Ingestable devices and assemblies for delivering therapeutic drugs

Abstract

A payload delivery module (120) for an ingestionable device comprises a piston (121), a hollow needle (122), a membrane (129), a fluid dosage form (130), and a valve (125). The piston (121) has an interior (121c). The needle (122) is coupled to the piston (121). The membrane (129) is coupled to the piston (121) to define a reservoir in the interior (121c). The fluid dosage form (130) is disposed within the reservoir and contains at least one therapeutic agent. The valve (125) is coupled to the piston (121) to control the flow of the fluid dosage form from the reservoir to the needle (122).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits and priority of U.S. Provisional Applications No. 63 / 520,558 filed on 18 August 2023, No. 63 / 591,503 filed on 19 October 2023, No. 63 / 609,739 filed on 13 December 2023, and No. 63 / 625,112 filed on 25 January 2024. The entire contents of the aforementioned applications are incorporated herein by reference. [Background technology]

[0002] Therapeutic drugs and other therapeutic agents can be administered to a subject by ingestion or parenteral injection (e.g., subcutaneously, intramuscularly, or intravenously) to provide the desired therapeutic effect. However, these routes of administration have several drawbacks. For example, some therapeutic agents, such as biological agents containing large (macro) molecules, are not suitable for ingestion because these molecules cannot be enzymatically broken down in the gastrointestinal (GI) tract of the subject and / or pass through the tight junctions of the epithelial layer of the GI tract wall. Other types of therapeutic agents may otherwise be poorly tolerated in the GI tract and result in low systemic uptake. With parenteral injection, subjects may experience pain and discomfort at the time of administration, which can significantly impact medication adherence and quality of life.

[0003] Ingestable devices have been proposed to address some of the challenges associated with the conventional oral and parenteral delivery of various therapeutic drugs. For example, some ingestible devices are designed to actively deliver therapeutic drugs to GI wall tissue. However, most of these devices have limited design flexibility. For example, most devices cannot incorporate different delivery mechanisms with different delivery modes to deliver different dosage forms (e.g., solid and liquid dosage forms). Therefore, to enable the incorporation of different delivery mechanisms on the same device platform, most of these devices would need to undergo a substantial redesign, requiring a considerable number of additional components or a different device platform to be fully utilized. Thus, it is sometimes desirable to provide ingestible devices with sufficient design flexibility to allow the incorporation of different delivery mechanisms.

[0004] These and other challenges encountered with existing drug delivery modalities are addressed by embodiments of the present disclosure. The ingestible devices, payload delivery modules, delivery assemblies, methods for manufacturing them, and methods and uses thereof for delivering one or more therapeutic drugs may also offer one or more additional advantages over existing drug delivery devices. [Overview of the project]

[0005] Embodiments of this disclosure generally relate to ingestible devices, assemblies, and methods for delivering one or more therapeutic agents into the luminal wall or surrounding tissue of a target GI (e.g., the peritoneum or peritoneal cavity). In some embodiments, the devices and assemblies disclosed herein may have a modular design that allows for the incorporation of different delivery mechanisms in different delivery modes to enable the delivery of different dosage forms and / or doses using interchangeable components on the same device platform. In this way, the devices and assemblies disclosed herein may enable the use of a common device platform to deliver a wide range of doses and dosage forms to accommodate most therapeutic regimens. These and other advantageous features will become apparent to those skilled in the art who read this disclosure.

[0006] In one embodiment, a payload delivery module for an ingestible device includes a piston, a hollow needle, a membrane, a fluid dosage form, and a valve. The piston includes an interior. The hollow needle is coupled to the piston. The membrane is coupled to the piston to define a reservoir inside. The fluid dosage form is disposed within the reservoir and contains at least one therapeutic agent. The valve is coupled to the piston to control the flow of the fluid dosage form from the reservoir to the needle.

[0007] In another embodiment, a payload delivery module for an ingestible device includes a piston, a hollow needle, a plunger, a fluid dosage form, and a valve. The piston includes an interior. The hollow needle is coupled to the piston. The plunger is movably coupled to the piston to define a reservoir inside. The fluid dosage form is disposed within the reservoir and contains at least one therapeutic agent. The valve is coupled to the piston to control the flow of the fluid dosage form from the reservoir to the needle.

[0008] In another embodiment, a payload delivery module for an ingestible device includes a piston, a cartridge, and a solid dosage form. The piston includes a base and an elongated section. The cartridge includes a container. The solid dosage form is disposed within the container and contains at least one therapeutic agent.

[0009] In another embodiment, a payload delivery module for an ingestionable device includes a piston, a membrane, and a valve. The piston includes an interior, a needle port, and a filling port. The membrane is coupled to the piston to define an interior reservoir for containing a fluid dosage form. The valve is coupled to the piston between the membrane and the needle port.

[0010] In another embodiment, a payload delivery module for an ingestionable device includes a piston, a plunger, and a valve. The piston includes an internal, needle port, and filling port. The plunger is movably coupled to the piston to define an internal reservoir for containing a fluid dosage form. The valve is coupled to the piston between the plunger and the needle port.

[0011] In one or more of the embodiments described above, the piston is configured to be releasably coupled to the housing and movably disposed within the housing.

[0012] In one or more of the embodiments described above, the valve is configured to control the flow of a fluid dosage form from the reservoir to the needle in response to the axial movement of the module relative to the housing.

[0013] In one or more embodiments of the above-described models, the piston includes a lateral wall defining a release feature for releasably coupling the piston to the housing. In some embodiments, the release feature is defined by the outer circumferential surface of the piston. In some embodiments, the release feature includes a press-fit feature.

[0014] In one or more embodiments of the above-described models, the valve includes a seal coupled to a piston to contain a fluid dosage form in a reservoir. In some embodiments, the valve further includes a puncture member coupled to the piston adjacent to the seal, configured to move relative to the piston to penetrate the seal. In some embodiments, the puncture member is configured to create a substantially liquid-tight seal with the piston when it penetrates the seal. In some embodiments, the valve further includes a base projecting from the outer surface of the piston and a tip coupled to the base. In some embodiments, the base is integral with the piston. In some embodiments, the base is configured to deform to allow the tip to move relative to the piston and penetrate the seal.

[0015] In one or more embodiments of the above-described models, the valve includes a base protruding from the outer surface of a piston and a plug adjacent to the base and releasably coupled to the piston. In some embodiments, the plug creates a substantially liquid-tight seal between the membrane and the piston for containing a fluid dosage form in a reservoir. In some embodiments, the base is configured to deform to release the plug from the piston, allowing the fluid dosage form to flow into the needle.

[0016] In one or more of the embodiments described above, the membrane includes a flexible material that allows the membrane to deform when the valve opens due to pressure applied to the outer surface of the membrane.

[0017] In any one or more of the embodiments described above, the film includes a metallized film or a coating.

[0018] In one or more of the embodiments described above, the plunger is configured to move relative to the piston when the valve opens in response to pressure applied to the outer surface of the plunger.

[0019] In one or more embodiments of any of the above aspects, the reservoir defines a volume for containing up to approximately 250 μl of fluid. In some embodiments, the reservoir defines a volume for containing approximately 50 - 200 μl of fluid.

[0020] In one or more embodiments of any of the above aspects, the needle has a critical length in the range of approximately 3.5 - 12 mm such that the needle delivers the fluid dosage form into the peritoneal cavity through the GI lumen wall.

[0021] In one or more embodiments of any of the above aspects, the needle has a critical length in the range of approximately 1.5 - 3 mm such that the needle delivers the fluid dosage form into a layer of the GI lumen wall.

[0022] In one or more embodiments of any of the above aspects, the needle comprises a biodegradable material that enables degradation of at least a portion of the needle within the GI lumen wall or surrounding tissue. In some embodiments, the needle includes a body and a tip coupled to the body, the body is formed from a first material, the tip is formed from a second material, and the second material has a greater hardness than the hardness of the first material.

[0023] In one or more embodiments of any of the above aspects, the payload delivery module further includes a cover releasably coupled to the piston. In some embodiments, the cover defines a portion of the housing for holding the payload delivery module.

[0024] In one or more embodiments of any of the above aspects, the solid dosage form is shaped as a needle structure or is contained within a needle structure. In some embodiments, the elongated section of the piston is configured to eject the needle structure from the container as a projectile into the GI lumen wall or surrounding tissue.

[0025] In one or more embodiments of any of the above aspects, at least one therapeutic agent is one or more selected from small molecules, peptides, polypeptides, proteins, hormones, antibodies, or nucleic acids.

[0026] In any one or more embodiments of the above-described models, at least one therapeutic agent is one or more selected from immunosuppressants, chemotherapeutic agents, central nervous system (CNS) agents, antidiabetic agents, enzyme replacement therapy (ERT) agents, anti-infective agents, C-type natriuretic peptide (CNP), programmed cell death ligand 1 (PD-L1) protein, monoclonal antibodies, anticoagulants, blood coagulation factors, insulin, incretins or combinations thereof, or oligonucleotides.

[0027] In one or more embodiments of the above-described embodiments, at least one therapeutic agent comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is MALAT1. In one or more embodiments of the above-described embodiments, at least one therapeutic agent comprises one or more blood coagulation factors or their mimics selected from factor VIII, factor IX, or factor X. In one or more embodiments of the above-described embodiments, at least one therapeutic agent comprises an anti-PCSK9 antibody. In one or more embodiments of the above-described embodiments, at least one therapeutic agent comprises a TNF-α inhibitory antibody. In some embodiments, the TNF-α inhibitory antibody comprises adalimumab or its analogues. In one or more embodiments of the above-described embodiments, at least one therapeutic agent comprises an anti-interleukin antibody. In some embodiments, the anti-interleukin antibody targets interleukin 4 and interleukin 13. In some embodiments, the anti-interleukin antibody comprises dupilumab or its analogues. In some embodiments, the anti-interleukin antibody targets at least one of interleukin 12 or interleukin 23. In some embodiments, the anti-interleukin antibody comprises ustekinumab or an analog thereof. In some embodiments, the anti-interleukin antibody targets interleukin-2. In one or more embodiments of the above embodiments, at least one therapeutic agent comprises parathyroid hormone (PTH) or an analog thereof. In one or more embodiments of the above embodiments, at least one therapeutic agent comprises amylin or an analog thereof. In one or more embodiments of the above embodiments, at least one therapeutic agent comprises one or more incretins or their mimics selected from GLP-1, GLP-2, GIP, PYY, or glucagon receptor agonists.

[0028] In another embodiment, a delivery assembly for an ingestible device is provided herein, comprising a housing and a payload delivery module as described herein coupled to the housing. In some embodiments, the housing includes a proximal end, a distal end, a piston chamber located between the proximal and distal ends, and a housing release feature. The proximal end includes a first opening for receiving force internally, and the distal end includes a second opening for discharging the dosage form. In some embodiments, the housing further includes a body and a cover coupled to the body. The body includes the second opening and the piston chamber, and the cover includes the first opening and the housing release feature. In some embodiments, the piston is disposed within the piston chamber and is releasably coupled to the housing release feature. In some embodiments, a seal is coupled to the housing at the second opening. In some embodiments, the housing further includes a vent channel for discharging gas. In some embodiments, the force is gas pressure. In some embodiments, a housing release feature is configured to release a piston in response to a threshold gas pressure applied to the module through a first opening, where the threshold gas pressure is approximately 10–40 psi. In some embodiments, the housing release feature is located on the lateral wall of the housing. In some embodiments, the housing release feature includes a press-fit feature. In some embodiments, the housing release feature extends circumferentially around the housing. In some embodiments, if the payload delivery module contains a fluid dosage form, the module is configured to move axially within the piston chamber to insert a hollow needle into the GI lumen wall or surrounding tissue through a second opening, and to discharge the fluid dosage form through the hollow needle into the GI lumen wall or surrounding tissue in response to a force received through the first opening. In some embodiments, the fluid dosage form is discharged from the reservoir when a valve opens in response to sufficient axial movement of the module relative to the housing. In some embodiments, the fluid dosage form is discharged through the hollow needle after it has penetrated the GI lumen wall or surrounding tissue.In some embodiments, when the payload delivery module includes a solid dosage form, the cartridge is coupled to a housing and configured such that a piston moves axially within a piston chamber in response to a force received through a first opening, thereby ejecting the solid dosage form from the container as a projectile into the GI lumen wall or surrounding tissue.

[0029] In another embodiment, an ingestionable device is provided herein, comprising an expandable member and a delivery assembly described herein coupled to the expandable member. In some embodiments, the device further includes a gas generating mechanism coupled to the expandable member. In some embodiments, the gas generating mechanism is configured to generate gas to expand the expandable member at a location within the target GI tubule, thereby oriented and positioning the delivery assembly relative to the GI lumen wall. In some embodiments, the location is the target small intestine. In some embodiments, the gas generating mechanism includes a plurality of reactants separated from each other by a biodegradable release. In some embodiments, upon expansion of the expandable member, the delivery assembly is configured to deliver a dosage form through the GI lumen wall into the target peritoneum or peritoneal cavity for systemic uptake of at least one therapeutic agent. In some embodiments, upon expansion of the expandable member, the delivery assembly is configured to deliver a dosage form into a layer of the GI lumen wall for systemic uptake of at least one therapeutic agent. In some embodiments, the expandable member includes a balloon. In some embodiments, the device further includes an ingestible enclosure, and an expandable member and a delivery assembly are disposed within the ingestible enclosure. In some embodiments, the ingestible enclosure includes a biodegradable material that allows for the decomposition of at least a portion of the ingestible enclosure within the GI tube. In some embodiments, the device further includes a coating disposed on at least a portion of the ingestible enclosure. The coating is configured to decompose at a selected pH within the GI tube. In some embodiments, the ingestible enclosure is a swallowable capsule of size 00 or size 000.

[0030] In another embodiment, a method is provided herein for preparing an ingestible device for delivering a therapeutic agent into the luminal wall or surrounding tissue of a target GI, the method comprising filling a dosage form containing the therapeutic agent into a payload delivery module as described herein.

[0031] In another embodiment, a method is provided herein for delivering a therapeutic agent into the luminal wall or surrounding tissue of a subject in need of the therapeutic agent, the method comprising the subject ingesting an ingestible device as described herein.

[0032] In another embodiment, a method for delivering one or more therapeutic agents to a patient in need by swallowing an ingestible device described herein is provided herein. Similarly, in some embodiments, the use of an ingestible device described herein for delivering one or more therapeutic agents to a patient in need by swallowing the ingestible device is provided herein. In some embodiments, at least one therapeutic agent comprises a therapeutically effective dose of the therapeutic agent in liquid form. Upon swallowing the device, an expandable member expands within the patient's GI duct, thereby delivering a therapeutically effective dose of the therapeutic agent into the luminal wall or surrounding tissue of the GI duct. In some embodiments, at least one therapeutic agent comprises a therapeutically effective dose of an oligonucleotide. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises MALAT1 ASO. In some embodiments, at least one therapeutic agent comprises a therapeutically effective dose of a TNF-α inhibitory antibody. In some embodiments, the TNF-α inhibitory antibody comprises adalimumab. In some embodiments, adalimumab is HUMIRA® or its biosimilar. In some embodiments, the therapeutically effective dose of adalimumab is about 3 to 11 mg. In some embodiments, at least one therapeutic agent contains a therapeutically effective dose of an anti-interleukin antibody. In some embodiments, the anti-interleukin antibody targets interleukin 4 and interleukin 13. In some embodiments, the anti-interleukin antibody contains dupilumab. In some embodiments, dupilumab is DUPIXENT® or its biosimilar. In some embodiments, the therapeutically effective dose of dupilumab is about 16 to 30 mg. In some embodiments, the therapeutically effective dose of dupilumab is about 20 to 25 mg. In some embodiments, the anti-interleukin antibody targets at least one of interleukin 12 or interleukin 23. In some embodiments, the anti-interleukin antibody contains ustekinumab. In some embodiments, ustekinumab is STELARA® or its biosimilar.In some embodiments, the therapeutically effective dose of anti-interleukin antibody delivered to the patient results in a bioavailability in the patient that is substantially the same as that of a subcutaneous dose of anti-interleukin antibody. In some embodiments, the therapeutically effective dose of anti-interleukin antibody delivered to the patient results in a bioavailability in the patient that is higher than that of a subcutaneous dose of anti-interleukin antibody. In some embodiments, the therapeutically effective dose of anti-interleukin antibody delivered to the patient results in a bioavailability in the patient that is C of that of a subcutaneous dose of anti-interleukin antibody. max Exceeding C max This results in a therapeutically effective dose of anti-interleukin antibody delivered to the patient, which is equivalent to the subcutaneous dose of anti-interleukin antibody in the patient. max t is less than max In some embodiments, the therapeutic agent comprises at least one incretin in a therapeutically effective dose. In some embodiments, the at least one incretin is an incretin triagonist comprising GLP-1, GIP, and a glucagon receptor agonist. In some embodiments, the therapeutically effective dose of the incretin triagonist delivered to the patient results in a weight loss in the patient that is substantially the same as the weight loss produced by a subcutaneous dose of the incretin triagonist.

[0033] In another embodiment, a modular delivery assembly for an ingestible device for delivering a dosage form into the lumen wall or surrounding tissue of a target GI includes a housing having a proximal end, a distal end, and an interior located between the proximal and distal ends. The proximal end includes a first opening for receiving force into the interior. The distal end includes a second opening for discharging the dosage form. The interior includes a receptacle configured to receive a module selected from a first payload delivery module containing a fluid dosage form and a second payload delivery module containing a solid dosage form. The housing further includes a release feature for releasably coupling the module to the housing. In some embodiments, the first payload delivery module has a first delivery mode, and the second payload delivery module has a second delivery mode different from the first delivery mode. In some embodiments, the first delivery mode includes inserting a hollow needle into the lumen wall or surrounding tissue of the GI and discharging a fluid dosage form through the hollow needle into the lumen wall or surrounding tissue of the GI. In some embodiments, the second delivery mode includes ejecting the solid dosage form as a projectile from a second payload delivery module into the GI lumen wall or surrounding tissue.

[0034] In another embodiment, a delivery assembly for an ingestible device includes a housing and a payload delivery module. The housing includes a proximal end, a distal end, a piston chamber located between the proximal and distal ends, and a release feature. The proximal end includes a first opening for receiving force internally, and the distal end includes a second opening for discharging the dosage form. The payload delivery module is disposed within the housing and includes a piston and a dosage form comprising at least one therapeutic agent. The piston is releasably coupled to the release feature and configured to move axially within the piston chamber between the proximal and distal ends in response to a force discharging the dosage form from the housing.

[0035] In another embodiment, the ingestible device includes an expandable member and a delivery assembly as described herein, coupled to the expandable member. The delivery assembly contains a fluid dosage form comprising at least one therapeutic agent. The expandable member is configured to expand within the target GI tubule to position the delivery assembly relative to the GI lumen wall. Upon expansion of the expandable member, the delivery assembly is configured to deliver the fluid dosage form through the GI lumen wall into the target peritoneum or peritoneal cavity for systemic uptake of at least one therapeutic agent.

[0036] In another embodiment, the ingestionable device includes a housing, a piston, a hollow needle, a fluid dosage form, and a force generating mechanism. The piston is movably disposed within the housing. The hollow needle is coupled to the piston. The fluid dosage form is disposed within the housing and contains at least one therapeutic agent. The force generating mechanism is operably coupled to the piston. In some embodiments, the hollow needle has a critical length in the range of about 3.5 to 12 mm such that, upon ingestion of the device, the hollow needle is configured to deliver the fluid dosage form through the GI lumen wall into the peritoneal cavity of the subject for systemic uptake of at least one therapeutic agent. In some embodiments, the hollow needle has a critical length in the range of about 1.5 to 3 mm such that, upon ingestion of the device, the hollow needle is configured to deliver the fluid dosage form into the layers of the GI lumen wall for systemic uptake of at least one therapeutic agent.

