JP7232805B2 - Anti-interleukin antibody formulations for delivery into the intestinal lumen using a swallowable drug delivery device - Google Patents

Description

(Cross reference to related application)
This application is based on U.S. Provisional Patent Application No. 6124/612/9, filed May 8, 2015, entitled "Anti-Interleukin Antibody Preparations For Delivery Into A Lumen Of The Intestinal Tract Using A Swallowable Drug Delivery Device." the aforementioned applications are hereby incorporated by reference for all purposes. This application is also a continuation-in-part of U.S. patent application Ser. and this U.S. patent application is filed May 15, 2014, U.S. Provisional Patent Application No. 60/793, entitled "Pharmaceutical Compositions And Methods For Fabrication Of Solid Masses Comprising Polypeptides And/Or Proteins." claims the benefit of priority under All aforementioned applications are incorporated herein by reference for all purposes.

This application also incorporates by reference for all purposes the following US patents and provisional patent applications: 「Ｓｗａｌｌｏｗａｂｌｅ Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｄｅｖｉｃｅ ａｎｄ Ｍｅｔｈｏｄｓ ｏｆ Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ」と題する、２０１０年１２月２３日に出願された米国特許出願１２／９７８，２３３号；「Ｔｈｅｒａｐｅｕｔｉｃ Ａｇｅｎｔ Ｐｒｅｐａｒａｔｉｏｎ ｆｏｒ Ｄｅｌｉｖｅｒｙ Ｉｎｔｏ ａ Ｌｕｍｅｎ ｏｆ Ｔｈｅ Ｉｎｔｅｓｔｉｎａｌ Ｔｒａｃｔ Ｕｓｉｎｇ ａ Ｓｗａｌｌｏｗａｂｌｅ U.S. Patent Application No. 12/978,164, filed December 23, 2010, entitled "Swallowable Drug Delivery Device and Methods of Drug Delivery"; . U.S. patent application Ser.米国特許出願第１３／５３２，５８９号；「Ｔｈｅｒａｐｅｕｔｉｃ Ａｇｅｎｔ Ｐｒｅｐａｒａｔｉｏｎｓ ｆｏｒ Ｄｅｌｉｖｅｒｙ ｉｎｔｏ Ａ Ｌｕｍｅｎ ｏｆ ｔｈｅ Ｉｎｔｅｓｔｉｎａｌ Ｔｒａｃｔ ｕｓｉｎｇ ａ Ｓｗａｌｌｏｗａｂｌｅ Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｄｅｖｉｃｅｓ」と題する米国特許第８，８０９，２６９号；および「Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏｍｐｏｕｎｄｓ Ａｎｄ Ｍｅｔｈｏｄｓ Ｆｏｒ U.S. Provisional Patent Application No. 62/156,105, filed May 1, 2015, entitled "Fabrication Of Solid Masses Composing Polypeptides And/Or Proteins";

(Background of the Invention)
field of invention.
Embodiments of the present invention relate to swallowable drug delivery devices. More specifically, embodiments of the present invention relate to swallowable drug delivery devices for delivering drugs and other therapeutic agents to the small intestine.

In recent years, the development of new drugs has been increasing for the treatment of various diseases, but many of them have limited applications because they cannot be administered orally. This is due to a number of reasons including poor oral tolerance with complications including gastric irritation and bleeding; breakdown/degradation of drug compounds in the stomach; and poor, slow or uneven absorption of the drug. to cause. Conventional alternative drug delivery methods, such as intravenous and intramuscular delivery, involve pain and infection risks from needle sticks, the need to use sterile technique, and the associated risks of maintaining IV lines in patients for extended periods of time. It has many drawbacks. Other drug delivery approaches have been utilized, such as implantable drug delivery pumps, but these approaches require semi-permanent implantation of the device and can also have many of the limitations of IV delivery. Accordingly, improvements for the delivery of drugs and other therapeutic agents, including the need for improved delivery of various anti-interleukin antibodies and other interleukin-neutralizing proteins for the treatment of various autoimmune diseases. There is a need for a done method.

(Brief summary of the invention)
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 swallowable devices for delivering drugs and other therapeutic agents within the gastrointestinal (GI) tract. Certain embodiments provide swallowable devices, such as capsules, for delivering drugs and other therapeutic agents within the walls of the small intestine or other GI organs. Embodiments of the present invention are particularly useful for delivery of therapeutic agents that are poorly absorbed, poorly tolerated, and/or degraded in the GI tract (e.g., various interleukin-neutralizing proteins, particularly antibodies). . Moreover, embodiments of the present invention have previously only been possible by other forms of parenteral administration, including administration in intravenous form or various nonvascular parenteral injection forms such as intramuscular or subcutaneous injection. It can be used for delivery of such interleukin-neutralizing proteins that were not or were preferably delivered by these forms of parenteral administration.

In one aspect of the invention, the invention provides a therapeutically effective dose of at least one interleukin-neutralizing protein (IN protein or INP, also known as interleukin-binding protein or IB-protein), such as one or more A therapeutic agent formulation for delivery to the small intestinal wall or other location in the intestinal tract is provided that includes antibodies that bind interleukins (herein, anti-interleukin antibodies or AI antibodies) or their receptors. Such interleukins can include one or more of interleukins 1-36 (eg, interleukin 1, interleukin 17a and their respective analogs and derivatives). AI antibodies used in one or more embodiments of therapeutic formulations may be full-length antibodies or antigen-binding portions thereof. The formulation is contained in an embodiment of a swallowable capsule (or such device) such that it is delivered from the capsule into the intestinal wall to release said dose of AI antibody or other IN-protein from within the intestinal wall. shape (eg, tissue-penetrating shape) and material consistency. The formulation may be in solid, liquid or powder form. Preferably, a formulation comprising an AI antibody or other IN protein is shaped (e.g., into a tissue-penetrating shape) such that the formulation is stored for long periods of time as well as inserts it into the intestinal wall, and mechanical forces exerted on the formulation It is a solid form that allows to have

IN-proteins may be selected from immunoglobulin molecules known in the art or functional variants thereof, such variants retaining the characteristic binding properties of interleukin binding proteins. there is Examples of specific immunoglobulin molecules that can be used include scFv (single chain variable fragment); monoclonal antibodies; human antibodies; chimeric antibodies; humanized antibodies; single domain antibodies; ab')2; Fv (variable fragment); disulfide-linked Fv, and bispecific or bispecific antibodies. Most preferably the binding protein is a human antibody.

Another aspect of the invention provides an interleukin-neutralizing protein comprising any one of the binding proteins disclosed herein (AI antibodies and AI17 antibodies, e.g., secukinumab), wherein The binding protein prevents the selected interleukin from binding to its interleukin's receptor or attenuates the ability of the selected interleukin to bind to its interleukin's receptor. It is possible to neutralize and/or inhibit one or more biological actions of Leukins 1-36. Such neutralizing effects are selected to: 1) prevent or inhibit the interleukin from binding to the interleukin's receptor and subsequently causing one or more biological effects; or 2) to bind to a receptor for that particular interleukin so as to prevent the interleukin from activating the receptor and causing one or more biological effects. This can be achieved by selecting binding proteins. For example, according to one embodiment, an AI antibody that binds interleukin-17, such as secukinumab, can be selected. According to another embodiment, an AI antibody that binds to the interleukin-17 receptor, such as brodalumab, can be selected. Inhibited biological effects resulting from the use of one or more embodiments of AI antibodies or other IB-proteins can include one or more of the following: Th1 modulation; Th2 modulation (which (2001) Cytokine and Growth Factor Rev. 12:53-72); Nk modulation; Neutrophil modulation; Monocyte- eosinophil modulation; B-cell modulation; cytokine modulation; chemokine modulation; adhesion molecule modulation; Also according to one or more embodiments, AI antibodies or other IN-proteins are selected to treat various autoimmune and/or inflammatory conditions associated with activity of the selected interleukin. can be selected to inhibit the biological effects of interleukins that In preferred embodiments, such conditions include rheumatoid arthritis, psoriasis including plaque-type psoriasis, psoriatic arthritis, fibrosis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, multiple sclerosis and ankylosing One more of spondylitis can be included.

In many embodiments, the dose of the selected AI antibody, AI-17 antibody or other IN-protein delivered by the swallowable capsule embodiment is for selected conditions described herein ( psoriasis, rheumatoid arthritis, etc.), while avoiding the adverse effects associated with the infused or injected dose (e.g., intravenous, intramuscular, subcutaneous, etc.) of the antibody. can be minimized. Collectively, the term infusion or injectable dose shall be referred to herein as "parenteral injection", and the dose of AI antibody (or other therapeutic agent described herein) delivered by injection or infusion. Delivery shall be referred to herein as "parenteral injection delivery" or "parenteral injection." Such adverse effects include, but are not limited to, anaphylactic shock or other anaphylactic/allergic reactions (eg, dyspnea, edema, watery eyes, respiratory stasis), immunogenic reactions to IN-proteins. (including immunogenic neutralization of the delivered IN-protein by the patient's own antibodies), headache, fever and other related effects. In certain embodiments, this can be achieved by adjusting the delivery dose of AI antibodies or other IN-proteins to daily versus monthly or biweekly doses, the latter dose being common for AI antibodies. for secukinumab, brodalumab or ixekizumab. When minimizing the immune response, this results in delivering doses of AI antibodies to the upper or middle portion of the small intestine and lower sections of the intestine, e.g., Peyer's patches, as discussed in further detail herein. can also be achieved by avoiding the ileum containing Other benefits of delivery of AI antibodies (versus injection) in smaller doses to the small intestine include i) a higher therapeutic index; and ii) variation in plasma concentrations of AI antibodies or other IN proteins (herein (known as % Steady State Variation), as described in further detail.

In another aspect, the invention provides methods for treating diseases or conditions associated with the biological activity of interleukin-17 molecules, such as interleukin-17a molecules. Various embodiments of such methods administer solid anti-interleukin 17 antibody (AI17 antibody) dosages as the shape of a tissue-penetrating member, which may be dart-like or needle-like or other shape with a pointed tip. Including providing. Dosages are orally delivered to the small intestine by an orally ingested swallowable capsule or other swallowable device. Upon entering the small intestine (or other location within the intestinal tract), a mechanical force (e.g., from an expandable member within the capsule) is applied to the tissue-penetrating member such that the tissue-penetrating member remains within the intestinal wall. The solid dosage thus penetrates the intestinal wall and is inserted therein. A therapeutically effective dose of AI17 antibody is then released into the blood stream from the solid dosage AI17 antibody within the intestinal wall to inhibit the activity of the interleukin-17 molecule, thereby treating the disease or condition. In certain embodiments, the interleukin-17 molecule that is inhibited refers to interleukin-17A. In these and related embodiments, the AI antibody may refer to secukinumab, brodalumab or ixekizumab and one or more of its antigen binding portions which may be in the form of variants or derivatives of the three aforementioned antibodies. These or other AI-17 antibodies may be useful in interleukin-17a biologics including, for example, plaque-type psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, Crohn's disease and inflammatory bowel disease. A therapeutically effective dose can be delivered within the wall of the small intestine to treat one or more diseases or conditions associated with the activity. Also, in certain embodiments, the swallowable capsule has a coating or other coating selected to degrade at the pH of the small intestine so as to insert a solid dose of AI17 antibody into a selected location in the small intestine, such as the jejunum. including similar materials of Also, in certain embodiments, when placed in the small intestinal wall, the solid AI17 antibody or other AI antibody is released into the mesenteric vasculature surrounding the intestinal wall and then into the portal vein and then into the liver. can be configured as At this point, the released AI17 antibody then binds to interleukin or interleukin receptors in the liver and then to other parts of the body, including one or more of the lungs, heart, bone, cartilage, lymph nodes, etc. It binds substantially (eg, greater than 10% of the delivered AI17 antibody that binds to interleukins present at non-liver sites) interleukins present at tissue sites. The benefit of this approach in these and related embodiments is that the liver contains high concentrations of interleukin-producing tissue and binds to interleukins released from that tissue at the site of their release, thereby allowing them to diffuse throughout the body. It is possible to neutralize or otherwise inhibit significant amounts of interleukins (eg, interleukin 17a, etc.) prior to treatment. This allows antibodies to be taken up in significant amounts by other tissue sites in the body (e.g. heart, lungs, etc.) before reaching the liver and thus binding to interleukins released by the liver. In contrast to conventional approaches using parenteral injection delivery of AI17 antibody (or similar antibodies), the amount of AI17 antibody is significantly reduced.

In another aspect, the invention provides methods for delivering therapeutic agents within the wall of the small intestine, including therapeutic agents such as capsules, actuators, and INP formulations (e.g. formulations comprising one or more anti-interleukin antibodies). A method is provided that includes swallowing a drug delivery device that includes an embodiment of the formulation. The actuator initiates delivery of the therapeutic agent formulation into the wall of the small intestine in response to conditions within the small intestine, such as pH. The actuator may also include a coating or other similar coating selected to decompose at a small intestinal pH corresponding to a selected location within the small intestine to activate the actuator at a selected location within the small intestine, such as the jejunum. It may include or be operatively connected to a material. In certain embodiments, the actuator can include a release element or coating on the capsule that is degraded by a selected pH within the small intestine. Once degraded, the element or coating initiates delivery of the therapeutic agent formulation by one or more delivery means, e.g., by expansion of one or more balloons operably connected to a tissue-penetrating member. and the tissue-penetrating member contains the therapeutic agent formulation and is configured to penetrate and enter the wall of the small intestine when the balloon is expanded. When the tissue-penetrating member is inserted into the intestinal wall or surrounding tissue (eg, peritoneal wall), it degrades and releases the therapeutic agent into the bloodstream. Since the therapeutic agent formulation is delivered directly into the wall of the small intestine, the time period (herein t _max ) is shorter than the corresponding period for achieving the aforementioned maximum concentrations when the agent is injected into the body, non-vascularly, such as by intramuscular or subcutaneous injection. In various embodiments, the time period for achieving C _max upon insertion of the therapeutic formulation into the wall of the small intestine using one or more embodiments of the present invention (e.g., swallowable device embodiments) is It may be about 80%, 50%, 30%, 20% or even 10% of the time to achieve C _max through the use of non-vascular injection of the therapeutic agent. In other embodiments, the C _max achieved by insertion of said therapeutic formulation into the wall of the small intestine using one or more embodiments of the present invention, e.g. It is greater than the C _max achieved by ingestion of the therapeutic in conventional oral forms (eg, pills) that are not inserted into the intestinal wall. In various embodiments, the C _max achieved by insertion of said therapeutic formulation into the wall of the small intestine using one or more embodiments of the present invention (e.g., swallowable device embodiments) is equal to said therapeutic agent is 5, 10, 20, 30, 40, 50, 60, 70, 80 or even 100 times greater than when delivered in a pill or other oral form. In other related embodiments, the composition can be configured to provide extended release of the therapeutic agent with a selectable t _1/2 (wherein the t _1/2 is in the bloodstream or at other times in the body). is the time required for the concentration of therapeutic agent at a location to reach half its original C _max value after reaching C _max ). For example, the selectable t _1/2 can be 6 or 9 or 12 or 15 or 18 or 24 hours.

In another aspect, the present invention provides swallowable devices for delivering drugs or other therapeutic agent formulations within the walls of the small or large intestine or other organs of the gastrointestinal tract. The device comprises a capsule sized to be swallowed and passed through the gastrointestinal tract; a deployable aligner located within the capsule for aligning the long axis of the capsule with the long axis of the small intestine; a delivery mechanism for delivering into the wall; and a deployment member for deploying at least one of said aligner or said delivery mechanism. The capsule wall may degrade upon contact with fluids in the GI tract, but may also be provided with an outer coating or layer that degrades only at the higher pHs found in the small intestine, and , serves to protect the underlying capsule wall from degradation in the stomach before the capsule reaches the small intestine where drug delivery begins due to degradation of the coating. When used, such materials allow targeted delivery of therapeutic agents in selected portions of the intestinal tract, such as the small intestine. Suitable external coatings can include various enteric coatings such as various copolymers of acrylic acid (particular examples include EUDRAGIT available from EVONIK industries), methacrylic acid and ethyl acrylate. In certain embodiments, the outer coating is designed to avoid the lower part of the small intestine (ileum), which contains Peyer's patches, which are aggregated lymphoid nodules in which therapeutic agent formulations are delivered and which produce macrophages and other immune-related cells. Additionally, it can be configured to degrade at the pH found in the upper (eg duodenum) or middle (jejunum) of the small intestine. An example of such a coating that degrades at duodenal or jejunal pH is EUDRAGIT. In a specific embodiment to achieve p, the coating has an ambient pH of about 1-2 feet, which corresponds to a location within the distal duodenum or proximal jejunum approximately 30-60 cm (1-2 feet) below the pylorus of the stomach. It is configured not to start decomposition/dissolution until 6.5. Since the jejunum is approximately 8 feet (approximately 240 cm) in humans, this is sufficient for the coating to dissolve completely and release the tissue-penetrating member well before the ileum, the section of the small intestine containing the Peyer's patches. Time is passing. By delivering the therapeutic agent to a location in the small intestine that is free of Peyer's patches, the generation of immune-related cells and subsequent immune response to the therapeutic agent (eg, production of various interleukins) is minimized. Thus, in use, such controlled placement or delivery of a therapeutic agent to the upper or other selected portion of the small intestine eliminates or otherwise minimizes or otherwise minimizes a patient's immune response to a particular therapeutic agent. Reduce.

Another embodiment of the capsule comprises at least one guide tube; one or more tissue penetrating members positioned within said at least one guide tube; a delivery member; and an actuation mechanism. The tissue-penetrating member typically comprises a hollow needle or other similar structure having a lumen and a tissue-penetrating end for penetration to a selectable depth into the intestinal wall. In various embodiments, the device can include second and third tissue-penetrating members, with a number of additional contemplated members. Each tissue penetrating member may contain the same drug or may contain different drugs. In preferred embodiments having multiple tissue-penetrating members, the tissue-penetrating members can be distributed symmetrically along the circumference of the capsule to anchor the capsule on the intestinal wall during drug delivery. In some embodiments, all or a portion of the tissue-penetrating member (eg, tissue-penetrating end) can be manufactured from the drug formulation itself. In these and related embodiments, the drug formulation comprises a needle or arrow-like structure (with or without barbs) configured to penetrate and reside within the intestinal wall. can have Other shapes with pointed tips, though

A fail-safe mechanism for the tissue-penetrating member to degrade in the small intestine, thereby removing the tissue-penetrating member from the intestinal wall if the component should become lodged in the intestinal wall. can be manufactured from a variety of biodegradable materials such as PGLA, maltose or other sugars or polyethylene oxide to provide Additionally, in these and related embodiments, selectable portions of the capsule can be made from such biodegradable materials to allow controllable disassembly of the entire device into smaller pieces. . Such embodiments facilitate passage of the device through the GI tract and elimination through the GI tract. In certain embodiments, the capsule can comprise a seam of biodegradable material that controllably degrades to produce capsule pieces of selectable size and shape to facilitate passage through the GI tract. The seams can be prestressed, perforated or otherwise treated to accelerate degradation. The concept of using biodegradable seams to cause controlled degradation within the GI tract of swallowable devices can be applied to other swallowable devices, such as swallowable cameras, to facilitate GI tract transit. and the likelihood of the device becoming stuck in the GI tract.

The delivery member is configured to advance the drug from the capsule through the tissue-penetrating member lumen and into the intestinal wall. Typically, at least a portion of the delivery member is advanceable within the tissue-penetrating member lumen. The delivery member may have a piston or similar structure sized to fit within the lumen of the delivery member. The distal end of the delivery member (the end that penetrates the tissue) may have a plunger element that advances the drug into and forms a seal with the tissue-penetrating member lumen. do. The plunger element may be internal to the delivery member or the plunger element may be attached to the delivery member. Preferably, said delivery member is configured to travel a fixed distance within the needle lumen to deliver a fixed or metered dose of drug into the intestinal wall. This may involve selection of the diameter of the delivery member (eg, the diameter may taper distally), the diameter of the tissue-penetrating member (which may narrow at its distal end), the use of stops, and/or It can be accomplished by one or more of the triggering mechanisms. For embodiments of devices having a tissue-penetrating member made from a drug (eg, a drug arrow), the delivery member is adapted to advance the arrow from the capsule and enter tissue.

The delivery member and tissue-penetrating member can be configured for delivery of drugs in liquid, semi-liquid or solid form or all three forms. Solid form drugs can include both powders or pellets, individually or mixtures thereof. Semi-liquids can include slurries or pastes. The drug may be contained within the cavity of the capsule or, if liquid or semi-liquid, within a sealed reservoir. In some embodiments, the capsule can contain a first, second or third (or more) drug. Such drugs may be contained within the tissue-penetrating member lumen (if solid or powdered) or in a separate reservoir within the capsule body.

The actuation mechanism can be coupled to at least one of the tissue penetrating member or the delivery member. The actuation mechanism advances the tissue-penetrating member a selectable distance within the intestinal wall and advances the delivery member to deliver the drug and then exit the tissue-penetrating member from the intestinal wall. configured to In various embodiments, the actuation mechanism can include a pressurized spring mechanism configured to be released by a release element. Suitable springs include both coils (including conical springs) and leaf springs, although other spring configurations are also contemplated. In certain embodiments, the spring is configured to further reduce the length of the spring in its compressed state to a point where the compressed length of the spring is on the order of a few coils (e.g., 2 or 3) or only as thick as one coil. can be a cone shaped into a

In certain embodiments, the actuation mechanism includes a spring, a first motion converter, a second motion converter, and a track member. The release element is connected to the spring to retain the spring in compression so that disassembly of the release element releases the spring. The first motion converter is configured to convert motion of the spring to cause the tissue-penetrating element to enter and exit tissue. A second motion converter is configured to convert motion of the spring to advance the delivery member into the tissue-penetrating member lumen. The motion converter is pushed by the spring and follows a rod or other track member that serves to guide the converter's path. They are engaged (directly or indirectly) with the tissue penetrating member and/or delivery member to produce the desired motion. They are desirably configured to convert motion of the spring along its longitudinal axis into orthogonal motion of the tissue-penetrating member and/or delivery member, although conversion in other directions is also contemplated. . The motion converter may have a wedge-shaped, trapezoidal or curved shape, although other shapes are also contemplated. In certain embodiments, the first motion converter has a trapezoidal shape and includes a slot that engages a pin on the tissue-penetrating member that advances through the slot. . The slot may have a trapezoidal shape identical to or otherwise corresponding to the overall shape of the transducer, pushing the tissue-penetrating member between the upsloping portions of the trapezoid. and then help pull it back during the downhill portion. In one variation, one or both of the motion converters can include a cam or cam-like device rotated by a spring to engage the tissue penetrating and/or delivery member.

