discussed below. Other problems include the need to visit a doctor's clinic / clinic for injections and the need to administer the injection very slowly intravenously. Similarly, since coagulation factors are usually administered via peripheral intravenous injection, people with thin veins or children may have difficulty finding a vein and may have difficulty receiving an injection in that they can easily collapse. This problem can be particularly problematic in the case of children who require more frequent injections. Similarly, the injection itself can cause bleeding.

[0007] Many patients produce antibodies that inhibit or otherwise interfere with the action of clotting factors in response to administration of various clotting factors (also known as "inhibitors" or "inhibitory antibodies"). The production of inhibitor antibodies against factor VIII is a serious complication in the management of patients with hemophilia A. Inhibitory antibodies are produced in approximately 20% of patients with hemophilia A in response to therapeutic infusions of factor VIII. This is due to the high doses of factor VIII or other clotting factors being administered. If previously untreated patients with hemophilia A produce inhibitors, the inhibitors are usually produced within one year of treatment. In addition, autoantibodies that inactivate factor VIII are sometimes produced in individuals who previously had normal factor VIII levels. If the titer of the inhibitor is low enough, although there may be a risk of complications, the patient can be managed by increasing the dose of factor VIII. However, the titer of the inhibitor is often very high and cannot be overcome by factor VIII. Although treatments are available to eliminate or reduce the titer of these antibodies, they are expensive (e.g., on the order of $1 million per patient per year), time-consuming, and require regular intravenous administration of clotting factors. Similarly, these treatments are effective in only about three-quarters of patients.

[0008] Other routes of administration of factor VIII replacement therapy have been tested in the past, but they have not been very successful. Subcutaneous (SC) administration is limited by the amount of active ingredient that can be administered at one time and cannot reach therapeutic levels of these factors. Similarly, it is also limited by the sensitivity of these factors to protease-mediated degradation. Another concern is the increased immunogenicity of the SC route compared to the IV route, which can result in an increase or more rapid production of inhibitory antibodies compared to the IV injection route. Therefore, what is needed are compositions and methods for delivering clotting factors such as factor VII, factor VIII, factor IX, and factor X that are administered in a way that does not require injection, does not cause the production of inhibitor antibodies, or does not cause other immune responses to the clotting factors. SUMMARY OF THE INVENTION

Means for Solving the Problem

[0009] Brief Summary Embodiments of the present invention provide devices, systems, kits, and methods for delivering drugs and other therapeutic agents to various locations in the body. Many embodiments provide swallowable devices for delivering drugs, such as clotting proteins and other therapeutic agents, into peripheral tissues such as the gastrointestinal (GI) tract and the peritoneal cavity. Certain embodiments of the present invention provide swallowable devices, such as capsules, for delivering clotting proteins and other therapeutic agents into the wall of the small intestine and / or peripheral tissues (e.g., the abdominal wall or the peritoneal cavity). Such clotting proteins (CP) can include various clotting factors (also known as coagulation factors) including one or more of factor VII, factor VIII, factor IX, factor X, and von Willebrand factor. Embodiments of the present invention are particularly useful for the oral delivery of clotting proteins and other therapeutic agents that have poor absorption, poor tolerance, and / or degrade in the GI tract and thereby lose or have their bioactivity impaired. Similarly, embodiments of the present invention are particularly useful for the oral delivery of clotting factors and other clotting proteins for the treatment of hemophilia and other clotting disorders, which heretofore could only be delivered by injection. Further, embodiments of the present invention are particularly useful for delivering clotting factors such as factor VIII and produce little or no inhibitory antibodies that destroy or reduce the efficacy of the clotting factor. Still further, embodiments of the present invention are particularly useful for delivering clotting factors and other clotting proteins into the intestinal wall and peritoneal cavity so as to be rapidly taken up into the bloodstream.

[0010] In one aspect, the present invention provides a therapeutic agent preparation for delivery into the wall of the small intestine and / or surrounding tissue (e.g., the peritoneal cavity) or other locations within the intestinal tract, comprising a therapeutically effective dose of at least one coagulation factor (e.g., Factor VII, Factor VIII, Factor IX, Factor X, von Willebrand factor, etc.) together with its respective analogs and derivatives. The preparation is contained in an embodiment of a swallowable capsule (or similar device) and is delivered from the capsule into the intestinal wall or surrounding tissue (e.g., the abdominal wall and / or peritoneal cavity) and may have a shape and material compatibility to release a dose of the coagulation factor (CF) from within the surrounding tissue such as the intestinal wall or peritoneal cavity. Such shapes may correspond to various tissue-penetrating structures, including structures having pointed ends such as various dart-like or needle-like shapes or structures. In embodiments of the preparation delivered into the peritoneal cavity, the needle or other pointed end preferably has a straight or symmetric vertical tip or dart shape such that it can penetrate through the intestinal wall into the peritoneal cavity without being deflected by any asymmetry of the needle shape. The preparation can be in solid, liquid, or powder form. Preferably, the preparation containing CF is in solid form that can be stored over a long period of time and shaped (e.g., into a tissue-penetrating shape such as a needle shape) and has mechanical or other forces exerted on the preparation for inserting it into the intestinal wall and / or surrounding tissue such as the peritoneal cavity and / or abdominal wall. According to various embodiments, the coagulation factor can be selected from one or more of Factor VII, Factor VIII, Factor IX, Factor X, and von Willebrand factor, and / or its functional variants known in the art (e.g., analogs and derivatives) that retain the characteristic properties of the coagulation factor.

[0011] In another aspect, the invention provides a method of treating hemophilia or other coagulation disorders, the method comprising orally administering to a patient a preparation comprising a therapeutically effective amount of a coagulation factor (e.g., factor VIII) using one or more embodiments of the swallowable capsules described herein, thereby treating the coagulation disorder. In certain embodiments, the invention provides a method of orally delivering one or more of: i) a therapeutic amount of factor VII for treating one or more of factor VII deficiency, congenital hemophilia with inhibitors, acquired hemophilia or Glanzmann thrombasthenia; ii) a therapeutic amount of factor VIII for treating hemophilia A; iii) a therapeutic amount of factor IX for treating hemophilia B; iv) a therapeutic amount of factor X for treating factor X deficiency; and v) a therapeutic amount of von Willebrand factor for treating von Willebrand disease. Similarly, in certain embodiments described in more detail below, the swallowable capsule can be configured to deliver the coagulation factor preparation to a segment of the small intestine that does not have Peyer's patches. By such targeted delivery to the desired segment of the small intestine, suppression of the immune response to the coagulation factor occurs, including suppressing or minimizing the production of general antibodies such as IgG and specific inhibitor antibodies to the coagulation factor. When used, embodiments of this approach provide the benefits of improved long-term tolerance and efficacy to the delivered coagulation factor, thereby providing better long-term control of the patient's coagulation disorder without the need for expensive treatments to eliminate inhibitor antibodies.

[0012] The present invention also provides a method of treating a coagulation disorder, the method comprising the steps of selecting a patient having hemophilia or another coagulation disorder, and administering to the patient a therapeutically effective amount of a coagulation factor or other clotting protein using one or more embodiments of the swallowable capsules described herein. Next, the clotting time (e.g., prothrombin time) can be measured and monitored using methods known in the art to determine the efficacy of the treatment, and then the dosage (e.g., increase or decrease) and / or frequency of administration of the coagulation factor administered can be adjusted. In alternative or additional embodiments, the solid forms of the coagulation factors described herein may similarly be delivered by other swallowable devices.

[0013] In another aspect, the present invention provides a method for delivering a therapeutic agent into the wall of the small intestine and / or surrounding tissues such as the abdominal wall and abdominal cavity, the method comprising the step of swallowing a drug delivery device comprising embodiments of a therapeutic agent preparation such as a capsule, an actuator, and a CF or CP preparation (e.g., a preparation comprising one or more clotting factors). The actuator is responsive to conditions in the small intestine such as pH to effect delivery of the therapeutic agent preparation to surrounding tissues such as the wall of the small intestine and / or the peritoneal wall. In certain embodiments, the actuator may include a release element or coating on the capsule that degrades by a selected pH in the small intestine. Once degraded, the element or coating is operably coupled to one or more delivery means such as the expansion of one or more balloons configured to advance through the intestinal wall or surrounding tissue and into it when the balloon expands, to initiate delivery of the therapeutic agent preparation. In certain embodiments, the balloon or other advancing means is configured to advance a tissue penetrating member into the abdominal cavity through the intestinal wall and be retained within the abdominal cavity. When the tissue penetrating members are located in surrounding tissues such as the intestinal wall or abdominal cavity, they degrade to release the therapeutic agent into the bloodstream. In certain embodiments where the tissue penetrating members are located in and retained within the abdominal cavity, the tissue penetrating members containing the therapeutic agent preparation are configured to be degraded by tissue fluid within the abdominal cavity. Since the therapeutic agent preparation is delivered directly to the wall of the small intestine or surrounding tissues such as the abdominal wall or abdominal cavity, the period until the maximum concentration of CF or other therapeutic agent in the bloodstream or other locations in the body is achieved (described herein as t max as described) is shorter than the corresponding period until such maximum concentration is achieved when the therapeutic agent is non-intravascularly injected into the body, such as by intramuscular or subcutaneous injection. In various embodiments, the period until C max is achieved by inserting a therapeutic preparation into the intestinal wall using one or more embodiments of the present invention (e.g., an embodiment of a swallowable device) is shorter than the period until C maxcan be as little as about 80%, 50%, 30%, 20, or 10% of the period until achievement. As used herein, the term "about" generally refers to within 5% of the recited numerical value, although in some instances it may be greater or less. In other embodiments, one or more embodiments of the invention, such as embodiments of the swallowable device, are used to achieve C by inserting a therapeutic preparation into the intestinal wall max is achieved by ingesting the normal oral form (e.g., a pill) of the therapeutic agent, where the therapeutic agent is not inserted into the intestinal wall max can be higher. In various embodiments, one or more embodiments of the invention (such as embodiments of the swallowable device) are used to achieve C by inserting a therapeutic preparation into the intestinal wall max can be 5, 10, 20, 30, 40, 50, 60, 70, 80, or even 100 times higher than when the therapeutic agent is delivered in pill or other oral form. In other related embodiments, the composition can be configured to provide long-term release of the therapeutic agent at a selectable t 1 / 2 (i.e., the time required for the concentration of the therapeutic agent in the bloodstream or other location in the body to reach half of its initial C max value after reaching C max ). For example, the selectable t 1 / 2 can be 6, or 9, or 12, or 15 or 18, or 24 hours.

[0014] In another aspect, the present invention provides a swallowable device for delivering a drug or other therapeutic agent formulation to the wall of the small intestine or large intestine, peritoneum, or other organs of the gastrointestinal tract. The device includes a capsule sized to be swallowed and pass through the gastrointestinal tract, a deployable aligner positioned within the capsule for aligning the longitudinal axis of the capsule with the longitudinal axis of the small intestine, a delivery mechanism for delivering the therapeutic agent to the intestinal wall, and a deployment member for deploying at least one of the aligner or the delivery mechanism. The capsule wall is decomposable by contact with liquid in the GI tract but decomposes only at a higher pH found in the small intestine, serving to protect the underlying capsule wall so that the capsule does not decompose in the stomach before reaching the small intestine, and an outer coating or layer may also be included such that drug delivery is initiated by decomposition of the coating in the small intestine. When used, such materials enable targeted delivery of the therapeutic agent to a selected portion of the intestinal tract, such as the small intestine. Suitable outer coatings can include various enteric coatings, such as various copolymers of acrylic acid (specific examples include EUDRAGIT available from EVONIK industries), methacrylic acid, and ethyl acrylate. In certain embodiments, the outer coating is configured to decompose at a pH found in the upper (e.g., duodenum) or middle (jejunum) portion of the small intestine so as to avoid the lower (ileum) portion of the small intestine that contains Peyer's patches, aggregates of lymph nodes that produce macrophages and other immune-related cells, to which the therapeutic agent formulation is delivered to each of its parts. Examples of such coatings that decompose at the pH of the duodenum or jejunum can include EUDRAGIT. By delivering the therapeutic agent to a location in the small intestine that does not have Peyer's patches, subsequent immune responses, including the generation of various antibodies to certain therapeutic agents, such as inhibitor antibodies to factor VIII, are suppressed or otherwise minimized.Thus, when used, such controlled retention or delivery of a therapeutic agent to the upper, central, or selected portion of the small intestine can suppress the patient's immune response to a particular therapeutic agent (e.g., factor VIII or other clotting factors), thereby resulting in an increase in the efficacy and tolerance to the dose of a given therapeutic agent delivered orally as compared to a therapeutic agent delivered via intravenous or subcutaneous injection.

[0015] Another embodiment of the capsule includes at least one guide tube, one or more tissue penetrating members located within the at least one guide tube, a delivery member, and an actuating mechanism. The tissue penetrating members typically include a hollow needle or other similar structure and have a lumen and a tissue penetrating tip for penetrating into the intestinal wall to a selected depth. In various embodiments, the device may include second and third tissue penetrating members, although additional numbers are contemplated. Each tissue penetrating member may contain the same or different drugs. In a preferred embodiment having a plurality of tissue penetrating members, the tissue penetrating members can be symmetrically distributed around the capsule to fix the capsule to the intestinal wall during drug delivery. In some embodiments, all or a portion (e.g., the tissue penetrating tip) of the tissue penetrating member can be made from the drug preparation itself. In these and related embodiments, the drug preparation can have a needle, dart-like, or other elongated structure with a pointed tip (with or without barbs) configured to penetrate and be retained in the intestinal wall.

[0016] The tissue-penetrating member can be made of various biodegradable materials so as to decompose in the small intestine, and provides a fail-safe mechanism for removing it from the intestinal wall when the tissue-penetrating member is thus retained by the intestinal wall. Such biodegradable materials can correspond to one or more of PGLA, maltose or other sugars, polyethylene, oxidized polyethylene, or other biodegradable polymers known in the art. In addition, in these and related embodiments, the selectable portion of the capsule can be made of such biodegradable materials so that the entire device can be controllably broken down into small pieces. Such embodiments facilitate the passage and excretion of the device through the GI tract. In certain embodiments, the capsule can include seams of biodegradable materials that controllably break down to produce capsule pieces of selectable size and shape to facilitate passage through the GI tract. The seams can be pre-stressed and can be perforated or otherwise treated to accelerate decomposition. The idea of using biodegradable seams to effect controlled breakdown of a swallowable device in the GI tract can also be applied to other swallowable devices, such as swallowable cameras, to facilitate passage through the GI tract and to reduce the likelihood of the device becoming lodged in the GI tract.

[0017] The delivery member is configured to advance the drug from the capsule through the lumen of the tissue penetrating member to the intestinal wall. Typically, at least a portion of the delivery member is movable forward within the lumen of the tissue penetrating member. The delivery member may have a piston or similar structure sized to fit within the lumen of the delivery member. The distal end of the delivery member (the end that advances into the tissue) may have a plunger element that advances the drug within the lumen of the tissue penetrating member and also forms a seam with the lumen. The plunger element may be integral with the delivery member or attachable to the delivery member. Preferably, the delivery member is configured to move a fixed distance within the lumen of the needle to deliver a fixed or constant dose of the drug to the intestinal wall. This can be achieved by one or more of the selection of the diameter of the delivery member (e.g., the diameter may taper distally), the diameter of the tissue penetrating member (which may narrow at its distal end), the use of a tip and / or an actuation mechanism. In embodiments of the device having a tissue penetrating member made from the drug (e.g., a drug dart), the delivery member is adapted to advance the dart from the capsule into the tissue.

[0018] The delivery member and the tissue penetrating member can be configured to deliver the drug in liquid form, semi-liquid form, or solid form, or all three forms. The solid form of the drug can include both powders and pellets. The semi-liquid can include slurries or pastes. The drug can be contained within the cavity of the capsule or, in the case of a liquid or semi-liquid, within an enclosed reservoir. In some embodiments, the capsule can contain a first, second, or third drug (or more). Such drugs can be contained within the lumen of the tissue penetrating member (in the case of a solid or powder) or within individual reservoirs inside the capsule body.

[0019] The actuation mechanism can be coupled to at least one of the tissue penetrating member or the delivery member. The actuation mechanism is configured to advance the tissue penetrating member a selectable distance into the intestinal wall and, after advancing the delivery member to deliver the drug, to retract the tissue penetrating member from the intestinal wall. In various embodiments, the actuation mechanism can include a preloaded spring mechanism configured to be released by a release element. Suitable springs can include both coil springs (including conical springs) and leaf springs, although other spring structures are equally contemplated. In certain embodiments, the spring can be conical in shape to reduce the length of the spring in the compressed state such that the length of the spring when compressed is approximately the thickness of a few coils (e.g., 2 or 3) or even the thickness of only 1 coil.

[0020] In certain embodiments, the actuation mechanism includes a spring, a first motion converter, and a second motion converter, and a track member. The release element is coupled to the spring to hold the spring in a compressed state such that the spring is released by disassembly of the release element. The first motion converter is configured to convert the motion of the spring to move a tissue penetrating element into and out of tissue. The second motion converter is configured to convert the motion of the spring to advance a delivery member into the lumen of the tissue penetrating member. The motion converters are pushed by the spring and move along a rod or other track member that serves to guide the path of the converters. They engage (either directly or indirectly) the tissue penetrating member and / or the delivery member to produce the desired motion. They are preferably configured to convert the motion of the spring along its longitudinal axis into orthogonal motion of the tissue penetrating member and / or the delivery member, although other directions of conversion are contemplated as well. The motion converters can have a wedge, trapezoidal, or curved shape, although other shapes are contemplated as well. In certain embodiments, the first motion converter has a trapezoidal shape and can include a slot that engages a pin on the tissue penetrating member that moves within the slot. The slot can mirror the overall shape of the converter or otherwise have a corresponding trapezoidal shape and serves to push the tissue penetrating member between the upward sloping portions of the trapezoid and then return the tissue penetrating member between the downward sloping portions. In one variation, one or both of the motion converters can include a cam or cam-like device that is switched on by the spring and engages the tissue penetrating member and / or the delivery member.

[0021] In other variations, the actuation mechanism can also include an electromechanical device / mechanism such as a solenoid or piezoelectric device. In one embodiment, the piezoelectric device can include a shaped piezoelectric element having a non-deployed state and a deployed state. This element can be configured to become deployed upon application of a voltage and then return to the non-deployed state upon removal of the voltage. This and related embodiments enable repetitive motion of the actuation mechanism and both forward and subsequent reverse movement of the tissue penetrating member.

[0022] The release element is connected to at least one of the actuating mechanism or a spring connected to the actuating mechanism. In certain embodiments, the release element is connected to a spring positioned within the capsule to hold the spring in a compressed state. When the release element degrades, the spring is released to activate the actuating mechanism. In many embodiments, the release element comprises a material configured to degrade when exposed to chemical conditions in the small intestine or large intestine, such as pH. Typically, the release element is configured to degrade when exposed to a selected pH in the small intestine, such as about 7.0, 7.1, 7.2, 7.3, 7.4, 8.0, or higher pH. However, this can also be configured to degrade in response to other conditions in the small intestine, such as osmotic pressure, fluid content of the small intestine contents, viscosity of the contents, flora, compressive force, presence and / or concentration of various bile salts, etc. In certain embodiments, the release element can be configured to degrade in response to specific chemical conditions of the fluid in the small intestine, such as conditions that occur after ingestion of a meal (e.g., a meal rich in fat or protein).

[0023] Biodegradation of the release element by one or more conditions (e.g., pH, osmotic pressure, presence of bile salts, etc.) in the small intestine (or other location in the GI tract) can be achieved by the selection of the materials of the release element, the amount of cross-linking of those materials, and the thickness and other dimensions of the release element. Less cross-linking and / or thinner dimensions can increase the degradation rate, and vice versa. Suitable materials for the release element can include biodegradable materials such as various enteric materials configured to degrade when exposed to higher pH or other conditions in the small intestine. Enteric materials can be copolymerized or otherwise mixed with one or more polymers to obtain multiple specific material properties. Such properties can include, but are not limited to, rigidity, strength, flexibility, and hardness.

[0024] In certain embodiments, the release element may include a membrane or plug that covers or otherwise blocks the guide tube and holds the tissue penetrating member inside the guide tube. In these and related embodiments, the tissue penetrating member is coupled to a spring-loaded actuating mechanism such that when the release element is fully disassembled, it releases the tissue penetrating member, which then pops out of the guide tube and penetrates the intestinal wall. In other embodiments, the release element can be shaped to function as a latch that holds the tissue penetrating element in place. In these and related embodiments, the release element can be located outside or inside the capsule. In the internal embodiment, the capsule and the guide tube are configured to allow the entry of intestinal fluid into the capsule to enable the disassembly of the release element.

[0025] In some embodiments, the actuating mechanism can be actuated by a sensor such as a pH sensor or other chemical sensor that detects the presence of the capsule in the small intestine and sends a signal to the actuating mechanism (or an electronic controller coupled to the actuating mechanism to actuate the mechanism). Embodiments of the pH sensor can include an electrode-based sensor or a mechanically based sensor such as a polymer that contracts or expands when exposed to pH or other chemical conditions in the small intestine. In related embodiments, the expandable / contractable sensor can also include the actuating mechanism itself by using the mechanical movement from the expansion or contraction of the sensor.

[0026] According to another embodiment for detecting the presence of the device in the small intestine (or other locations in the GI tract), the sensor can include a strain gauge or other pressure / force sensor for detecting the number of peristaltic contractions the capsule undergoes within a particular location of the intestinal tract. In these embodiments, the capsule is desirably sized to be grasped by the small intestine during peristaltic contractions. Different locations within the GI tract have different numbers of peristaltic contractions. The small intestine has contractions at a frequency of 12 - 9 contractions per minute that decrease the length of the small intestine. Thus, according to one or more embodiments, detecting the number of peristaltic contractions can be used to determine not only whether the capsule is present in the small intestine but also its relative position within the small intestine.

[0027] As an alternative or supplement to internal active drug delivery, in some embodiments, the user may externally activate the actuating mechanism to deliver the drug by RF (radio frequency), magnetic, or other wireless signaling means known in the art. In these and related embodiments, the user may use a portable device (e.g., a portable RF device). This device includes not only the signaling means but also means for notifying the user when the device is present in the small intestine or other locations in the GI tract. The latter embodiments can be implemented by including an RF communication device on a swallowable device to transmit a signal to the user when the device is present in the small intestine or other locations (e.g., by transmitting an input signal from a sensor). The same portable device can also be configured to notify the user when the actuating mechanism is activated and the selected drug is being delivered. In this way, the user is provided with confirmation that the drug is being delivered. In another approach, an external auditory sensor is used to detect one or more unique frequencies of sound that may occur in embodiments using a chamber including a piston and cylinder mechanism operably coupled to a tissue penetrating member, by detecting the unique sound when the actuating mechanism is activated. By one or more of the foregoing approaches, the user can ingest other appropriate drugs / therapeutic agents and make other related decisions (e.g., for a diabetic patient, whether to eat a meal and which foods to eat). The portable device can also be configured to send a signal to the swallowable device to override the actuating mechanism and prevent, delay, or accelerate drug delivery. When used, such embodiments allow the user to intervene to prevent, delay, or accelerate drug delivery based on other symptoms and / or the patient's actions (e.g., eating a meal, deciding to sleep, taking other medications, exercising, etc.).

[0028] The user can also activate the activation mechanism externally for a selected period after swallowing the capsule. The period can be correlated with the typical transit time for food to move through the user's GI tract to a specific location in a tube such as the small intestine, or a range of transit times. External activation can be performed by any number of means including wireless steering means (e.g., using an RF transmission device), magnetic means (e.g., by use of a small version of a magnetic switch or release device incorporated into a swallowable device that is activated by an external magnet), or auditory means (e.g., an ultrasonic transmission device, and via a sound receiver and / or switch incorporated into the swallowable device).

[0029] Another aspect of the present invention provides a therapeutic agent preparation, such as various coagulation factors, for delivery into the wall of the small intestine (including surrounding tissues such as the abdominal wall or peritoneal cavity) or other walls of the intestinal tract, using the embodiments of the swallowable device described herein. The preparation contains a therapeutically effective dose of at least one therapeutic agent, such as a coagulation factor or other blood clotting protein. Similarly, this may include solids, liquids, or a combination of both and may contain one or more pharmaceutical excipients. The preparation is contained in an embodiment of a swallowable capsule that is delivered from the capsule into the intestinal wall, peritoneum, abdominal wall, or other surrounding tissues, and decomposes within the intestinal wall or surrounding tissues such as the peritoneum or peritoneal cavity to release the dose of the therapeutic agent, having shape and material compatibility. In certain embodiments, the preparation is configured to decompose within the fluid of the peritoneum or peritoneal cavity such that the coagulation factor or other therapeutic agent is dispersed along the serosa of the visceral peritoneum and / or parietal peritoneum. The preparation may also have a selectable surface area to volume ratio to enhance or otherwise control the rate of decomposition of the preparation in the wall of the small intestine or in surrounding tissues such as the peritoneum (e.g., visceral peritoneum) and peritoneal cavity or other body cavities. In various embodiments, the preparation can be configured to be coupled to an actuator or actuating mechanism, such as a release element, having a first configuration in which the preparation is contained in the capsule and a second configuration in which the preparation advances from the capsule into the wall of the small intestine and / or peritoneum. The dose of the drug or other therapeutic agent in the preparation can be dosed downward from the dose required for normal oral delivery methods so as to be able to reduce potential side effects caused by the drug.