[0037] The above general description and the following detailed description are provided as examples and are intended to provide further explanation without limitation. Other purposes, advantages, and novel features will be readily apparent to those skilled in the art from the following brief and detailed descriptions of the drawings. [Brief explanation of the drawing]

[0038] [Figure 1] This is a cross-sectional view of an example of an ingestible device that includes a modular delivery assembly that can incorporate different delivery mechanisms. [Figure 2]This is a partial cross-sectional view illustrating an example of an ingestible device in a folded state, as shown in Figure 1, which is placed inside a swallowable capsule. [Figure 3] Figure 1 is a cross-sectional view of an exemplary modular housing for an ingestible device. [Figure 4] Figure 1 is an exploded view of two different modular arrangements of a modular delivery assembly for an ingestible device. [Figure 5] Figure 1 is a partial cross-sectional view of an example of an ingestible device, including a first payload delivery module having a fluid dosage form. [Figure 6] This is a partial cross-sectional view of the device in Figure 5, in the second state when the fluid dosage form is discharged from the device. [Figure 7] This is a partial cross-sectional view of another example of the ingestible device of Figure 1, including another version of the first payload delivery module having a different valve arrangement. [Figure 8] This is a partial cross-sectional view of the device in Figure 7, in the second state when the fluid dosage form is discharged from the device. [Figure 9] This is a partial cross-sectional view of another example of the ingestible device of Figure 1, including yet another version of the first payload delivery module having a different valve arrangement. [Figure 10] This is a partial cross-sectional view of the device in Figure 9, in the second state when the fluid dosage form is discharged from the device. [Figure 11] This is a partial cross-sectional view of another example of the ingestible device shown in Figure 1, including yet another version of the first payload delivery module. [Figure 12] Figure 11 is a perspective view of the delivery assembly of an ingestible device. [Figure 13] This is a partial cross-sectional view of the payload delivery module of the device shown in Figure 11, before it is filled with a fluid formulation. [Figure 14] This is a partial cross-sectional view of the payload delivery module in Figure 13 after it has been filled with a fluid formulation. [Figure 15] Figure 13 is an exploded view of the payload delivery module. [Figure 16-19] Figure 11 illustrates the operating sequence of the device in a target GI tube for delivering a fluid dosage form into the GI lumen wall or surrounding tissue. [Figure 20] This is a partial cross-sectional view of another example of the ingestible device shown in Figure 1, including yet another version of the first payload delivery module. [Figure 21-22] An example of a needle for delivering a fluid dosage form is shown. [Figure 23-24] Another example of a needle for delivering a fluid dosage form is illustrated. [Figure 25-27] This illustrates an exemplary method for filling a payload delivery module with a fluid formulation. [Figure 28] This is a partial cross-sectional view of another example of the ingestible device shown in Figure 1, which includes a second payload delivery module having a solid dosage form. [Figure 29] This is a partial cross-sectional view of the device in Figure 28, in the second state when the solid dosage form is discharged from the device. [Figure 30] Figure 28 is a partial cross-sectional view of an exemplary delivery assembly having different housings for receiving the second payload delivery module. [Figure 31] This is a block diagram illustrating an exemplary method of delivering a dosage form from an ingestible device as described herein. [Figure 32] The plasma concentration-time curves obtained after administration of a single dose of lung adenocarcinoma metastasis-associated transcript 1 antisense oligonucleotide (MALAT1 ASO) in a canine study are shown (0.5 mg / kg MALAT1 ASO by intrajejunal injection mimicking oral delivery via the ingestible device described herein, or 0.5 mg / kg MALAT1 ASO by subcutaneous injection). [Figure 33]The following are plasma concentration-time curves obtained after a single dose of adalimumab in a canine study (11 mg of liquid adalimumab orally administered to four awake dogs via an ingestible device as described herein, or 4.5 mg of solid adalimumab orally administered to two awake dogs via an ingestible device configured to deliver its payload to the GI lumen wall or surrounding tissue, or 5 mg of liquid adalimumab administered to three dogs via subcutaneous injection). [Figure 34] The plasma concentration-time curves obtained after a single dose of dupilumab in a canine study are shown (16.5 mg or 30 mg doses of liquid dupilumab orally administered to six awake dogs via the ingestible device described herein, or 16.5 mg or 30 mg doses of liquid dupilumab subcutaneously administered to three dogs, respectively). [Figure 35] The images show the time course of body weight obtained after administration of a single dose of incretin triagonist in a canine study (0.12 mg / kg dose of RTJH23 incretin triagonist administered by intrajejunal injection to mimic oral delivery via the ingestible device described herein, or 0.12 mg / kg by subcutaneous injection). [Figure 36] Figure 35 shows the peak reduction in body weight and serum lipids from the same canine study. [Figure 37] The plasma concentration-time curves obtained after a single dose of ustekinumab in a canine study are shown (18 mg ustekinumab in liquid form administered orally to four awake dogs via an ingestable device as described herein, or 18 mg ustekinumab in liquid form administered subcutaneously to three dogs). [Modes for carrying out the invention]

[0039] Before discussing the details of the devices, assemblies, and methods of this disclosure, we provide some rules for the convenience of the reader.

[0040] Where used in this disclosure, the terms “e.g.,” “such as,” “for example,” “for example,” “for another example,” “example,” “as an example,” and “etc.” indicate that they precede or follow a list of one or more non-limiting examples, and it should be understood that other examples not listed are also within the scope of the invention.

[0041] As used herein, the singular terms “a,” “an,” and “the” may refer to multiple objects unless the context makes this clear. References to singular objects are not intended to mean “only,” but rather “one or more,” unless explicitly stated otherwise.

[0042] As used herein, a phrase in the form of "A / B" or "A and / or B" means (A), (B), or (A and B), and a phrase in the form of "at least one of A, B, or C" means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B and C).

[0043] The phrase "in an embodiment" or its variations (e.g., "in another embodiment" or "in one embodiment") is used herein to mean "in one or more embodiments" and in no event is the scope of this disclosure limited to the embodiments illustrated and / or described herein. Accordingly, components illustrated and / or described herein with respect to embodiments may be omitted or used in another embodiment (e.g., another embodiment illustrated and described herein, or another embodiment within the scope of this disclosure that is not illustrated and / or described herein).

[0044] The term “component” as used herein refers to one item from a set of one or more items that together constitute a device, composition, or system under consideration. A component may be a solid, powder, gel, plasma, fluid, gas, or other form. For example, a device may include several solid components assembled together to constitute the device, and further include fluid components placed within the device. Another example is a composition which may include a single component or two or more components mixed together to produce the composition. A composition may be in the form of a fluid, slurry, powder, or solid (e.g., a condensed or solidified form such as a tablet or micropill). A device or system may include one or more compositions and / or one or more other components.

[0045] The term “design” or its grammatical variations (e.g., “design” or “designed”) in this specification refers to properties intentionally incorporated based on, for example, estimated tolerances (e.g., component tolerances and / or manufacturing tolerances) and expected environmental conditions to be encountered (e.g., temperature, humidity, external or internal ambient pressure, external or internal mechanical pressure, stress due to external or internal mechanical pressure, product age, or shelf life, or, if introduced into the body, physiology, body chemistry, biological composition of body fluids or tissues, chemical composition of body fluids or tissues, pH, species, diet, health, sex, age, ancestry, disease, or tissue damage). It should be understood that different components, devices, compositions, or systems of the same design may have different actual values ​​with respect to their properties, as actual tolerances and environmental conditions before and / or after delivery may affect the properties. Design also includes deformation or modification before or after manufacturing.

[0046] The term “composed” or its grammatical variations (e.g., “structure” or “composition”) in this specification means a component, device, composition, or system manufactured in accordance with a concept or design, or a variation thereof, or a modification thereof (whether such change or modification occurs before, during, or after manufacture), regardless of whether such concept or design is incorporated into the document.

[0047] The term "body" in this specification refers to the body of an animal unless the context explicitly indicates otherwise.

[0048] The term “Subject” as used herein refers to a body to which or intended to be served by embodiments of this disclosure. For example, with respect to a human, the subject may be a patient receiving treatment from a medical professional. The terms “individual,” “subject,” and “patient” are used herein synonymously and may refer to any individual animal subject (e.g., a cow, a dog, a cat, a horse, or a human). In particular embodiments, the subject, individual, or patient is a human.

[0049] The term "fluid" as used herein refers to a liquid or gas, including moisture and humidity, unless the context indicates otherwise. The term "fluid environment" as used herein refers to an environment in which one or more fluids are present.

[0050] The term "ingest" or its grammatical variations (e.g., "ingesting," "ingestion," or "ingested") as used herein refers to taking something into the stomach, whether by swallowing or by other means of placement in the stomach (e.g., by placement in the stomach via an endoscope or via a port).

[0051] The term “degrade” or its grammatical variations (e.g., “degrading,” “degraded,” “degradable,” and “degradation”) as used herein means weakening by dissolution, chemical degradation, partial degradation, or complete degradation (including biodegradation), decomposition, chemical modification, mechanical degradation, or disintegration, including but not limited to dissolution, disintegration, deformation, deflation, or shrinkage. The term “non-degradable” means the expectation that degradation will be minimal or within a certain acceptable design percentage, at least over the expected period in the expected environment.

[0052] The term “degradation rate” or its grammatical variation (e.g., “rate of degradation”) refers herein to the rate at which a material degrades. The designed degradation rate of a material in a particular embodiment may be defined by the rate at which the material is expected to degrade under anticipated conditions (e.g., physiological conditions) at the target delivery site. The designed degradation time for a particular implementation may refer to the designed time to complete degradation, or the designed time to achieve sufficient partial degradation to accomplish the design objective (e.g., tearing). Therefore, for example, the designed degradation time may be specific to the components and / or specific to the anticipated conditions at the target delivery site. The designed degradation time may be short or long and may be defined in terms of approximate time, maximum time, or minimum time.

[0053] The terms “substantially,” “approximately,” and similar terms are used herein to describe and take into account, for example, small variations that may result from the manufacturing or assembly process. For example, when used in conjunction with numerical values, the terms refer to variations of values ​​of ±10% or less.

[0054] In this specification, the term "lumen" refers to the internal space of a tubular structure. Examples of lumens in the body include arteries, veins, and tubular cavities within organs.

[0055] The term "luminal wall" refers to the wall of a lumen, where the wall includes all layers from the inner to the outer periphery of the lumen, such as the mucosa, submucosa, muscular layer, serosal membrane, and outer wall of the lumen, along with the constituent blood vessels and tissues.

[0056] The terms “gastrointestinal tract” or “GI tract” are used herein to mean the intake / excretion system of the body, including, for example, the mouth, pharynx, esophagus, stomach, pylorus, small intestine, cecum, large intestine, colon, rectum, anus, and the valves or sphincters between them.

[0057] The term "GI lumen" generally refers to the lumen of any of the GI ducts (e.g., the lumen of the esophagus, stomach, small intestine, large intestine, or colon), while the term "GI lumen wall" refers to the lumen wall of the GI lumen.

[0058] As used herein, the terms “comprising,” “comprise,” “comprises,” “includes,” and “including” are intended to mean that a composition and method includes the elements listed, but does not exclude others.

[0059] Referring generally to the figures, embodiments of ingestible devices, assemblies, and methods for autonomously delivering a dosage form containing one or more therapeutic agents to the luminal wall or surrounding tissue of a target GI (e.g., the peritoneum or peritoneal cavity). In some embodiments, the devices and assemblies disclosed herein may have a modular design that allows different delivery mechanisms to be incorporated in different delivery modes to enable the delivery of different dosage forms and doses using interchangeable components on the same device platform. In this way, the devices and assemblies disclosed herein enable the use of a common device platform to deliver a wide range of therapeutic agents orally to address most treatment regimens.

[0060] Disclosed herein are ingestible devices, payload delivery modules, delivery assemblies, methods for manufacturing the same, and methods and uses thereof, for delivering one or more therapeutic agents that are advantageous in one or more respects over existing ingestible drug delivery devices.

[0061] According to non-limiting examples of this disclosure, an ingestionable device includes an expandable member and a delivery assembly coupled to the expandable member. The delivery assembly may include a modular housing advantageously configured to incorporate different payload delivery modules for oral delivery of different dosage forms and / or doses.

[0062] For example, in a first configuration, the delivery assembly may include a first payload delivery module comprising a piston for containing a fluid dosage form and a hollow needle coupled to the piston. The piston is disposed within a housing and can be releasably coupled to a release feature or trigger defined by the housing and the piston. After ingestion by the ingestible device, the expandable member can be expanded at a desired location within the target GI tubule for delivery of the fluid dosage form. During the expansion of the expandable member within the GI lumen, the piston is released from the release feature and moves within the housing, allowing the hollow needle to be inserted into the GI lumen wall or surrounding tissue. As described herein, the expansion of the expandable member can also provide the force necessary to expel the fluid dosage form through the hollow needle into the GI lumen wall or surrounding tissue for systemic uptake of the therapeutic agent contained in the fluid dosage form.

[0063] In a second configuration, distinct from the first, the delivery assembly may alternatively include a second payload delivery module comprising a piston and a cartridge containing a solid dosage form. The piston may have a different structure from the piston used in the first payload delivery module. However, the piston in this configuration may be housed within the same housing discussed above and may be releasably coupled to the housing via the same release feature or trigger arrangement. The cartridge may also be coupled to and housed within the same housing.

[0064] In other examples, the housing may have a different structure to accommodate a cartridge for the delivery of a solid dosage form, but may include the same release features or trigger arrangements as the first configuration discussed above to allow use with the same expandable member.

[0065] In other examples, the housing may have a different trigger arrangement but be coupled to the same expandable member and have the same operating sequence as the first configuration.

[0066] In yet another example, the second payload delivery module may be substantially the same as the first payload delivery module, but the piston may be configured to accommodate fluid dosage forms of different volumes to provide administration flexibility.

[0067] In any of the above configurations, the device can be configured to deliver the dosage form using substantially the same operating mechanism and operating sequence.

[0068] For example, after ingestion of an ingestible device, the expandable component can expand at a desired location within the target GI tubule for the delivery of a solid dosage form. During the expansion of the expandable component within the GI lumen, the piston can be released from its release feature in the same manner as the first payload delivery module discussed above, move within the housing, and eject the solid dosage form as a projectile from the cartridge into the target GI lumen wall or surrounding tissue. The solid dosage form may decompose within the GI lumen wall or surrounding tissue, releasing the therapeutic agent for systemic uptake.

[0069] In this way, the disclosed ingestible devices can autonomously deliver different dosage forms and / or doses from different delivery mechanisms using a common device platform.

[0070] As discussed below, the disclosed devices and assemblies can deliver (topically or systemically) various different types of therapeutic agents, such as biologics containing macromolecules that are typically unsuitable for delivery by ingestion to a subject. The disclosed devices and assemblies are advantageously configured to deliver different dosage forms that may contain different types of therapeutic agents, regardless of molecular size or weight, including small molecules, antivirals, anti-infective agents, peptides, polypeptides, proteins, hormones, antibodies, and nucleic acids. For example, without limitation, the devices and assemblies disclosed herein include immunosuppressants (e.g., adalimumab, ustekinumab), chemotherapeutic agents, central nervous system (CNS) drugs (e.g., antiparkinsonian agents, antiemetics), antidiabetic agents, enzyme replacement therapy (ERT) agents, PD-L1 agents, CNP agents, antibodies (e.g., nanobodies, monoclonal antibodies, anti-TNFα antibodies, anti-interleukin antibodies (e.g., targeting one or more of IL-1-36 such as IL-2, IL-4, IL-12, IL-13, IL-17, IL-23), anti-PCSK9 antibodies, anti-TL1A antibodies, antibody-drug conjugates (ADCs), bispecific antibodies, and their analogues), hormones (e.g., parathyroid hormone (PTH), follicle-stimulating hormone (FSH), human growth hormone (HGH), amylin, and their analogues), anticoagulants or blood coagulation factors (e.g., One or more therapeutic agents can be delivered, such as factor VIII, factor XI, factor X, or their mimics), insulin, incretins, or combinations thereof (e.g., one or more of the following: glucagon-like peptides (e.g., GLP-1, GLP-2), gastric suppressor peptide (GIP), glucagon, glucagon receptor (GCGR), peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), GIP receptor (GIPR), and their mimics), oligonucleotides (e.g., antisense oligonucleotides (ASOs), RNA interference (RNAi), aptamer RNA), DNA or siRNA transcripts, cells, cytotoxic agents, vaccines or other prophylactic agents, nutritional supplements, vasodilators or vasoconstrictors, delivery accelerators, delayers, excipients, diagnostic agents, or substances for cosmetic enhancement.

[0071] The disclosed ingestible devices and assemblies can be used to autonomously deliver dosage forms containing one or more therapeutic agents to provide treatment for several medical conditions and diseases. Examples of medical conditions and diseases that can be treated include, without limitation, cancer (lung cancer, pancreatic cancer, cervical cancer, gastric cancer, breast cancer, glioblastoma, colorectal cancer, multiple myeloma, leukemia, lymphoma, carcinoma, and melanoma), neutropenia, multiple sclerosis (MS), HIV, short bowel syndrome, mucopolysaccharidosis, hormonal disorders (e.g., hypothyroidism / hyperthyroidism, growth hormone disorders, infertility), osteoporosis, metabolic disorders (including hypertension, high cholesterol and triglycerides, diabetes and other glucose dysregulation, and weight disorders (e.g., obesity)), infections (focal or sepsis), epilepsy and other seizure disorders, CNS disorders (e.g., migraine prevention), coronary artery disease. Other conditions may include arterial arrhythmias (both atrial and ventricular), coronary ischemia, anemia, various autoimmune disorders (including multiple sclerosis, Guillain-Barré syndrome, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, hidradenitis suppurativa, juvenile idiopathic arthritis, uveitis, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and lupus), allergic diseases (e.g., eczema, asthma, and chronic sinusitis with nasal polyps), eosinophilic esophagitis, nodular prurigo, coagulation disorders (e.g., hemophilia, von Willebrand disease, coagulation factor deficiencies, hypercoagulable states, and deep vein thrombosis), and other conditions.

[0072] A non-limiting list of specific therapeutic agents, approved dosages, and associated indications that can be treated using the disclosed ingestible devices is provided in Table 1 below. Generally speaking, but not limited to, listed therapeutic agents with a daily equivalent dose of less than approximately 5 mg may be recomposed into solid dosage forms for delivery using the ingestible devices described herein, which are adapted for solid dosage form delivery. Listed therapeutic agents with a daily equivalent dose of less than approximately 60 mg may be delivered as liquid dosage forms without requiring recomposition using the ingestible devices described herein, which are adapted for fluid dosage form delivery.

[0073] The fluid dosage forms discussed herein may include liquids, slurries, gels, suspensions (including colloidal suspensions), gases, powders, or any combination thereof. The devices and assemblies of this disclosure can deliver fluid dosage forms used or approved for parenteral administration (e.g., subcutaneous, intravenous, or intraperitoneal injection) without requiring the recomposition or modification of the fluid dosage form.

[0074] The solid dosage forms discussed herein may include tablets, microneedles, slags, or compositions in other forms. For example, a solid dosage form may be formed by compressing a lyophilized powder containing one or more therapeutic agents and one or more additional components (e.g., excipients, binders, preservatives, lubricants). The compression process may be carried out in such a manner that substantially preserves the biological activity of the active therapeutic agent in the compressed solid dosage form. Examples of suitable solid dosage forms and associated forming processes are described in U.S. Patent No. 10,098,931 (and its related sub-applications), entitled "Pharmaceutical Compositions and Methods for Fabrication of Solid Masses Comprising Immunoglobulins," the entire contents of which are incorporated herein by reference.