In other variations, the actuation mechanism may also include an electromechanical device/mechanism, such as a solenoid or piezoelectric device. In one embodiment, the piezoelectric device can include a shaped piezoelectric element having an undeployed state and a deployed state. The element can be configured to deploy to the deployed state upon application of a voltage and then return to the undeployed state upon removal of the voltage. This and related embodiments allow reciprocation of the actuation mechanism to both advance the tissue-penetrating member and then withdraw it.

The release element is coupled to at least one of the actuation mechanism or a spring coupled to the actuation mechanism. In a particular embodiment, the release element is connected to a spring positioned to retain the spring in compression within the capsule. Disassembly of the release element releases the spring to activate the starting mechanism. In many embodiments, the release element comprises a material configured to degrade upon exposure to chemical conditions within the small or large intestine, such as pH. Typically, the release element is adapted to a selected pH within the small intestine, such as about 7.0, 7.1, 7.2, 7.3, 7.4, 8.0 or greater. Configured to degrade upon exposure. However, it can also be configured to degrade in response to other conditions within the small intestine. In certain embodiments, the release element is configured to degrade in response to specific chemical conditions in the fluid in the small intestine, such as the fluid generated after ingestion of a meal (e.g., a high-fat or high-protein meal). be able to.

Biodegradation of the release element from one or more conditions in the small intestine (or other location within the GI tract) depends on the material for the release element, the amount of cross-linking of such material, and the thickness and other dimensions of the release element. can be achieved by selection. Less cross-linking and/or thinner dimensions can increase the degradation rate and vice versa. Suitable materials for the release element may include biodegradable materials, such as various enteric materials that are configured to degrade upon exposure to higher pH or other conditions within the small intestine. The enteric materials can be copolymerized or otherwise mixed with one or more polymers to obtain a number of specific material properties in addition to biodegradation. Such properties may include, but are not limited to, stiffness, strength, flexibility and hardness.

In certain embodiments, the release element may comprise a film or plug that fits over or otherwise blocks the guide tube and the release element inside the guide tube. A tissue penetrating member is retained. In these and related embodiments, the tissue-penetrating member is configured such that a spring-loaded actuation mechanism releases the tissue-penetrating member upon sufficient disassembly of the release element, after which the tissue-penetrating member is released from the guide tube. It is connected to a spring-loaded actuation mechanism that pops out and penetrates the intestinal wall. In other embodiments, the release element can be shaped to act as a latch that holds the tissue-penetrating member in place. In these and related embodiments, the release element may be external or internal to the capsule. For internal embodiments, the capsule and guide tube are configured to allow intestinal fluids to enter the capsule interior to enable disassembly of the release element.

In some embodiments, a sensor that detects the presence of a capsule in the small intestine and sends a signal to the triggering mechanism (or to an electronic controller coupled to the triggering mechanism to trigger the triggering mechanism); The triggering mechanism can be triggered, for example, by a pH sensor or other chemical sensor. Embodiments of pH sensors can include electrode-based sensors, or can be mechanical-based sensors, such as polymers that shrink or stretch upon exposure to pH or other chemical conditions in the small intestine. In a related embodiment, the extendable sensor may itself constitute the actuation mechanism by using mechanical motion from extension or retraction of the sensor.

According to another embodiment for detecting that the device is in the small intestine (or other location in the GI tract), the sensor detects the number of peristaltic contractions the capsule is undergoing within a particular location in the intestinal tract. may include strain gauges or other pressure/force sensors for detecting In these embodiments, the capsule is desirably sized such that it is clamped by the small intestine during peristaltic contractions. Different locations within the GI tract have different numbers of peristaltic contractions. The small intestine has between 12 and 9 contractions per minute, decreasing in frequency down the length of the small intestine. Thus, according to one or more embodiments, detecting the number of peristaltic contractions can be used not only to determine whether a capsule is in the small intestine, but also to determine its relative position within the small intestine. can.

As an alternative or supplement to internally-activated drug delivery, in some embodiments, the user provides an activation mechanism for drug delivery by RF (radio frequency), magnetic or other wireless signal transmission means known in the art. can be started externally. In these and related embodiments, a user may use a handheld device (eg, a handheld RF device) that not only includes signal transmission means, but also that the device is capable of performing the function of the small intestine, the small intestine, the small intestine, or means to provide information to the user when in other locations within the GI tract. The latter embodiment includes an RF transmitter on the swallowable device for signaling the user (e.g., by signaling input from a sensor) when the device is in the small intestine or other location. It can be executed by letting The same portable device can also be configured to alert the user when the triggering mechanism has been activated and the drug(s) of choice has been delivered. In this way, the user is provided with confirmation that the medication has been delivered. In another approach, an external acoustic sensor detects sounds characteristic of an activated triggering mechanism, for example implemented using a chamber containing a piston and cylinder mechanism operably connected to a tissue-penetrating member. By detecting one or more natural frequencies of sound that can occur in the morphology, it can be used to detect when the triggering mechanism has been activated. One or more of the foregoing approaches involve the user taking other appropriate drugs/therapeutic agents and making other related decisions (e.g., whether a diabetic will eat a meal and which foods to eat). to eat). The portable device can also be configured to send a signal to the swallowable device to override the triggering mechanism, thereby preventing, delaying, or accelerating drug delivery. Expression devices can also be constructed. When used, such embodiments prevent, delay or delay drug delivery based on other symptoms and/or patient behavior (e.g., eating meals, deciding to fall asleep, exercise, etc.). Allows user intervention to accelerate.

The user can also externally activate the triggering mechanism after a selected period of time after swallowing the capsule. The duration can be correlated to a typical transit time or range of transit times for food to travel through the user's GI tract to a particular location within the tract, such as the small intestine. External activation may be through the use of wireless control means (e.g., using RF communication devices), magnetic means (e.g., miniature magnetic switches or releases built into the swallowable device that the user activates by external magnetism). ), or by any number of means including acoustic means (eg, by an ultrasonic transmission device and acoustic reception and/or switch built into the swallowable device).

Another aspect of the invention provides therapeutic agent formulations for delivery into the small intestinal wall (or other wall within the intestinal tract) using embodiments of the swallowable devices described herein. The formulation comprises a therapeutically effective dose of at least one therapeutic agent (eg, an antibody or other binding protein). It may also contain solids, liquids or a combination of both, and may contain one or more pharmaceutical excipients. The formulation is of a shape and material consistency such that it is contained within a swallowable capsule embodiment, is delivered from the capsule into the intestinal wall, and degrades within the intestinal wall to release the dose of therapeutic agent. have sex. The formulation may also have a selectable surface area to volume ratio to enhance or otherwise control the rate of degradation of the formulation within the walls of the small intestine or other body cavity. In various embodiments, coupled to an actuator, such as a release element or actuation mechanism, having a first configuration to contain the formulation within a capsule and a second configuration to allow the formulation to exit the capsule and enter the wall of the small intestine. The formulation can be configured to allow The dose of drug or other therapeutic agent in the formulation can be tapered from that required for conventional oral delivery methods, thereby reducing potential side effects from the drug.

In some embodiments, the formulation is shaped and otherwise configured to be received within the lumen of a tissue-penetrating member, e.g., a hollow needle, configured to be advanced from the capsule and into the wall of the small intestine. configured to In other embodiments, the formulation itself may constitute a tissue-penetrating member configured to penetrate the wall of the small intestine or other lumen within the intestinal tract. In such embodiments, the formulation is molded as or otherwise incorporated into the tissue-penetrating member. For example, in the latter case, by forming the formulation into shaped sections as cylinders or pellets, it is then loaded into a tissue-penetrating member made of a material configured to biodegrade within the wall of the small intestine. , is sealed.

Another aspect of the invention provides methods of delivering drugs and therapeutic agents to the GI tract wall using embodiments of swallowable drug delivery devices. Such methods can be used to deliver therapeutically effective amounts of a variety of drugs and other therapeutic agents. These include numerous large peptides and proteins that would otherwise require injection due to chemical degradation in the stomach, such as antibodies growth hormone, parathyroid hormone, insulin, interferon and other similar drugs. compound. Suitable drugs and other therapeutic agents that can be delivered by embodiments of the present invention include various antibodies (e.g., anti-interleukin antibodies, classes of antibodies that inhibit TNF), chemotherapeutic agents (e.g., interferons) , antibiotics, antivirals, insulin and related compounds, glucagon-like peptides (e.g. GLP-1, exenatide), parathyroid hormones, growth hormones (e.g. IFG and other growth factors), seizure inhibitors, immunosuppressants and antiparasitic agents, such as various antimalarial agents. Dosages of particular drugs can be adjusted for the patient's weight, age, condition or other parameters.

In various method embodiments of the present invention, drug-swallowable drug delivery device embodiments are used to administer multiple drugs for the treatment of multiple conditions or for the treatment of a specific condition (e.g., HIV AIDS treatment). (a mixture of protease inhibitors for In use, such embodiments may spare a patient the need to take multiple medications for a particular condition or conditions. The above embodiments also provide a means for ensuring that two or more drug regimens are delivered and absorbed into the small intestine and thus into the bloodstream at approximately the same time. Due to differences in chemical composition, molecular weight, etc., drugs may be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves. Embodiments of the present invention address this issue by injecting the desired drug mixtures at approximately the same time. This in turn allows the pharmacokinetic parameters of selected drug mixtures to be substantially synchronized (e.g., within e.g. 5% in time) (e.g. to achieve similar t _1/2 for different drugs). by), thus improving the efficacy of the selected mixture of drugs.

In another aspect, various embodiments of the present invention provide a solid mass comprising a drug such as an antibody or other immunoglobulin that has biological activity (e.g., binding affinity for an antigen) in the body of a mammal. wherein at least a portion of the biological activity of the antibody is retained after formation of a shaped mass from a precursor material such as a powder. Biological activity can be correlated with the structural integrity of an antibody or other drug after formation (e.g., by correlating biological activity assays with chemical assays), so that, at the compositional level, antibody selection can be percentage (eg, on a weight basis) is maintained after formation relative to that in the precursor material. Generally, the shape is formed by a compression process (eg, compression molding), although other processes such as non-compression molding are also contemplated. The drug may correspond to a peptide, antibody, immunoglobulin or other protein, wherein the biological activity of the drug in the shaped mass is at least 70% of that before compression, more preferably that before compression. At least 90%, even more preferably at least 95%. These numbers can also correspond to the weight percentage of drug remaining in the molded mass relative to that in the precursor material (e.g., biological activity assays and chemical assays as described above for weight composition). by correlating). In these and related embodiments, the molded mass can have a density within the range of about 1.00 to 1.15 mg/mm3, and in more preferred embodiments, 1.02 to 1.06 mg/mm3. Shapes generally include pellet shapes, but can also have tablets, cones, cylinders, cubes, spheres, or other similar shapes. Generally, pellets or other forms of shaped mass are then inserted into the tissue-penetrating member embodiments described herein.

Embodiments of the invention also provide a method for forming a solid shaped mass comprising an antibody, immunoglobulin or other protein, wherein the shaped mass is formed by shaping a precursor material and peptide in the shaped mass , at least a portion of the biological activity (eg, antigen-binding affinity, specificity, etc.) of the antibody or other protein is preserved after formation. In many embodiments, shaping is performed by compression of the precursor material, where the compression force is selected to minimize degradation of the biological activity of the protein or polypeptide. Other molding methods are also contemplated. Generally, the precursor material comprises a powder mix containing drug and one or more excipients. Precursor materials can also include liquids, slurries or pastes. Excipients can include one or more of lubricants, binders, bulking agents, and the like. The shaped mass may be in the form of tablets, microtablets, pills or slugs. According to one or more embodiments, the shaped mass produced using embodiments of the forming process has a density or particle size that correlates with a minimal level of biological activity of the protein or peptide (the shaped mass is formulated of the powder used to form the powder). The correlated properties can also be maintained consistently from lot to lot within selected ranges within a given lot of molded masses. The solid mass embodiments described herein can be configured for use in combination with any suitable drug delivery system for administration via any suitable route of administration for the condition to be treated. . Such routes of administration can include, but are not limited to, oral, sublingual or various parenteral delivery including, but not limited to, intravenous, intramuscular, intraventricular, intracardiac, intracranial. . For example, according to one embodiment, antibody-containing microtablets (e.g., microtablets containing anti-interleukin antibodies) can be taken orally and delivered to the small intestine, where the antibody is delivered to the wall of the small intestine. , where the tablet(s) dissolves and releases the antibody into the bloodstream, where it binds to selected target molecules (eg, interleukins) to treat one or more conditions (eg, rheumatoid arthritis). , multiple sclerosis, psoriasis). In another embodiment, insulin-containing microtablets can be injected or otherwise placed subcutaneously (eg, intramuscularly) where they dissolve and release the antibody into the bloodstream.