[0030] Typically, although not necessarily, the preparation is configured to exit the capsule and advance into the wall of the small intestine and / or the peritoneum (e.g., the visceral peritoneum) or into the abdominal cavity, e.g., being shaped and otherwise configured to be contained within the lumen of a hollow needle. The preparation itself may include a tissue penetrating member configured to advance into the wall of the small intestine and / or the abdominal wall, or other lumens of the intestinal tract. Such configurations of tissue penetrating members can include various shapes having pointed tips, including, for example, needles, darts, and other similar shapes. In certain embodiments, the tissue penetrating member includes various elongated shapes having pointed ends. This can also include various isomeric shapes having pointed ends, such as a triangle having a pointed end, a quadrilateral having a pointed end, a cone having a pointed end, or a hemisphere having a pointed end.

[0031] Another aspect of the present invention provides a method of delivering drugs and therapeutic agents to the wall of the GI tract using an embodiment of a swallowable drug delivery device. Such methods can be used to deliver therapeutically effective amounts of a variety of drugs and other therapeutic agents. These include a plurality of polymeric peptides and proteins, such as clotting factors, antibodies, growth hormones, parathyroid hormones, insulin, interferons, and other similar compounds, which would otherwise require injection due to chemical degradation in the stomach. Suitable drugs and other therapeutic agents that can be delivered by embodiments of the present invention include various clotting factors (e.g., factor VIII), antibodies (antibodies of the TNF inhibiting class), chemotherapeutic agents (e.g., interferon), antibiotics, antiviral agents, insulin and related compounds, glucagon-like peptides (e.g., GLP-1, exenatide), parathyroid hormone, growth hormones (e.g., IGF and other growth factors), anti-seizure agents, immunosuppressive agents, and anti-parasitic agents, such as various anti-malarial agents. The dosage of a particular drug can be titrated with respect to the patient's weight, age, condition, or other parameters.

[0032] In various method embodiments of the present invention, embodiments of a drug swallowable drug delivery device are used to deliver multiple drugs (e.g., a mixture of protease inhibitors for the treatment of HIV / AIDS) to treat multiple conditions or to treat a specific condition. When used, such embodiments eliminate the need for a patient to ingest multiple pharmaceuticals for a specific condition or multiple conditions. Similarly, such embodiments also provide a means of ensuring that a regimen of two or more drugs is delivered and absorbed in the small intestine and thus delivered and absorbed into the bloodstream at approximately the same time. Due to differences in chemical composition, molecular weight, etc., drugs can be absorbed from the intestine at different rates through the intestinal wall, thereby resulting in different pharmacokinetic distribution curves. Embodiments of the present invention address this problem by injecting the desired drug mixture directly into the intestinal wall at approximately the same time. This is then achieved by achieving the pharmacokinetic parameters of the selected drug mixture (e.g., for different drugs, similar t 1 / 2 by achieving), and improving the efficacy of the thus selected drug mixture (e.g., within 5% of the time, by substantially synchronizing).

[0033] In another aspect, various embodiments of the present invention are pharmaceutical compositions comprising a solid, shaped mass containing a drug such as a coagulation factor or an antibody having biological activity in a mammalian body, wherein at least a portion of the biological activity of the coagulation factor (or other blood coagulation protein) is maintained after forming the mass from a precursor material such as a powder. In the case of a coagulation factor, the biological activity may correspond to the promotion or acceleration of the coagulation process, including the promotion of the activation of one or more coagulation factors (e.g., the promotion of factor X activation as in the case of factor VIII). In the case of an antibody, the biological activity may correspond to the binding affinity for an antigen. The biological activity, at the composition level, is such that a selected percentage of the coagulation factor or other blood coagulation protein (e.g., based on weight) is maintained after formation compared to the percentage of the precursor material, and may correlate with the integrity of the structure of the coagulation factor (e.g., having no cleavage of any functional groups), or other blood coagulation protein or other drug after formation (e.g., by correlating a biological activity assay with a chemical assay). Typically, the shape is formed by a compression process (e.g., compression molding), but other processes such as non-compression molding or 3-D printing are also contemplated. The drug may correspond to a peptide, a coagulation factor, or other blood coagulation protein, an immunoglobulin, or other protein, but the biological activity of the drug in the shaped mass is at least 70% of the activity before compression, more preferably at least 90% of the activity before compression, and even more preferably at least 95%. These numbers may also correspond to the weight percentage of the drug remaining in the shaped mass compared to the weight percentage of the drug in the precursor material (e.g., by correlating a biological activity assay with a chemical assay for the above weight compositions). In these and related embodiments, the shaped mass has a density in the range of about 1.00 - 1.15 mg / mm 3 and, in more preferred embodiments, in the range of 1.02 - 1.06 mg / mm 3 . The shape typically includes a pellet shape, but may also have a tablet, cone, cylinder, cube, sphere, or other similar shape. Typically, next, the pellet or other form of the shaped mass is inserted into an embodiment of the tissue penetrating member described herein.

[0034] Embodiments of the present invention also provide a method of forming a solid, shaped mass comprising an immunoglobulin, a coagulation factor, or another coagulation protein, wherein the shaped mass is formed by shaping a precursor material and at least a portion of the biological activity (e.g., antigen-binding affinity, specificity, etc.) of a peptide, coagulation factor, or other blood clotting protein in the shaped mass is preserved after formation. In many embodiments, shaping is performed by compressing the precursor material, and the compression force is selected to minimize degradation of the biological activity of the protein or polypeptide. Other shaping methods such as non-compression molding and 3-D printing are also contemplated. Typically, the precursor material comprises a powder mixture comprising a drug and one or more excipients. The precursor material may also include a liquid, slurry, or paste. The excipient may include one or more of a lubricant, binder, bulking agent, etc. The shaped mass can be in the form of a tablet, microtablet, bolus, or slug. According to one or more embodiments, the shaped mass produced using embodiments of the forming process can have another property such as a density or particle size of the powder (used to formulate the shaped mass) that correlates with a minimum level of biological activity of the protein or peptide. Similarly, the correlated properties can be consistently maintained within a selected range within a given lot of the shaped mass as well as from lot to lot. Embodiments of the solid mass described herein can be configured to be used in combination with any suitable drug delivery system administered via any suitable route of administration for the condition being treated. Such routes of administration can include, but are not limited to, oral, sublingual, parenteral, intravenous, intramuscular, transdermal, intraventricular, intracardiac, or intracranial. For example, according to one embodiment, a coagulation factor-containing microtablet (e.g., a microtablet containing factor VII, factor VIII, etc.) can be orally ingested and delivered to the small intestine, where the coagulation factor is delivered to the wall of the small intestine and then to the retroperitoneum and intraperitoneum, where the tablet dissolves to release the coagulation factor. In another embodiment, the microtablet can be injected or otherwise placed subcutaneously (e.g., intramuscularly), where the tablet dissolves to release the coagulation factor or other blood clotting protein into the bloodstream.

[0035] Further details of these and other embodiments and aspects of the present invention will be described in more detail below with reference to the accompanying drawings.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0069] Detailed Description Embodiments of the present invention provide devices, systems, and methods for delivering agents to various locations in the body, as well as therapeutic compositions containing the agents. As used herein, the term "agent" refers to any form of pharmaceutical preparation that can include one or more drugs or other therapeutic agents, as well as one or more pharmaceutical excipients. Many embodiments provide a swallowable device for delivering an agent to the interior of the GI tract, including the wall of the small intestine. Certain embodiments provide a swallowable device, such as a capsule, for delivering an agent, such as a coagulation factor for the treatment of coagulation disorders, to the wall of the small intestine and / or the peritoneum and / or intraperitoneally, or within other GI organs. As used herein, "GI tract" refers to the esophagus, stomach, small intestine, large intestine, and anus, while "intestinal tract" refers to the small intestine and large intestine. Similarly, as used herein, the term "peritoneum" refers to one or both of the visceral peritoneum and the parietal peritoneum and is interchangeable with the term abdominal wall. Further, as used herein, the term abdominal cavity refers to the space between the parietal peritoneum and the visceral peritoneum. Similarly, as used herein, the term "about" means within 10% of a given stated numerical value of a parameter, variable, dimension, etc. (e.g., pharmacokinetic parameters such as t 1 / 2 , t max , C max , etc.), more preferably within 5% although not necessarily required.

[0070] Next, referring to FIGS. 1-11, an embodiment of a device 10 for delivering a medicament 100 to a delivery site DS of the intestinal tract, such as the wall of the small intestine and / or the abdominal wall or abdominal cavity, includes a capsule 20 including at least one guide tube 30, one or more tissue penetrating members 40 positioned in or otherwise movable through the at least one guide tube, a delivery member 50, an actuation mechanism 60, and a release element 70. The medicament 100, also described herein as preparation 100, typically includes at least one drug or therapeutic agent 101 and may include one or more pharmaceutically acceptable excipients known in the art. Collectively, one or more of the delivery member 50 and mechanism 60 may include means for delivering the medicament 100 to the wall of the intestinal tract. Other delivery means contemplated herein include one or more expandable balloons (e.g., delivery balloon 172) or other expandable devices / members described herein.

[0071] Device 10 can be configured to deliver a drug 100 in liquid, semi-liquid, or solid form, or all three forms. The solid form of the drug / preparation 100 can include both powders and pellets. The semi-liquid form can include slurries or pastes. In any form, the preparation 100 preferably has a shape and material compatibility such that after the drug is advanced from the device into the intestinal wall (or other luminal wall of the GI tract), it decomposes in the intestinal wall and releases a drug or other therapeutic agent 101, and the drug or other therapeutic agent 101 can correspond to one or more clotting factors for the treatment of hemophilia or other coagulation disorders described herein in various embodiments. For example, factor VIII in the case of treating hemophilia A and factor IX in the case of treating hemophilia B. The material compatibility of the preparation can include one or more of the hardness, porosity, and solubility of the preparation (in body fluids), as well as its shape having tissue-penetrating ends for penetrating into the peritoneal cavity through the intestinal wall. The material compatibility can be achieved by one or more of the following: i) the compression force used to make the preparation; ii) the use of one or more pharmaceutically known disintegrants; iii) the use of other pharmaceutical excipients; iv) the particle size and distribution of the preparation (e.g., micronized particles); and v) the use of micronization and other particle formation methods known in the art. Suitable shapes of the preparation 100 can include cylinders, cubes, rectangular prisms, cones, spheres, hemispheres, and combinations thereof. Similarly, the shape can be selected to define a specific surface area and volume of the preparation 100, and thus the ratio of both. Next, the ratio of surface area to volume can be used to achieve a selected rate of decomposition within the intestinal wall or other luminal wall within the GI tract. A larger ratio (e.g., a larger amount of surface area per unit volume) can be used to achieve a more rapid rate of decomposition, and vice versa. In certain embodiments, the ratio of surface area to volume can range from about 1:1 to 100:1, and in certain embodiments can be 2:1, 5:1, 20:1, 25:1, 50:1, and 75:1 (within about 5%). The preparation / drug 100 is typically pre-filled within the lumen 44 of the tissue-penetrating member 40, but can also be contained at another location within the interior 24 of the capsule 20, or in the case of a liquid or semi-liquid, within an enclosed reservoir 27.The agent can be pre-formed to conform to the lumen or can be filled, for example, in powder form. Typically, device 10 is configured to deliver a single drug 101 as part of agent 100. However, in some embodiments, device 10 can be configured to deliver multiple drugs 101 including a first, second, or third drug that can be formulated into a single or multiple agents 100. In embodiments having multiple agents / drugs, the agents can be contained within individual tissue penetrating members 40 or within individual compartments or reservoirs 27 within capsule 20. In another embodiment, as shown in the embodiment of FIG. 1b, a first dose 102 of agent 100 containing a first drug 101 can be filled into penetrating member 44 and a second dose 103 of agent 100 (containing the same or different drug 101) can be coated onto the surface 25 of the capsule. The drugs 101 in the two doses of agents 102 and 103 can be the same or different. In this way, biphasic drug release of the same or different drugs can be achieved. The second dose 103 of agent 100 can have an enteric coating 104 to ensure that it is released in the small intestine and similarly achieve sustained release of agent 100. The enteric coating 104 can include one or more enteric coatings described herein or known in the art.

[0072] System 11 for delivering agent 100 to the wall of the small intestine and / or the abdominal wall or other locations within the GI tract may include device 10 containing one or more agents 100 for treatment of a selected condition or multiple conditions. In some embodiments, the system may include portable device 13 described herein for communicating with device 10, as shown in the embodiment of FIG. 1b. System 11 may also be configured as a kit 14 including system 11 and a set of instructions 15, packaged in packaging 12 as shown in the embodiment of FIG. 1c. The instructions may direct the patient as to when to ingest device 10 in relation to one or more events such as dietary intake or physiological measurements such as blood glucose, cholesterol, etc. In such embodiments, kit 14 may include multiple devices 10 containing a regimen of agent 100 for a selected administration period, e.g., one day, one week, or several weeks, depending on the condition being treated.

[0073] The capsule 20 is sized to be swallowed and pass through the intestinal tract. The size can also be adjusted according to the amount of drug to be delivered, as well as the patient's weight and whether it is for adult or pediatric indication. The capsule 20 includes an outer surface 25 having an internal volume 24 and one or more openings 26 sized to fit the guide tube 30. In addition to other components of the device 10 (such as the actuation mechanism, etc.), the internal volume may include one or more compartments or reservoirs 27. One or more parts of the capsule 20 can be made from various biocompatible polymers including various biodegradable polymers that may include PGLA (poly(lactic-co-glycolic acid)) in the preferred embodiments. Other suitable biodegradable materials include various enteric materials described herein, as well as lactide, glycolide, lactic acid, glycolic acid, p-dioxanone, caprolactone, trimethylene carbonate, caprolactone, mixtures and copolymers thereof. As described in more detail herein, in various embodiments, the capsule 20 may include a seam 22 of biodegradable material so as to controllably degrade into small pieces 23 that more easily pass through the intestinal tract. In addition, in various embodiments, the capsule may include various radiopaque or echogenic materials for identifying the position of the device using fluoroscopy, ultrasound, or other medical imaging modalities. In certain embodiments, all or part of the capsule may include a radiopaque / echogenic marker 20m as shown in the embodiments of FIGS. 1a and 1b. When used, such materials not only enable the localization of the device 10 in the GI tract but also allow the determination of the transit time of the device through the GI tract.

[0074] In a preferred embodiment, the tissue penetration member 40 is positioned within a guide tube 30 that serves to guide and support the advancement of the member 40 into the tissue, such as the wall of the small intestine, and / or the abdominal wall, or other portions of the GI tract. The tissue penetration member 40 typically includes a hollow needle or other similar structure and has a tissue penetration tip 45 for penetrating into the lumen 44 and the intestinal wall IW to a selectable depth. The member 40 may also include a pin 41 for engaging with the motion converter 90 described herein. The depth of penetration can be controlled by the length of the member 40, the configuration of the motion converter 90 described herein, and in one embodiment, the placement of a barb or flange 40s on the member 40 that corresponds to the pin 41 described herein. The agent 100 is typically delivered to the tissue through the lumen 44. In many embodiments, the lumen 44 is pre-filled with the desired agent 100, and the agent 100 advances out of the lumen using a delivery member 50 or other advancing means (e.g., by a force applied to a degradable embodiment of the member 40). Alternatively, the agent 100 can advance into the lumen 44 from another location / compartment in the capsule 20. In some embodiments, all or part of the tissue penetration member 40 can be made from the agent 100 itself (e.g., a coagulation factor such as factor VII, factor VIII, factor IX, or factor X, or other clotting proteins). In these and related embodiments, the agent is configured to penetrate through the intestinal wall (e.g., the wall of the small intestine) or surrounding tissue (e.g., the abdominal wall or peritoneal cavity) after insertion and be retained therein, and can have a needle or dart-like structure (with or without barbs), or other elongated structure with a sharp tip. The darts can be sized and shaped according to the agent, dosage, and desired depth of penetration into the intestinal wall. The agent 100 can be formed into darts, pellets, or other shapes using various compression molding methods known in the pharmaceutical art.

[0075] In various embodiments, device 10 may include second 42 and third 43 tissue penetrating members 40, as shown in the embodiments of FIGS. 7a and 7b, although additional numbers are contemplated. Each tissue penetrating member 40 can be used to deliver the same or different agents 100. In a preferred embodiment, the tissue penetrating members 40 can be distributed substantially symmetrically around the outer periphery 21 of the capsule 20 to secure the capsule to the intestinal wall IW during delivery of the agent 100. Securing the capsule 20 in such a manner reduces the likelihood that the capsule will shift or move due to peristaltic contractions that occur during delivery of the agent. In certain embodiments, the amount of force for securing can be adjusted to the typical forces applied during peristaltic contractions of the small intestine. Securing can be further facilitated by configuring a portion or all of the tissue penetrating members 40 to have a curved or arcuate shape.

[0076] Delivery member 50 is configured to advance agent 100 through the tissue penetrating member lumen 44 and into the intestinal wall IW. Accordingly, at least a portion of delivery member 50 is advanceable within the tissue penetrating member lumen 44, and thus member 50 has a size and shape (e.g., a piston-like shape) configured to fit within delivery member lumen 44.

[0077] In some embodiments, the distal end 50d of the delivery member (the end that advances into the tissue) may have a plunger element 51 that advances the agent within the tissue penetration member lumen 44 and similarly forms a seal with the lumen. The plunger element 51 may be integral with the delivery member 50 or attachable to the delivery member 50. Preferably, the delivery member 50 is configured to move a fixed distance within the lumen of the needle to deliver a fixed or constant dose of the drug into the intestinal wall IW. This can be achieved by selection of the diameter of the delivery member (e.g., the diameter may taper distally), the diameter of the tissue penetration member (which may narrow at its distal end), the use of the tip, and / or one or more of the actuation mechanisms. However, in some embodiments, the stroke or travel distance of the member 50 can be adjusted in situ in response to various factors such as one or more sensed conditions in the GI tract. In situ adjustment can be achieved through the use of a logic resource 29 (including the controller 29c) coupled to an electromechanical embodiment of the actuation mechanism 60. This allows for variable dosing of the agent and / or variation in the distance at which the agent is injected into the intestinal wall.

[0078] The actuation mechanism 60 can be coupled to at least one of the tissue penetration member 40 or the delivery member 50. The actuation mechanism is configured to advance the tissue penetration member 40a a selectable distance into the intestinal wall IW, as well as advance the delivery member to deliver the agent 100 and then retract the tissue penetration member from the intestinal wall. In various embodiments, the actuation mechanism 60 may include a spring-loaded mechanism configured to be released by a release element 70. Suitable springs 80 can include both coil springs (including conical-shaped springs) and leaf springs, although other spring structures are equally contemplated. In certain embodiments, the spring 80 may be substantially conical in shape to reduce the length of the spring in the compressed state to the point where the length of the spring upon compression is approximately a few coils (e.g., 2 or 3) or the thickness of just 1 coil.

[0079] In certain embodiments, the actuating mechanism 60 may include a spring 80, a first motion converter 90, and a second motion converter 94, and a track member 98, as shown in the embodiments of FIGS. 2, 4, and 8a - 8c. The release element 70 is coupled to the spring 80 to hold the spring in a compressed state such that when the release element disassembles, the spring is released. The spring 80 may be coupled to the release element 70 by a latch or other connection element 81. The first motion converter 90 is configured to convert the movement of the spring 80 to advance and retract the tissue penetrating member 40 into and out of the intestinal wall or other tissue. The second motion converter 94 is configured to convert the movement of the spring 80 to advance the delivery member 50 into the tissue penetrating member lumen 44. The motion converters 90 and 94 are pushed by the spring and move along a paddle or other track member 98 that fits within the track member lumen 99 of the converter 90. The track member 98 serves to guide the path of the converter 90. The converters 90 and 94 engage the tissue penetrating member 40 and / or the delivery member 50 (either directly or indirectly) to produce the desired movement. They are along its longitudinal axis configured to convert the movement of the spring 80 into orthogonal movement of the tissue penetrating member 40 and / or the delivery member 50, although conversions in other directions are equally contemplated. The motion converter may have a wedge, trapezoidal, or curved shape, although other shapes are equally contemplated. In a particular embodiment, the first motion converter 90 has a trapezoidal shape 90t, as shown in the embodiments of FIGS. 2, 3, and 4, and may include a slot 93 that engages a pin 41 on the tissue penetrating member that moves within the slot. The slot 93 may also be shaped to mirror the overall shape of the converter 90 or otherwise have a corresponding trapezoidal shape 93t. The slot 93 serves to push the tissue penetrating member 40 between the upward sloping portions 91 of the trapezoid and then return it between the downward sloping portions 92. In one variant, one or both of the motion converters 90 and 94 may include a cam or cam-like device (not shown). The cam can be actuated by the spring 80 and can engage the tissue penetrating member and / or the delivery members 40 and 50. One or more components of the mechanism 60 that includes the motion converters 90 and 94 (as well as other components of the device 10) can be fabricated using various MEMS-based methods known in the art such that a selected amount of miniaturization can fit within the capsule 10. Similarly, as described herein, they can be formed from various biodegradable materials known in the art.

[0080] In other variations, the actuation mechanism 60 may also include electromechanical devices / machines such as solenoids or piezoelectric devices. In one embodiment, the piezoelectric device used in mechanism 60 may include a shaped piezoelectric element having a non-deployed state and a deployed state. This element can be configured to become deployed upon application of a voltage and then return to the non-deployed state upon removal of the voltage or other change in the voltage. This and related embodiments enable the repeated movement of the actuation mechanism 60, enabling both the forward movement and subsequent retraction of the tissue penetrating member. The voltage for the piezoelectric element can be obtained and generated using a battery or a piezoelectric-based energy converter that generates a voltage by mechanical deformation such as deformation caused by peristaltic contractions of the small intestine around the capsule compressing the capsule 20. Further description of piezoelectric-based energy converters is found in U.S. Patent Application No. 12 / 556,524, which is hereby incorporated by reference in its entirety for all purposes. In one embodiment, the deployment of the tissue penetrating member 40 can actually be induced by peristaltic contractions of the small intestine that provide the mechanical energy to generate the voltage for the piezoelectric element.

[0081] The release element 70 is typically coupled to the actuation mechanism 60 and / or a spring coupled to the actuation mechanism, although other configurations are equally contemplated. In a preferred embodiment, the release element 70 is coupled to a spring 80 located within the capsule 20 to hold the spring in a compressed state 85, as shown in the embodiment of FIG. 2. When the release element 70 disassembles, it releases the spring 80 to actuate the actuation mechanism 60. Thus, the release element 70 can also function as an actuator 70a in this way (the actuator 70 may also include the spring 80 and other elements of the mechanism 60). As will be described in more detail below, the release element 70 and the actuator 70a have a first configuration in which the therapeutic agent preparation 100 is contained within the capsule 20, and a second configuration in which the therapeutic agent preparation advances from the capsule into the wall of the small intestine and / or the abdominal wall or peritoneal cavity, or other luminal wall of the intestinal tract.

[0082] In many embodiments, the release element 70 comprises a material configured to degrade when exposed to chemical conditions in the small intestine or large intestine, such as pH. Typically, the release element 70 is configured to degrade when exposed to a selected pH in the small intestine, such as 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 8.0, or higher pH. The release element can also be configured to degrade within a specific range of pH, such as 7.0 to 7.5. In certain embodiments, the pH at which the release element 70 degrades (defined herein as the degradation pH) can be selected such that a particular drug is delivered to release the drug at a location in the small intestine corresponding to the selected pH. Further, in embodiments of the device 10 having multiple agents 100, the device can include a first release element 70 configured to degrade at a first pH (coupled to an activation mechanism for delivering the first drug), and a second release element 70 configured to degrade at a second pH (coupled to an activation mechanism for delivering the second drug) (additional numbers of release elements are contemplated for diverse numbers of drugs).

[0083] The release element 70 can also be configured to degrade in response to other conditions in the small intestine (or other GI location). In certain embodiments, the release element 70 can be configured to degrade in response to specific chemical conditions in the fluid of the small intestine, such as chemical conditions that occur after ingestion of a meal (e.g., a meal containing fat, starch, or protein). In this way, the release of the agent 100 can be substantially synchronous with, or otherwise concurrent with, the ingestion of a meal.

[0084] Various approaches are contemplated with respect to biodegradation of the release element 70. In certain embodiments, biodegradation of the release element 70 by one or more conditions in the small intestine (or other locations in the GI tract) can be achieved by one or more of the following approaches: i) selection of 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. A lower amount of cross-linking and / or thinner dimensions can increase the rate of degradation, and vice versa. Suitable materials for the release element can include biodegradable materials such as various enteric materials configured to degrade when exposed to a higher pH in the intestine. Suitable enteric materials include, but are not limited to, the following: cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methyl methacrylate ester, and other enteric materials known in the art. The selected enteric material can be copolymerized with one or more other polymers or otherwise combined to obtain a plurality of other specific material properties in addition to biodegradation. Such properties can include, but are not limited to, rigidity, strength, flexibility, and hardness.