[0075] In one or more embodiments, the solid dosage form may include a separate biodegradable structure for insertion into the GI lumen wall or surrounding tissue, which may degrade in vivo to release one or more therapeutic agents contained within. For example, the biodegradable structure may have a needle, arrow, hook, or other tapered / pointed structure sufficient to penetrate the GI lumen wall or surrounding tissue. The biodegradable structure may further define a cavity or reservoir for containing a compressed tablet or other composition (e.g., gel, liquid) containing the therapeutic agent for delivery into the GI lumen wall or surrounding tissue.

[0076] As will be described in more detail below, the disclosed devices and assemblies may be configured to deliver a dosage form into or through the layers of the GI lumen wall into the peritoneum or surrounding tissues such as the peritoneal cavity of the target. Oral delivery into the peritoneal space may be particularly advantageous for the efficient uptake of various therapeutic agents, such as CNS drugs, immunosuppressants, oligonucleotides, antibodies, hormones, blood clotting factors, and many other types of therapeutic agents, as described herein in Table 1, while avoiding the pain and inconvenience associated with parenteral administration.

[0077] Figure 1 illustrates an example of an ingestible device 100 according to one or more embodiments of the present disclosure. The device 100 includes an expandable member in the form of a balloon 102 and a delivery assembly 104 coupled to the balloon 102. In other examples, the device 100 may include an expandable member in the form of an accordion-shaped structure, a foldable wing, a patch, or other expandable structure.

[0078] However, it should be understood that the embodiments of the delivery assembly 104 and payload delivery module described herein may be used with or otherwise incorporated into a variety of other different device configurations not described herein. For example, embodiments of the delivery assembly 104 may be directly incorporated into a swallowable capsule, endoscope, or other ingestible enclosure, which may include a force generating mechanism operationally coupled to the delivery assembly 104. The force generating mechanism may include one or more of a spring, a gas generating mechanism, or other mechanisms for generating force within the ingestible enclosure. The generated force may be used to actuate the delivery assembly 104 to deliver the dosage form into the GI lumen wall or surrounding tissue through one or more openings within the enclosure. The openings may be temporarily covered by a coating, plug, shell, or other structure that can be disassembled in response to the conditions within the GI tube to reveal the opening in the presence of GI fluid or in response to a specific pH within the GI tube (e.g., pH in the small intestine).

[0079] As described herein, in one or more embodiments, the delivery assembly 104 may have a modular design consisting of common release features or triggers that allow for the incorporation of different payload delivery modules 106 (Schematically shown in Figure 1) for oral delivery of different dosage forms and / or doses into the GI lumen wall or surrounding tissue of a target after ingestion of the device 100. Each of the different payload delivery modules 106 may have a different delivery mode to provide design flexibility and facilitate delivery of different dosage forms and doses.

[0080] As shown in Figure 1, device 100 is in an unfolded state, but it should be understood that device 100 can be folded (e.g., rolled up, flattened, twisted) to fit into an ingestible enclosure for easier ingestion of device 100. For example, the ingestible enclosure may include a swallowable capsule (e.g., size 00, size 000, or other size capsules), an endoscope, or other enclosure suitable for ingestion by the subject.

[0081] Figure 2 illustrates a device 100 housed in an ingestible enclosure, shown as a folded, swallowable capsule 200, as an example. The capsule 200 includes an optional outer coating 202 housed on at least the outer portion of the capsule 200. The enclosure 200 and the outer coating 202, if present, are configured to allow ingestion of the device 100 and to temporarily protect the contents of the device 100 from disintegration within one or more portions of the target GI tube. As shown in Figure 2, the capsule 200 includes a first section 200a that at least partially overlaps a second section 200b in a press-fit configuration to define the capsule 200. The first and second sections 200a, 200b may be removably joined together to allow separation of the two sections.

[0082] In one or more embodiments, the capsule 200 can be degraded under certain conditions. Furthermore, different parts of the capsule 200 may be configured to degrade under different conditions or at different rates depending on the target site in the GI tube for delivering the dosage form. For example, part or all of the capsule 200 may be constructed of a material that degrades in water (e.g., in the presence of water in the form of humidity or moisture in the surrounding environment, such as inside the body) and / or when exposed to a pH level above a certain threshold or within a certain range (e.g., a pH level associated with a desired location or part of the GI tube, such as a pH level associated with a target site in the GI tube for delivering the dosage form (e.g., stomach, small intestine)). For example, the capsule 200 may be formed from or contain hydroxypropyl methylcellulose (HPMC) or other biodegradable materials or combinations of materials.

[0083] An optional outer coating 202 optionally covers part or all of the capsule 200. The outer coating 202 may consist of one or more layers. The various layers may be formed of the same or different materials. In one or more embodiments, the outer coating 202 may decompose under certain conditions, as described above with reference to the enclosure 200. An example of the outer coating 202 is an enteric coating, such as an enteric coating that decomposes and / or decomposes in water at a given rate when exposed to a solution having a pH level above a certain threshold or within a certain range. Another example of the outer coating 202 is a protective coating (e.g., wax), such as a coating that protects a portion of the outer surface of the capsule 200 from contact with fluids or tissues (e.g., body tissues or bodily fluids).

[0084] In one or more embodiments, the disintegration of the capsule 200 and / or the outer coating 202, if present, may allow fluid (e.g., gastric or intestinal fluid) to enter the capsule 200 and expand the balloon 102, as described in further detail herein. The capsule 200 and / or the outer coating 202 may, if present, define one or more disintegration areas for local disintegration, for example, to enable controlled disintegration and separation of the capsule 200. For example, the outer coating 202 may be selectively applied to only a specific area of ​​the capsule 200 (e.g., on the hemispherical ends of the capsule 200) to expose a selected portion of the capsule 200 (e.g., the middle portion of the capsule 200 between the ends), thereby defining an area of ​​the capsule 200 that can disintegrate and / or disintegrate faster than other areas of the capsule 200. This controlled disintegration of the capsule 200 may enable more consistent separation of the capsule 200 from the GI lumen, thereby enabling the delivery of various dosage forms into the GI lumen wall or surrounding tissue.

[0085] Referring again to Figure 1, the balloon 102 is a flexible and adjustable structure that can expand from a contracted state (e.g., folded) to an expanded state within a desired location in the target GI tube for delivery of a dosage form into the GI lumen wall or surrounding tissue. The balloon may be a monolithic structure or may consist of one or more sections joined together (e.g., sealed). The balloon 102 may be formed from or comprise one or more layers of material, such as a sheet-like material. Suitable materials for the balloon 102 may include, for example, hydroxypropyl methylcellulose (HPMC), polyvinyl acetate (PVA), polyethylene, lactide, glycolide, lactic acid, glycolic acid, paldioxanone, trimethylene carbonate, caprolactone, and mixtures and copolymers thereof.

[0086] As shown in Figure 1, the balloon 102 includes an inflator section 102a, a deflator section 102b, a lower section 102c, and an elongated section 102d extending between the inflator section 102a and the deflator section 102b. The lower section 102c extends downward (in the orientation shown in Figure 1) between the inflator section 102a and the deflator section 102b. The various sections of the balloon 102 collaboratively define a sealed interior 102e for housing various components of the device 100. As will be discussed below, the balloon 102 is configured to inflate at a desired location within the lumen of a GI tube (e.g., stomach, small intestine, large intestine) in response to a gas pressure generated within the interior 102e via a gas generation mechanism coupled to the balloon interior 102e.

[0087] The balloon 102 and the gas generation mechanism can collaboratively define the expandable component assembly of the device 100. In this way, and as described herein, the balloon 102 can facilitate the delivery of different dosage forms and doses from the delivery assembly 104 to the GI lumen wall or surrounding tissue.

[0088] In other examples, the balloon 102, or other expandable member, may be self-expandable (e.g., using a spring held in a compressed position or a shape memory material such as a wireframe structure), or may include a separate force generating mechanism for causing expansion. For example, the force generating mechanism may include one or a combination of a gas generating mechanism, a hydrogel, a pre-pressurized (e.g., compressed) spring, a flammable material (e.g., nitrocellulose), or other mechanisms configured to generate a force sufficient to cause the balloon 102 to expand within the GI tube of the subject.

[0089] The balloon 102 has a size and shape that occupies space within the GI lumen when the balloon 102 is inflated, and helps to facilitate the delivery of the dosage form into the GI lumen wall or surrounding tissue. For example, when the balloon 102 is inflated within the GI lumen, the outer circumference of the balloon 102 (e.g., the outer circumference of the lower section 102c and the elongated section 102d) presses against the surface of the lumen wall. The pressure exerted by the balloon 102 is sufficient to temporarily hold the balloon 102 (and consequently the delivery assembly 104) against the lumen wall for the delivery of the dosage form. Depending on the inner circumference of the lumen delivery site, the lower section 102c may remain partially folded when the balloon 102 is inflated, or it may be fully extended. For example, if the lumen is relatively large and there are no obstacles resisting the expansion of the balloon 102, the balloon 102 will assume a fully inflated configuration with the lower section 102d fully extended (as shown in Figure 1). However, if the lumen is relatively small, such that the circumference of the inner lumen is less than the maximum dimension of the fully inflated balloon 102, the lower section 106 remains partially folded. In this way, the balloon 102 can self-adjust to the size of the GI lumen to hold the balloon 102 in place for dosage form delivery, so that the same balloon 102 can be used for a wide range of GI lumen sizes (e.g., different inner circumferences).

[0090] The balloon 102 includes a deflation valve 112 configured to cause the balloon 102 to deflate once it has completed delivery of the dosage form into the GI lumen wall or surrounding tissue. In this way, the deflation valve 112 can facilitate the balloon 102 passing through the rest of the GI tube and exiting the target anus. In the example shown, the deflation valve 112 is configured as a detachable plug that temporarily covers the opening leading to the interior 102e. The detachable plug may be configured to decompose in response to contact with fluid (e.g., body fluid) in the GI tube, thereby allowing the gas contained in the interior 102e to exit through the opening. For example, the deflation valve 112 may be formed from or contain an enteric-coated material. The balloon 102 may include an optional flap 128 that temporarily covers the deflation valve 112 until the balloon 102 inflates, thereby preventing premature action (e.g., decomposition) of the deflation valve 112. For example, the flap 228 can be temporarily held in a folded position 128' around the flap folding axis 128a (e.g., by being glued, tucked, or otherwise held). The expansion of the balloon 102 can unfold the flap 128 from the folded position 128', exposing the deflation valve 112, allowing the fluid in the GI tube to reach the deflation valve 112 and cause its disintegration, thereby providing an opening for gas to be released and for deflation to occur.

[0091] Although the deflation valve 112 is shown located on the deflator section 102b, the deflation valve 112 may be located elsewhere on the balloon 102 according to other embodiments. Furthermore, the balloon 102 may include two or more deflation valves 112. The deflation valve 112 may be configured differently from the example shown in Figure 1. For example, in other embodiments, the deflation valve 112 may be configured as a disassembled and / or movable cover disposed over the opening of the balloon 102. In these embodiments, disassembly and / or movement of the cover away from the opening can allow gas to be released from the interior 102e through the opening, thereby enabling deflation.

[0092] The balloon 102 further includes a gas generation mechanism comprising a reactant reservoir 114, which is disposed within or otherwise coupled to the balloon interior 102e. The reactant reservoir 114 is configured to hold a first reactant 115 therein and to temporarily prevent the first reactant 115 from coming into contact with a second reactant 117, which is separately disposed within the balloon interior 102e. The first reactant 115 may be, for example, citric acid. The second reactant 117 may be, for example, a carbonate such as potassium bicarbonate. In other examples, the first reactant 115 and the second reactant 117 may be other types of reactants (e.g., acids and bases) that, when mixed, result in the formation of a gas sufficient to inflate the balloon 102. The second reactant 117 is shown disposed within the balloon interior 102e in an inflator section 104 near the first reactant 115. In other examples, the first reactant 115 and the second reactant 117 may be contained within other areas of the balloon 102, as long as they are temporarily separated from each other.

[0093] In other examples, balloon 102 may include different types of gas generation mechanisms, such as pressurized gas containers (e.g., carbon dioxide (CO2) cartridges), or other types of gas generation mechanisms that can be disposed within balloon 102 or other expandable members, or otherwise coupled (e.g., fluid coupling).

[0094] Still referring to Figure 1, the reactant reservoir 114 defines an internal volume for containing the first reactant 115. The reactant reservoir 114 can take various different forms and shapes, such as a balloon, bladder, container, or other structure. The reactant reservoir 114 may contain or be formed from a flexible polymer material to allow elastic deformation. The reactant reservoir 114 is selectively fluid-communicated with the inside of the balloon 102e via reactant conduits 118 and releases 116. The releases 116 are coupled to the reactant conduits 118 on the outer portion of the balloon 102 so that when the releases 116 are activated (e.g., decomposed), the first reactant 115 can be released from the reactant reservoir 114 into the inside of the balloon 102e via the reactant conduits 118. For example, the reactant reservoir 114 may be pressurized by a certain amount of the first reactant 115 disposed therein. The release 116 may be in the form of a disassemblable plug or clip that blocks the internal portion of the reactant conduit 118 to temporarily prevent the first reactant 115 from entering the interior 102e from the reservoir 114. When the fluid in the GI tube comes into contact with the release 116 (for example, when the capsule 200 and / or outer coating 202 disintegrates), the release 116 can then be disassembled to allow the reactant reservoir 114 to discharge the first reactant 115 into the balloon interior 102e via the reactant conduit 118.

[0095] In other examples, device 100 may include clips, bands, or other structures for holding a portion of balloon 102 in such a manner that it temporarily defines separate chambers within the balloon interior 102e for separately containing the first reactant 115 and the second reactant 117. For example, a portion of balloon 102 may be clamped or compressed by a detachable clip or band to temporarily define separate chambers within the balloon interior 102e. The chambers may be substantially sealed to each other to substantially prevent mixing of the first reactant 115 and the second reactant 117. The clip or band may be located on the outer portion of balloon 102 so that exposure to the fluid in the GI tube (e.g., during the decomposition of capsule 200 and / or outer coating 202) can cause the clip or band to decompose and subsequently be released from balloon 102. When a clip or band or other structure is released from the balloon 102, the separate chambers are no longer substantially sealed to each other, thereby allowing the first reactant 115 to mix with the second reactant 117 inside the balloon 102e.

[0096] Combining the first reactant 115 with the second reactant 117 within the interior 102e triggers a chemical reaction that results in the formation of a gas (e.g., CO2). The gas expands the balloon 102 into an inflated state within the GI lumen, resulting in substantial alignment of the elongated section 102d with the surface of the GI lumen wall, thereby resulting in substantially perpendicular alignment of the longitudinal axis of the delivery assembly 104 with respect to the lumen wall surface. Furthermore, the expansion of the balloon 102 within the GI lumen allows the delivery assembly 104 to be positioned relative to the surface of the GI lumen wall (e.g., in close proximity to or in contact with it). The substantial alignment of the elongated section 102d and the positioning / orientation of the delivery assembly 104 with respect to the GI lumen wall can advantageously help facilitate the delivery of the dosage form from the delivery assembly 104 into the GI lumen wall or surrounding tissue without exposing the dosage form to the GI lumen environment. Thus, the device 100 can substantially store a dosage form within a portion of the GI tubule for systemic uptake of one or more therapeutic agents contained therein, before delivery into the GI lumen wall or surrounding tissue.

[0097] Still referring to Figure 1, the delivery assembly 104 is coupled to the balloon 102 and is at least partially or completely located within the balloon interior 102e. In other examples, the delivery assembly 104 is positioned entirely outside the balloon interior 102e but can be in fluid communication with the balloon interior 102e. The delivery assembly 104 is shown to include a housing 105 and a payload delivery module 106. The payload delivery module 106 is schematically shown in Figure 1 to illustrate that the housing 105 may have a modular structure to accommodate different payload delivery modules 106 for the delivery of different dosage forms and / or doses, as will be described in more detail herein.

[0098] As shown in Figure 1, the housing 105 has a generally hollow cylindrical shape and includes a proximal housing end 105a, a distal housing end 105b, and a housing interior 105c located between the proximal housing end 105a and the distal housing end 105b. The housing 105 has a longitudinal axis 105d extending between the proximal housing end 105a and the distal housing end 105b. The proximal housing end 105a has a first opening 105aa for receiving forces within the housing interior 105c (e.g., gas pressure from the gas generation mechanism). The distal housing end 105b has a second opening 105bb for discharging the dosage form from the housing interior 105c into the GI lumen wall or surrounding tissue. The distal housing end 105b may also have an optional vent opening 105f extending into the housing interior 105c to function as pressure relief for the housing interior 105c and the balloon interior 202e. The interior of the housing 105c defines a receptacle or piston chamber therein for receiving the payload delivery module 106. The housing 105 further includes a housing release 105e (e.g., a release feature, trigger) located in the interior of the housing 105c. The housing release 105e extends laterally inward toward the longitudinal axis 105d and away from the side walls of the housing 105, the side walls defining the receptacle or piston chamber of the housing 105. As described herein, the housing release 105e can be configured to releasably couple different embodiments of the payload delivery module 106 within the interior of the housing 105c. For example, as will be described in more detail below, the housing release 105e is configured to release the payload delivery module 106 from the housing 105 in response to a threshold force applied to the payload delivery module 106 through a first opening 105aa, thereby causing axial movement of the payload delivery module 106 within the housing interior 105c between the proximal end 105a and the distal end 105b of the housing interior 105c to discharge the dosage form from the housing interior 105c through a second opening 105bb.

[0099] By positioning the housing release 105e laterally on the housing 105, the longitudinal space within the housing interior 105c can be optimized to accommodate, for example, the maximum dose within the payload delivery module 106. In other words, the housing interior 105c is not substantially obstructed along the longitudinal axis 105d due to the lateral positioning of the housing release 105e. This can be particularly advantageous for maximizing the dose within the interior 105c without requiring an increase in the size of the housing 105 or the balloon 102, and thereby without requiring an increase in the size of the ingestible enclosure into the oral delivery device 100.

[0100] According to other examples, the housing release 105e may be located at different locations on the housing 105. For example, the housing release 105e may be located at the proximal end 105a of the housing or the distal end 105b of the housing.

[0101] Referring here to Figure 3, the housing 105 is shown separately from the balloon 102, with the payload delivery module 106 not yet disposed within it. As shown in Figure 3, the housing 105 includes the body 107 and the cover 108 (including the housing release 105e). In another example, the housing 105 may be a one-piece, integrated structure with an integrated release feature (e.g., a release feature defined by the side walls of the body 107) without a separate cover.

[0102] The body 107 includes a distal housing end 105b, a second opening 105bb, a housing interior 105c, and an optional vent opening 105f. The body 107 has a longitudinal axis 105d. The body 107 is configured to be coupled (e.g., sealed, bonded) to the balloon 102 along an elongated portion 102d. For example, a portion of the housing 105 may be positioned through an opening in the balloon 102 within the balloon interior 102e. The elongated portion 102d of the balloon 102 may overlap with a portion of the outer surface of the body 107, thereby allowing the overlapping portion to be heat-sealed to the body 107, thereby coupling the housing 105 to the balloon 102. The body 107 further includes a cover mounting feature 107c to which a cover 108 is coupled.