Further details about these and other embodiments and aspects of the invention are described more fully below with reference to the accompanying drawings.
In certain embodiments, for example, the following are provided:
(Item 1)
A solid tissue-penetrating therapeutic formulation comprising a solid form of an anti-interleukin antibody (AI antibody), wherein the tissue-penetrating member is configured to penetrate and be inserted into the intestinal wall after oral ingestion by applying a mechanical force to the tissue-penetrating member. molded as a member wherein, after insertion, said tissue-penetrating member remains within the intestinal wall and releases AI antibodies into the blood stream to attenuate the biological effects of interleukins in the body; A therapeutic formulation wherein any adverse reactions from release are less than those associated with parenteral injection delivery of said AI antibody.
(Item 2)
A formulation according to item 1, wherein said attenuated biological effect of said interleukin is a pro-inflammatory response.
(Item 3)
Item 1, wherein said adverse reaction is one of an injection site reaction, anaphylactic reaction, anaphylactic shock, edema, headache, immunogenic reaction, generation of antibodies to said AI antibody or reduction in efficacy of said AI antibody. Formulation as described.
(Item 4)
The formulation of item 1, wherein said AI antibody comprises an antibody against a member of the interleukin-17 family of cytokines.
(Item 5)
5. The formulation of item 4, wherein said AI antibody is secukinumab.
(Item 6)
5. The formulation of item 4, wherein said AI antibody is ixekizumab.
(Item 7)
5. The formulation of item 4, wherein said AI antibody is brodalumab.
(Item 8)
2. The formulation of item 1, wherein said AI antibody is released from the intestinal wall into the blood stream to achieve C _max in a shorter period of time than the time period for an extravascular dose of said AI antibody to achieve C _max .
(Item 9)
9. The formulation of item 8, wherein the t _max of the AI antibody released from the tissue-penetrating member is about 50% of the t _max of the AI antibody at the extravascular dose.
(Item 10)
9. The formulation of item 8, wherein the t _max of the AI antibody released from the tissue-penetrating member is about 10% of the t _max of the AI antibody at the extravascular injection dose.
(Item 11)
9. The formulation of item 8, adapted for insertion into the wall of the small intestine.
(Item 12)
The formulation of item 1, wherein said extravascular injection is subcutaneous or intramuscular.
(Item 13)
The formulation of item 1, adapted for oral delivery in a swallowable capsule.
(Item 14)
A delivery means having a first configuration and a second configuration, the first configuration containing the formulation within a capsule, and the second configuration allowing the formulation to enter the intestinal wall from the capsule. 14. A formulation according to item 13, adapted to be operatively connected to a delivery means that allows
(Item 15)
to item 14, wherein said delivery means comprises at least one expandable balloon having an expanded and an unexpanded state, said first configuration being said unexpanded state and said second configuration being said expanded state; Formulation as described.
(Item 16)
2. The formulation of item 1, comprising a biodegradable material that degrades within the intestinal wall to release the AI antibody into the blood stream.
(Item 17)
A formulation according to item 1, wherein the biodegradable material comprises PGLA, polyethylene oxide, sugar or maltose.
(Item 18)
A formulation according to item 1, comprising at least one pharmaceutical excipient.
(Item 19)
19. The formulation of item 18, wherein said at least one pharmaceutical excipient comprises at least one of a binder, preservative or disintegrant.
(Item 20)
2. The formulation of item 1, wherein the tissue-penetrating member comprises a biodegradable material that degrades within the intestinal wall to release AI antibodies into the bloodstream.
(Item 21)
21. The formulation of item 20, wherein said biodegradable material comprises maltose or PGLA or polyethylene oxide.
(Item 22)
The formulation of item 1, wherein the weight percent of AI antibodies in said tissue-penetrating member comprises about 8 to 12%.
(Item 23)
The formulation of item 1, wherein the tissue-penetrating member comprises a retention feature for retaining the tissue-penetrating member within the intestinal wall after insertion.
(Item 24)
The formulation of item 1, wherein the AI antibody is housed within a shaped section of the tissue-penetrating member.
(Item 25)
25. The formulation of item 24, wherein said shaped section has a cylindrical or pellet shape.
(Item 26)
9. The formulation of item 8, wherein the _Cmax achieved by delivery of the formulation by insertion into the intestinal wall is substantially greater than the _Cmax achieved when the formulation is orally delivered without penetration into the intestinal wall. .
(Item 27)
27. The method of claim 26, wherein the C _max achieved by delivery of the formulation by insertion into the intestinal wall is at least about 100 times greater than the C _max achieved when the formulation is orally delivered without penetration into the intestinal wall. pharmaceutical formulation.
(Item 28)
The formulation of item 1, configured to provide extended release of the AI antibody.
(Item 29)
29. The formulation of item 28, configured to provide extended release of the AI antibody to produce a selectable t _1/2 .
(Item 30)
30. The formulation of item 29, wherein said t _1/2 is about 40 days.
(Item 31)
The formulation of item 1, wherein the dose of AI antibody in said formulation is in the range of about 1 to 5 mg.
(Item 32)
32. The formulation of item 31, wherein the dose of AI antibody in said formulation is in the range of about 2-4 mg.
(Item 33)
A therapeutic formulation comprising an anti-interleukin antibody (AI antibody), wherein the formulation is adapted to be inserted and retained within the intestinal wall after oral ingestion by applying a mechanical force to the formulation, wherein, upon insertion, the formulation is cleaved by the fluid in the intestinal wall to release AI antibodies from the intestinal wall into the bloodstream, achieving a t _1/2 greater than that of orally ingested AI antibodies that do not insert into _the intestinal wall, and that of AI antibodies A therapeutic formulation wherein any adverse reactions from said release are less than those associated with parenteral injection delivery of AI antibodies.
(Item 34)
34. The formulation of item 33, wherein the t _1/2 of said AI antibody that inserts into the intestinal wall is at least about 10 times greater than the t _1/2 of said orally ingested AI antibody that does not insert into the intestinal wall.
(Item 35)
A therapeutic formulation comprising a solid form of secukinumab, which is shaped as a solid tissue-penetrating member configured to penetrate and be inserted into the intestinal wall after oral ingestion by subjecting the tissue-penetrating member to a mechanical force, wherein the tissue-penetrating member is configured to undergo insertion. Thereafter, the tissue-penetrating member is placed within the intestinal wall and releases secukinumab into the blood stream to attenuate the pro-inflammatory response in the patient's body induced by the interleukin-17 molecule; A therapeutic formulation in which any adverse reactions are less than those associated with parenteral injection delivery of secukinumab.
(Item 36)
A therapeutic formulation comprising brodalumab in solid form, shaped as a solid tissue-penetrating member configured to penetrate and be inserted into the intestinal wall after oral ingestion by applying a mechanical force to the tissue-penetrating member, wherein The tissue-penetrating member is then placed in the intestinal wall to release brodalumab into the bloodstream and interact with the interleukin molecule receptor to attenuate the pro-inflammatory response in the patient's body induced by the interleukin-17 molecule. a therapeutic formulation wherein any adverse reactions from said release of brodalumab are less than those associated with parenteral injection delivery of brodalumab.
(Item 37)
A therapeutic formulation comprising a solid form of ixekizumab, which is shaped as a solid tissue-penetrating member configured to penetrate and be inserted into the intestinal wall after oral ingestion by applying a mechanical force to the tissue-penetrating member, wherein the tissue-penetrating member is configured to undergo insertion. Thereafter, the tissue-penetrating member is placed within the intestinal wall and releases ixekizumab into the bloodstream to attenuate the pro-inflammatory response in the patient's body induced by the interleukin-17 molecule; A therapeutic formulation in which any adverse reactions are less than those associated with parenteral injection delivery of ixekizumab.
(Item 38)
A method for treating a patient having a disease or condition associated with an interleukin-17 molecule, comprising:
providing a solid anti-interleukin 17 antibody (AI17 antibody) dosage shaped as a tissue-penetrating member and configured for oral delivery to the intestinal tract of said patient;
penetrating said solid dosage AI17 antibody into said patient's intestinal wall after oral ingestion by applying a mechanical force to said tissue-penetrating member such that said tissue-penetrating member remains in the intestinal wall; and in the intestinal wall. releasing said AI17 antibody from said solid dosage AI17 antibody into said patient's blood stream to treat said disease or condition, wherein any adverse reaction from said release of said AI17 antibody A method less than that associated with oral injection delivery.
(Item 39)
39. The method of item 38, wherein said parenteral injection is intramuscular or subcutaneous.
(Item 40)
wherein said formulation is adapted for oral delivery in a swallowable capsule;
39. The method of item 38, further comprising swallowing the capsule and allowing it to reach the small intestine; and penetrating the small intestine wall with the solid dose AI17 antibody in response to conditions within the small intestine.
(Item 41)
41. The method of item 40, wherein said condition is pH.
(Item 42)
41. The method of claim 40, wherein the conditions are at a pH of about 6.5 so that the solid dose AI17 antibody penetrates the wall of the duodenal or jejunal section of the small intestine and avoids the ileal section containing Peyer's patches. Method.
(Item 43)
39. The method of item 38, wherein said disease or condition is treated by reducing biological effects in the patient's body induced by interleukin-17 molecules.
(Item 44)
Th1 modulation; Th2 modulation; NK modulation; neutrophil modulation; monocyte-macrophage lineage modulation; and chemokine modulation.
(Item 45)
in item 38, wherein said adverse reaction is one of an injection site reaction, anaphylactic reaction, anaphylactic shock, edema, headache, immunogenic reaction, generation of antibodies to said AI17 antibody or reduced efficacy of said AI1 antibody. described method.
(Item 46)
39. The method of item 38, wherein the patient's immune response to the AI17 antibody is reduced compared to delivery of the AI17 antibody by parenteral injection.
(Item 47)
47. The method of item 46, wherein said immune response of said patient to said AI17 antibody is reduced by an amount within the range of 2 to 30 fold compared to intramuscular or subcutaneous injection.
(Item 48)
39. The method of item 38, wherein the incidence of allergic reactions to said AI17 antibody is reduced compared to delivery of said AI17 antibody by parenteral injection.
(Item 49)
49. The method of item 48, wherein said incidence of allergic reaction to said AI17 antibody is reduced by an amount within the range of about 2 to 30 fold compared to intramuscular or subcutaneous injection.
(Item 50)
In item 38, said AI17 antibody is released into the mesenteric vasculature such that it enters the portal vein and binds to interleukin in the liver before substantially binding to interleukin elsewhere in the body. described method.
(Item 51)
39. According to item 38, wherein said solid dosage AI17 antibody is inserted into a section of the intestinal wall prior to the section containing Peyer's patches such that any immune response to the AI17 antibody caused by Peyer's patches is minimized. the method of.
(Item 52)
52. The method of item 51, wherein said solid dose AI17 antibody is inserted into the wall portion of the duodenum or jejunum of the small intestine.
(Item 53)
39. The method of item 38, wherein said AI17 antibody released into the bloodstream from said solid dose AI17 antibody reaches Cmax in a shorter period of time than an extravascular dose of AI17 antibody achieves Cmax.
(Item 54)
54. The method of item 53, wherein the tmax of said AI17 antibody released from said solid dose AI17 antibody is less than about 50% of the tmax of said extravascular dose of AI17 antibody.
(Item 55)
55. The method of item 54, wherein the tmax of said AI17 antibody released from said solid dose AI17 antibody is less than about 30% of the tmax of said extravascular dose of AI17 antibody.
(Item 56)
39. The method of item 38, wherein steady-state diurnal variation in plasma concentrations of said AI17 antibody is significantly less than that of said parenteral injection when solid form AI17 antibody doses are administered daily.
(Item 57)
57. The method of item 56, wherein the stable diurnal variation in plasma concentration of said AI17 antibody is between about 0.12 and 0.26%.
(Item 58)
57. The method of item 56, wherein the stable diurnal variation in plasma concentration of said AI17 antibody is about 171 to 216 times less than said parenteral injection.
(Item 59)
39. The method of item 38, wherein said AI17 antibody is secukinumab.
(Item 60)
39. The method of item 38, wherein said AI17 antibody is brodalumab.
(Item 61)
39. The method of item 38, wherein said AI17 antibody is ixekizumab.
(Item 62)
39. The method of item 38, wherein the disease or condition to be treated is plaque-type psoriasis.
(Item 63)
39. The method of item 38, wherein the disease or condition to be treated is psoriatic arthritis.
(Item 64)
39. The method of item 38, wherein the disease or condition to be treated is ankylosing spondylitis.
(Item 65)
39. The method of item 38, wherein the disease or condition to be treated is rheumatoid arthritis.
(Item 66)
39. The method of item 38, wherein said disease or condition to be treated is Crohn's disease.
(Item 67)
39. The method of item 38, wherein said disease or condition to be treated is inflammatory bowel disease.
(Item 68)
39. The method of item 38, wherein said delivery of said solid AI17 antibody dosage has a therapeutic index in said patient that is substantially higher than that of an AI17 antibody dosage delivered by parenteral injection.
(Item 69)
69. The method of item 68, wherein said therapeutic index of said solid AI17 antibody is within a range of about 7 to 30 times higher than said therapeutic index of said AI17 antibody dosage delivered by parenteral injection.
(Item 70)
A method for treating a patient having a disease or condition associated with an interleukin-17 molecule, comprising:
providing a daily solid anti-interleukin 17 antibody (AI17 antibody) dosage shaped as a tissue-penetrating member and configured for oral delivery to the intestinal tract of said patient;
penetrating said solid dosage AI17 antibody into said patient's intestinal wall after oral ingestion by applying a mechanical force to said tissue-penetrating member such that said tissue-penetrating member is retained within said intestinal wall; and said AI17 antibody. releasing said AI17 antibody into said patient's bloodstream from said solid dosage AI17 antibody in the intestinal wall such that the daily variation in the plasma concentration of said disease or A method comprising treating a condition wherein any adverse reaction from said release of said AI17 antibody is less than that associated with parenteral injection delivery of said AI antibody.
(Item 71)
71. The method of item 70, wherein said disease or condition to be treated is selected from the group consisting of plaque-type psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, Crohn's disease and inflammatory bowel disease.
(Item 72)
71. The method of item 70, wherein the stable diurnal variation in plasma concentration of said AI17 antibody is about 171 to 216 times less than said parenteral injection.
(Item 73)
in item 70, wherein said adverse reaction is one of an injection site reaction, anaphylactic reaction, anaphylactic shock, edema, headache, immunogenic reaction, generation of antibodies to said AI17 antibody or reduced efficacy of said AI1 antibody. described method.
(Item 74)
71. The method of item 70, wherein the release of the solid AI17 antibody dosage has a therapeutic index in the patient that is substantially higher than the therapeutic index of an AI17 antibody dosage delivered by parenteral injection.
(Item 75)
75. The method of paragraph 74, wherein said therapeutic index of said solid AI17 antibody is within a range of about 7 to 30 times higher than said therapeutic index of said AI17 antibody dosage delivered by parenteral injection.
(Item 76)
1. A method for treating plaque-type psoriasis in a patient by inhibiting the biological activity of interleukin 17 molecules comprising:
providing a solid anti-interleukin 17 antibody (AI17 antibody) dosage shaped as a tissue-penetrating member;
penetrating the intestinal wall of the patient after oral ingestion by applying a mechanical force to the tissue-penetrating member such that the tissue-penetrating member remains in the intestinal wall; and a therapeutically effective dose. of said AI17 antibody from said solid dosage AI17 antibody in the intestinal wall into the blood stream of said patient to inhibit the biological activity of interleukin 17 molecule; A method wherein any adverse reactions are less than those associated with parenteral injection delivery of said AI antibody.
(Item 77)
77. The method of item 76, wherein said interleukin-17 molecule is interleukin-17A.
(Item 78)
77. The method of item 76, wherein said AI17 antibody is secukinumab.
(Item 79)
77. The method of item 76, wherein said AI17 antibody is brodalumab and said biological activity of said interleukin-17 molecule is inhibited by binding of said AI17 antibody to a receptor for said interleukin-17 molecule.
(Item 80)
77. The method of item 76, wherein said AI17 antibody is ixekizumab.
(Item 81)
77. The method of item 76, wherein said biological activity of said interleukin-17 molecule is inhibited by a minimal immune response in said patient to said AI17 antibody.
(Item 82)
77. The method of item 76, wherein the patient's immune response to the AI17 antibody is reduced compared to delivery of the AI17 antibody by parenteral injection.
(Item 83)
83. The method of item 82, wherein the immune response of the patient to the AI17 antibody is reduced by an amount within the range of about 2 to 30 fold compared to delivery of the AI17 antibody by parenteral injection.
(Item 84)
83. The method of item 82, wherein the incidence of allergic reactions to said AI17 antibody is reduced by an amount within the range of 2 to 30-fold compared to delivery of said AI17 antibody by parenteral injection.
(Item 85)
77. The method of item 76, wherein the therapeutic index of said solid AI17 antibody dosage is substantially higher than the therapeutic index of an AI17 antibody dosage delivered by parenteral injection.
(Item 86)
86. The method of item 85, wherein said therapeutic index of said solid AI17 antibody is within a range of about 7 to 30 times higher than said therapeutic index of said AI17 antibody dosage delivered by parenteral injection.
(Item 87)
NK modulation; neutrophil modulation; monocyte-macrophage lineage modulation; neutrophil modulation; 77. A method according to item 76, selected from the group.
(Item 88)
1. A method for treating psoriatic arthritis in a patient by inhibiting the activity of interleukin 17 molecule comprising:
providing a solid anti-interleukin 17 antibody (AI17 antibody) dosage shaped as a tissue-penetrating member;
penetrating the intestinal wall of the patient after oral ingestion by applying a mechanical force to the tissue-penetrating member such that the tissue-penetrating member remains in the intestinal wall; and a therapeutically effective dose. from said solid dosage AI17 antibody in the intestinal wall into the blood stream of said patient to inhibit the biological activity of said interleukin-17 molecule; any adverse reaction of is less than that associated with parenteral injection delivery of said AI antibody.
(Item 89)
77. The method of item 76, wherein said interleukin-17 molecule is interleukin-17A.
(Item 90)
77. The method of item 76, wherein said AI17 antibody is secukinumab.
(Item 91)
77. The method of item 76, wherein said AI17 antibody is brodalumab and said biological activity of said interleukin-17 molecule is inhibited by binding of said AI17 antibody to a receptor for said interleukin-17 molecule.
(Item 92)
77. The method of item 76, wherein said AI17 antibody is ixekizumab.
(Item 93)
In item 76, said AI17 antibody is released into the mesenteric vasculature such that it enters the portal vein and binds to interleukin in the liver before substantially binding to interleukin elsewhere in the body. described method.

FIG. 1a is a side view showing an embodiment of a swallowable drug delivery device.

Figure Ib is a side view showing an embodiment of a system comprising a swallowable drug delivery device.

FIG. 1c is a side view showing an embodiment of a kit including a swallowable drug delivery device and a set of instructions.

Figure Id is a side view showing an embodiment of a swallowable drug delivery device with a drug reservoir.

FIG. 2 is a side view illustrating an embodiment of a swallowable drug delivery device having a spring-loaded actuation mechanism for advancing a tissue-penetrating member into tissue;

FIG. 3 is a side view illustrating an embodiment of a swallowable drug delivery device having a spring-loaded actuation mechanism with a first motion converter.

FIG. 4 is a side view illustrating an embodiment of a swallowable drug delivery device having a spring-loaded actuation mechanism with first and second motion converters.

FIG. 5 is a perspective view illustrating the engagement of the first and second motion converters with the tissue penetrating member and the delivery member;

FIG. 6 is a cross-sectional view illustrating an embodiment of a swallowable drug delivery device having a single tissue-penetrating member and an actuation mechanism for advancing the tissue-penetrating member.

FIG. 7a is a cross-sectional view illustrating an embodiment of a swallowable drug delivery device having multiple tissue-penetrating members and an actuation mechanism for advancing the tissue-penetrating members.

Figure 7b is a cross-sectional view illustrating deployment of the tissue-penetrating member of the embodiment of Figure 7a to deliver the medicament to the delivery site and anchor the device within the intestinal wall during delivery.

Figure 8a is a side view illustrating positioning of the drug delivery device within the small intestine and deployment of the tissue penetrating member to deliver the drug. Figure 8a shows the device in the small intestine prior to deployment of the tissue penetrating member by a release element within the canal. FIG. 8b is a side view illustrating positioning of the drug delivery device within the small intestine and deployment of the tissue penetrating member to deliver the drug. Figure 8b shows the device in the small intestine with the release element disassembled and the tissue penetrating element deployed. FIG. 8c is a side view illustrating positioning of the drug delivery device within the small intestine and deployment of the tissue penetrating member to deliver the drug. Figure 8c shows the device in the small intestine with the tissue penetrating element retracted and drug delivered.

Figure 9a shows an embodiment of a swallowable drug delivery device comprising a capsule having a biodegradable seam positioned to effect controlled degradation of the capsule within the GI tract. Figure 9b shows the embodiment of Figure 9a after it has been broken down into smaller pieces in the GI tract.

Figure 10 shows an embodiment of a capsule having a biodegradable seam with pores and/or perforations to accelerate biodegradation of the capsule.

FIG. 11 is a side view illustrating use of an embodiment of the swallowable drug delivery device, including passage of the device through the GI tract and manipulation of the device to deliver the drug.

Figures 12a and 12b are side views illustrating an embodiment of a capsule for a swallowable drug delivery device comprising a cap and body coated with a pH sensitive biodegradable coating, Figure 12a being assembled. Figure 12b shows the capsule in its empty state and Figure 12b shows the capsule in its assembled state.

FIG. 13a illustrates an embodiment of an unfolded multi-balloon assembly containing a deployment balloon, an aligner balloon, a delivery balloon and multiple connecting tubes. Figure 13a shows an embodiment of the assembly for a single dome configuration of the deployment balloon. FIG. 13b illustrates an embodiment of an unfolded multi-balloon assembly containing deployment balloons, aligner balloons, delivery balloons and multiple connecting tubes. Figure 13b shows an embodiment of the assembly for a double dome configuration of the deployment balloon.

Figure 13c is a perspective view illustrating an embodiment of a nested balloon configuration that can be used with one or more embodiments of the balloons described herein, including the aligner balloon.

Figure 14a is a side view illustrating an embodiment of a multi-compartment deployment balloon; Figure 14a shows said balloon in an uninflated state with isolation valves closed. Figure 14b is a side view illustrating an embodiment of a multi-compartment deployment balloon. Figure 14b shows the balloon with the valve open and the chemical reactants mixed. Figure 14c is a side view illustrating an embodiment of a multi-compartment deployment balloon. Figure 14c shows the balloon in an inflated state.

Figures 15a-15g are side views illustrating the folding method of the multiple balloon assembly, the folding configuration in each figure being that Figure 15c relates to the folding stage specific to the double dome configuration and Figure 15d is the double dome configuration. FIG. 15e is for the final folding stage specific to the configuration, and FIGS. 15f and 15g are orthographic views for the final folding stage specific to the single dome configuration. It applies to both single-dome and double-dome configurations of deployment balloons, with one exception. Figures 15a-15g are side views illustrating the folding method of the multiple balloon assembly, the folding configuration in each figure being that Figure 15c relates to the folding stage specific to the double dome configuration and Figure 15d is the double dome configuration. FIG. 15e is for the final folding stage specific to the configuration, and FIGS. 15f and 15g are orthographic views for the final folding stage specific to the single dome configuration. It applies to both single-dome and double-dome configurations of deployment balloons, with one exception. Figures 15a-15g are side views illustrating the folding method of the multiple balloon assembly, the folding configuration in each figure being that Figure 15c relates to the folding stage specific to the double dome configuration and Figure 15d is the double dome configuration. FIG. 15e is for the final folding stage specific to the configuration, and FIGS. 15f and 15g are orthographic views for the final folding stage specific to the single dome configuration. It applies to both single-dome and double-dome configurations of deployment balloons, with one exception. Figures 15a-15g are side views illustrating the folding method of the multiple balloon assembly, the folding configuration in each figure being that Figure 15c relates to the folding stage specific to the double dome configuration and Figure 15d is the double dome configuration. FIG. 15e is for the final folding stage specific to the configuration, and FIGS. 15f and 15g are orthographic views for the final folding stage specific to the single dome configuration. It applies to both single-dome and double-dome configurations of deployment balloons, with one exception. Figures 15a-15g are side views illustrating the folding method of the multiple balloon assembly, the folding configuration in each figure being that Figure 15c relates to the folding stage specific to the double dome configuration and Figure 15d is the double dome configuration. FIG. 15e is for the final folding stage specific to the configuration, and FIGS. 15f and 15g are orthographic views for the final folding stage specific to the single dome configuration. It applies to both single-dome and double-dome configurations of deployment balloons, with one exception. Figures 15a-15g are side views illustrating the folding method of the multiple balloon assembly, the folding configuration in each figure being that Figure 15c relates to the folding stage specific to the double dome configuration, Figure 15d is the double dome configuration. FIG. 15e is for the final folding stage specific to the configuration, and FIGS. 15f and 15g are orthographic views for the final folding stage specific to the single dome configuration. It applies to both single-dome and double-dome configurations of deployment balloons, with one exception. Figures 15a-15g are side views illustrating the folding method of the multiple balloon assembly, the folding configuration in each figure being that Figure 15c relates to the folding stage specific to the double dome configuration, Figure 15d is the double dome configuration. FIG. 15e is for the final folding stage specific to the configuration, and FIGS. 15f and 15g are orthographic views for the final folding stage specific to the single dome configuration. It applies to both single-dome and double-dome configurations of deployment balloons, with one exception.

Figures 16a and 16b are orthographic views illustrating an embodiment of a final folded multi-balloon assembly with an accessory delivery assembly.

Figures 17a and 17b are orthogonal transparent views illustrating an embodiment of a final folded multi-balloon assembly inserted into a capsule.

Figure 18a is a side view of an embodiment of a tissue penetrating member.

FIG. 18b is a bottom view of an embodiment of a tissue penetrating member illustrating placement of tissue retention features;

FIG. 18c is a side view of an embodiment of a tissue penetrating member having a trocar tip and reverse tapered shaft;

Figure 18d is a side view of an embodiment of a tissue penetrating member having separate drug containing sections.

Figures 18e and 18f are side views showing assembly of an embodiment of a tissue penetrating member having a shaped drug containing section. Figure 18e shows the tissue penetrating member and shaped drug section prior to assembly. Figures 18e and 18f are side views showing assembly of an embodiment of a tissue penetrating member having a shaped drug containing section. Figure 18f shows after assembly.

FIG. 19 provides various views of the components and steps used to assemble an embodiment of the delivery assembly.

Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall. Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall. Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall. Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall. Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall. Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall. Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall. Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall. Figures 20a-20i provide a variety of diagrams illustrating how the swallowable device is operated to deliver pharmaceutical agents to the intestinal wall.

Figures 21a and 21b are tables illustrating various information on interleukins, including interleukins that one or more antibodies provided by embodiments of the present invention are configured to bind and/or neutralize. be. Figures 21a and 21b are tables illustrating various information on interleukins, including interleukins that one or more antibodies provided by embodiments of the present invention are configured to bind and/or neutralize. be.

Figures 22a and 22b are simulated plasma concentration profiles of secukinumab delivered daily via a swallowable capsule embodiment (Figure 22a) and monthly by injection using conventional means (Figure 22b).

Figures 23a and 23b are simulated plasma concentration profiles of brodalumab delivered daily via a swallowable capsule embodiment (Figure 23a) and monthly by injection using conventional means (Figure 23b).

(Detailed description of the invention)
Embodiments of the present invention provide devices, systems and methods for delivering pharmaceutical agents within various locations of the body. As used herein, the term “pharmaceutical product” refers to any form of pharmaceutical preparation that can include a drug or other therapeutic agent as well as one or more pharmaceutical excipients. Many embodiments provide a swallowable device for delivering pharmaceuticals within the GI tract. Certain embodiments provide swallowable devices, such as capsules, for delivering pharmaceutical agents to the walls of the small intestine or other GI organs. As used herein, "GI tract" refers to the esophagus, stomach, small intestine, large intestine and anus, while "intestinal tract" refers to the small and large intestine. Various embodiments of the present invention can be constructed and arranged for delivery of pharmaceutical agents into the entire GI tract as well as the intestinal tract. Also as used herein, the term "about" refers to 10% of a given specified numerical value for a parameter, variable, dimension, etc. (e.g., pharmacokinetic parameters such as t _1/2 , t _max , c _max , etc.) means within

1-11, an embodiment of device 10 for delivery of pharmaceutical agent 100 to a delivery site DS in the intestinal tract, such as the wall of the small intestine, comprises at least one guide tube 30 and said at least one one or more tissue penetrating members 40 that can be positioned within a guide tube or otherwise advanced within said at least one guide tube, a delivery member 50, a triggering mechanism 60, and a release element 70; Including capsule 20 provided. Pharmaceutical product 100, which may also be described herein as formulation 100, typically includes at least one drug or therapeutic agent 101, and also one or more pharmaceutical excipients known in the art. may contain. Collectively, one or more of delivery member 50 and mechanism 60 may comprise means for delivery of medicament 100 into the intestinal wall. Other delivery means contemplated herein include one or more expandable balloons (eg, delivery balloon 172) or other expandable devices/members described herein.

The device 10 can be configured for the delivery of medicaments 100 in liquid, semi-liquid or solid form, or all three forms. Solid forms of drug product/formulation 100 can include both powders or pellets. Semi-liquid forms can include slurries or pastes. In whatever form, the formulation 100 allows the pharmaceutical agent to exit the device, enter the intestinal wall (or other luminal wall within the GI tract), and then degrade within the intestinal wall, resulting in various embodiments. in a shape that allows release of a drug or other therapeutic agent 101, which may correspond to one or more of the anti-interleukin antibodies (or other interleukin-neutralizing proteins) described herein, and It desirably has material consistency. The material consistency may include one or more of hardness (in body fluids), porosity and solubility of the formulation. Said material consistency can be achieved by one or more of: i) the compression force used to make the formulation; iii) use of other pharmaceutical excipients; iv) particle size and distribution of formulations (e.g., micronized particles); and v) use of micronization and other particle formation methods known in the art. . Suitable shapes for formulation 100 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 formulation 100, and thus the ratio of the two. The surface area to volume ratio can also be used to achieve selected degradation rates within the intestinal or other lumenal walls within the GI tract. Higher ratios (eg, greater amounts of surface area per unit volume) can be used to achieve faster degradation rates, and vice versa. In certain embodiments, the surface area to volume ratio can range from about 1:1 to 100:1, including 2:1, 5:1, 20:1, 25:1, 50:1 and 75:1. (in this case about within 5%). The formulation/medicine 100 is typically pre-packaged within the lumen 44 of the tissue-penetrating member 40, but at another location within the interior 24 of the capsule 20 or, if liquid or semi-liquid, in a sealed reservoir. 27 can also be accommodated. The medicament may be pre-shaped to fit within the lumen or may be packaged, eg, in powder form. Typically, device 10 is configured to deliver a single drug 101 as part of pharmaceutical product 100 . However, in some embodiments, the device 10 can be configured for delivery of multiple drugs 101, including first, second or third drugs that can be formulated into single or multiple pharmaceuticals 100. . For embodiments having multiple pharmaceuticals/drugs, the pharmaceuticals can be contained in separate tissue-penetrating members 40 or in separate compartments or reservoirs 27 within capsule 20 . In another embodiment, a first dose 102 of pharmaceutical product 100 containing a first drug 101 can be packaged within penetrating member(s) 40 (containing the same or different drug 101). A second dose 103 of medicament 100 can be coated on the capsule surface 25 as shown in the embodiment of FIG. 1b. The drug 101 in the two doses of drug product 102 and 103 may be the same or different. Thus, bimodal pharmacokinetic release of the same or different drugs can be achieved. Second dose 103 of drug 100 may have an enteric coating 104 to ensure that it is released in the small intestine and to achieve sustained release of drug 100 . Enteric coating 104 can include one or more enteric coatings described herein or known in the art.

