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

Abstract

Embodiments provide devices, preparations, and methods for delivering therapeutic agents (TAs) such as coagulation factors (CFs), e.g., factor VIII (FVIII), including PEGylated and other forms of stabilized FVIII, into the GI tract. Many embodiments provide swallowable devices, such as capsules, for delivering TAs to the intestinal wall (IW). Embodiments also provide TA preparations contained within a capsule and configured to advance from the capsule into the IW and / or surrounding tissue (ST), degrade, and release the TA into the bloodstream to produce a therapeutic effect (e.g., improved clotting). The preparations can be operably coupled to a delivery means having a first configuration in which the preparation is contained in the capsule and a second configuration in which the preparation exits the capsule and advances into the IW or ST (e.g., the peritoneal cavity). Embodiments are particularly useful for delivering CFs for the treatment of coagulation disorders (e.g., hemophilia), where such CFs are poorly absorbed and / or degraded in the GI tract.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority and the benefit of U.S. Provisional Patent Application No. 62 / 843,221, filed on May 3, 2019, and U.S. Provisional Patent Application No. 62 / 845,209, filed on May 8, 2019, both of which are hereby incorporated by reference in their entirety for all purposes.

Background Art

[0002] Embodiments of the present invention relate to orally deliverable drugs and other therapeutic formulations, and to swallowable drug delivery devices for delivering such formulations to the lumen walls of the GI tract, such as the walls of the small intestine or surrounding tissues. More specifically, embodiments of the present invention relate to orally deliverable drug formulations for the treatment of coagulation disorders. Even more specifically, embodiments of the present invention relate to orally deliverable solid drug formulations for the treatment of hemophilia and von Willebrand disease, which contain coagulation proteins as coagulation factors VII, VIII, IX, and X, and in particular contain a stabilized form of factor VIII.

[0003] Over the past decade, for example, there has been an increase in the development of new drugs for the treatment of various diseases, including various coagulation disorders. Unfortunately, many of them have limited use because they cannot be administered orally. This is due to several reasons, including a decrease in oral tolerance with complications such as gastric inflammation and bleeding, breakdown / degradation of drug compounds in the stomach, and insufficient, slow, or unstable drug absorption. Conventional alternative drug delivery methods, such as intravenous and intramuscular delivery, have several drawbacks, including pain, the risk of infection from needle punctures, the requirement for the use of sterilization techniques, and the requirements and associated risks for maintaining a patient's IV line for a long period. Other drug delivery approaches, such as implanted drug delivery pumps, have been adopted, but these approaches require semi-permanent implantation of the device and may still have many of the limitations of IV delivery. Therefore, there is a need for improved and / or alternative methods for the delivery of drugs and other therapeutic agents.

[0004] There are several hereditary hemorrhagic diseases in the human population that can be fatal if left untreated. These include hemophilia A and B, the most common of which are caused by a decrease in the levels of coagulation factors in a patient's peripheral blood. They also include factor X deficiency, also known as factor VII deficiency and 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, the most common form of hemophilia, is caused by a deficiency of factor VIII (FVIII). Hemophilia B is caused by a decrease in the synthesis of factor IX (F IX) or the synthesis of a defective factor IX with reduced activity. The current form of hemophilia treatment involves replenishing the missing or defective coagulation factor with a recombinant or plasma-derived coagulation factor such as FVIII or FIX. Usually, these factors are injected intravenously.

[0005] However, the current forms of hemophilia treatment have many problems and drawbacks. In particular, some patients develop antibodies against replacement clotting factors, which can reduce their effectiveness and cause serious complications as discussed below. Other problems include the need to come to a hospital / clinic for injections and the need to administer intravenous injections very slowly. Also, since clotting factors are mostly administered via peripheral intravenous injection, people or children with small veins may have difficulty finding a vein and it may easily collapse, making it difficult for them to receive an injection. This problem can be particularly problematic in the case of children who require more frequent injections. Also, the injection itself can cause bleeding.

[0006] Many patients produce antibodies (known as "inhibitors" or "inhibitor antibodies") that inhibit or otherwise interfere with the action of clotting factors in response to receiving various clotting factor administrations. The development of inhibitor antibodies against factor VIII is a serious complication in the management of patients with hemophilia A. Inhibitor antibodies develop in approximately 20% of patients with hemophilia A in response to therapeutic infusion of factor VIII. This is due to high doses of factor VIII or other clotting factors administered. In untreated patients with hemophilia A who develop inhibitors, the inhibitors usually develop within one year of treatment. Additionally, autoantibodies that inactivate factor VIII occasionally occur in people with previously normal factor VIII levels. If the titer of the inhibitor is low enough, there are potential complications, but the patient can be managed by increasing the dose of factor VIII. However, it is often the case that the titer of the inhibitor is so high that it cannot be overcome by increasing the dose of factor VIII. There are treatments available to eliminate or reduce the titer of these antibodies, but they are costly (e.g., about $1 million per patient per year), time-consuming, and require regular intravenous administration of clotting factors. Also, these treatments work in only about three-quarters of patients.

[0007] Other routes of administration of factor VIII replacement therapy have been investigated in the past, but they have not been very successful. Subcutaneous (SC) administration is limited by the amount of active agent that can be administered at one time and cannot reach therapeutic levels of these factors. It is also limited by the sensitivity of these factors to proteolytic degradation. Another concern is the increased immunogenicity of the SC route compared to IV, which can result in an increase or more rapid production of inhibitory antibodies compared to the IV injection route. Thus, what is needed are compositions and methods for delivering clotting factors such as factor VII, factor VIII, factor IX, and factor X without the need for injection and in a manner that does not cause the generation of inhibitor antibodies or other immunogenic responses to the clotting factors.

[0008] List of related cases. This specification incorporates by reference for all purposes the following patent applications and patents: U.S. Provisional Patent Application No. 62 / 582,857, filed November 7, 2017, entitled "Clotting Factor Preparations For Delivery Into Tissue Of The Intestinal Tract Using A Swallowable Drug Delivery Device"; U.S. Patent Application No. 16 / 183,573, filed November 7, 2018, entitled "Clotting Factor Preparations For Delivery Into Tissue Of The Intestinal Tract Using A Swallowable Drug Delivery Device"; U.S. Provisional Patent Application No. 62 / 786,831, filed December 31, 2018, entitled "Therapeutic Agent Preparations And Methods For Drug Delivery Into A Lumen Of The Intestinal Tract Using A Swallowable Drug Delivery Device"; U.S. Provisional Patent Application No. 62 / 818,053, filed March 13, 2019, entitled "Therapeutic Agent Preparations And Methods For Drug Delivery Into A Lumen Of The Intestinal Tract Using A Swallowable Drug Delivery Device"; U.S. Provisional Patent Application No. 62 / 820,U.S. Patent Application No. 15 / 260,260, filed on September 8, 2016, entitled "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 on June 30, 2011, entitled "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 on June 29, 2011, entitled "Device, System and Method for the Oral Delivery of Therapeutic Compounds"; U.S. Patent Application No. 12 / 978,233, filed on December 23, 2010, entitled "Swallowable Drug Delivery Device and Methods of Drug Delivery"; U.S. Patent Application No. 12 / 978,164, filed on December 23, 2010, entitled "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 on December 23, 2010, entitled "Swallowable Drug Delivery Device and Method of Delivery"; U.S. Patent Application No. 13 / 532, filed on June 25, 2012, entitled "Device, System And Methods For The Oral Delivery Of Therapeutic Compounds"U.S. Patent No. 8,809,269 entitled "Therapeutic Agent Preparations Comprising Insulin for Delivery into a Lumen of the Intestinal Tract using a Swallowable Drug Delivery Device", U.S. Provisional Patent Application No. 61 / 993,907 entitled "Pharmaceutical Compositions And Methods For Fabrication Of Solid Masses Comprising Polypeptides And / Or Proteins", filed on May 15, 2014, U.S. Provisional Patent Application No. 62 / 156,105 entitled "Pharmaceutical Compounds And Methods For Fabrication Of Solid Masses Comprising Polypeptides And / Or Proteins", filed on May 1, 2015, U.S. Provisional Patent Application No. 62 / 159,134 entitled "Anti-Interleukin Antibody Preparations For Delivery Into A Lumen Of The Intestinal Tract Using A Swallowable Drug Delivery Device", filed on May 8, 2015, and U.S. Provisional Application No. 62 / 215,586 entitled "PCSK9 Antibody Preparations For Delivery Into A Lumen Of The Intestinal Tract Using A Swallowable Drug Delivery Device", filed on September 8, 2015 are hereby incorporated by reference in their entirety.,

Summary of the Invention

[0009] In one aspect, the present invention provides a therapeutic preparation for the treatment of a patient's coagulation disorder, the preparation comprising factor VIII (FVIII) in a solid stabilized form at a dosage exceeding 75 IU / kg body weight of the patient. The preparation typically has tissue-penetrating features such as a tapered or pointed end and is configured for oral delivery to the patient's intestine and insertion in solid form through the patient's intestinal wall into the patient's peritoneal cavity. After entering the peritoneal cavity, the preparation degrades in the serous fluid of the peritoneal cavity to release the stabilized form of FVIII into the bloodstream, generating a therapeutically effective plasma concentration of FVIII. Unexpectedly, intraperitoneal (IP) delivery of a dosage of stabilized FVIII, typically PEGylated FVIII, at least at the 75 IU / kg body weight threshold level has been found to provide a therapeutic result that is at least equivalent, and in some cases superior, to that achieved by intravascular (IV) delivery of the generally used dosage of stabilized FVIII.

[0010] As used herein and in the claims, "factor VIII" refers to all biologically active forms of factor VIII, including in particular factor VIIIA. For convenience, all biologically active forms of factor VIII are referred to herein as "factor VIII" or FVIII.

[0011] In certain embodiments of the therapeutic preparation of the present invention, the stabilized factor VIII may comprise PEGylated factor VIII. In further embodiments, the PEGylated factor VIII may be present in the therapeutic preparation in the range of 75 IU / kg body weight to 400 IU / kg body weight, often in the range of 100 IU / kg body weight to 350 IU / kg body weight, and often in the range of 150 IU / kg body weight to 300 IU / kg body weight. Typically, but not necessarily, the preparation is shaped as a solid tissue-penetrating member, and the solid tissue-penetrating member is configured to penetrate the intestinal wall in a direction engaging a tissue-penetrating end or a feature of the solid preparation against the inner surface of the intestinal wall and into the peritoneal cavity upon application of a force to the tissue-penetrating member.

[0012] The therapeutic preparation of the present invention, when delivered intraperitoneally to a patient, has a T in the range of 8 to 10 hours max, C in the range of about 2.5 IU / ml to 3.5 IU / ml max , achieve one or more of some target endpoints, including one or more of the area under the curve (AUC) in the range of 60 (IU*h) / mL to 70 (IU*h) / mL, and the ratio of the ascending curve portion to the descending curve portion in the range of 1:4 to 1:8.

[0013] The stabilized form of FVIII present in the therapeutic preparation of the present invention usually includes PEGylated FVIII (as described in more detail below), but in other examples, the stabilized FVIII can be chemically complexed with von Willebrand factor and / or, optionally, by Fc fusion, instead of or in addition to the PEGylated form of FVIII, it can be modified, for example, by combining two or more forms of stabilized and / or non-stabilized FVIII to form a mixed composition.

[0014] In another aspect, the present invention provides a method for treating a coagulation disorder in a patient. The method usually includes providing a stabilized factor VIII (FVIII), usually PEGylated FVIII formed as a solid tissue penetrating member, although not necessarily so, which can be in any of the forms described above with respect to the preparations of the present invention. The solid tissue penetrating member is usually orally ingested in a protected form that prevents both early penetration into the esophagus, stomach, and pylorus and degradation of the stabilized FVIII, and then, by applying force to the tissue penetrating member such that the tissue penetrating member is delivered into the peritoneal cavity, it penetrates through the patient's intestinal wall into the patient's peritoneal cavity. After entering the peritoneal cavity, the preparation usually dissolves in the serous fluid and releases a therapeutically effective dose of stabilized FVIII exceeding 75 IU / kg body weight into the bloodstream to treat the coagulation disorder.

[0015] In a specific example, FVIII is released into the bloodstream and T 1 / 2 (elimination half-life), C max (maximum concentration of the drug in the blood), T max (C maxGenerate a plasma concentration-time curve characterized by at least one pharmacokinetic parameter selected from the group consisting of time to reach (), area under the curve (AUC - a measure of drug exposure), bioavailability, or the ratio of the ascending curve portion to the descending curve portion. T max is typically in the range of 8 to 10 hours, and C max can be in the range of about 2.5 IU / ml to 3.5 IU / ml, the area under the curve (AUC) can be in the range of 60 (IU*h) / mL to 70 (IU*h) / mL, and the ratio of the ascending curve portion to the descending curve portion can be in the range of 1:4 to 1:8.

[0016] Preferred stabilized Factor VIII forms and concentrations include PEGylated Factor VIII at a concentration in the range of 75 IU / kg body weight to 400 IU / kg body weight, and PEGylated Factor VIII at a concentration in the range of 150 IU / kg body weight to 300 IU / kg body weight.

[0017] Embodiments of the present invention provide devices, systems, kits, and methods for delivering drugs and other therapeutic agents to various locations within the body. Many embodiments provide a swallowable device for delivering drugs, such as coagulation proteins, and other therapeutic agents within surrounding tissues such as the gastrointestinal (GI) tract and peritoneal cavity. Certain embodiments of the present invention provide a swallowable device, such as a capsule, for delivering coagulation proteins and other therapeutic agents to the wall of the small intestine and / or surrounding tissues (e.g., peritoneal wall or peritoneal cavity) as well as the wall of the stomach. Such coagulation proteins (CP) can include various coagulation factors (also known as clotting factors) including one or more of factors VII, VIII, IX, X, and von Willebrand factor. Embodiments of the present invention are particularly useful for the oral delivery of coagulation proteins and other therapeutic agents that are poorly absorbable, poorly resistant, and / or degraded within the GI tract. Embodiments of the present invention are also particularly useful for the oral delivery of coagulation factors and other coagulation proteins for the treatment of hemophilia and other coagulation disorders that were previously only deliverable by intravascular injection. Further, embodiments of the present invention are particularly useful for delivering coagulation factors, such as factor VIII, with minimal or no production of inhibitor antibodies that destroy or reduce the potency of the coagulation factors. Still further, embodiments of the present invention are particularly useful for delivering coagulation factors and other coagulation proteins to the intestinal wall and peritoneal cavity to reduce loss of biological activity while passing through the abdominal wall(s) and / or lymphatic tissue and to be rapidly taken up into the bloodstream.

[0018] In one aspect, the present invention provides a therapeutic preparation for delivery to the wall of the small intestine and / or surrounding tissue (e.g., peritoneal cavity) or other locations in the intestinal tract for the treatment of coagulation disorders such as hemophilia A, the preparation comprising a therapeutically effective dose of at least one coagulation factor. The coagulation factor can include at least one of factor VII, factor VIII, factor IX, factor X, von Willebrand factor, etc., together with their respective analogs, derivatives, and fragments. The preparation is included in an embodiment of a swallowable capsule (or similar device) and is delivered from the capsule to the intestinal wall or surrounding tissue (e.g., peritoneal wall and / or peritoneal cavity) to release a dose of coagulation factor (CF) from within the intestinal wall or from surrounding tissue such as the peritoneal cavity, and can have a viscosity of shape and material. Such shapes can correspond to various tissue-penetrating structures, including those having pointed ends such as various dart-like, or needle-like shapes, or other similar structures. In an embodiment of the preparation delivered to the peritoneal cavity, the needle or other pointed end preferably has a straight or symmetric vertical point or dart shape so that it can penetrate through the intestinal wall into the peritoneal cavity without being deflected by the asymmetry of the needle shape. The preparation can be in solid, liquid, or powder form, or a combination thereof. Preferably, the preparation containing CF is in solid form such that the preparation can be stored for a long period of time and can withstand mechanical or other forces exerted on the preparation for shaping it (e.g., into a tissue-penetrating shape such as a needle shape) and inserting it into the intestinal wall and / or surrounding tissue such as the peritoneal cavity and / or peritoneal wall. According to various embodiments, the coagulation factor can be selected from a coagulation factor comprising one or more of factor VII, factor VIII, factor IX, factor X, and von Willebrand factor, and / or their functional variants (e.g., analogs and derivatives) known in the art, such variants retaining the characteristic properties of the coagulation factor.

[0019] In certain embodiments, the present invention relates to the circulation half-life (T 1 / 2To increase the amount of factor VIII (or other clotting factor) in its stabilized form (also described as such), there is provided a therapeutic preparation for the treatment of coagulation disorders, comprising a stabilized form of factor VIII (or other clotting factor). Stabilization can be achieved by one or both of the following approaches: i) chemically complexing factor VIII (or other clotting factor) with a stabilizer, or ii) including in the therapeutic preparation containing factor VIII an excipient containing a stabilizer also described herein as a stabilizing excipient. Examples of chemical complex formation methods and agents include those via PEGylation (wherein the FVIII molecule is complexed with a PEG molecule) or Fc fusion, both of which are described in more detail herein. Examples of stabilizing excipients include protease inhibitors such as heparin and FTP, von Willebrand factor, albumin, and calcium. In use, delivery of the stabilized form of factor VIII advantageously decreases one or both of the dosage and frequency of administration of the drug.

[0020] In another aspect, the present invention provides a method for treating hemophilia or other coagulation disorders, 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 present invention provides a method for oral delivery of one or more of: i) factor VII deficiency, congenital hemophilia with inhibitors, acquired hemophilia, or Glanzmann thrombasthenia, ii) a therapeutic amount of factor VIII for the treatment of hemophilia A, iii) a therapeutic amount of factor IX for the treatment of hemophilia B, iv) a therapeutic amount of factor X for the treatment of factor X deficiency, v) a therapeutic amount of von Willebrand factor for the treatment of von Willebrand disease. Also, in certain embodiments described in more detail below, the swallowable capsule can be configured to deliver the coagulation factor preparation to a section of the small intestine without Peyer's patches. Such targeted delivery to the desired section of the small intestine results in a suppressed immune response to the coagulation factor, including suppressed or minimally suppressed production of common antibodies such as IgG and specific inhibitor antibodies to the coagulation factor. In use, embodiments of this approach offer the advantages of improved long-term tolerance and efficacy to the delivered coagulation factor, and in turn provide better long-term control of the patient's coagulation disorder without the need for expensive treatments to eliminate inhibitor antibodies.

[0021] The present invention also provides a method for treating a coagulation disorder, comprising selecting a patient having hemophilia or another coagulation disorder and administering to the patient a therapeutically effective amount of a coagulation factor or other coagulation protein using one or more embodiments of the swallowable capsules described herein. The clotting time (e.g., prothrombin time or whole blood clotting time (WBCT)) can then be measured and monitored using methods known in the art to determine the effectiveness of the treatment. The information can then be used to adjust the dosage (e.g., increase or decrease) and / or the dosing regimen (e.g., the frequency of administration of the administered coagulation factor). In alternative or additional embodiments, the solid forms of the coagulation factors described herein can also be delivered by other swallowable devices.

[0022] In another aspect, the present invention provides a method for delivering a therapeutic agent to surrounding tissues such as the wall of the small intestine and / or the peritoneal wall and peritoneal cavity, including swallowing a drug delivery device comprising embodiments of a capsule, an actuator, and a therapeutic agent preparation such as a coagulation protein or coagulation factor preparation (e.g., a preparation comprising one or more coagulation factors). The actuator operates the delivery of the therapeutic agent preparation to surrounding tissues such as the wall of the small intestine and / or the peritoneal wall in response to conditions in the small intestine such as pH. In certain embodiments, the actuator can include a release element or coating on a capsule that is degraded by a selected pH of the small intestine. When degraded, the element or coating is operably coupled to the expansion of one or more balloons, for example, that contain the therapeutic agent preparation and are configured to penetrate and advance through the intestinal wall when the balloon expands, to initiate delivery of the therapeutic agent preparation by one or more delivery means. In certain embodiments, the balloon or other advancing means advances the tissue penetration member(s) through the intestinal wall into the peritoneal cavity where it is configured to be retained. When the tissue penetration members are positioned in surrounding tissues such as the intestinal wall or peritoneal cavity, they degrade to release the therapeutic agent into the bloodstream. In certain embodiments where the tissue penetration members are positioned and retained in the peritoneal cavity, the tissue penetration member(s) containing the therapeutic agent preparation are configured to be degraded by tissue fluid in the peritoneal cavity.

[0023] In related embodiments, the present invention provides related methods for delivering a coagulation factor preparation or other therapeutic preparation to the intestinal wall or surrounding tissue that can achieve one or more pharmacokinetic parameters of delivery. Such parameters can include, for example, absolute bioavailability (also referred to as F and expressed as a percentage), T max T 1 / 2 C max and one or more of the area under the curve (or AUC). Absolute "bioavailability" is the amount of drug from a formulation that reaches the systemic circulation relative to an intravenous (IV) dose, where the IV dose is assumed to be 100% biologically available. T maxis the period in which the therapeutic agent (e.g., a coagulation factor) reaches its maximum concentration C in the bloodstream max and T 1 / 2 is the period required for the concentration of the therapeutic agent in the bloodstream (or elsewhere in the body) to reach half of the original C max after reaching C max Since the therapeutic preparation is delivered directly to the wall of the small intestine, or to surrounding tissues such as the peritoneal wall or peritoneal cavity, T max is faster (e.g., shorter) than the corresponding T max when the therapeutic agent is non-vascularly injected into the body, such as intramuscularly or subcutaneously. In various embodiments, one or more embodiments of the present invention (such as embodiments of a swallowable device) are used to achieve a T max by inserting a therapeutic preparation containing a coagulation factor or other therapeutic agent into the intestinal wall max that can be 80%, 50%, 30%, 20% or even 10% of the T max achieved by the use of non-vascular injection of the therapeutic agent. As used herein, the term "about" generally refers to within 5% of the recited value of a numerical value, although in some cases it can be larger or smaller. In certain embodiments where the therapeutic agent comprises a coagulation factor such as factor VIII, T max can range from about 5 to 13 hours. For example, in the case of ESPEROCT, T max can range from about 5.4 to 9 hours, and in certain embodiments is about 7.2 hours. In the case of other PEGylated FVIII, T max can range from about 7.8 to 13 hours, and in certain embodiments is about 10.4 hours. In the case of an antibody, e.g., IgG, T max can be about 24 hours, and T 1 / 2 can range from about 40.7 to 128 hours, and a specific value is about 87.7 hours.

[0024] Depending on the drug, T 1 / 2 can range from 5 to 50 hours. In certain embodiments comprising PEGylated factor VIII, or other forms of factor VIII that are stabilized (e.g., by being chemically complexed (e.g., bound or linked) with a stabilizer such as PEG), T 1 / 2can range from about 15.7 to 27.1 hours. In the case of ESPEROCT, T 1 / 2 can range from 16.3 to 27.1, with a particular embodiment being 21.7, and in the case of other PEGylated FVIII, can range from 11.25 to 18.75 hours, with a particular embodiment being 15 hours. Further ranges and particular values are contemplated. In embodiments where Factor VIII is complexed with von Willebrand factor, a further larger value of T 1 / 2 is contemplated.

[0025] In certain embodiments where the therapeutic preparation comprises a coagulation factor such as various forms of Factor VIII including PEGylated or other stabilized forms of Factor VIII, the absolute bioavailability of the therapeutic agent can range from about 11 to 60%. In the case of PEGylated FVIII, the bioavailability can range from about 11 to 60%. Further values are also contemplated. In embodiments using a stabilizing excipient such as calcium, von Willebrand factor, heparin, diisopropylfluorophosphate (DFP), or other protease inhibitors, a higher level of bioavailability is contemplated since Factor VIII is stabilized while passing through the peritoneal wall and entering the vascular system.

[0026] Also, in related embodiments, the therapeutic preparation, and related methods for their delivery to the wall or surrounding tissue of the small intestine, can be configured to generate a plasma / blood concentration versus time profile (also referred to as a plasma concentration-time profile or plasma concentration-time curve) of the therapeutic agent having a selected shape with C max or T max as a reference point. For example, the plasma concentration versus time profile can have an ascending portion and a descending portion, and the time taken for the concentration of the therapeutic agent to transition from the pre-delivery concentration to the C max level during the ascending portion (known as the rise time), and the C maxIt has a selected ratio to the time it takes to return from the level to the pre-delivery concentration (known as the decay time). In various embodiments, the ratio of the rise portion to the decay portion can be in the range of about 1 to 20, 1 to 10, and 1 to 5. In certain embodiments of therapeutic preparations containing a stabilized form of Factor VIII (e.g., by PEGylation), the ratio of the rise time to the decay time in the profile can be about 1 to 5 (e.g., in the case of ADYNOVATE) and about 1 to 11 (e.g., in the case of ESPEROCT). In certain embodiments of therapeutic preparations containing an antibody such as IgG, the ratio of the rise time to the decay time in the profile can be about 1 to 9.

[0027] In another aspect, the present invention provides a swallowable device for delivering a drug or other therapeutic preparation to the wall of the small intestine or large intestine 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 to align 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 within the GI tract, but may also include an outer coating or layer, which decomposes only at a higher pH found in the small intestine and serves to protect the underlying capsule wall from decomposing in the stomach before the capsule reaches the small intestine and drug delivery is initiated by decomposition of the coating at that point. In use, such materials enable targeted delivery of therapeutic agents to selected portions of the intestinal tract, such as the small intestine. Suitable outer coatings can include various enteric coatings such as various copolymers of acrylic acid (including specific examples such as EUDRAGIT available from EVONIK industries), methacrylic acid, and ethyl acrylate. In certain embodiments, the outer coating can be configured to decompose at a pH found in the upper (e.g., duodenum) or middle portion (jejunum) of the small intestine, such that the therapeutic preparation is delivered to those respective portions, avoiding the lower portion of the small intestine (ileum) that includes Peyer's patches, which are aggregated lymphoid nodules that produce macrophages and other immune-related cells. By delivering the therapeutic agent to a location in the small intestine without Peyer's patches, subsequent immune responses, including the production of various antibodies to specific therapeutic agents such as inhibitor antibodies to factor VIII, are suppressed or otherwise minimized.Accordingly, in use, such controlled placement or delivery of a therapeutic agent to the upper, middle, or other 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), and as a result, increase the effectiveness and tolerance to a given dosage of the therapeutic agent delivered orally as compared to that delivered via intravenous or subcutaneous injection.