[0103] The cover 108 is coupled to the body 107 via a cover mounting feature 107c and a complementary feature 108b on the cover 108 (e.g., press-fit, snap-fit, adhesive, ultrasonic welding). In the example shown in Figure 3, the cover 108 is snap-fitted to the body 107. The cover 108 includes a housing release 105e, a housing proximal end 105a, and a first opening 105aa. In other examples, the housing release 105e may be coupled to the cover 108 (e.g., adhesive, heat-sealed) or defined by a separate component formed integrally with the cover 108. In the example shown, the housing release 105e is generally ring-shaped and is configured as a press-fit feature for releasably coupling the payload delivery module 106 to the body 107. Specifically, in the example shown, the housing release 105e is configured as a projection extending laterally inward from the side wall of the body 107 toward the longitudinal axis 105d. The cover 108 further includes an inner wall 108a which can function as a guide or stabilizer during at least a portion of the axial movement of the payload delivery module 106, as will be described in more detail herein.

[0104] In other examples, the housing release 105e may be configured differently from the examples in Figures 1 and 3, such as a different type of press-fit feature (e.g., groove or channel, flexible finger), a brittle connection, or other type of feature, which is configured to release (e.g., deflect, break, move) the payload delivery module 106 at a threshold force greater than or equal to that received through the first opening 105aa.

[0105] Referring now to Figure 4, exploded views of two different modular configurations of the delivery assembly 104 according to one embodiment are shown. The first configuration of the delivery assembly 104, shown on the left side of Figure 4 as the first modular delivery assembly 104a, includes a housing 105 (e.g., body 107 and cover 108) and a first payload delivery module 120 (an embodiment of the payload delivery module 106) having a fluid dosage form 130 disposed therein. The first payload delivery module 120 is configured to be releasably coupled to the housing 105 and movably disposed within the housing 105.

[0106] According to an exemplary assembly process, in a first assembly step, the cover 108 is releasably coupled to the first payload delivery module 120 via a housing release 105e, which may occur before the payload delivery module 120 is filled with the fluid dosage form 130, as described herein. The subassembly of the cover 108 and the first payload delivery module 120 is then coupled to the body 107 via a cover mounting feature 107c, with the first payload delivery module 120 disposed within the housing interior 105c. The delivery assembly, including the housing 105 and the first payload delivery module 120, can then be coupled to the balloon 102.

[0107] Still referring to Figure 4, a second alternative configuration, shown on the right side of Figure 4 as a second modular delivery assembly 104b, includes a housing 105 and a second payload delivery module 140 (another embodiment of the payload delivery module 106) having a solid dosage form 150. As shown in Figure 4, the second payload delivery module 140 is collectively defined by an ejector 140a and a cartridge 140b. The ejector 140a is configured to be releasably coupled to the housing 105 and slidably disposed within the housing 105. The cartridge 140b contains the solid dosage form 150 and is configured to be coupled to the housing 105 at the distal end 105b of the housing (e.g., press-fit, snap-fit, or bonded).

[0108] According to an exemplary assembly process, in a first assembly step, the cover 108 is releasably coupled to the ejector 140a via the housing release 105e. Next, the subassembly of the cover 108 and ejector 140a is coupled to the body 107 via the cover mounting feature 107c, with the ejector 140a positioned within the housing interior 105c. In a third step, the cartridge 140b is coupled to the housing 105 at the housing distal end 105b. Alternatively, the cartridge 140b may be coupled to the housing 105 before or simultaneously with the coupling of the subassembly of the cover 108 and ejector 140a to the body 107.

[0109] As shown by the dotted line in the example in Figure 4, the housing 105 can be advantageously configured to receive either a first payload delivery module 120 or a second payload delivery module 140 within it, using a common release feature or trigger (e.g., housing release 105e). In this way, the housing 105, and consequently the device 100, can accommodate modules having different delivery mechanisms or different delivery modes to enable the delivery of different dosage forms and / or doses.

[0110] Still referring to Figure 4, the first payload delivery module 120 includes a piston 121, a needle 122, a valve 125, and a membrane 129. In other examples, at least a portion of the valve 125 may be coupled to the housing 105 or form part of the housing 105, as described herein, and may be configured to contact the piston 121 to control the flow of the fluid formulation 130.

[0111] The piston 121 is configured to releasably couple the first payload delivery module 120 to the housing 105. The piston 121 is further configured to selectively move (e.g., slide) within the housing interior 121c to advance the needle 122 from the housing 105 into the GI lumen wall or surrounding tissue. As shown in Figure 4, the piston 121 has a generally hollow cylindrical shape and has a piston proximal end 121a and a piston distal end 121b. The piston 121 has a piston interior 121c for accommodating the fluid dosage form 130. The piston proximal end 121a is open to the piston interior 121c to allow a force (e.g., gas pressure) to be applied to the surface of the membrane 129, as will be discussed in more detail herein. The piston distal end 121b is defined by a needle port 121f for coupling the needle 122 to the piston 121. The needle port 121f defines a piston fluid channel 121h through which the fluid dosage form 130 flows to the needle 122. The upper wall of the piston 121 adjacent to the distal end 121b includes a valve opening 121e for receiving a portion of the valve 125. The upper wall further includes a filling port 121g for filling a reservoir, which is partially defined by the piston interior 121c, as described herein, with the fluid dosage form 130.

[0112] Still referring to Figure 4, the lateral wall of the piston 121 (e.g., the outer surface) includes a piston release 121d (e.g., a release feature, a trigger) that is complementary to the housing release 105e for releasably coupling the first payload delivery module 120 to the housing 105. In the example shown, the piston release 121d is configured as a channel that is complementary to the projection of the housing release 105e to define the press-fit arrangement, although other structural configurations (e.g., projection, brittle connection) are intended depending on the structure of the housing release 105e. As described below, the piston release 121d is configured to release from the housing release 105e in response to a force that reaches or exceeds a threshold applied to the piston 121 through the first opening 105aa, thereby moving the piston 121 axially toward the GI lumen wall within the housing interior 105c. For example, the force could be a threshold gas pressure generated inside the balloon 102e by a gas generation mechanism (e.g., mixing of the first reactant 115 with the second reactant 117). In this example, the threshold gas pressure could be in the range of about 10 to 40 psi, including about 20 to 40 psi, such as about 20 psi, 25 psi, 30 psi, 35 psi, 40 psi, or any value in between.

[0113] In other examples, the force may be a mechanical or fluid force generated by a separate force generating mechanism operably coupled to the piston 121. For example, the force generating mechanism may be a spring, hydrogel, gas source, or other mechanism for generating the force applied to the piston 121.

[0114] An optional piston seal 128 is coupled to the piston 121 along its lateral wall. A piston seal 126 is configured to create a substantially liquid-tight seal between the piston 121 and the housing 105, for example, to substantially prevent gas in the balloon interior 102e from passing between the piston 121 and the housing 105. A piston seal 128 is further configured to allow relative (sliding) movement between the piston 121 and the housing 105.

[0115] The needle 122 is coupled to the piston 121 at the distal end 121b of the piston via the needle port 121f. The needle 122 generally has an elongated structure. In the example shown, the needle 122 is collectively defined by the needle body 123 and the needle tip 124. In other examples, the needle 122 may be a monolithic one-piece structure and / or may have other structural configurations such as a hook, arrow, or other tissue-penetrating structure. As shown in Figure 4, the needle body 123 has a generally hollow cylindrical shape with a needle fluid channel 123a extending longitudinally from the proximal end to the discharge opening 123b. The discharge opening 123b extends through the side wall of the needle body 123.

[0116] In other examples, such as those shown in Figures 21-24 discussed below, the needle body 123 may have multiple fluid channels and / or discharge openings. Furthermore, the needle fluid channel 123a may extend through the needle body 123 at its distal end, instead of through the side wall of the needle body 123.

[0117] The needle body 123 may be formed from or include a biodegradable material to allow for the in-situ disintegration of at least part or all of the needle body 123 upon delivery of the fluid dosage form 130. For example, the needle body 123 may be formed from or include polyethylene oxide (PEO), polyethylene glycol (PEG), polyglycolide-colactide (PGLA), or other materials or combinations of materials. In other examples, the needle body 123 may be formed from or include a substantially non-degradable material such as surgical-grade steel, polymeric material, or other materials or combinations of materials. In any of these examples of the needle 122, the payload delivery module 120 and / or housing 105 may include a biasing component (e.g., a spring) or other mechanism to cause the needle 122 to retract from the tissue into the housing interior 105c upon delivery of the fluid dosage form 130. For example, the biasing component may have sufficient biasing force to cause the needle 122 to retract from the tissue when the gas pressure inside the balloon 102 falls below a threshold, for example, the threshold gas pressure inside the balloon 102 immediately after the fluid dosage form 130 has been delivered.

[0118] The needle tip 124 is bonded to the needle body 123 (e.g., press-fitted, bonded) or formed integrally with it (e.g., insert-molded). The needle tip 124 has a sufficiently tapered or pointed shape to penetrate the GI lumen wall or surrounding tissue. The needle tip 124 may be formed from or contain biodegradable materials or a combination of materials such as magnesium, PEO, PEG, or other materials. The needle tip 124 may be formed from a material harder than the material of the needle body 123 to help facilitate the penetration of the needle body 123 into the GI lumen wall or surrounding tissue. For example, the needle tip 124 may be formed from surgical-grade steel, magnesium, or other materials, while the needle body 123 may be formed from PEO, PEG, or other relatively flexible materials.

[0119] To provide additional design flexibility, the needle 122 may have sufficient length to penetrate to a desired penetration depth, such as within the layers of the GI lumen wall or through the GI lumen wall into the surrounding tissue of the target (e.g., the peritoneum or peritoneal cavity), for the delivery of the fluid dosage form 130. The applicant advantageously determines that the needle penetration depth is a function of the location of the device within the GI tube for delivery, since the inner circumference of the GI lumen varies along its length, the thickness of the GI wall in its unstretched state, and the amount of elongation of the GI lumen wall due to the expansion of the expandable member 102, and the amount of elongation can vary the local wall thickness and depends on the inner circumference of the GI lumen.

[0120] Based on these factors, the needle 122 may have a critical length L1 in the range of approximately 3.5 to 12 mm (shown in Figure 6, defined by the distance between the distal end 105b of the housing 105 and the needle tip 124 when the balloon 102 is inflated, and the subsequent advance of the piston 121 inside the housing 105c).

[0121] In other examples, the needle 122 may have a critical length L1 in the range of approximately 1.5 to 3 mm in order to penetrate into a layer of the GI lumen wall, such as the submucosa, and discharge the fluid dosage form 130 therein.

[0122] Referring here to Figures 21 to 24, two alternative examples of the needle 122 are illustrated. In the first alternative example shown in Figures 21 and 22, the needle 522 is illustrated to have a discharge opening 523b located at or near the distal end of the needle 522. In particular, the needle 522 includes a needle body 523 having a needle fluid channel 523a that extends longitudinally from the proximal end 522a to the distal end 522b or the discharge opening 523b located near the distal end. The needle fluid channel 523a includes a first fluid channel section 523aa and a second fluid channel section 523ab. The first fluid channel section 523aa extends from the proximal end 522a and has a first diameter D1 that is centered along the longitudinal axis 523c of the needle body 523. The second fluid channel section 523ab extends from the first fluid channel section 523a to the distal end of the needle 522b or a nearby discharge opening 523b. The second fluid channel section 523ab has a second diameter D2 which is less than the first diameter D1 of the first fluid channel section 523aa. Furthermore, the second fluid channel section 523ab is positioned offset from the longitudinal axis 523c. In this way, the needle body 523 has a wall section 523d ​​having a local wall thickness greater than the rest of the wall thickness of the needle body 523. The needle tip 524 is bonded to the needle body 523 by the relatively thick wall section 523d ​​(e.g., press-fit, heat-seal) or formed integrally with it (e.g., insert-molded). Similar to the above example, the needle tip 524 has a tapered or pointed shape sufficient to penetrate the GI lumen wall or the surrounding tissue.

[0123] A second alternative example of needle 122 is illustrated in Figures 23-24 as needle 622. In this example, needle 622 includes two discharge openings located at or near the distal end of needle 622. Needle 622 may include three or more discharge openings according to other embodiments. As shown in Figures 23 and 24, needle 622 includes needle body 623 having needle fluid channel 623a extending longitudinally from the needle proximal end 622a to both a first discharge opening 623b1 and a second discharge opening 623b2 located opposite each other at or near the needle distal end 622b. The needle fluid channel 623a includes a first fluid channel section 623aa, a second fluid channel section 623ab, and a third fluid channel section 623ac. The first fluid channel section 623aa has a third diameter D3 that extends from the proximal end of the needle 622a and is centered along the longitudinal axis 623c of the needle body 623. The second fluid channel section 623ab extends from the first fluid channel section 623a to the distal end of the needle 622b or a first discharge opening 623b1 near thereto. Similarly, the third fluid channel section 623ac extends from the first fluid channel section 623a to the distal end of the needle 622b opposite the first discharge opening 623b1 or a second discharge opening 623b1 near thereto. Each of the second fluid channel section 623ab and the third fluid channel section 623ac has a fourth diameter D4 that is less than the third diameter D3 of the first fluid channel section 623aa. Furthermore, each of the second fluid channel section 623ab and the third fluid channel 623ac is positioned offset from the longitudinal axis 623c. In this way, the needle body 623 defines a wall section 623d that is centrally located along the longitudinal axis 623c. The needle tip 524 is bonded to the needle body 623 at the wall section 623d (e.g., press-fit, heat-seal) or formed integrally with it (e.g., insert-molded). As in other examples, the needle tip 624 has a shape that is sufficiently tapered or pointed to penetrate the GI lumen wall or the surrounding tissue.

[0124] Referring again to Figure 4, the valve 125 is collectively defined by the puncture member 126 and the reservoir seal 127. The puncture member 126 is movably coupled to the piston 121 at the valve opening 121e. In other examples, the puncture member 126 may be coupled to the housing 105 instead of the piston 121 so as to contact the valve opening 121e during full axial movement of the piston 121, as described herein. The puncture member 126 has a generally elongated shape with a tapered end 126a configured to penetrate the reservoir seal 127 during axial movement of the puncture member 126 relative to the piston 121. The puncture member 126 has a shaped section 126b for holding the puncture member 126 within the valve opening 121e during movement of the puncture member 126 relative to the piston 121. In the example shown in Figure 4, the shaped section 126b is configured as a channel extending radially inward from its side surface, contacting a complementary feature (e.g., a projection) on the piston 121 to hold the puncture member 126 on the piston 121 during relative movement. This structural configuration may also help create a substantial liquid-tight seal between the puncture member 126 and the piston 121 within the valve opening 121e to help prevent or minimize the fluid dosage form 130 from escaping through the valve opening 121e during delivery of the fluid dosage form 130. The puncture member 126 may be formed from or include a flexible material (e.g., silicone) to help facilitate a substantial liquid-tight seal with the piston 121.

[0125] The reservoir seal 127 is coupled (e.g., bonded) to the piston 121 at a valve opening 121e adjacent to the puncture member 126 inside the piston interior 121c. The reservoir seal 127 is configured to contain the fluid dosage form 130 inside the piston interior 121c. As will be discussed in more detail below, the reservoir seal 127 is further configured to open (e.g., tear, peel, break) in response to the puncture member 126 coming into contact with the reservoir seal 127. The reservoir seal 127 may be formed from or include a breakable or punctureable material such as foil or film material (e.g., aluminum foil).

[0126] The membrane 129 is bonded to the piston 121 within the piston interior 121c. In the example shown, the membrane 129 is bonded to the inner surface of the piston 121 defining the piston interior 121c. In this example, the membrane 129 may be bonded to the piston 121 by heat sealing, bonding, or other means. The membrane 129 extends circumferentially around the piston 121 so as to surround at least a portion or all of the piston interior 121c. In this way, the membrane 129, the piston 121, and the reservoir seal 127 cooperate to define a reservoir 129a for containing the fluid dosage form 130 therein. The membrane 129 may extend axially beyond the piston interior 121c to expand the volume of the reservoir 129. Depending on the size of the membrane 129, the reservoir 129a may define a volume for containing up to approximately 250 μl or more of fluid. For example, the reservoir 129a can define a volume for accommodating approximately 50 μl to approximately 200 μl of fluid, including 50 μl to 250 μl of fluid, such as 50 μl, 100 μl, 150 μl, or 200 μl of fluid, or any value in between, or it can accommodate 200 μl or 250 μl of fluid, or any value in between. As described herein, the membrane 129 is configured to deform (e.g., compress, bend, flex, contract) relative to the piston 121 when the valve 125 is opened in order to discharge the fluid dosage form 130 from the reservoir 129a.

[0127] Additionally or alternatively, as described herein with respect to the example shown in Figure 20, a plunger (not shown in Figure 4, but shown as plunger 931 in Figure 20) may be movably coupled to the piston 121 in the piston interior 121c. The plunger may also extend circumferentially around the piston 121 so as to enclose at least a portion or all of the piston interior 121c. The plunger may include a circumferential seal for forming a liquid-tight seal with the inner surface of the piston 121 such that the plunger, piston 121, and reservoir seal 127 cooperate to define a reservoir 129a for containing the fluid dosage form 130 therein. The plunger may be configured to move (e.g., translate, slide) relative to the piston 121 to discharge the fluid dosage form 130 from the reservoir 129a when the valve 125 is opened, as described in further detail herein.

[0128] After the fluid dosage form 130 has been filled (partially or completely) into the reservoir 129a, the filling port 121g of the piston 121 can be substantially fluidly sealed by heat-sealing a portion of the piston 121 including the filling port 121g, for example, as will be further described with respect to Figures 25-27. In other examples, a separate seal (e.g., silicone or aluminum foil) may be coupled to the piston 121 at the filling port 121g. Additionally or alternatively, the filling port 121g may include a partition (e.g., a silicone partition) so that the filling port 121g can self-seal after the fluid dosage form 130 has been filled into the reservoir 129a. In any case, the reservoir 129a can be filled with the fluid dosage form 130 before the piston 121 is coupled to the housing 105 and balloon 102. This can advantageously allow for the flexibility associated with the sterile assembly of the device 100a.

[0129] For example, referring to Figures 25-27, an exemplary method for filling a first payload delivery module 120 with a fluid dosage form 130 is illustrated. The disclosed method may be carried out in a sterile environment, such as an isolator or other sufficiently sterile environment. One or more steps of the disclosed process may be carried out manually or automatically using various instruments known to those skilled in the art. Although only a single payload delivery module 120 is shown in Figures 25-27, it should be understood that multiple payload delivery modules 120 may be filled substantially simultaneously with each other using the disclosed method. Furthermore, the disclosed method may be used in conjunction with any of the other exemplary payload delivery modules described herein that are configured to contain a fluid dosage form.

[0130] In the first filling step 700a shown in Figure 25, the assembled first payload delivery module 120 (including a piston 121, (optionally) a needle 122, a valve 125, and a membrane 129 (and / or plunger)) is positioned in the fixture 702. In other examples, the first payload delivery module 120 may include a cover 108 that is removably coupled together via a piston release 121d and a housing release 105e before filling (see, for example, the payload delivery module 920 in Figure 13), and the cover 108 may help define axial stops or support features for the membrane 129 and / or plunger during the filling process. In the example shown, the first payload delivery module 120 is positioned in the fixture recess 702a of the fixture 702. The fixture recess 702a extends longitudinally to the fixture opening 702b located below the fixture recess 702a, so that the vacuum generator 704 can be fluidly coupled to the inside of the piston 121c. The vacuum generator 704 may be a vacuum pump or other device for generating negative pressure.

[0131] Still referring to Figure 25, the conduit 706 is fluidically coupled to the reservoir 129a via the filling port 121g. The conduit 706 may be configured as a tube, pipe, cannula, or other conduit suitable for delivering the fluid dosage form 130 to the reservoir 129a. The conduit 706 is fluidically coupled to the dosage container 708 via a control valve 710. The dosage container 708 contains a certain volume of the fluid dosage form 130 disposed therein. The dosage container 708 may be configured as a funnel, a sealed container, or other type of container or reservoir sufficient to hold the fluid dosage form 130 therein. In the example shown, the internal volume of the dosage container 708 is maintained at ambient pressure. The control valve 710 is configured to selectively control the flow of the fluid dosage form 130 from the dosage container 708 to the reservoir 129a via the conduit 706. The control valve 710 may be configured as a pinch valve, an on / off valve, or another type of fluid control valve.