System 11 for delivery of pharmaceutical agents 100 into the wall of the small intestine or other location within the GI tract contains one or more pharmaceutical agents 100 for treatment of selected condition(s). can include a device 10 that In some embodiments, the system can comprise a portable device 13 as described herein for communicating with device 10, as shown in the embodiment of Figure 1b. System 11 may be configured as a kit 14 comprising system 11 packaged in packaging 12 and a set of instructions 15, as shown in the embodiment of Figure Ic. The instructions can inform the patient when to use the device 10 for one or more events, such as meal intake or physiological measurements, such as blood sugar, cholesterol, and the like. In such embodiments, the kit 14 contains multiple regimens of the pharmaceutical agent 100 over a selected administration period, e.g. A device 10 may be provided.

Capsule 20 is sized to be swallowed and passed through the intestinal tract. The size can also be adjusted according to the amount of drug to be delivered and patient weight and adult versus pediatric use. Capsule 20 comprises an interior volume 24 and an exterior surface 25 having one or more apertures 26 sized for guide tube 30 . In addition to other components of device 10 (eg, an activation mechanism, etc.), the interior volume may comprise one or more compartments or reservoirs 27 . One or more portions of capsule 20 can be manufactured from a variety of biocompatible polymers known in the art, including a variety of biodegradable polymers that biodegrade. The polar polymer may include PGLA (polylactic-co-glycolic acid) in preferred embodiments. Other suitable biodegradable materials include the various enteric materials described herein, as well as lactide, glycolide, lactic acid, glycolic acid, paradioxanone, caprolactone, trimethylene carbonate, caprolactone, and blends and blends thereof. copolymers. As described in further detail herein, in various embodiments, the capsule 20 is seamed 22 with a biodegradable material so as to controllably break down into smaller pieces 23 that are more easily passed through the intestinal tract. can be provided. Additionally, in various embodiments, the capsule can include various radiopaque or echogenic materials for localization of the device using fluoroscopy, ultrasound, or other medical imaging modalities. . In a specific embodiment, all or part of the capsule can include radiopaque/echogenic markers 20m, as shown in the embodiment of Figures 1a and 1b. In use, such materials not only allow the orientation of the device 10 within the GI tract, but also the determination of transit time of the device through the GI tract.

In a preferred embodiment, tissue-penetrating member 40 is located within guide tube 30, which guides and supports entry of member 40 into tissue, such as the wall of the small intestine wall or other portion of the GI tract. Helpful. 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 a selectable depth of intestinal wall IW. Member 40 may also include pin 41 for engagement with motion converter 90 described herein. Penetration depth can be controlled by the length of member 40, the configuration of motion converter 90 described herein, and the placement of stops or flanges 40s on member 40, said stops or flanges 40s In some embodiments, it may correspond to pin 41 described herein. Pharmaceutical agent 100 is typically delivered to tissue through lumen 44 . In many embodiments, lumen 44 is prepackaged with the desired pharmaceutical agent 100, which is delivered using delivery member 50 or other advancement means (e.g., member 40 can be deflated). is advanced from the lumen (by force applied to the possible embodiment). Alternatively, medicament 100 may enter lumen 44 from another location/compartment of capsule 20 . In some embodiments, all or a portion of tissue-penetrating member 40 can be manufactured from medicament 100 itself. In these and related embodiments, the medicament is needle or arrow-like (with or without barbs) configured to penetrate and reside in an intestinal wall, such as the small intestinal wall. structure. The arrow can be sized and shaped according to the drug, dose, and desired depth of penetration into the intestinal wall. Various compression molding techniques known in the pharmaceutical arts can be used to form the pharmaceutical product 100 into arrows, pellets, or other shapes.

In various embodiments, the device 10 can include second 42 and third 43 tissue penetrating members 40 as shown in the embodiment of Figures 7a and 7b, although additional members are also contemplated. Each tissue penetrating member 40 can be used to deliver the same or different pharmaceutical agents 100 . In a preferred embodiment, tissue-penetrating members 40 may be distributed substantially symmetrically around perimeter 21 of capsule 20 to anchor the capsule on intestinal wall IW during delivery of medicament 100 . Anchoring the capsule 20 in such a manner reduces the likelihood that the capsule will be displaced or moved by peristaltic contractions that occur during drug delivery. In specific embodiments, the amount of anchoring force can be tailored to typical forces applied during peristaltic contractions of the small intestine. Anchoring may be further aided by a portion or all of the tissue penetrating member 40 configured to have a curved or arcuate shape.

Delivery member 50 is configured to advance medicament 100 through tissue-penetrating member lumen 44 and enter intestinal wall IW. Accordingly, at least a portion of delivery member 50 is advanceable within tissue-penetrating member lumen 44 such that member 50 is sized and shaped (e.g., piston) configured to fit within delivery member lumen 44 . similar shape).

In some embodiments, the distal end 50d of the delivery member (the tissue-entering end) can have a plunger element 51 that advances a medicament into the tissue-penetrating member lumen 44 . and form a seal with the lumen. Plunger element 51 may be built into delivery member 50 or attached to delivery member 50 . Preferably, delivery member 50 is configured to travel a fixed distance within needle lumen 44 to deliver a fixed or metered dose of drug within intestinal wall IW. This may involve selection of the diameter of the delivery member (eg, the diameter may taper distally), the diameter of the tissue-penetrating member (which may narrow at its distal end), the use of stops, and/or It can be accomplished by one or more of the triggering mechanisms. However, in some embodiments, the stroke or travel distance of 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 accomplished through the use of logic resources 29 (including controller 29c) coupled to the electromechanical embodiment of triggering mechanism 60. FIG. This allows for different doses of medication and/or variations in the distance at which the medication is injected into the intestinal wall.

A triggering 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 within the intestinal wall IW, as well as advance the delivery member to deliver the medicament 100 and then retract the tissue-penetrating member. It is also configured to exit the intestinal wall. In various embodiments, activation mechanism 60 may include a spring-loaded mechanism configured to be released by release element 70 . Suitable springs 80 include both coils (conical springs) and leaf springs, although other spring configurations are also contemplated. In certain embodiments, the spring 80 is made substantially conical to extend the compressed spring length further to a point where the compressed length of the spring is on the order of a few coils (e.g., 2 or 3) or only on the order of 1 coil thick. can be reduced.

In certain embodiments, the actuation mechanism 60 includes a spring 80, a first motion converter 90 and a second motion converter 94, and a track member, as shown in the embodiments of Figures 2, 4 and 8a-8c. 98 can be included. Release element 70 is connected to spring 80 to hold the spring in compression so that disassembly of the release element releases the spring. Spring 80 may be connected to release element 70 by a latch or other connecting element 81 . First motion converter 90 is configured to convert the motion of spring 80 to cause tissue-penetrating member 40 to enter and exit the intestinal wall or other tissue. Second motion converter 94 is configured to convert motion of spring 80 to cause delivery member 50 to enter tissue-penetrating member lumen 44 . Motion converters 90 and 94 are pushed by springs and travel along rods or other track members 98 that fit within track member lumens 99 of converters 90 . A track member 98 helps guide the path of the converter 90 . Transducers 90 and 94 are engaged (directly or indirectly) with tissue-penetrating member 40 and/or delivery member 50 to produce the desired motion. They are configured in shape and other features to translate motion of spring 80 along its longitudinal axis into orthogonal motion of tissue-penetrating member 40 and/or delivery member 50, but in other directions. Conversion of is also contemplated. The motion converter may have a wedge-shaped, trapezoidal or curved shape, although other shapes are also contemplated. In certain embodiments, the first motion converter 90 has a trapezoidal shape 90t and includes a slot 93, as shown in the embodiment of FIGS. It may engage a pin 41 on the tissue penetrating member that passes through the slot. The slot 93 may have a trapezoidal shape 93t that is identical to or otherwise corresponds to the overall shape of the transducer 90 . The slots 93 serve to push the tissue-penetrating member 40 during the uphill portion 91 of the trapezoid and then pull it back in during the downhill portion 92 . In one alternative embodiment, one or both of motion converters 90 and 94 may include cams or cam-like devices (not shown). The cams may be rotated by spring 80 into engagement with tissue penetrating members and/or delivery members 40 and 50 . Mechanism 60, including motion transducers 90 and 94, is constructed using various MEMS-based methods known in the art to allow a selected amount of miniaturization to fit within capsule 10. One or more components (as well as other components of device 10) can be manufactured. They can also be formed from various biodegradable materials known in the art, as described herein.

In other alternative embodiments, actuation mechanism 60 may also include an electromechanical device/mechanism, such as a solenoid or piezoelectric device. In one embodiment, the piezoelectric device used in mechanism 60 can include a shaped piezoelectric element having an undeployed state and a deployed state. The element can be configured such that application of a voltage causes it to deploy, and then removal of the voltage or other change in voltage returns it to its undeployed state. This and related embodiments allow for reciprocating motion of actuation mechanism 60 to both advance the tissue-penetrating member and then withdraw it. A voltage is generated using a piezoelectric-based energy converter or a battery that generates a voltage by mechanical deformation, such as deformation resulting from compression of the capsule 20 by peristaltic contraction of the small intestine around the capsule, to obtain the voltage for the piezoelectric element. be able to. Further description of piezoelectric-based energy converters can be found in US patent application Ser. No. 12/556,524, which is fully incorporated herein by reference for all purposes. In one embodiment, deployment of tissue-penetrating member 40 may actually be induced from peristaltic contractions of the small intestine that provide mechanical energy for generating the voltage for the piezoelectric element.

Release element 70 is typically coupled to actuation mechanism 60 and/or a spring coupled thereto; however, other configurations are contemplated. In a preferred embodiment, the release element 70 is connected to a spring 80, as shown in the embodiment of FIG. . Disassembly of the release element 70 releases the spring 80 and activates the activation mechanism 60 . Accordingly, release element 70 can thus function as actuator 70a (actuator 70 may also include spring 80 and other elements of mechanism 60). As described further below, the release element 70/actuator 70a is configured in a first configuration to contain the therapeutic agent formulation 100 in the capsule 20 and to advance the therapeutic agent formulation from the capsule into the small intestinal wall or intestinal tract. has a second configuration for entering the other lumen wall of the

In many embodiments, release element 70 comprises a material configured to degrade upon exposure to chemical conditions, such as pH, within the small or large intestine. Typically, the release element 70 is at a selected pH within the small intestine, e.g. or configured to degrade upon exposure to pH greater than. The release element can also be configured to degrade within a particular pH range, such as 7.0 to 7.5. In certain embodiments, the pH at which the release element 70 degrades (defined herein as the degradation pH) is selected for the particular drug to be delivered and is delivered at a location in the small intestine corresponding to the selected pH. Drug can be released. Further, for embodiments of device 10 having multiple pharmaceutical agents 100, the device includes a first release element 70 configured to decompose at a first pH (the triggering mechanism for delivering the first drug). and a second release element 70 configured to degrade at a second pH (coupled to the triggering mechanism for delivering the second drug) (various Additional numbers of release elements are contemplated for any number of drugs).

The release element 70 can also be configured to degrade in response to other conditions within the small intestine (or other GI location). In certain embodiments, release element 70 is designed to degrade in response to certain chemical conditions in the fluid in the small intestine, such as conditions occurring after ingestion of a meal (eg, a meal containing fat, starch or protein). Can be configured. Thus, release of pharmaceutical agent 100 can be substantially synchronized or otherwise timed with meal intake.

Various approaches are contemplated for biodegradation of release element 70 . In certain embodiments, biodegradation of release element 70 from one or more conditions within the small intestine (or other location within the GI tract) can be achieved by one or more of the following approaches: ii) the amount of crosslinking in those materials; and iii) the thickness and other dimensions of the release elements. Less cross-linking and/or thinner dimensions can increase the degradation rate and vice versa. Suitable materials for the release element can include biodegradable materials, such as various enteric materials that are configured to degrade upon exposure to 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. / methacrylic acid methyl ester as well as other enteric materials known in the art. Selected enteric materials can be copolymerized or otherwise combined with one or more other polymers to obtain a number of other specific material properties in addition to biodegradation. Such properties may include, but are not limited to, stiffness, strength, flexibility and hardness.

In an alternative embodiment, the release element 70 can include a film or plug 70p that fits over or otherwise blocks the guide tube 30 and prevents the guide tube from A tissue penetrating member 40 is retained therein. In these and related embodiments, the tissue-penetrating member 40 is configured such that upon sufficient disassembly of the release element, the tissue-penetrating member releases the tissue-penetrating member, after which the tissue-penetrating member emerges from the guide tube and penetrates the intestinal wall. and a spring-loaded starting mechanism. In still other embodiments, release element 70 can be shaped to act as a latch to hold tissue-penetrating member 40 in place. In these and related embodiments, the release element may be located outside or inside capsule 20 . In the latter case, capsule 20 and/or guide tube 30 allow intestinal fluids to enter the capsule to allow disassembly of the release element.

In some embodiments, the triggering mechanism 60 can be triggered by a sensor 67, such as a pH sensor 68 or other chemical sensor, that detects the presence of a capsule in the small intestine. Sensor 67 can then send a signal to triggering mechanism 60 or to electronic controller 29c coupled to triggering mechanism 60 to trigger the mechanism. Embodiments of pH sensor 68 may include an electrode-based sensor, or it may be a mechanical-based sensor, such as a polymer that shrinks or stretches upon exposure to selected pH or other chemical conditions in the small intestine. can be In related embodiments, the extendable sensor 67 may itself constitute the actuation mechanism 60 by using mechanical motion from extension or retraction of the sensor.

According to another embodiment for detecting devices within the small intestine (or other location within the GI tract), sensor 67 detects the number of peristaltic contractions undergone by the capsule within a particular location within the intestinal tract. (In such embodiments, the capsule 20 is desirably sized to be clamped by the small intestine during peristaltic contractions). Different locations within the GI tract have different numbers of peristaltic contractions. The small intestine has between 12 and 9 contractions per minute, decreasing in frequency down the length of the small intestine. Thus, according to one or more embodiments, detecting the number of peristaltic contractions can be used not only to determine whether capsule 20 is in the small intestine, but also to determine its relative position within the small intestine. can. In use, these and related embodiments enable release of pharmaceutical agent 100 at specific locations within the small intestine.

As an alternative or supplement to internally activated drug delivery (e.g., use of release elements and/or sensors), in some embodiments, the user can dispense the drug via RF, magnetic or other wireless signal transmission means known in the art. An activation mechanism 60 for delivering 100 can be activated externally. In these and related embodiments, a user uses a portable communication device 13 (eg, a portable RF device, such as a mobile phone) as shown in the embodiment of FIG. 1b to receive signals from device 10. 17 can be sent. In such embodiments, the swallowable device may include a transmitter 28, such as an RF transceiver chip or other similar communication device/circuitry. Portable device 13 not only includes signaling means, but may also include means for providing information to the user when device 10 is in the small intestine or other location within the GI tract. The latter embodiment is implemented by using a logic resource 29 (e.g., processor 29) coupled to transmitter 28 for signaling to detect when the device is in the small intestine or other location. The user can be signaled (eg, by signaling input from a sensor). Logic resource 29 may include a controller 29c (either in hardware or software) for controlling one or more aspects of its process. The same portable device can also be configured to alert the user (eg, using processor 29 and transmitter 28) when triggering mechanism 60 has been activated and medication of choice 100 has been delivered. Thus, the user is provided with confirmation that the medication 100 has been delivered. This allows the user to take other appropriate medications/therapeutic agents as well as make other related decisions (e.g. whether a diabetic eats or does not eat a meal and what food should be eaten). ) is also possible. The handheld device can also be configured to send a signal to the swallowable device 10 overriding the triggering mechanism 60 so as to prevent, delay or accelerate the delivery of the medication 100. It is also possible to configure the portable device to When used, such embodiments prevent, delay or delay the delivery of pharmaceutical agents based on other symptoms and/or patient behavior (e.g., eating meals, deciding to fall asleep, exercising, etc.). Allows user intervention to accelerate. The user may also externally activate the triggering mechanism 60 after a selected period of time after swallowing the capsule. The duration can be correlated to a typical transit time or range of transit times for food to travel through the user's GI tract to a particular location within the tract, such as the small intestine.

In certain embodiments, the capsule 20 is controllably disintegrated to produce capsule pieces 23 of selectable size and shape to facilitate passage through the GI tract, as shown in the embodiment of Figures 10a and 10b. A seam 22 of biodegradable material may be provided. Seam 22 may also include pores or other openings 22p for fluid to enter the seam to accelerate biodegradation, as shown in the embodiment of FIG. Other means for accelerating biodegradation of the seam 22 may include prestressing the seam and/or providing the seam with perforations 22f, also shown in the embodiment of FIG. . In still other embodiments, the seam 22 can be broken up into smaller pieces using ultrasound applied externally or by an endoscope (or other minimally invasive technique) ultrasonic energy; For example, it may be constructed of materials that are readily degraded by absorption of high frequency ultrasound (HIFU) and/or have structures that are readily degraded as previously described.

Suitable materials for seam 22 can include one or more of the biodegradable materials described herein, such as PGLA, glycolic acid, and the like. The seam 22 can be attached to the capsule body 20 using various bonding methods known in the polymer art, such as molding, hot melt bonding, and the like. Additionally, for embodiments of capsule 20 that are also manufactured from biodegradable materials, more rapid biodegradation of seam 22 can be achieved by one or more of: i) more rapid biodegradation; ii) prestressing the seam or iii) perforating the seam. Applying the concept of using a biodegradable seam 22 to cause controlled degradation of a swallowable device within the GI tract to other swallowable devices, such as swallowable cameras (or other swallowable imaging devices). to facilitate GI tract transit and reduce the likelihood of such devices becoming stuck in the GI tract. Embodiments of the biodegradable seam 22 can thus be adapted to swallowable imaging devices and other swallowable devices.

Another aspect of the present invention is a method of delivery of drugs and other therapeutic agents (in the form of pharmaceutical agents 100) to the GI tract wall using one or more embodiments of the swallowable drug delivery device 10. offer. An exemplary embodiment of such a method will now be described. The described drug delivery embodiment takes place within the small intestine SI. However, it should be understood that this is exemplary and that embodiments of the present invention can be used for drug delivery in numerous locations within the GI tract, including the stomach and large intestine. For ease of discussion, swallowable drug delivery device 10 is sometimes referred to herein as a capsule. As explained above, in various embodiments the device 10 can be packaged in a hermetic packaging 12 as a kit 11, which comprises the device 10 and a set of instructions 15. ing. If the patient is using a portable device 13, the patient enters data into the device 13 manually or by means of a bar code 18 (or other identifying indicia 18) on the instructions 15 or packaging 12. You can receive instructions to do so. If using barcodes, the patient would scan the barcode using the barcode reader 19 on the device 13 . After opening the packaging 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 can use the device 10 with meals (before, during or after meals) or in connection with physiological measurements. Capsule 20 is sized to pass through the GI tract by peristaltic action, passing through the patient's stomach S and into the small intestine SI, as shown in the embodiment of FIG. According to one or more embodiments of the present invention, upon entering the small intestine, release element 70 is broken down by the basic pH within the small intestine (or other chemical or physical conditions specific to the small intestine) to Mechanism 60 is activated to deliver drug 100 into the wall of small intestine SI. For embodiments that include a hollow needle or other hollow tissue-penetrating member 40, drug delivery is accomplished by advancing the needle 40 to a selected distance within the mucosa of the intestinal wall IW using a triggering mechanism 60, followed by delivery. Advancement of member 50 injects the medicament through needle lumen 40 . The delivery member 50 is retracted (eg, by spring recoil), after which the needle 40 is retracted back into the body of the capsule, thereby removing it from the intestinal wall. For embodiments of device 10 having multiple needles, a second or third needle 42, 43 may also be used to deliver additional doses of the same drug or separate drugs 101. FIG. Needle advancement can occur substantially simultaneously or can occur sequentially. In preferred embodiments using multiple needles, the needle advancements can occur substantially simultaneously to anchor the device 10 within the small intestine during drug delivery.

After drug delivery, the device 10 passes through the intestinal tract, including the large intestine LI, and is eventually excreted. For embodiments of capsule 20 having biodegradable seams 22 or other biodegradable portions, as shown in the embodiment of FIGS. Facilitates excretion from the intestinal tract. In certain embodiments having a biodegradable tissue-penetrating needle/member 40, when the needle is to be affixed to the intestinal wall, the needle biodegrades to release the capsule 20 from the wall.

For embodiments of device 10 that include sensor 67, activation of mechanism 60 may be accomplished by a sensor sending a signal to activation mechanism 60 and/or processor 29/controller 29c coupled to the activation mechanism. . For embodiments of device 10 with external activation capability, the user can externally activate activation mechanism 60 after a selected period of time after swallowing the capsule. The duration can be correlated to a typical transit time or range of transit times for food to travel through the user's GI tract to a particular location within the tract, such as the small intestine.