[0028] Another embodiment of the capsule includes at least one guide tube, one or more tissue penetrating members positioned within the at least one guide tube, a delivery member, and an actuation mechanism. The tissue penetrating members typically include a hollow needle or other similar structure and have a lumen and a tissue penetrating end for penetrating the intestinal wall to a selectable depth. In various embodiments, the device can include second and third tissue penetrating members with the contemplated additional numbers. Each tissue penetrating member can contain the same or different drugs. In a preferred embodiment having multiple tissue penetrating members, the tissue penetrating members can be symmetrically distributed around the capsule so as to fix the capsule to the intestinal wall during drug delivery. In some embodiments, all or a portion of the tissue penetrating member (e.g., the tissue penetrating end) can be manufactured from the drug preparation itself. In these and related embodiments, the drug preparation can have a needle, dart, or other elongated structure (with or without barbs) configured to penetrate and remain held within the intestinal wall.

[0029] The tissue-penetrating member can be manufactured from various biodegradable materials so as to degrade within the small intestine (or other GI lumen), and thus, a fail-safe mechanism can be provided to remove the tissue-penetrating member from the intestinal wall in the event that this component becomes retained in the intestinal wall. Such biodegradable materials can correspond to one or more of poly(glycolide-co-lactide) (PGLA), polylactic-co-glycolic acid (PLGA), maltose or other sugars, polyethylene, polyethylene oxide, or other biodegradable polymers known in the art. Further, in these and related embodiments, the selectable portion of the capsule can be manufactured from such biodegradable materials to enable the entire device to controllably degrade into small fragments. Such embodiments facilitate the passage and excretion of the device through the GI tract. In certain embodiments, the capsule can include a biodegradable seam that controllably degrades to produce fragments of selectable size and shape to facilitate passage through the GI tract. The seam can be prestressed, perforated, or otherwise treated to accelerate degradation. The concept of using a biodegradable seam to cause controlled degradation of a swallowable device within the GI tract can also be applied to other swallowable devices such as a swallowable camera, facilitating passage through the GI tract and reducing the likelihood that the device becomes lodged in the GI tract.

[0030] 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 capable of advancing within the lumen of the tissue penetrating member. The delivery member can have a piston or similar structure sized to fit within the delivery member lumen. The distal end of the delivery member (the end that advances into the tissue) can have a plunger element that advances the drug within the lumen of the tissue penetrating member and forms a seal with the lumen. The plunger element can be integral or attachable to the delivery member. Preferably, the delivery member is configured to move a fixed or measured dose of the drug a fixed distance within the lumen of the needle to deliver it 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 can taper distally), the diameter of the tissue penetrating member (which can be narrowed at its distal end), the use of a stop, and / or the actuation mechanism. For embodiments of devices having a tissue penetrating member (e.g., a drug dart) made from the drug, the delivery member is adapted to advance the dart from the capsule into the tissue.

[0031] The delivery member and the tissue penetrating member can be configured for delivery of a drug in liquid, semi-liquid, or solid form, or all three. Solid forms of the drug can include both powders and pellets. Semi-liquids 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 a sealed 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 in a separate reservoir within the capsule body.

[0032] 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 not only advance the tissue penetrating member a selectable distance into the intestinal wall, but also to advance the delivery member to deliver the drug and then withdraw the tissue penetrating member from the intestinal wall. In various embodiments, the actuation mechanism can include a pre - incorporated spring mechanism that is configured to be released by a release element. Suitable springs can include both coil springs (including conical springs) and leaf springs, and other spring structures are also contemplated. In certain embodiments, the spring is shaped in a conical shape and the length of the spring can be reduced to a point where the compressed length of the spring is approximately the thickness of several coils (e.g., two or three) or even only one coil.

[0033] In certain embodiments, the actuating mechanism includes a spring, a first motion converter, a second motion converter, and a track member. The release element is coupled to the spring and holds the spring in a compressed state such that disassembly of the release element releases the spring. The first motion converter is configured to convert the motion of the spring to insert and withdraw the tissue penetrating element into and from the tissue. The second motion converter is configured to convert the motion of the spring to advance the delivery member into the lumen of the tissue penetrating member. The motion converters are pushed by the spring and travel along a rod or other track member that helps guide the path of the converters. They engage (either directly or indirectly) with the tissue penetrating member and / or the delivery member to produce the desired motion. Desirably, they are configured to convert motion along the longitudinal axis of the spring into orthogonal motion of the tissue penetrating member and / or the delivery member, although conversions in other directions are contemplated. The motion converters can have a wedge shape, a trapezoidal shape, or a curved shape, and other shapes are contemplated. 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 travels within the slot. The slot can have a trapezoidal shape that reflects or otherwise corresponds to the overall shape of the converter and serves to push the tissue penetrating member between the upward sloping portions of the trapezoid and then pull it back between the downward sloping portions. In one variant, one or both of the motion converters can include a cam or cam-like device that rotates by the spring and engages the tissue penetrating member and / or the delivery member.

[0034] In other variants, the actuating mechanism can also include an electromechanical device / machine such as a solenoid or a piezoelectric device. In one embodiment, the piezoelectric device can include a shaped piezoelectric element having a non-deployed state and a deployed state. The element can be configured to move to the deployed state upon application of a voltage and return to the non-deployed state upon removal of the voltage. This embodiment and related embodiments enable reciprocating motion of the actuating mechanism to both advance and then withdraw the tissue penetrating member.

[0035] The release element is coupled to at least one of the actuating mechanism or a spring coupled to the actuating mechanism. In certain embodiments, the release element is coupled to a spring positioned within the capsule so as to hold the spring in a compressed state. The decomposition of the release element releases the spring and actuates the actuating mechanism. In many embodiments, the release element comprises a material configured to decompose when exposed to chemical conditions in the small intestine or large intestine, such as pH. Typically, the release element is configured to decompose 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 greater. However, it can also be configured to decompose in response to other conditions in the small intestine, such as osmotic pressure, liquid content of the small intestinal 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 decompose in response to specific chemical conditions in the fluid within the small intestine, such as those that occur after ingestion of a meal (e.g., a meal rich in fat or protein).

[0036] Biodegradation of the release element from one or more conditions in the small intestine (or other locations in the GI tract), such as pH, osmolality, presence of bile salts, etc., can be achieved by 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. A lower amount of cross-linking or a thinner dimension can result in a faster rate of decomposition, and vice versa. Suitable materials for the release element can include biodegradable materials such as various intestinal materials configured to decompose when exposed to higher pH or other conditions in the small intestine. The intestinal materials can be copolymerized or otherwise mixed with one or more polymers to obtain some specific material properties in addition to biodegradation. Such properties include, but are not limited to, rigidity, strength, flexibility, and hardness.

[0037] In certain embodiments, the release element can include a film or a plug that either conforms to or otherwise occludes the guide tube and holds the tissue penetrating member within the guide tube. In these and related embodiments, the tissue penetrating member is coupled to a spring-actuated mechanism such that when the release element is sufficiently disassembled, the tissue penetrating member is released and 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 a predetermined position. In these and related embodiments, the release element can be located externally or internally to the capsule. In the internal embodiment, the capsule and the guide tube are configured to allow penetration of intestinal fluid into the capsule and enable disassembly of the release element.

[0038] In some embodiments, the actuation mechanism can be actuated by a sensor such as a pH or other chemical sensor that detects the presence of the capsule in the small intestine and sends a signal to the actuation mechanism (or an electronic control device coupled to the actuation mechanism for actuating the mechanism). Embodiments of pH sensors can include electrode-based sensors or mechanical-based sensors such as polymers that contract or expand when exposed to pH or other chemical conditions in the small intestine. In related embodiments, the expandable / contractable sensor can also include the actuation mechanism itself by using mechanical movement from the expansion or contraction of the sensor.

[0039] According to another embodiment for detecting that the device is 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 is receiving within a particular location in the intestinal tract. In these embodiments, the capsule is preferably sized to be gripped by the small intestine during peristaltic contractions. Different locations within the GI tract have different numbers of peristaltic contractions. The small intestine has 12 to 9 contractions per minute, and the frequency decreases with the length of the intestine. Thus, according to one or more embodiments, detection of the number of peristaltic contractions can be used to determine not only whether the capsule is in the small intestine, but also the relative location within the intestine.

[0040] As an alternative or supplement to internally actuated drug delivery, in some embodiments, a user may externally actuate an actuating mechanism to deliver a drug by RF (radio frequency), magnetic, or other wireless signal means known in the art. In these and related embodiments, the user may use a handheld device (e.g., a handheld RF device) that includes not only the signal means but also means for notifying the user when the device is in the small intestine or other locations in the GI tract. The latter embodiments may be implemented by including an RF transmitter in the swallowable device to send a signal to the user when the device is in the small intestine or other locations (e.g., by sending an input from a sensor as a signal). The same handheld device may also be configured to alert the user when the actuating mechanism is actuated and the selected drug(s) are delivered. In this way, the user is provided with confirmation that the drug has been delivered. In another approach, an external acoustic sensor may be used to detect a sound unique to the actuating mechanism being actuated, e.g., one or more unique frequency sounds that may occur in embodiments using a chamber that includes a piston and cylinder mechanism operably coupled to a tissue penetrating member, to detect when the actuating mechanism has been actuated. One or more of the foregoing approaches enable the user to not only take other appropriate drugs / therapeutics but also make other related decisions (e.g., for a diabetic, whether to eat a meal, which foods to eat). The handheld device may also be configured to send a signal to the swallowable device to disable the actuating mechanism and thus prevent, delay, or accelerate drug delivery. In use, such embodiments enable the user to intervene to prevent, delay, or accelerate drug delivery based on other symptoms and / or the patient's actions (e.g., deciding to eat a meal, go to bed, take other medications, exercise, etc.).

[0041] After swallowing the capsule, the user can also externally activate the activation mechanism for a selected period of time. The period can be correlated with the normal transit time or a range of transit times of food moving through the user's GI tract to a specific location within the tract, such as the small intestine. External activation can be performed by any number of means, including wireless control means (e.g., using an RF communication device), magnetic means (e.g., by using a small magnetic switch or initiator incorporated into a swallowable device that the user activates with an external magnet), or acoustic means (e.g., via an ultrasonic transmitter and an acoustic receiver and / or switch incorporated into the swallowable device).

[0042] Another aspect of the present invention provides pharmaceutical preparations such as various coagulation factors for delivery to the wall of the small intestine (including surrounding tissues such as the peritoneal wall or peritoneal cavity) or other walls of the intestinal tract using the embodiments of the swallowable devices described herein. The preparation contains at least one therapeutic agent such as a therapeutically effective dose of a coagulation factor or other coagulation protein. It can also include solids, liquids, or combinations of both and can contain one or more pharmaceutical excipients. The preparation is included in an embodiment of a swallowable capsule and is delivered from the capsule to the intestinal wall, peritoneum, peritoneal cavity wall, or other surrounding tissues, decomposes within the intestinal wall or surrounding tissues such as the peritoneum or peritoneal cavity, and has a shape and material consistency for releasing a dose of the therapeutic agent. In certain embodiments, the preparation is configured to decompose in 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 the parietal peritoneum. The preparation can also have a selectable surface area to volume ratio to increase 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 in other body lumens. In various embodiments, the preparation can be configured to be coupled to an actuator such as a release element or activation mechanism having a first configuration in which the preparation is contained in the capsule and a second configuration in which the preparation exits the capsule and advances to the wall of the small intestine and / or peritoneum. The dose of the drug or other therapeutic agent in the preparation can be tapered from the dose required by conventional oral delivery methods, thereby reducing potential side effects from the drug.

[0043] Typically, but not necessarily, the preparation is shaped and otherwise configured to be contained within the lumen of a tissue penetrating member, such as a hollow needle, configured to exit the capsule and advance into the wall of the small intestine and / or the peritoneum (e.g., the visceral peritoneum, for example). Also, the preparation itself may include a tissue penetrating member configured to advance into the wall of the small intestine and / or the peritoneum, or other lumen of the intestinal tract. Such configurations of the tissue penetrating member can include various shapes having a pointed tip, including, for example, needles, darts, and other similar shapes. In certain embodiments, the tissue penetrating member includes various elongated shapes having a pointed end. It can also include various isosceles shapes having a pointed end, such as a triangle, a square having a pointed end, a conical shape having a pointed end, or a hemispherical shape having a pointed end.

[0044] Another aspect of the invention provides a method for delivery of 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 for delivery of therapeutically effective amounts of various drugs and other therapeutic agents. These include coagulation factors, antibodies, growth hormones, parathyroid hormones, insulin, interferons, and other similar compounds, or several polymeric peptides and proteins that 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 invention include various coagulation factors (e.g., factor VIII), antibodies (antibodies of the TNF inhibiting class), chemotherapeutic agents (e.g., interferons), 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), antiepileptic agents, immunosuppressive agents, and antiparasitic agents such as various antimalarial agents. The dosage of a particular drug can be titrated according to the patient's weight, age, condition, or other parameters.

[0045] In various method embodiments of the present invention, embodiments of a drug swallowable drug delivery device can be used to deliver a plurality of drugs (e.g., a mixture of protease inhibitors for the treatment of HIV / AIDS) for the treatment of multiple conditions or a particular condition. In use, such embodiments enable a patient to forgo the need to take multiple medications for a particular condition or multiple conditions. Also, such embodiments provide means for ensuring that regimens of two or more drugs are delivered and absorbed into the small intestine and thereby the bloodstream at approximately the same time. Due to differences such as chemical composition, molecular weight, drugs can be absorbed from the intestine through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves. Embodiments of the present invention address this problem by injecting a desired drug mixture into the intestinal wall at approximately the same time. This then improves (e.g., by substantially synchronizing within 5% in time) the pharmacokinetic parameters of the selected mixture of drugs (e.g., achieving the same T for different drugs), thereby improving the effectiveness of the selected mixture of drugs. 1 / 2 by achieving), thereby

[0046] In another aspect, various embodiments of the present invention provide a pharmaceutical composition comprising a solid-shaped mass containing a drug such as a coagulation factor or an antibody having biological activity within the body of a mammal, and at least a part of the biological activity of the coagulation factor (or other coagulation protein) is maintained after the formation of the mass formed 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 promoting the activation of one or more coagulation factors (e.g., promoting 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 to an antigen. The biological activity may correlate with the structural integrity of the coagulation factor (e.g., having no cleavage of any functional groups) or after the formation of other coagulation proteins or other drugs (e.g., by correlating a bioactivity assay with a chemical assay), such that at the composition level, a selected percentage (e.g., on a weight basis) of the coagulation factor or other coagulation protein is maintained after formation as compared to that of the precursor material. Usually, the shape is formed by a compression process (e.g., compression molding), but other processes such as non-compression molding or 3D printing are also contemplated. The drug may correspond to a peptide, a coagulation factor or other coagulation protein, an immunoglobulin or other protein, and the biological activity of the drug in the formed mass is at least 70% of the biological activity before compression, more preferably at least 90% of the biological activity before compression, and even more preferably at least 95%. These values may also correspond to the weight percentage of the drug remaining in the formed mass as compared to that in the precursor material (e.g., by correlating a bioactivity assay with a chemical assay of the weight composition as described above). In these embodiments and related embodiments, the formed mass has a density in the range of about 1.00 and 1.15 mg / mm 3 and, in a more preferred embodiment, 1.02 and 1.06 mg / mm 3 . The shape usually includes a pellet shape, but may also have a tablet shape, a conical shape, a cylindrical shape, a cube, a sphere, or other similar shapes. Then, usually, the pellet or other form of the formed mass is inserted into the embodiments of the tissue-penetrating member described herein.

[0047] Embodiments of the present invention also provide a method for forming a shaped solid mass comprising an immunoglobulin, a coagulation factor, or other coagulation protein, the shaped mass being formed by shaping a precursor material, and at least a portion of the biological activity (e.g., antigen-binding affinity, specificity, etc.) of the peptide, coagulation factor, or other coagulation protein in the shaped mass being retained after formation. In many embodiments, shaping is performed by compression of the precursor material, and the compression force is selected to minimize degradation of the biological activity of the protein or polypeptide. Other shaping methods are contemplated, such as non-compression molding and 3D printing. 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 at least one of a lubricant, a binder, a bulking agent, and the like. The shaped mass can be in the form of a tablet, microtablet, pill, or slug. According to one or more embodiments, the shaped mass produced using an embodiment of the forming process can have another property, such as density or particle particle size, that correlates to a minimum level of biological activity of the protein or peptide (of the powder used to formulate the shaped mass). Also, the correlating property can be consistently maintained not only between lots but also within a selected range within a given lot of the shaped mass. 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.) is orally ingested and delivered to the small intestine, the coagulation factor is delivered to the wall of the small intestine, and subsequently enters the peritoneum and peritoneal cavity, and the tablet(s) dissolve(s) to release the coagulation factor. In another embodiment, the microtablet can be injected or otherwise placed subcutaneously (e.g., intramuscularly), and the microtablet can dissolve to release the coagulation factor or other coagulation protein into the bloodstream.

[0048] The following numbered items describe other examples, aspects, and embodiments of the invention described herein.

[0049] 1. A therapeutic preparation for the treatment of a patient's coagulation disorder, the preparation comprising, in solid form, a stabilized form of Factor VIII (FVIII) or Factor VIII analog (FVIIIA) at a dose of 100 IU / kg body weight, the preparation being formed as a solid tissue penetrating member, the solid tissue penetrating member being configured to penetrate the patient's intestinal wall upon application of a force to the tissue penetrating member and be inserted into the patient's peritoneal cavity after oral ingestion, the tissue penetrating member being retained within the peritoneal cavity after insertion and degraded in the serous fluid of the peritoneal cavity to release the stabilized form of FVIII or FVIIIA into the bloodstream, T 1 / 2 T max A therapeutic preparation that generates a plasma concentration-time curve characterized by at least one pharmacokinetic parameter selected from the group consisting of T, area under the curve (AUC), bioavailability, or the ratio of the ascending curve portion to the descending curve portion.

[0050] 2. T 1 / 2 is in the range of about 14 to 18.75 hours, the preparation according to item 0.

[0051] 3. T 1 / 2 is in the range of about 14 to 16 hours, the preparation according to item 2.

[0052] 4. T 1 / 2 is about 15 hours, the preparation according to item 3.

[0053] 5. T 1 / 2 is in the range of about 16.25 to 27.13 hours, the preparation according to item 1.

[0054] 6. T 1 / 2 is in the range of about 21 to 22 hours, the preparation according to item 5.

[0055] 7. T 1 / 2 is about 21.7 hours, the preparation according to item 6.

[0056] 8.T max is the preparation according to item 1, which is in the range of about 10 to 11 hours.

[0057] 9.T max is the preparation according to item 8, which is about 10.4 hours.

[0058] 10. The AUC of the preparation according to item 1 is in the range of about 11 to 39 (IU*h) / mL.

[0059] 11. The AUC of the preparation according to item 10 is about 20 (IU*h) / mL.

[0060] 12. The AUC of the preparation according to item 1 is in the range of about 17 to 60 (IU*h) / mL.

[0061] 13. The AUC of the preparation according to item 12 is about 20 (IU*h) / mL.

[0062] 14. The ratio of the ascending part to the descending part of the curve of the preparation according to item 1 is about 1:5.

[0063] 15. The ratio of the ascending part to the descending part of the curve of the preparation according to item 1 is about 1:11.

[0064] 16. The stabilized form of FVIII or FVIIIA in the preparation according to item 1 is chemically modified.

[0065] 17. The stabilized form of FVIII or FVIIIA in the preparation according to item 16 is modified by PEGylation.

[0066] 18. The stabilized form of FVIII or FVIIIA in the preparation according to item 16 is chemically complexed with von Willebrand factor.

[0067] 19. The preparation according to item 16, wherein the stabilized form of FVIII or FVIIIA is modified by Fc fusion.

[0068] 20. The preparation according to item 1, further comprising a stabilizing excipient.

[0069] 21. The preparation according to item 20, wherein the stabilizing excipient comprises at least one of calcium, von Willebrand factor (VWF), heparin, albumin, and DFP.

[0070] 22. The preparation according to item 20, wherein the stabilizing excipient comprises von Willebrand factor present in a 1:1 molar ratio with the dose of factor VIII.

[0071] 23. The preparation according to item 1, further comprising an anticoagulant.

[0072] 24. The preparation according to item 23, wherein the production of inhibitor antibodies against the released FVIII or FVIIIA is minimized due to the reduced aggregation of the FVIII or FVIIIA molecules.

[0073] 25. At least one of bioavailability, AUC, or C max is increased in the preparation according to item 23 due to the reduced aggregation of the FVIII or FVIIIA molecules.

[0074] 26. The preparation according to item 25, wherein at least one of the pharmacokinetic parameters is increased by at least about 10%.

[0075] 27. The preparation according to item 23, wherein the anticoagulant comprises at least one of arginine, glutamic acid, leucine, trehalose, or Pluronic® F68.

[0076] 28. The preparation according to item 27, wherein the anticoagulant comprises trehalose, and the weight ratio of the anticoagulant to FVIII or FVIIIA is in the range of about 1:25 to 25:1.

[0077] 29. The preparation according to item 23, wherein the anti-aggregation agent contains arginine, glutamic acid, and leucine, and the weight ratio of the anti-aggregation agent to FVIII or FVIIIA is in the range of about 1:15 to 15:1.

[0078] 30. The preparation according to item 23, wherein the anti-aggregation agent contains Pluronic F68, and the weight ratio of the anti-aggregation agent to FVIII or FVIIIA is in the range of about 1:5.

[0079] 31. The preparation according to item 1, wherein the preparation contains a drug configured to enhance the permeability of the peritoneal wall to FVIII or FVIIIA.

[0080] 32. The preparation according to item 32, wherein the permeability enhancer is hyaluronidase.

[0081] 33. The preparation according to item 32, wherein the weight ratio of hyaluronidase to FVIII or FVIIIA is in the range of about 1:50 to 50:1.

[0082] 34. The preparation according to item 32, wherein the permeability enhancer enhances the uptake of FVIII or FVIIIA into the patient's lymphoid tissue.

[0083] 35. At least one of bioavailability, AUC, or C max increases due to the increased permeability of the peritoneal wall in the preparation according to item 32.

[0084] 36. The preparation according to item 35, wherein at least one of the pharmacokinetic parameters increases in the range of about 8 - 12%.

[0085] 37. The preparation according to item 36, wherein at least one of the pharmacokinetic parameters increases by at least about 10%.

[0086] 38. The preparation according to item 1, wherein FVIII or FVIIIA is recombinant modified FVIII or FVIIIA.

[0087] 39. The recombinant modified FVIII or FVIIIA is the preparation according to item 38, which is modified from the wild-type version of FVIII.

[0088] 40. The recombinant modified FVIII or FVIIIA is the preparation according to item 38, which contains a deletion in the B domain of the FVIII or FVIIIA molecule.

[0089] 41. The stabilized form of FVIII or FVIIIA is the preparation according to item 1, which is modified via an Fc fusion.

[0090] 42. The tissue penetration member is structured as a shaft with a pointed end, which is the preparation according to item 1.

[0091] 43. The tissue penetration member has a dart-shaped or needle-shaped structure, which is the preparation according to item 42.

[0092] 44. The force is a mechanical force, which is the preparation according to item 1.

[0093] 45. A therapeutic preparation for the treatment of a patient's coagulation disorder, the preparation contains a coagulation factor in solid form, the preparation is shaped as a tissue penetration member, at least a part of the surface of the tissue penetration member contains a coagulation-promoting coating, the tissue penetration member is configured to penetrate the patient's intestinal wall by applying a force to the tissue penetration member and be inserted into the patient's peritoneal cavity after oral ingestion, the coagulation-promoting coating dissolves to reduce or prevent bleeding at the site of tissue penetration, the tissue penetration member is retained in the peritoneal cavity and decomposed in the serous fluid of the peritoneal cavity to release the coagulation factor into the bloodstream to treat the coagulation disorder.

[0094] 46. The coagulation-promoting coating contains a coagulation factor, which is the preparation according to item 45.

[0095] 47. The tissue penetration member is structured as a shaft with a pointed end, which is the preparation according to item 45.

[0096] 48. The coagulation factor is the preparation according to item 45, comprising factor VIII or a factor VIII analog.

[0097] 49. A method for treating a patient's coagulation disorder, the method comprising, in solid form, a stabilized form of factor VIII (FVIII) or factor VIII analog (FVIIIA) at a dose of 100 IU / kg body weight, wherein the solid dose of FVIII or FVIIIA provides a shaped article as a tissue penetrating member, and by applying a force to the tissue penetrating member such that the tissue penetrating member is delivered into the peritoneal cavity, after oral ingestion, causing the solid dose of FVIII or FVIIIA to penetrate through the intestinal wall into the peritoneal cavity, and releasing a therapeutically effective amount of FVIII or FVIIIA from the solid dose in the peritoneal cavity into the bloodstream to treat the coagulation disorder, wherein the release of FVIII or FVIIIA into the bloodstream is characterized by a plasma concentration-time curve selected from the group consisting of T 1 / 2 T max C max and generating a plasma concentration-time curve characterized by at least one pharmacokinetic parameter selected from the group consisting of area under the curve (AUC), bioavailability, or the ratio of the ascending curve portion to the descending curve portion.