[0132] As shown in Figure 25, the control valve 710 is in the off position, with substantially all of the fluid dosage form 130 located in the dosage form container 708 and a section of conduit 706 located upstream of the control valve 710. Before connecting conduit 706 to the filling port 121g, any residual air between the membrane 129 inside the piston interior 121c and the piston 121 can be removed, for example, by applying positive pneumatic pressure to the outer surface of the membrane 129 through the piston interior 121c from the proximal end of the piston 121a. The residual air can then be pushed outward through the filling port 121g before connecting conduit 706 thereto.

[0133] Referring here to Figure 26, in the second filling step 700b, the control valve 710 is opened to allow the fluid dosage form 130 to flow from the dosage container 708 through the conduit 706 to the reservoir 129a via gravity. When the control valve 710 is opened, a vacuum is applied to the inside of the piston 121c through the vacuum generator 704 via the fixture opening 702b. As a result of the applied vacuum and the ambient pressure maintained inside the dosage container 708, the membrane 129 is pulled longitudinally toward the proximal end of the piston 121a, which then causes the fluid dosage form 130 to flow into the reservoir 129a (as indicated by the unidirectional arrow in Figure 26) until the reservoir 129a is substantially filled. In this way, the reservoir 129a can be filled with the fluid dosage form 130 without the use of a metering pump or other complex / expensive equipment. Furthermore, this approach facilitates filling a substantial volume defined by the reservoir 129a using the fluid dosage form 130.

[0134] However, in other examples, a fluid pump may be used to fill the reservoir 129a. In these examples, the fluid pump may form part of the dosage container 708 or be fluidly coupled to the dosage container 708 in a different manner.

[0135] Referring here to Figure 27, in the third filling step 700c, once the reservoir 129a is substantially filled with the fluid dosage form 130, the control valve 710 is closed, and the filling port 121g is substantially fluidically sealed to accommodate a certain volume of the fluid dosage form 130 in the reservoir 129a. For example, the filling port 121g may be heat-sealed using a heat source (e.g., a hot knife) to melt a portion of the material of the piston 121 that defines the filling port 121g. Once the heat seal and filling port 121g have cooled sufficiently, the first payload delivery module 120 can be removed from the fixture 708 for subsequent assembly with the needle 122 (if not yet assembled with the piston 121 in a sterile environment), housing 105, and balloon 102. The assembly with balloon 102 can advantageously be performed outside of a sterile environment.

[0136] As discussed below, and in the example shown in Figure 27, the membrane 129 is a flexible structure that deforms (e.g., compresses, bends, flexes, shrinks) in response to the gas pressure generated within the balloon interior 102e (from the reaction of the first reactant 115 and the second reactant 117) reaching or exceeding a threshold, thereby allowing the fluid dosage form 130 to be discharged from the reservoir 129a to the needle 122. Before discharging the fluid dosage form 130, the membrane 129 is further configured to move the payload delivery module 120 axially relative to the housing 105 in response to the gas pressure generated within the balloon 102 being applied to the outer surface of the membrane 129. The membrane 129 may have a surface profile in a relaxed state (i.e., when not filled with the fluid dosage form 130, as shown in Figure 25) that is complementary to the inner surface profile of the piston 121 defining the piston interior 121c. For example, the membrane 129 can be vacuum-formed by using the piston 121 as a mold, or by using another mold having the same / similar dimensions as the piston 121, such that the membrane substantially mimics the inner surface profile of the piston interior 121c. In this way, the membrane 129 can be sufficiently deformed to discharge a substantial portion of the fluid dosage form 130 from the reservoir 129a. For example, the device 100 may be configured such that the membrane 129 is sufficiently deformed to discharge about 95–100% of the volume of the fluid dosage form contained in the reservoir 129a, including about 95%, 96%, 97%, 98%, 99%, 100%, or any value in between. Furthermore, such complementary shapes of the membrane 129 can help facilitate the sufficient discharge of the reservoir 129a for subsequent filling with the fluid dosage form 130 during assembly, as described above with respect to Figures 25–27.

[0137] The membrane 129 may be formed from or include a flexible polymer material (e.g., polyethylene terephthalate (PET)) or other flexible material or combination of materials having sufficiently low moisture and gas permeability for use with the fluid dosage form 130. The membrane 129 may further include a film or coating (e.g., metallized polyethylene, titanium metallized film) to help minimize or eliminate water vapor transfer to the fluid dosage form 130 through the membrane 129, thereby helping to extend the shelf life of the fluid dosage form 130. The film or coating may be disposed on the outer surface of the membrane 129 that is not in contact with the fluid dosage form 130. The membrane 129 may be formed from a single material or a combination of materials. Furthermore, the membrane 129 may include one or more layers of material. The membrane 129 may have a monolithic structure. In other examples, the membrane 129 may consist of multiple sections or components joined together (e.g., sealed or sewn). The membrane 129 may have other suitable shapes, such as cylindrical, elliptical, spherical, cubic, or other shapes.

[0138] As will be discussed in more detail with reference to Figure 6, once the gas pressurizing the balloon 102 reaches a desired location within the target GI tube, it can pass through the first opening 105aa and pressurize the membrane 129 on the piston 121. When the gas pressure reaches or exceeds a threshold (e.g., the pressure associated with the complete or partial inflation of the balloon 102 within the desired location in the GI lumen), the pressure releases the payload delivery module 120 (including the fluid dosage form 130) from the housing release 105e, causing it to move axially along the longitudinal axis 105d relative to the housing 105 so that the needle 122 penetrates the GI lumen wall. Upon sufficient axial movement of the payload delivery module 120 relative to the housing 105, the valve 125 is configured to open (e.g., by the puncture member 126 contacting the housing 105 and puncturing the reservoir seal 127) to allow the fluid dosage form 130 to flow from the reservoir 129a into the piston fluid channel 121h and the needle 122. Next, the gas pressure applied to the membrane 129 deforms the membrane 129 relative to the piston 121, thereby discharging the fluid dosage form 130 through the piston fluid channel 121h, the needle fluid channel 123a, and the discharge opening 123b for delivery into the lumen wall of the target GI or the surrounding tissue.

[0139] Referring again to Figure 4, the second payload delivery module 140 includes an ejector 140a and a cartridge 140b.

[0140] The ejector 140a is configured to be releasably coupled to the housing 105 within the housing interior 105c. The ejector 140a is further configured to selectively move (e.g., slide) within the housing interior 121c to eject the solid dosage form 150 as a projectile into the GI lumen wall or surrounding tissue. As shown in Figure 4, the ejector 140a includes a piston 142 and an optional piston seal 144. The piston 142 has a generally hollow cylindrical base section at the piston proximal end 142a and a generally elongated section at the piston distal end 142b. The piston proximal end 142a is generally planar and is configured to receive a force (e.g., gas pressure) through the housing proximal end 105a, as will be discussed in more detail herein, to cause axial movement of the ejector 140a relative to the housing 105. The distal end 142b of the piston is generally elongated and tapered to discharge the solid dosage form 150 from the cartridge 140b into the GI lumen wall or surrounding tissue.

[0141] An optional piston seal 144 is coupled to the outer circumference of the piston 142. The piston seal 144 is configured to create a substantially liquid-tight seal between the piston 142 and the housing 105, for example, to substantially prevent gas in the balloon interior 102e from passing between the piston 142 and the housing 105. The piston seal 144 is further configured to allow relative (sliding) movement between the piston 142 and the housing 105.

[0142] Similar to piston 121, the lateral walls (e.g., outer surface) of the base section of piston 142 include a piston release 142c (e.g., release feature, trigger) complementary to the housing release 105e for releasably coupling ejector 140a to housing 105. In the example shown, the piston release 142c is configured as a channel complementary to the projection of housing release 105e to define a press-fit arrangement, although other structural configurations (e.g., projection, brittle connection) are intended depending on the structure of housing release 105e. As described below, piston 142 is configured to release from housing release 105e in response to a force reaching or exceeding a threshold applied to piston 142 through a first opening 105aa, causing piston 142 to move axially toward the GI lumen wall within housing interior 105c. For example, the force may be the gas pressure generated inside the balloon 102e by a gas generation mechanism (e.g., mixing of the first reactant 115 with the second reactant 117). In this example, the threshold gas pressure may be in the range of about 10 to 40 psi, including about 20 to 40 psi, such as about 20 psi, 25 psi, 30 psi, 35 psi, 40 psi, or any value in between. In other examples, the force may be a mechanical or fluid force generated by a separate mechanism (e.g., a spring, hydrogel) operationally coupled to the piston 142.

[0143] Still referring to Figure 4, the cartridge 140b includes a container 146 and a solid dosage form 150 disposed therein. The cartridge 140b is configured to be coupled to the housing 105 at the distal end 105b of the housing via the container 146. Specifically, in the example shown, the container 146 has a generally hollow cylindrical shape with a proximal end 146a and a distal end 146b. The distal end 146b includes a flange 146d for coupling the cartridge 140b to the housing 105b at the distal end 105b via a press-fit arrangement. In other examples, the container 140b and housing 105 may include different types of mounting interfaces, such as a snap-fit ​​interface, a bayonet attachment, or other interfaces.

[0144] In yet another example shown in Figure 30, which will be discussed in more detail below, the housing 105 may have a sleeve or similar structure defined at the distal end 105b of the housing to receive a container 146 therein.

[0145] Still referring to Figure 4, the cavity 146c (e.g., internal) extends from the proximal end 146a of the container to the distal end 146b of the container. The cavity 146c is configured to receive the solid dosage form 150 within it. The proximal end 146a of the container includes an opening to the cavity 146c but includes a first seal 148a bonded to it (e.g., glued). The first seal 148a is configured to be penetrated or punctured by the distal end 142b of the piston in order to eject the solid dosage form 150 from the container 146 as a projectile. Similarly, the distal end 146b of the container includes an opening to the cavity 146c but includes a second seal 148b bonded to it (e.g., glued). In this way, the first seal 148a and the second seal 148b can substantially seal the cavity 146c to provide a substantially sterile environment for storing the solid dosage form 150 for subsequent delivery into the GI lumen wall or surrounding tissue. Similar to the first seal 148a, the second seal 148b is configured to be penetrated or punctured by the solid dosage form 150 to allow the solid dosage form 150 to be discharged from the container 146 into the GI lumen wall or surrounding tissue. The first seal 148a and the second seal 148b may be formed from or include a punctureable or breakable material such as foil (e.g., aluminum foil), film, or other material or combination of materials.

[0146] The solid dosage form 150 is shown to comprise a needle structure 152 and a composition 154 disposed therein. The needle structure 152 has a generally elongated shape with a tapered or pointed end sufficient to puncture the second seal 148b and penetrate the GI lumen wall or surrounding tissue. The needle structure 152 is further configured to receive force from the ejector 140a at the end opposite the tapered end in order to propel or eject the needle structure 152 from the container 146 as a projectile. The needle structure 152 may be formed from or comprise a biodegradable material (e.g., PEO, PE) so as to decompose in situ upon delivery into the GI lumen wall or surrounding tissue, thereby exposing the composition 154 for systemic uptake of one or more therapeutic agents contained therein.

[0147] Composition 154 is shown as a solid cylindrical member disposed inside the needle structure 152. Composition 154 may contain one or more therapeutic agents as described herein, along with one or more additional components such as binders, preservatives, disintegrants, lubricants, or other components. As described above, composition 154 may be a compressed tablet formed from a lyophilized powder containing one or more biologically active therapeutic agents. Composition 154 may have a weight of about 1 to 3 milligrams (mg) and may contain one or more therapeutic agents in doses of about 1 to 10 mg. In the example shown, composition 154 is configured to degrade in situ to release one or more therapeutic agents contained therein for systemic uptake in the subject upon exposure to the GI lumen or surrounding tissue environment (e.g., sufficient degradation of the needle structure 152).

[0148] In other examples, composition 154 may be a different composition such as a gel, liquid, suspension, powder, or other composition to be contained in the cavity of the needle structure 152.

[0149] In yet another example, composition 154 itself may be formed (e.g., compressed in a mold) into the shape of a needle or other tapered / pointed structure to penetrate the GI lumen wall or surrounding tissue without a separate needle structure 152.

[0150] Figure 5 is a partial cross-sectional view of an ingestible device 100a (an embodiment of the ingestible device 100), which includes a first modular delivery assembly 104a coupled to a balloon 102. The device 100a is shown in a first state before inflation of the balloon 102 within a desired location on a target GI tube for delivery of a fluid dosage form 130. As shown in Figure 5, the first payload delivery module 120 is releasably coupled to the housing 105 and slidably disposed within the housing 105. Specifically, the piston 121 is releasably coupled to the housing 105 via a press-fit arrangement between the piston release 121d and the housing release 105e. The first payload delivery module 120 is positioned within the housing interior 105c with the needle 122 positioned adjacent to the second opening 105bb. The needle seal 110 is bonded (e.g., glued) to the housing 105 at the distal end 105b of the housing to substantially seal the second opening 105bb, thereby helping to maintain the sterility of the needle 122 inside the housing interior 105c. The needle seal 110 may be formed from a breakable material such as foil material (e.g., aluminum foil). The needle 122 is configured to puncture the needle seal 110 and penetrate the GI lumen wall or surrounding tissue.

[0151] An optional vent container 132 is shown coupled to the housing 105 at or near the distal end 105b of the housing. The vent container 132 is coupled (e.g., heat-sealed, bonded) around the housing 105 and to the upper surface of the distal end 105b of the housing adjacent to the second opening 105bb to define a generally ring-shaped (e.g., donut-shaped) structure having an internal volume 132a. The internal volume 132a is in fluid communication with the housing interior 105c via the vent opening 105f to capture pressurized residual air contained in the housing interior 105c above the piston 121 after the piston 121 has been operated (i.e., moved axially). The internal volume 132a may be larger than the volume of the housing interior 105c to ensure that substantially all of the residual air contained in the housing interior 105c is captured within the vent container 132 without causing significant or arbitrary expansion of the vent container 132. In this way, the vent container 132 can help prevent pressurized residual air inside the housing 105c exiting the vent opening 105f from interfering with the needle 122 when deployed from the housing 105. The vent container 132 may be formed from or include a flexible material or combination of materials, such as a flexible polymer material (e.g., hydroxypropyl methylcellulose (HPMC), PE). The vent container 132 may optionally be used in combination with any of the exemplary devices and assemblies described herein.

[0152] Figure 6 illustrates the ingestible device 100a in a second state after the device 100a has reached a desired location within the target GI tube (e.g., stomach, small intestine, large intestine) for delivery of the fluid dosage form 130. In this example, the device 100a is shown in the small intestine. As shown in Figure 6, the balloon 102 is inflated by gas generated within the balloon interior 102e such that the elongated section 102d is substantially aligned with the surface of the GI lumen wall and the distal end 105b of the housing 105 is oriented and positioned relative to (e.g., in close proximity to or in contact with) the surface of the lumen wall (as discussed above with reference to Figures 1 and 2). The gas generated within the balloon interior 102e exerts pressure (indicated by a unidirectional arrow 160) against the outer surface of the membrane 129 through the first opening 105aa of the housing 105. When the gas pressure reaches or exceeds a threshold (e.g., a pressure associated with the fully or partially inflated state of the balloon 102, such as approximately 10–40 psi), the piston release 121d overcomes the press-fit interface with the housing release 105e. As a result, the entire payload delivery module 120, including the fluid dosage form 130, moves axially relative to the housing 105 toward the lumen wall along the longitudinal axis 105d, such that the needle tip 124 advances through the needle seal 110 and penetrates the lumen wall or surrounding tissue. During at least a portion of the axial movement of the payload delivery module 120, the axial orientation of the piston 121 may be assisted by the inner wall 108a protruding from the cover 108.

[0153] The axial movement of the payload delivery module 120 may generate back pressure from the residual air contained within the housing interior 105c above the piston 121. Therefore, the vent opening 105f may allow for the release of the resulting back pressure generated within the housing interior 105c and the gas contained within the balloon interior 102e after the delivery of the fluid dosage form 130, in order to facilitate the axial movement of the piston 121 relative to the housing 105. An optional vent container 132 may capture substantial or all of the residual air from the housing interior 105c to help minimize potential interference between the air exiting the vent opening 105f and the needle 122 as the needle 122 advances through the second opening 105bb.

[0154] In the example shown in Figure 6, the needle 122 advances through the lumen wall into the peritoneal cavity of the target. In other examples, the needle 122 has different lengths or advances to different penetration depths, such as within layers of the GI lumen wall (e.g., mucosa, submucosa, muscle, serosa), in order to discharge the fluid dosage form 130 inside. When the payload delivery module 120 has made sufficient axial movement relative to the housing 105 (e.g., thereby allowing the needle 122 to advance to the desired penetration depth), the puncture member 126 moves relative to the piston 121 within the valve opening 121e and engages with the inner surface of the housing 105 near the distal end 105b to penetrate the reservoir seal 127. When the puncture member 126 penetrates the reservoir seal 127, the gas pressure applied to the membrane 129 (represented by a unidirectional arrow 160) deforms the membrane 129 inward relative to the piston 121 toward the needle 122, in order to discharge the fluid dosage form 130 from the reservoir 129a through the reservoir seal 127 to the needle 122. As a result, the fluid dosage form 130 is guided into the peritoneal cavity through the piston fluid channel 121h, the needle fluid channel 123a, and the needle discharge opening 123b. In this way, one or more therapeutic agents contained in the fluid dosage form 130 can be delivered to the subject for systemic uptake.

[0155] As described above, the fluid dosage form 130 remains in the reservoir 129a while the gas pressure in the balloon 102 is applied to the membrane 129 until the puncture member 126 punctures the reservoir seal 127. In this way, the device 100a can substantially avoid discharging the fluid dosage form 130 into the luminal environment and allow for a sequential timing between penetrating the GI luminal wall and discharging the fluid dosage form 130 in order to ensure delivery of the fluid dosage form 130 into the GI luminal wall or surrounding tissue for systemic uptake.

[0156] Once the delivery of the fluid dosage form 130 is complete, one or more components of the device 100a (e.g., balloon 102, needle 122) can subsequently decompose within the GI lumen wall or surrounding tissue, or within other areas of the GI tube. For example, one or more components of the device 100a may be formed from or include one or more biodegradable materials to facilitate the in-situ decomposition of such components before, during, or after the delivery of the fluid dosage form 130. Examples of biodegradable materials that may be suitable for use with various components of the device 100a include, for example, hydroxypropyl methylcellulose (HPMC), polyvinyl acetate (PVA), PEO, PEG, PGLA, lactide, glycolide, lactic acid, glycolic acid, paldioxanone, trimethylene carbonate, caprolactone, and mixtures and copolymers thereof.

[0157] In one or more embodiments, particularly in embodiments in which the needle 122 is substantially indestructible or includes substantially indestructible parts, the device 100a may be configured to retract the needle 122 from the GI lumen wall into the housing interior 105c once the delivery of the fluid dosage form 130 is complete (for example, using a biasing component such as a spring coupled to the needle 122). In any of these embodiments, the vent opening of the housing 105 and / or the deflation valve 112 may release a substantial amount of gas contained within the balloon interior 102a to allow for substantial deflation of the balloon 102 and subsequent movement of the device 100a through the remainder of the GI tube to exit the target anus.