[0085] In an alternative embodiment, the release element 70 can include a coating or plug 70p that covers or otherwise blocks the guide tube 30 and holds the tissue penetrating member 40 inside the guide tube. In these and related embodiments, the tissue penetrating member 40 is coupled to a spring-loaded actuating mechanism such that when the release element is sufficiently degraded, it releases the tissue penetrating member, which then pops out of the guide tube and penetrates through the intestinal wall. In still other embodiments, the release element 70 can be shaped to function as a latch that holds the tissue penetrating element 40 in place. In these and related embodiments, the release element can be located external or internal to the capsule 20. In the latter case, the capsule 20 and / or the guide tube 30 can be configured to allow entry of intestinal fluid into the capsule to enable degradation of the release element.

[0086] In some embodiments, the actuating mechanism 60 can be actuated by a sensor 67 that detects the presence of the capsule in the small intestine, such as a pH sensor 68 or other chemical sensor. The sensor 67 can then send a signal to the actuating mechanism 60 or an electronic controller 29c coupled to the actuating mechanism 60 to actuate the mechanism. Embodiments of the pH sensor 68 can include an electrode-based sensor or can be a mechanically-based sensor such as a polymer that contracts or expands when exposed to a selected pH or other chemical condition in the small intestine. In related embodiments, the expandable / contractable sensor 67 can also include the actuating mechanism 60 itself by using the mechanical movement from the expansion or contraction of the sensor.

[0087] According to another embodiment for detecting that the device is in the small intestine (or other location in the GI tract), the sensor 67 can include a pressure / force sensor such as a strain gauge for detecting the number of peristaltic contractions that the capsule 20 undergoes inside a particular location in the intestinal tract. In such embodiments, the capsule 20 is desirably sized to be grasped by the small intestine during peristaltic contractions. Different locations within the GI tract have different numbers of peristaltic contractions. The small intestine has contractions at a frequency that reduces the length of the small intestine having 12 to 9 contractions per minute. Thus, according to one or more embodiments, detecting the number of peristaltic contractions can be used to determine not only whether the capsule 20 is present in the small intestine, but also its relative position within the intestine. When used, these and related embodiments enable the release of the drug 100 at a particular location in the small intestine.

[0088] As an alternative or supplement to internal activated drug delivery (e.g., using release elements and / or sensors), in some embodiments, a user may externally activate the actuating mechanism 60 by RF, magnetic, or other wireless signaling means known in the art to deliver the medicament 100. In these and related embodiments, the user may use a portable communication device 13 (e.g., a portable RF device such as a mobile phone) as shown in the embodiment of FIG. 1b to send a received signal 17 from the device 10. In such embodiments, the swallowable device may include a communication device 28, such as an RF transceiver chip or other similar communication device / circuit. The portable device 13 may include not only signaling means but also means to notify the user when the device 10 is present in the small intestine or other locations in the GI tract. The latter embodiments are implemented through the use of a logic resource 29 (e.g., a processor 29) coupled to the communication device 28, which can detect when the device is present in the small intestine or other locations and transmit a signal to singe the user (e.g., by transmitting an input signal from a sensor). The logic resource 29 may include a controller 29c (either hardware or software) to control one or more aspects of the process. The same portable device may also be configured to notify the user (e.g., using the processor 29 and the communication device 28) when the actuating mechanism 60 is activated and the selected medicament 100 is delivered. In this way, the user is provided with confirmation that the medicament 100 has been delivered. This allows the user to take other appropriate drugs / therapeutic agents and make other related decisions (e.g., for a diabetic patient, whether to eat a meal and which foods to eat). The portable device may also be configured to send a signal to the swallowable device 10 to prevent, delay, or accelerate the delivery of the medicament 100 by overriding the actuating mechanism 60. When used, such embodiments allow the user to intervene to prevent, delay, or accelerate the delivery of the medicament based on other symptoms and / or the patient's actions (e.g., deciding to eat a meal, go to sleep, exercise, etc.).The user may also externally activate the actuating mechanism 60 during a selected period after swallowing the capsule. The period may correlate with a typical transit time or range of transit times for food to move through the user's GI tract to a particular location in a tube such as the small intestine.

[0089] In certain embodiments, the capsule 20 may include a seam 22 of biodegradable material that controllably degrades to yield capsule pieces 23 of selectable size and shape to facilitate passage through the GI tract, as shown in the embodiments of FIGS. 10a and 10b. The seam 22 may also include holes or other openings 22p for fluid to enter into the seam to accelerate biodegradation, as shown in the embodiment of FIG. 10. Other means of accelerating biodegradation of the seam 22 may include pre-stressing the seam and / or including perforations 22f in the seam, as also shown in the embodiment of FIG. 10. In yet other embodiments, the seam 22 may be constructed of a material that is readily degraded by absorption of ultrasonic energy, such as high intensity focused ultrasound (HIFU), and / or may have a structure that readily degrades, such that the capsule can be broken into pieces using ultrasound applied externally or by an endoscope (or other minimally invasive method).

[0090] Suitable materials for the seam 22 can include one or more biodegradable materials described herein, such as PGLA, glycolic acid, etc. The seam 22 can be attached to the capsule body 20 using various joining methods known in the polymer art, such as molding, hot melt bonding, etc. Further, in embodiments of the capsule 20 similarly made from biodegradable materials, more rapid biodegradation of the seam 22 can be achieved by one or more of the following: i) the step of making the seam from a more rapidly biodegradable material, ii) the step of pre-stressing the seam, or iii) the step of making holes in the seam. The idea of using a biodegradable seam 22 to effect 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 devices) to facilitate passage through the GI tract and reduce the likelihood that such a device will become lodged in the GI tract. Accordingly, embodiments of the biodegradable seam 22 can also be adapted for swallowable imaging devices and other swallowable devices.

[0091] Another aspect of the present invention provides a method of delivering a drug and other therapeutic agents (in the form of agent 100) into the wall of the GI tract using one or more embodiments of the swallowable drug delivery device 10. Exemplary embodiments of such methods are described below. The described embodiments of drug delivery occur in the small intestine SI. However, this is exemplary, and it should be recognized that embodiments of the present invention can be used to deliver drugs at multiple locations in the GI tract, including the stomach and large intestine. For ease of discussion, the swallowable drug delivery device 10 is sometimes referred to herein as a capsule. As described above, in various embodiments, the device 10 can be packaged as a kit 11 within a sealed packaging 12 that includes the device 10 and a set of instructions 15. If the patient is using a portable device 13, the patient may be instructed to enter data into the device 13 either manually or via a barcode 18 (or other identification indicator 18) located on the instructions 15 or the packaging 12. When using a barcode, the patient uses a barcode reader 19 on the device 13 to scan the barcode. After opening the packaging 12, reading the instructions 15, and entering any necessary data, the patient swallows an embodiment of the swallowable drug delivery device 10. Depending on the drug, the patient may ingest the device 10 with a meal (before, during, or after a meal) or in relation to a physiological measurement. The capsule 20 is sized to pass through the GI tract and into the patient's stomach S and then, through peristalsis, to the small intestine SI as shown in the embodiment of FIG. 11. Upon entering the small intestine, the release element 70 is decomposed by the basic pH of the small intestine (or other chemical or physiological conditions unique to the small intestine), activating the activation mechanism 60 in accordance with one or more embodiments of the present invention to deliver the agent 100 to the wall of the small intestine SI. In embodiments that include a hollow needle or other hollow tissue-penetrating member 40, drug delivery is performed using the activation mechanism 60. After advancing the member 40 a selected distance into the mucosa of the intestinal wall IW, the agent is injected through the lumen 44 of the needle by advancement of the delivery member 50. The delivery member 50 is retracted, and then the member 40 is retracted into the body of the capsule (e.g., by the spring reaction) and removed from the intestinal wall.In an embodiment of the device 10 having a plurality of needles, the second or third needles 42, 43 can likewise be used to deliver an additional dose of the same drug or an individual drug 101. The advancement of the needles or other tissue penetrating members 40 can be performed substantially simultaneously or sequentially. In a preferred embodiment using a plurality of needles, the advancement of the needles can be performed substantially simultaneously to fix the device 10 in the small intestine during drug delivery. Referring now to FIGS. 11A - E, in many embodiments including embodiments where the drug 101 includes a coagulation factor CF, the device 10 including the actuation mechanism 50 is configured to advance a needle or other tissue penetrating member 40 through the intestinal wall IW and the abdominal wall or peritoneum P, such as the visceral peritoneum PV, into the peritoneal cavity PC. Upon entering the peritoneal cavity PC, the needle is degraded by the serous fluid and other fluids in the peritoneal cavity PC, releasing the coagulation factor CF into the serous fluid and other peritoneal fluids and then into the bloodstream by diffusion of the coagulation factor CF or other drug 101 into the vascular system of the peritoneum including the vascular systems of the visceral and parietal peritoneum. In these and related embodiments, the positioning of the tissue penetrating member 140 within the peritoneal cavity PC can be facilitated by configuring the member 140 to have a symmetrically pointed tip 145 and by increasing the amount of reactant to generate an increase in pressure for ejecting the member 140 through the intestinal wall IW and then into the peritoneal cavity PC. They can also be facilitated by increasing the amount of reactant 165 in the balloon 160 to generate an increased amount of gas 169 and then increase the gas pressure for injecting the member 140 into the peritoneal cavity. In various embodiments of the device 10 configured for delivery of the tissue penetrating member 140 into the peritoneal cavity PC, the amount by weight of the reactant 165 (e.g., potassium bicarbonate, sodium bicarbonate, etc.) can be increased in the range of 10 - 30% compared to the case where the member 140 is located only within the intestinal wall IW.

[0092] After drug delivery, the device 10 then passes through the intestinal tract including the large intestine LI and is ultimately excreted. In embodiments of the capsule 20 having a biodegradable seam 22 or other biodegradable portion, as shown in the embodiments of FIGS. 9a and 9b, the capsule breaks down into small pieces in the intestinal tract, facilitating passage through and excretion from the intestinal tract. In certain embodiments having a biodegradable tissue penetrating needle / member 40, even if the needle becomes stuck in the intestinal wall, the needle biodegrades to release the capsule 20 from the wall.

[0093] In embodiments of the device 10 that include a sensor 67, actuation of the mechanism 60 can be performed by a sensor that sends a signal to the actuation mechanism 60 and / or a processor 29 or controller 29c coupled to the actuation mechanism. In embodiments of the device 10 that include external actuation capabilities, the user may externally activate the actuation mechanism 60 for a selected period of time after swallowing the capsule. The period may correlate with the typical transit time or range of transit times for food to move through the user's GI tract to a particular location in a tube such as the small intestine.

[0094] One or more embodiments of the above-described method can be used for the delivery of a preparation 100 containing a therapeutically effective amount of a variety of drugs and other therapeutic agents 101 to treat a variety of diseases and conditions. These include, for example, a plurality of polymeric peptides and proteins that would otherwise require injection due to chemical decomposition in the stomach, including the various clotting factors described herein. The dosage of a particular drug can be titrated with respect to the patient's weight, age, or other parameters. Similarly, the dosage of drug 101 to achieve a desired effect or therapeutic effect (e.g., insulin for blood glucose regulation) when delivered by one or more embodiments of the present invention can be lower than the amount required when the drug is delivered by normal 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 no degradation of the drug by gastric acid and other digestive fluids, and the fact that all of the drug, rather than just a small portion, is delivered into the wall of the small intestine and / or the abdominal wall (or other lumens such as the intestinal tract, e.g., the large intestine, stomach, etc.). Depending on the drug 101, the dosage 102 delivered in the preparation 100 can range from 100 to 5% of the dosage delivered by normal oral delivery (e.g., a pill) to achieve the desired therapeutic effect (e.g., blood glucose regulation, seizure regulation, etc.), although even lower amounts are contemplated. The reduction of a particular dosage can be titrated based on the particular drug, the amount of degradation that occurs in the GI tract in the case of normal oral methods, the comparison of the dosing frequency with the dosing frequency using the embodiments of the swallowable capsule described herein, the condition being treated, as well as the patient's weight, age, and condition. For some drugs where the level of degradation in the intestinal tract is known, a standard dosage reduction (e.g., 10 - 20%) can be used. For drugs that are more susceptible to degradation and have poor absorption, a greater amount of dosage reduction can be used. In this way, by reducing the dosage ingested, the potential toxicity and other side effects (e.g., stomach cramps, irritable bowel, bleeding, etc.) associated with the particular drug or drugs delivered by device 10 can be reduced. This in turn improves patient compliance since the patient experiences a reduction in both the severity and incidence of side effects.Additional benefits of embodiments using reduced dosages of drug 101 include a reduced likelihood that a patient will develop resistance to the drug (requiring higher dosages), and in the case of antibiotics, a reduced likelihood that a patient will develop resistant strains of bacteria. Similarly, other levels of dosage reduction can be achieved with respect to patients who have undergone gastric bypass surgery and other techniques in which sections of the small intestine have been removed or the effective length of its function (e.g., digestion) has been effectively shortened.

[0095] In addition to the delivery of a single drug, embodiments of the swallowable drug delivery device 10 and methods of using the same can be used to deliver multiple drugs for the treatment of multiple conditions or for the treatment of a particular condition (e.g., protease inhibitors for the treatment of HIV / AIDS). When used, such embodiments eliminate the need for a patient to take multiple medications with respect to a particular condition or multiple conditions. Similarly, they also provide a means for facilitating the delivery of a regimen of two or more drugs such that they are absorbed in the small intestine and thus absorbed into the bloodstream at approximately the same time. Due to differences in chemical composition, molecular weight, etc., drugs are absorbed through the intestinal wall at different rates, thereby resulting in different pharmacokinetic distribution curves. Embodiments of the present invention address this problem by injecting the desired drug mixture substantially simultaneously. This in turn improves the pharmacokinetics, and thus the efficacy, of the selected drug mixture. In addition, the elimination of the need to take multiple drugs is particularly beneficial for patients with one or more long-term chronic conditions, including patients with impaired cognitive or physical abilities.

[0096] In various applications, embodiments of the above methods can be used to deliver a preparation 100 comprising a drug and therapeutic agent 101 and provide treatment of a plurality of medical conditions and diseases. Medical conditions and diseases that can be treated by embodiments of the present invention include, but are not limited to: cancer, hormonal conditions (e.g., low / high, thyroid hormone condition, growth hormone condition), osteoporosis, hypertension, elevated cholesterol and triglycerides, diabetes and other glucose regulation disorders, infectious diseases (local or systemic, e.g., sepsis), epilepsy and other seizure disorders, osteoporosis, coronary arrhythmias (both atrial and ventricular), coronary ischemic anemia or other similar conditions. Still other conditions and diseases are similarly contemplated.

[0097] In many embodiments, the treatment of a particular disease or condition can be carried out without the need to inject a coagulation factor or other clotting protein or other therapeutic agent (or other parenteral delivery forms, such as suppositories), and instead, rely only on the therapeutic agent delivered to the wall of the small intestine and / or the abdominal wall, or other parts of the GI tract. Similarly, the patient does not need to ingest the normal oral form of the drug or other therapeutic agent, and in this case, can also rely only on the delivery to the wall of the small intestine and / or the abdominal wall using an embodiment of a swallowable capsule. In other embodiments, the therapeutic agent delivered to the wall of the small intestine and / or the abdominal wall can be delivered in relation to the injectable dose of the therapeutic agent. For example, the patient may ingest the dose of the therapeutic agent daily using an embodiment of a swallowable capsule, but may need to ingest the injectable dose only every few days or only when the patient's condition requires it (e.g., hyperglycemia). The same applies to therapeutic agents delivered conventionally in oral form (e.g., the patient can ingest a swallowable capsule and, if necessary, the normal oral form of the therapeutic agent). The dosage delivered in such embodiments (e.g., the swallowed and injected doses) can be set as needed (e.g., appropriate dosages can be determined using standard dose-response curves and other pharmacokinetic methods). Similarly, in embodiments using therapeutic agents that can be delivered by normal oral means, the dosage delivered using an embodiment of a swallowable capsule can be set lower than the dosage normally given for oral delivery of the therapeutic agent because the therapeutic agent decomposes little or not at all in the stomach or other parts of the intestinal tract (again, standard dose-response curves and other pharmacokinetic methods can be applied herein). than the dosage normally given for oral delivery of the therapeutic agent.

[0098] Various embodiments of a preparation 100 containing one or more drugs or other therapeutic agents 101 for the treatment of various diseases and conditions are described next with reference to dosage. These embodiments, including specific therapeutic agents and their respective dosages, are exemplary, and it should be recognized that the preparation 100 may include a plurality of other therapeutic agents (as well as therapeutic agents known in the art) described herein that are configured to be delivered into the luminal wall of the intestinal tract (e.g., the wall of the small intestine) using various embodiments of the device 10. The dosage may be higher or lower than the dosage described and can be adjusted using one or more methods described herein or known in the art.

[0099] In certain embodiments, the therapeutic agent preparation 100 may include a therapeutically effective dose of growth hormone for the treatment of one or more growth disorders and wound healing. In one embodiment, the preparation 100 may contain a therapeutically effective amount of growth hormone in the range of about 0.1 to 4 mg, particularly in the ranges of 0.1 to 1, 1 to 4, 1 to 2, and 2 to 4 mg, although even larger ranges are contemplated. The specific dosage can be set based on one or more of the following factors: i) the specific condition being treated and its severity (e.g., the level and specific type of hypercholesterolemia or dyslipidemia); ii) the patient's weight; iii) the patient's age; and iv) the frequency of administration (e.g., comparison of daily vs. twice daily).

[0100] The drug delivery compositions and components of known drug delivery systems may be used and / or modified for use in some embodiments of the invention described herein. For example, microneedles and other microstructures used to deliver drugs through the skin surface by a drug patch may be modified and incorporated into the capsules described herein for use instead of delivering a drug preparation to the luminal wall of the gastrointestinal tract, such as the wall of the small intestine and / or the abdominal wall. Suitable polymeric microneedle structures are available from Corium of California, for example, and may be sold as the MicroCor™ microdelivery system technology. Other components of the MicroCor™ patch delivery system, including drug formulations or components, may also be incorporated into the capsules described herein. Alternatively, various vendors formulate combinations of polymers or other drug delivery matrices with selected drugs and other drug preparation components to produce desired shapes (e.g., the releasable tissue-penetrating shapes described herein) having desired drug release characteristics and are commercially available for such use. Such vendors may include, for example, Corium, SurModics of Minnesota, BioSensors International of Singapore, and the like.

[0101] One advantage and feature of various embodiments of the therapeutic compositions described herein is that the coagulation factor (e.g., Factor VIII) or other biologic agent (e.g., peptide or protein) drug payload is protected from degradation and / or hydrolysis by the action of peptidases and proteases in the gastrointestinal (GI) tract by being encapsulated within or otherwise contained within a swallowable capsule or other swallowable device. These enzymes are ubiquitous throughout the living system. The GI tract is particularly protease-rich since its function is to break down complex proteins and peptides in the individual's diet into smaller segments, release amino acids, and then the amino acids are absorbed from the intestine. The devices and compositions described herein are designed to protect the therapeutic peptide, coagulation factor, or other protein from the action of these GI proteases and to deliver the peptide or protein payload directly to the intestinal wall. In various embodiments of the compositions described herein, there are two configurations that serve to protect the protein or peptide payload from the action of GI proteases. First, in certain embodiments, the capsule shell containing the deployment engine and mechanics does not dissolve until it reaches the duodenum and the intestinal segments below the duodenum due to a pH-sensitive coating on the outer surface of the capsule that prevents its dissolution at the low pH of the stomach. Second, in certain embodiments, hollow polymer microspheres (e.g., polyethylene, oxidized polyethylene, maltose, silicone, etc.) contain the actual therapeutic peptide or protein, and the polymer microspheres are designed to rapidly penetrate the intestinal muscle when the outer capsule shell dissolves and the microspheres themselves gradually dissolve in the intestinal muscle wall to release the drug payload. Thus, the peptide, coagulation factor, other protein payload is not exposed to the action of GI proteases and thus does not undergo proteolysis-mediated degradation in the GI tract. This in turn contributes to the high bioavailability of the therapeutic peptide or protein as compared to the bioavailability expected when the peptide or protein is exposed to GI proteases without using one or both of the approaches described above.In particular, in embodiments of a composition comprising a compound that binds to a specific receptor or other target region on a molecule, such an approach preserves the binding affinity and specificity of the compound and binds it to the desired receptor.

[0102] The clotting factors or other blood clotting proteins provided by embodiments of the present invention are particularly useful for treating various blood clotting disorders. Specific blood clotting disorders that can be treated include hemophilia A and B, as well as von Willebrand disease. Such embodiments provide for the delivery of clotting factors and other blood clotting proteins with specific pharmacokinetic properties that are advantageous compared to intravenous, subdermal, or intramuscular injection. They also enable the use of dosages that provide one or more of the following advantages, including a higher therapeutic ratio, a reduced incidence of allergic reactions (e.g., anaphylactic shock; including myalgia and neurocognitive and ophthalmic events), and a reduced immunogenicity and / or immunogenic response (compared to subcutaneous and / or intramuscular injection). In one embodiment, the reduction in the incidence of allergic reactions can be determined by comparing the incidence in a patient population administered a clotting factor or other blood clotting protein by standard injection (e.g., intramuscular, intravenous, etc.) to the frequency in a patient population administered a clotting factor or other blood clotting protein by oral delivery of a conventional compound, and then using that reduction to model the expected reduction in the incidence of allergic reactions in a patient population with respect to one or more of the clotting factors (e.g., factor VIII) or other blood clotting proteins.

[0103] Dosage

[0104] According to one or more embodiments, the dosage of a coagulation factor or other blood clotting protein administered using one or more embodiments of a swallowable capsule is typically a therapeutically effective amount, but this is not necessarily required. As used herein, the phrase "therapeutically effective amount" means: i) a detectable improvement in one or more clinical measurements of blood clotting for a given blood clotting disorder (e.g., clotting time such as prothrombin time); or ii) a dosage of a coagulation factor (e.g., Factor VII, Factor VIII, Factor IX, Factor X) or other blood clotting protein that inhibits, prevents, weakens, or delays the symptoms of a blood clotting disorder such as hemophilia (A or B) or von Willebrand disease. According to various embodiments, the therapeutically effective amount of a coagulation factor (e.g., Factor VII, Factor VIII, Factor IX, and Factor X) delivered by embodiments of the present invention can range from about 1000 to 10,000 IU, and in certain embodiments is 1400, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 50000, 6000, 7000, 7500, 8000, 9000, 9100, and 9500 IU. In embodiments where the dosage of the drug is determined by weight, the therapeutically effective amount of the coagulation factor can range from about 0.1 to 10 mg, and in certain embodiments can be about 1.5 to 10 mg, 1 to 5 mg, 1 to 3 mg, about 0.03 to 1.73 mg, about 0.02 to 1.15 mg, and about 0.34 to about 1 mg, although other ranges are equally contemplated. The specific dosage can be selected according to one or more of the specific coagulation factor being delivered (e.g., Factor VII, Factor VIII, etc.), the condition being treated, the clinical situation (e.g., prophylactic or acute bleeding), the patient's weight, age, and gender. Table 1 sets forth exemplary dosages for the treatment of hemophilia A and B with Factor VIII and Factor XI, respectively, in various clinical situations, in IU / kg patient body weight. Other dosages for these and other blood clotting disorders and other conditions (e.g., intracranial hemorrhage) are described in more detail herein.

Table 1

[0105] According to various embodiments, the dosage of a particular coagulation factor (e.g., the coagulation factors listed in Table 1) can be set (i.e., adjusted) based on the measurement of coagulation time such as prothrombin time. Therefore, for example, in the case of a longer coagulation time, the dosage of the coagulation factor can be increased, and in the case of a shorter coagulation time, the dosage can be decreased. In this way, the dosage of the coagulation factor delivered according to the embodiments of the present invention can be optimized for a given patient over the treatment period taking into account conditions such as growth, diet, and other drugs that can affect the blood clotting / clotting properties including the coagulation time. In certain embodiments, a list of swallowable capsules having different dosages of a particular coagulation factor (e.g., Factor VIII) can be provided to the patient, and then the dosage to be used can be selected from the list based on the measurement of the coagulation time. In certain embodiments, a table or other information for the patient to select a particular dosage of a coagulation factor based on the coagulation time or related measurements may be provided. According to some embodiments, the table or other information can be stored electronically in one or more memory or logic resources of a mobile phone, tablet, or other computer device as well as the cloud.

[0106] In related or additional embodiments, the measurement of prothrombin time or other coagulation times can be used to select the optimal source of coagulation factor for a given patient and coagulation disorder. For example, in the case of Factor VIII, the prothrombin time can be used to select plasma-derived Factor VIII compared to the genetically modified Factor VIII molecules described herein based on producing and maintaining a coagulation time within the normal physiological range, e.g., 25 - 30 seconds.