[0098] 50. T 1 / 2 is in the range of about 14 to 18.75 hours, the method according to item 49.

[0099] 51. T 1 / 2 is in the range of about 14 to 16 hours, the method according to item 50.

[0100] 52. T 1 / 2 is about 15 hours, the method according to item 51.

[0101] 53. T 1 / 2 is in the range of about 16.25 to 27.125 hours, the method according to item 49.

[0102] 54. T 1 / 2 is in the range of about 21 to 22 hours, the method according to item 53.

[0103] 55.T 1 / 2 is the method according to item 54, which is about 21.7 hours.

[0104] 56T max is the method according to item 49, which is in the range of about 10 to 11 hours.

[0105] 57.T max is the method according to item 56, which is about 10.4 hours.

[0106] 58. The AUC is the method according to item 49, which is in the range of about 11 to 39 (IU*h) / mL.

[0107] 59. The AUC is the method according to item 58, which is about 20 (IU*h) / mL.

[0108] 60. The AUC is the method according to item 49, which is in the range of about 17 to 60 (IU*h) / mL.

[0109] 61. The AUC is the method according to item 60, which is about 20 (IU*h) / mL.

[0110] 62. The ratio of the ascending part to the descending part of the curve is the method according to item 49, which is about 1:5.

[0111] 63. The ratio of the ascending part to the descending part of the curve is the method according to item 49, which is about 1:11.

[0112] 64. The stabilized form of FVIII or FVIIIA is chemically modified by the method according to item 49.

[0113] 65. The stabilized form of FVIII or FVIIIA is modified by PEGylation by the method according to item 64.

[0114] 66. The stabilized form of FVIII or FVIIIA is chemically complexed with von Willebrand factor by the method according to item 49.

[0115] 67. The method according to item 49, wherein the stabilized form of FVIII or FVIIIA is modified by Fc fusion.

[0116] 68. The method according to item 49, wherein the AUC is about 20 (IU*h) / mL.

[0117] 69. The method according to item 49, wherein the ratio of the ascending part to the descending part of the curve is about 1:5.

[0118] 70. The method according to item 49, wherein the ratio of the ascending part to the descending part of the curve is about 1:11.

[0119] 71. The method according to item 49, wherein the stabilized form of FVIII or FVIIIA is chemically modified.

[0120] 72. The method according to item 71, wherein the stabilized form of FVIII or FVIIIA is modified by PEGylation.

[0121] 73. The method according to item 71, wherein the stabilized form of FVIII or FVIIIA is chemically complexed with von Willebrand factor.

[0122] 74. The method according to item 71, wherein the stabilized form of FVIII or FVIIIA is modified by Fc fusion.

[0123] 75. The method according to item 49, wherein a therapeutically effective amount of FVIII or FVIIIA is released into the bloodstream by the degradation of the solid dosage of FVIII or FVIIIA in the serous fluid of the peritoneal cavity.

[0124] 76. The method according to item 49, wherein the tissue penetration member comprises degradation characteristics configured to enhance the rate of degradation of the tissue penetration member in the serous fluid of the peritoneal cavity.

[0125] 77. The method according to item 49, wherein the surrounding tissue is the peritoneal wall or the peritoneal cavity.

[0126] 78. The surrounding tissue is the peritoneal cavity, and the method further comprises releasing FVIII or FVIIIA from the peritoneal cavity into the bloodstream, the method according to item 49.

[0127] 79. The method according to item 49, further comprising monitoring the clotting time of the patient.

[0128] 80. The method according to item 79, further comprising adjusting the dose of FVIII or FVIIIA in the subsequent solid form dosing response to the monitored clotting time of the patient.

[0129] 82. The method according to item 80, wherein the clotting time test is monitored using the prothrombin time test.

[0130] 84. The method according to item 79, further comprising reducing the dose of the orally administered clotting factor when the clotting time of the patient falls below the threshold level.

[0131] 85. The method according to item 84, wherein the threshold level is in the range of about 25 to 30 seconds.

[0132] 86. The method according to item 49, further comprising delivering a solid dose clotting factor to a section of the small intestine, and the patient's immune response to the delivered clotting factor is reduced.

[0133] 87. The method according to item 86, wherein the section of the small intestine comprises a compartment without Peyer's patches.

[0134] 88. The method according to item 86, wherein the production of inhibitor antibodies against the released FVIII or FVIIIA is minimized or eliminated.

[0135] 89. The method according to item 86, wherein the section of the small intestine is the duodenum or the jejunum.

[0136] 90. The method according to item 86, wherein the serum titer of the patient inhibitor antibody against the coagulation factor increases by only up to about 10% in response to the release of the coagulation factor into the patient's bloodstream.

[0137] 91. The method according to item 86, wherein the serum titer of interleukin-7 increases by only up to about 10% in response to the release of the coagulation factor into the patient's bloodstream.

[0138] 92. The method according to item 49, wherein the patient's immune response against the coagulation factor is reduced as compared to the delivery of the coagulation factor by intramuscular injection or subcutaneous injection.

[0139] 93. The method according to item 92, wherein the patient's immune response against the coagulation factor is reduced by an amount in the range of about 2-fold to 30-fold as compared to intramuscular injection or subcutaneous injection.

[0140] 94. The method according to item 49, wherein the preparation contains an anticoagulant.

[0141] 95. The method according to item 94, wherein the production of inhibitor antibodies against the released FVIII or FVIIIA is minimized due to the reduction of the aggregation of FVIII or FVIIIA molecules.

[0142] 96. At least one of bioavailability, AUC, or C max increases due to the reduction of the aggregation of FVIII or F molecules according to the method of item 94.

[0143] 97. At least one of the pharmacokinetic parameters increases by at least about 10% according to the method of item 96.

[0144] 98. The anticoagulant contains at least one of arginine, glutamic acid, leucine, trehalose, or poloxamer F68 according to the method of item 96.

[0145] 99. The method according to item 49, wherein the preparation contains a drug configured to enhance the permeability to FVIII or FVIIIA of the peritoneal wall.

[0146] 100. The method according to item 99, wherein the permeability enhancer is hyaluronidase.

[0147] 101. The method according to item 99, wherein the permeability enhancer enhances the uptake of FVIII or FVIIIA into the patient's lymphoid tissue.

[0148] 102. At least one of bioavailability, AUC, or C max increases due to the increased permeability of the peritoneal wall, according to the method of item 99.

[0149] 103. At least one of the pharmacokinetic parameters increases by at least about 10%, according to the method of item 102.

[0150] 104. At least one of the pharmacokinetic parameters increases in the range of about 8 - 12%, according to the method of item 103.

[0151] Further details of these and other embodiments and aspects of the present invention will be more fully described below with reference to the accompanying drawings.

Brief Description of the Drawings

[0152]

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[0153] Embodiments of the present invention provide devices, systems, and methods for delivering a drug to various locations within the body, as well as therapeutic compositions containing the drug. As used herein, the term "drug" refers to any form of pharmaceutical preparation that can include another drug or other therapeutic agent, as well as one or more pharmaceutical excipients. Many embodiments provide a swallowable device for delivering a drug within the GI tract, including within the wall of the small intestine. Certain embodiments provide a swallowable device, such as a capsule, for delivering a drug, such as a clotting factor for the treatment of coagulation disorders, to the small intestine and / or peritoneum and / or peritoneal cavity or the wall of other GI organs. As used herein, "GI tract" refers to the esophagus, stomach, small intestine, large intestine, and anus, and "intestinal tract" refers to the small intestine and large intestine. Also, 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 peritoneal wall. Further, as used herein, the term peritoneal cavity refers to the space between the parietal peritoneum and the visceral peritoneum. Also, 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 ), more preferably, although necessarily, within 5%.

[0154] Referring now to FIGS. 1-11, an embodiment of a device 10 for delivering a medicament 100 to a delivery site DS within the intestinal tract, such as the wall of the small intestine and / or the peritoneal wall or peritoneal cavity, includes a capsule 20 that includes at least one guide tube 30, one or more tissue penetrating members 40 positioned within or otherwise advanceable within 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 a preparation 100, typically includes at least one drug or therapeutic agent 101 and may include one or more pharmaceutical 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.

[0155] Device 10 can be configured for delivery of a drug 100 in liquid, semi-liquid, or solid form, or all three. The solid form of the drug / preparation 100 can include both powders and pellets. The semi-liquid form can include slurries or pastes. Whatever the form, the preparation 100 preferably has a consistency of shape and material such that the drug exits the device and advances to the intestinal wall (or other luminal wall within the GI tract) and then decomposes at the intestinal wall to release a drug or other therapeutic agent 101 that, in various embodiments, can correspond to one or more clotting factors for the treatment of hemophilia or other clotting disorders described herein. For example, Factor VIII for the treatment of hemophilia A and Factor IX for the treatment of hemophilia B. The consistency of the material of the preparation can include at least one of hardness, porosity, and solubility of the preparation (in body fluids) as well as a shape having a tissue-penetrating end for penetrating through the intestinal wall into the peritoneal cavity. The consistency of the material 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 pharmaceutical disintegrants known in the art, iii) the use of other pharmaceutical excipients, iv) the particle size and distribution of the preparation (e.g., microparticles), and v) the use of micronization and other particle formation methods known in the art. Suitable shapes for the preparation 100 can include cylindrical, cubic, rectangular, conical, spherical, hemispherical, and combinations thereof. Also, the shape can be selected to define a particular surface area and volume of the preparation 100 and thus the ratio between the two. Next, the ratio of surface area to volume can be used to achieve a selected rate of decomposition within the intestine or other luminal wall within the GI tract. A larger ratio (e.g., a larger surface area per unit volume) can be used to achieve a faster rate of decomposition, and vice versa. In certain embodiments, the surface area to volume ratio can range from about 1:1 to 100:1, and certain embodiments are 2:1, 5:1, 20:1, 25:1, 50:1, and 75:1 (within about 5%). The preparation / drug 100 is typically pre-packed within the lumen 44 of the tissue-penetrating member 40, but can be included in another location within the interior 24 of the capsule 20 or, in the case of a liquid or semi-liquid, in another location within the sealed reservoir 27.The agent can be pre-formed to conform to the lumen or can be packed, for example, in the form of a powder. Usually, device 10 will be configured to deliver a single drug 101 as part of agent 100. However, in some embodiments, device 10 can be configured for the delivery of a plurality of drugs 101 including a first, second, or third drug that can be formulated with a single or multiple agents 100. For embodiments having multiple agents / drugs, the agents can be contained within separate tissue penetrating members 40 or within separate compartments or reservoirs 27 within capsule 20. In another embodiment, a first dose 102 of agent 100 containing a first drug 101 can be packed into the penetrating member(s) 40, and a second dose 103 of agent 100 (containing the same or a different drug 101) can be coated onto the surface 25 of the capsule as shown in the embodiment of FIG. 1B. The drugs 101 in the two doses 102 and 103 of the agent can be the same or different. In this way, a biphasic pharmacokinetic 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 also to achieve a timed release of agent 100. The enteric coating 104 can include one or more enteric coatings described herein or known in the art.

[0156] System 11 for delivering agent 100 to the wall of the small intestine and / or the peritoneal 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 handheld device 13 described herein for communicating with device 10, as shown in the embodiment of FIG. 1B. System 11 may also be configured as kit 14 including a set of system 11 and instructions for use 15, packaged in package 12, as shown in the embodiment of FIG. 1C. The instructions can indicate to the patient when to take device 10 in relation to one or more events such as dietary intake or physiological measurements such as blood glucose, cholesterol. In such embodiments, kit 14 can include multiple devices 10 containing a regimen of agent 100 for a selected dosing period, e.g., one day, one week, or multiple weeks, depending on the condition being treated.

[0157] 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 the use is for an adult or a child. The capsule 20 includes an internal volume 24 and an outer surface 25 having one or more openings 26 sized for the guide tube 30. In addition to other components of the device 10 (such as an actuating mechanism, etc.), the internal volume can include one or more compartments or reservoirs 27. One or more portions of the capsule 20 can be manufactured from various biocompatible polymers known in the art, including various biodegradable polymers that can include PLGA 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 can include a biodegradable material seam 22 so as to controllably degrade into smaller fragments 23 that more easily pass through the intestinal tract. Further, in various embodiments, the capsule can include various radiopaque or echogenic materials for device localization using fluoroscopy, ultrasound or other medical imaging methods. In certain embodiments, all or a portion of the capsule can include a radiopaque / echogenic marker 20m as shown in the embodiments of FIGS. 1A and 1B. In use, such materials not only enable localization of the device 10 within the GI tract, but also enable determination of the transit time of the device through the GI tract.

[0158] In a preferred embodiment, the tissue penetrating member 40 is positioned within a guide tube 30 that serves to guide and support the advancement of the member 40 into tissue such as the wall of the small intestine and / or the peritoneal wall or other locations within the GI tract. The tissue penetrating member 40 typically includes a hollow needle or other similar structure and has a lumen 44 and a tissue penetrating end 45 for penetrating the intestinal wall IW to a selectable depth. The member 40 may also include a pin 41 for engagement 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 stopper or flange 40s on the member 40 that corresponds to the pin 41 described herein. The agent 100 is typically delivered to the tissue via the lumen 44. In many embodiments, the lumen 44 is pre-filled with the desired agent 100 that exits the lumen and advances (e.g., by the force imparted to a foldable embodiment of the member 40) using a delivery member 50 or other advancing means. Alternatively, the agent 100 can advance from another location / compartment within the capsule 20 into the lumen 44. In some embodiments, all or a portion of the tissue penetrating member 40 can be fabricated from the agent 100 itself (e.g., a clotting factor such as factor VII, factor VIII, factor IX, factor X, or other clotting proteins). In these and related embodiments, the agent can have a pointed end, dart-shaped structure (with or without barbs) or an elongate structure configured to penetrate and remain within the surrounding tissue such as the intestinal wall (e.g., the wall of the small intestine) or the peritoneal wall or peritoneal cavity after insertion. 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.

[0159] In various embodiments, device 10 can include a second 42 and a third 43 tissue penetrating member 40, as shown in the embodiments of FIGS. 7A and 7B, and 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 perimeter 21 of the capsule 20 so as to fix the capsule to the intestinal wall IW during delivery of the agent 100. Fixing the capsule 20 in such a manner reduces the likelihood that the capsule will be displaced or moved by peristaltic contractions that occur during delivery of the agent. In certain embodiments, the amount of fixing force can be adjusted to the normal force imparted during peristaltic contractions of the small intestine. Fixing can be further facilitated by configuring some or all of the tissue penetrating members 40 to have a curved or arcuate shape.

[0160] Delivery member 50 is configured to advance agent 100 through tissue penetrating member lumen 44 to the intestinal wall IW. Thereby, at least a portion of delivery member 50 is advanceable within tissue penetrating member lumen 44, whereby member 50 has a size and shape (e.g., a piston-like shape) configured to fit within delivery member lumen 44.

[0161] In some embodiments, the distal end 50d of the delivery member (the end that advances into the tissue) can have a plunger element 51 that advances the agent within the tissue penetrating member lumen 44 and also forms a seal with the lumen. The plunger element 51 can be integral or attachable to the delivery member 50. Preferably, the delivery member 50 is configured to move a fixed or metered dose of drug a fixed distance within the lumen of the needle 44 to deliver it to the intestinal wall IW. This can be achieved by one or more of the selection of the diameter of the delivery member (e.g., the diameter can be tapered distally), the diameter of the tissue penetrating member (which can be narrowed at its distal end), the use of a stopper, and / or the actuation mechanism. However, in some embodiments, the stroke or travel distance of the member 50 can be adjusted in situ in response to various factors such as one or more sensed conditions within the GI tract. In situ adjustment can be achieved by the use of a logic resource 29 (including a control device 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.

[0162] The actuation mechanism 60 can be coupled to at least one of the tissue penetrating member 40 or the delivery member 50. The actuation mechanism is configured to advance the tissue penetrating member 40 a selectable distance into the intestinal wall IW, advance the delivery member to deliver the agent 100, and then withdraw the tissue penetrating member from the intestinal wall. In various embodiments, the actuation mechanism 60 can include a spring - type 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, and other spring structures are also contemplated. In a particular embodiment, the spring 80 is shaped substantially conically and can be compressed to reduce the length of the spring to the point where the compressed length of the spring is approximately the thickness of several coils (e.g., two or three) or even only one coil.

[0163] In certain embodiments, the actuating mechanism 60 can 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 disassembly of the release element releases the spring. The spring 80 can be coupled to the release element 70 by a latch or other connecting element 81. The first motion converter 90 is configured to convert the motion of the spring 80 to advance and retract the tissue penetrating member 40 in and out of the intestinal wall or other tissue. The second motion converter 94 is configured to convert the motion 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 travel along a rod 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 (either directly or indirectly) with the tissue penetrating member 40 and / or the delivery member 50 to produce the desired motion. They have shapes and other features configured to convert motion along the longitudinal axis of the spring 80 into orthogonal motion of the tissue penetrating member 40 and / or the delivery member 50, although conversions in other directions are contemplated. The motion converters can have a wedge shape, a trapezoidal shape, or a curved shape, and other shapes are contemplated. In certain embodiments, the first motion converter 90 has a trapezoidal shape 90t and can include a slot 93, as shown in the embodiments of FIGS. 2, 3, and 4, the slot engaging a pin 41 on the tissue penetrating member that travels within the slot. The slot 93 can also have a trapezoidal shape 93t that reflects or otherwise corresponds to the overall shape of the converter 90. The slot 93 serves to push the tissue penetrating member 40 between the upward sloping portions 91 of the trapezoid and then pull it back between the downward sloping portions 92. In one variant, one or both of the motion converters 90 and 94 can include a cam or cam - like device (not shown). The cam can be rotated by the spring 80 to engage the tissue penetrating and / or delivery members 40 and 50.One or more components of mechanism 60 (as well as other components of device 10) that include motion transducers 90 and 94 can be manufactured using various MEMS-based methods known in the art to enable a selected amount of miniaturization to fit within capsule 10. Also, as described herein, they can be formed from various biodegradable materials known in the art.

[0164] In other variations, the actuation mechanism 60 can also include mechanisms such as electromechanical devices / solenoids or piezoelectric devices. In one embodiment, the piezoelectric device used in mechanism 60 can include a shaped piezoelectric element having a non-deployed state and a deployed state. This element can be configured to go to the deployed state upon application of a voltage and return to the non-deployed state upon removal of the voltage or other change in the voltage. This embodiment and related embodiments enable reciprocating motion of the actuation mechanism 60 to both advance and then retract the tissue penetrating member. The voltage of the piezoelectric element can be generated using a battery or a piezoelectric-based energy converter that generates a voltage from mechanical deformation such as compression of capsule 20 by peristaltic contractions of the small intestine around the capsule. A detailed description of the piezoelectric-based energy converter is described in U.S. Patent Application No. 12 / 556,524, which is hereby incorporated by reference in its entirety for all purposes. In one embodiment, deployment of the tissue penetrating member 40 can actually be triggered from peristaltic contractions of the small intestine that provide mechanical energy for generating a voltage in the piezoelectric element.

[0165] The release element 70 is typically coupled to the actuating mechanism 60 and / or a spring coupled to the actuating mechanism, although other configurations are contemplated. In a preferred embodiment, the release element 70 is coupled to a spring 80 positioned within the capsule 20 so as to hold the spring in a compressed state 85, as shown in the embodiment of FIG. 2. Disassembly of the release element 70 releases the spring 80 and actuates the actuating mechanism 60. Thus, the release element 70 can thus function as an actuator 70a (the actuator 70a may also include the spring 80 and other elements of the mechanism 60). As will be further described 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 advances from the capsule to the wall of the small intestine and / or the peritoneal wall or peritoneal cavity or other luminal wall of the intestinal tract.

[0166] 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, for example, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 8.0 or higher. The release element can also be configured to degrade within a specific range of pH, such as 7.0 - 7.5, for example. In certain embodiments, the pH at which the release element 70 degrades (defined herein as the degradation pH) can be selected for a particular drug to be delivered such that the drug is released at a location within the small intestine corresponding to the selected pH. Further, for 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 the actuating mechanism for delivering the first drug) and a second release element 70 configured to degrade at a second pH (coupled to the actuating mechanism for delivering the second drug) (additional numbers of release elements are contemplated for various numbers of drugs).

[0167] Release element 70 can also be configured to degrade in response to other conditions in the small intestine (or other GI locations). In certain embodiments, release element 70 can be configured to degrade in response to specific chemical conditions in the fluid within the small intestine, such as those that occur after ingestion of a meal (e.g., a meal containing fat, starch, or protein). In this way, the release of agent 100 can be substantially synchronized with or otherwise timed to coincide with the digestion of a meal.

[0168] Various approaches are contemplated for the biodegradation of release element 70. In certain embodiments, the biodegradation of release element 70 from one or more conditions in the small intestine (or other locations in the GI tract) can be achieved by the following approaches: i) selection of the materials of the release element, ii) the amount of cross-linking of those materials, and iii) one or more of the thickness and other dimensions of the release element. A lower amount of cross-linking or a thinner dimension can result in a faster rate of degradation, and vice versa. Suitable materials for the release element can include biodegradable materials such as various enteric materials that are configured to degrade when exposed to the higher pH within the intestine. Suitable enteric materials include, but are not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymerized methacrylic acid / methyl methacrylate ester, and other enteric materials known in the art. The selected enteric material can be copolymerized with or otherwise combined with one or more other polymers to obtain several other specific material properties in addition to biodegradability. Such properties include, but are not limited to, rigidity, strength, flexibility, and hardness.

[0169] In alternative embodiments, the release element 70 can include a film or plug 70p that conforms to or otherwise occludes the guide tube 30 and holds the tissue penetrating member 40 within the guide tube. In these and related embodiments, the tissue penetrating member 40 is coupled to a spring-actuated mechanism such that when the release element is fully disassembled, the tissue penetrating member is released and then pops out of the guide tube and penetrates the intestinal wall. In still other embodiments, the release element 70 can be shaped to function as a latch that holds the tissue penetrating member 40 in a predetermined position. In these and related embodiments, the release element can be located externally or internally of the capsule 20. In the latter case, the capsule 20 and / or the guide tube 30 can be configured to allow penetration of intestinal fluid into the capsule to enable disassembly of the release element.

[0170] In some embodiments, the actuating mechanism 60 can be actuated by a sensor 67 such as a pH sensor 68 or other chemical sensor that detects the presence of the capsule within the small intestine. The sensor 67 can then send a signal to the actuating mechanism 60 or to an electronic control device 29c coupled to the actuating mechanism to actuate the mechanism. Embodiments of the pH sensor 68 can include an electrode-based sensor or it can be a mechanically-based sensor such as a polymer that contracts or expands when exposed to a selected pH or other chemical condition within the small intestine. In related embodiments, the expandable / contractable sensor 67 can also include the actuating mechanism 60 itself by using mechanical movement from the expansion or contraction of the sensor.

[0171] According to another embodiment for detecting that the device is in the small intestine (or other locations in the GI tract), sensor 67 can include a pressure / force sensor such as a strain gauge for detecting the number of peristaltic contractions that the capsule 20 is receiving within a particular location of the intestinal tract. In such an embodiment, the capsule 20 is preferably sized so as to be gripped by the small intestine during peristaltic contractions. Different locations within the GI tract have different numbers of peristaltic contractions. The small intestine has 12 to 9 contractions per minute, and the frequency decreases with the length of the intestine. Thus, according to one or more embodiments, detection of the number of peristaltic contractions can be used to determine not only whether the capsule 20 is in the small intestine, but also the relative location within the intestine. In use, these embodiments and related embodiments enable the release of drug 100 at a particular location in the small intestine.

[0172] As an alternative or supplement to internally actuated drug delivery (e.g., using release elements and / or sensors), in some embodiments, the user may externally actuate the actuation mechanism 60 to deliver the agent 100 by RF, magnetic, or other wireless signal means known in the art. In these and related embodiments, the user may transmit the received signal 17 from the device 10 using a handheld communication device 13 (e.g., a handheld RF device such as a mobile phone) as shown in the embodiment of FIG. 1B. In such embodiments, the swallowable device may include a transmitter 28 such as an RF transceiver chip or other similar communication device / circuit. The handheld device 13 may include not only signal means but also means for notifying the user when the device 10 is in the small intestine or other locations in the GI tract. The latter embodiments may be implemented using a logic resource 29 (e.g., a processor 29) coupled to the transmitter 28 that signals the detection of when the device is in the small intestine or other locations and signals it to the user (e.g., by signaling an input from a sensor). The logic resource 29 may include a control device 29c (either hardware or software) for controlling one or more aspects of the process. The same handheld device may also be configured to warn the user when the actuation mechanism 60 is actuated and the selected agent 100 is delivered (e.g., using the processor 29 and the transmitter 28). In this way, the user is provided with confirmation that the agent 100 has been delivered. This enables the user to not only take other appropriate drugs / therapeutics but also make other related decisions (e.g., for a diabetic, whether to eat a meal, which foods to eat). The handheld device may also be configured to transmit a signal to the swallowable device 10 to disable the actuation mechanism 60 and thus prevent, delay, or accelerate the delivery of the agent 100. In use, such embodiments enable the user to intervene to prevent, delay, or accelerate the delivery of the agent based on other symptoms and / or the patient's actions (e.g., deciding to eat a meal, sleep, exercise, etc.).After swallowing the capsule, the user can also externally activate the activation mechanism 60 for a selected period. The period can be correlated with the normal transit time or range of transit times of food moving through the user's GI tract to a specific location within the tract, such as the small intestine.