One or more embodiments of the above methods can be used to deliver formulations 100 containing therapeutically effective amounts of various drugs and other therapeutic agents 101 to treat various diseases and conditions. These include many large peptides and proteins that would otherwise require injection due to chemical degradation in the stomach. Individual drug dosages can be adjusted for patient weight, age or other parameters. Also, the dose of drug 101 (e.g., insulin for blood sugar regulation) to achieve a desired or therapeutic effect when delivered by one or more embodiments of the present invention may be less than the drug by conventional oral delivery. is delivered (eg, a swallowable pill that is digested in the stomach and absorbed through the wall of the small intestine). This is because the acid and other digestive fluids in the stomach do not degrade the drug, and the entire small intestine (or other lumen of the intestinal tract, such as the large intestine, stomach, etc.), as opposed to only a small portion of the drug. Due to being delivered intramurally. Depending on the drug 101, the dose 102 delivered in the formulation 100 is less than the dose delivered by conventional oral delivery (e.g., the pill) to achieve the desired therapeutic effect (e.g., glycemic control, seizure control, etc.). It may range from 100 to 5%, although even lower amounts are also contemplated. Specific dose reductions may vary depending on the specific drug, amount of degradation that occurs in the GI tract for conventional oral methods, frequency of dosing versus dosing using the swallowable capsule embodiments described herein, treatment It can be adjusted based on the condition being treated and the weight, age and condition of the patient. For some drugs (with known levels of degradation in the intestinal tract) standard dose reductions can be used (eg 10 to 20%). Larger dose reductions can be used for drugs that are more susceptible to degradation and malabsorption. Thus, reducing potential toxicity and other side effects (e.g., stomach cramps, diarrhea, irritable bowel effects, bleeding, etc.) of the particular drug(s) delivered by device 10, as the ingested dose is reduced. can be done. This also improves patient compliance as both patient severity and incidence of side effects are reduced. Additional benefits of embodiments that utilize dose reduction of the drug 101 include a reduced likelihood that a patient will develop resistance to the drug (requiring higher doses) and, in the case of antibiotics, a patient will develop resistant strains. can be reduced. Other dose reduction levels are also achieved for patients undergoing gastric bypass and other procedures in which a section(s) of the small intestine has been removed or its working (e.g., digestive) length has been effectively shortened. can do.

In addition to single drug delivery, embodiments of the swallowable drug delivery device 10 and their methods of use can be used to administer multiple drugs for the treatment of multiple conditions or the treatment of a specific condition (e.g., HIV AIDS). protease inhibitors for treatment) can be delivered. In use, such embodiments may spare a patient the need to take multiple medications for a particular condition or conditions. The above embodiments also provide a means for facilitating the delivery and absorption of two or more drug regimens into the small intestine and thus into the bloodstream at approximately the same time. Due to differences in chemical composition, molecular weight, etc., drugs may be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic distribution curves. Embodiments of the present invention address this issue by injecting the desired drug mixtures substantially simultaneously. This in turn improves the pharmacokinetics and thus the efficacy of the selected drug mixture. Additionally, eliminating the need to take multiple medications is particularly beneficial for patients with one or more long-term chronic conditions, including those with cognitive or physical disabilities.

In various applications, embodiments of the methods described above can be used to deliver formulations 100 containing drugs and therapeutic agents 101 to provide treatment for numerous medical conditions and diseases. Medical conditions and diseases that can be treated with embodiments of the present invention include, but are not limited to, cancer, hormonal conditions (e.g. hypo/hyperthyroid, growth hormone conditions), osteoporosis, hypertension, high cholesterol and triglycerides. , diabetes and other glucose dysregulation, infections (local or systemic, e.g. sepsis), epilepsy and other seizure disorders, osteoporosis, coronary arrhythmias (both arterial and venous), coronary ischemia, anemia or other similar state can be mentioned. Still other conditions and diseases are also contemplated.

In many embodiments, there is no need for injection (or other parenteral delivery forms such as suppositories) of antibodies or other therapeutic agents, but instead delivery within the wall of the small intestine or other portion of the GI tract. Treatment of a particular disease or condition can depend solely on the therapeutic agent administered. Similarly, patients need not take conventional oral forms of drugs or other therapeutic agents, but again rely only on delivery within the small intestinal wall using swallowable capsule embodiments. good too. In other embodiments, the therapeutic agent(s) to be delivered within the wall of the small intestine can be delivered with an injectable dose of the agent. For example, a patient can receive a daily dose of therapeutic using a swallowable capsule embodiment, but only injections every few days or when the patient's condition (e.g., hyperglycemia) dictates. It is only necessary to take a dose. The same is true for therapeutic agents traditionally delivered in oral form (e.g., the patient can ingest the swallowable capsule and, if desired, the conventional oral form of the agent). can). The dose delivered in such embodiments (e.g., swallowed and injected dose) can be adjusted as needed (e.g., standard dose-response curves and other pharmacokinetic methods can be used to determine appropriate dosages). can be determined). Also, for embodiments using therapeutic agents that can be delivered by conventional oral means, the dose delivered using swallowable capsule embodiments may be within the stomach or in other parts of the intestinal tract. Because there is little or no degradation of the agent at high temperature, it can be adjusted below the dosage normally given for oral delivery of the agent (again, standard dose-response curves and other pharmacokinetic methods). may apply).

Various embodiments of formulations 100 containing one or more drugs or other therapeutic agents 101 for treatment of various diseases and conditions will now be described in terms of dosage. These embodiments, including the specific therapeutic agents and respective dosages, are exemplary, and that formulation 100 may be applied to the luminal wall of the intestinal tract (e.g., the small intestinal wall) using various embodiments of device 10 . It should be understood that it can include numerous other therapeutic agents described herein (as well as those known in the art) configured for delivery into the . Further, said dosages may be higher or lower than those described herein, and said dosages may be reduced using one or more methods described herein or known in the art. Dosage can be adjusted.

In one group of embodiments, therapeutic agent formulation 100 can include a therapeutically effective dose of growth hormone for the treatment of one or more growth disorders as well as wound healing. In one embodiment, formulation 100 may contain a therapeutically effective amount of growth hormone in the range of about 0.1-4 mg, with specific ranges of 0.1-1, 1-4, 1-2 and 2-4 mg, with even greater ranges contemplated. A particular dose can be adjusted based on one or more of the following factors: i) the particular condition being treated and its severity (e.g., inhibited growth versus wound healing); iii) age of the patient; and iv) frequency of dosing (eg, once daily vs. twice daily).

Utilizing drug delivery compositions and components of known drug delivery systems in some embodiments of the invention described herein and/or in some embodiments of the invention described herein can be modified for use in For example, microneedles and other microstructures used to deliver drugs through the skin surface in drug patches can be modified and provided within capsules described herein and can alternatively be used in the gastrointestinal tract. can be used to deliver drug formulations to the luminal wall of the body, such as the wall of the small intestine. Suitable polymeric microneedle structures, such as MicroCor™ microdelivery system technology, are commercially available from Corium, California. Other components of the MicroCor™ patch delivery system, including formulations or ingredients, can also be incorporated into the capsules described herein. Alternatively, a polymer or other drug delivery matrix with a drug of choice and other drug formulation components to produce a desired shape with desirable drug release properties (e.g., releasable tissue-penetrating shapes described herein). Various providers are commercially available for prescribing combinations of Such providers may include, for example, Corium, SurModics of Minnesota, BioSensors International of Singapore, or the like.

One advantage and feature of various embodiments of the therapeutic compositions described herein is that the antibody is encapsulated or otherwise contained in a swallowable capsule or other swallowable device. Degradation of payloads of (e.g. AI antibodies such as secukinumab) or other biological (e.g. peptide or protein) drugs in the gastrointestinal (GI) tract by the action of peptidases and proteases before delivery into the intestinal wall and to be protected from hydrolysis. These enzymes are ubiquitous in biological systems. The GI tract is particularly rich in proteases, the function of which 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. be done. The devices and compositions described herein are designed to protect therapeutic peptides, antibodies or other proteins from the action of these GI proteases, and to deliver such peptide or protein loads directly into the intestinal wall. designed to There are two features of various embodiments of the compositions described herein that help protect a protein or peptide load from the action of GI proteases. First, in certain embodiments, the capsule shell housing the deployment engine and mechanical parts is highly sensitive to the duodenum, thanks to a pH-sensitive coating on the outer surface of the capsule that prevents dissolution of the capsule at the low pH of the stomach. It does not dissolve until it reaches the duodenal and lower bowel segments. Second, in certain embodiments, hollow polymeric microlancers (e.g., polyethylene oxide, maltose, silicone, etc.) house the actual therapeutic peptides or proteins; It is designed to penetrate the intestinal muscle as soon as possible; and the microspear itself slowly dissolves into the intestinal muscle wall to release the drug load. Therefore, the protein burden of the peptide or antibody is not exposed to the action of GI proteases and thus not proteolytically degraded in the GI tract. This in turn contributes to high bioavailability of therapeutic peptides or proteins, as would be expected if one or both of the above approaches were not used and the peptides or proteins were exposed to GI proteases. In particular, in the case of antibody-containing composition embodiments, such an approach may involve the binding of the antibody to allow it to bind to a target antigen (e.g., one or more members of the interleukin family of cytokines). Preserves affinity and specificity.

Anti-Interleukin Antibodies As discussed above, various embodiments of the present invention, in any case, use a specific interleukin or antibody thereof to prevent the interleukin from attaching to its receptors. Therapeutic compositions are provided that include antibodies or other binding proteins that attenuate the biological effects of one or more members of the interleukin family by binding to the interleukin's receptor. A brief discussion of interleukins is provided next. Interleukins are a group of cytokines that play important roles in the immune system, both as signaling molecules and secreted proteins involved in the humoral and cellular responses of the immune system (they are both secreted proteins and signaling molecules). form). Especially for the IL-17 family of cytokines, numerous immunomodulatory functions have been reported, presumably due to their induction of many immune signaling molecules. IL-17's most notable role is its involvement in the induction and mediation of proinflammatory responses. IL-17 is commonly associated with allergic responses. IL-17 also regulates many other cytokines (IL-6, G-CSF, GM-CSF, IL-1β, IL-1β, its involvement in inducing the production of TGF-β, TNF-α, etc.), chemokines (including IL-8, GRO-α and MCP-1) and prostaglandins (eg PGE2). Cytokine release triggers many functions, including airway remodeling, which is a hallmark of the IL-17 response. Increased chemokine expression attracts other cells, including neutrophils but not eosinophils. IL-17 function is also essential for a subset of CD4+ T cells called helper T17 (Th17) cells. As a result of these roles, the IL-17 family is involved in many immune systems, including rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, lupus, allograft rejection and anti-tumor immunity. / associated with autoimmune-related diseases.

As discussed above, various embodiments of the present invention attenuate the biological effects of one or more members of the interleukin family, which in turn are useful in various autoimmune and/or inflammatory diseases and Antibodies or other binding proteins are provided to treat one or more diseases or conditions associated with the release of such interleukins, such as conditions. According to various embodiments, such anti-interleukin antibodies, AI antibodies herein can correspond to full-length antibodies or antigen-binding portions thereof. They also generally, but not necessarily, include monoclonal antibodies that are human or humanized using methods known in the art. As used herein, the term "antibody" refers to four polypeptide chains, two heavy (H) chains and two light (L) chains, or any antibody thereof that retains the requisite epitope binding characteristics of an Ig molecule. It refers to any immunoglobulin (Ig) molecule that is composed of functional fragments, mutants, variants or derivatives. Also, as used herein, "epitope" means a segment or feature of a protein capable of specific binding to an antibody. Also, as used herein, "anti-interleukin antibody (AI antibody)", "AI antibody portion" or "AI antibody fragment" and/or "AI antibody variant" and the like refer to at least a portion of an immunoglobulin molecule at least one complementarity determining region (CDR) of a heavy or light chain or ligand binding portion thereof, a heavy or light chain variable region, a heavy or light chain constant region, a framework region or Any portion thereof, or any protein or peptide-containing molecule comprising at least one portion of an interleukin receptor (eg, IL-17 receptor) or binding protein that can be incorporated into an antibody of the invention. Such AI antibodies include, but are not limited to, at least one activity or binding of an interleukin of choice (eg, IL-17a, IL-17b, etc.), or IL-17 receptor. to specific ligands, such as when modulating, decreasing, increasing, antagonizing, agonizing, alleviating, alleviating, blocking, inhibiting, abrogating and/or interfering with an activity or binding of the body in vitro, in situ and/or in vivo. Optionally affect further.

In various embodiments, the AI antibodies described herein are any of the interleukin 1-36 family of interleukins (some of which are listed in Figures 21a and 21b), and analogs and derivatives thereof. or one that targets one. In many embodiments, the invention provides antibodies against any one of the interleukin 1-36 family of interleukins, including analogs and derivatives thereof, that can be delivered to the small intestinal wall or other target tissue sites. or other binding proteins are provided. In specific embodiments, the invention provides antibodies that bind to members of the interleukin-17 family of antibodies, preferred examples of which include secukinumab and ixekizumab; and activation of receptors to which specific interleukin-17 binds. Antibodies are provided that bind to the interleukin 17 family of receptors, preferred examples include brodalumab, to block .

AI antibodies or other binding proteins provided by embodiments of the present invention may be used for rheumatoid arthritis, psoriasis, plaque-type psoriasis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease and ulcerative arthritis. It is particularly useful for treating several autoimmune diseases and/or inflammatory conditions, including colitis (other diseases and conditions are listed in Figures 21a and 21b). Such compositions provide delivery of AI antibodies with desirable pharmacokinetic properties, particularly those that are advantageous for intravenous, subcutaneous or intramuscular injection. They provide one or more of the benefits including reduced incidence of allergic/anaphylactic reactions, including anaphylactic shock; and reduced immunogenicity (versus subcutaneous and/or intramuscular injection). It also allows usage.

Anti-Interleukin-17 Antibodies As discussed herein, some embodiments of the present invention provide AI antibodies (or antibodies to their selected receptors) that can be delivered to the small intestinal wall or other target tissue sites. Other IB-proteins) for neutralizing or otherwise inhibiting the biological actions of interleukins from the interleukin 17 family of cytokines by blocking or modulating the ability of antibodies to adhere. The targeting interleukin family of interleukin-17 antibodies includes IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25) and IL-17F. Although all members of the IL-17 family have similar protein structures, four highly conserved cysteine residues critical to their three-dimensional shape, they share sequence similarity to any other known cytokine. does not have A number of immunoregulatory functions have been reported for the IL-17 family of cytokines, probably due to their induction of many immune signaling molecules. The most notable role of the IL-17 family of cytokines (also called IL-17) is its involvement in inducing and mediating proinflammatory responses, including inflammatory signaling. IL-17 is commonly associated with allergic responses. IL-17 interleukin is expressed in many other cytokines (IL-6, G-CSF, GM-CSF, IL-1β, IL-1β, TGF-β, TNF-α, etc.), chemokines (including IL-8, GRO-α and MCP-1) and prostaglandins (eg PGE2) production. Cytokine release triggers many functions, including airway remodeling, which is a hallmark of the IL-17 response. Increased chemokine expression attracts other cells, including neutrophils but not eosinophils. IL-17 function is also essential for a subset of CD4+ T cells called helper T17 (Th17) cells.

Owing to the above roles, the IL-17 family of interleukins has been shown to play a role in, for example, rheumatoid arthritis, psoriatic arthritis, asthma, lupus, allograft rejection, anti-tumor immunity and most recently psoriasis and plaque-type psoriasis. linked or otherwise associated with many immune/autoimmune related diseases, including; In particular, increased expression of three IL-17 subtypes (A, C and F) has been implicated in the pathogenesis of inflammation in psoriasis. Accordingly, embodiments of the present invention that provide antibodies against one or more IL-17 interleukins or receptors of the interleukin-17 family of interleukins (herein anti-IL-17 antibodies or AI17 antibodies) include these and to treat one or more of other immune/autoimmune conditions. This is particularly the case for embodiments of the invention that deliver the AI17 antibody to the small intestinal wall (or other target site within the intestinal tract), because the antibody can be injected IV, intramuscularly, or parenterally. because it allows for improved pharmacokinetics and reduced allergic and other adverse reactions when delivered by other forms of Here again, the AI17 antibody attaches to the interleukin itself or to the interleukin's receptor, so that the receptor is activated by the interleukin and, in turn, the otherwise biological effects of such activation. can be configured to prevent impeding the weakening of the The biological effects that are inhibited or attenuated can include one or more of the following: Th1 modulation; Th2 modulation (Nakanishi K. et al., ( 2001) Cytokine and Growth Factor Rev. 12:53-72); and NK modulation. Various embodiments of specific AI17 antibodies are discussed in further detail below.

Secukinumab Secukinumab selectively binds to and inhibits and/or neutralizes the activity of interleukin-17A (IL-17A), which has been implicated in several immune/autoimmune-related conditions, including plaque-type psoriasis. , human monoclonal antibodies (mAbs). It is the first IL-17A inhibitor approved by the FDA for the treatment of moderate-to-severe plaque-type psoriasis in adult patients who is a candidate for systemic therapy. It has also shown positive clinical results for the treatment of ankylosing spondylitis, psoriatic arthritis and is being evaluated for the treatment of multiple sclerosis and rheumatoid arthritis. Accordingly, various embodiments contemplate delivery of therapeutically effective amounts of secukinumab into the wall of the small intestine (or other target tissue sites or other locations within the intestinal tract) for one or more of the following treatments: Do: Psoriasis, including plaque-type psoriasis, ankylosing spondylitis, psoriatic arthritis, multiple sclerosis, rheumatoid arthritis. The dose of secukinumab for such treatment can be delivered using the various embodiments of the swallowable capsules described herein and is in the range of about 1-40 mg per day. (which can be delivered by one or more swallowable capsules or multiple capsules given during the day), a specific dosage range for the treatment of plaque-type psoriasis is About 20-40 mg. For these and other dosing, daily doses can begin after a loading dose, which can be administered via injection (eg, IV, intramuscular or subcutaneous) or other delivery methods. Dosage is determined by patient weight, age, severity of condition, amount of loading dose and therapeutic efficacy index known in the art for a given condition, e.g., psoriasis area and severity index for treatment of plaque-type psoriasis. (PASI) as well as one or more of the Investigator's Global Assessment Revised 2011 (IGA), and can be adjusted for individual patients. Further description of secukinumab, including formulations, dosages and clinical uses, are hereby incorporated by reference in their entirety for all purposes, US patent application Ser. /358,504.

Brodalumab Brodalumab has a high affinity for the receptor for interleukin-17A (IL-17A), a molecule implicated in several immune/autoimmune-related conditions, including plaque-type psoriasis as shown above. A human monoclonal antibody (mAb) that binds and inhibits and/or neutralizes its activity. Brodalumab binds to the interleukin-17 (IL-17) receptor and blocks inflammatory signaling by blocking the binding of several IL-17 cytokines (eg, A, F and A/F) to the receptor. It is the only investigational therapeutic in development that inhibits transmission. Accordingly, it is one of these receptors, including without limitation one or more of plaque-type psoriasis, ankylosing spondylitis, psoriatic arthritis, multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease. It will have efficacy for treatment of any condition involving single or multiple activations. It has also shown positive clinical results in a Phase 3 study for the treatment of plaque-type psoriasis. Accordingly, various embodiments provide delivery of a therapeutically effective amount of brodalumab to the small intestinal wall (or other target tissue sites or other locations within the intestinal tract) for the treatment of one or more of the following conditions: Contemplated: psoriasis, including plaque-type psoriasis, ankylosing spondylitis, psoriatic arthritis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and other similar conditions. Brodalumab doses for such treatments can be delivered using the various embodiments of swallowable capsules described herein and range from about 1-20 mg per day. (which can be delivered by one or more swallowable capsules or multiple capsules given during the day), a specific dosage range for the treatment of plaque-type psoriasis is About 9-14 mg. For these and other medications, daily doses can begin after a loading dose, which can be administered via injection or other means of delivery. Dosage is determined by patient weight, age, severity of condition, amount of loading dose and therapeutic efficacy index known in the art for a given condition, e.g., psoriasis area and severity index for treatment of plaque-type psoriasis. (PASI) as well as one or more of the Investigator's Global Assessment Revised 2011 (IGA), and can be adjusted for individual patients. Further description of brodalumab, including dosages and clinical uses, can be found in Coimbra et al., entitled "Brodalumab: an evidence-based review of its potential in the treatment of moderate-to-severe psoriasis. Core Evid. July 21, 2014; Vol. 9; pp. 89-97.

Ixekizumab Ixekizumab is a human monoclonal antibody (mAb) that selectively binds to interleukin-17A (IL-17A) and inhibits and/or neutralizes its activity, such activity being associated with several immune/self Implicated in immune-related conditions. Ixekizumab has also shown positive clinical results for the treatment of psoriatic arthritis and plaque-type psoriasis. Accordingly, various embodiments provide delivery of therapeutically effective amounts of ixekizumab into the small intestinal wall (or other target tissue sites or other locations within the intestinal tract) for the treatment of one or more of the following conditions: Contemplated: psoriasis, including plaque-type psoriasis, ankylosing spondylitis, psoriatic arthritis, multiple sclerosis, rheumatoid arthritis. Doses of ixekizumab for such treatments can be delivered using the various embodiments of swallowable capsules described herein and range from about 1-40 mg per day. specific dose ranges for the treatment of psoriatic arthritis or plaque-type psoriasis, which can be delivered by one or more swallowable capsules or multiple capsules given during the day is about 2.5-5.5 mg per day. For these and other medications, daily doses can begin after a loading dose, which can be administered via injection or other means of delivery. Dosage is determined by patient weight, age, severity of condition, amount of loading dose and therapeutic efficacy index known in the art for a given condition, e.g., psoriasis area and severity index for treatment of plaque-type psoriasis. (PASI) as well as one or more of the Investigator's Global Assessment Revised 2011 (IGA), and can be adjusted for individual patients. Further description of ixekizumab, including formulations, dosages and clinical uses, can be found in US patent application Ser. No. 14/195,885, which is hereby incorporated by reference in its entirety for all purposes.