[0158] Figure 7 is a partial cross-sectional view of an ingestible device 300a (an embodiment of the ingestible device 100), including another version of the payload delivery module 120 (shown as payload delivery module 320) having a different valve arrangement. Apart from the valve arrangement, the structure of the payload delivery module 320 is the same as that of the payload delivery module 120. Thus, for efficiency, similar reference numbers refer to similar components among the examples, but are increased by only 200 (e.g., membrane 329 is equivalent to membrane 129). In this example, the payload delivery module 320 does not include a valve opening on the piston 321. Rather, the payload delivery module 320 includes a valve 325 collectively defined by a base 321h, a puncture member 326, and a reservoir seal 327.

[0159] Still referring to Figure 7, the base 321h has a dome shape and is formed integrally with the piston 321. In other examples, the base 321h may be a separate component coupled to the piston 321. Furthermore, the base 321h may have a shape other than a dome, such as a trapezoid or other shape. As described below, the base 321h protrudes from the outer surface of the piston 321 and is configured to deform inward toward the reservoir seal 327 (e.g., deflect, bend, or invert) upon contact with the inner surface of the housing 305 in response to the axial movement of the piston 321 relative to the housing 305.

[0160] The puncture member 326 is coupled (e.g., press-fitted) to or positioned adjacent to the base 321h. The puncture member 326 is also pivotally coupled to a portion 305g of the housing 305 adjacent to the distal end 321b of the housing within the piston interior 321c. In the example shown, the portion 305g is configured as a frustoconical projection that defines a column to which the puncture member 326 is pivotally coupled (e.g., press-fitted). In particular, the puncture member 326 is cantilevered from the portion 305g to allow pivoting of the puncture member 326 with respect to the base 321h when the base 321h contacts the housing 305. The puncture member 326 further includes a tip 326a positioned adjacent to the reservoir seal 327 and configured to penetrate the reservoir seal 327 when the base 321h deforms.

[0161] Figure 8 illustrates the ingestible device 300a in a second state after the device 300a has reached a desired location within the target GI tube (e.g., stomach, small intestine, large intestine) for delivery of the fluid dosage form 330. In this example, the device 300a is shown in the small intestine. As shown in Figure 8, upon sufficient axial movement of the payload delivery module 320 relative to the housing 305 (e.g., thereby advancing the needle 322 to the desired penetration depth), the base 321h engages with the inner surface of the housing 305 near the distal end 305b of the housing to deform the base 321h inward toward the reservoir seal 327. As a result, the tip 326a of the puncture member 326 moves in response to the deformation of the base 321h and punctures the reservoir seal 327. When the tip 326a punctures the reservoir seal 327, the gas pressure applied to the membrane 329 (represented by a unidirectional arrow 360) deforms the membrane 129 inward toward the needle 322 relative to the piston 321, in order to discharge the fluid dosage form 330 from the reservoir 329a through the reservoir seal 327 to the needle 322. As a result, the fluid dosage form 330 is guided into the peritoneal cavity through the piston fluid channel 321h, the needle fluid channel 323a, and the needle discharge opening 323b. In this way, one or more therapeutic agents contained in the fluid dosage form 330 can be delivered to the subject for systemic uptake.

[0162] Figure 9 is a partial cross-sectional view of an ingestible device 400a (an embodiment of ingestible device 100), which includes another version of the payload delivery module 120 (shown as payload delivery module 420) having a different valve arrangement. Apart from the valve arrangement, the structure of the payload delivery module 420 is the same as that of the payload delivery module 120. Thus, for efficiency, similar reference numbers refer to similar components among the examples, but are increased by only 300 (e.g., membrane 429 is equivalent to membrane 129). In this example, the payload delivery module 420 does not include a valve opening or reservoir seal on the piston 421. Rather, the payload delivery module 420 includes a valve 425 collectively defined by the base 421h and the plug 426.

[0163] Still referring to Figure 9, the base 421h has a dome shape and is integrally formed with the piston 421, as in the structure of the base 321h described above with reference to Figures 7 and 8. In other examples, the base 421h may be a separate component coupled to the piston 421. Furthermore, the base 421h may have a shape other than a dome, such as a trapezoid or other shape. As described below, the base 421h protrudes from the outer surface of the piston 421 and is configured to deform inward toward the reservoir 429a (e.g., deflect, bend, invert) upon contact with the inner surface of the housing 405 in response to the axial movement of the piston 421 relative to the housing 405. In various examples, the valve 425 may include one or more bases 421h positioned along the upper portion of the piston 421.

[0164] The plug 426 includes a sealing portion 426a and a mounting portion 426b. The sealing portion 426a may be coupled (e.g., bonded, fastened) to the mounting portion 426b or formed integrally with the mounting portion 426b (e.g., insert molded). The sealing portion 426a is releasably coupled to the piston 421 in the piston fluid channel 421h. In the example shown, the sealing portion 426a is press-fitted into the piston fluid channel 421h to substantially prevent the fluid formulation 430 from entering the piston fluid channel 421h, thereby substantially fluidically sealing the reservoir 429a from the piston fluid channel 421h. For example, the sealing portion 426a may be formed from or include a material configured to create a fluid seal with the piston 421, such as a flexible polymer material (e.g., silicone) or other material or combination of materials. The mounting portion 426b is either coupled to the base 421h or in other contact with the base 421h in order to enable the transmission of force from the base 321h to the plug 426.

[0165] Figure 10 illustrates the ingestible device 400a in a second state after the device 400a has reached a desired location within the target GI tube (e.g., stomach, small intestine, large intestine) for delivering the fluid dosage form 430. In this example, the device 400a is shown in the small intestine. As shown in Figure 10, when the payload delivery module 420 has made sufficient axial movement relative to the housing 405 along the longitudinal axis 405d (e.g., thereby advancing the needle 422 to the desired penetration depth), the base 421h engages with the inner surface of the housing 405 near the distal end 405b to deform the base 421h inward toward the reservoir 429a. In this example, the base 421h is deformed into an inverted position within the piston interior 421c. The deformation of the base 421h causes the mounting portion 426b to move axially toward the reservoir 429a, thereby releasing the sealing portion 426a from the needle port 421f and the piston fluid channel 421h. When the seal portion 426a is released from the piston fluid channel 421h, the gas pressure applied to the membrane 429 (represented by the unidirectional arrow 460) deforms the membrane 429 inward relative to the piston 421 toward the needle 422 in order to discharge the fluid dosage form 430 from the reservoir 429a to the needle 422. As a result, the fluid dosage form 430 is guided into the peritoneal cavity through the piston fluid channel 421h, the needle fluid channel 423a, and the needle discharge opening 423b. In this way, one or more therapeutic agents contained in the fluid dosage form 430 can be delivered into the target's bloodstream for systemic uptake.

[0166] Figure 11 is a partial cross-sectional view of an ingestible device 900a (an embodiment of ingestible device 100), including yet another version of the payload delivery module 120 (indicated as payload delivery module 920) having a different valve arrangement and vent path. The payload delivery module 920 and housing 905 are otherwise identical to the payload delivery module 120 and housing 105, respectively. Thus, for efficiency, similar reference numbers refer to similar components among the examples, but are increased by only 800 (e.g., membrane 929 is equivalent to membrane 129).

[0167] As shown in Figures 11 and 13-15, the payload delivery module 920 includes a valve 925 collectively defined by a puncture member 926 and a reservoir seal 927. In this example, the puncture member 926 is a single unit comprising a puncture member tip 926a, a puncture member body 926b, and a puncture member arm 926c. The puncture member 926 is coupled to the piston 921 via the puncture member arm 926c (e.g., heat staking, press-fit) such that the puncture member body 926b and tip 926a are positioned adjacent to the valve opening 921e above the reservoir seal 927. In other examples, the puncture member 926 (e.g., tip 926a) is coupled to the housing 905 or forms part of the housing 905. As described herein, the puncture member body 926b and tip 926a are configured to move via deformation of the puncture member arm 926c in response to sufficient axial movement of the payload delivery module 920 relative to the housing 905. The puncture member tip 926a is configured to puncture the reservoir seal 927 in response to the puncture member base 926b engaging with the housing 905 during sufficient axial movement of the payload delivery module 920. The puncture member base 926b is further configured to create a substantially liquid-tight seal with the piston 921 via an interference fit of the valve opening 921e once the puncture member tip 926a has punctured the reservoir seal 927. The puncture member base 926b may include a separate seal (e.g., silicone) to help create a substantially liquid-tight seal with the piston 921. The puncture member 926 may be formed from or include a polymer material such as polypropylene, polyethylene, or other materials or combinations of materials (e.g., surgical-grade steel).

[0168] Figure 13 illustrates the payload delivery module 920 before filling the reservoir 929a with fluid dosage form 930 via the filling port 921g. In this example, the payload delivery module 920 is shown without the needle 922 coupled to the needle port 921f. Furthermore, the cover 908 is shown as being releasably coupled to the piston 921 via a housing release feature 905e and a piston release feature 921d, so that the cover 908 can function as a stop feature for the membrane 929 during the filling process. It should be understood that the payload delivery module 920 can be filled with fluid dosage form 930 in the same manner as the payload delivery module 120, as described herein with respect to Figures 25-27.

[0169] Figure 14 illustrates the payload delivery module 920 after the reservoir 929a has been filled with the fluid dosage form 930. The payload delivery module 920 is shown with a needle 922 coupled to a needle port 921f and a substantially fluidly sealed filling port 921g. The payload delivery module 920 can then be coupled to the body 907 of the housing 905 via a cover 908 to define the delivery assembly 904a.

[0170] Referring to Figures 11 and 12, the vent seal 911 (not shown in Figure 12 for clarity) is coupled to the housing 905 above the needle seal 910. The housing 905 further includes one or more vent channels 905f oriented laterally with respect to the longitudinal axis 905d. The vent channels 905f extend laterally from a second opening 905bb to the outermost periphery of the housing 905 to provide a vent path from the inside of the housing 905c to the GI lumen environment. The lateral orientation of the vent channels 905f is advantageous because gas is discharged laterally away from the longitudinal axis 905d, thus helping to prevent back pressure from pushing (e.g., stretching) the GI lumen wall away from the device 900a when the needle 922 punctures the GI lumen wall. As shown in Figures 11 and 12, the vent channel 905f is located between the vent seal 911 (not shown in Figure 12) and one or more slots located within the housing 905, and is partially defined by them. The needle 922 is configured to penetrate both the needle seal 910 and a portion of the vent seal 911. However, the vent seal 911 remains intact, covering the vent channel 905f, to allow for lateral gas release from the housing 905 and the inside of the balloon 902e into the GI lumen environment upon puncture of the needle seal 910.

[0171] Referring to Figures 16–19, an exemplary operating sequence of the ingestible device 900a in the target GI duct after ingestion is shown. Figure 16 illustrates the device 900a in a second state after it has reached a desired location in the target GI duct (e.g., stomach, small intestine, large intestine) for delivery of the fluid dosage form 930. In this example, the device 900a is shown in the small intestine. As shown in Figure 16 and as discussed above with reference to Figures 1 and 2, the balloon 902 (not shown) is inflated by gas (represented by a directional arrow 960) generated within the balloon interior 902e (not shown) such that the elongated section 902d is substantially aligned with the surface of the GI lumen wall and the distal end 905b of the housing is oriented and positioned relative to (e.g., in close proximity to or in contact with) the surface of the GI lumen wall.

[0172] Referring to Figure 17, when the gas pressure reaches or exceeds a threshold (e.g., a pressure associated with the fully or partially inflated state of balloon 902 (not shown), such as a pressure of approximately 10–40 psi), the piston release 921d overcomes the press-fit interface with housing release 905e. As a result, the entire payload delivery module 920, including the fluid dosage form 930, moves axially relative to the housing 905 toward the GI lumen wall along the longitudinal axis 905d, such that the needle tip 924 advances through portions of the needle seal 910 and vent seal 911 and penetrates the GI lumen wall or surrounding tissue.

[0173] The axial movement of the payload delivery module 920 can generate back pressure from residual air contained within the housing interior 905c above the piston 921. Thus, the vent channel 905f can allow for the release of the back pressure resulting from the generation within the housing interior 905c, which is laterally separated from the housing 905 during needle seal 910 puncture, and the gas contained within the balloon interior 902e (not shown) after delivery of the fluid dosage form 930. The gas contained within the housing interior 905c moves longitudinally through the second opening 905bb and then laterally through the vent channel 905f, entering the GI lumen environment so that the distal end of the housing 905b remains positioned relative to the GI lumen wall.

[0174] Referring to Figure 18, when the payload delivery module 920 has made sufficient axial movement relative to the housing 905 (e.g., so that the needle 922 advances to the desired penetration depth, in this example, to the peritoneal cavity), the puncture member body 926b engages with the inner surface of the housing 905 near the distal end 905b of the housing. This then deforms (e.g., bends, pivots) the puncture member 926 relative to the piston 921 via the puncture member arm 926c so that the puncture member tip 926a advances through the valve opening 921e and punctures the reservoir seal 927. The sufficient relative movement of the puncture member 926 creates a substantial liquid-tight seal between the puncture member body 926b and the piston 921 in the valve opening 921e via an interference fit.

[0175] Referring to Figures 18 and 19, when the puncture member 926 punctures the reservoir seal 927, the gas pressure applied to the membrane 929 (represented by the directional arrow 960) deforms the membrane 929 inward toward the needle 922 relative to the piston 921, thereby discharging the fluid dosage form 930 from the reservoir 929a to the needle 922 through the punctured opening in the reservoir seal 927. As a result, the fluid dosage form 930 is guided into the peritoneal cavity through the piston fluid channel 921h, the needle fluid channel 923a, and the needle discharge opening 923b until the reservoir 929a is substantially discharged from the fluid dosage form 930. In this way, one or more therapeutic agents contained in the fluid dosage form 930 can be delivered to the subject for systemic uptake.

[0176] As described above, the fluid dosage form 930 remains in the reservoir 929a until the puncture member 926 punctures the reservoir seal 927, while the gas pressure in the balloon 902 (not shown) is applied to the membrane 929. In this way, the device 900a can substantially avoid discharging the fluid dosage form 930 into the luminal environment and allow for sequential timing between penetrating the GI luminal wall or surrounding tissue and discharging the fluid dosage form 930 in order to ensure delivery of the fluid dosage form 930 into the GI luminal wall or surrounding tissue for systemic uptake.

[0177] Figure 20 illustrates an ingestible device 900a' (another embodiment of the ingestible device 100) which includes a different version of the payload delivery module 920 (indicated as payload delivery module 920a) having a plunger 931 instead of a membrane 929. Payload delivery module 920a is the same as payload delivery module 920 except as described above. Therefore, for efficiency, similar reference numbers refer to similar components among the examples.

[0178] As shown in Figure 20, the plunger 931 is movably (e.g., slidably) coupled to the piston 921 in the piston interior 921c to define a reservoir 931a for containing the fluid dosage form 930. In this example, the plunger 931 includes a seal 932 coupled to its outer circumference to seal and engage the piston 921 to substantially contain the fluid dosage form 930 in the reservoir 931a. It is shown that the plunger 931 is partially disposed in the piston interior 921c to allow relative sliding motion between the plunger 931 and the piston 921. The reservoir 931a can define a volume for containing about 50 to 250 μl of fluid, including about 50 μl, 100 μl, 150 μl, 200 μl, 250 μl, or any value in between.

[0179] The payload delivery module 920a can be filled with the fluid dosage form 930 in the same manner as the payload delivery module 920 described herein. For example, a vacuum can be drawn onto the plunger 931 through the first opening 905aa to fill the reservoir 931a with the fluid dosage form 930 until the plunger 931 contacts the cover 908.

[0180] Device 900a may have the same operating sequence as device 900 described herein. For example, when the puncture member 926 penetrates the reservoir seal 927, the gas pressure (not shown) applied to the plunger 931 through the opening 905aa moves the plunger 931 toward the needle 922 relative to the piston 921, thereby discharging the fluid dosage form 930 from the reservoir 931a to the needle 922 through the punctured opening in the reservoir seal 927. As a result, the fluid dosage form 930 is guided into the GI lumen wall or surrounding tissue through the piston fluid channel 921h, the needle fluid channel 923a, and the needle discharge opening 923b until the reservoir 931a is substantially discharged from the fluid dosage form 930.

[0181] Figure 24 is a partial cross-sectional view of an ingestible device 100b (another embodiment of the ingestible device 100), which includes a second modular delivery assembly 104b coupled to a balloon 102. The device 100b is shown in a first state before inflation of the balloon 102 in a desired location on a target GI tube for delivery of a solid dosage form 150. As shown in Figure 24, a second payload delivery module 140 is coupled to the housing 105. Specifically, the ejector 140a is releasably coupled to the housing 105 via a press-fit arrangement between a piston release 142c and a housing release 105e. The cartridge 140b is coupled to the housing 105 at the distal end 105b of the housing via a press-fit arrangement.

[0182] Figure 25 illustrates the ingestible device 100b in a second state after the device 100b has reached a desired location within the target GI tube (e.g., stomach, small intestine, large intestine) for delivery of the fluid dosage form 150. In this example, the device 100b is shown in the small intestine. As shown in Figure 25, the balloon 102 is inflated by gas generated within the balloon interior 102e such that the elongated section 102d is substantially aligned with the surface of the GI lumen wall and the distal end 105b of the housing 105 is oriented and positioned relative to (e.g., in close proximity to or in contact with) the surface of the GI lumen wall (as discussed above with reference to Figures 1 and 2). The generated gas within the interior 102e exerts pressure (indicated by a unidirectional arrow 160) against the outer surface of the piston 142 at the proximal end 142a of the piston through the first opening 105aa of the housing 105. When the gas pressure reaches or exceeds a threshold (e.g., a pressure associated with the fully or partially inflated state of balloon 102, such as approximately 10–40 psi), the piston release 142c overcomes the press-fit interface with the housing release 105e. As a result, the piston 142 moves axially relative to the housing 105 along the longitudinal axis 105d toward the GI lumen wall, such that the distal end 142b of the piston advances through the first seal 148a and applies force to the surface of the solid dosage form 150 (e.g., the bottom surface of the needle structure 152). In response to the applied force, the solid dosage form 150 advances from the container interior 146c as a projectile through the second seal 148b along the longitudinal axis 105d, penetrates the GI lumen wall, and enters the peritoneum / peritoneal cavity.

[0183] In the example shown in Figure 25, the solid dosage form 150 advances into the peritoneal cavity of the target by partially passing through the GI lumen wall. In other examples, the solid dosage form 150 is discharged to different penetration depths, such as entering a layer of the GI lumen wall or completely entering the peritoneum / peritoneal cavity to release one or more therapeutic agents contained therein. Once penetrated to the desired depth, the needle structure 152 may disintegrate in place (partially or completely) to expose the composition 154 to body tissues and / or body fluids, thereby allowing the composition 154 to disintegrate and release one or more therapeutic agents contained therein. In this way, one or more therapeutic agents contained in the composition 154 can be delivered to the target to treat a disease or condition.

[0184] As with other examples described herein, one or more components of the ingestible device 100b (e.g., balloon 102, needle structure 152) may be configured to degrade within the GI lumen wall or surrounding tissue, or within other areas of the GI tube, upon completion of delivery of the solid dosage form 150.

[0185] Referring here to Figure 26, a partial cross-sectional view of another example of housing 105 is illustrated as housing 805, which includes a sleeve 805g for receiving cartridge 140b. Housing 805 may be constructed in the same way as housing 105, having the same opening feature 105e, except as described above. Thus, for efficiency, similar reference numbers refer to similar components among the examples, but are increased by only 700 (for example, housing interior 805c is equivalent to housing interior 105c).