[0173] In certain embodiments, the capsule 20 can include a seam 22 of biodegradable material that controllably degrades, as shown in the embodiments of FIGS. 10A and 10B, to produce capsule fragments 23 of selectable sizes and shapes to facilitate passage through the GI tract. The seam 22 can also include pores or other openings 22p for fluid penetration into the seam, as shown in the embodiment of FIG. 10, to accelerate biodegradation. Other means for accelerating biodegradation of the seam 22 can include prestressing 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 can be constructed of and / or have a structure of a material that is readily degraded by absorption of ultrasonic energy, such as high intensity focused ultrasound (HIFU), enabling the capsule to be broken down into smaller fragments using ultrasound applied externally or by an endoscope (or other minimally invasive method).

[0174] Suitable materials for the seam 22 can include one or more biodegradable materials described herein, such as PGLA, glycolic acid. The seam 22 can be attached to the capsule body 20 using various joining methods known in polymer technology, such as molding, hot melt bonding, etc. Further, for embodiments of the capsule 20 also manufactured from biodegradable materials, faster biodegradation of the seam 22 can be achieved by one or more of the following: i) manufacturing the seam from a faster biodegradable material, ii) applying prestress to the seam, or iii) creating holes in the seam. The concept of using a biodegradable seam 22 to cause controlled degradation of a swallowable device within the GI tract can also be applied to other swallowable devices, such as a swallowable camera (or other swallowable imaging device), facilitating passage through the GI tract and reducing the likelihood that such a device will become lodged in the GI tract. Thus, embodiments of the biodegradable seam 22 can be adapted for swallowable imaging devices and other swallowable devices.

[0175] Another aspect of the present invention provides a method for delivery of drugs and other therapeutic agents (in the form of agent 100) to the wall of the GI tract using one or more embodiments of the swallowable drug delivery device 10. Exemplary embodiments of such a method will now be described. The described embodiments of drug delivery occur in the small intestine SI. However, this is exemplary, and it should be understood that embodiments of the present invention can be used to deliver drugs at several locations within the GI tract, including the stomach and large intestine. For ease of discussion, the swallowable drug delivery device 10 may be referred to herein as capsule 10. As described above, in various embodiments, the device 10 can be packaged as a kit 11 within a sealed package 12 that includes the device 10 and a set 15 of instructions for use. When a patient is using the handheld device 13, the patient may be instructed to manually enter data into the device 13, either via the instructions 15 or a barcode 18 (or other identifying indicia 18) located on the package 12. When a barcode is used, the patient scans the barcode using the barcode reader 19 on the device 13. After opening the package 12, reading the instructions 15, and entering any required data, the patient swallows an embodiment of the swallowable drug delivery device 10. Depending on the drug, the patient may take the device 10 in conjunction with a meal (before, during, or after) or a physiological measurement. The capsule 20 is sized to pass through the GI tract and moves through the patient's stomach S and into the small intestine SI via peristalsis, 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 physical conditions specific to the small intestine) to activate the actuating mechanism 60 in accordance with one or more embodiments of the present invention and deliver the agent 100 to the wall of the small intestine SI. For embodiments that include a hollow needle or other hollow tissue penetrating member 40, drug delivery is achieved by using the actuating mechanism 60 to advance the member 40 a selected distance into the mucosa of the intestinal wall IW, and then the drug is injected through the needle lumen 44 by advancement of the delivery member 50. The delivery member 50 is withdrawn 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 embodiments of the device 10 having multiple needles, the second or third needles 42, 43 can also be used to deliver additional doses of the same drug or separate drugs 101. The advancement of the needles or other tissue penetrating members 40 can be performed substantially simultaneously or sequentially. In a preferred embodiment using multiple needles, the advancement of the needles can be performed substantially simultaneously to fix the device 10 to the small intestine during drug delivery. Referring now to FIGS. 11A - E, in many embodiments where the drug 101 includes one that contains the coagulation factor CF, the device 10 including the actuation mechanism 50 is configured to advance the needle or other tissue penetrating member 40 through the intestinal wall IW and the peritoneal wall or peritoneum P, for example, the visceral peritoneum PV, into the peritoneal cavity PC. Once there, the needle is degraded by the serosa and other fluids in the peritoneal cavity PC, releasing the coagulation factor CF into the serosa and other peritoneal cavity 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 into 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 increased pressure for advancing the member 140 that passes through the intestinal wall IW and the visceral peritoneum PV and reaches the peritoneal cavity PC. They can also be facilitated by increasing the amount of reactant 165 within the balloon 160 to generate an increased amount of gas 169 and then increasing it for the gas pressure to propel 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% beyond that for positioning the member 140 only against the intestinal wall IW.

[0176] After drug delivery, device 10 then passes through the intestinal tract including the large intestine LI and is ultimately excreted. For embodiments of capsule 20 having biodegradable seam 22 or other biodegradable portions, the capsule degrades into smaller fragments within the intestinal tract, as shown in the embodiments of FIGS. 9A and 9B, to facilitate passage through and excretion from the intestinal tract. In certain embodiments having biodegradable tissue penetrating needle / member 40, if the needle becomes clogged in the intestinal wall, the needle biodegrades to release capsule 20 from the wall.

[0177] For embodiments of device 10 including sensor 67, actuation of mechanism 60 can be accomplished by a sensor that sends a signal to actuation mechanism 60 and / or a processor 29 or control device 29c coupled to the actuation mechanism. For embodiments of device 10 including an external actuation function, a user can externally actuate actuation mechanism 60 after swallowing the capsule for a selected period of time. The period can be correlated to the normal transit time or range of transit times of food moving through the user's GI tract to a particular location within a tube such as the small intestine.

[0178] One or more embodiments of the above-described methods can be used for the delivery of a preparation 100 comprising a therapeutically effective amount of various drugs and other therapeutic agents 101 for treating various diseases and conditions. These include, for example, various clotting factors described herein, some polymeric peptides and proteins, or else injections would be required due to chemical breakdown in the stomach. The dosage of a particular drug can be titrated according to the patient's weight, age, or other parameters. Also, when delivered by one or more embodiments of the present invention, the dosage of a drug 101 (e.g., insulin for blood glucose regulation) to achieve a desired effect or therapeutic effect can be less than the amount required when the drug (e.g., a swallowable tablet that is digested in the stomach and absorbed through the wall of the small intestine) is delivered by conventional oral delivery. This is due to the fact that there is no breakdown of the drug by acids and other digestive fluids in the stomach, and the fact that not just a portion but all of the drug is delivered to the wall of the small intestine and / or the peritoneal 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 with the preparation 100 can range from 100 to 5% of the dosage delivered by conventional oral delivery (e.g., tablets) to achieve a desired therapeutic effect (e.g., blood glucose regulation, seizure regulation, etc.), and even lower amounts are contemplated. The specific dosage reduction can be titrated based on the particular drug, the amount of breakdown occurring in the GI tract of the conventional oral method, the frequency of administration versus the dose using the embodiments of the swallowable capsule described herein, the condition being treated, and the patient's weight, age, condition. For some drugs (having a known level of breakdown in the intestinal tract), a standard reduction can be employed (e.g., 10 - 20%). For drugs with a stronger tendency to break down and poor absorption, a larger reduction can be used. In this way, since the intake dosage is reduced, the potential toxicity and other side effects (e.g., stomach cramps, irritable bowel, bleeding, etc.) of a particular drug or drugs delivered by the device 10 can be reduced. This in turn improves patient compliance as both the severity and incidence of side effects in the patient are reduced.Additional advantages of embodiments employing a reduced dose of drug 101 include a reduced likelihood that a patient will develop drug resistance (require a higher dose), and in the case of antibiotics, a reduced likelihood that a patient will develop resistant strains. Also, other levels of weight loss can be achieved for patients who have undergone gastric bypass surgery and other procedures in which segments of the small intestine have been removed or the length of its action (e.g., digestion) has been effectively shortened.

[0179] In addition to the delivery of a single drug, embodiments of the swallowable drug delivery device 10 and methods of using them can be used to deliver multiple drugs (e.g., protease inhibitors for the treatment of HIV / AIDS) for the treatment of multiple conditions or a particular condition. In use, such embodiments make it possible for a patient to forgo the need to take multiple medications for a particular condition or multiple conditions. Also, they provide means for facilitating the delivery and absorption of a regimen of two or more drugs into the small intestine, and thus the bloodstream, at substantially the same time. Due to differences such as chemical composition, molecular weight, drugs can be absorbed from the intestinal wall at different rates, 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 pharmacokinetics and thus the effectiveness of the selected drug mixture. Further, eliminating the need to take multiple drugs is particularly beneficial for patients suffering from one or more long-term chronic conditions, including patients with reduced cognitive or physical ability.

[0180] In various applications, embodiments of the above methods can be used to deliver a preparation 100 containing a drug and therapeutic agent 101 to provide treatment for several medical conditions and diseases. Medical conditions and diseases that can be treated in embodiments of the present invention include, but are not limited to, cancer, hormonal conditions (e.g., hypothyroidism / hyperthyroidism, growth hormone status), osteoporosis, hypertension, high cholesterol and triglycerides, diabetes and other glucose regulation disorders, infections (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 also contemplated.

[0181] In many embodiments, treatment of a particular disease or condition can be effected without the need to inject a clotting factor or other clotting protein or other therapeutic agent (or delivery in other parenteral forms such as suppositories), but rather depends only on the therapeutic agent(s) delivered to the wall of the small intestine and / or the peritoneal wall or other portions of the GI tract. Similarly, the patient need not take the conventional oral form of a drug or other therapeutic agent, but rather depends only on delivery to the wall of the small intestine and / or the peritoneal wall using an embodiment of a swallowable capsule. In other embodiments, the therapeutic agent(s) delivered to the wall of the small intestine and / or the peritoneal wall can be delivered in combination with an injected dose of the drug(s). For example, a patient may take a daily dose of a therapeutic agent using an embodiment of a swallowable capsule, but take an injected dose only every few days or only when the patient's condition requires it (e.g., hyperglycemia). The same applies to therapeutic agents that are conventionally delivered in oral form (e.g., a patient can take a swallowable capsule and take the drug in conventional oral form as needed). The doses delivered in such embodiments (e.g., swallowed and injected doses) can be increased incrementally as needed (e.g., using standard dose response curves and other pharmacokinetic methods to determine appropriate doses). Also, for embodiments using therapeutic agents that can be delivered by conventional oral means, the doses delivered using an embodiment of a swallowable capsule can be tapered down relative to the doses normally given for oral delivery of the drug since there is little or no degradation of the drug within the stomach or other portions of the intestinal tract (again, standard dose response curves and other pharmacokinetic methods can be applied).

[0182] Next, various embodiments of a preparation 100 comprising one or more drugs or other therapeutic agents 101 for the treatment of various diseases and conditions are described with reference to dosages. These embodiments, which include specific therapeutic agents and their respective dosages, are exemplary, and it is to be understood that the preparation 100 can include several other therapeutic agents (and those known in the art) described herein that are configured for delivery to the luminal wall (e.g., the small intestine wall) within the intestinal tract using various embodiments of the device 10. The dosages can be greater or less than those described and can be adjusted using one or more methods described herein or known in the art.

[0183] In certain groups of embodiments, the therapeutic agent preparation 100 can include a therapeutically effective dose of growth hormone for the treatment of one or more growth disorders and for wound healing. In one embodiment, the preparation 100 can include a therapeutically effective amount of growth hormone in the range of about 0.1 to 4 mg, with specific ranges being 0.1 to 1, 1 to 4, 1 to 2, and 2 to 4 mg, and even larger ranges being contemplated. Specific dosages can be titrated based on one or more of the following factors: i) the specific condition being treated and its severity (e.g., hemophilia A, von Willebrand disorder, etc.), ii) the patient's weight, iii) the patient's age, and iv) the frequency of dosing (e.g., daily or twice daily).

[0184] The drug delivery compositions and components of known drug delivery systems can be employed and / or modified for use in some embodiments of the invention described herein. For example, the microneedles and other microstructures used for delivering drugs through the skin surface using a drug patch can be modified and included within the capsules described herein and, instead, the drug preparation can be used to deliver to the luminal wall of the gastrointestinal tract, such as the wall of the small intestine. Suitable polymeric microneedle structures may be commercially available from Corium of California, such as the MicroCor™ microdelivery system technology. Other components of the MicroCor™ patch delivery system, including the drug formulation or ingredients, can also be incorporated into the capsules described herein. Alternatively, various providers are commercially available for formulating combinations of polymers or other drug delivery matrices with selected drugs and other drug preparation ingredients to produce desired shapes (such as the releasable tissue-penetrating shapes described herein) having desired drug release characteristics. Such providers can include, for example, Corium, SurModics of Minnesota, BioSensors International of Singapore, and the like.

[0185] One advantage and feature of various embodiments of the therapeutic compositions described herein is that they are encapsulated or otherwise contained within a swallowable capsule or other swallowable device, a coagulation factor (e.g., factor VIII), or other biological (e.g., peptide or protein), and the drug payload is protected from degradation and / or hydrolysis by the action of peptidases and proteases within the gastrointestinal (GI) tract. These enzymes are ubiquitous throughout the biological system. The GI tract is particularly rich in proteases, and its function is to break down complex proteins and peptides in the diet into smaller segments and release amino acids, which are then absorbed from the intestine. The compositions described herein are designed to protect the therapeutic peptide, coagulation factor, or protein from the action of these GI proteases and deliver the peptide or protein payload directly to the intestinal wall. There are two characteristics of various embodiments of the compositions described herein that help protect the protein or peptide payload from the action of GI proteases. First, in certain embodiments, the capsule shell, which includes deployment engines and machinery, does not dissolve until it reaches the duodenum and intestinal segments below the duodenum due to a pH-sensitive coating on the outer surface of the capsule that prevents dissolution at the low pH of the stomach. Second, in certain embodiments, hollow polymeric microspheres (e.g., polyethylene, polyethylene oxide, maltose, silicone, etc.) contain the actual therapeutic peptide or protein, and the polymeric microspheres are designed to penetrate the intestinal muscle as soon as the outer capsule shell dissolves, and the microspheres themselves slowly dissolve in the intestinal muscle wall to release the drug payload. Thus, the peptide, coagulation factor, or other protein payload is not exposed to the action of GI proteases and is not subject to degradation by proteolysis in the GI tract. This, in turn, contributes to the high bioavailability of the therapeutic peptide or protein as compared to what would be expected if one or both of the above approaches were not used and the peptide or protein were exposed to GI proteases.In particular, for embodiments of compositions comprising compounds that bind to specific receptors or other target regions on a molecule, such an approach retains the binding affinity and specificity of the compound and enables it to bind to the desired receptor.

[0186] The coagulation factors or other coagulation proteins provided by embodiments of the present invention are particularly useful for treating various coagulation disorders. Specific coagulation disorders that can be treated include hemophilia A and B and von Willebrand disease. Such embodiments result in the delivery of coagulation factors and other coagulation proteins with specific pharmacokinetic properties that are advantageous compared to intravenous, subcutaneous, or intramuscular injection. They also enable the use of dosages that provide one or more of the following advantages: a higher therapeutic ratio, a reduced incidence of allergic reactions (including, for example, anaphylactic shock, 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 reduced incidence of allergic reactions is determined by comparison of such incidence in a patient population administered a coagulation factor or other coagulation protein by standard injection (e.g., intramuscular, intravenous, etc.) or oral delivery of a conventional compound, and the reduction is then used to model the predicted reduction in the known incidence of allergic reactions in a patient population of one or more of the coagulation factors (e.g., factor VIII) or other coagulation proteins.

[0187] Embodiments of Factor VIII Dosage According to one or more embodiments, the dosage of a coagulation factor or other coagulation protein administered using one or more embodiments of a swallowable capsule is generally, but not necessarily, a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to i) a detectable improvement in one or more clinical measurements of coagulation (such as coagulation time, e.g., prothrombin time) for a given coagulation disorder, or ii) a dosage of a coagulation factor (e.g., Factor VII, Factor VIII, Factor IX, Factor X) or other coagulation protein that results in suppression, prevention, alleviation, or delay of symptoms of a coagulation disorder such as hemophilia (A or B) or von Willebrand disease. According to various embodiments, a 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 specific embodiments are 1400, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 50000, 6000, 7000, 7500, 8000, 9000, 9100, and 9500 IU. For embodiments in which the dosage of the drug is determined by weight, a therapeutically effective amount of a coagulation factor can range from about 0.1 to 10 mg, and specific embodiments are 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, and other ranges are contemplated. A specific dosage can be selected depending on one or more of the specific coagulation factor being delivered (e.g., Factor VII, Factor VIII, etc.), the condition being treated, the clinical context (e.g., prophylaxis or acute bleeding), the patient's weight, age, and gender. Table 1 lists exemplary dosages in IU per kg of patient body weight for the treatment of hemophilia A and B with Factor VIII and Factor IX, respectively, in various clinical settings. Other dosages for these and other coagulation disorders and other conditions (e.g., intracerebral hemorrhage) are described in more detail herein.

Table 1

[0188] According to various embodiments, the dosage of a particular coagulation factor (such as those listed in Table 1) can be incrementally increased (i.e., adjusted) based on coagulation time measurements such as prothrombin time or whole blood clotting time. Thus, for example, if a patient exhibits a longer clotting time, the dosage of the coagulation factor can be increased, and if the clotting time is shorter, the dosage can be decreased. In this way, the dosage of the coagulation factor delivered by embodiments of the present invention is optimized for a given patient over the course of treatment and can account for conditions such as growth, diet, and other drug therapies that can affect blood clotting / clotting properties, including clotting time. In certain embodiments, a patient is provided with an inventory of swallowable capsules having different dosages of a particular coagulation factor (e.g., Factor VIII), and can then select the dosage to use from the inventory based on coagulation time measurements. In certain embodiments, a patient can be provided with a table or other information for selecting a particular dosage of a coagulation factor based on coagulation time or related measurements (from the inventors of the swallowable capsule). According to some embodiments, the table or other information can be electronically stored in one or more memories or logic resources of a mobile phone, tablet, or other computing device, as well as in the cloud.

[0189] In related or additional embodiments, prothrombin time or other coagulation time measurements can be used to select the optimal source of a coagulation factor for a given patient and coagulation disorder. For example, in the case of Factor VIII, prothrombin time can be used to select whether plasma-derived Factor VIII or the recombinant Factor VIII molecules described herein will converge and maintain the clotting time within the normal physiological range, e.g., 25 - 30 seconds.

[0190] Embodiments for reducing or preventing local bleeding from penetration of a tissue penetrating member into the small intestine or other GI lumen wall.

[0191] In various embodiments, the tissue penetrating members 40, 140 can be specifically configured to reduce the likelihood of any potential bleeding resulting from the insertion of the tissue penetrating member into the small intestine and / or the peritoneum. Referring now to FIG. 18H, in certain embodiments, this can be achieved by placing a rapidly dissolving layer or a coating 101c of a coagulation factor 101 (e.g., factor VIII) on all or a portion of the surface 140s of the tissue penetrating member 140, and the coagulation factor is released immediately at the tissue site (e.g., small intestine, peritoneum, etc.) where the tissue penetrating member enters. This enables the coagulation factor to rapidly initiate coagulation at that site and prevent or minimize any bleeding at or near that site. In additional or alternative embodiments, one or more rapid hemostatic agents (described below) known in the art can also be used, either alone or in combination with a coagulation factor(s) (e.g., coagulation factor VIII) delivered by the tissue penetrating member 140, for the surface coating 101c of the tissue penetrating member (TPM) 140. Referring now to FIGS. 15G, 20H, and 20I, in yet other additional or alternative embodiments, another coagulation factor 101 (e.g., factor VIII) is coated on all or a portion of the delivery balloon 172 such that when the balloon expands to insert the TPM140(s) into the tissue of the small intestine (SI) or other locations (e.g., peritoneal wall, etc.), the surface 172f contacts the wall of the small intestine (or other GI lumen wall) and coats the entry point of the TPM with a coagulation factor such as a coagulation factor or a rapid hemostatic agent. Desirably, the coating 101c of the coagulation factor 101 is positioned at the central portion of the surface 172f of the balloon 172 or has the maximum amount of active ingredient or thickness at those locations. In additional or alternative embodiments, the size and pressure of the deployment balloon 130 can also be configured such that the amount of coagulation factor can slightly penetrate the endothelial surface including the tight adhesion of the small intestine wall. In this way, the coagulation factor is present within the small intestine wall and immediately initiates coagulation from the penetration of the tissue penetrating member. In additional or alternative embodiments, the coagulation factor coated on either the TPM140 or the delivery balloon 172 can include a rapid hemostatic agent (RHA) known in the medical art.In addition to the coagulation factors (which the patient lacks) delivered by the TPM140, these RHAs can themselves be coated on the TPM140 or the balloon 130. Such RHAs can include one or more factor concentrates, mucoadhesives, or coagulation accelerators. A more complete list and description of such RHAs can be found in Khoshmohabat et al.: Overview of Agents Used for Emergency Hemostasis. Trauma Mon. 2016 Feb 6;21(1), which is hereby incorporated by reference in its entirety for all purposes.

[0192] Advantages of delivery of coagulation factors and other coagulation proteins to the intestinal wall or other locations in the intestinal tract. In use, embodiments of the present invention that provide delivery of coagulation factors or other coagulation proteins to the intestinal wall and / or peritoneal wall and adjacent tissues (e.g., peritoneal wall or peritoneal cavity) or other target sites in the intestinal tract, such as the large intestine, for treatment of one or more of the above or conditions, provide several advantages over coagulation factors in injected form (e.g., factors VII, VIII, IX, and X). Such advantages can include, but are not limited to, i) a higher therapeutic ratio, ii) more consistent maintenance of CF within the therapeutic range or zone, iii) a reduction in the incidence and severity of side effects including one or more of anaphylactic shock or other allergic reactions (including at the injection site), bruising and bleeding at the injection site, nasopharyngitis, upper respiratory tract infections, influenza, low back pain, myalgia, neurocognitive events, and ophthalmic events, and a reduction in immunogenicity and / or immunogenic reactions including the development of inhibitory antibodies described herein. These advantages are due to one or more of the following, namely, i) a much lower dose delivered by embodiments of the present invention, ii) the dose being delivered as a daily result versus weekly or monthly, and iii) the dose being delivered orally versus intravascularly.

[0193] In many embodiments, the therapeutic ratio of the dosage of a coagulation factor or other 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., intravenously, intramuscularly, or subcutaneously, etc., weekly, biweekly, or monthly). In various embodiments, the term "significantly" corresponds to an increase in the therapeutic ratio of 2-fold or more, e.g., 7-fold to 30-fold or more. For coagulation factors such as factor VII, VIII, IX, or X, which are delivered at a dosage usually 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 be increased in the range of 3-fold to 7-fold when delivered at a daily oral dosage using the swallowable device provided by the present invention, while for the monthly injected dosage of a coagulation factor, the therapeutic ratio can be increased 30-fold when delivered at a daily oral dosage according to embodiments of the present invention. Further, an increase can be obtained if the oral administration of the coagulation factor (or other coagulation protein) is given multiple times a day. Similar improvements (e.g., 2-fold, 3-fold, 30-fold or more) can be seen in the incidence rate of one or more of immunogenicity / immune response (relative to intramuscular and / or subcutaneous injection), allergic reaction, and other side effects. Immunogenicity / immune response is the production by the body of antibodies (e.g., inhibitor antibodies) against the administered coagulation protein / coagulation factor, which neutralizes or otherwise reduces the clinical effect of the coagulation factor or other coagulation protein. The incidence rate and severity of allergic reactions are reduced 2-fold to 30-fold because the antibody is given in a daily dose for a weekly or less frequent period, during which the immune system tends to be desensitized (the degree of allergic reaction can be determined using methods known in the art and can be correlated with one or more in vitro tests known in the art). Similarly, the degree of reduction in immunogenicity, including the production of inhibitor antibodies against one or more coagulation factors such as factor VIII, can be reduced by 2 to 30-fold or more.This is due to three factors, namely: 1) the dose is not delivered subcutaneously and / or intramuscularly (which tends to exacerbate such reactions); 2) the dose is delivered in much smaller amounts, e.g., 7- to 30-fold less, depending on whether the injected dose is delivered weekly, bi-weekly, monthly, etc.; and 3) as described above, the dose of the coagulation factor (or other coagulation protein) is delivered to the upper part of the small intestine, avoiding the Peyer's patches and subsequent production of immune cells and other immune responses. The amount of the immune response to a given coagulation factor (e.g., Factor VIII, etc.) can be quantified using another immunological assay method known in the art for measuring, for example, the production of antibodies (e.g., inhibitor antibodies) generated against the delivered coagulation factor (e.g., Factor VIII) or other coagulation protein), and / or the percentage of the administered coagulation factor neutralized by the patient's own antibodies (e.g., inhibitor antibodies). In these embodiments and related embodiments, the dosage and dosing regimen of the coagulation factor (or other coagulation protein) can be configured to result in a minimal immune response in the patient, where minimal means less than 10%, more preferably less than 5%, of the delivered coagulation factor (or other coagulation protein) neutralized by the patient's own antibodies.

[0194] In other embodiments, the immune response and / or allergic response to the administered coagulation factor (or other coagulation protein) can be quantified by measuring the difference in the serum titer of antibodies against a given coagulation factor (e.g., Factor VIII) when administered orally daily versus intravenous doses every two or three days, bi-weekly, or monthly. In these embodiments and related embodiments, the dosage and dosing regimen of the coagulation factor (or other coagulation protein) can be configured to result in 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 coagulation factor (e.g., Factor VIII).