[0107] Advantages of delivering coagulation factors and other clotting proteins to the intestinal wall or other locations in the intestinal tract

[0108] When used, a coagulation factor or other clotting t for the treatment of one or more of the above conditions Embodiments of the present invention that provide delivery of proteins to the intestinal wall and / or abdominal wall and adjacent tissues (e.g., the abdominal wall or peritoneal cavity), or other target sites in the intestinal tract, such as the large intestine, offer many advantages compared to coagulation factors in injectable form (e.g., Factor VII, Factor VIII, Factor IX, and Factor X). Such advantages can include, but are not limited to, i) a higher therapeutic ratio; ii) a reduction in the incidence and severity of adverse reactions, including one or more of anaphylactic shock, or other allergic reactions (including at the injection site), hives and bleeding at the injection site, nasopharyngitis, upper respiratory infections, influenza, back pain myalgia, neurocognitive events, and ophthalmic events, as well as the generation of inhibitory antibodies described herein; and iii) a reduction in immunogenicity and / or immunogenic reactions. These benefits are due to one or more of the following: i) the fact that the doses delivered by embodiments of the present invention are significantly lower; ii) the doses are delivered daily rather than weekly or monthly; and iii) the doses are delivered orally rather than intravenously.

[0109] In many embodiments, the therapeutic ratio of the dosage of a coagulation factor or other blood coagulation protein delivered orally according to embodiments of the present invention can be significantly increased compared to the therapeutic ratio of a coagulation factor such as factor VIII delivered by injection (e.g., weekly, once every two weeks, or monthly, such as intravenously, intramuscularly, or subcutaneously). In various embodiments, the term "significantly" corresponds to an increase in the therapeutic ratio of two-fold or higher, such as 7 to 30-fold or higher. For coagulation factors such as factor VII, factor VIII, factor IX, or factor X, which are typically delivered at a dosage every 2 to 3 days per week when injected (e.g., intravenously, intramuscularly, or subcutaneously), the therapeutic ratio (e.g., toxic dosage / effective dosage) can increase in the range of 3 to 7-fold when a daily oral dosage is delivered using the swallowable device provided by the present invention. However, when the dosage of the coagulation factor is injected monthly, the therapeutic ratio can increase 30-fold when an oral dosage according to embodiments of the present invention is delivered daily. Further, an increase can be obtained when the oral dosage of the coagulation factor (or other blood coagulation protein) is administered multiple times a day. Similar improvements (e.g., two-fold, three-fold, 30-fold, or even greater) can be observed in the incidence rate of one or more of immunogenicity / immune response (compared to intramuscular and / or subcutaneous injection), allergic reactions, and other adverse reactions. Immunogenicity / immune response is the production in the body of antibodies (e.g., inhibitory antibodies) against the administered blood coagulation protein / coagulation factor, which neutralizes or otherwise impairs the clinical efficacy of the coagulation factor or other blood coagulation protein. The reduction in the incidence rate and severity of allergic reactions from one-half to one-thirtieth is due to the fact that the antibody is administered at a daily dosage rather than at a cycle of twice or less every two weeks, which tends to desensitize the immune system (the degree of allergic reaction can be determined using methods known in the art and can correlate with one or more in vitro tests known in the art). Similarly, the degree of reduced immunogenicity, including the production of inhibitory antibodies against one or more coagulation factors such as factor VIII, can be reduced to one-half to one-thirtieth or lower.This is due to three factors: 1) the dose not being delivered subcutaneously and / or intramuscularly (which tends to exacerbate such responses); 2) the dose being delivered in a smaller amount, e.g., 1 / 7 to 1 / 30 of the amount, depending on whether the injected dose is delivered weekly, once every two weeks, once a month, etc.; and 3) as discussed above, the dose of the clotting factor (or other coagulation protein) being delivered to the upper part of the small intestine, avoiding the Peyer's patches and subsequent production of immune cells and other immune responses. One or more immunoassays known in the art can be used to quantify the amount of the immune response to a given clotting factor (e.g., Factor VIII, etc.), for example, the production of antibodies (e.g., inhibitor antibodies) generated against the delivered clotting factor (e.g., Factor VIII) or other coagulation protein), and / or the percentage of the administered clotting factor neutralized by the patient's own antibodies (e.g., inhibitor antibodies). In these and related embodiments, the dosage and dosing regimen of the clotting factor (or other coagulation protein) can be configured to produce a minimal immune response in the patient, where minimal means less than 10%, more preferably less than 5%, of the delivered clotting factor (or other coagulation protein) being neutralized by the patient's own antibodies.

[0110] In other embodiments, the immune response and / or allergic response to the administered clotting factor (or other coagulation protein) can be quantified by measuring the difference in the serum titer of antibodies against a given clotting factor (e.g., Factor VIII) when administered as a daily oral dose compared to when administered as an intravenous dose once every two days, or once every three days, once every two weeks, or once a month. In these and related embodiments, the dosage and dosing regimen of the clotting factor (or other coagulation protein) can be configured to produce a minimal immune response in the patient, where minimal means an increase of less than 10%, more preferably less than 5%, in the serum concentration of the patient's own antibodies (e.g., inhibitor antibodies) against the administered clotting factor (e.g., Factor VIII).

[0111] In related approaches, the serum titer of cytokines (e.g., interleukins, such as interleukin 7) and / or white blood cells can be measured with respect to the dosage and administration of a given coagulation factor. In these and related embodiments, the dosage and dosing regimen of the coagulation factor or other blood clotting protein can be configured to produce a minimal immune response in the patient, where minimal means an increase of less than 10%, more preferably less than 5%, in one or more serum concentrations of the patient's white blood cells and / or a particular cytokine (e.g., interleukin 7). In related embodiments, the immune response can be quantified by using a change in the percentage of white blood cells (e.g., an increase in the % of eosinophils or basophils present in an allergic reaction). In these and related embodiments, the dosage and dosing regimen of the coagulation factor or other blood clotting protein can be configured to produce a minimal immune response in the patient, where minimal means a change of less than 10% in the percentage of a particular type of white blood cell (e.g., eosinophils) in the patient's total white blood cell count.

[0112] Another advantage achieved when delivering the daily dose of various coagulation factors or other blood clotting proteins by means of ordinary injection means (e.g., by intravenous, intramuscular, or subcutaneous injection) with longer intervals between doses (e.g., once every 2 days or 3 days, once every 2 weeks, once a month) compared to delivering them daily is the reduction of the variation in the plasma concentration profile of the patient with respect to a specific coagulation factor or other blood clotting protein, whereby a more flat plasma concentration is obtained over time. Using the pharmacokinetic model described in more detail in Attachment 1, plasma concentration curves were generated for the delivery of alirocumab at a delivery interval of once every 2 weeks compared to a daily dose (dose set downward from once every 2 weeks) (Figures 21a and 21b). As can be seen from the figures, the amount of daily variation in the curve is considerably less for alirocumab delivered orally according to an embodiment of the present invention. Similarly, a value known as "% steady state variation" was calculated for each of these antibodies using the equation shown and described in detail in Attachment 2. The value reflects the amount of daily variation in the plasma concentration of a given drug. As shown in Table 2 below, the calculated amount of steady state variation in the plasma concentration of a specific antibody was significantly reduced (from 66.3% to 0.39%) compared to when the antibody was delivered daily by subcutaneous injection according to an embodiment of the present invention. The result is a reduction of approximately 170-fold in the steady state variation of alirocumab. The model has also been used to show the reduction of steady state plasma variation of two anti-interleukin antibodies, namely secukinumab and brodalumab (as described in U.S. Patent Application No. 15 / 150,379, which is hereby incorporated by reference in its entirety for all purposes), and the results are shown in Table 3. In these examples, the reduction in steady state variation was between 171 and 216-fold. Thus, the model consistently shows a 170 to 216% reduction in the steady state plasma concentration of a given drug (e.g., a coagulation factor) when the drug is administered daily using an embodiment of the present invention compared to injecting once every 2 weeks or monthly using subcutaneous injection. Using such a model, similar absolute values (e.g., 0.12 to 0.39%) and reductions in % steady state variation are expected for the various coagulation factors described herein.Such advantages of reduction include one or more of: reduction of the risk of adverse events, reduction of allergic reactions and immunogenicity (e.g., reduction in the incidence and amount of inhibitory antibodies against certain clotting factors such as factor VIII), as well as the period for which a patient maintains a therapeutic range of a given clotting factor being longer, and the ability to treat more favorably and consistently a clotting disorder for which the clotting factor is intended, such as hemophilia. Reduction of steady-state variability can also be used to quantify reduction of the patient's immune response to a particular clotting factor, such as reduction in the number of inhibitor antibodies. Such reduction can be in the form of a proportion (e.g., direct proportion, fractional proportion, etc.), or a linear or quadratic proportion. [Table 2] [Table 3]

[0113] Embodiments of a therapeutic composition comprising factor VIII

[0114] As discussed above, various embodiments of the present invention provide therapeutic compositions comprising a clotting factor such as factor VIII for treating a clotting disorder such as hemophilia A or hemophilia B.

[0115] A brief description of the factor VIII compound is provided below. Factor VIII (also referred to herein as FVIII or F8) is a glycoprotein that amplifies the coagulation signaling cascade upon injury and enables timely coagulation. The gene encoding FVIII is located on the long arm of the X chromosome Xq28 {Thompson, 2003 #37}, and is composed of 26 exons, which are intercalated by introns of various sizes. FVIII is synthesized as a 19-amino acid long signal peptide and a 2332-amino acid sequence. It is mainly produced by the liver. The kidneys, spleen, and lymphocytes produce a small amount of FVIII. Cultured human cell lines are unable to express FVIII, and currently, it is produced using Chinese hamster ovary cells, baby hamster kidney cells, or human fetal kidney cells genetically modified with human FVIII cDNA.

[0116] The FVIII molecule is composed of three different types of domains: the A1, A2, and A3 domains are homologous to each other and are essential for catalytic activity; the B domain is highly variable between species, is highly glycosylated, but is not essential for the protein's procoagulant activity {Kaufman, 1997 #36}, and the C1 and C2 domains are involved in binding to other coagulation factors (FIX and FX) and phospholipids.

[0117] FVIII is produced from its mRNA on ribosomes inside the endoplasmic reticulum (ER), and then the signal peptide is cleaved in the ER lumen, and the protein is glycosylated in the B domain by oligosaccharides rich in mannose residues. Binding to ER chaperones including Bip (immunoglobulin-binding protein), calnexin, and calreticulin also occurs in the lumen, and Bip transports FVIII aggregates to the cytosol for degradation. Deletion of the B domain increases the secretion of FVIII, presumably because binding to Bip is inhibited. Another chaperone, ERGC-53, is responsible for the transfer of FVIII to the Golgi apparatus after Bip dissociates from the protein. ERGC-53 binds to mannose residues on the B domain. In the Golgi apparatus, FVIII undergoes further glycosylation, disulfide bond formation, and folding. Two peptide bonds are cleaved within the B domain, and the resulting secreted protein is a heterodimer formed by a heavy chain and a light chain. Some missense mutations in hemophilia patients cause a reduction in FVIII secretion due to increased transport of the protein from the ER to the cytosol for degradation and increased Golgi degradation.

[0118] Circulating FVIII is stabilized by its binding to von Willebrand factor (VWF) that occurs on the B domain. The half-life of circulating FVIII is approximately 18 hours in healthy subjects. The half-life of recombinant FVIII in hemophilia subjects ranges from 10 to 20 hours depending on blood type and VWF levels. The peak activity of FVIII is detectable 1 to 2 hours after intravenous administration. FVIII is removed from the circulation via binding to the low-density lipoprotein-related receptor protein (LRP), a multi-ligand endocytosis receptor of the liver {Saenko, 1999 #39}.

[0119] The Factor VIII used in embodiments of the present invention that include formulation 100 typically includes human Factor VIII and may be in a naturally occurring form or a recombinant form. The former includes Factor VIII derived from human plasma. The latter includes variants of wild-type Factor VIII that have the same or higher biological activity compared to the wild-type activity, but differ from wild-type Factor VIII by one or more amino acid insertions, deletions, or substitutions.

[0120] Type of Factor VIII Delivered by Embodiments of the Present Invention

[0121] Various embodiments of the present invention contemplate the delivery of multiple different types of available Factor VIII replacement therapies. The first is plasma-derived concentrated Factor VIII. Typically, such plasma-derived factors are extracted from pooled human plasma and purified to minimize pathogen contamination (e.g., ALPHANATE and HUMATEP). The second is recombinant human Factor VIII produced in mammalian cell lines from recombinant DNA technology, which results in a full-length human Factor VIII protein (e.g., HELIXATE, KOGENATE, RECOMBINATE, and ADVATE). The third is recombinant human Factor VIII that has been modified from the wild-type version, with the most common modification being deletion of the B domain (e.g., REFACTO, AFSTYLA, and NOVOEIGHT). Finally, some products contain recombinant Factor VIII, wild-type or analogs, that have been modified by Fc fusion or PEGylation to increase their half-life in circulation (ADYNOVATE and ELOCTATE).

[0122] A brief description of the types of Factor VIII mentioned above is shown below.

[0123] ADVATE

[0124] ADVATE (Recombinant Antihemophilic Factor, available from Shire Corporation) is a purified glycoprotein consisting of 2,332 amino acids that is synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line and contains no plasma or albumin. The CHO cell line used for the production of ADVATE is derived from the cell line used for the biosynthesis of RECOMBINATE. ADVATE has been shown to be equivalent to RECOMBINATE with respect to its biochemical and physicochemical properties and its nonclinical in vivo pharmacology. The rAHF synthesized by CHO cells has the same biological effect as human antihemophilic factor (hAHF) with respect to coagulation. Structurally, the recombinant protein has a heterogeneous combination of heavy and light chains similar to the combination found in AHF (human). ADVATE is formulated as a sterile, nonpyrogenic powder for intravenous injection. von Willebrand factor (VWF) is co-expressed with Factor VIII and serves to stabilize it in culture. The final product contains less than 2 ng of VWF per IU of rAHF. The specific activity of ADVATE is 4,000 to 10,000 International Units / mg of protein. For prophylaxis, Factor VIII at a dose of 20 to 40 IU / kg body weight can be used every other day (3 to 4 times a week).

[0125] ADYNOVATE

[0126] ADYNOVATE (available from Shire Corporation) is recombinant full-length human coagulation factor VIII (2,332 amino acids with a molecular weight (MW) of 280 kDa conjugated by covalent bonds to one or more polyethylene glycol (MW 20 kDa) molecules). The therapeutic activity of ADYNOVATE is derived from its parent drug substance, ADVATE, which is produced by recombinant DNA technology from a CHO cell line. ADVATE is purified from the culture medium using a series of chromatography columns. The ADVATE molecules are then conjugated by covalent bonds to polyethylene glycol, which targets mainly lysine residues. PEGylation of the factor VIII molecule increases its half-life, thereby reducing the number of injections required to maintain therapeutic levels of activity in circulation. For routine prophylaxis, after administration of a loading dose of 55 IU / kg twice weekly to increase baseline activity, administration is then carried out at 40 - 50 IU / kg body weight twice weekly. An accurate, individualized dosing regimen must be determined for each patient. Adynovate is a lyophilized powder in single-use vials available in different strengths.

[0127] ALPHANATE

[0128] ALPHANATE (available from Grifols Biologics, Inc.) is a sterile, lyophilized concentrate of Factor VIII complexed with von Willebrand factor purified from pooled human plasma. The extracted proteins are subjected to several processes and chemical treatments to ensure sterility and minimize the viral load. The procoagulant activity of both factors is reported in International Units (IU). The final product is stabilized by the addition of human albumin. One IU of Factor VIII in this product is approximately equivalent to the Factor VIII activity of 1 mL of fresh human plasma. The specific activity of the product is at least 5 IU / mg protein. For prophylaxis in patients with hemophilia A, the dosing and frequency of infusion in IU should be determined by an experienced physician on a case-by-case basis. When the pharmacokinetic profile was evaluated in 12 adult patients with severe hemophilia A, the mean half-life was 17.9 ± 9.6 hours and was 96.7 ± 14.5% at 10 minutes after infusion. The recovery rate at 10 minutes after infusion was also determined as an increase of 2.4 ± 0.4 IU of FVIII / dL plasma per IU / kg body weight of infused FVIII.

[0129] ELOCTATE

[0130] ELOCTATE is available from Biogen Corporation. The active ingredient in ELOCTATE is a B-domain deleted recombinant factor VIII, Fc fusion protein (BDD-rFVIIIFc). BDD-rFVIIIFc is a recombinant protein consisting of a B-domain deleted analog of human coagulation factor VIII covalently linked to the human immunoglobulin G1 (IgG1) Fc domain sequence. The factor VIII portion of the molecule has a 90 kDa heavy chain and an 80 kDa light chain (similar to the endogenous factor VIII), which are linked by 14 (out of 908) amino acids from the central B domain. The FVIII portion has post-translational modifications equivalent to those of the endogenous factor VIII. The Fc domain of the molecule contains the hinge, CH2, and CH3 regions of IgG1. BDD-rFVIIIFc contains 1890 amino acids with an apparent molecular weight of 220 kDa. Most of the expressed protein is cleaved into a two-chain molecule, but ELOCTATE may also contain up to 39% of a single-chain non-processing form. Both molecules have been shown to have equivalent factor VIII activity. The protein is produced from a human fetal kidney cell line and purified from the cell culture medium. Eloctate is supplied as a sterile, non-pyrogenic lyophilized powder with sterile water for reconstitution and IV injection. This is available in different strengths. For routine prophylaxis, 50 IU / kg every 4 days is recommended. The dosage must be adjusted based on the patient's response, with dosing in the range of 25 - 65 IU / kg at 3 - 5 day intervals.

[0131] HUMATE-P

[0132] HUMATE-P (available from CLS Behring) is a purified, sterile, lyophilized concentrate of factor VIII (FVIII) and von Willebrand factor (VWF) for the treatment of patients with hemophilia A and von Willebrand disease. Humate-P is purified from the cryoprecipitate fraction of pooled human plasma. One international unit (IU) of VWF or FVIII is approximately equivalent to the amount of activity of VWF or FVIII in 1.0 mL of pooled fresh human plasma. Depending on the PK of the individual patient, dosing may be repeated every 6, 8, or 12 hours.

[0133] HELIXATE FS and KOGENATE FS

[0134] HELIXATE FS (available from CLS Behring) and KOGENATE FS (available from Bayer corporation) are produced by introducing full-length human Factor VIII into baby hamster kidney cells. The resulting Factor VIII protein is then purified and does not contain proteins of animal origin. The biological activity of this product is the same as that of plasma-derived human Factor VIII. The active pharmaceutical ingredient is the same for both Helixate FS and Kogenate since both APIs are produced by Bayer, and Helixate FS is distributed by CLS Behring based on an agreement between the two companies. The recommended prophylactic dosing regimens for both drugs are 25 IU / kg three times a week for adults and 25 IU / Kg every other day for children.

[0135] RECOMBINATE

[0136] RECOMBINATE (available from Baxter Healthcare Corporation) is a glycoprotein synthesized by a Chinese hamster ovary (CHO) cell line that has been genetically engineered to co-express human factor VIII and von Willebrand factor (VWF). The CHO cell line secretes recombinant factor VIII (rFVIII) into the cell culture medium. Factor VIII complexed with VWF is purified from the culture medium using a series of chromatography columns. The synthetic rFVIII produced by the CHO cells has the same biological activity as human factor VIII. Structurally, the protein has a combination of heavy and light chains similar to the combination found in human factor VIII. RECOMBINATE is formulated as a sterile, non-pyrogenic, lyophilized powder preparation of concentrated recombinant factor VIII for intravenous injection. One international unit (IU) of this preparation contains approximately 1.5 μg of factor VIII protein. The final product contains less than 2 ng of rVWF per IU of rFVIII, which has no clinically relevant effect in patients with von Willebrand disease. The product does not contain a preservative. One IU of this product causes a peak factor VIII activity that is two-fold higher than the patient's baseline, assuming the patient's baseline is <1%. Thus, to increase the FVIII activity in a patient by X%, the IU dose must be approximately (X * Kg) / 2. In a PK study involving 69 patients, the mean half-life of RECOMBINATE in circulation was 14.6 ± 4.9 hours (n = 67). The actual baseline recovery rate observed for RECOMBINATE was 123.9 ± 47.7 IU / dL (n = 23), and the ratio of the actual recovery rate calculated for RECOMBINATE to the predicted recovery rate was 121.2 ± 48.9%.

[0137] Delivery of factor VIII products via embodiments of the present invention

[0138] As described herein, various embodiments of the present invention, including the swallowable device 10 and the therapeutic preparation 100, can be adapted for the oral delivery of factor VIII replacement therapy for the treatment of various coagulation disorders. According to one embodiment, a forward prophylactic dosing regimen for the oral delivery of factor VIII using an embodiment of the device 10 corresponds to once-daily oral administration, and the amount of IU per tablet will be calculated based on the recommendations of the manufacturer of the active pharmaceutical ingredient. Other embodiments contemplate more frequent (e.g., twice-daily) or less frequent (once every 2, 3, 5, 7 or other number of days) delivery. More specific dosing regimens for specific types of factor VIII are described below.

[0139] Dosing regimens for specific types of factor VIII

[0140] Helixate FS and Kogenate FS have a recommended dosage of 25 IU / kg three times a week (approximately every two days). For these compounds, the total dosage for a 70 kg adult is 1750 IU every two days, which converts to 875 IU / day when orally delivered by an embodiment of the oral device 10 / capsule 20. Both Helixate FS and Kogenate FS have a specific activity of 4000 IU / mg protein, so a daily dose of 875 IU converts to approximately 0.22 mg of factor VIII, which can be easily delivered by one oral capsule 20 once daily. Eloctate is administered every four days at a dose of 50 IU / Kg. Thus, the total dosage for a normally-weighted 70 kg adult is 3500 IU every four days, which corresponds to approximately 875 IU / capsule / day when orally delivered by an embodiment of the capsule 20. Since the specific activity of Eloctate is 4000 - 10020 IU / mg protein, a daily dose range of 0.22 - 0.00 mg can be administered by one oral capsule. The recommended dosages of Afstyla and Adynovate are approximately 20 - 50 IU / kg every two or three days.

[0141] For a 70 kg adult, the range is 1400 - 3500 IU every two days / every three days, which corresponds to approximately 700 - 1750 IU / day when administered every two days, or approximately 467 - 1167 IU / day when administered every three days. Thus, these dosages correspond to a daily dose between 467 - 1750 IU (depending on the patient and the active ingredient) when orally delivered by an embodiment of device 10. In the case of Afstyla, having a specific activity of 7400 - 16000 IU / mg of factor VIII, a dosage range of 0.03 - 0.24 mg is delivered daily by one oral device. Finally, in the case of Adynovate, having a specific activity of 2700 - 8000 IU / mg, the daily dosage range delivered orally by one capsule 20 would be 0.06 - 0.65 mg. All of these dosages can be increased (e.g., doubled) to account for a decrease in bioavailability for a particular route of administration (e.g., delivery into the abdominal cavity). Even if the dosage is doubled, the daily administration of one device of oral device 10 / capsule 20 would be sufficient to administer the therapeutic dosage of factor VIII.

[0142] In some Factor VIII products (e.g., Advate®, ReFacto®, NovoEight®), the specific activity of 1 milligram of Factor VIII protein is reported in the prescribing information, facilitating the calculation of the weight (e.g., mg) of the drug administered using an embodiment of capsule 10 to achieve the desired therapeutic effect (e.g., improvement in coagulation, reduction in coagulation time, etc.). For example, the recommended dosing regimen for Advate is every other day at 20 - 40 IU / kg. For a 70 Kg adult, this is every other day at 1400 - 2800 IU / day and 700 - 1400 IU / day. Since the specific activity of Advate is 4000 - 10,000 IU / mg protein (e.g., Factor VIII), the therapeutic range in mg of the drug would be in the range of 0.07 - 0.14 mg (considering the dose in IU and the highest activity of the factor at 10,000 IU / mg) or 0.175 - 0.35 mg (considering the dose in IU and the lowest activity of the factor at 4000 IU / mg). These doses can be administered by one oral device 10 / capsule 20 / day. Similar calculations for ReFacto, which has a dosing regimen of 40 - 225 IU / kg per day, would thus be 280 - 15750 IU for a 70 kg adult, and when the activity of the factor is 9110 IU / mg, it converts to a daily dose range of 0.03 - 1.73 mg, and when the activity of the factor is 13700 IU / mg, it converts to 0.02 - 1.15 mg. One capsule per day can deliver these therapeutic ranges. NovoEight has a factor specific activity of 8340 IU / mg, and the dosing regimen of every other day at 20 - 60 IU / kg takes into account the overall prophylactic dosing range for children and adults, combining the minimum and maximum doses into a single range. For adults, according to one or more embodiments, the low daily dose of NovoEight would be 2800 IU / day (assuming, for example, 70 Kg patient × 2 × 20 IU / kg), and the high dose would be 8400 IU / day (assuming 70 Kg × 2 × 60 IU / kg). Converting to milligrams, the dose range would be approximately 0.34 - about 1 mg / day when delivered orally using an embodiment of capsule 20 or by other oral delivery means contemplated by embodiments of the present invention.Various embodiments of the device 10 and the capsule 20 can be readily configured to deliver any of the above dosages of the Factor VIII product by producing needles 40, 140 that contain such dosages. In particular, a single needle 40 or 140 can be configured to contain any of these dosages.