[0186] As shown in Figure 26, the sleeve 805g has a substantially cylindrical shape and extends longitudinally from the distal end 805b of the housing. The sleeve 805g can advantageously help axially align the cartridge 140b within the housing interior 805c. The sleeve 805g can also help hold the cartridge 140b against the housing 805 via a press-fit arrangement.

[0187] Referring here to Figure 27, an exemplary method 1000 for delivering a dosage form into the lumen wall or surrounding tissue of a subject using an ingestible device 100 is illustrated. In the first step, the subject ingests the device 100 (e.g., by swallowing the device 100) (step 1001). As a result of ingestion, the enclosure 200 and / or outer coating 202 disintegrate at least partially (or almost completely) when the device 100 reaches the desired location in the GI tube for dosage form delivery (step 1002). In response to the disintegration of the enclosure 200 and / or outer coating 202, a release 116 is activated to inflate the balloon 102 in the GI lumen (step 1003). The inflation of the balloon 102 in the GI lumen causes the delivery assembly 104 to be oriented and positioned relative to the GI lumen wall (step 1004). When the gas pressure inside the balloon 102e reaches or exceeds a threshold, the gas pressure applied to the payload delivery module 106 causes the payload delivery module 106 to deliver the dosage form into the GI lumen wall or surrounding tissue, as described herein (step 1005). In this way, the device 100 can deliver one or more therapeutic agents contained in the dosage form to a target for systemic uptake.

[0188] Treatment drugs As described above, the ingestible devices, payload delivery modules, and assemblies described herein can accommodate at least one therapeutic agent. The identity of the therapeutic agent is not particularly limited. In one or more embodiments, at least one therapeutic agent comprises one or more selected from small molecules, peptides, polypeptides, proteins, antibodies, hormones, or nucleic acids. In one or more embodiments, at least one therapeutic agent is one or more selected from immunosuppressants, chemotherapeutic agents, central nervous system (CNS) agents, antidiabetic agents, enzyme replacement therapy (ERT) agents, anti-infective agents, monoclonal antibodies, anticoagulants, blood clotting factors, insulin, incretins or combinations thereof, or oligonucleotides. In one or more embodiments, at least one therapeutic agent comprises an antisense oligonucleotide (ASO). In one or more embodiments, the ASO is MALAT1 ASO. In one or more embodiments, at least one therapeutic agent comprises a C-type natriuretic peptide (CNP). In one or more embodiments, at least one therapeutic agent comprises a programmed cell death ligand 1 (PD-L1) protein. In one or more embodiments, at least one therapeutic agent comprises a monoclonal antibody. In one or more embodiments, the monoclonal antibody comprises a TNF-α inhibitory antibody. In one or more embodiments, the TNF-α inhibitory antibody comprises adalimumab or an analog thereof. In one or more embodiments, the monoclonal antibody comprises an anti-protease proprotein convertase subtilisin / kexin type 9 (anti-PCSK9) antibody. In one or more embodiments, the monoclonal antibody comprises an anti-interleukin antibody. In one or more embodiments, the anti-interleukin antibody targets interleukin-4 and interleukin-13. In one or more embodiments, the anti-interleukin antibody comprises dupilumab or an analog thereof. In one or more embodiments, the anti-interleukin antibody targets interleukin-2. In one or more embodiments, the anti-interleukin antibody targets at least one of interleukin-12 or interleukin-23. In one or more embodiments, the anti-interleukin antibody comprises ustekinumab or an analog thereof.In one or more embodiments, at least one therapeutic agent comprises parathyroid hormone (PTH) or an analogue thereof. In one or more embodiments, at least one therapeutic agent comprises amylin or an analogue thereof. In one or more embodiments, at least one therapeutic agent comprises one or more incretins or analogues selected from GLP-1, GLP-2, GIP, PYY, or glucagon receptor agonists.

[0189] Metastasis-associated transcript 1 (MALAT1) is a large, largely unspliced ​​non-coding ribonucleic acid (RNA). MALAT1 is closely involved in various pathological processes, from diabetic complications to cancer. For example, MALAT1 regulates the expression of metastasis-related genes. In fact, metastatic tumors are dependent on MALAT1 and cannot survive without it. Therefore, increased MALAT1 expression correlates with decreased overall survival in various types of cancer, suggesting that this gene may be a prognostic factor. Gene deletion or systemic knockdown of MALAT1 using MALAT1 ASO has been shown to slow tumor growth, with significant differentiation into cystic tumors and a reduction in metastasis. Therefore, MALAT1 ASO may be a potential therapy for inhibiting the progression of certain cancers, such as lung cancer, pancreatic cancer, and cervical cancer. MALAT1 ASO is typically administered by subcutaneous injection, but can be delivered according to this disclosure. For example, MALAT1 formulated as a liquid dosage form can be used in one embodiment of an ingestible device described herein (i.e., an embodiment of an ingestible device 100 configured to deliver a fluid dosage form). For example, a suitable amount of MALAT1 formulated as a liquid dosage form can be loaded into an embodiment of an ingestible device described herein, configured to deliver a fluid dosage form, such as MALAT1 formulated as a liquid dosage form at a dose of 0.5 mg / kg to the target being treated, or at a concentration of 10 mg / ml.

[0190] Adalimumab, marketed under the brand name HUMIRA® and its biosimiras, is a fully human, high-affinity, recombinant antitumor necrosis factor (TNF) alpha monoclonal antibody used to treat rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, hidradenitis suppurativa, juvenile idiopathic arthritis, and uveitis. Adalimumab is a molecule containing 1330 amino acids and has a molecular weight of approximately 148 kDa. Adalimumab inhibits the interaction of TNF alpha with p55 (TNFR1) and p75 (TNFR2) cell surface TNF receptors, thereby consequently disrupting cytokine-driven inflammatory processes. Adalimumab is currently available as an injectable preparation and can be delivered in accordance with this disclosure. For example, adalimumab formulated as a liquid dosage form can be used in one embodiment of an ingestive device described herein (i.e., an embodiment of an ingestive device 100 configured to deliver a fluid dosage form). For example, a suitable amount of adalimumab formulated as a liquid dosage form (e.g., HUMIRA®) can be loaded into an embodiment of an ingestive device described herein configured to deliver a fluid dosage form, as illustrated in Example 2. For example, each device may contain a therapeutically effective dose of adalimumab in the range of about 3 to 11 mg, such as about 3 mg, 5 mg, 7 mg, 9 mg, 11 mg, or any value in between, or an amount of adalimumab effective to deliver any such therapeutically effective dose.

[0191] Dupilumab, marketed under the brand name DUPIXENT®, is a monoclonal antibody that blocks human IL-4 and IL-13 and is used to treat allergic diseases such as eczema, asthma, and nasal polyps that cause chronic sinusitis. Dupilumab is also used to treat eosinophilic esophagitis and nodular prurigo. Dupilumab is currently available as an injectable but can be delivered in accordance with this disclosure. For example, dupilumab formulated as a liquid dosage form can be used in one embodiment of an ingestable device described herein (i.e., an embodiment of an ingestable device 100 configured to deliver a fluid dosage form). For example, a preferred dose of dupilumab formulated as a liquid dosage form (e.g., DUPIXENT®) can be loaded into an embodiment of an ingestable device described herein, configured to deliver a fluid dosage form, as illustrated in Example 3. For example, each device may contain a therapeutically effective dose of dupilumab in the range of approximately 16–30 mg, such as approximately 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, or any value in between, or may contain an amount of dupilumab effective to deliver any such therapeutically effective dose. In other examples, each device may contain a therapeutically effective dose of dupilumab in the range of approximately 20–25 mg, such as approximately 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, or any value in between, or may contain an amount of dupilumab effective to deliver any such therapeutically effective dose.

[0192] RTJH23 is a monomolecule triagonist manufactured by Jiangsu Hengrui Pharmaceuticals. RTJH23 has physiological effects on GLP-1, GIP, and glucagon receptors, resulting in weight loss due to early satiety (and blood glucose control in diabetic patients). RTJH23 is currently available as an injectable preparation, but can be delivered in accordance with this disclosure. For example, RTJH23 or another incretin agonist formulated as a liquid dosage form can be used in one embodiment of an ingestive device described herein (i.e., an embodiment of an ingestive device 100 configured to deliver a fluid dosage form). For example, a suitable amount of an incretin triagonist formulated as a liquid dosage form (e.g., RTJH23) can be loaded into an embodiment of an ingestive device described herein, configured to deliver a fluid dosage form. For example, RTJH23 can be administered in a dose of 0.12 mg / kg and / or a volume dose of 0.05 ml / kg, as illustrated in Example 4.

[0193] Ustekinumab, marketed under the brand name STELARA® and its biosimilars, is a recombinant human IgG1κ monoclonal antibody produced in a mouse cell line (Sp2 / 0) that acts as a human interleukin-12 and human interleukin-23 antagonist. Ustekinumab is used to treat moderate to severe psoriasis vulgaris, psoriatic arthritis, moderate to severe Crohn's disease, and moderate to severe ulcerative colitis. Ustekinumab is administered by subcutaneous or intravenous injection, but can be delivered in accordance with this disclosure. For example, ustekinumab formulated as a liquid dosage form can be used in one embodiment of an ingestive device described herein (i.e., an embodiment of an ingestive device 100 configured to deliver a fluid dosage form). For example, a preferred dose of ustekinumab formulated as a liquid dosage form (e.g., Celltrion CT-P43 biosimira of STELARA®) can be loaded into an embodiment of an ingestible device described herein, configured to deliver the fluid dosage form, as illustrated in Example 5. For example, ustekinumab can be administered in a dose of 18 mg, as illustrated in Example 5. In other examples, each device may contain a therapeutically effective dose of ustekinumab in the range of about 10–22 mg, such as about 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, or any value in between, or may contain an amount of ustekinumab effective to deliver any such therapeutically effective dose.

[0194] Table 1 below lists some other specific therapeutic agents, approved dosages, and related indications that may be used to treat patients in accordance with this disclosure. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0195] Embodiment The following non-limiting embodiments are included in this disclosure.

[0196] Embodiment 1: A payload delivery module for an ingestionable device, the payload delivery module comprising: a piston including an interior; a hollow needle coupled to the piston; a membrane coupled to the piston to define a reservoir inside; a fluid dosage form disposed in the reservoir, comprising at least one therapeutic agent; and a valve coupled to the piston to control the flow of the fluid dosage form from the reservoir to the needle.

[0197] Embodiment 2: A payload delivery module for an ingestionable device, the payload delivery module comprising: a piston including an interior; a hollow needle coupled to the piston; a plunger movably coupled to the piston to define a reservoir inside; a fluid dosage form disposed in the reservoir, comprising at least one therapeutic agent; and a valve coupled to the piston to control the flow of the fluid dosage form from the reservoir to the needle.

[0198] Embodiment 3: A payload delivery module for an ingestionable device, the payload delivery module comprising: a piston including a base and an elongated section; a cartridge including a container; and a solid dosage form disposed within the container, comprising at least one therapeutic agent.

[0199] Embodiment 4: A payload delivery module for an ingestionable device, the payload delivery module comprising: a piston including an internal, needle port and filling port; a membrane coupled to the piston to define an internal reservoir for containing a fluid dosage form; and a valve coupled to the piston between the membrane and the needle port.

[0200] Embodiment 5: A payload delivery module for an ingestionable device, the payload delivery module comprising: a piston including an internal, needle port and filling port; a plunger movably coupled to the piston to define an internal reservoir for containing a fluid dosage form; and a valve coupled to the piston between the plunger and the needle port.

[0201] Embodiment 6: A payload delivery module according to any one of Embodiments 1 to 5, wherein the piston is configured to be releasably coupled to a housing and movably disposed within the housing.

[0202] Embodiment 7: A payload delivery module according to any one of Embodiments 1, 2, 4, and 5, wherein a valve is configured to control the flow of a fluid dosage form from a reservoir to a needle in response to the axial movement of the module relative to the housing.

[0203] Embodiment 8: A payload delivery module according to any one of Embodiments 1 to 5, wherein the piston includes a lateral wall defining a release feature for releasably coupling the piston to the housing. Embodiment 9: A payload delivery module according to Embodiment 8, wherein the release feature is defined by the outer circumferential surface of the piston. Embodiment 10: A payload delivery module according to Embodiment 8 or 9, wherein the release feature includes a press-fit feature.

[0204] Embodiment 11: A payload delivery module according to any one of Embodiments 1, 2, 4, and 5, wherein the valve comprises a seal coupled to a piston to contain a fluid dosage form in a reservoir. Embodiment 12: A payload delivery module according to Embodiment 11, wherein the valve further comprises a puncture member coupled to the piston adjacent to the seal, the puncture member being configured to move relative to the piston to penetrate the seal. Embodiment 13: A payload delivery module according to Embodiment 12, wherein the puncture member is configured to create a substantially liquid-tight seal with the piston when it penetrates the seal. Embodiment 14: A payload delivery module according to Embodiment 11, wherein the valve further comprises a base protruding from the outer surface of the piston and a tip coupled to the base. Embodiment 15: A payload delivery module according to Embodiment 14, wherein the base is integral with the piston. Embodiment 16: A payload delivery module according to Embodiment 14 or 15, wherein the base is configured to deform to allow the tip to move relative to the piston and penetrate the seal.

[0205] Embodiment 17: A payload delivery module according to any one of Embodiments 1, 2, 4, and 5, wherein the valve comprises a base protruding from the outer surface of a piston and a plug adjacent to the base and releasably coupled to the piston. Embodiment 18: A payload delivery module according to Embodiment 17, wherein the plug creates a substantially liquid-tight seal between the membrane and the piston and the needle for containing a fluid dosage form in a reservoir. Embodiment 19: A payload delivery module according to Embodiment 17 or 18, wherein the base is configured to deform to release the plug from the piston and allow the fluid dosage form to flow into the needle.

[0206] Embodiment 20: A payload delivery module according to Embodiment 1 or 4, wherein the membrane includes a flexible material to allow deformation of the membrane when the valve opens due to pressure applied to the outer surface of the membrane.

[0207] Embodiment 21: The payload delivery module according to Embodiment 1 or 4, wherein the film comprises a metallized film or a coating.

[0208] Embodiment 22: The payload delivery module according to Embodiment 2 or 5, wherein the plunger is configured to move relative to the piston when the valve opens in response to pressure applied to the outer surface of the plunger.

[0209] Embodiment 23: A payload delivery module according to any one of Embodiments 1, 2, 4, or 5, wherein the reservoir defines a volume for containing up to approximately 250 μl of fluid. Embodiment 24: A payload delivery module according to Embodiment 23, wherein the reservoir defines a volume for containing approximately 50 to 200 μl of fluid.

[0210] Embodiment 25: The payload delivery module according to Embodiment 1 or 4, wherein the needle has a critical length in the range of about 3.5 to 12 mm so that the needle can deliver a fluid dosage form into the peritoneal cavity through the GI lumen wall.

[0211] Embodiment 26. The payload delivery module according to Embodiment 1 or 4, wherein the needle has a critical length in the range of about 1.5 to 3 mm so that the fluid dosage form is delivered into the layer of the GI lumen wall.

[0212] Embodiment 27: A payload delivery module according to Embodiment 1 or 4, wherein the needle comprises a biodegradable material that allows for the decomposition of at least a portion of the needle within the GI lumen wall or surrounding tissue. Embodiment 28: A payload delivery module according to Embodiment 27, wherein the needle comprises a body and a tip coupled to the body, the body being formed from a first material and the tip being formed from a second material, the second material having a hardness greater than that of the first material.

[0213] Embodiment 29: A payload delivery module according to any one of Embodiments 1 to 5, further comprising a cover releasably coupled to a piston. Embodiment 30: A payload delivery module according to Embodiment 29, wherein the cover defines a portion of a housing for holding the payload delivery module.

[0214] Embodiment 31: The payload delivery module according to Embodiment 3, wherein the solid dosage form is molded as a needle structure or housed in a needle structure.

[0215] Embodiment 32: The payload delivery module according to Embodiment 31, wherein an elongated section of the piston is configured to discharge a needle structure from the container as a projectile into the GI lumen wall or surrounding tissue.

[0216] Embodiment 33: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent is one or more selected from small molecules, peptides, polypeptides, proteins, hormones, antibodies, or nucleic acids.

[0217] Embodiment 34: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent is one or more selected from immunosuppressants, chemotherapeutic agents, central nervous system (CNS) agents, antidiabetic agents, enzyme replacement therapy (ERT) agents, anti-infective agents, C-type natriuretic peptide (CNP), programmed cell death ligand 1 (PD-L1) protein, monoclonal antibodies, anticoagulants, blood coagulation factors, insulin, incretins or combinations thereof, or oligonucleotides.

[0218] Embodiment 35: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent comprises an antisense oligonucleotide (ASO). Embodiment 36: A payload delivery module according to Embodiment 35, wherein the ASO is MALAT1.

[0219] Embodiment 37: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent comprises one or more blood coagulation factors or their mimics selected from factor VIII, factor IX, or factor X.

[0220] Embodiment 38: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent comprises an anti-PCSK9 antibody.

[0221] Embodiment 39: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent comprises a TNF-α inhibitory antibody. Embodiment 40: A payload delivery module according to Embodiment 39, wherein the TNF-α inhibitory antibody comprises adalimumab or an analogue thereof.

[0222] Embodiment 41: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent comprises an anti-interleukin antibody. Embodiment 42: A payload delivery module according to Embodiment 41, wherein the anti-interleukin antibody targets interleukin 4 and interleukin 13. Embodiment 43: A payload delivery module according to Embodiment 42, wherein the anti-interleukin antibody comprises dupilumab or an analog thereof. Embodiment 44: A payload delivery module according to Embodiment 41, wherein the anti-interleukin antibody targets at least one of interleukin 12 or interleukin 23. Embodiment 45: A payload delivery module according to Embodiment 44, wherein the anti-interleukin antibody comprises ustekinumab or an analog thereof. Embodiment 46: A payload delivery module according to Embodiment 41, wherein the anti-interleukin antibody targets interleukin 2.

[0223] Embodiment 47: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent comprises parathyroid hormone (PTH) or an analogue thereof.

[0224] Embodiment 48: A payload delivery module according to any one of Embodiments 1 to 3, wherein at least one therapeutic agent comprises amylin or an analogue thereof.

[0225] Embodiment 49: A payload delivery module according to any one of Embodiments 1 to 3, comprising one or more incretins or their mimics, wherein at least one therapeutic agent is selected from GLP-1, GLP-2, GIP, PYY, or a glucagon receptor agonist.