Benefits of Delivery of AI-17 Antibodies to the Intestinal Wall or Other Locations in the Intestinal Tract In use, into the small intestinal wall (or other target sites in the intestinal tract) for the treatment of one or more of the above conditions. Embodiments of the invention that provide delivery of secukinumab, brodalumab, ixekizumab, or other AI antibodies or IN-proteins of , offer several advantages over injectable forms of these compounds. Such benefits can include a higher therapeutic index, reduced incidence and severity of adverse reactions, including one or more of the following: anaphylactic shock or other allergic reactions (including injection site ); and nasopharyngitis, upper respiratory tract infections and headaches (the latter three mentioned in clinical trials of one or more of secukinumab, brodalumab or ixekizumab), and decreased immunogenicity and/or or an immunogenetic reaction. In the latter case, such an immunogenic reaction may result in the development of antibodies in the patient against the AI17 antibody itself, resulting in one or more of the adverse reactions described above, as well as reduced efficacy as well as reduced efficacy of the drug. It also results in the need for higher doses and/or a vicious cycle of undesirable immune responses that can render the compound of little benefit to the patient. These benefits are: i) much smaller doses of AI17 antibody (or other AI antibodies or IN-proteins) delivered by embodiments of the present invention; ii) doses delivered daily versus weekly or monthly. and iii) by one or more of the fact that the dose is delivered intravascularly orally.

In many embodiments, the therapeutic index of the dosage of AI17 antibody orally delivered according to embodiments of the present invention is the AI17 delivered by injection (e.g., intravenously, intramuscularly or subcutaneously, weekly, biweekly or monthly). It can be significantly increased over that of the antibody(ies). In various embodiments, the term "significantly" corresponds to an increase in the therapeutic index of 2-fold or more, such as 7- to 30-fold greater, or more. For AI17 antibodies (or other AI antibodies or IN-proteins) that are typically delivered in weekly doses when injected (e.g., intravenously, intramuscularly or subcutaneously), the present invention provides The therapeutic index (e.g., toxic dose/effective dose) can be increased approximately 7-fold when delivered in daily oral doses using a swallowable device, whereas the monthly injected dose of AI17 antibody In some cases, the therapeutic index can be increased by about 30-fold when delivered in daily oral doses according to embodiments of the present invention. Both of these values are believed to be substantially higher than those corresponding to parenteral injection delivery (eg, intramuscular, subcutaneous, etc.) of AI17 antibody or similar molecules in such embodiments. A further increase in therapeutic index can be obtained when oral doses of AI17 antibody are given multiple times a day. Also, similar improvements (e.g., 7-fold, 30-fold or even more fold) relative to intramuscular, subcutaneous or other parenteral injections may be observed in immunogenicity/immune responses, allergic reactions and other adverse reactions. are seen in the incidence of one or more of Immunogenicity/immune response is the production of antibodies by the body to the administered AI17 antibody that neutralize or otherwise reduce the clinical efficacy of the AI17 antibody. Due to the fact that antibodies are given in daily versus monthly doses, which tend to reduce the sensitivity of the immune system, reductions in the incidence of allergic reactions can be from 2-fold to up to 30-fold ( The extent of an 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 immunogenicity and/or immune response that is reduced can be from 2-fold to as much as 30-fold or more due to three possible factors: 1) the dose is subcutaneous; and/or not delivered intramuscularly (which tend to exacerbate such responses); 2) the dose is much smaller, e.g. whether the injected dose is delivered weekly, biweekly, monthly, etc. and 3) as discussed above, Dose AI-17 antibody is delivered to the upper small intestine, where Peyer's patch and subsequent immunization Avoid generating cellular and other immune responses. The amount of immune response to a given AI17 antibody (e.g., secukinumab) is known in the art, e.g., to measure the generation of antibodies generated against the delivered AI17 antibody or other AI antibodies. It can be quantified using one or more immunological assays. In certain embodiments, the dosage of the AI17 antibody can be configured to produce a minimum in the patient, wherein a minimum of less than 10%, more preferably less than 5% of the AI17 antibody delivered It means that it is neutralized by the patient's own antibodies.

Referring now to Figures 22-24, doses of various AI17 antibodies (or other AI antibodies or IN-proteins) can be administered to these antibodies by conventional means (eg, by intravenous, intramuscular or subcutaneous injection). Another benefit achieved by delivering daily doses versus the bi-weekly or monthly doses used for injection of is the reduction of diurnal variation in patient plasma concentration profiles for specific antibodies, which , which in turn leads to a much smoother plasma concentration profile. Using the pharmacokinetic model described in more detail in Appendix 1, secukinumab at monthly or biweekly delivery periods versus daily doses (adjusted downward from monthly or biweekly doses) (Figures 22a and 22b) and Plasma concentration curves were generated for the delivery of brodalumab (Figures 23a and 23b). As seen in Figures 22a, 22b, 23a and 23b, the amount of diurnal variation in the curves is much smaller for both secukinumab and brodalumab when their antibodies are delivered monthly or biweekly. A value known as the "% Steady State Variation" was also calculated for each of these antibodies using the formula shown and detailed in Appendix 2. This value reflects the amount of diurnal variation in the plasma concentration of a given drug. As shown in Table 1 below, the amount of steady-state variation in plasma concentration of a particular antibody when delivered in daily doses versus monthly or biweekly subcutaneous injections according to embodiments of the present invention is significantly reduced. Specifically, there was an approximately 216-fold reduction in steady-state diurnal variability for secukinumab and an approximately 171-fold reduction for brodalumab, both of which are considered significant reductions in these embodiments. It is The patient benefits of such a reduction include one or more of the following: reduced risk of adverse events or allergic reactions, reduced immunogenicity; Rheumatoid arthritis) for a longer period of time (e.g., 4 to 24 hours) during which a patient is kept within the therapeutic index (range) of a given antibody, which allows the antibody to treat rheumatoid arthritis better and more consistently

Embodiments of Delivery of AI17 Antibodies into the Portal Vein and Liver Also, in certain embodiments, tissue-penetrating members 40/140 containing solid AI17 antibodies or other AI antibodies, when placed within the wall of the small intestine, are able to penetrate the intestine. It can be configured to discharge into the walled mesenteric vasculature, then into the portal vein and then into the liver. At this point, the released AI17 antibody then binds to interleukin or interleukin receptors in the liver and then to other cells in the body, including one or more of the lungs, heart, bone, cartilage, lymph nodes, etc. substantially (eg, greater than 10% of the AI17 antibody delivered that binds to interleukins present at non-hepatic sites) to interleukins present at tissue sites in the liver. The benefit of this approach in these and related embodiments is that the liver contains high concentrations of interleukin-producing tissue and therefore interleukins such as interleukin-17A, which bind interleukins released from liver tissue at the site of their release. By doing so, they are able to neutralize or otherwise inhibit significant amounts of these interleukins (such as interleukin 17a) before they diffuse throughout the body. This allows antibodies to be taken up in significant amounts by other tissue sites in the body (e.g. heart, lungs, etc.) before reaching the liver and thus binding to interleukins released by the liver. In contrast to conventional approaches using parenteral injection delivery of AI17 antibody (or similar antibodies), the amount of AI17 antibody is significantly reduced.

Pharmacokinetic Metrics Embodiments of the invention that deliver AI antibodies or other IN proteins within the intestinal wall (eg, small intestine) also provide benefits with respect to one or more pharmacokinetic metrics. In this context, noteworthy pharmacokinetic metrics include _Cmax , the peak plasma concentration of the drug after dosing; _tmax , the time to reach _Cmax ; and t1 _/2 , the plasma concentration of the drug at Examples include, but are not limited to, the time required to reach half the _Cmax value after reaching _Cmax . These metrics can be measured using standard pharmacokinetic measurement techniques known in the art. In one approach, administration of an AI antibody or other therapeutic agent, either through the use of a swallowable device or by non-vascular injection, begins and follows a set time interval (e.g., 1 minute, 5 minutes, ½ hours, 1 hour, etc.). Then, using one or more suitable analytical methods, such as GC-mass spectroscopy, LC-mass spectroscopy, HPLC or various ELISAs (enzyme-linked immunosorbent assays), which can be adapted to that particular drug, Concentrations of drugs in plasma can be measured. Measurements from plasma samples can then be used to generate concentration versus time curves (also referred to herein as concentration profiles). The peak of this concentration curve corresponds to _Cmax and the time at which this occurs corresponds to _tmax . The time in the curve at which the concentration reaches half its maximum value (ie, C _max ) after reaching C _max corresponds to t _1/2 , also known as the elimination half-life of the drug. The initiation time for the determination of _Cmax is the time at which the injection was given for nonvascular injections, and the time at which the swallowable device embodiment is injecting one or more tissue-penetrating members (containing the drug) into the small intestine. or based on the time of entry into other locations in the GI tract, such as the large intestine. In the latter case, this time is determined by one or more means, including a remote control embodiment of a swallowable device that deploys a tissue-penetrating member within the intestinal wall in response to an external control signal (e.g., RF signal). , or by one or more means for swallowable device embodiments that transmit an extracorporeal detectable RF or other signal when the tissue-penetrating member is deployed. Other means for detecting tissue-penetrating member deployment into the small intestine are contemplated, such as one or more medical imaging modalities including, for example, ultrasound or fluoroscopy. Suitable animal models, such as dogs, pigs, rats, etc., can be used to model human pharmacokinetic responses in any one of these studies.

Accordingly, various embodiments of the present invention provide therapeutic compositions 100 (also referred to herein as formulations) comprising AI antibodies or other IN proteins. The composition is adapted for insertion into the intestinal wall after oral ingestion, and upon insertion, the composition releases the AI antibody from the intestinal wall into the blood stream to provide a faster rate than an extravascular dose of AI antibody. reach _max . In other words, an inserted form of AI antibody reaches C _max in a shorter time (eg, a smaller t _max ) than a dose of AI antibody injected extravascularly. Extravascular injected administration can include one or more of subcutaneous, intramuscular or other extravascular injection sites used in the art. To achieve these results, the dose of AI antibody in the composition delivered within the intestinal wall and the dose delivered by extravascular injection can be, but need not be, equivalent. Please note. In various embodiments, the composition is about 80%, or 50%, or 30%, or 20%, or 10% of the t _max of an extravascular dose of an AI antibody (e.g., intestinal wall, e.g., small intestine to achieve the t _max of AI antibodies (by release of AI antibodies from the intestinal wall into the bloodstream). Such extravascular doses of AI antibodies can be, for example, subcutaneous or intramuscular. In certain embodiments, the C _max achieved by delivery of the AI antibody by insertion into the intestinal wall is the C _max achieved when the AI antibody is orally delivered without being inserted into the intestinal wall, e.g., a pill , for example 5, 10, 20, 30, 40, 50, 60, 70, 80, or even 100 times greater than the C _max achieved by other conventional oral forms of AI antibodies or related compounds . In some embodiments, the AI antibody (or other IN protein) composition is configured to provide long-term release of the AI antibody, which can include a period within the range of about 1 to 60 days; In certain embodiments, 6-24 hours, 12-24 hours, 12-36 hours, 1-2 days, 1-5 days, 1-10 days, 1-20 days, 2 days, 3 days, 5 days, Periods of 7, 10, 15, 20, 30, 40, 45, 50 and 60 days. Compositions can also be configured to provide extended release of AI antibodies with a selectable t _1/2 . For example, selectable t _1/2 can be 6, or 9, or 12, or 15 or 18, 24, 36, 48 and 60 hours.

Any suitable dose of AI antibody (or other IN protein) for a particular patient may be used in various embodiments of the invention, depending on factors such as weight, age, and the like. For example, the dose of AI antibody or other IN protein administered ranges from about 1 to 10 mg, with specific ranges of 1-5, 1-4, 2-4, 2-5 and 2-3 mg, individual doses may be 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 mg. When administered subcutaneously, AI antibodies generally have a t _max in the bloodstream of about 130 hours. Thus, the t _max of the AI antibody when administered with a therapeutic AI antibody composition described herein is, for example, about 80% of the t _max of the AI antibody when it is injected subcutaneously, or 50% %, or 30%, or 20%, or 10%. moreover

Various embodiments are AI antibody (or other IN-protein) compositions adapted for insertion into the intestinal wall after oral ingestion, wherein, upon insertion, the AI antibody (or other IN-protein) to achieve a t _1/2 greater than the t _1/2 of an orally ingested dose of said AI antibody (or other IN-protein) that does not penetrate the intestinal wall. offer. For example, the t _1/2 of the intestinal wall-inserted dose may be 100 or 50 or 10 or 5 times greater than the non-intestinal wall-inserted dose.

The AI antibody (or other IN-protein) may be in solid form, eg, a solid form composition configured to degrade within the intestinal wall, the solid form composition comprising, eg, pointed It may have tissue penetrating features such as tips. Said AI antibody (or other IN-protein) composition may comprise at least one biodegradable material and/or at least It may contain one pharmaceutical excipient.

Various embodiments of the AI antibody (or other IN-protein) compositions described herein can be adapted for oral delivery in swallowable capsules. In certain embodiments, a mechanism having a first configuration and a second configuration, wherein the therapeutic insulin composition is contained within a capsule in the first configuration and the AI antibody in the second configuration. Such swallowable capsules can be adapted to be operably linked to a mechanism that causes the (or other IN-protein) composition to exit the capsule and enter the intestinal wall. Such operably linked mechanisms may be expandable members, expandable balloons, valves, tissue penetrating members, valves coupled to expandable balloons, or tissue penetrating members coupled to expandable balloons. at least one of

In some embodiments, the AI antibody (or other IN-protein) can be configured to be delivered intraluminally of a tissue-penetrating member, and/or the AI antibody (or other IN-protein) can be The protein) composition can be shaped as a tissue-penetrating member capable of penetrating the intestinal wall. The tissue-penetrating member may be sized to be completely received within the intestinal wall and/or may include tissue-penetrating features for penetrating the intestinal wall and/or A deployment feature may be included for deployment of the tissue-penetrating member within a wall. Detention features may include, for example, barbs. In some embodiments, the tissue-penetrating member is configured to penetrate the intestinal wall upon application of a force (e.g., mechanical force) to a surface of the tissue-penetrating member, and optionally the tissue-penetrating member having sufficient stiffness and/or column strength to fully penetrate the wall and/or the surface of the penetrating member is configured to be operatively coupled to an expandable balloon that exerts force upon expansion; and/or the tissue-penetrating member is configured to disengage from the force-applying structure when the direction of the force changes. In various embodiments, the column strength of the tissue penetrating member can range from about 1 to 20 lb, 7 to 20 lb, 8 to 12 lb, and 7, 8, 9, 10 and 11 lb.

Various aspects of the present invention also provide other embodiments of swallowable delivery devices for delivery of medicament 100, in addition to those described above. According to one or more such embodiments, the swallow delivery device is one for use in delivering one or more tissue-penetrating members comprising pharmaceutical agent 100 into the wall of an intestine, such as the small intestine. Or it can include multiple expandable balloons or other expandable devices. 12-20, another embodiment of a device 110 for delivery of a pharmaceutical agent 100 to a delivery site DS in the gastrointestinal (GI) tract is sized to be swallowed and pass through the intestinal tract. It can include a capsule 120, a deployment member 130, one or more tissue penetrating members 140 containing pharmaceutical agents 100, a deployable aligner 160, and a delivery mechanism 170. In some embodiments, pharmaceutical agent 100 (also referred to herein as formulation 100 ) may itself constitute tissue-penetrating member 140 . A deployable aligner 160 is positioned within the capsule and configured to align the capsule with an intestine, such as the small intestine. Typically, this entails aligning the long axis of the capsule with the long axis of the intestine; however, other alignments are also contemplated. Delivery mechanism 170 is configured to deliver medicament 100 within the intestinal wall and typically includes a delivery member 172, such as an expandable member. Deployment member 130 is configured for deployment of at least one of aligner 160 or delivery mechanism 170 . Further, as described herein, all or a portion of the capsule wall is degradable upon contact with liquid in the GI tract to allow the liquid in the GI tract to trigger delivery of pharmaceutical agent 100 by device 110. is. As used herein, "GI tract" refers to the esophagus, stomach, small intestine, large intestine and anus, while "intestinal tract" refers to the small and large intestine. Various embodiments of the present invention can be configured and arranged for delivery of pharmaceutical agent 100 into both the intestinal tract and the entire GI tract.

Device 110 with tissue-penetrating member 140 can be configured for delivery of liquid, semi-liquid or solid form of pharmaceutical agent 100 or a combination of all three forms. In any form, the pharmaceutical agent 100 will degrade within the intestinal wall (small or large intestine) or other lumen wall within the GI tract as the pharmaceutical agent is forced out of the device 110 and into the wall. It desirably has a material consistency that allows it to release the drug or other therapeutic agent 101 over time. Material consistency of pharmaceutical product 100 may include one or more of hardness (in bodily fluids), porosity and solubility of the formulation. Said material consistency can be achieved by selection and use of one or more of: i) compression force used to make the formulation; iii) use of other pharmaceutical excipients; iv) particle size and distribution of formulations (e.g., micronized particles); and v) micronized and other particles known in the art. Use of forming methods.

Capsule 120 is sized to be swallowed and passed through the intestinal tract. This size can be adjusted according to patient weight and adult versus pediatric use as well as the amount of drug to be delivered. Typically, the capsule has a tubular shape with curved ends similar to vitamins. In these and related embodiments, capsule length 120L may range from 0.5 to 2 inches and diameter 120D may range from 0.1 to 0.5 inches, although other dimensions are contemplated. Capsule 120 comprises a capsule wall 121w having an outer surface 125 and an inner surface 124 defining an interior space or volume 124v. In some embodiments, the capsule wall 121w can comprise one or more apertures 126 sized for outward advancement of the tissue-penetrating member 140. As shown in FIG. In addition to other components of device 110 (eg, expandable members, etc.), the interior volume can comprise one or more compartments or reservoirs 127 .

Although the capsule can be manufactured from a variety of biodegradable gelatin materials known in the pharmaceutical arts, the capsule protects the cap from degradation in the stomach (due to acid, etc.) and is subsequently removed from the small intestine. Various enteric coatings 120c can also be provided that are configured to degrade at higher pH's found in or in other regions of the intestinal tract. In various embodiments, capsule 120 may be formed from multiple parts, one or more of which may be biodegradable. In many embodiments, the capsule 120 may be formed from two portions 120p, for example, a body portion 120P'' (herein body 120p'') and a cap portion 120p' (herein cap 120p), wherein the cap fits over the body, for example by sliding it over or under the body (although other mechanisms are also contemplated). One part, e.g. cap 120p', can comprise a first coating 120c' configured to decompose above a first pH (e.g., pH 5.5) and the other part, e.g. 120p" can include a second coating 120c" configured to decompose above a second higher pH (eg, 6.5). Since both inner surface 124 and outer surface 125 of capsule 120 are coated with coatings 120c' and 120c'', both portions of the capsule are substantially preserved until contacted with a fluid having a selected pH. In the case of the body 120p'', this allows maintaining the structural integrity of the body 120p'' to retain the balloon 172 within the body portion and not deploy until the balloon 130 is expanded. Coatings 120c′ and 120c″ can include various methacrylate and ethyl acrylate based coatings, such as those manufactured by Evonik Industries under the tradename EUDRAGIT. These and other dual coating configurations of capsule 120 allow mechanisms in one portion of capsule 120 to fire before those in other portions of the capsule. This is because the intestinal fluid first enters where the lower pH coating has degraded, thus activating triggers (eg, degradable valves) that are responsive to such fluids. In use, such dual-coated embodiments of capsule 120 provide targeted drug delivery to specific locations within the small intestine (or other locations within the GI tract) as well as increased reliability of the delivery process. This is because the deployment of certain components, such as the aligner 160, begins in the upper region of the small intestine (e.g., duodenum) to align the capsule within the intestine for optimal drug delivery (e.g., to the small intestinal wall). and provide sufficient time for 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. due to the fact that we get

As discussed above, one or more portions of capsule 120 can be manufactured from various biocompatible polymers known in the art, including various biodegradable polymers. Included are, in preferred embodiments, cellulose, gelatin materials and PGLA (polylactic-co-glycolic acid). Other suitable biodegradable materials include lactide, glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone, trimethylene carbonate, caprolactone, blends thereof, as well as various enteric materials described herein. copolymers.

In various embodiments, the capsule wall 120w can degrade upon contact with fluids in the GI tract, such as fluids in the small intestine. In a preferred embodiment, the capsule wall is configured to remain intact during passage through the stomach, but then degrade in the small intestine. In one or more embodiments, this can be achieved through the use of an outer coating or outer layer 120c on the capsule wall 120w, which degrades only at pHs higher than those found in the small intestine, allowing the capsule to It helps protect the underlying capsule wall from degradation in the stomach before it reaches the small intestine (at which point the drug delivery process is initiated by degradation of the coating, as described herein). In use, such coatings allow targeted delivery of therapeutic agents in selected portions of the intestinal tract, such as the small intestine.

Similar to capsule 20, in various embodiments, capsule 120 includes various radiopaque materials for localization of the device using one or more medical imaging modalities such as fluoroscopy, ultrasound, MRI, and the like. may contain sexual, echogenic or other material.

As further discussed herein, in many embodiments one or more of deployment member 130 , delivery member 172 or deployable aligner 160 are shaped and sized to fit within capsule 120 . It can correspond to an expandable balloon. Accordingly, for ease of discussion, deployment member 130, delivery member 172 and deployable aligner 160 will be referred to herein as balloons 130, 160 and 172; Devices are also contemplated in these elements, as well as various shape memory devices (e.g., expansions made from shape memory biodegradable polymer spires) having expansion shapes and sizes corresponding to the internal volume 124v of capsule 120, for example. expandable baskets), expandable piezoelectric devices and/or chemically expandable devices.