[0143] Embodiments explaining the adjustment of the dosage of Factor VIII and other coagulation factors

[0144] In various embodiments, adjustments may be made with respect to a change in the titer (expressed as IU / mg) of a factor or any of the clotting factors described herein from a given source or batch. Thus, for example, when increasing the titer (e.g., increased IU / mg for factor VIII or other clotting factors), the mg per capsule can be decreased, thereby reducing the number of capsules required. Similarly, a reduction in the bioavailability of a given clotting factor delivered via the oral administration route according to embodiments of the oral device 10 can be tolerated in the dosage in comparison to the bioavailability of the drug when delivered by IV infusion. In particular, such a reduction in the bioavailability of the clotting factor within the oral device 10 delivered to a specific location in the GI tract, such as one or more of the small intestinal wall, peritoneum, or abdominal cavity, can be tolerated. For example, in the case of delivery of factor VIII (or other clotting factors described herein) to the peritoneal cavity according to embodiments of the oral device 10, the bioavailability is approximately 50% of the bioavailability of factor VIII administered by IV infusion. See "Intravascular of VWF and Factor VIII following Intraperitoneal Injection and differences from Intravenous and Subecutaneous Injection in Mice." Q. Shi. et. al., Hemophilia (2012), 18, 639 - 646, which is hereby incorporated by reference in its entirety for all purposes. Thus, any of the dosages of factor VIII described with respect to the mg of drug per capsule or the number of capsules ingested may be doubled or another amount increased in comparison to other decreases in bioavailability.

[0145] Embodiments of a therapeutic composition comprising factor VII

[0146] As discussed above, various embodiments of the present invention provide therapeutic compositions containing clotting factors such as Factor VII for the treatment of various coagulation disorders such as congenital and acquired hemophilia. Accordingly, a brief description of Factor VII compounds is provided below. Factor VII (described as EC 3.4.21.21, blood coagulation Factor VII, activated blood coagulation Factor VIIa, formerly known as proconvertin) is one of the proteins that causes blood to clot in the coagulation cascade. Factor VII is used as replacement therapy in hemophilia patients with Factor VII deficiency and in patients who produce inhibitory antibodies against one or more of the clotting factors including Factor VIII. It is also used off-label for the control of bleeding in trauma patients and the treatment of intracerebral hemorrhage. It is an enzyme of the serine protease class, produced by hepatocytes and excreted into the circulation. The excreted glycoprotein is a single chain of 406 amino acids with a mass of approximately 50 KD, which is converted to its active form by proteolytic cleavage and other mechanisms. Several factors including Factor IXa, Factor Xa, Factor XIIa, or thrombin can effect proteolytic cleavage of Factor VII. After proteolysis of the 38 - 60 amino acid sequence, FVII is converted into two chains connected by disulfide bonds, including the active form or FVIIa. The light chain (152 amino acids) contains domains of epidermal growth factor and carboxylated glutamic acid residues that bind to abnormal phospholipids and calcium ions, while the heavy chain (254 amino acids) contains serine protease activity that catalyzes the activation of Factor IX and Factor X to their active forms.

[0147] As used herein, the term "Factor VII" includes both uncut FVII (zymogen) and the activated form of Factor VII, also known as Factor VIIa. Similarly, various embodiments of Factor VII can correspond to a polypeptide having the amino acid sequence positions 1-406 of human wild-type human Factor VII (disclosed in U.S. Patent No. 4,784,950), or a polypeptide comprising FVII derived from another species (e.g., bovine, porcine, canine, murine). Other forms of FVII contemplated and delivered by embodiments of the present invention can include natural allelic variants of Factor VII that may exist, and any form or degree of glycosylation or other post-translational modifications. The term "Factor VII" also includes variants of Factor VII having the same or higher biological activity compared to wild-type activity, and these particular variants include polypeptides that differ from wild-type Factor VIIa by one or more amino acid insertions, deletions, or substitutions. The term "biological activity of Factor VII" includes, for example, the ability to generate thrombin on the surface of activated platelets.

[0148] A typical dose of Factor VIIa for the treatment of bleeding episodes in hemophilia patients with inhibitors is to repeat 90 μg / kg every 2-6 hours until hemostasis is achieved. Doses of 13.3-22 μg / kg are used for FVII replacement therapy, and 20-160 μg / kg are used for trauma and intracerebral hemorrhage patients. Unfortunately, Factor VIIA has a short half-life of 2-4 hours and requires frequent IV injections. Subcutaneous injection has been studied as an alternative to intravenous injection to extend the half-life of Factor VIIA, but the bioavailability of Factor VII by subcutaneous injection is only 21-30%. Considering this low bioavailability, subcutaneous injection is not a very efficient or practical route of administration for Factor VII. Therefore, delivery of Factor VII or Factor VIIa by embodiments of the swallowable delivery device 10 represents several distinct advantages, including increased bioavailability and reduction or elimination of the need for multiple infusions throughout the day. The latter factor provides a significant improvement in the patient's quality of life by eliminating the need for travel to the hospital or for in-home infusions.

[0149] Delivery of Factor VII products via embodiments of the present invention

[0150] According to one embodiment, a forward prophylactic dosing regimen for oral delivery of Factor VII using an embodiment of device 10 corresponds to once-daily oral administration, and the IU amount per tablet is calculated based on the recommendations of the active pharmaceutical ingredient manufacturer. Other embodiments contemplate more frequent (e.g., twice-daily) or less frequent (once every 2, 3, 5, 7, or other number of days) delivery. The specific dosage of Factor VII that can be delivered by an embodiment of device 10 ranges from about 10 to 90 μg / kg, with specific dosages being every 2-3 hours in the range of 70-90 μg / kg in patients with acquired hemophilia, every 4-6 hours in the range of 15-30 μg / kg in patients with congenital Factor VII deficiency, every 2 hours at 90 μg / kg in patients with congenital hemophilia A or B with inhibitors, or every 2-4 hours at 90 μg / kg in patients with Glanzmann thrombasthenia. During bleeding episodes, the dosages under the aforementioned conditions are administered until hemostasis is achieved (e.g., bleeding stops and / or is significantly reduced). In patients with congenital hemophilia A or B with inhibitors, after hemostasis is achieved, a dose of 90 μg / kg may be administered every 3-6 hours to maintain the hemostatic plug achieved by early administration. Also, conversion to active units with the unit name of IU for the aforementioned dosages can be allowed.

[0151] Types of Factor VII delivered by embodiments of the present invention

[0152] Multiple types of factor VII contained in the therapeutic preparation 100 may be delivered by embodiments of the present invention. In various embodiments, the types of factor VII contained in the therapeutic preparation 100 typically include human factor VII or factor VIIa, which may be in natural form or recombinant form. The former includes factor VII or factor VIIa derived from human plasma. The latter has the same or higher biological activity compared to wild-type activity, but is different from wild-type factor VII or factor VIIa by one or more amino acid insertions, deletions, or substitutions, and includes variants of wild-type factor VII or factor VIIa. Specific commercially available types of factor VII that may be used by embodiments of the present invention include, but are not limited to, Novoseven®, Novoseven RT®, and Aryoseven® described below. These and other forms of factor VII can be obtained / produced in various ways, for example, from the non-cryoprecipitable fraction of human plasma or by genetic manipulation from cells or transgenic animals. According to certain embodiments, human factor VII is produced in the milk of non-human transgenic mammals genetically engineered to produce this protein. Preferably, this is the milk of transgenic rabbits or goats. Secretion of factor VII by the mammary gland of a mammal enables its secretion into the milk of the transgenic mammal and requires tissue-dependent expression control of factor VII. Such control methods are well known in the art. Control of expression is carried out using sequences that express the protein in specific tissues of the animal. These include the promoter sequences WAP, beta-casein, beta-lactoglobulin, and signal peptide sequences. In particular, the process for extracting the protein of interest from the milk of transgenic animals is described in European Patent No. 0264166.

[0153] NOVOSEVEN and NOVSEVEN RT

[0154] According to one or more embodiments, the type of Factor VII delivered by an embodiment of device 10 may correspond to NovoSeven®, which is a recombinant human Factor VIIa available from NovoNordisk Corporation and has received FDA approval for uncontrolled bleeding in hemophilia patients. This may also correspond to a variant of NovoSeven, also known as NovoSeven RT, which is also available from NovoNordisk. In particular, Novaseven RT is manufactured at room temperature and can be stored without refrigeration. In related or additional embodiments, this may correspond to a biosimilar of Factor VIIa, such as AryoSeven® available from Aryogen Pharmed.

[0155] A brief overview of NovaSeven is provided below, which also applies to Novaseven RT. NovoSeven is a vitamin K-dependent glycoprotein consisting of 406 amino acid residues (MW 50K daltons). Although recombinant, NovoSeven is structurally similar to Factor VIIa derived from human plasma. The pharmacokinetic profile of NovaSeven is different when comparing the dosing for the treatment of hemophilia to the dosing for the treatment of congenital Factor VII deficiency. According to clinical trials reported by NovoNordisk in the prescribing information of NovoSeven, the pharmacokinetics of a single dose of NovoSeven (17.5, 35, and 70 μg / kg) showed dose-dependent behavior in 15 subjects with hemophilia A or B. The median apparent volume of distribution at steady state was 103 mL / kg (range, 78 - 139). The median clearance was 33 mL / kg / hour (range 27 - 49). The median residence time was 3.0 hours (range, 2.4 - 3.3), and t 1 / 2It was 2.3 hours (range, 1.7 - 2.7). The median in vivo plasma recovery rate was 44% (30 - 71%). In a clinical trial regarding the treatment of factor VII deficiency, the pharmacokinetics of a single dose of NovoSeven at 15 and 30 μg / kg body weight did not show significant differences in dose-independent parameters between the two doses used: systemic clearance (70.8 - 79.1 mL / hour×kg), volume of distribution at steady state (280 - 290 mL / kg), mean residence time (3.75 - 3.80 hours), and half-life (2.82 - 3.11 hours). The mean in vivo plasma recovery rate was approximately 20% (18.9% - 22.2%).

[0156] Dosing regimens of NovaSeven and NovoSeven RT

[0157] The dosing regimens of NovaSeven and Novaseven RT for patients with acquired hemophilia and congenital factor VII deficiency are described below, along with the rationale for each coagulation disorder. These regimens apply to both NovaSeven and NovaSeven RT. The recommended dose of NovaSenven or NovaSeven RT for the treatment of hemophilia patients is repeated every 2 - 3 hours in the range of 70 - 90 μg / kg patient body weight until hemostasis is achieved. Thus, for a 70 kg patient, the required dose would be 4.9 - 6.3 mg of NovaSeven rFVIIa every 2 - 3 hours. Considering that the bioavailability of FVII is approximately 50% when delivered intraperitoneally, the average dosing for a 70 kg patient would be every 2 - 3 hours in the range of 9.8 - 12.6 mg. In an embodiment of capsule 20 configured to have a drug between about 3 mg - 9 mg, this would be about 1 - 3 capsules every 2 - 3 hours.

[0158] For patients with congenital factor VII deficiency, the recommended dose of NovoSeven or NovoSeven RT is 15 - 30 μg / kg body weight every 4 hours. Thus, for a 70 kg patient, the required dose of the drug is every 4 hours in the range of 1.05 - 2.10 mg. Considering the reduced (50%) bioavailability of factor VII via intraperitoneal delivery, the required dose of NovoSeven or NovoSeven RT would be about 2.10 - 4.20 mg every 4 hours. In an embodiment of capsule 20 configured to have about 1 mg - 4 mg of the drug, this would be about 1 - 2 capsules every 4 hours.

[0159] Embodiment of a therapeutic composition comprising factor IX

[0160] As discussed herein, various embodiments of the present invention provide therapeutic compositions comprising a coagulation factor such as factor IX for treating various coagulation disorders such as congenital and acquired hemophilia. Accordingly, a brief description of factor IX compounds is provided below. Coagulation factor IX (FIX) is an important component in the coagulation cascade and is responsible for the hemostatic response to injury. It is synthesized in the liver as a single-chain glycoprotein with a molecular weight of 57,000. Deficiency of FIX causes hemophilia B. FIX is activated by activated factor IX (FIXa) in the intrinsic coagulation pathway. FIXa, together with factor VIIIc, extends the coagulation cascade by activating factor X (FX) to factor Xa, thus converting prothrombin to thrombin and resulting in the formation of a fibrin clot. Activation of FIX involves two steps. In the first step, an internal peptide bond is cleaved, resulting in the formation of an intermediate of two chains cross-linked by disulfide bonds. Next, a second specific peptide bond in the amino-terminal region of the heavy chain is cleaved to form activated factor IX (FIXa). FIX therapy has been shown to temporarily restore hemostasis in patients suffering from hemophilia. Several FIX replacement products and therapies are currently commercially available. These include: Alphanine SD, Alprolin, Bebulin, Bebulin VH, Benefix, Idelvion, Ixinity, Immunine, Mononine, Profilnine SD, Proplex and Rixubis. A brief description of the five types of factor IX mentioned above is provided below.

[0161] Mononine (CSL Behring)

[0162] Mononine (registered trademark) is the human-derived form of Factor IX available from CLS Behring. It is purified from irrelevant plasma-derived proteins by using immunoaffinity chromatography. Specifically, a mouse monoclonal antibody against FIX is used as an affinity ligand to capture and extract FIX. Mononine is injected intravenously. The dosage of FIX in Mononine depends on the patient's body weight and the desired FIX (IU / dL). A 1 ml formulation of Mononine consists of 100 IU of FIX (each IU represents one active FIX), mannitol, polysorbate 80, histidine, sodium hydroxide, and / or hydrochloric acid.

[0163] Two clinical trials (patients, n = 81) conducted by Behring regarding the use of Mononine for the treatment of hemophilia B have been reported in the prescribing information for Mononine (see http: / / labeling.cslbehring.com / pi / us / mononine / en / mononine-prescribing-information.pdf). The trials evaluated both the safety and efficacy of Mononine. Infusion of FIX complex concentrates containing varying, but significant amounts of other liver-dependent blood clotting proteins (e.g., factor II, factor VII, and factor X) into patients with hemophilia B resulted in a recovery rate of infused FIX in the range of approximately 0.57 - 1.1 IU / dL per IU / kg body weight, and the plasma half-life of factor IX was in the range of approximately 23 - 31 hours. Five patients (6%) reported adverse reactions. The doses administered ranged between 71 - 161 IU / kg for 36 subjects. The average recovery rate showed a tendency to decrease as the dose of Mononine increased: 1.09 ± 0.52 K (n = 38) at doses >75 - 95 IU / kg, 0.98 ± 0.45 K (n = 21) at doses >95 - 115 IU / kg, 0.70 ± 0.38 K (n = 2) at doses >115 - 135 IU / kg, 0.67 K (n = 1) at doses >135 - 155 IU / kg, and 0.73 ± 0.34 K (n = 5) at doses >155 IU / kg. Of the 36 subjects who received these high doses, only 1 (2.8%) reported an adverse experience (''difficulty concentrating'') possibly related to Mononine; the subject recovered. No thromboembolic complications were observed or reported for any patient. A small percentage of patients showed hypersensitivity reactions, including anaphylaxis. Other reactions included, but were not limited to, headache, nausea, fever, chills, flushing, vomiting, tingling, fatigue, and urticaria. The dosing regimen depends on the FIX level during hemostasis in patients undergoing minor and / or major surgery. Pharmacokinetic (PK) and pharmacodynamic (PD) data have not been reported for Mononine.

[0164] Idelvion (CSL Behring)

[0165] Idelvion, available from CSL Behring, is recombinant factor IX fused to recombinant albumin. This fusion form of the drug increases the half-life of factor IX in Idelvion several-fold compared to the half-life of plasma-derived FIX. For example, for a single dose of 75 IU / kg of Idelvion, t 1 / 2 was determined to be 104 hours. C max was determined to be 82 IU / dL, and the clearance ratio (Cl) was 0.84 ml / h / kg. The average volume of distribution (V ss ) was determined to be 1.20 dL / kg. Overall, the PK parameters of Idelvion were similar when compared between single and repeated dosing. For routine prophylaxis, the dosage for patients (>12 years) is approximately 25 - 40 IU / kg body weight every 7 days. Dosages for the control and prevention of bleeding episodes depend on various parameters (e.g., body weight, desired FIX increase), as well as the patient's condition.

[0166] Rixubis (Baxter pharmaceuticals)

[0167] Rixubis (also known as BAX326) is a recombinant form of coagulation factor IX available from Baxter Pharmaceuticals for the treatment of hemophilia in adults and children. BAX326 was produced using a recombinant Chinese hamster ovary (CHO) cell clone in suspension culture. Its amino acid sequence is identical to the sequence of the Ala-148 allele type of pdFIX (Immunine), and its structural and functional characteristics are also similar. The CHO cell line secreting FIX is purified by affinity chromatography. The specific activity of Rixubis was determined to be >200 IU / mg protein. The formulation of Rixubis consists of L-histidine, sodium chloride, calcium chloride, mannitol, sucrose, and polysorbate 80. After administration, Rixubis temporarily corrects the coagulation defect in hemophilia patients by increasing the plasma level of FIX and decreasing the (in-vitro thromboplastin time) aPTT. Mean C max was determined to be 0.95 IU / dL, but the mean clearance ratio (Cl) was 6.0 ml / kg / hour. The mean value of the apparent volume of distribution (V ss ) was 178.6 mL / kg. The half-life was measured to be 25.4 hours. The above PK data are for repeated dosing of Rixubis. The recommended dose is 0.7 IU of plasma (0.7% of normal) for patients older than 12 years.

[0168] AlphaNine SD (Alpha Therapeutic Corporation)

[0169] Coagulation Factor IX (Human), AlphaNine® SD is a purified, solvent-detergent treated, virus filtered preparation of Factor IX derived from human plasma. It contains at least 150 IU of Factor IX / mg of protein, Factor VII (proconvertin), Factor II (prothrombin), and Factor X (Stuart-Prower factor) below the limit of detection (less than 0.04 units of Factor VII, less than 0.05 units of Factor II, and less than 0.05 units of Factor X per IU of Factor IX). AlphaNine SD is a sterile, lyophilized preparation intended for intravenous administration only. Each vial is a single-dose container. AlphaNine SD is labeled by the potency of Factor IX expressed in International Units (IU). The AlphaNine SD formulation contains 0.04 units of heparin, 0.2 mg of dextrose, 1.0 μg of polysorbate 80, and 0.10 μg of tri(n-butyl) phosphate per IU of Factor IX. It does not contain a preservative. AlphaNine SD is a purified Factor IX preparation containing at least 150 IU of Factor IX activity per mg of total protein. AlphaNine SD contains non-therapeutic levels of Factor II, Factor VII, and Factor X.

[0170] BeneFIX (Pfizer)

[0171] BeneFIX, Recombinant Factor IX, is a purified protein produced by recombinant DNA technology. The product is formulated as a sterile, nonpyrogenic lyophilized powder preparation intended to be reconstituted for intravenous injection. It is available as single-use vials containing the stated amount of Factor IX activity expressed in International Units (IU). Each vial nominally contains 250, 500, 1000, 2000, or 3000 IU of recombinant Factor IX. The potency (in IU) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International Standard for Factor IX Concentrates. 1 IU is the amount of Factor IX activity present in 1 mL of pooled normal human plasma. After reconstitution of the lyophilized drug product, the excipient concentrations are sodium chloride, L-histidine, 0.8% sucrose, glycine, and polysorbate 80. The specific activity of BeneFIX is greater than or equal to 200 IU per milligram of protein. It has a primary amino acid sequence identical to the Ala148 allele type of human Factor IX and has structural and functional characteristics similar to endogenous Factor IX. BeneFIX is produced by a well-characterized, genetically engineered Chinese hamster ovary (CHO) cell line. The CHO cell line secretes recombinant Factor IX into defined cell culture media and the recombinant Factor IX is purified by a chromatographic purification process.

[0172] Dosage regimens for specific types of Factor IX

[0173] The standard dosing regimen for Factor IX can be calculated using the following formula: body weight (kg) × desired increase in plasma concentration of Factor IX (e.g., % or IU / dL plasma) × reciprocal of the actual increase in Factor IX (IU / dL plasma / IU / kg body weight). For daily prophylactic treatment of patients with Factor IX deficiency, the recommended dosing regimen of Mononine is 20 - 30 IU / kg every 24 hours. Thus, for a 70 kg adult, this is 1400 - 2100 IU. Similarly, since the specific activity of Factor IX in Mononine is approximately 190 IU / mg, the amount in terms of weight of Factor IX required for a 70 kg person is in the range of approximately 7 mg - 10.6 mg / day. Embodiments of the oral delivery device 10 containing capsules 20 can be configured to deliver between 3 - 9 mg of therapeutic agent (e.g., clotting factor) per tablet, depending on the number of tissue penetrating members 140 contained in the capsule. Using an embodiment of capsule 20 containing approximately 3 mg of drug, this would be approximately 3 - 4 capsules per day, and in the case of 4 mg per tablet, this would be 2 - 3 capsules per day. In various embodiments, the desired delivery dose can be achieved by a first capsule configured to deliver a first dose of Factor IX (e.g., 5 mg) and a second capsule configured to deliver a second dose (e.g., 2 mg). Such embodiments of the plurality of devices 10 can be configured as a daily dosing regimen for delivering Factor IX or other clotting factors described herein. The above calculations are based on the potency (e.g., IU / mg) of commercially available Factor IX. As described above for Factor VIII, it can be adjusted to account for the reduced bioavailability when the intraperitoneal administration of the drug is compared to intravenous injection.

[0174] Some recombinant forms of factor IX, such as Rixubis, are administered at a dosage of 40 - 60 IU / kg body weight (e.g., 2800 IU - 4200 IU for a 70 kg subject) twice a week. The specific activity of Rixubis has been reported to be 200 IU / mg (dosage, 0.25 mg / kg). Thus, this amounts to 14 mg - 21 mg of factor IX protein once every two weeks. Using an embodiment of capsule 10 having a dosage range of 3 - 7 mg, this would be approximately 2 - 7 capsules twice a week. Other dosing schedules, including daily, are also contemplated. For example, in the case of a 3 mg dosage / capsule and 21 mg / week, the patient can take 1 capsule / day. In the case of a 3 mg capsule and 42 mg / week, this would be 2 capsules / day.

[0175] In the case of the long-acting Idelvion or Alprolix (having a specific activity of 55 - 84 IU / mg), drug administration is less frequent. An initial dose of 75 IU / kg / week (for a 70 kg patient, approximately 70 mg / week) is recommended and can be gradually increased up to 100 IU / kg (about 100 mg / week for a 70 kg patient). In the case of AlphaNine, the dosage for a 70 kg patient is equivalent to 2800 IU (for a 70 kg patient, 18.6 mg / week of AlphaNine). Similar dosages apply to other FIXs, such as BeneFIX. For example, a 70 kg person receiving Benefix (FIX) therapy (2000 IU) requires 10 mg of protein. The dosing regimen depends on the patient's prophylaxis. Pfizer reports in its prescribing information that for routine prophylaxis, BeneFIX is administered at a dosage of 72.5 IU / kg twice a week, which amounts to approximately 0.36 mg / kg patient body weight. For a 70 kg patient, this then amounts to approximately 25 mg twice a week or a dosage of 50 mg / week. In the case of capsules having 8 - 9 mg of drug (using multiple tissue penetrating members), this would be approximately 3 capsules twice a week, or if administered daily, about 1 capsule / day.

[0176] As described above with respect to Factor VIII, adjustment of the dosage of Factor IX products can be readily done to account for the reduced bioavailability of Factor IX in any of the above commercial types when delivered intraperitoneally.

[0177] Embodiments of a therapeutic composition comprising Factor X

[0178] As discussed above, various embodiments of the present invention provide therapeutic compositions comprising Factor X for the treatment of various coagulation disorders such as congenital and acquired hemophilia. Accordingly, a brief overview of Factor X compounds is presented below. Factor X (EC 3.4.21.6) is a serine protease involved in the coagulation cascade. It is a vitamin K-dependent protein synthesized in the liver. The FX gene (F10) is 22 kb in length and is located at 13q34-ter, 2.8 kb downstream of the F7 gene. The coding sequence is homologous to other vitamin K-dependent proteins and is split into 8 exons, each of which encodes a specific domain within the protein: exon 1 encodes the signal peptide, exon 2 encodes the propeptide and Gla domain, exon 3 encodes the aromatic amino acid stacked domain, exons 4 and 5 each encode an epidermal growth factor-like region, exon 6 encodes the activation domain, and exons 7 and 8 encode the catalytic domain. The mature two-chain form of FX consists of a 139-amino acid light chain and a heavy chain linked by a disulfide bond. The light chain contains the GLA domain and two epidermal growth factor domains, and the heavy chain contains the catalytic serine protease domain. The complete 59 kDa two-chain protein circulates in plasma at a concentration of 10 μg / ml.

[0179] The active form of factor X (also known as FXa) is a catalytic serine protease that is produced when the zymogen is cleaved in the heavy chain and releases a 52-residue activation peptide containing the His236, Asp228, and Ser379 catalytic sites. Activation occurs through the extrinsic pathway via the tissue factor:FVIIa complex together with calcium ions on the phospholipid surface. Intrinsic pathway activation occurs through the serine protease FIXa and its cofactor FVIIIa in the presence of calcium ions on the phospholipid surface. Factor Xa is the most important activator of prothrombin, cleaving prothrombin to generate thrombin, which forms a complex with FVa, Ca++, and phospholipids. FXa can also activate FV and FVIII (Brown DL 2008). FXa is inhibited by forming a complex with antithrombin, and the complex is rapidly excreted from the circulation.