[0195] In related approaches, the serum titers of cytokines (such as interleukins like interleukin 7) and / or white blood cells can be measured for a given dosage and administration of a coagulation factor. In these embodiments and related embodiments, the dosage and administration regimen of the coagulation factor or other coagulation protein can be configured to result in 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 one or more of the patient's white blood cells and / or a particular cytokine (such as interleukin 7). In related embodiments, the immune response can be quantified by using a change in the differential of white blood cells (such as an increase in the % of eosinophils or basophils that occur in an allergic reaction). In these embodiments and related embodiments, the dosage and administration regimen of the coagulation factor or other coagulation protein can be configured to result in 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 (such as eosinophils) in the patient's total white blood cell count.

[0196] Another advantage achieved by delivering doses of various coagulation factors or other coagulation proteins at daily doses, as opposed to longer intervals between doses (e.g., every 2 or 3 days, every other week, or monthly doses) by conventional injection means (e.g., by intravenous, intramuscular, or subcutaneous injection), is a reduction in the variability of the patient plasma concentration profile for a particular coagulation factor or other coagulation protein, thereby resulting in a much smoother plasma concentration over time. Using the pharmacokinetic model described in more detail in Appendix 1, plasma concentration curves were generated for the delivery of alirocumab at an every-other-week delivery period (Figure 24A) and a tapered daily dose from an every-other-week dose (Figure 24A). As can be seen from the figure, the amount of daily variability in the curve is much less for alirocumab delivered orally according to embodiments of the present invention. Also, using the equations shown in detail and described in Appendix 2, a value known as the “% steady state variability” was calculated for each of these antibodies. The value reflects the amount of within-day variability in the plasma concentration of a given drug. As shown in Table 2 below, the calculated amount of steady state variability in the plasma concentration of a particular antibody was significantly reduced (from 66.3% to 0.39%) when the antibody was delivered at a daily dose according to embodiments of the present invention as opposed to subcutaneous injection. As a result, the steady state variability of alirocumab was reduced by approximately 1 / 170. The model was also used to show a reduction in steady state plasma variability for two anti-interleukin antibodies, secukinumab and brodalumab (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 cases, the reduction in steady state variability was from 171-fold to 216-fold. Thus, the model consistently shows a 170-216% reduction in the steady state plasma concentration of a given drug (e.g., a coagulation factor) when the drug is given at a daily dose using embodiments of the present invention as opposed to every other week or monthly using subcutaneous injection. Using such a model, similar absolute values (e.g., 0.12-0.39%) and reductions in % steady state variability are expected for the various coagulation factors described herein.The advantages of such a decrease include, among others, a decrease in the risk of adverse events, a decrease in allergic reactions and immunogenicity (e.g., a decrease in the incidence and production of inhibitor antibodies against specific clotting factors such as factor VIII), and the ability of the clotting factor to more appropriately and consistently treat a clotting disorder such as hemophilia, since the period during which the patient remains within the therapeutic range of a given clotting factor is longer. The decrease in steady-state variability can also be used to quantify a decrease in the patient's immune response to a specific clotting factor, such as a decrease in the number of inhibitor antibodies. Such a decrease can be proportional (e.g., directly proportional, partially proportional, etc.) or in the form of a first- or second-order proportion. [Table 2] [Table 3]

[0197] Embodiments of a therapeutic composition comprising factor VIII As described above, various embodiments of the present invention provide a therapeutic composition comprising a clotting factor such as factor VIII for the treatment of a clotting disorder such as hemophilia A or hemophilia B.

[0198] Next, a brief description of the Factor VIII compound is presented. Factor VIII (also referred to herein as FVIII or FVIII) is a glycoprotein that amplifies the coagulation signaling cascade and enables timely coagulation upon injury. The gene encoding FVIII is located on the long arm of the X chromosome Xq28 {Thompson, 2003 #37} and consists of 26 exons, which are inserted 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. There is no cultured human cell line that can express the currently produced FVIII using Chinese hamster ovary cells, baby hamster kidney cells, or human fetal kidney cells genetically engineered with human FVIII cDNA.

[0199] The FVIII molecule consists of three different types of domains, namely, the A1, A2, and A3 domains that are homologous to each other and essential for catalytic activity, the B domain that varies greatly among species and is highly glycosylated but not essential for the protein's coagulation-promoting activity {Kaufman, 1997 #36}, and the C1 and C2 domains that are involved in the binding of other coagulation factors (FIX and FX) and phospholipids.

[0200] FVIII is produced from mRNA on ribosomes within the endoplasmic reticulum (ER), the signal peptide is then cleaved within the ER lumen, and the protein is glycosylated on the B domain with oligosaccharides rich in mannose residues. Attachment to ER chaperones, including Bip (immunoglobulin binding protein), calnexin, and calreticulin, also occurs within the lumen, and Bip transports FVIII aggregates to the cytosol for degradation. Deletion of the B domain increases FVIII secretion, presumably because binding to Bip is inhibited. Another chaperone, ERGC-53, is involved in the transfer of FVIII to the Golgi after Bip dissociates from the protein. ERGC-53 binds to the mannose residues of the B domain. In the Golgi, FVIII undergoes further glycosylation, formation of disulfide bonds, 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 decrease in FVIII secretion due to increased transport of the protein to the cytosol for degradation from the ER and increased Golgi degradation.

[0201] Circulating FVIII is stabilized by binding to von Willebrand factor (VWF) that occurs in the B domain. The half-life of circulating FVIII is approximately 18 hours in normal subjects. The half-life of recombinant FVIII in hemophilia subjects ranges from 10 to 20 hours, depending on blood type and VWF levels. The maximal activity of FVIII is detectable after 1 to 2 hours of intravenous administration. FVIII is removed from the circulation via binding to the low-density lipoprotein receptor-related protein (LRP), a multi-ligand endocytosis receptor of the liver {Saenko,1999 #39}.

[0202] The Factor VIII used in embodiments of the present invention, which comprises formulation 100, typically comprises human Factor VIII and can 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 the insertion, deletion, or substitution of one or more amino acids.

[0203] Types of Factor VIII delivered according to embodiments of the present invention Various embodiments of the present invention contemplate the delivery of several different types of available Factor VIII replacement therapies. The first is plasma-derived concentrated Factor VIII. Typically, such plasma-derived Factor VIII is extracted from pooled human plasma and purified to minimize contamination by pathogens (e.g., ALPHANATE and HUMATE-P). The second is recombinant human Factor VIII produced in mammalian cell lines from recombinant DNA technology that yields full-length human Factor VIII protein (e.g., HELIXATE®, KOGENATE®, RECOMBINATE®, and ADVATE®). The third is recombinant human Factor VIII modified from the wild-type version, and the most common modification is B-domain deletion (e.g., REFACTO, AFSTYLA, and NOVOEIGHT). Finally, some products contain Factor VIII, either wild-type or recombinant, or any analog thereof, which is T 1 / 2Also known as, it is modified to increase the half-life in circulation. Examples of such modifications include PEGylation and Fc fusion. PEGylation is the covalent attachment of PEG (polyethylene glycol) chains to a drug or other therapeutic agent. PEG is also non-toxic and biocompatible. Due to these material properties of PEG and other material properties, PEG is well-suited to increasing the circulation half-life of unstable drug molecules, including unstable biotherapeutics such as factor VIII or other coagulation factors. In particular, the hydrophilicity of the PEG polymer allows the binding of water molecules to form a water layer on the surface of the PEGylated drug. This increases the hydrodynamic radius of the biopharmaceutical, hindering and decreasing renal clearance. In addition, PEGylation provides steric hindrance against proteolysis, binding of opsonin proteins, and interaction with clearance receptors such as the RES or cell surfaces. PEGylation of lipid particles containing therapeutic proteins such as FVIII is an alternative option that confers the protective and beneficial effects of PEG on the particles without the risk of altering important functions by covalently binding to the protein. Within the particle itself, FVIII is either encapsulated in the lumen or inserted into the lipid bilayer. The protein can be released from the particle in vivo and participate in necessary intermolecular interactions such as binding to VWF. Next, a brief description of the above types of factor VIII is presented.

[0204] Embodiments of stabilized factor VIII delivery according to embodiments of the present invention In certain embodiments, the present invention provides a therapeutic preparation for the treatment of coagulation disorders comprising a stabilized form of Factor VIII (or other coagulation factor) so as to increase the circulating half-life of the drug, and thereby its AUC, as well as another one of bioavailability. Stabilization can be achieved by one or both of the following approaches: i) chemically complexing a given type of Factor VIII (e.g., wild or recombinant) with a stabilizer, or ii) including in the therapeutic preparation 100 comprising Factor VIII an excipient comprising a stabilizer. Examples of chemical complexing methods and agents include those by PEGylation in which the FVIII molecule is complexed with a PEG molecule or by Fc fusion, both of which are described in more detail herein. For example, von Willebrand factor, or other stabilizers for chemical complexing, including one or more hydrogels, may also be considered.

[0205] In various embodiments, the stabilizer / excipient can be heterogeneously mixed with the Factor VIII product in the formulation of the therapeutic preparation 101. Alternatively, it can also be applied as a coating. Examples of stabilizing excipients include calcium, von Willebrand factor, albumin, and non-chelating protease inhibitors such as heparin and DFP (diisopropylfluorophosphate). In certain embodiments, the stabilizing excipient included in the preparation 101 comprising Factor VIII can include a combination of heparin, DFP, and calcium. In the case of von Willebrand factor (VWF), in certain embodiments, it can be mixed with a specific Factor VIII in a ratio of about 1:1, whereby most of the Factor VIII of TPM140 binds rapidly to VWF to form an FVIII:VWF complex that protects the stability of FVIII when passing through the intestinal wall and / or peritoneal wall. In the case of calcium, it is desirable to include a sufficient amount of this chemical such that when the drug section 142 dissolves in tissue (e.g., the wall of the small intestine or the peritoneal wall or peritoneal cavity) and moves through the peritoneal wall into the portal vein or other vascular systems, it is surrounded by a liquid containing the calcium concentration normally found in the blood, e.g., 8.6 - 10.3 mg / dl. Considering the small size of TPM140 in the mm range and the low amount of Factor VIII usually contained therein (1 - 3 mg), the amount of calcium contained within TPM140 can be less than 2 mg, including 1, 0.5, and 0.254 mg in certain embodiments. In use, the delivery of the stabilized form of Factor VIII reduces one or both of the required dosage and the frequency of drug administration. Also, since the plasma concentration of Factor VIII in the patient is maintained within the desired therapeutic range over a long period, the incidence of bleeding is also reduced.

[0206] Embodiment of a Factor VIII preparation containing an anticoagulant.

[0207] In various embodiments, the stabilizer / excipient can include a drug configured to reduce or eliminate aggregation of FVIII or FVIIIA molecules in vivo and / or during lyophilization or other manufacturing processes used to manufacture FVIII or FVIIIA therapeutic preparations. Such preparations have several advantages as will be described hereinafter. Recombinant factor VIII (rFVIII) has a potential to develop immunogenicity in 25-30% of patients receiving treatment for hemophilia A. The main cause of immunogenicity is the formation of aggregates, either during the manufacturing process or in vivo. Thus, embodiments of the present invention contemplate including in a therapeutic agent an FVIII, FVIIIA (or other clotting factors described herein) drug that can protect factor VIII protein from aggregation due to compression stress and other forces or reactions during the manufacturing (lyophilization) process used to create the FVIII, FVIIIA preparation 101 and / or to create the drug moiety 142 (also referred to as a microtablet). Examples of such anti-aggregants that can be included as excipients in the preparation 101 include amino acids such as arginine (positively charged), glutamic acid (negatively charged), and leucine (non-polar). Such drugs can stabilize rFVIII during lyophilization and storage by preventing protein-protein interactions and additional hydrogen-bonding interactions between components in the formulation. Another example of an anti-aggregant includes poloxamer F-68, a non-ionic surfactant. In particular, poloxamer F-68 functions to protect FVIII from stress during the lyophilization and microtabletization processes (processes used to compress or otherwise form the drug section 142 and / or the TPM 14).

[0208] Embodiment of a factor VIII preparation containing a permeability enhancer.

[0209] Considering the large size of FVIII, membrane permeability, particularly serosal or other peritoneal permeability, can play an important role in enhancing protein uptake into the lymphatic system during intraperitoneal delivery according to embodiments of the device 10 and capsule 20. Accordingly, embodiments of the present invention contemplate the addition of a membrane permeability enhancer to the therapeutic preparation 101 and / or the drug moiety 142 to facilitate the uptake of FVIII through the peritoneum. An example of such a permeability enhancer includes hyaluronidase. This compound allows the solution of FVIII or FVIIIA formed by the dissolution / bio-degradation of TPM140 and / or the drug moiety 142 to spread over a wider area of the peritoneum when it degrades. Hyaluronic acid also enhances the diffusion capacity and bioavailability of FVIII, FVIIIA, or other coagulation factor preparations 101 in the form injected / delivered into the jejunum. This, in turn, results in another improvement in the C max , bioavailability, and one of the other AUCs. For example, if the addition of hyaluronidase further increases the uptake of FVIII by 10%, the C max , and the previously defined AUC for PEGylated FVIII increase proportionally. This increase is reflected in an 8 - 12% increase in the bioavailability of PEGylated FVIII. Table 4 below provides exemplary weight ratios of FVIII or FVIIIA molecules (or other coagulation factors described herein) to excipients in the drug moiety 142 / preparation 101 for various stabilizers, anticoagulants, and permeability enhancers described herein.

Table 4

[0210] ADVATE (recombinant antihemophilic factor (rAHF), available from Shire Corporation) is a purified glycoprotein consisting of 2,332 amino acids, synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line and free of plasma or albumin. The CHO cell line used for the production of ADVATE is derived from that used for the biosynthesis of RECOMBINATE. ADVATE has been shown to be comparable to RECOMBINATE with respect to its biochemical and physicochemical properties, as well as its nonclinical in vivo pharmacological actions. rAHF synthesized by CHO cells has the same biological effect on coagulation as human antihemophilic factor (hAHF). Structurally, the recombinant protein has a combination of heterogeneous heavy and light chains similar to that found in human antihemophilic factor. ADVATE is formulated as a sterile, nonpyrogenic powder for intravenous injection. von Willebrand factor (VWF) is co-expressed with factor VIII and helps to stabilize it in culture. The final product contains less than 2 ng of VWF per 1 IU of rAHF. The specific activity of ADVATE is 4,000 to 10,000 international units per milligram of protein. For prophylaxis, factor VIII at a dose of 20 to 40 IU per kilogram of body weight can be used every other day (3 to 4 times a week).

[0211] PEGylated FVIII ADYNOVATE® PEGylated FVIII (available from Shire Corporation) is recombinant full-length human coagulation factor VIII (2,332 amino acids with a molecular weight (MW) of 280 kDa) covalently linked to one or more polyethylene glycol molecules (MW 20 kDa).

[0212] ESPEROCT ESPEROCT (registered trademark), available from Novo Nordisk, is a recombinant analogue of human coagulation factor VIII (FVIII) conjugated with the chemical name of a 40 kDa polyethylene glycol (PEG) molecule. The official chemical name of ESPEROCT is turoctocog alfa pegol (abbreviated as N8-GP), which is a PEGylated version of turoctocog alfa. It was approved by the FDA in February 2019. N8-GP has indications for use in adults and children of all ages with hemophilia A for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding symptoms, and perioperative management of bleeding. Basically, N8-GP is identical to turoctocog alfa, a recombinant human coagulation factor VIII (rFVIII), and has a truncated B domain made from the sequence encoding 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the naturally occurring B domain. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without the addition of any human or animal-derived substances

[11] . During secretion, some rFVIII molecules are cleaved at the C-terminus of the heavy chain (HC) at amino acid 720, and a monoclonal antibody that binds to the C-terminus at this position is used in the purification process, enabling the isolation of intact rFVIII. It was developed by Novo Nordisk and approved by the US FDA on October 16, 2013. However, the essential difference between turoctocog alfa and N8-GP is the specific attachment of a 40 kDa polyethylene glycol (PEG) group to specific O-glycans of the truncated B domain of the general turoctocog alfa rFVIII structure. This modification to the general turoctocog alfa rFVIII structure extends the in vivo half-life of N8-GP and converts it into an extended half-life factor VIII molecule for factor VIII replacement therapy in patients with hemophilia A. N8-GP has been shown to provide effective regular prophylaxis for people with severe hemophilia A with a fixed dosing regimen of one injection every 4 days in adults and adolescents, or every 3 - 4 days (twice a week) in children. Additionally, N8-GP provided effective prophylaxis and maintained a low mean annual bleeding rate (ABR) of 1.18.Furthermore, N8-GP was also found to be effective in the treatment and management of bleeding episodes and in the perioperative management of bleeding. Across clinical trials and all age groups, N8-GP was shown to have high tolerability and no safety concerns were identified. The overall safety profile of N8-GP is similar to that reported for other long-acting FVIII products.

[0213] ALPHANATE ALPHANATE (registered trademark, 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 viral load. The coagulation-promoting activities of both factors are reported in international units (IU). The final product is stabilized by the addition of human albumin. 1 IU of factor VIII contained 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 per mg of protein. For prophylaxis in patients with hemophilia A, the dosage in IU and frequency of infusion are determined on a case-by-case basis by an experienced physician. The pharmacokinetic profile was evaluated in 12 adult patients with severe hemophilia A and the mean half-life was 17.9 ± 9.6 hours at 96.7 ± 14.5% at 10 minutes after infusion. The recovery at 10 minutes after infusion was also determined as 2.4 ± 0.4 IU factor VIII increase / dL plasma per 1 IU factor VIII / kg body weight infused.

[0214] ELOCTATE ELOCTATE (registered trademark) is available from Biogen Corporation. The active ingredient of 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 endogenous factor VIII), which are joined by 14 out of 908 amino acids from the central B domain. The FVIII portion has post-translational modifications comparable to endogenous factor VIII. The Fc domain of the molecule contains the hinge, CH2, and CH3 regions of IgG1. BDD-rFVIIIFc contains 1,890 amino acids with an apparent molecular weight of 220 kDa. Most of the expressed protein is cleaved into a two-chain molecule, although ELOCTATE may also contain up to 39% of the single-chain, unprocessed form. Both molecules have been shown to have equivalent factor VIII activity. The protein is produced by a human fetal kidney cell line and purified from the cell culture medium. ELOCTATE is provided as a sterile, non-pyrogenic, lyophilized powder containing reconstitution and IV injection water. It is available in different potencies. For routine prophylaxis, 50 IU / kg every 4 days is recommended. The dosage needs to be adjusted based on the patient's response and administration is in the range of 25 - 65 IU / kg at 3 - 5 day intervals.

[0215] HUMATE-P HUMATE(registered trademark)-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 fresh pooled human plasma. Depending on the PK of the individual patient, dosing can be repeated every 6, 8, or 12 hours.

[0216] HELIXATE FS and KOGENATE FS HELIXATE(registered trademark) FS (available from CLS Behring) and KOGENATE(registered trademark) FS (available from Bayer Corporation) are manufactured by introducing full-length human factor VIII into baby hamster kidney cells. The resulting factor VIII protein is then purified and does not contain animal proteins. The biological activity of this product is the same as that of plasma-derived human factor VIII. The active ingredient is the same in both HELIXATE FS and KOGENATE FS, because both APIs are produced by Bayer and HELIXATE FS is distributed by CLS Behring under an agreement between the two companies. The recommended prophylactic dosing regimen for both drugs is 25 IU / kg three times a week in adults and 25 IU / kg every other day in children.

[0217] RECOMBINATE RECOMBINATE (registered trademark, 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 medium using a series of chromatography columns. The synthetic rFVIII produced by the CHO cells has the same biological effects as human factor VIII. Structurally, the protein has a combination of heavy and light chains similar to that 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 recombinant VWF (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 twice the patient's baseline, assuming the patient's baseline is less than 1%. Therefore, to increase the patient's FVIII activity by X%, the IU dose needs to be approximately (X * kg) / 2. In a PK study of 69 patients, the mean circulating half-life of RECOMBINATE was 14.6 ± 4.9 hours (n = 67). The actual baseline recovery observed with RECOMBINATE was 123.9 ± 47.7 IU / dL (n = 23), and the calculated ratio of the actual to expected recovery with RECOMBINATE was 121.2 ± 48.9%.

[0218] Delivery of factor VIII product via embodiments of the present invention. As described herein, various embodiments of the present invention, including the swallowable device 10 and the therapeutic preparation 100, can be adapted for oral delivery of factor VIII replacement therapy for the treatment of various coagulation disorders. According to one embodiment, the expected prophylactic dosing regimen for oral delivery of factor VIII using an embodiment of the device 10 corresponds to one tablet per day orally, and the amount of IU per tablet is calculated based on the recommendations of the manufacturer of the pharmaceutical active ingredient. Other embodiments contemplate more frequent (e.g., twice a day) or less frequent (once every 2, 3, 5, 7, or other number of days) delivery. More specific dosing regimens for particular types of factor VIII are described below.

[0219] Dosing regimens for particular types of factor VIII HELIXATE® FS and KOGENATE® FS have a recommended dose of 25 IU / kg three times a week (about every 2 days). For these compounds, the total dose for a 70 kg adult is 1750 IU every 2 days, which is 875 IU per day when delivered orally in the form of the oral device 10 / capsule 20. Since both HELIXATE FS and KOGENATE FS have a specific activity of 4000 IU per mg of protein, a daily dose of 875 IU corresponds to approximately 0.22 mg of factor VIII, which can be easily delivered by a single oral capsule 20 per day. ELOCTATE is administered at a dose of 50 IU / kg every 4 days. Thus, the total dose for a 70 kg adult, which is a normal body weight, is 3500 IU every 4 days, which corresponds to approximately 875 IU per capsule per day when delivered orally in the form of capsule 20. Since the specific activity of ELOCTATE is 4000 - 10020 IU per mg of protein, a daily dose range of 0.22 - 0.00 mg can be administered in a single oral capsule. The recommended doses of AFSTYLA and PEGylated FVIII are approximately 20 - 50 IU / kg every 2 or 3 days.

[0220] Next, the range for a 70 kg adult is 1400 - 3500 IU every 2 / 3 days, which corresponds to approximately 700 - 1750 IU per day if the administration occurs every 2 days, or approximately 467 - 1167 IU per day if the administration occurs every 3 days. Thus, these dosages correspond to a daily dose between 467 - 1750 IU (depending on the patient and the active ingredient) when orally delivered in embodiments 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 by one oral device per day. Finally, in the case of PEGylated FVIII having a specific activity of 2700 - 8000 IU / mg, the daily dosage range administered orally by a single capsule 20 is 0.06 - 0.65 mg. All of these dosages can be adjusted, for example increased (e.g., 2-fold, 3-fold, 4-fold, etc.), to account for a decrease in bioavailability for a particular route of administration (e.g., delivery into the peritoneal cavity versus IV injection). Even in cases where the dosage is 2-fold, 3-fold, etc., a single device daily oral device 10 / capsule 20 is sufficient to administer a therapeutic dose of factor VIII.

[0221] For 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 (such as mg) of the drug to be administered using embodiments of device 10 to achieve the desired therapeutic effect (e.g., improvement in coagulation, shortening of coagulation time, etc.). For example, the recommended dosing regimen for ADVATE is 20 - 40 IU / kg every other day. For a 70 kg adult, this is 1400 - 2800 IU every other day, or 700 - 1400 IU per day. Since the specific activity of ADVATE is 4000 - 10,000 IU per mg of protein (e.g., Factor VIII), the therapeutic range of the drug in mg is in the range of 0.07 - 0.14 mg (considering the dose in IU and a maximum factor activity of 10,000 IU / mg) or 0.175 - 0.35 mg (considering the dose in IU and a minimum factor activity of 4000 IU / mg). These doses can be administered by a single oral device 10 / capsule 20 per day. A similar calculation for REFACTO, which has a daily dosing regimen of 40 - 225 IU / kg and thus 280 - 15750 IU for a 70 kg adult, results in a daily dose range of 0.02 - 1.15 mg when the factor activity is 9110 IU / mg and 0.03 - 1.73 mg when the factor activity is 13700 IU / mg. One capsule per day can deliver these therapeutic ranges. NOVOEIGHT has a specific factor activity of 8340 IU / mg and a dosing regimen of 20 - 60 IU / kg every other day, considering the entire prophylactic dosing range for children and adults with a combination of the lowest and highest doses in a single range. For adults, according to one or more embodiments, the daily low dose of NOVOEIGHT is 2800 IU / day (assuming, for example, a 70 kg patient × 2 × 20 IU / kg) and the high dose of 8400 IU / day (assuming 70 kg X 2 X 60 IU / kg). When converted to milligrams and delivered orally using embodiments of capsule 20 or other oral delivery means contemplated by embodiments of the present invention, the dose range is approximately 0.34 - approximately 1 mg per day.Various embodiments of the device 10 and the capsule 20 can be readily configured to deliver any of the aforementioned doses of Factor VIII product by manufacturing a needle or other form of tissue penetrating member 40, 140 that contains such a dose. In particular, a single needle or other form of tissue penetrating member 40 or 140 can be configured to contain any of these doses.

[0222] Embodiments that explain the adjustment of the administration of Factor VIII and other coagulation factors In various embodiments, adjustments can be made for variations in the potency (expressed as IU / mg) of a given source or batch of Factor VIII or any of the clotting factors described herein. Thus, for example, in the case of an increase in potency (e.g., an increase in IU per mg of Factor VIII or other clotting factor), the mg per capsule can be decreased, resulting in a decrease in the number of capsules required. Also, a decrease in the bioavailability of a given clotting factor delivered via the oral route of administration according to an embodiment of the oral device 10, relative to the bioavailability of the drug when delivered by IV infusion, can be taken into account in the dosage. In particular, such reduced bioavailability of a clotting factor within the oral device 10 delivered to a specific location within the GI tract, such as one or more of the small intestinal wall, peritoneum, or peritoneal cavity, can be considered. For example, in the case of delivery of Factor VIII (or other clotting factors described herein) to the peritoneal cavity according to an embodiment of the oral device 10, the bioavailability can be about 50% of the bioavailability of intravenously infused Factor VIII. See “Intravascular of VWF and Factor VIII following Intraperitoneal Injection and differences from Intravenous and Subcutaneous 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, either the mg of drug per capsule, or the number of capsules taken, for any of the described Factor VIII dosages can be increased by a factor of two, or another amount, compared to other decreases in bioavailability.