One or more of balloons 130, 160 and 172 may comprise various polymers known in the medical device arts. In preferred embodiments, such polymers include low density PE (LDPE), linear low density PE (LLDPE), medium density PE (MDPE) and high density PE (HDPE) and other forms of polyethylene known in the art. can include one or more types of polyethylene (PE), which can correspond to In more than one embodiment using polyethylene, the material can be crosslinked using polymer irradiation methods known to do so in the art. In certain embodiments, radiation-based cross-linking can be used to control balloon inflation diameter and shape by reducing the compliance of the balloon material. Radiation doses can be selected to achieve a particular amount of cross-linking, resulting in a particular amount of compliance for a given balloon, e.g. A compliant balloon material can be produced. Other suitable polymers include PET (polyethylene terephthalate), silicones and polyurethanes. In various embodiments, the balloons 130, 160 and 172 are known in the art to allow the physician to locate the position and physical state (e.g., uninflated, inflated or punctured) of the balloons. Various radiopaque materials such as barium sulfate may also be included. Balloons 130, 160 are shaped and sized to approximately correspond to the internal volume 124v of capsule 120 using various balloon blowing methods known in the balloon catheter art (e.g., mold blowing, free blowing, etc.). and 172 can be produced. In various embodiments, one or more of balloons 130, 160 and 172 and various corresponding features (eg, connecting tubes) can have a unitary structure formed from a single mold. Embodiments utilizing such a unitary structure provide the benefits of improved manufacturability and reliability because fewer joints must be made between one or more components of device 110 .

Suitable shapes for balloons 130, 160 and 172 include various cylindrical shapes with tapered or curved end portions (examples of such shapes include hot dogs). In some embodiments, the inflated size (e.g., diameter) of one or more of balloons 130, 160 and 172 is such that expansion forces (e.g., due to circumferential stress) cause capsule 120 to break apart. In other words, it may be larger than capsule 120 . In other related embodiments, the inflated size of one or more of balloons 130, 160 and 172 is such that when inflated i) capsule 120 induces peristaltic contractions that cause contraction of the small intestine surrounding the capsule. and/or ii) may be sized such that small bowel folds are tolerably obliterated. Both of these results allow for improved contact between the capsule/balloon surface and the intestinal wall to deliver tissue-penetrating member 40 over selected areas of capsule and/or delivery balloon 172 . Desirably, the walls of balloon 130, 160 or 172 are thin, in the range of 0.005 to 0.0001", more preferably 0.004, 0.003, 0.002, 0.001 and 0.0005". In addition, in various embodiments, one or more of balloons 130, 160 and 172 may have a wall thickness in the range of 0.005 to 0.0001, with specific embodiments It is possible to have a nested balloon configuration with inflation chambers 160IC and extension fingers 160EF as shown in embodiment 13c.Connecting tubing 163 connecting inflation chambers 160IC is narrow to allow gas 168 only to pass through. Sometimes, the connecting tubing 36 connecting the two halves of the balloon 130 can be larger to allow the passage of water.

As noted above, aligner 160 typically includes an expandable balloon, which will be referred to herein as aligner balloon 160 or balloon 160 for ease of discussion. Balloon 160 can be manufactured using the materials and methods described above. It has an unexpanded state and an expanded state (also called expanded state). In its expanded or deployed state, balloon 160 is positioned such that forces exerted on capsule 120 by peristaltic contractions of small intestine SI help align long axis 120LA of capsule 120 parallel to long axis LAI of small intestine SI. The length of capsule 120 is lengthened. This also helps to vertically align the shaft of tissue-penetrating member 140 with the surface of intestinal wall IW to enhance and optimize penetration of tissue-penetrating member 140 into intestinal wall IW. In addition to helping to align capsule 120 within the small intestine, aligner 160 is also configured to push delivery mechanism 170 out of capsule 120 prior to inflation of delivery balloon 172, thus causing the delivery balloon and/or The mechanism is not blocked by the capsule. In use, this push function of the aligner 160 is useful for therapeutic agent delivery because it is not necessary to wait for certain portions of the capsule (e.g., those on the delivery mechanism) to degrade before drug delivery can occur. Improve certainty.

Balloon 160 can be fluidly connected to one or more components of device 110, including balloons 130 and 172, by polymer tubing or other fluid connections 162, which connect balloons 160 and 130 to each other. and tube 164 for connecting balloons 160 and 172 . Tube 163 is adapted to expand/inflate balloon 160 by pressure from balloon 130 (e.g., pressure created by mixing of chemical reactants within balloon 130) and/or one or both of balloons 130 and 160. are configured to otherwise allow the passage of liquid between balloons 130 and 160 to initiate a gas generating chemical reaction for inflation of the balloon. A tube 164 connects balloon 160 to 172 to allow inflation of balloon 172 by balloon 160 . In many embodiments, tube 164 includes or is connected to a control valve 155 that is 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 connected to the valve and a distal portion 164d leading from the valve. Typically, proximal portion 164p and distal portion 164d are connected to valve housing 158 as described below.

Valve 155 may include a triangular or other shaped section 156 of material 157 that is positioned within chamber 158c of valve housing 158 (or may be positioned directly within tubing 164). Section 157 may mechanically disintegrate (e.g., tear, shear, delaminate, etc.) at a selected pressure to allow passage of gas through tube 164 and/or valve chamber 158c. Configured. Suitable materials 157 for valve 155 may include beeswax or other forms of wax, and various adhesives known in the medical arts with selectable sealing/bursting pressures. Valve fitting 158 is arranged such that section 156 of material 157 seals the walls of chamber 158c together (as shown in the embodiment of FIG. 13b) or otherwise blocks passage of fluid through the chamber. It typically comprises a thin cylindrical compartment (made from a biodegradable material) that is Selection of one or more of the size and shape of section 156 and selection of material 157 (eg, for properties such as adhesive strength, shear strength, etc.) can control the opening pressure of valve 155 . In use, control valve 155 allows for ordered inflation of balloons 160 and 172 such that balloon 160 is fully or otherwise substantially inflated before balloon 172 is inflated. This also causes balloon 160 to push balloon 172 along with the remainder of delivery mechanism 170 out of capsule 120 (typically out of body portion 120p′) before balloon 172 is inflated, thus tissue-penetrating member 140 being pushed out of capsule 120 (typically out of body portion 120p′). deployment is not impeded by capsule 120 . In use, such an approach is both in terms of achieving a desired depth of penetration of tissue-penetrating members 140 contained in capsule 120 and delivering a greater number of tissue-penetrating members 140 contained in capsule 120. Penetration of the tissue-penetrating member 140 into the intestinal wall IW is more reliable because its entry into the intestinal wall IW is not impeded by the capsule wall 120w.

As explained above, the expanded length 160l of the aligner balloon 160 is sufficient to align the capsule 120 with the transverse axis of the small intestine from the peristaltic contractions of the intestine. Suitable expanded lengths 1601 for the aligner 160 may range between about 1/2 to 2 times the length 1201 of the capsule 120 before expansion of the aligner 160 . Suitable shapes for the aligner balloon 160 can include various elongated shapes such as hot dog-like shapes. In a specific embodiment, the balloon 160 can comprise a first section 160' and a second section 160'', wherein expansion of the first section 160' displaces the delivery mechanism 170 from the capsule 120 ( Second section 160 ″ is used to inflate delivery balloon 172 , typically configured to advance from ). In these and related embodiments, the first section 160' expands first to push the mechanism 170 out of the capsule (typically out of the body portion 120p') and the second section 160" expands to deliver. First section 160 ′ and second section 160 ″ can be configured to have telescoping expansion to expand member 172 . This is so that the first section 160' will expand first (due to its smaller volume) and the second section 160'' will not expand until the first section 60' has substantially expanded. Second, it can be achieved by constructing the first section 160' to have a smaller diameter and volume than the second section 160''. In one embodiment, this is facilitated by the use of a control valve 155 (described above) connecting sections 160' and 160'' that does not allow gas to pass through section 160'' until a minimum pressure is reached in section 160'. can be In some embodiments, the aligner balloon can contain chemical reactants that react upon mixing with water or other liquids from the deploying balloon.

In many embodiments, deployment member 130 includes an expandable balloon known as deployment balloon 130 . In various embodiments, deployment balloon 30 is configured to facilitate deployment/expansion of aligner balloon 160 through the use of gas, eg, generation of gas 169 from chemicals. The gas causes a solid chemical reactant 165, such as an acid 166 (eg, citric acid) and a base 166 (eg, potassium bicarbonate, sodium bicarbonate, and the like) to react and then combine them with water or other It can be generated by mixing with an aqueous liquid 168 . A stoichiometric method can be used to select amounts of reactants to create a selected pressure in one or more of balloons 130 , 160 and 72 . Reactant 165 and liquid can be stored separately in balloons 130 and 160 and then brought together in response to a triggering event such as pH conditions in the small intestine. Reactant 165 and liquid 168 may be stored in either balloon, but in a preferred embodiment liquid 168 is stored in balloon 130 and reactant 165 is stored in balloon 160 . By means of a connector tube 163 which also typically comprises isolation means 150, such as a detachable valve 150 described below, to allow the passage of liquid 168 to initiate the reaction and/or the resulting gas 169. Balloon 130 can be coupled to aligner balloon 160 . For embodiments in which balloon 130 contains a liquid, tube 163 allows passage of sufficient water from balloon 130 to balloon 60 to produce the desired amount of gas to inflate balloon 160 as well as balloon 172 . diameter sufficient for Also, when balloon 130 contains liquid, one or both of balloon 30 and tube 63 are configured to allow passage of liquid to balloon 160 by one or more of the following: i) compressive force exerted on balloon 130 by peristaltic contractions of the small intestine against exposed balloon 130; and ii) uptake of liquid by tube 163 due to capillary action.

Tubing 163 typifies a detachable isolation valve or other isolation means 150 that isolates the contents of balloon 130 (eg, water 158) from the contents of balloon 160 (eg, reactant 165) until the valve is detached. be prepared. Valve 150 may be manufactured from a material degradable by liquid water, such as maltose, such that the valve opens when exposed to water with various liquids in the gastrointestinal tract. It can also be made from materials that can degrade in response to the higher pH found in intestinal fluids, such as methacrylate-based coatings. The valve is preferably located at a location on tube 163 that projects above balloon 130 and/or is otherwise sufficiently exposed so that valve 150 is exposed to intestinal fluids that enter the capsule upon disassembly of cap 120p'. exposed. In various embodiments, valve 150 can be positioned to lie on or even protrude above balloon 130 (as shown in the embodiment of FIGS. 16a and 16b), resulting in Valve 150 is clearly exposed to intestinal fluids when cap 120p' disassembles. Various embodiments of the present invention provide numerous structures for isolation valve 150, such as a beam-like structure (in which case the valve includes a beam that compresses tube 163 and/or connecting section 136), or a collar-type structure. (in which case the valve includes a collar on tube 163 and/or connecting section 136). Still other valve constructions are also contemplated.

Balloon 130 has a deployed state and an undeployed state. In the deployed state, deployment balloon 130 can have a domed shape 130d corresponding to the shape of the distal end of the capsule. Other shapes 130s for the deployed balloon 130 are also contemplated, such as spherical, tubular, and the like. Reactant 165 typically includes at least two reactants 166 and 167, for example an acid such as citric acid and a base such as sodium bicarbonate. Other reactants 165 are also contemplated, including other acids, such as acetic acid, and bases, such as sodium hydroxide. When the valve or other isolation means 150 is opened, the reactants mix in the liquid and produce a gas, such as carbon dioxide, which inflates the aligner balloon 160 or other expandable member.

13b, the deployment balloon 130 actually includes a first balloon 130' and a second balloon 130'' connected by a tube 36 or other connecting means 136 (eg, connecting section). Connecting tube 136 is degradable by liquids such as those described above and/or liquids having a particular pH, such as the basic pH found in the small intestine (eg, 5.5 or 6.5). An isolation valve 150 is typically provided. The two balloons 130' and 130'' each have a half-dome shape 130hs that allows the balloons 130' and 130'' to fit within the distal portion of the capsule when in the expanded state. One balloon can contain chemical reactant(s) 165 (e.g., sodium bicarbonate, citric acid, etc.) and the other can contain liquid water 168, Thus, when the bulb is disassembled, the two components mix to form a gas that inflates one or both of balloons 130 ′ and 130 ″ and in turn aligner balloon 160 .

In yet another embodiment, balloon 130 can include a multi-compartment balloon 130mc that is formed or otherwise constructed to have multiple compartments 130c. Typically, compartment 130c comprises at least a first compartment 134 and a second compartment 135 separated by an isolation valve 150 or other isolation means 150 as shown in the embodiment of Figure 14a. In many embodiments, compartments 134 and 135 have at least a small connecting section 136 between them where isolation valve 150 is typically located. As shown in the embodiment of Figure 14a, a liquid 168 (typically water) can be placed in the first compartment 134 and one or more reactants 165 (which are (typically solid, but liquids can also be used) can be placed in the second compartment 135 . When valve 150 is opened (eg, from decomposition caused by fluid in the small intestine), liquid 168 enters compartment 135 (or vice versa, or both) and reactant(s) 165 mix with the liquid. A gas 169 such as carbon dioxide is generated, which inflates balloon 130 and can also be used to inflate one or more of balloons 160 and 172 .

Reactant 165 typically includes at least a first reactant 166 and a second reactant 167, for example an acid such as citric acid and a base such as sodium or potassium bicarbonate. As discussed herein, in various embodiments, placing them in one or more of balloon 130 (including sections 134 and 135 or halves 130′ and 130″) and balloon 160 Additional reactants are also contemplated, including other combinations of acids and bases that produce an inert gas with the product.For embodiments using citric acid and sodium or potassium bicarbonate, see 2 The ratio between the two reactants (eg, citric acid to potassium bicarbonate) can range from about 1:1 to about 1:4, with a specific ratio of about 1:3. Article 165 has little or no absorbed water, so prior to placing one or more of the reactants, such as sodium or potassium bicarbonate, within balloon 130 (eg, by vacuum drying). Other reactants 165 are also contemplated, including other acids, such as acetic acid, and bases.The amount of a particular reactant 165, including a combination of reactants, depends on the particular chemical reaction and Using the known stoichiometric formula for balloon inflation volume and the ideal gas law (e.g., PV=nRT), balloon 130 can be selected to produce a particular pressure in certain embodiments. , 160 and 172, i) to achieve a particular penetration depth into the intestinal wall and to produce a particular diameter for one or more of balloons 130, 160 and 172 and iii) produce a selected pressure to exert a selected amount of force on the intestinal wall IW. The amounts and ratios of reactants (e.g., citric acid and potassium bicarbonate) are adjusted to achieve pressures in the range of 10 to 15 psi, although lower and higher pressures are also contemplated in one or more of Furthermore, known stoichiometric equations can be used to determine the amounts and ratios of reactants to achieve these pressures.

In various embodiments of the invention that use chemical reactants 165 to generate gas 169, said chemical reactants, alone or in combination with deployment balloon 130, aligner balloon 160 and delivery mechanism 170 (delivery balloon 172). ) may be configured to deploy one or both of the . The deployment engine 180 may include an embodiment using two deployment balloons 130 and 130'' (dual dome configuration as shown in Figure 13b) or may also include a multi-compartment balloon 130mc as shown in Figure 14a. Other forms of deployment engine 180, such as the use of expandable piezoelectric materials (which expand upon application of a voltage), springs and other shape memory materials, and various thermally expandable materials, are also possible in various implementations of the present invention. Contemplated by form.

One or more of expandable balloons 130, 160 and 172 typically also include a vent valve 159 to aid in venting the balloon after inflation. The vent valve 159 decomposes upon exposure to fluid in the small intestine and/or liquid in one of the balloon's compartments to create an opening or channel for escape of gas within a particular balloon. It can include a biodegradable material configured to. Desirably, vent valve 159 is configured to decompose at a slower rate than valve 150 to allow sufficient time for balloons 130, 160 and 172 to inflate before the vent valve decomposes. In various embodiments of the compartmentalized balloon 130, the vent valve 159 may correspond to a degradable section 139 located on the distal portion 131 of the balloon as shown in the embodiment of Figure 14a. In this and related embodiments, when the degradable section 139 degrades from exposure to said liquid, the balloon wall 132 tears or otherwise breaks apart providing a high degree of assurance of rapid venting. offer. Multiple degradable sections 139 can be positioned at various locations within balloon wall 132 .

In various embodiments of balloon 172, vent valve 159 is a tube valve 173 attached to distal end 172e of delivery balloon 172 (opposite the distal end connected to the aligner balloon) as shown in the embodiment of Figure 13b. can correspond to Tube valve 173 includes a hollow tube 173t having a lumen blocked at selected location 173l with a material 173m such as maltose that degrades upon exposure to fluid such as fluid in the small intestine. Position 173l of blocking material 173m within tube 173t provides sufficient time for delivery balloon 172 to inflate and deliver tissue-penetrating member 40 to intestinal wall IW before the blocking material dissolves and opens valve 173. selected to provide. Typically, this is near, but not quite, the end 173e of tube 173t to allow the liquid time to wick up the tube lumen before reaching material 173m. According to one or more embodiments, when the vent valve 173 is open, it not only helps vent the delivery balloon 172, but it also helps vent the aligner balloon 160 and the deployment balloon . In many embodiments, these three are fluidly connected (aligner balloon is fluidly connected to delivery balloon 172 and deployment balloon 130 is fluidly connected to aligner balloon 160). It is from. Opening of the vent valve 173 by placing it at the distal end 172e of the delivery balloon 172, which is pushed out of the capsule 120 by inflation of the aligner balloon 160, so that the vent valve is well exposed to the fluids in the small intestine. can encourage A similar tube vent valve 173 may be located on one or both of the aligner balloon 162 and deployment balloon 130 . In these latter two cases, the blocking material within the tube valve is configured to degrade over a period of time to allow sufficient time for inflation of the delivery balloon 172 and penetration of the tissue-penetrating member 140 into the intestinal wall. be able to.

Additionally, to further assist in guaranteed venting, when the balloon (e.g., balloons 130, 160, 172) is fully inflated, it contacts and is punctured by piercing element 182. Additionally, one or more piercing elements 182 can be attached to the inner surface 124 of the capsule. Piercing element 182 can include a short protrusion from surface 124 with a sharp tip. In another alternative or additional embodiment for balloon venting, one or more of the tissue penetrating members 140 can be coupled directly to the wall 172w of the balloon 172 and pulled away from the balloon when they are removed. can be configured to rupture the wall of the balloon in the process.

A discussion of tissue-penetrating member 140 is now presented. Tissue-penetrating member 140 is 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. can do. The latter material is used to impart desired structural and material properties to the penetrating member (e.g., columnar strength for insertion into the intestinal wall, or porosity and hydrophilicity for controlled drug release). selected for 18a-18f, in many embodiments, a shaft 144 and a needle point 145 or other sharp tip to facilitate penetration of the tissue of the intestinal wall, as shown in the embodiment of FIG. 18a. Penetrating member 140 may be formed to have 145 . In a preferred embodiment, tip 145 has a trocar shape as shown in the embodiment of Figure 18c. Tip 145 can include various degradable materials such as sucrose or other sugars (either in the body of the tip or as a coating) that increase the hardness and tissue-penetrating properties of the tip. Once placed within the intestinal wall, the penetrating member 140 is degraded by intestinal fluids within the wall tissue such that the drug or other therapeutic agent 101 dissolves in the fluid and is absorbed into the bloodstream. One or more of the size, shape and chemical composition of tissue-penetrating member 140 can be selected to allow dissolution and absorption of drug 101 within a matter of seconds, minutes or even hours. Dissolution rate can be controlled through the use of various disintegrants known in the pharmaceutical arts. Examples of disintegrants include, but are not limited to, various starches such as sodium starch glycolate, and various crosslinked polymers such as carboxymethylcellulose. The choice of disintegrant can be tailored specifically to the environment within the wall of the small intestine.

Tissue-penetrating member 140 also typically includes one or more tissue-dwelling features 143, such as barbs or hooks, for deploying the penetrating member within the tissue of the intestinal wall IW after advancement. To enhance tissue placement, such as two or more barbs symmetrically or otherwise distributed about and along the member shaft 144 as shown in the embodiment of FIGS. 18a and 18b. The deployment features 143 can be arranged in a variety of patterns 143p. Additionally, in many embodiments, the penetrating member also includes grooves or other mating features 146 for attachment to coupling components on delivery mechanism 170 .

Tissue-penetrating member 140 desirably is removably coupled to platform 175 (or other component of delivery mechanism 170) for removal of tissue-penetrating member 140 from the balloon after penetration of tissue-penetrating member 140 into the intestinal wall. configured to Detachability is defined by: i) the close fit or fit between opening 174 in platform 175 and member shaft 144; ii) the configuration of tissue retention features 143 on 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 can be used as a result of balloon venting (in this case, when the balloon deflates or is otherwise withdrawn from the intestinal wall). 143 holds the penetrating member 140 within the tissue) and/or is dislodged as a result of forces exerted on the capsule 120 by peristaltic contractions of the small intestine.

In a specific embodiment, the removability and deployment of the tissue-penetrating member 140 within the intestinal wall IW is enhanced by configuring the tissue-penetrating member shaft 144 to have a reverse taper 144t as shown in the embodiment of Figure 18c. can be improved. The taper 144t on the shaft 144 is configured such that the application of peristaltic contractile forces from the intestinal wall to the shaft results in the shaft being forced inward (eg, squeezing inward). This is because the shaft taper 144t converts the laterally applied peristaltic force PF into an orthogonal force OF acting to push the shaft inwardly of the intestinal wall. In use, such a reverse tapered shaft configuration assists in retaining the tissue-penetrating member 140 within the intestinal wall such that degassing of the balloon 172 removes it from the platform 175 (or other component of the delivery mechanism 170). In a further embodiment, tissue-penetrating member 140 having a reverse tapered shaft also includes one or more retention features 143 that further enhance retention of the tissue-penetrating member within the intestinal wall IW when inserted. be prepared.