[0180] Factor X deficiency is autosomal recessive and affects 1 in 500,000 to 1 in 1,000,000 individuals in the general worldwide population. It is classified into two types of deficiency: type I, in which both the level and activity of the FX protein are decreased, and type II, in which the protein level is not affected but the activity is reduced. The symptoms are classified into a wide range of severities, from mild to moderate and severe, depending on the circulating levels of functional FX.

[0181] Current treatment for FX deficiency is replacement therapy with complexes extracted from human plasma. Commercially available products containing FX that form complexes with various amounts of other clotting factors include Factor X P (CSL Behring) and Coadex (BDI Pharma). The description of each of these compounds, together with the dosing regimen and rationale, is explained next.

[0182] Coagadex

[0183] Coagadex is manufactured by BDI Pharma. Coagadex contains approximately 100 IU / mL of Factor X and the following inactive ingredients: chloride, phosphate, citrate, sucrose, and sodium. The specific activity of Coagadex is typically between 80 and 137 IU / mg of protein. The dosage and duration of treatment depend on the severity of Factor X deficiency, the location and extent of bleeding, and the patient's clinical status. The dosage to achieve the desired in vivo peak increase in Factor X level can be determined using the following formula: Dose (IU) = Body weight (kg) × Desired increase in Factor X (IU / dL) × 0.7. Thus, for a 70 kg patient, the dosage of Factor X administered can be determined to be 1960 IU, assuming a desired Factor X increase of approximately 40%. Plasma levels of Factor X between 10% and 40% have been described as effective for hemostasis. Based on a half-life of 24 to 40 hours, administration of Factor X every 24 hours should generally be sufficient if continuous treatment is required.

[0184] Based on the above estimation, the amount of Factor X protein in 1960 IU is determined to be 14.3 mg, and the specific activity of Factor X is considered to be 137 IU / mg of protein. Considering that the bioavailability of intraperitoneal delivery is approximately 50% compared to IV administration (the dosage for intraperitoneal delivery needs to be doubled), for a 70 kg patient, the required dosage is converted to approximately 28.6 mg every 24 hours. For a 50 kg patient, the dosage would be approximately 20 mg, and for an 80 kg patient, the dosage would be 33 mg. Considering this dosage range of 20 - 33 mg, in the embodiment of Device 10 / Capsule 20, it has between approximately 4 and 9 mg of drug per capsule (e.g., contained in 2 - 3 tissue penetrating members 140). This results in approximately 2 - 8 capsules every 24 hours.

[0185] Factor X P (Behring)

[0186] Factor X P is manufactured by CLS Behring and supplied as a powder containing approximately 600 - 1200 IU of human coagulation factor X and as a solvent for injection solutions. The formulation also consists of 600 IU of human coagulation factor IX, an important coagulation factor in the treatment of hemophilia. The specific activity of factor X varies in the range of 4 - 60 IU / mg protein for factor X to 3 - 38 IU / mg protein. The dosage and duration of treatment depend on the severity of factor X deficiency, the location and extent of bleeding, and the patient's clinical condition. The calculation of the required dosage of factor X is based on the empirical finding that 1 unit of FX / kg body weight raises plasma factor X activity by approximately 1.5% of normal activity. The required dosage is determined using the following formula: Dosage (IU) = body weight [kg] × desired factor X increase [% or IU / dl] × 0.7. Thus, for a 70 kg patient, the dosage of factor X to be administered is determined to be 1960 IU, assuming a desired factor X increase of approximately 40%. Plasma levels of factor X between 10 - 40% are described as effective for hemostasis. Based on the half-life of factor X of 24 - 40 hours, administration of FX every 24 hours should generally be sufficient when continuous treatment is required. Based on the above estimates, since the specific activity of coagulation factor X is considered to be 60 IU / mg protein for factor X, the amount of factor X protein in 1960 IU is determined to be 32.6 mg. Considering that the bioavailability of intraperitoneal delivery is approximately 50% compared to IV administration, the required dosage for a 70 kg patient is converted to approximately 65.2 mg of the drug every 24 - 40 hours. In an embodiment of device 10 / capsule 20 having between approximately 5 - 9 mg / capsule of the drug, this would be approximately 7 capsules every 24 - 40 hours.

[0187] Embodiments of coagulation factors or biological equivalents of other coagulation proteins described herein

[0188] Various embodiments of the present invention also contemplate the use of compositions and proteins that include proteins having amino acid sequences different from the coagulation factors (e.g., including Factor VII, Factor VIIa, Factor VIII, Factor IX, and Factor X) described herein, as well as analogs and derivatives thereof. Suitable analogs of Factor VII and Factor VIIa, and methods for making them, include those described in U.S. Patent Application No. 12 / 354,509, which is incorporated herein by reference for all purposes. Suitable analogs of Factor VIII and methods for making them include the analogs and methods described in U.S. Patent No. 5,112,950, which is incorporated herein by reference for all purposes. Suitable analogs of Factor IX and methods for making them include the analogs and methods described in U.S. Patent Application No. 12 / 302,167, which is incorporated herein by reference for all purposes. Suitable analogs of Factor X and methods for making them include the analogs and methods described in U.S. Patent No. 6,905,846, which is incorporated herein by reference for all purposes. Such variant analogs of coagulation factors may include one or more additions, deletions, or substitutions of amino acids (e.g., leucine for lysine, etc.) when compared to the amino acid sequence of the parent procoagulant protein (e.g., Factor VIII), but still exhibit a biological activity (e.g., coagulation function) that is essentially equivalent to the biological activity of the described coagulation protein with respect to the ability of the variant to function in the coagulation cascade. In certain embodiments, the variant may include a deletion of the B domain of the Factor VIII molecule. Variants may also include modifications of the Factor VIII molecule via Fc fusion or PEGylation, such variant forms being selected to increase the circulating half-life of the selected Factor VIII molecule. Similar approaches may be used to increase the circulating half-life of one or more of Factor VII, Factor IX, and Factor X.

[0189] Pharmacokinetic measurements related to the delivery of coagulation factors or other procoagulant proteins into the intestinal wall or surrounding tissue

[0190] Embodiments of the present invention that deliver one or more coagulation factors (e.g., factor VII, factor VIII, factor IX, factor X, etc.) or other blood clotting proteins into the intestinal wall (e.g., small intestine) or surrounding tissue (e.g., peritoneal tissue) also provide advantages with respect to one or more pharmacokinetic measurements. Pharmacokinetic measurements of note in this regard are the peak plasma concentration of the drug after administration, C max ; C max ; the time t max ; it takes to reach C max ; and after reaching C max ; the time t 1 / 2 ; it takes for the plasma concentration of the drug to reach half of its C max ; value, including but not limited to these. These measurements can be made using standard pharmacokinetic measurement techniques known in the art. For example, in one approach, plasma samples can be taken at set intervals (e.g., 1 minute, 5 minutes, 1 / 2 hour, 1 hour, etc.) from the start of administration of the coagulation factor or other blood clotting protein or other therapeutic agent by use of a swallowable device or by non-vascular injection until after administration. Next, the drug concentration in the plasma can be measured using one or more appropriate analytical methods such as GC-mass spectrometry, LC-mass spectrometry, HPLC, or various ELISAs (enzyme-linked immunosorbent assays) that can be adapted for a particular drug. A concentration-versus-time curve (also referred to herein as a concentration profile) can then be generated using the measurements from the plasma samples. The peak of the concentration curve corresponds to C max ; and the time at which this occurs corresponds to t max ; After reaching C max ; the time it takes for the concentration to reach half of its maximum value (i.e., C 1 / 2 ) corresponds to t maxThe start time of the determination may be based on the time of injection in the case of non-vascular injection, and the point in time when an embodiment of the swallowable device advances one or more tissue penetrating members (containing the drug) into the small intestine or other location of the GI tract (e.g., the large intestine). In the latter case, this time may be determined using one or more means, including a remote control embodiment of the swallowable device that deploys the tissue penetrating member within the intestinal wall in response to an external control signal (e.g., an RF signal), or an embodiment of the swallowable device that sends an RF or other signal detectable outside the body when the tissue penetrating member is deployed. Other means of detecting the deployment of the tissue penetrating member within the small intestine are contemplated, such as one or more medical imaging modalities including, for example, ultrasound or fluoroscopy. In any one of these studies, an appropriate animal model may be used to model the pharmacokinetic response in humans, such as dogs, pigs, rats, etc.

[0191] Thus, various embodiments provide a therapeutic composition 100 (also referred to herein as a preparation) comprising a clotting factor (e.g., Factor VII, Factor VIII, Factor IX, or Factor X), or other clotting protein or other therapeutic agent. The composition is adapted for insertion into the intestinal wall after oral ingestion, and after insertion, the composition releases the clotting factor or other clotting protein from the intestinal wall into the bloodstream, resulting in a more rapid C increase than a dose of clotting factor or other clotting protein injected extravascularly. max i.e., the t of a dose of extravascularly injected clotting factor or other clotting protein max For a period shorter than (e.g., smaller than t max ) for the insertion of clotting factors or other blood clotting proteins, max It should be noted that the dose of clotting factor or other clotting protein in the composition delivered into the intestinal wall and the dose delivered by extravascular injection can be, but need not be, equivalent to achieve these results. In various embodiments, the composition provides a t with respect to the clotting factor or other clotting protein (e.g., by release of the clotting factor from the intestinal wall or surrounding tissues (e.g., peritoneal tissue) into the bloodstream) relative to the dose of clotting factor injected extravascularly. maxt is about 80%, or 50%, or 30%, or 20%, or 10% max is configured to achieve. Such an extravascular injection dose of a coagulation factor can be, for example, a subcutaneous injection or an intramuscular injection. In certain embodiments, C is achieved by delivery by insertion of a coagulation factor or other clotting protein into the intestinal wall or surrounding tissue max is, without inserting the coagulation factor or other clotting protein into the intestinal wall, achieved, for example, when orally delivered by a pill of the coagulation factor or other clotting protein or other conventional oral form max is substantially higher, for example 5, 10, 20, 30, 40, 50, 60, 70, 80 or even 100 times higher. In some embodiments, the coagulation factor (or other clotting protein) composition is configured to produce a long-term release of the coagulation factor (or other clotting protein) that can include a period in the range of about 1 to 60 days, in certain embodiments 6 to 12 hours, 6 to 24 hours, 12 to 24 hours, 12 to 36 hours, 1 to 2 days, 1 to 3 days, 1 to 5 days, 1 to 10 days, 1 to 20 days, 2 days, 3 days, 5 days, 7 days, 10 days, 15 days, 20 days, 30 days, 40 days, 45 days, 50 days, and 60 days. Similarly, the composition can be configured to produce a long-term release of the coagulation factor (or other clotting protein) having a selectable t 1 / 2 can also be configured to produce a long-term release of the coagulation factor (or other clotting protein) having a selectable t 1 / 2 can be 6, or 9, or 12, or 15, or 18, 24, 36, 48 and 60 hours.

[0192] Any suitable dose of a coagulation factor (or other clotting protein) for a particular patient may be used depending on factors such as body weight, age, condition, other drugs being taken, etc. For example, the dose of a coagulation factor (e.g., factor VII, factor VIII, factor IX, or factor X) or other clotting protein administered can be in the range of about 1 to 10 mg, particularly in the range of 1 to 5, 1 to 4, 2 to 4, 2 to 5 and 2 to 3 mg, as well as the individual doses of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 mg. When administered subcutaneously, the coagulation factor typically has a t in the bloodstream of about 130 hours maxIt has. Therefore, when administered in the therapeutic coagulation factor (e.g., factor VIII) compositions described herein, the t of the coagulation factor max is shortened, e.g., the t of the coagulation factor when administered subcutaneously max is shortened to about 80%, or 50%, or 30%, or 20%, or 10% of that.

[0193] Various embodiments also provide coagulation factor (or other blood coagulation protein) compositions adapted for insertion into the intestinal wall and / or abdominal wall after oral ingestion, and when inserted, the composition releases the coagulation factor (or other blood coagulation protein) from the intestinal wall or surrounding tissue (e.g., peritoneal tissue) into the bloodstream, and the t of the oral ingestion dose of the coagulation factor (or other blood coagulation protein) not inserted into the intestinal wall 1 / 2 with a longer t 1 / 2 is achieved. For example, the t of the dose inserted into the intestinal wall 1 / 2 can be 100, or 50, or 10, or 5 times longer than the dose not inserted into the intestinal wall.

[0194] According to one or more embodiments, the coagulation factor (or other blood coagulation protein) can be in solid form, e.g., a solid form composition configured to decompose in the intestinal wall such as the wall of the small intestine or the abdominal wall. Similarly, the solid form composition can have a tissue penetrating body such as a sharp tip. In one or more embodiments, the solid form coagulation factor (e.g., factor VIII) composition can be in the form of a shaft with a sharp tip, e.g., a needle or dart, and can be inserted through the intestinal wall or abdominal wall. The coagulation factor (or other blood coagulation protein) composition may include at least one biodegradable material and / or at least one pharmaceutical excipient including a biodegradable polymer, e.g., PGLA, or a sugar, e.g., maltose. In other embodiments, the coagulation factor (or other blood coagulation protein) can be in semi-solid or liquid form encapsulated or otherwise made in an embodiment of a tissue penetrating member.

[0195] Various embodiments of the coagulation factor (or other blood clotting protein) compositions described herein may be adapted for oral delivery in a swallowable capsule. In certain embodiments, such a swallowable capsule is operably linked to a mechanism having a first configuration in which the coagulation factor (or other blood clotting protein) composition is contained within the capsule and a second configuration in which it advances out of the capsule and into the intestinal wall and / or surrounding tissue (e.g., peritoneal tissue). Such an operably linked mechanism may include at least one of an expandable member, an expandable balloon, a valve, a tissue penetrating member, a valve linked to an expandable balloon, or a tissue penetrating member linked to an expandable balloon.

[0196] In some embodiments, a coagulation factor (e.g., factor VII, factor VIII, factor IX, or factor X) or other blood clotting protein may be configured to be delivered within the lumen of the tissue penetrating member, and / or the coagulation factor (or other blood clotting protein) composition may be shaped as a tissue penetrating member that can advance within the intestinal wall. The tissue penetrating member may be sized to be completely contained within the intestinal wall and / or may include a tissue penetrating body that penetrates the intestinal wall and / or may include a retaining body for retaining the tissue penetrating member within the intestinal wall. The retaining body may include barbs, for example. In some embodiments, the tissue penetrating member is configured to advance into the intestinal wall or surrounding tissue (e.g., peritoneal tissue) by applying a force (e.g., a mechanical force) to the surface of the tissue penetrating member. Desirably, the tissue penetrating member has sufficient rigidity and / or strength of the columnar portion to fully advance into the intestinal wall and / or to the surface of the penetrating member upon application of a mechanical force or other force (e.g., an electromagnetic force). In various embodiments, the strength / rigidity of the columnar portion of the tissue penetrating member can range from about 1 to 20 lbs, 7 to 20 lbs, or 8 to 12 lbs, and individual embodiments are 7, 8, 9, 10, and 11 lbs. The strength of the columnar portion can be achieved by one or more selections of the material of the tissue penetrating member and the diameter. In many embodiments, the tissue penetrating member is configured to be operably coupled to an expandable balloon or other expandable member that applies a force upon expansion. In some embodiments, the tissue penetrating member is configured to be directly coupled to a structure that applies a force (e.g., a spring, a shaft, etc., or even an expandable device). In these and related embodiments, the tissue penetrating member is configured to detach from the structure that applies the force when the direction of the force changes.

[0197] Various aspects of the present invention also provide, in addition to the above embodiments, other embodiments of a swallowable delivery device for the delivery of agent 100. According to one or more such embodiments, the swallowable delivery device can include one or more expandable balloons or other expandable devices for use in delivering one or more tissue-penetrating members containing agent 100 into the intestinal wall, such as the small intestine. Referring now to FIGS. 12 - 20, another embodiment of a device 110 for delivering agent 100 to a delivery site DS in the gastrointestinal (GI) tract can include a capsule 120 sized to be swallowed and pass through the digestive tract, a deployment member 130, one or more tissue-penetrating members 140 containing agent 100, a deployable aligner 160, and a delivery mechanism 170. In some embodiments, agent 100 (also referred to herein as formulation 100) can itself include tissue-penetrating member 140. The deployable aligner 160 is positioned within the capsule and is configured to align the capsule with the intestine, such as the small intestine. Typically, this involves aligning the longitudinal axis of the capsule with the longitudinal axis of the intestine. However, other alignments are equally contemplated. The delivery mechanism 170 is configured to deliver agent 100 into the intestinal wall and typically includes a delivery member 172, such as an expandable member. The deployment member 130 is configured to deploy at least one of the aligner 160 or the delivery mechanism 170. As described in detail herein, all or a portion of the capsule wall is decomposable by contact with a liquid in the GI tract, and those liquids can trigger the delivery of agent 100 by device 110. As used herein, "GI tract" refers to the esophagus, stomach, small intestine, large intestine, and anus, while "intestinal tract" refers to the small intestine and large intestine. Various embodiments of the present invention can be configured and arranged to deliver agent 100 to both the intestinal tract and the entire GI tract.

[0198] The device 110 including the tissue-penetrating member 140 can be configured to deliver the agent 100 in liquid, semi-liquid, or solid form, or all three combinations. In whatever form, the agent 100 preferably has the consistency of a material such that after the agent exits the device 110 and advances into the intestinal wall (small intestine or large intestine) or other luminal wall of the GI tract, it decomposes within the intestinal wall or surrounding tissue (e.g., peritoneum or other abdominal cavity) to release the drug or other therapeutic agent 101 into the wall or surrounding tissue and then into the bloodstream. The consistency of the material of the agent 100 can include one or more of the hardness, porosity, and solubility (in body fluids such as those found in the wall of the small intestine or the abdominal cavity, e.g., serous fluid) of the preparation. The consistency of the material of the agent 100 can be achieved by one or more of the following: i) the compressive force used to make the preparation; ii) the use of one or more pharmaceutically known disintegrants; iii) the use of other pharmaceutical excipients; iv) the particle size and distribution of the preparation (e.g., micronized particles); and v) the use of micronization and other particle formation methods known in the art.

[0199] The capsule 120 is sized to be swallowed and pass through the intestinal tract. The size can also be adjusted depending on the amount of drug to be delivered as well as the patient's weight and whether it is for adult or pediatric use. Typically, the capsule has a tubular shape with curved ends similar to a vitamin. In these and related embodiments, the length 120L of the capsule can range from 0.5 to 2 inches and the diameter 120D can range from 0.1 to 0.5 inches, although other dimensions are contemplated. The capsule 120 includes a capsule wall 121w and has an outer surface 125 and an inner surface 124 that define an internal space or volume 124v. In some embodiments, the capsule wall 121w can include one or more openings 126 sized to advance the tissue-penetrating member 140 outwardly. In addition to other components of the device 110 (e.g., expandable members, etc.), the internal volume can include one or more compartments or reservoirs 127.

[0200] The capsule can be made of various biodegradable gelatin materials known in the pharmaceutical art, but can also include various enteric coatings 120c configured to protect the cap from degradation in the stomach (by acids, etc.) and then degrade at a higher pH found in the small intestine or other regions of the intestinal tract. In various embodiments, the capsule 120 can be formed from a plurality of parts, one or more of which can be biodegradable. In many embodiments, the capsule 120 can be formed from two parts 120p, such as a body portion 120p” (referred to herein as the “body 120p”) and a cap portion 120p’ (referred to herein as the “cap 120p”), and the cap can be adapted to the body, for example, by sliding over or under the body (other arrangements are equally contemplated). One part, such as the cap 120p’, can include a first coating 120c’ configured to degrade above a first pH (e.g., pH 5.5), and a second part, such as the body 120p”, can include a second coating 120c” configured to degrade above a second, higher pH (e.g., 6.5). Both the inner 124 and outer 125 surfaces of the capsule 120 are coated by the coatings 120c’ and 120c”, thereby substantially preserving any part of the capsule until it contacts a fluid having the pH it was selected for. In the case of the body 120p”, this can maintain the structural integrity of the body 120p” such that the balloon 172 is maintained inside the body portion and does not deploy until the balloon 130 expands. The coatings 120c’ and 120c” can include various methacrylate and ethyl acrylate-based coatings, such as coatings manufactured by Evonik Industries under the trade name EUDRAGIT. These and other double coating configurations of the capsule 120 allow a mechanism in one part of the capsule 120 to operate before a mechanism in another part of the capsule. This is due to the fact that the intestinal fluid first enters the part where the coating is degrading at a lower pH, thus activating a trigger (e.g., a degradable valve) that responds to such a fluid.When used, such an embodiment of the double coating of the capsule 120 provides targeted drug delivery to a specific location in the small intestine (or other location in the GI tract) as well as increased reliability of the delivery process. This can be achieved by configuring the deployment of certain components, such as the aligner 160, to begin in the region of the upper part of the small intestine (e.g., the duodenum), thereby allowing the capsule to be aligned in the intestine so that the drug is optimally delivered (e.g., to the intestinal wall), and due to the fact that the deployment / activation of other components provides sufficient time to achieve drug delivery into the intestinal wall while the capsule still remains in the small intestine or other selected location.

[0201] As discussed above, one or more parts of the capsule 120 can be made from various biocompatible polymers known in the art that include various biodegradable polymers, and in preferred embodiments, they can include cellulose, gelatin materials, and PGLA (poly(lactic acid - co - glycolic acid)). Other suitable biodegradable materials include the various enteric materials described herein as well as lactide, glycolide, lactic acid, glycolic acid, p-dioxanone, caprolactone, trimethylene carbonate, caprolactone, mixtures and copolymers thereof.

[0202] In various embodiments, the wall 120w of the capsule is configured to be decomposable by contact with liquids in the GI tract, such as liquids in the small intestine. In a preferred embodiment, the capsule wall remains intact while passing through the stomach but is then configured to decompose in the small intestine. In one or more embodiments, this can be achieved by the use of an outer coating or layer 120c on the capsule wall 120w, which decompose only at a higher pH found in the small intestine and serve to protect the underlying capsule wall from decomposing inside the stomach before the capsule reaches the small intestine (the point at which the drug delivery process is initiated by the decomposition of the coating). When used, such coatings enable targeted delivery of therapeutic agents to a selected portion of the intestinal tract, such as the small intestine including the wall of the small intestine.

[0203] Similar to capsule 20, in various embodiments, capsule 120 may include one or more medical imaging modalities known in the art, such as fluoroscopy, ultrasound, MRI, etc., and various radiopaque, echogenic, or other materials for device localization. Such materials can be arranged as separate bands or other shapes on the capsule to easily provide a visual indicator of the capsule in the intestinal tract using one or more medical imaging modalities. They may also be configured such that a physician can distinguish whether the capsule is deployed or not. For example, according to one embodiment, when a balloon or other expandable member expands, markers can be placed around the central region of the capsule such that the markers are torn and become indistinguishable under imaging and / or have different shapes when imaged.

[0204] As further discussed herein, in many embodiments, one or more of deployment member 130, delivery member 172, or deployable aligner 160 may correspond to an expandable balloon that is shaped and sized to fit within capsule 120. Thus, for ease of discussion, deployment member 130, delivery member 172, and deployable aligner 160 are referred to herein as balloons 130, 160, and 172, respectively, although other devices, including various expandable devices, are similarly contemplated with respect to these elements. For example, various shape memory devices (e.g., an expandable basket made from a coil of shape memory biodegradable polymer), expandable piezoelectric devices, and / or chemically expandable devices having an expanded shape and size corresponding to the internal volume 124v of capsule 120 may be included.

[0205] One or more of balloons 130, 160, and 172 may include various polymers known in the art of medical devices. In preferred embodiments, such polymers may include one or more types of polyethylene (PE) corresponding to low density PE (LDPE), linear low density PE (LLDPE), medium density PE (MDPE), and high density PE (HDPE), as well as other forms of polyethylene known in the art. In one or more embodiments using polyethylene, the material may be cross-linked using polymer irradiation methods known in the art. In certain embodiments, radiation-based cross-linking may be used to control the diameter and shape upon inflation of the balloon by reducing the compliance of the balloon material. The amount of radiation may be selected such that a particular amount of cross-linking is achieved and then a particular amount of compliance results for a given balloon, for example, increased radiation exposure can be used to produce a stiffer and less compliant balloon material. Other suitable polymers may include PET (polyethylene terephthalate), silicone, and polyurethane. In various embodiments, balloons 130, 160, and 172 may also include various radiopaque materials known in the art, such as barium sulfate, so that a physician can confirm the position and physical state of the balloon (e.g., deflated, inflated, or perforated). Balloons 130, 160, and 172 can be fabricated using various balloon blowing methods (e.g., blow molding, free blowing method, etc.) known in the art of balloon catheters to have a shape and size that generally corresponds to the internal volume 124v of capsule 120. In various embodiments, one or more of balloons 130, 160, and 172, as well as various connecting structures (e.g., connecting tubes), may have a single construct formed in a single mold. Embodiments using such a single construct provide the advantage of improved manufacturability and reliability due to fewer joints that must be made between one or more components of device 110.