[0223] Embodiments of a therapeutic composition comprising Factor VII As described 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 the Factor VII compound is presented. Factor VII (EC 3.4.21.21, blood coagulation Factor VII, described as 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 for hemophilia patients with Factor VII deficiency and for patients who express inhibitor antibodies to one or more of the clotting factors including Factor VIII. It is also used off-label for controlling bleeding in trauma patients and for treating cerebral hemorrhage. It is an enzyme of the serine protease class, produced by hepatocytes and excreted into the circulatory system. The excreted glycoprotein is a single chain of 406 amino acids with a mass of approximately 50 kDa and is converted to the active form by proteolytic cleavage and other mechanisms. Several factors including Factor IXa, Factor Xa, Factor XIIa, or thrombin can lead to the proteolytic cleavage of Factor VII. After proteolysis of a 38 - 60 amino acid sequence, FVII is converted into two chains connected by disulfide bonds, including the active form or FVIIa. The light chain (152aa) contains domains for epidermal growth factor and an unusual phospholipid binding, as well as carboxylated glutamic acid residues that bind calcium ions, and the heavy chain (254aa) contains serine protease activity that catalyzes the activation of Factor IX and Factor X to their active forms.

[0224] As used herein, the term "Factor VII" includes both uncut FVII (zymogen) and the active form of Factor VII known as Factor VIIa. Also, various embodiments of Factor VII can correspond to polypeptides that include the 1-406 polypeptide sequence of wild-type human Factor VII (disclosed in U.S. Patent No. 4,784,950), or to 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 variations of Factor VII that may exist, as well as any form or degree of glycosylation or other post-translational modifications. The term "Factor VII" also includes variants of Factor VII that have 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 the insertion, deletion, or substitution of one or more amino acids. The term "biological activity of Factor VII" includes, for example, the ability to generate thrombin on the surface of activated platelets.

[0225] Typical doses of Factor VIIa for the treatment of bleeding episodes in hemophilia patients using inhibitors are 90 μg / kg, repeated every 2 - 6 hours until hemostasis is achieved. Doses of 13.3 - 22 μg / kg are used for FVII replacement therapy, and doses of 20 - 160 μg / kg are used for trauma and intracranial hemorrhage patients. Unfortunately, Factor VIIA has a short half-life of 2 - 4 hours and requires frequent IV injections. To extend the half-life of Factor VIIA, subcutaneous injection has been investigated as an alternative to intravenous injection, 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 for the administration of Factor VII. Thus, delivery of Factor VII or Factor VIIa by embodiments of the swallowable delivery device 10 presents several distinct advantages, including increased bioavailability and the reduction or elimination of the need for multiple infusions during the day. The latter factor provides a significant improvement in the quality of life of the patient by eliminating the need to go to the hospital or for home infusions.

[0226] Delivery of Factor VII product via embodiments of the present invention.

[0227] According to one embodiment, the expected prophylactic dosing regimen for oral delivery of Factor VII using an embodiment of device 10 corresponds to 1 tablet per day orally, and the amount of IU per tablet is calculated based on the recommendations of the manufacturer of the pharmaceutical active ingredient. Other embodiments contemplate more frequent (e.g., twice a day) 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 can range from about 10 - 90 μg / kg, and for patients with acquired hemophilia, 70 - 90 μg / kg every 2 - 3 hours, for patients with congenital Factor VII deficiency, 15 - 30 μg / kg every 4 - 6 hours, for patients with congenital hemophilia A or B with inhibitors, 90 μg / kg every 2 hours, or for patients with Glanzmann thrombasthenia, 90 μg / kg every 2 - 4 hours, are specific dosage ranges. The dosages described above are administered during bleeding episodes until hemostasis is achieved (e.g., bleeding stops and / or significantly decreases). In the case of patients with congenital hemophilia A or B with inhibitors, after hemostasis is achieved, a dose of 90 μg / kg can be administered every 3 - 6 hours to maintain the hemostatic plug achieved by previous administrations. It is also possible to consider converting the above dosages to active units in terms of IU unit names.

[0228] Types of Factor VII delivered by embodiments of the present invention According to embodiments of the present invention, several types of Factor VII can be used to deliver a therapeutic preparation 100. In various embodiments, the types of Factor VII included in the therapeutic preparation 100 typically include human Factor VII or Factor VIIa, and can be in a naturally occurring form or a 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 the wild-type activity, but is a mutant of wild-type Factor VII or Factor VIIa that differs from the wild-type Factor VII or Factor VIIa by one or more amino acid insertions, deletions, or substitutions. Specific commercial types of Factor VII that can be used according to embodiments of the present invention include, but are not limited to, NOVOSEVEN®, NOVOSEVEN RT®, and ARYOSEVEN® described below. These forms and other forms of Factor VII can be obtained / produced in various ways, for example, from non-frozen precipitation fractions from human plasma, or by genetic engineering from cells or transgenic animals. According to certain embodiments, human Factor VII is produced in the milk of non-human transgenic mammals that have been genetically engineered to produce this protein. Preferably, it is the milk of transgenic rabbits or goats. Secretion of Factor VII by the mammary gland enables secretion into the milk of the transgenic mammal and involves tissue-dependent regulation of Factor VII expression. Such control methods are well known in the art. Expression control is carried out using sequences that enable expression of the protein in specific tissues of the animal. These include the promoter sequences WAP, β-casein, β-lactoglobulin, and signal peptide sequences. In particular, the process for extracting the protein of interest from the milk of transgenic animals is described in the patent European Patent EP0264166.

[0229] NOVOSEVEN and NOVOSEVEN RT According to one or more embodiments, the type of factor VII delivered by an embodiment of device 10 may correspond to NOVOSEVEN®, a recombinant human factor VIIa (available from NovoNordisk Corporation) that has received FDA approval for uncontrolled bleeding in hemophilia patients. It may also correspond to a variant of NOVOSEVEN known as NOVOSEVEN® RT, also available from NovoNordisk. In particular, NOVOSEVEN RT is manufactured at room temperature, enabling it to be stored without refrigeration. In related or additional embodiments, it may correspond to a biosimilar of factor VIIa, such as ARYOSEVEN® available from Aryogen Pharmed.

[0230] A summary of the overview of NOVOSEVEN is provided, and this overview also applies to NOVOSEVEN 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. When comparing administrations for the treatment of hemophilia vs congenital factor VII deficiency, the pharmacokinetic profile of NOVOSEVEN is different. According to clinical studies reported by NovoNordisk in the prescribing information for NOVOSEVEN, the single-dose pharmacokinetics of NOVOSEVEN (17.5, 35, and 70 μg / kg) showed dose-proportional 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 / hr (range 27 - 49). The mean 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 was 44% (30 - 71%). In clinical trials regarding the treatment of factor VII deficiency, the pharmacokinetics of single-dose NOVOSEVEN at doses of 15 and 30 μg per kg of body weight did not show a significant difference between the two doses with respect to the dose-dependent parameters, namely, systemic clearance (70.8 - 79.1 mL / hr×kg), volume of distribution at steady state (280 - 290 mL / kg), mean residence time (3.75 - 3.80 hr), and half-life (2.82 - 3.11 hr). The mean in vivo plasma recovery rate was approximately 20% (18.9% - 22.2%).

[0231] Dosing regimens of NOVOSEVEN and NOVOSEVEN RT The dosing regimens of NOVOSEVEN and NOVOSEVEN RT for patients with acquired hemophilia and congenital factor VII deficiency are explained together with the theoretical basis for each coagulation disorder. These regimens apply to both NOVOSEVEN and NOVOSEVEN RT. The recommended dose of NOVOSEVEN or NOVOSEVEN RT for the treatment of hemophilia patients is in the range of 70 - 90 μg per kg of patient body weight, repeated every 2 - 3 hours until hemostasis is achieved. Thus, for a 70 kg patient, the required dose is 4.9 - 6.3 mg of NOVOSEVEN rFVIIa every 2 - 3 hours. Considering that the bioavailability of FVII by intraperitoneal delivery is approximately 50%, the average dose for a 70 kg patient is in the range of 9.8 - 12.6 mg every 2 - 3 hours. In an embodiment of 20 capsules configured to carry a drug between about 3 mg and 9 mg, this would be about 1 - 3 capsules every 2 - 3 hours.

[0232] In the case of 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, in the case of a 70 kg patient, the required dose of the drug is in the range of 1.05 - 2.10 mg every 4 hours. Considering the reduction in bioavailability of factor VII by peritoneal delivery (50%), the required dose of NOVOSEVEN or NOVOSEVEN RT is approximately 2.10 - 4.20 mg every 4 hours. In an embodiment of capsule 20 configured to carry a drug between about 1 mg and 4 mg, this would be approximately 1 - 2 capsules every 4 hours.

[0233] Embodiment of a therapeutic composition comprising factor IX As discussed herein, various embodiments of the present invention provide therapeutic compositions comprising clotting factors such as factor IX for the treatment of various clotting disorders such as congenital and acquired hemophilia. Thus, a brief description of factor IX compounds is presented. Coagulation factor IX (FIX) is an important element of the coagulation cascade and is the causative agent of 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 leads to hemophilia B. FIX is activated by activated factor IX (FIXa) of the intrinsic coagulation pathway. FIXa in combination with factor VIIIc promotes the coagulation cascade by activating factor X (FX) to Xa, resulting in the conversion of prothrombin to thrombin and causing the formation of a fibrin clot. Activation of FIX consists of two steps. First, an internal peptide bond is cleaved, resulting in the formation of a two-chain intermediate cross-linked by disulfide bond(s). 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. There are several FIX replacement products and therapies currently available on the market. They include, among others, Alphanine SD, Alprolin, Bebulin, Bebulin VH, Benefix, Idelvion, Ixinity, Immunine, Mononine, Profilnine SD, Proplex, and Rixubis. A brief description of five of the above types of factor IX is presented below.

[0234] Mononine (CSL Behring) Mononine (registered trademark) is the human-derived form of Factor IX available from CLS Behring. It is purified from foreign plasma-derived proteins using immunoaffinity chromatography. Specifically, a mouse monoclonal antibody against FIX is used as an affinity ligand to capture and extract FIX. Mononine is administered 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.

[0235] There were two clinical studies (patients, n = 81) conducted by Behring on the use of Mononine for the treatment of hemophilia B, as reported in the prescribing information for Mononine (see http: / / labeling.cslbehring.com / pi / us / mononine / en / mononine-prescribing-information.pdf). The studies evaluated both the safety and efficacy of Mononine. Infusion of FIX complex concentrates containing various but significant amounts of other liver-dependent blood coagulation proteins (e.g., factor II, factor VII, and factor X) into patients with hemophilia B resulted in FIX recovery ranging from approximately 0.57 to 1.1 IU / dL increase per IU / kg body weight infused, and the plasma half-life of factor IX ranged from approximately 23 to 31 hours. Five patients (6%) reported side effects. The doses administered to 36 subjects ranged from 71 to 161 IU / kg. The average recovery tended to decrease as the dose of Mononine increased. That is, 1.09 ± 0.52 K (n = 38) at doses exceeding 75 - 95 IU / kg, 0.98 ± 0.45 K (n = 21) at doses exceeding 95 - 115 IU / kg, 0.70 ± 0.38 K (n = 2) at doses exceeding 115 - 135 IU / kg, 0.67 K (n = 1) at doses exceeding 135 - 155 IU / kg, and 0.73 ± 0.34 K (n = 5) at doses exceeding 155 IU / kg. Of the 36 subjects who received these high doses, only 1 (2.8%) reported an adverse experience that might be related to Mononine ("difficulty concentrating", the subject recovered). No thrombotic complications were observed or reported for any patient. A very small number of patients showed hypersensitivity reactions, including anaphylaxis. Other reactions include, but are not limited to, headache, nausea, fever, chills, flushing, vomiting, pruritus, fatigue, and dizziness. The dosing regimen depends on the FIX level during hemostasis in patients undergoing minor and / or major surgery. Pharmacokinetic (PK) and pharmacodynamic (PD) data for Mononine have not been reported.

[0236] Idelvion (CSL Behring) Idelvion, available from CSL Behring, is a recombinant Factor IX fused with recombinant albumin. This fusion drug increases the half-life of Factor IX in Idelvion several-fold compared to the half-life of plasma-derived FIX. For example, in the case of a single dose of 75 IU / kg Idelvion, T 1 / 2 was determined to be 104 hours. C max was determined to be 82 IU / dL, but the clearance (Cl) rate was 0.84 mL / h / kg. The mean 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 doses. For routine prophylaxis, the dose for patients (>12 years) is approximately 25 - 40 IU / kg body weight every 7 days. The dose for the control and prevention of bleeding episodes depends not only on the patient's condition but also on various parameters (e.g., body weight, desired FIX increase).

[0237] Rixubis (Baxter pharmaceuticals) Rixubis (registered trademark), also known as BAX326, is a recombinant coagulation Factor IX available from Baxter Pharmaceuticals for the treatment of hemophilia in adults and children. BAX326 was developed using recombinant Chinese hamster ovary (CHO) cell clones in suspension culture. Its amino acid sequence is identical to that of the Ala-148 allele type pdFIX (Immunine), and its structural and functional characteristics are also the same. The CHO cell line that secretes FIX is purified by affinity chromatography. The specific activity of Rixubis was determined to exceed 200 IU per milligram of 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 disorder in hemophilia patients by increasing the plasma level of FIX and decreasing the (in vitro thromboplastin time) aPTT. Mean C maxwas determined to be 0.95 IU / dL, while the mean clearance rate (Cl) was 6.0 mL / kg / hr. The mean 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 relate to the repeated dosing of Rixubis. The recommended dose for patients over 12 years old is 0.7 IU of plasma (0.7% of normal).

[0238] AlphaNine SD (Alpha Therapeutic Corporation) AlphaNine® SD, a coagulation factor IX (human), is a purified, solvent-detergent-treated, virus-filtered preparation of factor IX derived from human plasma. It contains a minimum of 150 IU of factor IX / mg of protein, and factor VII (proconvertin), factor II (prothrombin), and factor X (Stuart-Prower factor) are below the limit of detection (less than 0.04 factor VII units, less than 0.05 factor II units, and less than 0.05 factor X units per IU of factor IX). AlphaNine SD is a sterile, lyophilized preparation intended only for intravenous administration. Each vial is a single-dose container. AlphaNine SD is labeled with the factor IX potency expressed in international units (IU). The AlphaNine SD preparation 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. No preservatives are included. AlphaNine SD is a purified preparation of factor IX containing more than 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.

[0239] BeneFIX (Pfizer) BeneFIX (registered trademark), that is, recombinant coagulation factor IX, is a purified protein produced by recombinant DNA technology. The product is formulated as a sterile, non-pyrogenic, lyophilized powder preparation intended for intravenous injection. It is available in single-use vials containing the labeled amount of factor IX activity expressed in international units (IU). Each vial contains nominally 250, 500, 1000, 2000, or 3000 IU of recombinant coagulation factor IX. The potency (IU) is determined using the World Health Organization (WHO) international standard for factor IX concentrates by the one-stage in vitro clotting method. 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 concentrations of the excipients are sodium chloride, L-histidine, 0.8% sucrose, glycine, and polysorbate 80. The specific activity of BeneFIX is 200 IU or more per milligram of protein. It has the same primary amino acid sequence as human factor IX of the Ala148 allele type and has structural and functional characteristics similar to those of the endogenous factor IX. BeneFIX is produced by a genetically engineered Chinese hamster ovary (CHO) cell line that has been extensively characterized. The CHO cell line secretes recombinant factor IX into a defined cell culture medium, and the recombinant factor IX is purified by a chromatographic purification process.

[0240] Dosing regimens for specific types of factor IX 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 per 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 amounts to 1400 - 2100 IU. Also, since the specific activity of Factor IX in Mononine is approximately 190 IU / mg, the weight of Factor IX required for a 70 kg person ranges from approximately 7 mg to 10.6 mg per day. Embodiments of the oral delivery device 10 containing 20 capsules can be configured to deliver 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 amounts to approximately 3 - 4 capsules per day, and when it is 4 mg per tablet, it amounts to 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 can be configured to deliver a second dose (e.g., 2 mg). Such embodiments of multiple devices 10s can be configured as a daily dosing regimen for the delivery of Factor IX or other clotting factors described herein. The above calculations are based on the potency (e.g., IU / mg) of commercially available forms of Factor IX. As described above for Factor VIII, adjustments can be made to account for the decreased bioavailability of the drug with intraperitoneal administration relative to intravenous injection.

[0241] Some recombinant factor IX, such as Rixubis, is administered at a dosage of 40 - 60 IU / kg body weight (e.g., for a 70 kg subject, 2800 IU - 4200 IU) twice a week. The specific activity of Rixubis has been reported as 200 IU / mg (dosage, 0.25 mg / kg). Thus, this amounts to 14 mg - 21 mg of factor IX protein every other week. Using an embodiment of device 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 contemplated. Thus, for example, with a dosage of 3 mg per capsule and 21 mg per week, the patient could take 1 capsule per day. For 3 mg capsules and 42 mg per week, this would be 2 capsules per day.

[0242] In the case of long - acting Idelvion or Alprolix (having a specific activity of 55 - 84 IU / mg), drug administration is not as 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 to 100 IU / kg (which would be approximately 100 mg / week for a 70 kg patient). In the case of AlphaNine, the dosage for a 70 kg patient is 2800 IU (18.6 mg / week of AlphaNine for a 70 kg patient). Similar dosages are replicated for other FIX 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 patient prophylaxis. Pfizer reports in the 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 of the patient's body weight. For a 70 kg patient, this would be a dosage of approximately 25 mg / week or 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 approximately 1 capsule per day if administered daily.

[0243] As described above for Factor VIII, the adjustment of the dosage of Factor IX product can be readily made taking into account the decreased bioavailability of Factor IX in any of the above-described commercial forms when delivered intraperitoneally.

[0244] Embodiments of a therapeutic composition comprising Factor X As described 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. Thus, a brief description of the Factor X compound is presented here. 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 eight exons, each of which encodes a specific domain within the protein. Exon 1 encodes the signal peptide, exon 2 encodes the propeptide and the gamma-carboxyglutamic acid (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 is composed 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.

[0245] Active Factor X (known as FXa) is a catalytic serine protease that is generated when prothrombin is cleaved at the heavy chain to release 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 with calcium ions on the phospholipid surface. Intrinsic pathway activation occurs through 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 in 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 removed from circulation.

[0246] Factor X deficiency is autosomal recessive and affects 1 in 500,000 to 1 in 1,000,000 of the general population worldwide. There are two classified 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 decreased. Symptoms range from mild to moderate and severe, depending on the functional FX circulating level.

[0247] Current treatments for FX deficiency are replacement therapies with complexes extracted from human plasma. Commercially available products containing FX complexed with other coagulation factors in various amounts include Factor X P (CSL Behring) and Coagadex (BDI Pharma). Next, each of these compounds will be described, along with the dosing regimen and rationale.

[0248] Coagadex Coagadex (registered trademark) is manufactured by BDI Pharma. Coagadex contains approximately 100 IU / mL of Factor X, and the following inactive ingredients, namely chloride, phosphate, citrate, sucrose, and sodium. The specific activity of Coagadex is usually 80 - 137 IU per 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 condition. The dosage to achieve the desired in vivo peak increase in Factor X level can be calculated using the following formula: Dosage (IU) = Body weight (kg) × Desired Factor X increase (IU / dL) × 0.7. Thus, for a 70 kg patient, the administered dosage of Factor X is determined to be 1960 IU, and the desired increase in Factor X is estimated to be approximately 40%. Plasma levels of Factor X of 10 - 40% are described as having a hemostatic effect. Based on a half-life of 24 - 40 hours, if continuous treatment is required, administration of Factor X every 24 hours is usually sufficient.

[0249] Based on the above estimation, the amount of 1960 IU of Factor X protein is determined to be 14.3 mg, and the specific activity of coagulation Factor X is considered to be 137 IU Factor X / mg protein. Considering that the bioavailability of intraperitoneal delivery is approximately 50% relative to IV administration (the dosage for intraperitoneal delivery needs to be doubled), the dosage required for a 70 kg patient is approximately 28.6 mg every 24 hours. For a patient weighing 50 kg, the dosage is approximately 20 mg, and for a patient weighing 80 kg, the dosage is 33 mg. Considering this dosage range of 20 - 33 mg, in the case of an embodiment of the device 10 / capsule 20 having between approximately 4 - 9 mg of drug per capsule (for example, contained in two to three tissue penetrating members 140). This amounts to approximately 2 - 8 capsules every 24 hours.

[0250] Factor X P (Behring) Factor X P® is produced by CLS Behring and results as a powder and solvent for an injectable solution containing approximately 600 - 1200 IU of human coagulation factor X. The formulation also contains 600 IU of human coagulation factor IX, an important coagulation factor in the treatment of hemophilia. The specific activity of factor X varies between 4 - 60 IU factor X / mg protein and 3 - 38 IU factor X / mg protein. The dosage and duration of treatment depend on the severity of factor X deficiency, the location and extent of bleeding, as well as 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 per kg of body weight raises the plasma factor X activity by approximately 1.5% of normal activity. The required dose is determined using the following formula: Dose (IU) = body weight [kg] × desired factor X increase [% or IU / dl] × 0.7. Thus, for a 70 kg patient, the dose of factor X administered is determined to be 1960 IU, and the desired increase in factor X is estimated to be approximately 40%. Plasma levels of factor X of 10 - 40% are described as having a hemostatic effect. Based on a half-life of factor X of 24 - 40 hours, if continuous treatment is required, administration of FX every 24 hours is usually sufficient. Based on the above estimate, the amount of 1960 IU of factor X protein is determined to be 32.6 mg, and the specific activity of coagulation factor X is considered to be 60 IU factor X / mg protein. Considering that the bioavailability of intraperitoneal delivery is approximately 50% for IV administration, the dose required for a 70 kg patient would be approximately 65.2 mg of drug every 24 - 40 hours. In the case of an embodiment of device 10 / capsule 20 having approximately 5 - 9 mg of drug per capsule, this would be approximately 7 capsules every 24 - 40 hours.

[0251] Embodiments of biological equivalents of the coagulation factors or other coagulation proteins described herein Various embodiments of the present invention also contemplate compositions and uses of coagulation or other proteins that have an amino acid sequence and have the same or equivalent level of biological activity (e.g., coagulation function) that is within 10%, more preferably within 5%, even more preferably within 2% of the biological activity of a particular coagulation factor (e.g., Factor VIII), but is different from the coagulation factors (e.g., including Factor VII, Factor VIIa, Factor VIII, Factor IX, and Factor X) and their analogs and derivatives described herein. 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 those 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 those 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 those described in U.S. Patent No. 6,905,846, which is incorporated herein by reference for all purposes. Such mutant analog coagulation factors may include one or more additions, deletions, or substitutions of amino acids (e.g., leucine or lysine, etc.) when compared to the amino acid sequence of the parent coagulation protein (e.g., Factor VIII), but still exhibit a biological activity (e.g., coagulation function) that is essentially equivalent to that of the described coagulation protein with respect to the ability of the mutant to function in the coagulation cascade. In certain embodiments, the mutant may include a deletion in the B domain of the Factor VIII molecule. The mutant may also include modifications of the Factor VIII molecule via Fc fusion or PEGylation, and such mutations are selected to increase the circulating half-life of the selected Factor VIII molecule. Similar approaches can be used to increase the circulating half-life of one or more of Factor VII, Factor IX, and Factor X.

[0252] Pharmacokinetic measurement criteria for the delivery of coagulation factors or other coagulation proteins to the intestinal wall or surrounding tissues. 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 coagulation proteins to the intestinal wall (e.g., small intestine) or surrounding tissues (e.g., peritoneal tissue) also offer advantages with respect to one or more pharmacokinetic measurement criteria. In this regard, notable pharmacokinetic measurement criteria include C, the peak plasma concentration of the drug after administration max , C max , the time T max to reach, and the time T max required for the plasma concentration of the drug to reach half of the C max value after reaching C 1 / 2 . These measurement criteria can be measured using standard pharmacokinetic measurement techniques known in the art. For example, in one approach, plasma samples are taken at the start of administration of the coagulation factor or other coagulation protein or other therapeutic composition, either by use of a swallowable device or by non-vascular injection, and at subsequent set time intervals (e.g., 1 minute, 5 minutes, 1 / 2 hour, 1 hour, etc.). The concentration of the drug in the plasma can then be measured using one or more appropriate analytical methods such as GC-Mass Spec, LC-Mass Spec, HPLC, or various ELISAs (enzyme-linked immunosorbent assays) that can be adapted to specific drugs such as coagulation factors. Also, various activity assays can be used to measure the drug concentration (pharmacokinetics) in terms of quality and also to measure the pharmacodynamics of the drug. One group of such assays for coagulation factors includes coagulation time measurements such as prothrombin time. The measured values from the plasma samples can then be used to create a concentration (derived directly and / or indirectly through biological activity) versus time curve (also referred to herein as a concentration profile). The peak of the concentration curve corresponds to C max , and the time at which this occurs corresponds to T max . The concentration, after reaching C max , reaches a maximum value (i.e., C maxThe time of the curve to reach half of () is T 1 / 2 which corresponds to this value and is also known as the elimination half-life of the drug. C max The start time for the determination of () can be based on the time of injection in the case of non-vascular injection and the time when an ingestible device embodiment advances one or more tissue penetrating members (including the drug) to the small intestine or other locations in the gastrointestinal tract (e.g., the large intestine). In the latter case, this time can be determined using one or more means including remotely controlled embodiments of an ingestible device that deploy the tissue penetrating member to the intestinal wall in response to an external control signal (e.g., an RF signal), or embodiments of an ingestible device that transmit an RF or other signal detectable outside the body when the tissue penetrating member is deployed. Other means for detecting the deployment of the tissue penetrating member to the small intestine are contemplated, such as one or more medical imaging methods including ultrasound or fluoroscopy. In any of these studies, appropriate animal models, such as dogs, pigs, rats, etc., can be used to model the pharmacokinetic response in humans.