As explained above, tissue-penetrating member 140 can be manufactured from numerous drugs and other therapeutic agents 101 in various embodiments. Also, according to one or more embodiments, the tissue-penetrating member may be made entirely of drug 101 (eg, AI antibodies, etc.) or may be composed of other component components, such as various pharmaceutical excipients. It may further comprise excipients (eg, binders, preservatives, disintegrants, etc.), polymers with desired mechanical properties, and the like. Further, in various embodiments, one or more tissue-penetrating members 140 may carry drugs 101 (or other therapeutic agents) that are the same or different than other tissue-penetrating members. The former configuration allows delivery of larger amounts of a particular drug 101, while the latter allows for two or more drug treatment regimens that require substantially simultaneous delivery of multiple drugs. It becomes possible to deliver many different drugs into the intestinal wall almost simultaneously. In embodiments of device 110 having multiple delivery assemblies 178 (eg, two, one on each side of balloon 172), a first assembly 178' carries a tissue-penetrating member having a first drug 101 thereon. A second assembly 178 ″ can carry a tissue penetrating member having a second drug 101 .

Typically, the drug or other therapeutic agent 101 carried by tissue-penetrating member 140 is mixed with biodegradable material 105 to form tissue-penetrating member 140 . Materials 105 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. be able to. In such embodiments, penetrating member 140 may comprise a substantially heterogeneous mixture of drug 101 and biodegradable material 105 . Alternatively, tissue-penetrating member 140 has a portion 141 formed substantially of biodegradable material 105 and another section formed of or containing drug 101, as shown in the embodiment of Figure 18d. 142. In one or more embodiments, sections 142 may correspond to pellets, slugs, cylinders, or other shaped sections 142s of drug 101 . Shaped section 142s can be preformed as a separate section, which is then inserted into cavity 142c within tissue-penetrating member 140 as shown in the embodiment of Figures 18e and 18f. Alternatively, section 142s can be formed by addition of drug formulation 100 to cavity 142c. In embodiments where drug formulation 100 is added to cavity 142c, the formulation can be added as a powder, liquid, or gel that is poured or injected into cavity 142c. Shaped section 142s may be formed from drug 101 itself or from a drug formulation containing drug 101 and one or more binders, preservatives, disintegrants and other excipients. Sometimes it is done. Suitable binding agents include polyethylene glycol (PEG) and other binding agents known in the art. In various embodiments, the PEG or other binder may comprise a range of about 10 to 90 weight percent of section 142s, and in preferred embodiments for insulin formulations comprise about 25 to 90 weight percent. Sometimes. Other excipients that can be used as binders include PLA, PLGA, cyclodextrin, cellulose, methylcellulose, maltose, dextrin, sucrose and PGA. Further information regarding weight percentages of excipients in section 142 can be found in Table 2. For ease of discussion, section 142 is referred to as pellets in this table, but the data in the table also apply to other embodiments of section 142 described herein.

In various embodiments, the weight of tissue-penetrating member 140 can range between 10 and 15 mg, although higher and lower weights are contemplated. For embodiments of tissue-penetrating member 140 made from maltose, the weight may range from about 11 to 14 mg. In various embodiments, depending on the drug 101 and the desired dose to be delivered, the weight percent of drug in member 140 can range from about 0.1 to about 15%. In an exemplary embodiment, these weight percentages correspond to embodiments of member 140 made from maltose or PGLA, although they are not included in any of the biodegradable materials 105 used to make member 140. also applies. The weight percent of drug or other therapeutic agent 101 in member 140 can, of course, be adjusted according to the desired dose, as well as to provide structural and stoichiometric stability of the drug, as well as in the blood or body. can also be adjusted to achieve the desired concentration profile of the drug in other tissues. Specific adjustments within the weight percent range can be made using various stability tests and models known in the art (e.g., using the Arrhenius equation) and/or known drug chemical degradation rates. Table 2 lists ranges of doses and weight percents of insulin and numerous other drugs that can be delivered by tissue-penetrating member 140 . In some cases, the table lists ranges and single values for doses. It should be understood that these values are exemplary and that other values recited herein, including the claims, are also contemplated. Further, embodiments of the present invention take into account variations around these values, including, for example, ±1, ±5, ±10, ±25 and even larger variations. Such variations are considered to be within the scope of embodiments claiming a particular value or range of values. The table also lists drug weight percents in section 142 for various drugs and other therapeutic agents, again referred to herein as pellets for ease of discussion. Again, embodiments of the present invention take into account the variations discussed above.

Tissue-penetrating member 140 can be manufactured using one or more polymer and pharmaceutical manufacturing techniques known in the art. For example, drug 101 (with or without biodegradable material 105) may be in solid form, with the addition of one or more binders, molding, compression or other similar methods. can be used to shape it into the tissue penetrating member 140 . Alternatively, the drug 101 and/or drug formulation 100 may be solid or liquid, by adding it to the liquid form of the biodegradable material 105, followed by molding or other methods known in the polymer arts. The mixture can be made into the penetrating member 140 using a forming method.

Desirably, embodiments of tissue-penetrating member 140 that include drug or other therapeutic agent 101 and biodegradable material 105 result in substantial thermal degradation of any drug, including drugs such as various peptides and proteins. Do not allow the temperature to form. This can be accomplished through the use of room temperature curable polymers and room temperature molding and solvent evaporation techniques known in the art. In certain embodiments, the amount of thermally decomposed drug or other therapeutic agent within the tissue-penetrating member is desirably less than about 10% by weight, and more preferably less than 5%, and even more preferably less than 1%. be. The thermal decomposition temperature(s) of a particular drug is known or can be determined using methods known in the art, and this temperature is then used to determine the temperature of thermal decomposition of the drug. and specific polymer processing methods (eg, molding, curing, solvent evaporation methods, etc.) can be selected and adjusted to minimize the associated levels.

Delivery mechanism 170 will now be described. Typically, this mechanism includes a delivery assembly 178 (containing tissue-penetrating member 140) attached to delivery balloon 172, as shown in the embodiment of Figures 16a and 16b. Inflation of the delivery balloon provides a mechanical force to engage the delivery assembly 172 outwardly from the capsule into the intestinal wall IW and insert the tissue-penetrating member 140 into that 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 plane 172f can be configured to pressurize the intestinal wall (IW) upon expansion of the balloon 172 to insert the tissue penetrating member (TPM) 140 into the intestinal wall. Position TPMs 140 (either by themselves or as part of a delivery assembly 178 as described below) on one or both sides 172f of balloon 172 to allow insertion of drug-containing TPMs 40 on both sides of the intestinal wall. can be made Said face 172f of balloon 172 may have sufficient surface area to allow placement on each face of multiple drug-containing TPMs 140 .

Referring now to Figure 19, assembly of the delivery assembly 178 will be described. In a first step 300, one or more tissue penetrating members 140 can be removably coupled to a biodegradable advancement structure 175, which can correspond to a support platform 175 (also known as platform 175). In a preferred embodiment, platform 175 includes one or more openings 174 for insertion of member 140 as shown at step 300 . Apertures 174 are sized to allow insertion and placement of members 140 into platform 175 prior to expansion of balloon 172, while allowing their removal from the platform once they have penetrated the intestinal wall. size. The support platform 175 can then be placed within the support structure 176 as shown in step 301 . The carrier structure 176 may correspond to a well structure 176 having sidewalls 176s and a bottom wall 176b that define a cavity or opening 176c. Platform 175 is desirably attached to the inner surface of bottom wall 176b using an adhesive or other bonding method known in the art. Well structure 176 can include various polymeric materials and can be formed using vacuum forming techniques known in the polymer processing arts. In many embodiments, the opening 176o can be covered with a protective film 177 as shown in step 302. FIG. Protective film 177 functions as a barrier to protect tissue-penetrating member 140 from moisture and oxidation as described below, but has properties selected such that tissue-penetrating member 140 can still penetrate the film. Film 177 can include various water and/or oxygen impermeable polymers, desirably so as to be biodegradable in the small intestine and/or to keep the digestive tract inert. configured to pass through It may also have a multilayer structure with specific layers selected for their impermeability to given substances, such as oxygen, water vapor, and the like. In use, embodiments utilizing protective film 177 help increase the shelf life of therapeutic agent 101 within tissue-penetrating member 140 , which in turn helps increase the shelf life of device 110 . Taken together, tissue-penetrating member 140 , well structure 176 and support platform 175 with attached film 177 may comprise delivery assembly 178 . A delivery assembly 178 having one or more drugs or therapeutic agents 101 contained in a tissue penetrating member 40 or other drug delivery means may be prefabricated and stored for subsequent use in manufacturing device 110 at a later date. can do. The shelf life of assembly 178 can be further enhanced by filling cavity 176c of closure assembly 178 with an inert gas such as nitrogen.

Referring back to FIGS. 16a and 16b, assemblies 178 can be located on one or both sides 172f of balloon 172. As shown in FIG. In a preferred embodiment, the assembly 178 is located on both sides 172f (as shown in FIG. 16a) so as to distribute the force substantially evenly on both sides of the intestinal wall IW upon expansion of the balloon 172. FIG. Assembly 178 can be attached to surface 172f using adhesives or other bonding methods known in the polymer arts. As balloon 172 is inflated, TPM 140 penetrates film 177, penetrates the intestinal wall IW, and is detached from platform 175 when balloon 172 is deflated. It is retained there by a portion (eg, reverse tapered shaft 144t).

In various embodiments, one or more of balloons 130, 160 and 172 are placed inside capsule 120 and folded, folded or otherwise folded to maintain a space within interior volume 124v of the capsule. can be packaged in any desired configuration. Folding can be accomplished using preformed folds or other folding features or methods known in the medical balloon art. In certain embodiments, balloons 130, 160 and 172 can be folded in orientations selected to achieve one or more of the following: i) preserve space; and iii) facilitate the desired balloon inflation sequence. The embodiments shown in Figures 15a-15f illustrate embodiments of folding methods and various folding sequences. However, it should be understood that this folding sequence and resulting balloon orientation is exemplary and others may be used. In this and related embodiments, the folding can be done by hand, by an automated machine, or by a combination of both. Also, in many embodiments, as shown in the embodiment of FIGS. 13a and 13b, a single multi-balloon assembly 7 (described herein) includes balloons 130, 160, 170, valve chambers 158, and various connecting tubing 162. Folding can be aided in the book by using assembly 7). 13a shows an embodiment of assembly 7 having a single dome configuration for balloon 130, while FIG. 13b shows an embodiment of assembly 7 having a double balloon/dome configuration for balloon 130. FIG. Assembly 7 can be manufactured using thin polymer films that are vacuum formed into the desired shape using various vacuum forming and other related methods known in the polymer processing arts. Suitable polymer films include polyethylene films having a thickness ranging from about 0.003" to about 0.010", with a specific embodiment of 0.005". In preferred embodiments, the assembly is manufactured to have a unitary construction to obviate the need to bond one or more components of the assembly (eg, balloons 130, 160, etc.). However, the assembly 7 may be manufactured from multiple parts (e.g. halves) or components (e.g. balloons) and then joined together using various joining techniques known in the polymer/medical device arts. It is also contemplated that

15a-15f, 16a-16b and 17a-17b, in a first folding step 210, the balloon 160 along with the balloon 172 is fitted over the valve fitting 158, and in the process, the opposite side of the valve fitting 158 is folded. (see Figure 15a). Then, at step 211, the balloon 172 is folded at right angles to the folded combination of balloon 160 and valve 158 (see Figure 15b). Then, in step 212 for the double dome embodiment of balloon 130, the two halves 130' and 130'' of balloon 130 are folded over each other, leaving valve 150 exposed (see, for example, 15c, balloon 130 is folded on itself (see FIG. 15e) for the single dome embodiment of FIG. A final folded assembly 8 for the double dome configuration shown in Fig. 15e and a final folded assembly 8' for the single dome configuration shown in Figs. Assembly 8 (typically two faces 72f of balloon 72) is attached in step 214 to obtain final assembly 9 (shown in the embodiment of FIGS. 16a and 16b), which is then inserted into capsule 120. The final assembled version of the device 110 with the assembly 9 inserted after the insertion step 215 is shown in Figures 17a and 17b.

20a-20i, the use of device 110 to deliver pharmaceutical agent 101 to a site within the GI tract, such as the wall of the small or large intestine, will now be described. It should be understood that the steps and their order are exemplary and that other steps and orders are also contemplated. After device 110 enters small intestine SI, cap coating 120c' is degraded by the basic pH in the upper small intestine, which causes cap 120p' to degrade as shown in step 400 of FIG. 20b. Valve 150 is then exposed to fluid in the small intestine, which causes the valve to begin to disintegrate as shown in step 401 of Figure 20c. Balloon 130 then expands (due to gas 169 production) at step 402, as shown in FIG. 20d. Section 160' of balloon 160 then begins to expand at step 403 to begin pushing assembly 178 out of the capsule body, as shown in Figure 20e. Then, at step 404, sections 160' and 160'' of balloon 160 are fully inflated to fully push assembly 178 out of the capsule body, as shown in FIG. The capsule length 120l is stretched to help align the LAI, during which time the pressure within the balloon 60 increases (due to the balloon being fully inflated and having nowhere else for the gas 169 to go). valve 155 begins to fail, then, as shown in Figure 20g, at step 405, valve 155 is fully opened to inflate balloon 172, and balloon 172 is fully pushed out of body 120p. ) pushes the now fully exposed assembly 178 radially outward into the intestinal wall IW.Then, at step 406, as shown in FIG. , advances the tissue-penetrating member into the intestinal wall IW.Then, at step 407, balloon 172 (along with balloons 160 and 130) is deflated so that it is pulled back, leaving the tissue-penetrating member indwelling in the intestinal wall IW. Also, the capsule body portion 120p'' is completely degraded (due to the degradation of the coating 120c'') along with the other biodegradable portions of the device 110. Any portion that was not degraded It is carried distally by the small intestine by peristaltic contractions from digestion and is eventually excreted.

Appendix/Examples Various embodiments of the present invention are further illustrated with reference to the following Appendix/Examples. It should be recognized that these examples are presented for illustrative purposes only, and that the invention is not limited to the information or details therein.

Appendix 1 Pharmacokinetic modeling of secukinumab and brodalumab plasma concentrations Assumptions used in the secukinumab model

The dosing schedule is 300 mg weekly SC (subcutaneous) for 4 weeks then 300 mg every 4 weeks.

The initial weekly dose of 300 mg can be considered a loading dose, compensating for the time required for drug concentrations to reach steady state (t = day 0 to approximately day 150 in Figure 22a).

If only the 300 mg every 4 weeks portion of the dosing schedule is modeled, it can still be seen what the steady state concentration reached is. See Figure 22a.

Pharmacokinetic parameters are document prepared by Novartis published on September 12, 2014 and available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM419023.pdf , taken from the title "Secukinumab (AIN457), ADVISORY COMMITTEE BRIEFING MATERIAL: AVAILABLE FOR PUBLIC RELEASE". A one-compartment model with first-order absorption and elimination was used.

Since the absorption rate _{constant (} k _a ) value is not given, 0.6 days ^{− 1} was used.

At steady state, the drug concentration peak is 47.9 mg/L and the drug concentration trough is 26.9 mg/L. The steady state drug concentration, C _ss , average of the two is 37.4 mg/L. Assume this is the target drug concentration for pharmacological activity.

For daily dosing using embodiments of the present invention, a small dose can be administered daily and receive the pharmacokinetic profile shown in Figure 22b.

Using this dosing scheme, steady-state drug concentrations are a maximum of 38.0 mg/L and a minimum of 37.9 mg/L for C _ss =37.95 mg/L. Moreover, the same target drug concentration can be reached with much lower diurnal variation. Peak concentrations are lower, preventing potential adverse events and formation of anti-drug antibodies, and trough concentrations are higher, reducing the likelihood of low biological activity.

Assumptions Used in the Model of Brodalumab Pharmacokinetic Model A phase II study whose results were reported in June 2014 used a dosing schedule of 140 or 280 mg at weeks 1, 2, 4, 6, 8 and 10 All patients were then switched to 280 mg every 2 weeks. Using the biweekly 280 mg dosing scenario from this study, it was assumed that the first two weekly injections included the loading dose. See Figure 23a.

Pharmacokinetic parameters were obtained from the following papers and used in a two-compartment model: Endres, CJ., Salinger, DH, Kock, K. et al., "Population Pharmacokinetics of Brodalumab in Healthy Adults and Adults with Psoriasis From Single and Multiple Dose Studies.” J Clin Pharmacol, 2014, 54(11):1230-1238.

Brodalumab elimination may actually be underestimated because the model is simplified by not incorporating the combined Michaelis-Manton elimination used in the publication.

Peak drug level is 55.4 mg/L and trough drug level is 45.1 mg/L. This gives a C _ss of 50.3 mg/L. Assume this is the target drug concentration.

Daily dosing using embodiments of the present invention can give 20 mg per day to reach the target concentration. See Figure 23b.

For C _ss =51.46 mg/L, the peak drug level is 51.49 mg/L and the trough level is 51.43 mg/L. Similar to secukinumab, lower fluctuations in daily drug levels can help avoid adverse events and help maintain consistent pharmacological activity.

Appendix 2: Models and calculations used for calculation of steady-state fluctuations in serum drug concentrations of secukinumab, brodalumab and alirocumab.
% Steady State Variation is a metric that provides an indication of how much variation there is in a patient's plasma/serum concentration of a drug over time. It is desirable to minimize steady state fluctuations for several reasons. First, higher drug concentrations required for pharmacological activity are more likely to result in adverse events. In addition to specific effects such as opportunistic infections of IL-17 inhibitors and cardiovascular events of PCSK9 inhibitors, antibody therapy can cause anti-drug antibody production. These anti-drug antibodies can target drugs and neutralize them by blocking binding sites or marking drugs for destruction. Patients who develop anti-drug antibodies to a drug no longer respond to that drug and must be placed on a different regimen. On the other hand, drug concentrations lower than necessary for pharmacological activity are also undesirable. No pharmacological activity during these periods, and thus lower drug potency, is more likely. In order to effectively treat the target disorder, it is ideal to maintain a constant, stable level of pharmacological activity.

For the three antibodies shown in Table 1 the % steady state variation was calculated. Values were determined using existing pharmacokinetic simulations described in Appendix 1. The specific formula used to calculate the % Steady State Variation is shown below:

It calculates the difference between the peak steady-state concentration (Css,peak) and the trough steady-state concentration (Css,trough) and divides by the average steady-state concentration (Css,avg) to give the serum drug relative to the average steady-state drug concentration. Percent change in concentration is given. Steady-state variation serves as a quantitative measure by which one can predict how much serum drug concentrations will change during a single dosing period.

It is clear from the above data that daily dosing using embodiments of the present invention allows for much lower steady-state fluctuations in plasma concentrations of the same drug than conventional subcutaneous dosing. In addition to the expected benefits of less frequent, less intense adverse events and maintenance of pharmacological activity, administration by injection into the small intestine using embodiments of the present invention may occur with subcutaneous administration. Avoid injection site reactions.

CONCLUSION The foregoing description of various embodiments of the present invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Many modifications, variations and refinements will be apparent to those skilled in the art. For example, device embodiments can be sized or otherwise adapted for various pediatric and neonatal applications and various veterinary applications (including, but not limited to, bovine, canine, equine, feline, ovine and porcine). can be adapted to Those skilled in the art will also recognize that numerous equivalents to the specific devices and methods described herein may be ascertained using no more than routine experimentation. Such equivalents are considered to be within the scope of this invention and are covered by the following appended claims.

Elements, features or acts from one embodiment can be readily recombined or substituted with one or more elements, features or acts from other embodiments to create numerous additions within the scope of the invention. can form an embodiment of Further, any element shown or described as being combined with other elements can exist as a stand-alone element in various embodiments. Accordingly, the scope of the invention is not limited to the specifics of the described embodiments, but instead is limited only by the appended claims.

Claims (14)

A therapeutic formulation comprising an anti-interleukin antibody (AI antibody) in solid form, said formulation being shaped as a solid tissue-penetrating member and placed inside a swallowable capsule, said tissue-penetrating member comprising said formulation adapted to be orally delivered to a patient using a delivery means operably connected to
The formulation is responsive to pH at a location in the patient's small intestine anterior to the ileum , thereby avoiding an immune response by the Peyer's patches to the AI antibody . adapted to penetrate and be inserted into surrounding tissue,
Here, after insertion, the tissue-penetrating member remains in the wall or surrounding tissue and degrades, releasing the AI antibodies into the bloodstream to attenuate the biological effects of interleukins within the patient. , therapeutic formulations. 2. The formulation of claim 1, wherein the pH is about 6.5 such that the formulation penetrates the wall of the duodenal or jejunal portion of the small intestine and avoids the ileum containing the Peyer's patches. 2. The formulation of claim 1, wherein said AI antibodies comprise antibodies against members of the interleukin-17 family of cytokines. wherein stable fluctuations in daily plasma concentrations of said AI antibody released from daily administration of said formulation are significantly reduced compared to biweekly or monthly subcutaneous injections of said AI antibody; Item 4. The formulation according to item 3 . 4. The formulation of claim 3 , wherein the stable diurnal variation in daily plasma concentration of anti-interleukin 17 antibody (AI17 antibody) from daily administration is between about 0.12-0.26%. 4. The therapeutic index of the anti-interleukin 17 antibody (AI17 antibody) delivered by said formulation is in the range of about 7 to 30 times higher than the therapeutic index of the AI17 antibody dosage delivered by parenteral injection. Formulation as described. 4. The formulation of claim 3 , wherein said AI antibody is secukinumab. 4. The formulation of claim 3 , wherein said AI antibody is ixekizumab. 4. The formulation of claim 3 , wherein said AI antibody is brodalumab. 2. The method of claim 1, wherein the AI antibody is released from the wall or surrounding tissue into the bloodstream to achieve the _Cmax in a shorter period of time than an extravascular dose of the AI antibody achieves the _Cmax . pharmaceutical formulation. Said delivery means having a first configuration and a second configuration, said delivery means containing said formulation within said capsule in said first configuration and said delivery means in said second configuration 2. The formulation of claim 1, wherein the formulation is caused to enter the wall from the capsule by applying a force to the surface of the formulation from. 2. The formulation of claim 1, comprising a biodegradable material that degrades within the wall or surrounding tissue to release the AI antibody into the bloodstream. 2. The formulation of claim 1, wherein at least about 70% by weight of said AI antibodies in said formulation are biologically active. The formulation of claim 1, wherein the formulation has a density within the range of about 1.00-1.15 mg/mm ³ or about 1.02-1.06 mg/mm ³ .

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