[0206] Suitable shapes for balloons 130, 160, and 172 include various cylindrical shapes having tapered or curved end portions (examples of such shapes include hot dogs). In some embodiments, the size (e.g., diameter) of one or more of balloons 130, 160, and 172 upon inflation can be larger than capsule 120 in order to break apart the capsule by the inflation force (e.g., due to hoop stress). In other related embodiments, the size of one or more of balloons 130, 160, and 172 upon inflation can be such that, upon inflation, i) capsule 120 contacts the wall of the small intestine sufficiently to induce peristaltic contractions that cause contraction of the small intestine around the capsule, and / or ii) is sized to remove the folds of the small intestine. Any of these results enable improved contact between the capsule / balloon surface and the intestinal wall in order to deliver tissue penetrating member 40 over a selected area of the capsule and / or delivery balloon 172. Desirably, the walls of balloons 130, 160, and 172 are thin and can have wall thicknesses in the range of 0.005 to 0.0001 inches, more preferably in the range of 0.005 to 0.0001, and in certain embodiments 0.004, 0.003, 0.002, 0.001, and 0.0005. Additionally, in various embodiments, one or more of balloons 130, 160, or 172 can have a nested balloon configuration having an inflation chamber 160IC and extended fingers 160EF as shown in the embodiment of FIG. 13c. The connection tube 163 connecting the inflation chamber 160IC can be made narrow to allow only gas 168 to pass through, while the connection tube 36 connecting the two halves of balloon 130 can be made larger to allow water to pass through.

[0207] As described above, the aligner 160 typically includes an expandable balloon, which will be referred to herein as the aligner balloon 160 or the balloon 160 for ease of discussion. The balloon 160 can be fabricated using the materials and methods described above. It has a non-expanded and an expanded state (also referred to as a deployed state). In its expanded or deployed state, the balloon 160 elongates the length of the capsule 120 such that the force exerted by peristaltic contractions of the small intestine SI on the capsule 120 aligns the longitudinal axis 120LA of the capsule 120 parallel to the longitudinal axis LAI of the small intestine SI. This in turn serves to align the shaft of the tissue penetrating member 140 perpendicular to the surface of the intestinal wall IW, enhancing and optimizing the penetration of the tissue penetrating member 140 into the intestinal wall IW. In addition to serving to align the capsule 120 in the small intestine, the aligner 160 is also configured to push the delivery mechanism 170 out of the capsule 120 prior to inflation of the delivery balloon 172 so that the delivery balloon and / or mechanism are not obstructed by the capsule. When used, this push-out function of the aligner 160 improves the reliability of delivery of the therapeutic agent since there is no need to wait for a particular portion of the capsule (e.g., that overlying the delivery mechanism) to degrade before drug delivery can occur.

[0208] Balloon 160 can be hydraulically connected to one or more components of device 110 including balloons 130 and 172 by a polymeric tube or other fluidic connection 162 that can include a tube 163 for connecting balloons 160 and 130 and a tube 164 for connecting balloons 160 and 172. Tube 163 is configured to expand / inflate balloon 160 by pressure from balloon 130 (e.g., pressure generates a mixture of chemical reactants within balloon 130) and / or to initiate a gas-generating chemical reaction to pass liquid between balloons 130 and 160 to inflate one or both of balloons 130 and 160. Tube 164 connects balloon 160 to balloon 172 to enable inflation of balloon 172 by balloon 160. In many embodiments, tube 164 includes or is connected to a control valve 155 configured to open at a selected pressure to control inflation of balloon 172 by balloon 160. Thus, tube 164 can include a proximal portion 164p connecting to the valve and a distal portion 164d extending from the valve. Typically, the proximal and distal portions 164p and 164d are connected to the valve housing 158 as described below.

[0209] Valve 155 may include a triangular or other shaped section 156 of material 157 that is disposed within chamber 158c of valve housing 158 (alternatively, this may be disposed directly within tube 164). Section 157 is configured to mechanically break down (e.g., tear, shear, split into thin layers, etc.) at a selected pressure so as to allow gas to pass through tube 164 and / or into valve chamber 158c. Suitable materials 157 for valve 155 may include beeswax or other forms of wax, and various adhesives known in the medical arts having selectable sealing forces / failure pressures. Valve fitting 158 typically includes a thin cylindrical section (made of biodegradable material) in which section 156 of material 157 is disposed so as to either seal the walls of chamber 158c together or otherwise impede the passage of fluid through the chamber (as shown in the embodiment of FIG. 13b). The release pressure of valve 155 can be controlled through one or more selections of the size and shape of section 156 and the selection of material 157 (e.g., with respect to properties such as adhesive strength, shear strength, etc.). When used, control valve 155 allows for sequential inflation of balloons 160 and 172 such that balloon 160 inflates fully or otherwise substantially before balloon 172 inflates. This then allows balloon 160 to push balloon 172 along with the remainder of delivery mechanism 170 away from capsule 120 (typically from body portion 120p') before balloon 172 inflates so that deployment of tissue penetrating member 140 is not impeded by capsule 120. When used, such an approach improves the reliability of penetration of tissue penetrating member 140 into intestinal wall IW both with respect to achieving a desired depth of penetration and delivering a greater number of penetrating members 140 contained within capsule 120 since advancement of the member into the intestinal wall IW is not impeded by capsule wall 120w.

[0210] As described above, the length 160l of the alignment balloon 160 during inflation is sufficient for the capsule 120 to align with the transverse axis of the small intestine due to intestinal peristaltic contractions. A suitable length 160l of the alignment balloon 160 during inflation can include a range between about 1 / 2 to 2 times the length 120l of the capsule 120 before inflation of the alignment balloon 160. Suitable shapes of the alignment balloon 160 can include various elongated shapes such as a hot dog-like shape. In certain embodiments, the balloon 160 can include a first section 160' and a second section 160", where the expansion of the first section 160' is configured to advance the delivery mechanism 170 from the capsule 120 (typically from the body portion 120p'), and the second section 160" is used to inflate the delivery balloon 172. In these and related embodiments, the first and second sections 160' and 160" can be configured to have a telescoping inflation where the first section 160' inflates first to push the mechanism 170 from the capsule (typically from the body portion 120p'), and the second section 160" inflates to inflate the delivery member 172. This can be achieved by configuring the first section 160' to have a smaller diameter and volume than the second section 160" such that the first section 160' inflates first (due to its smaller volume) and the second section 160" does not inflate until the first section 160' is substantially inflated. In one embodiment, this can be facilitated by the use of a control valve 155 (described above) connecting the sections 160' and 160" that does not allow gas to pass into section 160" until a minimum pressure reaches section 160'. In some embodiments, the alignment balloon can contain a chemical reactant that reacts with water or a mixture with other liquids from the deployed balloon.

[0211] In many embodiments, the deployment member 130 includes an expandable balloon, also known as the deployment balloon 130. In various embodiments, the deployment balloon 130 is configured to facilitate the deployment / expansion of the alignment balloon 160 by use of gas, such as the generation of gas 169 from chemical substances. The gas may be generated by the reaction of solid chemical reactants 165, such as an acid 166 (e.g., citric acid) and a base 166 (e.g., potassium bicarbonate, sodium bicarbonate, etc.), which is then mixed with water or other aqueous liquid 168. The amount of reactants can be selected using stoichiometric methods to produce a selected pressure in one or more of balloons 130, 160, and 72. The reactants 165 and the liquid are stored separately in balloons 130 and 160 and are then mixed in response to a trigger event, such as pH conditions in the small intestine. The reactants 165 and the liquid 168 can be stored in either balloon, but in a preferred embodiment, the liquid 168 is stored in balloon 130 and the reactants 165 are stored in balloon 160. To initiate the reaction by passing the liquid 168 through and / or to obtain the gas 169, the balloon 130 may be connected to the alignment balloon 160 by a connecting tube 163, which typically also includes a separating means 150, such as the decomposable valve 150 described below. In embodiments where the balloon 130 contains liquid, the tube 163 has a sufficient diameter to allow sufficient water to pass from the balloon 130 to the balloon 160 to inflate the balloon 160 and to produce the desired amount of gas to inflate the balloon 172. Similarly, when the balloon 130 contains liquid, one or both of the balloon 130 and the tube 163 are configured to pass the liquid to the balloon 160 by one or more of: i) the compressive force applied to the balloon 130 by peristaltic contractions of the small intestine on the exposed balloon 130; and ii) the wicking of the liquid through the tube 163 by capillary action.

[0212] The tube 163 typically includes a decomposable separation valve or other separating means 150 that separates the contents of the balloon 130 (e.g., water 158) from the contents of the balloon 160 (e.g., reactants 165) until the valve decomposes. The valve 150 can be made of a material such as maltose that is decomposable by liquid water so that the valve opens when exposed to water along with various liquids in the digestive tract. It can also be made of a material that is decomposable in response to a higher pH found in intestinal fluid, such as a methacrylate-based coating. The valve is desirably located at a position on the tube 163 that protrudes above the balloon 130 and / or is otherwise sufficiently exposed so that when the cap 120p' decomposes, the valve 150 is exposed to the intestinal fluid that enters the capsule. In various embodiments, the valve 150 can be positioned such that it is present on the surface of the balloon 130 and / or even protrudes therefrom so as to be clearly exposed to the intestinal fluid when the cap 120p' decomposes (as shown in the embodiments of FIGS. 16a and 16b). Various embodiments of the present invention provide a plurality of structures for the separation valve 150, such as a beam-like structure (including a beam that presses the valve downward against the tube 163 and / or the connection section 136), or a collar-type structure (the valve includes a collar that is present above the tube 163 and / or the connection section 136). Still other valve structures are similarly contemplated.

[0213] The balloon 130 (or other expandable deployment device 130) has a deployed state and a non-deployed state. In the deployed state, the deployed balloon 130 can have a dome shape 130d that corresponds to the shape of the end of the capsule. Other shapes 130s for the balloon 130 in the deployed state, such as spherical, tubular, etc., are similarly contemplated. The reactants 165 typically include at least two reactants 166 and 167, such as an acid like citric acid and a base like sodium bicarbonate. Other acids, such as acetic acid, and bases, such as sodium hydroxide, for other reactants 165 are similarly contemplated. When the valve or other separating means 150 opens, the reactants mix in the liquid and produce a gas, such as carbon dioxide, that expands the liner balloon 160 or other expandable member.

[0214] In an alternative embodiment shown in FIG. 13b, the deployment balloon 130 can actually include first and second balloons 130' and 130" that are connected by a tube 36 or other connecting means 136 (e.g., a connecting section). The connecting tube 136 typically includes a separation valve 150 that is decomposable by a liquid having a specific pH such as the above-mentioned liquid and / or a basic pH (e.g., 5.5 or 6.5) found in the small intestine. Each of the two balloons 130' and 130" has a semi-dome shape 130hs, whereby they can conform to the end portion of the capsule when in the expanded state. One balloon can contain a chemical reactant 165 (e.g., sodium bicarbonate, citric acid, etc.), water 168 of other liquid, whereby when the valve decomposes, the two components mix to form a gas, inflating one or both of the balloons 130' and 130", and then inflating the liner balloon 160. In an embodiment of the capsule 10 configured to deliver a therapeutic agent intraperitoneally, an additional amount of reactant can be added to the balloon 130' or 130" to increase the generated pressure.

[0215] In still other alternative embodiments, balloon 130 may include a multi-compartment balloon 130mc formed or otherwise constructed to have a plurality of compartments 130c. Typically, compartments 130c include at least first and second compartments 134 and 135 separated by a separation valve 150 or other separation means 150, as shown in the embodiment of FIG. 14a. In many embodiments, compartments 134 and 135 have at least a small connecting section 136 therebetween, which is where separation valve 150 is typically located. As shown in the embodiment of FIG. 14a, a liquid 168, typically water, can be disposed within the first compartment 134, and one or more reactants 165 (typically solids, although liquids may be used as well) can be disposed within the second compartment 135. When valve 150 opens (e.g., due to degradation caused by fluid within the small intestine), liquid 168 enters compartment 135 (or vice versa or both), the reactants 165 mix with the liquid, producing a gas 169 such as carbon dioxide to expand balloon 130, which can then be used to expand one or more of balloons 160 and 172.

[0216] The reactant 165 typically includes at least first and second reactants 166 and 167, such as an acid like citric acid, and a base such as sodium bicarbonate or potassium bicarbonate. As contemplated herein, in various embodiments, they can be placed in one or more of balloon 130 (including compartments 134 and 135, or halves 130' and 130"), and balloon 160. Additional reactants including other combinations of acids and bases that produce inert gas by-products are likewise contemplated. In embodiments using citric acid and sodium bicarbonate or potassium bicarbonate, the ratio between the two reactants (e.g., the ratio of citric acid to potassium bicarbonate) can range from about 1:1 to about 1:4, and a particular ratio is about 1:3. Desirably, the solid reactant 165 absorbs little or no water. Thus, one or more of the reactants, such as sodium bicarbonate or potassium bicarbonate, can be pre-dried (e.g., by vacuum drying) before being placed within balloon 130. Other reactants 165 including other acids, such as acetic acid, and bases are likewise contemplated. The amount of a particular reactant 165 including the combination of reactants can be selected to produce a particular pressure using known stoichiometric formulas for a particular chemical reaction as well as the volume of the inflated balloon and the ideal gas law equation (e.g., PV = nRT). In certain embodiments, the amount of reactant can be selected to: i) produce a particular diameter for one or more of balloons 130, 160, and 172 to achieve a particular depth of penetration within the intestinal wall; and iii) exert a selected amount of force against the intestinal wall IW by producing a selected pressure in one or more of balloons 130, 160, and 172. In certain embodiments, the amount and ratio of reactants (e.g., citric acid and potassium bicarbonate) can be selected to achieve a pressure in the range of 10 - 15 psi in one or more of balloons 130, 160, and 172, although smaller and larger pressures are also contemplated. Again, the amount and ratio of reactants to achieve these pressures can be determined using known stoichiometric formulas.

[0217] In various embodiments of the present invention for generating gas 169 using chemical reactant 165, the chemical reactant may include a deployment engine 180 for deploying one or both of an alignment balloon 160 and a delivery balloon 172, either alone or in combination with a deployment balloon 130. The deployment engine 180 may also include embodiments using two deployment balloons 130 and 130” (the double dome configuration shown in FIG. 13b), or the multi-compartment balloon 130mc shown in FIG. 14a. Other forms of the deployment engine 180, such as expandable piezoelectric materials (which expand upon application of a voltage), springs, and other shape memory materials, as well as the use of various thermally expandable materials, are also contemplated by various embodiments of the present invention.

[0218] One or more of the expandable balloons 130, 160, and 172 typically include a contraction valve 159 that serves to contract the balloon after inflation. The contraction valve 159 may include a biodegradable material that is configured to decompose when exposed to fluid in the small intestine and / or liquid in one of the compartments of the balloon, creating an opening or channel for releasing the gas within a particular balloon. Desirably, the contraction valve 159 is configured to decompose at a slower rate than the valve 150 to allow the balloons 130, 160, and 172 to inflate for a sufficient period of time before the contraction valve decomposes. In various embodiments of the compartmentalized balloon 130, the contraction valve 159 may correspond to a degradable section 139 located at the distal end portion 131 of the balloon as shown in the embodiment of FIG. 14a. In this and related embodiments, when the degradable section 139 decomposes upon exposure to liquid, the balloon wall 132 is either torn or otherwise decomposes to provide for rapid contraction. Multiple degradable sections 139 can be placed at various locations within the balloon wall 132.

[0219] In various embodiments of balloon 172, the constriction valve 159 may correspond to a tube valve 173 attached to the end 172e of the delivery balloon 172 (opposite the end connected to the aligner balloon), as shown in the embodiment of FIG. 13b. The tube valve 173 includes a hollow tube 173t having a lumen that is blocked at a selected location 173l by a material 173m such as maltose or other sugar that degrades when exposed to a fluid such as fluid in the small intestine. The location 173l of the blocking material 173m in the tube 173t is selected to provide sufficient time for the delivery balloon 172 to expand and deliver the tissue penetrating member 40 into the intestinal wall IW before the blocking material dissolves and opens the valve 173. Typically, this is near the end 173e of the tube 173t, but not so close as to allow time for liquid to wick into the tube lumen before it reaches the material 173m. According to one or more embodiments, when the constriction valve 173 opens, this contracts not only the delivery balloon 172, but also the aligner balloon 160 and the deployment balloon 130, because in many embodiments all three are in fluid communication (the aligner balloon is in fluid communication with the delivery balloon 172 and the deployment balloon 130 is in fluid communication with the aligner balloon 160). The opening of the constriction valve 173 can be facilitated by positioning the constriction valve at the end 172e of the delivery balloon 172 that is pushed out of the capsule 120 by the inflation of the aligner balloon 160 so that the constriction valve is well exposed to the liquid in the small intestine. Similar tube constriction valves 173 can also be located on one or both of the aligner balloon 162 and the deployment balloon 130. In these latter two examples, the blocking material in the tube valve can be configured to degrade over a period sufficient to allow inflation of the delivery balloon 172 and advancement of the tissue penetrating member 140 into the intestinal wall.

[0220] In addition, as a further backup to ensure contraction, one or more piercing elements 182 can be attached to the inner surface 124 of the capsule such that when the balloon (e.g., balloons 130, 160, 172) is fully inflated, it contacts and is pierced by the piercing element 182. The piercing element 182 can include a short protrusion having a pointed tip extending from the surface 124. In another alternative or additional embodiment of the balloon contraction means, one or more tissue penetrating members 140 can be directly connected to the wall 172w of the balloon 172 and configured to be pulled away from the balloon when they are detached to tear the balloon wall in the process.

[0221] Considerations of the tissue-penetrating member 140 are shown below. In one or more embodiments, the tissue-penetrating member 140 can be made from various drugs and other therapeutic agents 101, one or more pharmaceutical excipients (e.g., disintegrants, stabilizers, etc.), and one or more biodegradable polymers. The latter materials are selected to impart the desired structural and material properties to the penetrating member (e.g., column strength for insertion into the intestinal wall, or porosity, and hydrophilicity for controlling drug release). Referring now to FIGS. 18a-18f, in many embodiments, the penetrating member 140 can be formed to have a shaft 144 and a needle tip 145 or other sharp tip 145 so as to be able to easily penetrate the tissue of the intestinal wall, as shown in the embodiment of FIG. 18a. In a preferred embodiment, the tip 145 has a trocar shape, as shown in the embodiment of FIG. 18c. The tip 145 can include various degradable materials (within the body of the tip or as a coating), such as sucrose or other sugars, that increase the hardness and tissue-penetrating properties of the tip. When placed within the intestinal wall or surrounding tissue (e.g., abdominal wall or peritoneal cavity), the penetrating member 140 is degraded by the interstitial fluid within the wall tissue and / or the serous fluid within the peritoneal cavity, and the drug or other therapeutic agent 101 dissolves in those fluids and is absorbed into the bloodstream. In embodiments where the tissue-penetrating member is located in the peritoneal cavity, the tissue-penetrating member is configured to be degraded by the fluid within the peritoneal cavity, which includes the serous fluid within the peritoneal cavity, such that a coagulation factor or other therapeutic agent within the peritoneal cavity is transported into the bloodstream through the visceral and parietal abdominal walls. One or more of the size, shape, and chemical composition of the tissue-penetrating member 140 can be selected to allow for the dissolution and absorption of the drug 101 over a period of seconds, minutes, or even hours. The dissolution rate can be controlled through various means, including the use of various disintegrants known in the pharmaceutical art. Examples of disintegrants include, but are not limited to, various starches such as sodium starch glycolate, and various cross-linked polymers such as carboxymethyl cellulose. The selection of the disintegrant can be specifically tailored to the fluid and environment within the small intestine and / or the walls of the peritoneum or peritoneal cavity.In certain embodiments, the tissue penetrating member 140 may include a degradation or dissolution form 147 (referred to herein as form 147) that accelerates or otherwise enhances the degradation and / or dissolution of the tissue penetrating member 140 in the serous fluid or other fluid in the peritoneal cavity PC, thereby enhancing the release of the coagulation factor or other therapeutic agent 101 into the bloodstream. In certain embodiments, the form 147 may correspond to an opening or hole 148 that is partial or through the tissue penetrating member 140, as shown in FIG. 18g. The hole or opening 149 allows tissue fluid (e.g., serous fluid) to enter into the interior 140i of the member 140. The form 147 may also correspond to one or more channels or grooves 149 on the surface 140 of the member 140, as shown in FIGS. 18h and 18i. The channels or grooves 149 enhance the surface area of the member 140 that is available for contact with tissue fluid, thus enhancing the dissolution and / or degradation rate of the tissue penetrating member. In additional or related embodiments, the form 147 that includes the opening 148 or groove 149 serves as a mechanically weak point (e.g., a seam in the case of the groove 149) and may be positioned and configured such that when it is located within the peritoneal cavity PC, the tissue penetrating member is easily ruptured or broken into small pieces by mechanical forces applied to the tissue penetrating member 140 by the body. Such forces may include one or more of the forces due to the movement of internal organs (e.g., the intestines) and the forces due to the contraction of the abdominal muscles or the movement of the abdominal wall due to breathing. When used, such a degradation form 147 enhances the dissolution and / or degradation rate of the tissue penetrating member by enhancing the surface area for contact with tissue fluid, by allowing the penetrating member to be easily degraded into small pieces that have even more surface area for contact with tissue fluid. Desirably, but not necessarily, one or more forms 147 are positioned and otherwise configured such that they have sufficient column strength to advance the tissue penetrating member out of the capsule 20 by mechanical forces applied to the end 140e of the tissue penetrating member opposite the still sharp tip 145 while they cause the member 140 to be degraded by the forces applied by the body. Such forces are applied by components of the delivery member 50 or the actuation mechanism 60.In various embodiments, such columnar strength of the tissue penetrating member 140 having one or more decomposition / dissolution forms 147 can range from 0.1 to 1 lbs.

[0222] The tissue penetrating member 140 also typically includes one or more tissue retaining forms 143, such as barbs or hooks, for retaining the penetrating member within the tissue of the intestinal wall IW or peritoneum after advancement. The retaining forms 143 can be arranged in various patterns 143p, such as two or more barbs that are symmetrically or otherwise distributed around and along the member shaft 144, to enhance tissue retention, as shown in the embodiments of FIGS. 18a and 18b. Additionally, in many embodiments, the penetrating member also includes a recess or other engagement form 146 for attachment to the coupling component on the delivery mechanism 170.

[0223] The tissue penetrating member 140 is configured to be removably coupled, preferably to the platform 175 (or other component of the delivery mechanism 170), such that after advancement of the tissue penetrating member 140 into the intestinal wall, the penetrating member detaches from the balloon. The detachability can be effected by a variety of means including: i) a snug fit or conformity between the opening 174 in the platform 175 and the member shaft 144; ii) the configuration and placement of the tissue retaining forms 143 on the penetrating member 140; and iii) the depth of penetration of the shaft 144 into the intestinal wall. One or more of these factors are used to configure the penetrating member 140 to detach as a result of forces exerted on the capsule 120 by balloon contraction (the retaining forms 143 retain the penetrating member 140 in the tissue as the balloon contracts or is otherwise pulled back from the intestinal wall) and / or peristaltic contractions of the small intestine.

[0224] In certain embodiments, the detachable and retention of the tissue penetrating member 140 in the intestinal wall IW can be enhanced by configuring the shaft 144 of the tissue penetrating member to have a reverse taper 144t as shown in the embodiment of FIG. 18c. The taper 144t on the shaft 144 is configured such that the peristaltic contraction force from the intestinal wall causes the shaft to be inwardly directed (e.g., squeezed inwardly). This is by converting the laterally applied peristaltic force PF into an orthogonal force OF that acts to direct the shaft inwardly within the intestinal wall by the shaft taper 144t. When used, such a reverse taper shaft configuration serves to hold the tissue penetrating member 140 within the intestinal wall so as to detach from the platform 175 (or other components of the delivery mechanism 170) upon contraction of the balloon 172. In additional embodiments, the tissue penetrating member 140 having a reverse taper shaft may include one or more retention formations 143 to further enhance the retention of the tissue penetrating member within the intestinal wall IW after insertion.

[0225] As discussed above, in various embodiments, the tissue penetrating member 140 can be made from a plurality of drugs and other therapeutic agents 101. Similarly, according to one or more embodiments, the tissue penetrating member may be made entirely from a drug 101 (e.g., a coagulation factor such as factor VIII), or may likewise have other components, such as various pharmaceutical excipients (e.g., binders, preservatives, disintegrants, etc.), polymers that impart desired mechanical properties, and the like. Further, in various embodiments, one or more tissue penetrating members 140 can have the same or different drugs 101 (or other therapeutic agents) as other tissue penetrating members. The former configuration allows for delivery of a greater amount of a particular drug 101 (e.g., a particular coagulation factor), while the latter configuration enables delivery of two or more different drugs to the intestinal wall substantially simultaneously to facilitate a drug treatment regimen that requires substantially simultaneous delivery of multiple drugs. In embodiments of the device 110 having a plurality of delivery assemblies 178 (e.g., two, one on each side of the balloon 172), the first assembly 178' can have a tissue penetrating member having a first drug 101, and the second assembly 178'' can have a tissue penetrating member having a second drug 101.