[0253] Accordingly, various embodiments provide a therapeutic composition 100 (also referred to herein as a preparation) that includes a coagulation factor (e.g., factor VII, factor VIII, factor IX, or factor X) or other coagulation protein or other therapeutic agent. The composition is adapted for insertion into the intestinal wall after oral ingestion, and upon insertion, the composition releases the coagulation factor or other coagulation protein from the intestinal wall into the bloodstream, reaching C max faster than a dose of a coagulation factor or other coagulation protein injected extravascularly, i.e., in a shorter period (e.g., a smaller T max ) than a dose of a coagulation factor or other coagulation protein injected extravascularly, reaching C max of the inserted form of the coagulation factor or other coagulation protein. It should be noted that the dose of the coagulation factor or other coagulation protein in the composition delivered to the intestinal wall and the dose delivered by extravascular injection can be comparable to achieve these results, but this is not necessary. In various embodiments, the composition has a t maxabout 80%, or 50%, or 30%, or 20%, or 10% of T of a coagulation factor or other coagulation protein (e.g., by release of the coagulation factor into the blood stream from the intestinal wall or surrounding tissue (e.g., the wall of the small intestine)) max is configured to achieve. Such a dose of the coagulation factor injected outside the blood vessels can be, for example, a subcutaneous injection or an intramuscular injection. In certain embodiments, C achieved by delivering a coagulation factor or other coagulation protein by insertion into the intestinal wall or surrounding tissue max is substantially greater, such as 5, 10, 20, 30, 40, 50, 60, 70, 80, or even 100 times greater, than C achieved when the coagulation factor or other coagulation protein is delivered orally, e.g., by pill or other conventional oral forms of the coagulation factor or other coagulation protein, without being inserted into the intestinal wall max In some embodiments, the coagulation factor (or other coagulation protein) composition is configured to produce a long-term release of the coagulation factor (or other coagulation protein) that may include a period in the range of about 1 day to 60 days, and certain embodiments are 6 - 12 hours, 6 - 24 hours, 12 - 24 hours, 12 - 36 hours, 1 - 2 days, 1 - 3 days, 1 - 5 days, 1 - 10 days, 1 - 20 days, 2 days, 3 days, 5 days, 7 days, 10 days, 15 days, 20 days, 30 days, 40 days, 45 days, 50 days, 60 days. Also, the composition can be configured to produce a long-term release of the coagulation factor (or other coagulation protein) at a selectable T 1 / 2 For example, the selectable T 1 / 2 can be 6, or 9, or 12, or 15, or 18, 24, 36, 48, or 60 hours.

[0254] Depending on factors such as body weight, age, condition, and other drugs being taken, any dose of a coagulation factor (or other coagulation protein) suitable for a particular patient can be used. For example, the dose of a coagulation factor (e.g., Factor VII, Factor VIII, Factor IX, or Factor X) or other coagulation protein administered can range from about 1 to 10 mg, and specific ranges are 1 to 5, 1 to 4, 2 to 4, 2 to 5, and 2 to 3 mg, and individual doses are 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 mg. When administered subcutaneously, the coagulation factor typically has a T max in the bloodstream of about 130 hours. Thus, when administered with the therapeutic coagulation factor (e.g., Factor VIII) composition described herein, the T max of the coagulation factor is reduced to, for example, about 80%, or 50%, or 30%, or 20%, or 10% of the T max of the coagulation factor when administered subcutaneously.

[0255] Various embodiments also provide a coagulation factor (or other coagulation protein) composition adapted for insertion into the intestinal wall and / or abdominal wall after oral ingestion, and upon insertion, the composition releases the coagulation factor (or other coagulation protein) from the intestinal wall or surrounding tissue (e.g., peritoneal tissue) into the bloodstream to achieve a T 1 / 2 greater than the T 1 / 2 of the oral ingestion dose of the coagulation factor (or other coagulation protein) that is not inserted into the intestinal wall. For example, the T 1 / 2 of a dose inserted into the intestinal wall can be 100, or 50, or 10, or 5 times greater than that of a dose not inserted into the intestinal wall.

[0256] According to one or more embodiments, the coagulation factor (or other coagulation protein) can be in a solid form, such as a composition in solid form configured to degrade in the intestinal wall, such as the wall of the small intestine or the peritoneal wall. Also, according to one or more embodiments, the solid form composition can include tissue-penetrating features, such as a sharp tip. According to certain embodiments, the solid form coagulation factor (e.g., Factor VIII) composition can be in the form of a shaft having a sharp tip, such as a needle or dart, allowing the composition to penetrate and be inserted into the intestinal wall or peritoneal wall. The coagulation factor (or other coagulation protein) can include at least one biodegradable material and / or can include at least one pharmaceutical excipient, such as a biodegradable polymer like PLGA or a sugar like maltose. In other embodiments, the coagulation factor (or other coagulation protein) can be in a semi-solid or liquid form encapsulated or otherwise manufactured within an embodiment of a tissue-penetrating member.

[0257] Various embodiments of the coagulation factor (or other coagulation protein) compositions described herein can be adapted to be orally delivered in a swallowable capsule. In certain embodiments, such a swallowable capsule can be adapted to be operably coupled to a mechanism having a first configuration and a second configuration, and the coagulation factor (or other coagulation protein) composition can be contained within the capsule in the first configuration and exit the capsule and advance to the intestinal wall and / or surrounding tissue (e.g., peritoneal tissue) in the second configuration. Such an operably coupled mechanism can include at least one of an expandable member, an expandable balloon, a valve, a tissue-penetrating member, a valve coupled to an expandable balloon, or a tissue-penetrating member coupled to an expandable balloon.

[0258] In some embodiments, a coagulation factor (e.g., Factor VII, VIII, IX, or X) or other coagulation protein can be configured to be delivered within the lumen of the tissue penetrating member, and / or the coagulation factor (or other coagulation protein) composition can be shaped as a tissue penetrating member capable of advancing through the intestinal wall. The tissue penetrating member can be sized to be completely contained within the intestinal wall and / or can include tissue penetrating features for penetrating the intestinal wall and / or can include retention features for retaining the tissue penetrating member within the intestinal wall. The retention features can include, for example, barbs. In some embodiments, the tissue penetrating member is configured to advance into the intestinal wall or surrounding tissue (e.g., peritoneal tissue) by application of 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 column strength to fully advance into the intestinal wall and / or the surface of the penetrating member by application of a mechanical or other force (e.g., electromagnetic force). In various embodiments, the column strength / rigidity of the tissue penetrating member can range from about 1 to 20 pounds, 7 to 20 pounds, or 8 to 12 pounds, and individual embodiments are 7, 8, 9, 10, and 11 pounds. The column strength can be achieved by selection of one or more of the material selection and diameter of the tissue penetrating member. 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 force applying structure (e.g., a spring, shaft, etc., or an expandable device). In these and related embodiments, the tissue penetrating member is configured to separate from the force applying structure when the direction of the force changes.

[0259] Various aspects of the present invention also provide, in addition to those described above, 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 to the wall of the intestine, such as the small intestine. Referring now to FIGS. 12 - 20, another embodiment of device 110 for the delivery of agent 100 to delivery site DS within the gastrointestinal (GI) tract can include a capsule 120 sized to be swallowed and pass through the intestinal 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 preparation 100) can itself include tissue-penetrating member 140. The deployable aligner 160 is positioned within the capsule and configured to align the capsule with the intestine, such as the small intestine. Typically, this requires aligning the longitudinal axis of the capsule with the longitudinal axis of the intestine, although other alignments are contemplated. The delivery mechanism 170 is configured to deliver agent 100 to the intestinal wall (and, in some embodiments, to the peritoneum) and typically includes a delivery member 172, such as an expandable balloon or expandable member. The deployment member 130 is configured to deploy at least one of the aligner 160 or the delivery mechanism 170. As further described herein, all or a portion of the capsule wall is decomposable upon contact with liquids within the GI tract, enabling those liquids to 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, and "intestinal tract" refers to the small intestine and large intestine. Various embodiments of the present invention can be configured and arranged for the delivery of agent 100 to both the intestinal tract and the entire GI tract.

[0260] The device 110, which includes the tissue penetrating member 140, can be configured for the delivery of a drug 100 in liquid, semi-liquid, or solid form (e.g., one or more of the clotting factors described herein), or all three combinations. Regardless of the form, the drug 100 preferably has a material consistency such that the drug exits the device 110 and advances to the intestinal wall (small intestine or large intestine) or other luminal walls within the GI tract and then decomposes within the intestinal wall or surrounding tissue (e.g., peritoneum or other peritoneal cavity) to release the drug or other therapeutic agent 101 into the wall or surrounding tissue and into the bloodstream. The material consistency of the drug 100 can include one or more of the hardness, porosity, and solubility of the preparation (such as in a body fluid, e.g., serous fluid, found in the wall of the small intestine or peritoneal cavity). The material consistency of the drug 100 can be achieved by selecting and using one or more of the following: i) the compression force used to make the formulation, ii) the use of one or more pharmaceutical disintegrants known in the art, iii) the use of other pharmaceutical excipients, iv) the particle size and distribution of the formulation (e.g., micronized particles), and v) the use of micronization and other particle formation methods known in the art.

[0261] The capsule 120 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 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, with other dimensions contemplated, and the diameter 120D can range from 0.1 to 0.5 inches. The capsule 120 includes a capsule wall 121w having an outer surface 125 and an inner surface 124 that define an internal space or internal volume 124v. In some embodiments, the capsule wall 121w can include one or more openings 126 sized for the advancement of the tissue penetrating member 140 to the outside. In addition to other components of the device 110 (such as expandable members, etc.), the internal volume can include one or more compartments or reservoirs 127.

[0262] The capsule can be manufactured from various biodegradable gelatin materials known in the pharmaceutical field, 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 multiple 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” (here the body 120p”) and a cap portion 120p’ (here the cap 120p), and the cap can fit onto the body, for example, by sliding over the top or bottom of the body (other arrangements are 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). Since both the inner 124 and outer 125 surfaces of the capsule 120 are coated with the coatings 120C’ and 120c”, any part of the capsule is substantially preserved until it contacts a fluid having a selected pH. In the case of the body 120p”, this allows the structural integrity of the body 120p” to be maintained to hold the balloon 172 within the body portion and not deploy until the balloon 130 expands. The coatings 120C’ and 120c” can include various methacrylate and ethyl acrylate-based coatings, such as those manufactured by Evonik Industries under the trademark EUDRAGIT. These and other double-coating configurations of the capsule 120 allow the mechanism of one part of the capsule 120 to be actuated before the mechanism of the other part of the capsule. This is due to the fact that intestinal fluid first enters the portion where the lower pH coating has degraded and then actuates a trigger (such as a degradable valve) that reacts to such liquid.In use, such embodiments of the double coating of capsule 120 provide for targeted drug delivery to a specific location in the small intestine (or other location in the GI tract), as well as improved certainty in the delivery process. This is because the deployment of certain components, such as aligner 160, can be configured to begin in the upper region of the small intestine (e.g., the duodenum), the capsule can be aligned within the intestine for optimal delivery of the drug (e.g., to the intestinal wall), and because the fact that the capsule is able to provide sufficient time for the deployment / activation of other components to achieve drug delivery to the intestinal wall while the capsule is still in the small intestine or other selected location.

[0263] As discussed above, one or more portions of capsule 120 can be manufactured from various biocompatible polymers known in the art, including in preferred embodiments cellulose, gelatin materials, and various biodegradable polymers that can include PLGA. 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.

[0264] In various embodiments, the wall 120w of the capsule is configured to be decomposable by contact with liquids within the GI tract, such as liquids within the small intestine. In preferred embodiments, the capsule wall is configured to remain intact while passing through the stomach, but then to decompose in the small intestine. In one or more embodiments, this can be achieved by use of an outer coating or outer layer 120c on the capsule wall 120w, which decomposes only at the higher pH found in the small intestine and serves to protect the underlying capsule wall from decomposition in the stomach before the capsule reaches the small intestine (at which point the drug delivery process is initiated by decomposition of the coating as described herein). In use, such a coating enables targeted delivery of a therapeutic agent, for example, in a selected portion of the intestinal tract, including within the wall of the small intestine.

[0265] Similar to capsule 20, in various embodiments, capsule 120 can include various radiopaque, echogenic, or other materials known in the art, such as fluoroscopy, ultrasound, MRI, etc., for device localization. Such materials can be arranged on the capsule in a separate band or other shape so as to readily provide a visual indicator of the capsule within the intestinal tract using one or more medical imaging modalities. They can also be configured to enable a physician to identify whether the capsule has been deployed. For example, according to one embodiment, when a balloon or other expandable member expands, a marker is torn, and under imaging, it is no longer identifiable and / or has a different shape during imaging, and the marker can be arranged around the central region of the capsule.

[0266] As further discussed herein, in many embodiments, one or more of deployment member 130, delivery member 172, or deployable aligner 160 can 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 as balloons 130, 160, and 172, however, other devices including various expandable devices are also contemplated for these elements, for example, various shape memory devices (e.g., an expandable basket made from a shape memory biodegradable polymer spire), expandable piezoelectric devices, and / or chemically expandable devices having an expanded shape and size corresponding to the internal volume 124v of capsule 120.

[0267] One or more of balloons 130, 160, and 172 may include various polymers known in the medical device field. In a preferred embodiment, such polymers may include low density PE (LDPE), linear low density PE (LLDPE), medium density PE (MDPE), and high density PE (HDPE), and one or more types of polyethylene (PE) that may correspond to other forms of polyethylene known in the art. In another embodiment using polyethylene, the material may be crosslinked using polymer irradiation methods known in the art. In certain embodiments, radiation-based crosslinking can be used to control the inflated diameter and shape of the balloon by reducing the compliance of the balloon material. The amount of radiation can be selected to achieve a particular amount of crosslinking and then to produce a particular amount of compliance for a given balloon, for example, increased irradiation can be used to produce a harder, 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, to enable a physician to confirm the position and physical state of the balloon (e.g., non-inflated, inflated, or punctured). Balloons 130, 160, and 172 can be manufactured using various balloon blowing methods known in balloon catheter technology (e.g., mold blow molding, free blow molding, etc.) 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 and various connection features (e.g., connecting tubes) can have a single structure formed from a single mold. Embodiments employing such a single structure provide the advantage of improved manufacturability and certainty as there is a need for fewer junctions between one or more components of device 110.

[0268] Suitable shapes for balloons 130, 160, and 172 include various cylindrical shapes having tapered or curved ends (examples of such shapes including hot dogs). In some embodiments, the inflated size (e.g., diameter) of one or more of balloons 130, 160, and 172 may be larger than capsule 120 to release the capsule from the inflation force (e.g., due to hoop stress). In other related embodiments, the inflated size of one or more of balloons 130, 160, and 172, when inflated, is such that i) capsule 120 makes sufficient contact with the wall of the small intestine to induce peristaltic contractions that cause contractions of the small intestine around the capsule, and / or ii) the folds of the small intestine are made unobtrusive to allow for them. Both of these results enable improved contact between the capsule / balloon surface and the intestinal wall to deliver tissue penetrating member 40 across a selected region of the capsule and / or delivery balloon 172. Desirably, the walls of balloons 130, 160, and 172 are thin and can have a wall thickness in the range of about 0.005 to 0.0001 inches, more preferably in the range of about 0.005 to 0.0001, with specific embodiments being about 0.004, 0.003, 0.002, 0.001, and 0.0005.) Further, 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 connecting tube 163 connecting the inflation chamber 160IC can be made narrow to allow only the passage of gas 168, while the connecting tube 36 joining the two halves of balloon 130 can be made larger to allow the passage of water.

[0269] As shown above, the aligner 160 typically includes an expandable balloon, which is referred to herein as the aligner balloon 160 or balloon 160 for ease of discussion. The balloon 160 can be manufactured using the materials and methods described above. It has a non-expanded state and an expanded state (also referred to as a deployed state). In its expanded or deployed state, the balloon 160 extends the length of the capsule 120 such that the force exerted by peristaltic contractions of the small intestine SI on the capsule 120 serves to align 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 within the small intestine, the aligner 160 is also configured to push the delivery mechanism 170 out of the capsule 120 prior to the expansion of the delivery balloon 172 so that the delivery balloon and / or mechanism is not obstructed by the capsule. In use, this extrusion function of the aligner 160 improves the certainty of therapeutic agent delivery as it does not require waiting for a particular portion of the capsule (e.g., the portion covering the delivery mechanism) to be degraded before drug delivery can occur.

[0270] Balloon 160 can be fluidly coupled to one or more components of device 110 including balloons 130 and 172 by a polymer tube, or other fluid coupling 162 that may include tube 163 for coupling balloons 160 and 130 and tube 164 for coupling balloons 160 and 172. Tube 163 is configured to allow balloon 160 to expand / inflate by pressure from balloon 130 (e.g., pressure generated by a mixture of chemical reactants within balloon 130) and / or to allow passage of liquid between balloons 130 and 160 to initiate a gas that produces a chemical reaction for expansion of one or both of balloons 130 and 160. Tube 164 connects balloon 160 to balloon 172 to allow balloon 160 to inflate balloon 172. In many embodiments, tube 164 includes or is coupled 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 that connects to the valve and a distal portion 164d that leads away from the valve. Typically, proximal and distal portions 164p and 164d are connected to valve housing 158 as described below.

[0271] The valve 155 may include a triangular or other shaped section 156 of a material 157 disposed within the chamber 158c of the valve housing 158 (alternatively, may be disposed directly within the tube 164). The section 157 is configured to mechanically decompose (e.g., be torn, sheared, delaminated, etc.) at a selected pressure to allow passage of gas through the tube 164 and / or the valve chamber 158c. Suitable materials 157 for the valve 155 can include beeswax or other forms of wax, and various adhesives known in the medical field having selectable sealing force / rupture pressure. The valve fixture 158 typically includes a thin cylindrical section (made of a biodegradable material) in which the section 156 of the material 157 is disposed (as shown in the embodiment of FIG. 13B) to seal the walls of the chamber 158c together or otherwise impede the passage of fluid through the chamber. The release pressure of the valve 155 can be controlled by selection of one or more of the size and shape of the section 156, as well as the selection of the material 157 (e.g., with respect to properties such as adhesive strength, shear strength, etc.). In use, the control valve 155 allows for the sequential inflation of the balloons 160 and 172 such that the balloon 160 is fully or otherwise substantially inflated before the balloon 172 inflates. This then allows the balloon 160, along with the remaining delivery mechanism 170, to push the balloon 172 out of the capsule 120 (typically from the body portion 120p') before the balloon 172 expands so that the deployment of the tissue penetrating member 140 is not impeded by the capsule 120. In use, such an approach improves the certainty of penetration of the tissue penetrating member 140 into the intestinal wall IW from both the perspective of achieving the desired penetration depth, since the advancement of the member into the intestinal wall IW is not impeded by the capsule wall 120w, and delivering more of the penetrating members 140 included in the capsule 120.

[0272] As described above, the inflated length 160l of the aligner balloon 160 is sufficient to align the capsule 120 with the transverse axis of the small intestine against intestinal peristaltic contractions. A suitable inflated length 160l of the aligner 160 can include a range between about 1 / 2 to 2 times the length 120l of the capsule 120 before inflation of the aligner 160. Suitable shapes for the aligner balloon 160 can include various elongated shapes such as the shape of a hot dog. In certain embodiments, the balloon 160 can include a first section 160' and a second section 160", and the expansion of the first section 160' is configured to advance the delivery mechanism 170 from the capsule 120 (usually, 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 out of the capsule (usually 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' has 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 permit the passage of gas to the section 160" until a minimum pressure is reached in the section 160'. In some embodiments, the aligner balloon can include a chemical reactant that reacts upon mixing with water or other liquid from the deploying balloon.

[0273] In many embodiments, the deployment member 130 includes an expandable balloon 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 through the use of gas, e.g., the generation of gas 169 from chemical substances. The gas can be generated by the reaction of solid reactants 165 such as an acid 166 (e.g., citric acid) and a base 166 (e.g., potassium bicarbonate, sodium bicarbonate, etc.), which are then mixed with water or other aqueous liquids 168. The amount of reactants is selected using stoichiometric methods and can generate a selected pressure in one or more of balloons 130, 160, and 72. The reactants 165 and the liquid can be stored separately in balloons 130 and 160 and then combined in response to a trigger event such as the pH conditions of 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 allow the liquid 168 to pass through and initiate the reaction and / or the resulting gas 169, the balloon 130 can typically be coupled to the alignment balloon 160 by a connector tube 163 that also includes a separation means 150 such as the degradable valve 150 described below. For embodiments where the balloon 130 contains liquid, the tube 163 has a diameter sufficient to allow enough water to pass from the balloon 130 to the balloon 60 to inflate the balloon 160 and, moreover, to generate a desired amount of gas to inflate the balloon 172. Also, when the balloon 130 contains liquid, one or both of the balloon 130 and the tube 163 are configured to allow the liquid to pass to the balloon 160 by one or more of: i) the compressive force applied to the balloon 130 by the peristaltic contractions of the small intestine on the exposed balloon 130, and ii) the suction of the liquid through the tube 163 by capillary action.

[0274] The tube 163 typically includes a decomposable separation valve or other separation 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 from a material such as maltose that is decomposable by liquid water, such that the valve opens when exposed to water along with various liquids within the digestive tract. It can also be made from a material that decomposes in response to a higher pH found in intestinal fluid, such as a methacrylate-based coating. The valve is desirably positioned at a location on the tube 163 that protrudes above the balloon 130 and / or is otherwise sufficiently exposed such 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 on or protruding above the surface of the balloon 130 (as shown in the embodiments of FIGS. 16A and 16B), such that when the cap 120p' decomposes, it is clearly exposed to the intestinal fluid. Various embodiments of the present invention provide several structures for the separation valve 150, such as a beam-like structure (the valve includes a beam that pushes down on the tube 163 and / or the connection section 136), or a collar-type structure (the valve includes a collar that is on the tube 163 and / or the connection section 136). Still other valve structures are also contemplated.

[0275] 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 of the deployed balloon 130 are also contemplated, such as spherical, tubular, etc. 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 reactants 165 that include other acids, such as acetic acid, and bases, such as sodium hydroxide, are also contemplated. When the valve or other separation means 150 opens, the reactants mix in the liquid and generate a gas, such as carbon dioxide, that expands the alignment balloon 160 or other expandable member.

[0276] In an alternative embodiment shown in FIG. 13B, the deployment balloon 130 can actually include first and second balloons 130' and 130" 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 such as that described above and / or a liquid having a specific pH (e.g., 5.5 or 6.5) such as the basic pH found in the small intestine. The two balloons 130' and 130" can each have a half-dome shape 130hs, which allows the ends of the capsule to fit when they are in the expanded state. One balloon can contain a chemical reactant 165 (e.g., sodium bicarbonate, citric acid, etc.), and the other can contain liquid water 168, such that when the valve decomposes, the two components mix to form a gas, inflating one or both of the balloons 130' and 130", and then the aligner balloon 160. In the case of an embodiment of the device 10 configured for delivery of a therapeutic agent into the peritoneal cavity, an additional amount of reactant can be added to the balloon 130' or 130" to increase the pressure generated.

[0277] In yet another alternative embodiment, the balloon 130 can be formed to have a plurality of compartments 130c or include other structured multi-compartment balloons 130mc. Typically, the compartments 130c include at least first and second compartments 134 and 135 that are 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 connection section 136 therebetween, which is where the 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 but liquids can also be used) can be disposed within the second compartment 135. When the valve 150 is opened (e.g., by degradation caused by fluid in the small intestine), the liquid 168 enters the compartment 135 (or vice versa, or both), the reactant 165 mixes with the liquid, generating a gas 169 such as carbon dioxide, expanding the balloon 130, and then this can be used to expand one or more of balloons 160 and 172.

[0278] 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 disposed 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 also contemplated. For embodiments using citric acid and sodium bicarbonate or potassium bicarbonate, the ratio between the two reactants (e.g., citric acid vs. potassium bicarbonate) can range from about 1:1 to about 1:4, and a particular ratio is about 1:3. Desirably, solid reactant 165 has little or no absorbed 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 disposed within balloon 130. Other acids, such as acetic acid, and other reactants 165 including bases are also contemplated. The amount of a particular reactant 165 including the combination of reactants can be selected using the known stoichiometry of a particular chemical reaction, as well as the inflated volume of the balloon and the ideal gas law (e.g., PV = nRT) to produce a particular pressure. In certain embodiments, the amount of reactants is selected to produce a selected pressure in one or more of balloons 130, 160, and 172 to i) achieve a particular depth of penetration into the intestinal wall, ii) produce a particular diameter of one or more of balloons 130, 160, and 172, and iii) exert a selected amount of force on intestinal wall IW. 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, with smaller and larger pressures being contemplated. Again, the amount and ratio of reactants to achieve these pressures can be determined using known stoichiometry.