[0226] Typically, a drug or other therapeutic agent 101 of the tissue penetrating member 140 is mixed with a biodegradable material 105 to form the tissue penetrating member 140. The material 105 may include one or more biodegradable polymers such as PGLA, cellulose, and maltose or other biodegradable materials described herein or known in the art. In such embodiments, the penetrating member 140 may include a substantially non-uniform mixture of the drug 101 and the biodegradable material 105. Alternatively, the tissue penetrating member 140 may include a portion 141 substantially formed from the biodegradable material 105 and an individual section 142 formed from or containing the drug 101, as shown in the embodiment of FIG. 18d. In one or more embodiments, the section 142 may correspond to a pellet, slug, cylindrical, or other shaped section 142s of the drug 101. The formed sections 142s may be pre-formed as individual sections, as shown in the embodiments of FIGS. 18e and 18f, and then inserted into the cavity 142c of the tissue penetrating member 140. Alternatively, the sections 142s may be formed by adding the drug preparation 100 to the cavity 142c. In embodiments where the drug preparation 100 is added to the cavity 142c, the preparation may be added as a powder, liquid, or gel that is poured or injected into the cavity 142c. The formed sections 142s may be formed from the drug 101 itself or from a drug preparation containing the drug 101 and one or more binders, preservatives, disintegrants, and other excipients. Suitable binders include polyethylene glycol (PEG) and other binders known in the art. In various embodiments, PEG or other binders may be included in the range of about 10-90 weight percent of the section 142s, but in a preferred embodiment of an insulin preparation may be included in the range of about 25-90 weight percent. Other excipients that may be used as binders in the tissue penetrating member 140 may include, for example, PLA, PLGA, cyclodextrin, cellulose, methylcellulose, maltose, dextrin, sucrose, and PGA, and combinations thereof. Further information regarding the weight percent of excipients in the section 142 may be found in Table 4.For ease of examination, section 142 is referred to as pellets in the table, but the data in the table is also applicable to other embodiments of section 142 described herein.

[0227] In various embodiments, the weight of the tissue penetrating member 140 can range from about 10 to 15 mg, although larger and smaller weights are contemplated. In embodiments of the tissue penetrating member 140 made from maltose, the weight can range from about 11 to 14 mg. In various embodiments, depending on the drug 101 and the desired dosage to be delivered, the weight percentage of the drug in the member 140 can range from about 0.1 to about 15%. In exemplary embodiments, these weight percentages correspond to embodiments of the member 140 made from maltose or PGLA, although they are also applicable to any of the biodegradable materials 105 used in the fabrication of the member 140, such as polyethylene and other similar materials. The weight percentage of the drug or other therapeutic agent 101 in the member 140 can be adjusted according to the desired dosage, as well as to provide the desired concentration profile of the drug in the blood or other tissues of the body, in order to achieve the desired structural and stoichiometric stability of the drug. Various stability tests and models known in the art (e.g., using the Arrhenius equation) and / or known drug chemical degradation rates can be used to make specific adjustments to the weight percentage range. Table 4 describes the dosage and weight percentage ranges of insulin and a plurality of other drugs that can be delivered by the tissue penetrating member 140. In some examples, the table lists ranges as well as single values with respect to dosage. It should be recognized that these values are exemplary and that other values recited herein, including those recited in the claims, are also contemplated. Additionally, embodiments of the present invention also contemplate variations around these values, including variations of, for example, ±1, ±5, ±10, ±25, and even larger. Such variations are considered to fall within the scope of embodiments that claim a particular value or range of values. The table also describes the weight percentage of the drug in compartment 142 with respect to various drugs and other therapeutic agents. In this case, compartment 142 can have any number of shapes, but for ease of discussion, is referred to as a pellet. Similarly, according to some embodiments, the amount of drug described in Table 4 may be dispersed throughout the tissue penetrating member 140 and need not be contained in compartment 142.

Table 4

[0228] The tissue-penetrating member 140 can be fabricated using one or more polymers and pharmaceutical fabrication techniques known in the art. For example, the drug 101 (with or without the biodegradable material 105) can be in solid form and then one or more binders can be added and formed into the shape of the tissue-penetrating member 140 using molding, compression, or other similar methods. The use of 3-D printing and related fabrication methods is also contemplated. Alternatively, the drug 101 and / or the drug preparation 100 can be in solid or liquid form and then added to the biodegradable material 105 in liquid form, and then the mixture is formed into the penetrating member 140 using molding or other forming methods known in the polymer art. In some embodiments, the tissue-penetrating member can have an outer layer or coating with a slower degradation rate in the intestinal wall (or surrounding tissue such as the peritoneal cavity) and then in the internal body that penetrates the tissue to slow the rate of drug release into the bloodstream. In various embodiments, the outer coating or layer can have a biodegradation rate that is 10, 25, 50, 100, 200, 500, or 1000% slower than the degradation rate of the internal core. When used, such embodiments of the slower-degrading outer coating of the tissue-penetrating member 140 allow for a slow release of the drug 101. Such embodiments are particularly useful, for example, in situations where it is desirable to maintain therapeutic levels of the drug over a long period of time for various clotting factors as well as insulin.

[0229] Desirably, embodiments of the tissue penetrating member 140 that include a drug or other therapeutic agent 101 and a degradable material 105 are formed at a temperature at which no substantial thermal degradation of the drug, including various peptides and proteins such as clotting proteins, occurs. This can be achieved through the use of room temperature curable polymers as well as room temperature forming and solvent evaporation techniques known in the art. In certain embodiments, the amount of thermally degraded drug or other therapeutic agent within the tissue penetrating member is desirably less than about 10 wt%, more preferably less than 5%, and even more preferably less than 1%. The thermal degradation temperature for a particular drug is known or can be determined using methods known in the art, and this temperature can then be used to select and adjust a particular polymer processing method (e.g., molding, curing, solvent evaporation methods, etc.) to minimize the temperature and associated levels of drug thermal degradation.

[0230] Provide an explanation of the delivery mechanism 170. Typically, the mechanism includes a delivery assembly 178 (containing the tissue penetrating member 140) attached to a delivery balloon 172, as shown in the embodiments of FIGS. 16a and 16b. When the delivery balloon expands, it provides a mechanical force to engage the delivery assembly 172 outward from the capsule and within the intestinal wall IW, thereby inserting the tissue penetrating member 140 into the wall. In various embodiments, the delivery balloon 172 can have an elongated shape with two relatively flat surfaces 172f connected by an articulated accordion-like body 172b. The flat surfaces 172f can be configured to push against the intestinal wall (IW) as the balloon 172 expands, thereby inserting the tissue penetrating member (TPM) 140 into the intestinal wall. The TPM 140 (either alone or as part of the delivery assembly 178 described below) can be positioned on one or both surfaces 172f of the balloon 172, allowing for insertion of the drug-containing TPM 140 on the opposite side of the intestinal wall IW. The surfaces 172f of the balloon 172 can have sufficient surface area to accommodate multiple drug-containing TPM 140 on each surface.

[0231] Next, referring to FIG. 19, an explanation regarding the assembly of the delivery assembly 178 is provided below. In a first step 300, one or more tissue penetrating members 140 can be detachably coupled to a biodegradable forward structure 175 that can correspond to a support platform 175 (also known as platform 175). In a preferred embodiment, platform 175 includes one or more openings 174 for inserting tissue penetrating members 140 (also referred to as members 140 as well) as shown in step 300. The openings 174 allow for the insertion and retention of members 140 in the platform 175 prior to the expansion of balloon 172, but are sized such that they can be detached from the platform as they penetrate into the intestinal wall. Next, the support platform 175 can be positioned within a carrier structure 176 as shown in step 301. The carrier structure 176 can correspond to a well structure 176 having sidewalls 176s and a bottom wall 176b that define a cavity or opening 176c. The platform 175 is preferably attached to the inner surface of the bottom wall 176b using an adhesive or other bonding method known in the art. The well structure 176 may include various polymeric materials and may be formed using vacuum forming techniques known in the field of polymer processing. In many embodiments, the opening 176o can be covered by a protective film 177 as shown in step 302. The protective film 177 functions as a barrier to protect the tissue penetrating member 140 from humidity and oxidation, but still has properties selected such that the tissue penetrating member 140 can penetrate through the film as described below. The film 177 can desirably include various water and / or oxygen impermeable polymers configured to be biodegradable in the small intestine and / or pass inertly through the digestive tract. This may also have a multi-layer construction with a specific layer selected to be impermeable to certain substances, such as oxygen, water vapor, etc. When used, embodiments using the protective film 177 serve to increase the shelf life of the therapeutic agent 101 in the tissue penetrating member 140 and then increase the shelf life of the device 110.Collectively, the support platform 175 with the tissue penetrating member 140 attached, the well structure 176, and the film 177 may constitute the delivery assembly 178. The delivery assembly 178 having one or more drugs or therapeutic agents 101 contained within the tissue penetrating member 40 or other drug delivery means can be pre-manufactured, stored, and then used at a later date for the manufacture of the device 110. The shelf life of the assembly 178 can be further enhanced by filling the cavity 176c of the sealed assembly 178 with an inert gas such as nitrogen.

[0232] Referring again to FIGS. 16a and 16b, the assembly 178 can be positioned on one or both faces 172f of the balloon 172. In a preferred embodiment, the assembly 178 is positioned on both faces 172f (as shown in FIG. 16a) to provide a substantially equal force distribution on the opposite side of the intestinal wall IW when the balloon 172 is expanded. The assembly 178 may be attached to the face 172f using an adhesive or other connection methods known in the polymer art. When the balloon 172 expands, the TPM 140 penetrates into the film 177 and enters the intestinal wall IW, where it is held by the retaining element 143 and / or other retaining formations of the TPM 140 (e.g., the reverse tapered shaft 144t), and detaches from the platform 175 when the balloon 172 contracts.

[0233] In various embodiments, one or more of balloons 130, 160, and 172 can be packed inside capsule 120 in a folded, stacked, or other desired configuration to conserve space within the internal volume 124v of the capsule. The folding can be done using pre-formed creases or other folding geometries or methods known in the medical balloon art. In certain embodiments, balloons 130, 160, and 172 can be folded in a selected direction to achieve one or more of the following: i) conserve space; ii) result in a desired orientation of a particular inflated balloon; and iii) facilitate balloon inflation in a desired order. The embodiments shown in FIGS. 15a - 15f illustrate folding methods and embodiments of various folding arrangements. However, it should be recognized that this folding arrangement and the resulting balloon orientations are exemplary and others may be used as well. In this and related embodiments, the folding can be done manually, by automated equipment, or by a combination of both. Similarly, in many embodiments, the folding can be facilitated using a single multi-balloon assembly 7 (assembly 7 herein) that includes balloons 130, 160, 170; valve chambers 158, and various connecting tubes 162, as shown in the embodiments of FIGS. 13a and 13b. FIG. 13a shows an embodiment of assembly 7 having a single dome construction of balloon 130, and FIG. 13b shows an embodiment of assembly 7 having a double balloon / dome configuration of balloon 130. Assembly 7 can be made using a thin polymer film vacuum formed into a desired shape using various vacuum forming methods and other related methods known in the art of polymer processing. Suitable polymer films include polyethylene films having a thickness in the range of about 0.003 - about 0.010 inches, and in certain embodiments, a thickness of 0.005 inches. In a preferred embodiment, the assembly is made to have a single construction such that it is not necessary to connect one or more components of the assembly (e.g., balloons 130, 160, etc.).However, similarly, the assembly 7 is contemplated to be made from a plurality of parts (e.g., halves) or components (e.g., balloons) and then joined using various joining methods known in the art of polymers / medical devices.

[0234] Next, referring to FIGS. 15a - 15f, 16a - 16b and 17a - 17b, in a first folding step 210, the balloon 160 is folded over the valve fitting 158 and the balloon 172 moves over the opposite side of the valve fitting 158 in the process (see FIG. 15a). Next, in step 211, the balloon 172 is folded at a right angle with respect to the folded combination of the balloon 160 and the valve 158 (see FIG. 15b). Next, in step 212, with respect to the double dome embodiment of the balloon 130, the two halves 130' and 130" of the balloon 130 are folded over each other to expose the valve 150 (see FIG. 15c for the single dome embodiment of the balloon 130 and FIG. 15e for when it is folded over itself). A final folding step 213 can be performed, whereby the folded balloon 130 is folded 180° with respect to the opposite side of the valve fitting 158 and the balloon 160, resulting in the final folded assembly 8 of the double dome configuration shown in FIG. 15e, and the final folded assembly 8' of the single dome configuration shown in FIGS. 15e and 15f. Next, one or more delivery assemblies 178 are attached to the assembly 8 in step 214 (typically to two faces 72f of the balloon 72), resulting in the final assembly 9 (shown in the embodiments of FIGS. 16a and 16b), which is then inserted into the capsule 120. After the insertion step 215, the final assembled version of the device 110 with the assembly 9 inserted is shown in FIGS. 17a and 17b.

[0235] Next, with reference to FIGS. 20a - 20i, a method of delivering an agent 101, such as a coagulation factor (e.g., factor VIII) or other clotting protein, to a site in the GI tract, such as the wall of the small or large intestine, the peritoneum, or the abdominal cavity, using device 110 is provided. It should be recognized that the steps and their order are exemplary, and other steps and orders are equally contemplated. When device 110 enters the small intestine SI, the cap coating 120c' is decomposed by the basic pH in the upper part of the small intestine, causing the decomposition of cap 120p' as shown in step 400 of FIG. 20b. Next, valve 150 is exposed to the fluid in the small intestine and begins to decompose as shown in step 401 of FIG. 20c. Next, in step 402, balloon 130 expands (by the generation of gas 169) as shown in FIG. 20d. Next, in step 403, section 160' of balloon 160 begins to expand and begins to push assembly 178 out of the capsule body as shown in FIG. 20e. Next, in step 404, sections 160' and 160'' of balloon 160 fully expand to completely push assembly 178 out of the capsule body and extend the length 120l of the capsule, thereby aligning the transverse axis 120AL of the capsule with the transverse axis of the small intestine LAI as shown in FIG. 20f. During this time, valve 155 begins to cease functioning due to the increased pressure in balloon 60 (due to the fact that the balloon is fully inflated and there is no outlet for gas 169). Next, in step 405, as shown in FIG. 20g, valve 155 fully opens, inflates balloon 172, and then radially outwardly pushes the now fully exposed assembly 178 (fully extruded from body 120p'') into the intestinal wall IW. Next, in step 406, balloon 172 continues to expand and advances the tissue penetration member into the intestinal wall IW as shown in FIG. 20h. Next, in step 407, balloon 172 (along with balloons 160 and 130) contracts to pull back and holds the tissue penetration member within the intestinal wall IW. Similarly, the body portion 120p'' of the capsule completely decomposes (due to the decomposition of coating 120c'') along with the other biodegradable parts of device 110.Any undigested portion is carried distally through the small intestine by peristaltic contractions from digestion and ultimately excreted.

Example

[0236] Enclosures / Examples Various embodiments of the present invention will be described in detail with reference to the following enclosures / examples. It should be recognized that these examples are shown for illustrative purposes only and that the present invention is not limited to that information or details.

[0237] Enclosure 1 Modeling of Alirocumab Serum Concentration vs. Time

[0238] The following assumptions and / or data were used for the modeling of alirocumab serum concentration vs. time.

[0239] The subcutaneous dosing schedule was 150 mg SC (subcutaneous) weekly for 2 weeks, which corresponds to an approximate daily dosing schedule of 21.4 mg / day using an embodiment of the present invention.

[0240] The monoclonal antibody was obtained from Regeneron / Sanofi. It targets proprotein convertase subtilisin / kexin type 9 (PCSK9) to reduce low-density lipoprotein (LDL).

[0241] The pharmacokinetic parameters were obtained from the paper by Lunven, C., Paehler, T., Poitiers, F., et al. entitled "A randomized study of the relative pharmacokinetics, pharmacodynamics, and safety of Alirocumab, a fully human monoclonal antibody to PCSK9, after single subcutaneous administration at three different injection sites in healthy subjects." Cardiovascular Therapeutics, 2014, 32:297.301.

[0242] ka was not reported, but 0.5 days -1 was selected, and T max was 4.3 days.

[0243] The study reported PK parameters for three different injection sites and found that all three were equivalent. For this single simulation, the parameters used were the three mean values.

[0244] When reaching the steady state for the daily dosing simulated using the embodiments of the present invention, the drug concentration was in the range of 10.06 mg / L to 20.05 mg / L, and an average value of 15.06 mg / L was obtained.

[0245] Using the embodiments of the present invention, the daily dosing of approximately 10.5 mg per dose corresponded approximately to the dose of 150 mg once every two weeks.

[0246] Regarding the daily dosing using the embodiments of the present invention, a smaller amount can be administered daily to obtain the pharmacokinetic profile shown in Figure 21b.

[0247] Upon reaching the steady state, the concentration of alirocumab was in the range of 15.41 mg / L to 15.47 mg / L, the average steady state concentration was 15.44 mg / L, and it was higher than the 15.06 value for subcutaneous injection every two weeks.

[0248] The reduction in the daily variation of this drug concentration prevents adverse events and the formation of anti-drug antibodies, and the higher trough concentration ensures that the biological activity of alirocumab is maintained. Appendix 2: Models and calculations used for the calculation of steady state variation of alirocumab serum concentration

[0249] The % steady state variation is a measurement that provides an indication of how much the plasma / serum concentration of a drug in a patient varies over time. It is desirable to minimize the steady state variation for several reasons. First, drug concentrations higher than the amount required for pharmacological activity are more likely to cause adverse events. With respect to the cause of factor VIII or other coagulation factors, such adverse events include the production of anti-drug antibodies that inhibit or otherwise weaken the biochemical effects of coagulation events. Patients who produce anti-drug antibodies against a drug no longer respond to that drug and must undergo a different regimen. On the other hand, drug concentrations lower than the concentration required for pharmacological activity are also undesirable. There is a higher likelihood of no pharmacological activity during these periods, and thus a higher likelihood of lower drug efficacy. To effectively treat the targeted disorder, it is ideal to maintain a certain and consistent level of pharmacological activity.

Table 5

[0250] Calculations were performed on the % steady state variation for the antibodies shown in Table 2. The values were determined using the existing pharmacokinetic simulations described in Appendix 1. The specific formula used to calculate the % steady state variation is shown below.

Equation

[0251] The above equation calculates the difference between the peak steady-state concentration (C ss,peak ) and the trough steady-state concentration (C ss,trough ), divides by the mean steady-state concentration (C ss,avg ), and results in the percent change in serum drug concentration compared to the mean steady-state drug concentration. Steady-state variability serves as a quantitative measure of how much change in serum drug concentration the inventors can predict over a single dosing period.

[0252] From the data, it is clear that daily dosing using embodiments of the present invention allows for significantly lower steady-state variability for the same drug compared to subcutaneous dosing. In addition to the expected advantages of fewer and less intense adverse events and maintenance of pharmacological activity, dosing via injection into the small intestine using embodiments of the present invention avoids injection site reactions that can occur with subcutaneous dosing.

[0253] Conclusion

[0254] The foregoing description of various embodiments of the invention has been presented for purposes of illustration and description. The invention is not intended to be limited to the exact forms disclosed. Many modifications, variations, and refinements will be apparent to those skilled in the art. For example, embodiments of the devices and therapeutic preparations (e.g., in the form of tissue-penetrating members) can be sized and otherwise adapted for various pediatric and neonatal applications as well as for various veterinary applications (e.g., adjusted dosages for the therapeutic preparations). Similarly, those skilled in the art can recognize or confirm multiple equivalents to the specific devices and methods described herein using nothing more than routine experimentation. For example, in the case of clotting factors such as Factor VIII, biological equivalents to the disclosed clotting factors, including analogs and derivatives, are specifically contemplated. Such equivalents are considered to be within the scope of the invention and are included in the following appended claims.

[0255] Elements, features, or acts from one embodiment can be readily recombined or substituted with one or more elements, features, or acts from other embodiments to form a plurality of additional embodiments within the scope of the present invention. Moreover, elements shown or described in combination with other elements may exist as separate elements in various embodiments. Still further, embodiments of the present invention also contemplate the exclusion or negative recitation of elements, forms, chemical substances, therapeutic agents, features, values, or steps, etc., if such are positively recited. Accordingly, the scope of the present invention is not limited to the details of the described embodiments, but instead is limited only by the appended claims.

Claims

**Claim 1** A swallowable device for treating coagulation disorders in a patient, said swallowable device comprising: a swallowable capsule; a tissue-penetrating member disposed within said capsule, said tissue-penetrating member consisting of, or containing, a coagulation factor preparation comprising a liquid, semi-liquid, or solid form of a coagulation factor having a bioactivity that promotes or accelerates coagulation in said patient; an actuating mechanism operably connected to said tissue-penetrating member; said actuating mechanism having a first configuration and a second configuration, said tissue-penetrating member being contained within said capsule in said first configuration and, in said second configuration, being advanced from said capsule by applying a force from said actuating mechanism to said tissue-penetrating member, whereby, after oral ingestion of said capsule, said tissue-penetrating member is advanced through the intestinal wall of said patient and inserted into the abdominal cavity of said patient; a swallowable device, wherein after insertion, said tissue-penetrating member is retained within said abdominal cavity and said tissue-penetrating member is decomposed in the serous fluid of the abdominal cavity to release said coagulation factor having said bioactivity into the bloodstream to promote or accelerate coagulation in said patient and treat said coagulation disorder. **Claim 2** The device according to claim 1, wherein said tissue-penetrating member has a columnar strength sufficient to advance through said intestinal wall and into said abdominal cavity by applying said force. **Claim 3** The device according to claim 1, wherein said tissue-penetrating member is structured as a shaft having a pointed end. **Claim 4** The device according to claim 3, wherein said pointed tip is straight. **Claim 5** The device according to claim 3, wherein said tissue-penetrating member includes a degradable form configured to enhance the rate of decomposition of said tissue-penetrating member in the serous fluid of the abdominal cavity. **Claim 6** The device according to claim 5, wherein said degradable form includes an opening in said tissue-penetrating member. **Claim 7** The device according to claim 5, wherein said degradable form includes channels on the surface of said tissue-penetrating member. **Claim 8** The device according to claim 5, wherein said degradable form is positioned such that said tissue-penetrating member has a columnar strength sufficient to advance through said intestinal wall and be inserted into said abdominal cavity by applying a force to the end of said tissue-penetrating member. **Claim 9** The device according to claim 5, wherein said degradable form is positioned and configured to facilitate breakage or damage of said tissue-penetrating member by a force applied to the abdominal cavity by the patient's body.

10. The device according to claim 1, wherein the force is a mechanical force.

11. The device according to claim 1, wherein the actuating mechanism comprises an expandable member.

12. The device according to claim 11, wherein the actuating mechanism comprises a spring.

13. The device according to claim 11, wherein the actuating mechanism comprises an expandable balloon.

14. The device according to claim 1, wherein the capsule comprises a biodegradable material configured to be decomposed by contact with a fluid in the gastrointestinal (GI) tract of the patient.

15. The device according to claim 14, wherein the capsule further comprises an external coating or layer configured to decompose at a selected pH in the patient's GI tract.

16. The device according to claim 15, wherein the selected pH is determined according to the location of the patient's small intestine.

17. The device according to claim 1, wherein the coagulation factor comprises factor VIII (F8) or a factor VIII analog (F8A).

18. The dosage of F8 or F8A in the preparation is (i) in the range of 0.01 to 3 mg, (ii) in the range of 400 to 10,000 IU, (iii) in the range of 467 to 1167 IU, (iv) in the range of 700 to 1750 IU, and is selected from any one of the above, the device according to claim 17.

19. The device according to claim 1, wherein the coagulation factor comprises factor VII (F7) or a factor VII analog (F7A).

20. The dosage of F7 or F7A in the preparation is (i) in the range of 0.03 to 3 mg, (ii) in the range of 1.5 to 10 mg, (iii) in the range of 4.9 to 6.3 mg, and the coagulation disorder to be treated is acquired hemophilia, (iv) in the range of 1.5 to 2.1 mg, and the coagulation disorder to be treated is congenital factor VII deficiency, (v) in the range of 400 to 10,000 IU, (vi) in the range of 500 to 2,000 IU, and is selected from any one of the above, the device according to claim 19.

21. The device according to claim 1, wherein the coagulation factor comprises factor IX (F9) or a factor IX analog (F9A).

22. The dosage of F9 or F9A in the preparation is (i) in the range of 0.03 to 3 mg, (ii) in the range of 400 to 10,000 IU, (iii) in the range of 500 to 2,000 IU, in the range of 7 to 10.6 mg, wherein the coagulation disorder to be treated is hemophilia B, The device according to claim 21, selected from any of **Claim 23** The device according to claim 1, wherein the coagulation factor comprises factor X (F10) or factor X analog (F10A). **Claim 24** The dosage of F10 or F10A in the preparation is (i) in the range of 0.03 to 3 mg, (ii) in the range of 20 to 33 mg, wherein the coagulation disorder to be treated is factor X deficiency, (iii) in the range of 400 to 10,000 IU, (iv) in the range of 500 to 2,000 IU, The device according to claim 23, selected from any of **Claim 25** The device according to claim 1, wherein the tissue penetrating member has a column strength in the range of 1 to 20 pounds.

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