[0279] In various embodiments of the present invention for generating gas 169 using chemical reactant 165, the chemical reactant can include a deployment engine 180 for deploying one or both of an alignment balloon 160 and a delivery mechanism 170 including a delivery balloon 172, either alone or in combination with a deployment balloon 130. The deployment engine 180 can also include embodiments using two deployment balloons 130 and 130” (dual dome configuration as shown in FIG. 13B), or a multi-compartment balloon 130mc as shown in FIG. 14A. Other forms of the deployment engine 180 are also contemplated by various embodiments of the present invention, such as the use of expandable piezoelectric materials (which expand upon application of a voltage), springs, and other shape memory materials, as well as various thermally expandable materials.

[0280] One or more of the expandable balloons 130, 160, and 172 typically also include a contraction valve 159 that serves to contract the balloon after inflation. The contraction valve 159 can include a biodegradable material configured to create an opening or channel for releasing gas within a particular balloon and to decompose upon exposure to fluid within the small intestine and / or liquid within one of the compartments of the balloon. Desirably, the contraction valve 159 is configured to decompose at a slower rate than the valve 150 to provide sufficient time for inflation of the balloons 130, 160, and 172 before the contraction valve decomposes. In various embodiments of the compartmentalized balloon 130, the contraction valve 159 can correspond to a degradable section 139 positioned on the end 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 will either tear or otherwise come apart, providing a high assurance of rapid contraction. Multiple degradable sections 139 can be placed at various locations within the balloon wall 132.

[0281] 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 coupled 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 with 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 within the tube 173t is selected such that the blocking material dissolves and provides sufficient time for the delivery balloon 172 to expand and deliver the tissue penetrating member 40 to the intestinal wall IW before opening the valve 173. Typically, this is near the end 173e of the tube 173t but not so much as to give time for the liquid to be sucked into the tube lumen before reaching the material 173m. According to one or more embodiments, when the constriction valve 173 opens, it serves to constrict not only the delivery balloon 172 but also the aligner balloon 160 and the deployment balloon 130 because in many embodiments all three are fluidly connected (the aligner balloon is fluidly connected to the delivery balloon 172 and the deployment balloon 130 is fluidly connected to the aligner balloon). 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 expansion of the aligner balloon 160 such that the constriction valve is well exposed to the liquid in the small intestine. A similar tube constriction valve 173 can also be positioned on one or both of the aligner balloon 160 and the deployment balloon 130. In these latter two cases, the blocking material within the tube valve can be configured to degrade over a period of time to provide sufficient time for the expansion of the delivery balloon 172 and the advancement of the tissue penetrating member 140 into the intestinal wall.

[0282] Further, as an additional backup for reliable 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, the balloon contacts and is pierced by the piercing element 182. The piercing element 182 can include a short protrusion from the surface 124 having a sharp tip. In another alternative or additional embodiment of the means for balloon contraction, one or more of the tissue penetrating members 140 can be directly coupled to the wall of the balloon 172 at 172w and configured to be pulled away from the balloon when they are removed, in the process tearing the balloon wall.

[0283] Next, the tissue penetration member 140 will be considered. In one or more embodiments, the tissue penetration member 140 can be manufactured 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 desired structural and material properties to the penetration member (e.g., column strength for insertion into the intestinal wall, or porosity and hydrophilicity for control of drug release). Referring now to FIGS. 18A - 18F, in many embodiments, the penetration member 140 can be formed to have a shaft 144 and a needle tip 145 or other sharp tip 145 so as 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 such as sucrose or other sugars (either within the body of the tip or as a coating) that increase the hardness and tissue penetration characteristics of the tip. When the penetration member 140 is placed in the intestinal wall or surrounding tissue (e.g., peritoneal wall or peritoneal cavity), it is degraded by the interstitial fluid in the wall tissue and / or the serous fluid in the peritoneal cavity, and as a result, the drugs or other therapeutic agents 101 dissolve in those fluids and are absorbed into the bloodstream. In embodiments where the tissue penetration member is placed in the peritoneal cavity, the tissue penetration member is degraded by the fluid in the cavity that includes the serous fluid in the cavity, whereupon the clotting factors or other therapeutic agents are then configured to be transported to the bloodstream across the visceral and parietal peritoneal walls. One or more of the size, shape, and chemical composition of the tissue penetration member 140 can be selected to enable dissolution and absorption of the drug 101 in seconds, minutes, or even hours. The dissolution rate can be controlled through various means, including using 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 wall of the small intestine and / or the liquid and environment in the peritoneum or peritoneal cavity.In certain embodiments, the tissue penetrating member 140 may include a degradation or dissolution feature 147 (referred to herein as feature 147) configured to accelerate or otherwise enhance the degradation and / or dissolution of the tissue penetrating member 140 in serous fluid and other fluids within the peritoneal cavity PC to enhance the release of the clotting factor or other therapeutic agent 101 into the bloodstream. In certain embodiments, feature 147 may correspond to an opening or hole 148 that partially or entirely passes through the tissue penetrating member 140, as shown in FIG. 18G. The hole or opening 149 allows the intrusion of tissue fluid (e.g., serous fluid) into the interior 140i of the member 140. Feature 147 may also correspond to one or more channels or grooves 149 on the surface 140s of the member 140, as shown in FIGS. 18H and 18I. The channels or grooves 149 enhance the surface area of the member 140 available for contact with tissue fluid and thus enhance the rate of dissolution and / or degradation of the tissue penetrating member. In additional or related embodiments, feature 147, including the opening 148 or groove 149, functions as a mechanical weakness (e.g., a seam in the case of groove 149) such that when the tissue penetrating member is disposed within the peritoneal cavity PC, it is positioned and configured to allow the tissue penetrating member 140 to be easily broken down or fragmented into smaller pieces by mechanical forces applied by the body to the tissue penetrating member. Such forces may include one or more of the forces from the movement of internal organs (e.g., the intestine) and the forces from the contraction of abdominal muscle tissue or the movement of the abdominal wall from respiration. In use, such degradation features 147 enhance the rate of dissolution and / or degradation of the tissue penetrating member by enhancing the surface area for contact with tissue fluid and by allowing the penetrating member to be easily broken down into smaller pieces that have a larger surface area for contact with tissue fluid. Desirably, although not necessarily, one or more features 147 allow the member 140 to be broken down by forces applied by the patient's body while also positioning and otherwise configuring the tissue penetrating member to have sufficient column strength to advance from the capsule 20 by mechanical forces applied to the end 140e of the tissue penetrating member opposite the sharp tip 145.Such forces are applied by components of the delivery member 50 or the actuation mechanism 60. In various embodiments, such column strength of the tissue penetrating member 140 having one or more frangible / dissolvable features 147 can range from 0.1 to 1 pound.

[0284] The tissue penetrating member 140 also typically includes one or more tissue retention features 143, such as spines or hooks, for retaining the penetrating member within the tissue of the intestinal wall IW or peritoneum after advancement. The retention features 143 can be arranged in various patterns 143p, such as 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. Further, in many embodiments, the penetrating member also includes a recess or other mating feature 146 for attachment to a coupling component on the delivery mechanism 170.

[0285] The tissue penetrating member 140 is preferably configured to be removably coupled to the platform 175 (or other components of the delivery mechanism 170), such that after advancement of the tissue penetrating member 140 into the intestinal wall, the penetrating member is removed from the balloon. Removability can be achieved by various means, including i) the fit or conformity between the opening 174 of the platform 175 and the member shaft 144, ii) the configuration and arrangement of the tissue retention features 143 on the penetrating member 140, and iii) the depth of penetration of the shaft 144 into the intestinal wall. Using one or more of these factors, the penetrating member 140 is configured to be removed as a result of the force exerted on the capsule 120 by the balloon (when the balloon contracts or is otherwise pulled back from the intestinal wall and the retention features 143 hold the penetrating member 140 within the tissue), and / or by peristaltic contractions of the small intestine.

[0286] In certain embodiments, removability and retention of the tissue penetrating member 140 in the intestinal wall IW can be enhanced by configuring the tissue penetrating member shaft 144 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 application of peristaltic contraction forces from the intestinal wall to the shaft results in the shaft being pushed inward (e.g., compressed inward). This is due to the conversion of the laterally applied peristaltic force PF into an orthogonal force OF that acts to push the shaft inward into the intestinal wall by the shaft taper 144t. In use, such a reverse taper shaft configuration serves to hold the tissue penetrating member 140 within the intestinal wall such that it is removed 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 also include one or more retention features 143 to further enhance retention of the tissue penetrating member within the intestinal wall IW once inserted.

[0287] As described above, in various embodiments, the tissue penetrating member 140 can be manufactured from several drugs and other therapeutic agents 101. Also, according to one or more embodiments, the tissue penetrating member can be manufactured entirely from a drug 101 (e.g., a coagulation factor such as factor VIII), or can also have other components, such as various pharmaceutical excipients (e.g., binders, preservatives, disintegrants, etc.), polymers that impart desired mechanical properties, etc. Further, in various embodiments, one or more tissue penetrating members 140 can carry the same or different drugs 101 (or other therapeutic agents) than other tissue penetrating members. The former configuration allows for the delivery of a greater amount of a particular drug 101 (e.g., a particular coagulation factor), and the latter allows for the delivery of two or more different drugs to the intestinal wall substantially simultaneously, facilitating drug treatment regimens that require substantial simultaneous delivery of multiple drugs. In embodiments of the device 110 having multiple delivery assemblies 178 (e.g., two, one on each side of the balloon 172), a first assembly 178' can carry a tissue penetrating member having a first drug 101, and a second assembly 178'' can carry a tissue penetrating member having a second drug 101.

[0288] Typically, the drug or other therapeutic agent 101 carried by the tissue penetrating member 140 is mixed with the biodegradable material 105 to form the tissue penetrating member 140. The material 105 can include one or more biodegradable polymers such as PGLA, cellulose, and sugars such as maltose or other biodegradable materials described herein or known in the art. In such embodiments, the penetrating member 140 can include a substantially non-uniform mixture of the drug 101 and the biodegradable material 105. Alternatively, the tissue penetrating member 140 can include a portion 141 substantially formed from the biodegradable material 105 and a separate section 142 formed from or including the therapeutic agent 101 (e.g., factor VIII or other coagulation factor CF), as shown in the embodiment of FIG. 18D. In one or more embodiments, the section 142 can correspond to a pellet, slug, cylinder, or other formed section 142s that includes the drug 101. The formed section 142s can be pre-formed as separate sections, as shown in the embodiments of FIGS. 18E and 18F, and then inserted into the cavity 142c within the tissue penetrating member 140. Alternatively, the section 142s can 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 can be injected into the cavity 142c or added as a powder, liquid, or gel that is injected. The formed section 142s can be formed from the drug 101 itself or from a drug preparation that includes the drug 101 and one or more binders, preservatives, disintegrants, and other excipients. Suitable binders include polyethylene glycol (PEG) and other binders known in the art. In various embodiments, the PEG or other binder can range from about 10 to 90 weight percent of the section 142s, and preferred embodiments are insulin preparations of about 25 to 90 weight percent. Other excipients that can be used in the binder of the tissue penetrating member 140 can include, for example, PLA, PLGA, PGLA, cyclodextrin, cellulose, methylcellulose, maltose, dextrin, sucrose, and PGA, and combinations thereof.Further information regarding the weight percentages of the excipients in Section 142 can be found in Table 5. For ease of discussion, Section 142 is referred to as pellets in the table, but the data in Table 5 is also applicable to other embodiments of Section 142 described herein.

[0289] In various embodiments, the weight of the tissue penetrating member 140 can range from about 10 to 15 mg, with larger and smaller weights contemplated. For 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 delivery dosage, the weight percentage of the drug in the member 140 can range from about 0.1 to about 15%. In an exemplary embodiment, these weight percentages correspond to embodiments of the member 140 made from maltose or PLGA, but are applicable to any of the biodegradable materials 105 used in the manufacture of the member 140, such as polyethylene, polyethylene oxide (PEO), 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, providing for the structural and stoichiometric stability of the drug and also achieving the desired concentration profile of the drug in the blood or other tissues of the body. Specific adjustments to the weight percentage range can be made using various stability tests and models known in the art (e.g., using the Arrhenius equation) and / or the known rate of chemical degradation of the drug. Table 5 lists the dosage and weight percentage ranges of insulin and several other drugs that can be delivered by the tissue penetrating member 140. In some cases, Table 5 lists both ranges and single values of dosages. It should be understood that these values are exemplary and that other values recited herein, including those within the claims, are also contemplated. Further, embodiments of the present invention also contemplate variations around these values, including, for example, variations of ±1, ±5, ±10, ±25, and even larger amounts. Such variations are considered to be within the scope of embodiments that claim a particular value or range of values. Table 5 also lists the weight percentage of the drug in section 142 of various drugs and other therapeutic agents. Again, section 142 can have any of several shapes, but for ease of discussion is referred to as a pellet. Also, according to some embodiments, the amount of drug listed in Table 5 can be dispersed throughout the tissue penetrating member 140 and need not be included in section 142.

Table 5

[0290] The tissue-penetrating member 140 can be manufactured using one or more polymer and pharmaceutical manufacturing techniques known in the art. For example, the drug 101 (regardless of the presence or absence of the biodegradable material 105) can be in solid form and then formed into the shape of the tissue-penetrating member 140 using molding, compression, or other similar methods, with one or more binders added. The use of 3D printing and related manufacturing methods is also contemplated. Alternatively, the drug 101 and / or the pharmaceutical preparation 100 can be in solid or liquid form and then added to the biodegradable material 105 in liquid form, and the mixture is then formed into the penetrating member 140 using molding or other forming methods known in polymer technology. In some embodiments, the tissue-penetrating member can have an outer layer or coating that has a slower degradation rate in the intestinal wall (or surrounding tissue such as the peritoneal cavity), and then an inner body for tissue penetration 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 rate of the inner core. In use, such embodiments with a more slowly degrading outer coating of the tissue-penetrating member 140 allow for a delay in the release of the drug 101. Such embodiments are particularly useful in situations where it is desirable to maintain therapeutic levels of the drug over an extended period, for example, in the case of various clotting factors and insulin.

[0291] 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, such as a protein that includes various peptides and clotting proteins, occurs. This can be achieved by using room temperature curable polymers and room temperature molding and solvent evaporation techniques known in the art. In certain embodiments, the amount of drug or other therapeutic agent that is thermally degraded 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 decomposition temperature(s) of a particular drug are known or can be determined using methods known in the art, and this temperature can then be used to select and adjust a particular polymer processing method (e.g., molding, curing, solvent evaporation method, etc.) to minimize the temperature and the level of thermal degradation of the associated drug.

[0292] The delivery mechanism 170 will be described. Generally, the mechanism includes a delivery assembly 178 (including the tissue penetrating member 140) attached to a delivery balloon 172, as shown in the embodiments of FIGS. 16A and 16B. The inflation of the delivery balloon provides a mechanical force to engage the delivery assembly 172 outwardly from the capsule to the intestinal wall IW so as to insert 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 the intestinal wall (IW) upon expansion of the balloon 172 to insert the tissue penetrating member (TPM) 140 into the intestinal wall. The TPM 140 (either by itself or as part of the delivery assembly 178 described below) can be positioned on one or both surfaces 172f of the balloon 172 to enable insertion of the TPM 140-containing drug on both sides of the intestinal wall IW. The surfaces 172f of the balloon 172 can have a surface area sufficient to allow placement of several drugs containing the TPM 140 on each surface. Also, in the case of an embodiment of the device 10 for delivery of a coagulation factor CF (e.g., factor VIII) for treatment of coagulation, as described herein, all or part of the surface 172f can have a coating 101c of the coagulation factor or other rapid hemostatic agent at the site of the IW where the TPM(s) enter to apply the coagulation factor by pressure and prevent or reduce bleeding at that site.

[0293] Referring now to FIG. 19, the assembly of the delivery assembly 178 will now be described. In a first step 300, one or more tissue penetrating members 140 can be removably coupled to a biodegradable advancement structure 175 that can correspond to a support platform 175 (also known as platform 175). In a preferred embodiment, the platform 175 includes one or more openings 174 for insertion of the tissue penetrating member 140 (also referred to as member 140) as shown in step 300. The openings 174 are sized to allow insertion and retention of the member 140 within the platform 175 prior to expansion of the balloon 172, while allowing removal of the member from the platform as the member penetrates the intestinal wall. The support platform 175 can then be positioned within a transport structure 176 as shown in step 301. The transport structure 176 can correspond to a well structure 176 having side walls 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 joining method known in the art. The well structure 176 can include various polymeric materials and can be formed using vacuum forming techniques known in polymer processing technology. In many embodiments, the opening 176o can be covered with a protective film 177 as shown in step 302. The protective film 177 is selected to have properties such that it functions as a barrier to protect the tissue penetrating member 140 from humidity and oxidation while allowing the tissue penetrating member 140 to penetrate the film as described below. The film 177 can include various water and / or oxygen impermeable polymers that are biodegradable in the small intestine and / or are preferably configured to pass inertly through the gastrointestinal tract. It can also have a multi-layer structure with specific layers selected for their impermeability to a given substance, such as oxygen, water vapor, etc. In use, embodiments employing the protective film 177 serve to increase the shelf life of the therapeutic agent 101 in the tissue penetrating member 140 and, thus, the retention period of the device 110.Collectively, the support platform 175 to which the tissue penetrating member 140 is attached, the well structure 176, and the film 177 can include a 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 in the manufacture of the device 110. The shelf life of the assembly 178 can be further extended by filling the cavity 176c of the sealed assembly 178 with an inert gas such as nitrogen.

[0294] Next, referring back to FIGS. 16A and 16B, the assembly 178 can be positioned on one or both surfaces 172f of the balloon 172. In a preferred embodiment, the assembly 178 is positioned on both surfaces 172f so as to provide a substantially equal force distribution on both sides of the intestinal wall IW when the balloon 172 is expanded (as shown in FIG. 16A). The assembly 178 can be attached to the surface 172f using an adhesive or other joining methods known in polymer technology. When the balloon 172 is expanded, the TPM 140 penetrates the film 177, enters the intestinal wall IW, and is retained in the intestinal wall by the retaining element 143 and / or other retaining features of the TPM 140 (e.g., the reverse tapered shaft 144t), and is removed from the platform 175 when the balloon 172 contracts.

[0295] In various embodiments, one or more of balloons 130, 160, and 172 can be packed within capsule 120 in a folded, rolled, 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 features or methods known in medical balloon technology. In certain embodiments, balloons 130, 160, and 172 are folded in a selected orientation to achieve one or more of the following: i) conserve space, ii) generate a desired orientation of a particular deployed balloon, and iii) facilitate a desired sequence of balloon expansion. The embodiments shown in FIGS. 15A - 15F illustrate methods of folding and embodiments of various folding arrangements. However, it should be understood that this folding arrangement and the resulting balloon orientations are exemplary and other ones may be used. In this and related embodiments, the folding can be done manually, by an automated machine, or by a combination of both. Also, in many embodiments, the folding can be facilitated by using a single multi-balloon assembly 7 (herein assembly 7) that includes balloons 130, 160, 170, valve chamber 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 structure of balloon 130, and FIG. 13B shows an embodiment of assembly 7 having a dual-balloon / dome configuration of balloon 130. Assembly 7 can be manufactured using a polymeric thin film that is vacuum formed into a desired shape using various vacuum forming and other related methods known in polymeric processing technology. Suitable polymeric membranes include polyethylene membranes having a thickness in the range of about 0.003 to about 0.010 inches, with a particular embodiment being 0.005 inches. In a preferred embodiment, the assembly is manufactured to have a single structure so as to eliminate the need to couple one or more components of the assembly (e.g., balloons 130, 160, etc.).However, it is also contemplated that the assembly 7 may be manufactured from a plurality of parts (e.g., halves) or components (e.g., balloons), which are then joined using various joining methods known in the polymer / medical device art.

[0296] Referring now to FIGS. 15A-15F, 16A-16B, and 17A-17B, in a first folding step 210, balloon 160 is folded over onto valve fixture 158 and balloon 172 is flipped to the opposite side of valve fixture 158 in that process (see FIG. 15A). Next, in step 211, balloon 172 is folded at a right angle to the folded combination of balloon 160 and valve 158 (see FIG. 15B). Next, in step 212 of the dual dome embodiment of balloon 130, the two halves 130' and 130'' of balloon 130 are folded together with valve 150 remaining exposed (see FIG. 15C; for the single dome embodiment of balloon 130, it folds over itself, see FIG. 15E). The final folding step 213 is performed by folding the folded balloon 130 180° over to the opposite side of valve fixture 158 and balloon 160, generating a final folded assembly 8 for the dual dome configuration shown in FIG. 15E, and a final folded assembly 8' for the single dome configuration shown in FIGS. 15E and 15F. One or more delivery assemblies 178 are then attached in step 214 to the assembly 8 (typically, two faces 72f of balloon 72) to generate a final assembly 9 (shown in the embodiments of FIGS. 16A and 16B), which is then inserted into capsule 120. After the insertion step 215, a final assembled version of the device 110 with assembly 9 inserted therein is shown in FIGS. 17A and 17B.

[0297] Referring now to FIGS. 20A - 20I, a method of delivering an agent 101, such as a coagulation factor (e.g., factor VIII) or other coagulation proteins, to a site within the GI tract, such as the wall of the small or large intestine, the peritoneum, or the peritoneal cavity, using device 110, will be described. The steps and their order are exemplary, and it should be understood that other steps and orders are also contemplated. After device 110 enters the small intestine SI, as shown in step 400 of FIG. 20B, the cap coating 120C’ is degraded by the basic pH of the upper small intestine, causing degradation of cap 120p’. Next, valve 150 is exposed to the fluid within the small intestine and begins to degrade, as shown in step 401 of FIG. 20C. Next, in step 402, balloon 130 expands (for generation of gas 169), as shown in FIG. 20D. Next, in step 403, section 160’ of balloon 160 begins to expand and starts 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 and completely push assembly 178 out of the capsule body, extending the length 120l of the capsule to align capsule transverse axis 120AL with the transverse axis LAI of the small intestine, as shown in FIG. 20F. During this time, valve 155 begins to malfunction due to the increasing pressure within balloon 60 (due to the fact that the balloon is fully expanded and there is no other place for gas 169 to go). Next, in step 405, valve 155 fully opens, expanding balloon 172, and then balloon 172 radially outwardly pushes the fully exposed assembly 178 (fully pushed out of body 120p’’) into the intestinal wall IW, as shown in FIG. 20G. Next, in step 406, balloon 172 continues to expand to advance the tissue penetrating member into the intestinal wall IW, as shown in FIG. 20H. Next, in step 407, balloon 172 contracts and retracts (along with balloons 160 and 130), holding the tissue penetrating member in the intestinal wall IW. Also, the body portion 120p” of the capsule is completely degraded along with the other biodegradable parts of device 110 (due to degradation of coating 120c”).Any undigested portions are carried distally through the small intestine by peristaltic contractions due to digestion and are ultimately excreted.

[0298] Referring now to FIGS. 21 - 23, in various embodiments, therapeutic preparations, and associated methods for their delivery to the wall or surrounding tissues of the small intestine, are C max ...

Claims

**Claim 1** A therapeutic preparation for treating a coagulation disorder in a patient, wherein the therapeutic preparation comprises factor VIII in a stabilized form at a dosage of 75 IU or more per kg of the patient's body weight, the therapeutic preparation is formed as a biodegradable solid tissue penetrating member or is included in the solid tissue penetrating member, the solid tissue penetrating member has an elongated structure and a pointed end configured to penetrate the patient's intestinal wall and be inserted into the peritoneal cavity of the patient through the patient's intestinal wall when a force is applied, the solid tissue penetrating member is included in a swallowable device and is delivered from the device after oral ingestion, and the therapeutic preparation releases the factor VIII into the bloodstream. **Claim 2** The therapeutic preparation according to claim 1, wherein the stabilized factor VIII comprises PEGylated factor VIII. **Claim 3** The therapeutic preparation according to claim 2, wherein the PEGylated factor VIII is present in the therapeutic preparation in the range of 75 IU / kg body weight to 400 IU / kg body weight. **Claim 4** The therapeutic preparation according to claim 2, wherein the PEGylated factor VIII is present in the therapeutic preparation in the range of 150 IU / kg body weight to 300 IU / kg body weight. **Claim 5** The therapeutic preparation according to any one of claims 1 to 4, having a Tmax in the range of 6 to 10 hours. **Claim 6** The therapeutic preparation according to any one of claims 1 to 5, having a Cmax in the range of about 2.4 IU / ml to 4.0 IU / ml. **Claim 7** The therapeutic preparation according to any one of claims 1 to 6, having an area under the curve (AUC) in the range of 60 (IU*h) / mL to 70 (IU*h) / mL. **Claim 8** The therapeutic preparation according to any one of claims 1 to 7, having a ratio of the ascending curve portion to the descending curve portion in the range of 1:4 to 1:

8. **Claim 9** The therapeutic preparation according to claim 1, wherein the stabilized factor VIII comprises factor VIII chemically complexed with von Willebrand factor. **Claim 10** The therapeutic preparation according to claim 1, wherein the stabilized factor VIII comprises factor VIII modified by Fc fusion. **Claim 11** The therapeutic preparation according to any one of claims 1 to 10, wherein the therapeutic preparation is included in the solid tissue penetrating member. **Claim 12** The therapeutic preparation according to any one of claims 1 to 10, wherein the therapeutic preparation is formed as the solid tissue penetrating member. Factor VIII in a stabilized form, included in a biodegradable solid tissue penetrating member, having an elongated structure and a pointed end configured to penetrate the intestinal wall of a patient upon application of force, included in a swallowable device and configured to be delivered from said device after oral ingestion, providing said Factor VIII at a dosage of at least 75 IU per kg of the patient's body weight, delivering said Factor VIII through the intestinal wall of said patient into the peritoneal cavity of said patient, and releasing said Factor VIII into the bloodstream of said patient to treat a coagulation disorder of said patient, Factor VIII in a stabilized form for use in a method of treating a coagulation disorder of a patient.

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