[0226] Embodiment 50: A delivery assembly for an ingestionable device, wherein the delivery assembly comprises a housing and a payload delivery module according to any one of Embodiments 1 to 49 coupled to the housing. Embodiment 51: The delivery assembly according to Embodiment 50, wherein the housing comprises a proximal end, a distal end, a piston chamber located between the proximal and distal ends, and a housing release feature, the proximal end comprising a first opening for receiving force internally, and the distal end comprising a second opening for discharging a dosage form. Embodiment 52: The delivery assembly according to Embodiment 51, wherein the housing further comprises a body and a cover coupled to the body, the body comprising a second opening and a piston chamber, and the cover comprising a first opening and a housing release feature. Embodiment 53: The delivery assembly according to Embodiment 51 or 52, wherein a piston is disposed within the piston chamber and releasably coupled to the housing release feature. Embodiment 54: The delivery assembly according to any one of Embodiments 51 to 53, further comprising a seal coupled to the housing at a second opening. Embodiment 55: A delivery assembly according to any one of embodiments 51 to 54, wherein the housing further comprises a vent channel for discharging gas. Embodiment 56: A delivery assembly according to any one of embodiments 51 to 55, wherein the force is gas pressure. Embodiment 57: A delivery assembly according to embodiment 56, wherein the housing release feature is configured to release a piston in response to a threshold gas pressure applied to the module through a first opening, and the threshold gas pressure is about 10 to 40 psi. Embodiment 58: A delivery assembly according to any one of embodiments 51 to 57, wherein the housing release feature is located on the lateral wall of the housing. Embodiment 59: A delivery assembly according to any one of embodiments 51 to 58, wherein the housing release feature includes a press-fit feature. Embodiment 60: A delivery assembly according to any one of embodiments 51 to 59, wherein the housing release feature extends circumferentially around the housing.Embodiment 61: A delivery assembly according to any one of Embodiments 51 to 60, wherein, when the payload delivery module includes a fluid dosage form, the module is configured to move axially within a piston chamber to insert a hollow needle into the GI lumen wall or surrounding tissue through a second opening, and to discharge the fluid dosage form through the hollow needle into the GI lumen wall or surrounding tissue in response to a force received through a first opening. Embodiment 62: A delivery assembly according to Embodiment 61, wherein the fluid dosage form is discharged from a reservoir when a valve opens in response to sufficient axial movement of the module relative to the housing. Embodiment 63: A delivery assembly according to Embodiment 61 or 62, wherein the fluid dosage form is discharged through the hollow needle after the hollow needle has penetrated the GI lumen wall or surrounding tissue. Embodiment 64: A delivery assembly according to any one of Embodiments 51 to 60, wherein, when the payload delivery module includes a solid dosage form, the cartridge is coupled to a housing and a piston is configured to move axially within a piston chamber in response to a force received through a first opening, thereby ejecting the solid dosage form from the container as a projectile into the GI lumen wall or surrounding tissue.

[0227] Embodiment 65: An ingestible device comprising an expandable member and a delivery assembly according to any one of Embodiments 50 to 64 coupled to the expandable member. Embodiment 66: The ingestible device according to Embodiment 65, further comprising a gas generation mechanism coupled to the expandable member. Embodiment 67: The ingestible device according to Embodiment 66, wherein the gas generation mechanism is configured to generate gas to expand the expandable member at a location within the GI tubule of the subject, thereby oriented and positioning the delivery assembly relative to the GI lumen wall. Embodiment 68: The ingestible device according to Embodiment 67, wherein the location is the small intestine of the subject. Embodiment 69: The ingestible device according to any one of Embodiments 66 to 68, wherein the gas generation mechanism comprises a plurality of reactants separated from each other by a decomposable release. Embodiment 70: The ingestible device according to any one of Embodiments 65 to 69, wherein, upon expansion of the expandable member, the delivery assembly is configured to deliver a dosage form through the GI lumen wall into the peritoneum or peritoneal cavity of the subject for systemic uptake of at least one therapeutic agent. Embodiment 71: An ingestible device according to any one of embodiments 65 to 69, wherein, upon expansion of the expandable member, the delivery assembly is configured to deliver a dosage form into a layer of the GI lumen wall for systemic uptake of at least one therapeutic agent. Embodiment 72: An ingestible device according to any one of embodiments 65 to 71, wherein the expandable member includes a balloon. Embodiment 73: An ingestible device according to any one of embodiments 65 to 72, further comprising an ingestible enclosure, wherein the expandable member and the delivery assembly are disposed within the ingestible enclosure. Embodiment 74: An ingestible device according to embodiment 73, wherein the ingestible enclosure includes a biodegradable material that allows for the decomposition of at least a portion of the ingestible enclosure within the GI tube. Embodiment 75: An ingestible device according to embodiment 73 or 74, further comprising a coating disposed on at least a portion of the ingestible enclosure, wherein the coating is configured to decompose at a selected pH within the GI tube.Embodiment 76: An ingestible device according to any one of Embodiments 73 to 75, wherein the ingestible enclosure is a swallowable capsule of size 00 or size 000.

[0228] Embodiment 77: A method for preparing an ingestible device for delivering a therapeutic agent into the luminal wall or surrounding tissue of a target GI, the method comprising filling a dosage form containing the therapeutic agent into a payload delivery module according to any one of Embodiments 1 to 49.

[0229] Embodiment 78: A method for delivering a therapeutic agent into the luminal wall or surrounding tissue of a subject requiring the therapeutic agent, wherein the method comprises, depending on the subject, ingesting an ingestible device described in any one of Embodiments 65 to 76.

[0230] Embodiment 79: A method for delivering oligonucleotides to a patient in need, the method comprising administering to the patient by swallowing an ingestible device described in any one of Embodiments 65 to 76, wherein at least one therapeutic agent comprises an oligonucleotide in a liquid form in a therapeutically effective dose, and upon swallowing the device, an expandable member expands within the patient's GI duct, thereby delivering the therapeutically effective dose of oligonucleotide into the luminal wall or surrounding tissue of the GI duct. Embodiment 80: The method according to Embodiment 79, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). Embodiment 81: The method according to Embodiment 80, wherein the ASO comprises MALAT1 ASO.

[0231] Embodiment 82: A method for delivering a TNF-α inhibitory antibody to a patient in need, the method comprising administering to the patient by swallowing an ingestible device described in any one of Embodiments 65 to 76, wherein at least one therapeutic agent comprises a therapeutically effective dose of a TNF-α inhibitory antibody in liquid form, and upon swallowing the device, an expandable component expands within the patient's GI duct, thereby delivering a therapeutically effective dose of the TNF-α inhibitory antibody into the luminal wall or surrounding tissue of the GI duct. Embodiment 83: The method according to Embodiment 82, wherein the TNF-α inhibitory antibody comprises adalimumab. Embodiment 84: The method according to Embodiment 83, wherein the adalimumab is HUMIRA® or a biosimilar thereof. Embodiment 85: The method according to Embodiment 84, wherein the therapeutically effective dose is about 3 to 11 mg.

[0232] Embodiment 86: A method for delivering an anti-interleukin antibody to a patient in need, the method comprising administering to the patient by swallowing an ingestible device described in any one of Embodiments 65 to 76, wherein at least one therapeutic agent comprises an effective therapeutic dose of an anti-interleukin antibody in liquid form, and upon swallowing the device, an expandable component expands within the patient's GI tubule, thereby delivering the effective therapeutic dose of the anti-interleukin antibody into the luminal wall or surrounding tissue of the GI tubule. Embodiment 87: The method according to Embodiment 86, wherein the anti-interleukin antibody targets interleukin 4 and interleukin 13. Embodiment 88: The method according to Embodiment 87, wherein the anti-interleukin antibody comprises dupilumab. Embodiment 89: The method according to Embodiment 88, wherein dupilumab is DUPIXENT® or a biosimira thereof. Embodiment 90: The method according to Embodiment 89, wherein the effective therapeutic dose is about 16 to 30 mg. Embodiment 91: The method according to Embodiment 89, wherein the effective therapeutic dose is about 20 to 25 mg. Embodiment 92: The method according to Embodiment 86, wherein the anti-interleukin antibody targets at least one of interleukin 12 or interleukin 23. Embodiment 93: The method according to Embodiment 92, wherein the anti-interleukin antibody comprises ustekinumab. Embodiment 94: The method according to Embodiment 93, wherein ustekinumab is STELARA® or its biosimira. Embodiment 95: The method according to any one of Embodiments 86 to 94, wherein the therapeutically effective dose of the anti-interleukin antibody delivered to the patient provides in the patient substantially the same bioavailability as the subcutaneous dose of the anti-interleukin antibody. Embodiment 96: The method according to any one of Embodiments 86 to 94, wherein the therapeutically effective dose of the anti-interleukin antibody delivered to the patient provides in the patient a higher bioavailability than the subcutaneous dose of the anti-interleukin antibody. Embodiment 97: The therapeutically effective dose of the anti-interleukin antibody delivered to the patient provides in the patient a higher bioavailability than the subcutaneous dose of the anti-interleukin antibody. max Exceeding C maxThe method according to any one of embodiments 86 to 94, which brings about the following: Embodiment 98: The therapeutically effective dose of the anti-interleukin antibody delivered to the patient is the same as the subcutaneous dose of the anti-interleukin antibody in the patient. max t is less than max A method according to any one of embodiments 86 to 94, which brings about the following:

[0233] Embodiment 99: A method for delivering at least one incretin to a patient in need, the method comprising administering to the patient by swallowing an ingestible device described in any one of Embodiments 65 to 76, wherein at least one therapeutic agent comprises at least one incretin in a therapeutically effective dose in liquid form, and upon swallowing the device, an expandable member expands within the patient's GI duct, thereby delivering a therapeutically effective dose of at least one incretin into the luminal wall or surrounding tissue of the GI duct. Embodiment 100: The method according to Embodiment 99, wherein at least one incretin is an incretin triagonist comprising GLP-1, GIP, and a glucagon receptor agonist. Embodiment 101: The method according to Embodiment 100, wherein the therapeutically effective dose of the incretin triagonist delivered to the patient results in a weight loss in the patient that is substantially the same as that produced by a subcutaneous dose of the incretin triagonist.

[0234] Embodiment 102: A modular delivery assembly for an ingestable device for delivering a dosage form into the luminal wall or surrounding tissue of a target GI, wherein the delivery assembly comprises a housing having a proximal end, a distal end, and an interior located between the proximal and distal ends, the proximal end including a first opening for receiving force into the interior, the distal end including a second opening for discharging a dosage form, and the interior including a receptacle configured to receive a module selected from a first payload delivery module containing a fluid dosage form and a second payload delivery module containing a solid dosage form, and the housing further comprising a release feature for releasably coupling the module to the housing. Embodiment 103: The modular delivery assembly according to Embodiment 102, wherein the first payload delivery module has a first delivery mode, and the second payload delivery module has a second delivery mode different from the first delivery mode. Embodiment 104: A modular delivery assembly according to Embodiment 103, wherein the first delivery mode includes inserting a hollow needle into the GI lumen wall or surrounding tissue and discharging a fluid dosage form through the hollow needle into the GI lumen wall or surrounding tissue. Embodiment 105: A modular delivery assembly according to Embodiment 103 or 104, wherein the second delivery mode includes discharging a solid dosage form as a projectile from a second payload delivery module into the GI lumen wall or surrounding tissue.

[0235] Embodiment 106: A delivery assembly for an ingestionable device, the delivery assembly comprising a housing having a proximal end, a distal end, a piston chamber positioned between the proximal and distal ends, and a release feature, wherein the proximal end includes a first opening for receiving force internally and the distal end includes a second opening for discharging a dosage form; and a payload delivery module disposed within the housing, the payload delivery module comprising a piston and a dosage form comprising at least one therapeutic agent, wherein the piston is releasably coupled to the release feature and configured to move axially within the piston chamber between the proximal and distal ends in response to a force for discharging the dosage form from the housing.

[0236] Embodiment 107: An ingestible device comprising: an expandable member; and a delivery assembly coupled to the expandable member, the delivery assembly comprising a fluid dosage form comprising at least one therapeutic agent, wherein the expandable member is configured to expand within a target GI tubule to position the delivery assembly relative to the GI lumen wall, and upon expansion of the expandable member, the delivery assembly is configured to deliver the fluid dosage form through the GI lumen wall into the target peritoneum or peritoneal cavity for systemic uptake of at least one therapeutic agent.

[0237] Embodiment 108: An ingestionable device comprising a housing, a piston movably disposed within the housing, a hollow needle coupled to the piston, a fluid dosage form disposed within the housing, comprising a fluid dosage form containing at least one therapeutic agent, and a force generating mechanism operably coupled to the piston. Embodiment 109: The device according to Embodiment 108, wherein the hollow needle has a critical length in the range of about 3.5 to 12 mm such that, upon ingestion of the device, the hollow needle is configured to deliver the fluid dosage form through the GI lumen wall into the peritoneal cavity of the subject for systemic uptake of at least one therapeutic agent. Embodiment 110: The device according to Embodiment 108, wherein the hollow needle has a critical length in the range of about 1.5 to 3 mm such that, upon ingestion of the device, the hollow needle is configured to deliver the fluid dosage form into the layers of the GI lumen wall for systemic uptake of at least one therapeutic agent. [Examples]

[0238] The following embodiments are given to illustrate the present disclosure. However, it should be understood that the present disclosure should not be limited to the specific conditions or details of these embodiments.

[0239] Example 1 - Oral delivery of oligonucleotide dosage form to dogs In dogs weighing approximately 8 - 12 kg, a preliminary pharmacokinetic (PK) study was conducted to evaluate the oral delivery of a MALAT1 ASO liquid formulation obtained from AstraZeneca®. Four vials, each having a volume of 4 ml and a MALAT1 concentration of 10 mg / ml, were used in the study. Five anesthetized dogs each received, via an endoscope, a 0.5 mg / kg dose of MALAT1 ASO as a jejunal injection into the intestinal wall from the intestinal lumen or into the peritoneum or peritoneal cavity through the intestinal wall (collectively referred to in this study as the "transintestinal" route) to mimic oral administration of an ingestible device (i.e., an embodiment of the ingestible device 100 configured to deliver a fluid formulation) as described herein. After a one - week washout period, the same dogs each received a 0.5 mg / kg dose of MALAT1 ASO as a subcutaneous (sc) injection to compare the two routes of administration. Serum samples were collected at regular intervals including before dosing, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing. The results are shown in Figure 32.

[0240] As shown in Figure 32, the transintestinal and subcutaneous (sc) routes resulted in similar PK profiles with equivalent PK parameters including the maximum concentration (C max ), the time to reach C max (t max ), the half - life (t 1 / 2 ), and the area under the curve (AUC). These results support the use of the ingestible devices described herein for the oral delivery of MALAT1 ASO and other oligonucleotide liquid formulations to humans for the treatment of certain cancers such as, for example, lung cancer, pancreatic cancer, and cervical cancer.

[0241] Example 2 - Oral Delivery of a Tumor Necrosis Factor (TNF) Alpha Inhibiting Antibody Formulation to Dogs A preliminary PK study was conducted in dogs to evaluate the oral delivery of the liquid dosage form of HUMIRA® (adalimumab) using embodiments of the ingestible devices described herein (i.e., embodiments of the ingestible device 100 configured to deliver a liquid dosage form). After an overnight fast, four awake dogs weighing approximately 8–12 kg were orally administered and swallowed one device each. Each device contained a dose of approximately 11 mg of HUMIRA® (adalimumab) in liquid form.

[0242] The timing of drug administration was determined by tracking gastrointestinal passage and device deployment using fluoroscopy (t=0). Serum blood samples were collected over three weeks using a validated and qualified ELISA at intervals including 4, 6, 24, and 36 hours post-administration, and daily from day 2 (48 hours) to day 21 (504 hours). All four devices deployed and discharged the dosage form. Furthermore, all four dogs were able to excrete the devices after delivery, and there were no significant findings regarding residue.

[0243] Referring to Figure 33, the mean PK profiles of four oral administration devices were plotted against (1) the mean PK profile of orally administered ingestible devices containing a 4.5 mg solid dosage form adalimumab biosimilar, previously performed in two dogs using ingestible devices configured to deliver the payload into the GI lumen wall or surrounding tissue, and (2) the mean PK profile of adalimumab biosimilars with a 5 mg liquid subcutaneous (sc) injection dose, previously performed in three dogs. As shown in Figure 33, all four dogs administered an 11 mg liquid dose using the embodiment of the ingestible device described herein showed a signal to adalimumab and exhibited adalimumab levels below the quantification level at 12 days. Comparison of area under the curve (AUC) values ​​for the 4.5 mg solid dose, 5 mg SC injection, and 11 mg liquid dose showed a dose-proportional increase in adalimumab exposure levels. The coefficient of variation (%CV) between individual animals was similar across different groups. These results support the use of HUMIRA® and its biosimilars in liquid dosage forms, or other ingestible devices described herein, for orally delivering HUMIRA® and its biosimilars, or other TNF-α inhibitory antibodies to humans, for the treatment of certain autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, hidradenitis suppurativa, juvenile idiopathic arthritis, and uveitis.

[0244] Example 3 - Oral delivery of anti-interleukin (IL-4 and IL-13 targeting) antibody formulations to dogs A preliminary PK (pharmacokinetic) study was conducted in dogs to evaluate the oral delivery of the liquid dosage form of dupilumab using embodiments of the ingestible devices described herein (i.e., embodiments of ingestible device 100 configured to deliver the liquid dosage form) compared to a subcutaneous (SC) administered control. Six awake dogs weighing approximately 7.5–12.4 kg were orally administered and swallowed one device each after an overnight fast, while the SC control group included three awake dogs, each having received a certain dose of dupilumab via SC injection. Each ingestible device contained either a 16.5 mg or 30 mg dose of dupilumab in liquid form. The various dose groups are summarized in Table 2 below. [Table 2]

[0245] The timing of drug administration was determined by tracking gastrointestinal passage and the deployment of orally administered devices using fluoroscopy (t=0). Validated and qualified ProteoGenix was tested over a 3-week period at intervals including 4, 6, 24, and 36 hours post-administration, as well as daily from day 2 (48 hours) to day 21 (504 hours). TM Serum blood samples were collected using an ELISA device manufactured by [manufacturer name]. Twelve of the 14 devices successfully delivered dupilumab, and both oral and SC doses were well tolerated by all dogs. There were no clinically significant findings throughout the study. Mean results are shown in Figure 34, and mean PK parameters are summarized in Table 3 below. [Table 3]

[0246] As shown in Figure 34 and Table 3, oral administration of dupilumab via an ingestionable device resulted in a similar mean PK profile to the respective SC controls, including substantially the same or higher relative bioavailability. Oral administration of dupilumab via an ingestionable device also yielded a higher C than the SC controls. max and short t maxThese results support the use of the ingestible devices described herein for the oral delivery of dupilumab and other anti-interleukin antibodies to humans for the treatment of certain allergic diseases, such as asthma, eczema, chronic sinusitis with nasal polyps, and eosinophilic esophagitis.

[0247] Example 4 - Oral delivery of incretin triagonist formulations to dogs Preliminary pharmacokinetic (PK) and pharmacodynamic (PD) studies evaluating the oral delivery of the RTJH23 liquid dosage form were conducted in dogs weighing 11–13 kilograms (kg). After an overnight fast, five dogs in the first group each received a dose of 0.12 mg / kg of RTJH23 (0.05 ml / kg volume dose) as an intrajejunal injection via endoscope, either from inside the intestinal tract into the intestinal wall, or through the intestinal wall into the peritoneum or peritoneal cavity (collectively referred to in this study as the “enteral” route), to mimic oral administration of an ingestible device as described herein (i.e., embodiments of the ingestible device 100 configured to deliver the fluid dosage form). Five male dogs in the second group each received a dose of 0.12 mg / kg of RTJH23 (0.04 ml / kg volume dose) as a subcutaneous injection.

[0248] For PK evaluation, serum samples were collected over two weeks using a valid and qualified ELISA at intervals including before administration, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration, as well as on days 2, 4, 7, 10, and 14 after administration. For PD evaluation, dogs were monitored daily to determine body weight, fasting blood glucose, liver enzymes (ALT and AST), lipid profiles (total cholesterol, triglycerides, LDL, HDL), and heart rate. The time course of body weight is summarized in Figure 35, and the peak declines in body weight and serum lipids are summarized in Figure 36.

[0249] As shown in Figures 35 and 36, enteral and SC administration routes had substantially the same effect on weight loss, with a weight loss of over 10% observed on day 7 in dogs of both groups, which triggered the IACUC-mandated supplemental high-fat feeding intervention for all dogs for the remainder of the study. After the intervention on day 7, the rate of weight loss slowed, followed by a gradual increase in weight. The weight loss appeared to be due to an initial feeling of fullness leading to reduced calorie intake. Serum lipids also decreased in both groups along with weight loss. In addition, fasting glucose levels tended to be slightly elevated in both groups for up to 72 hours after administration. These results support the use of the ingestible devices described herein for the oral delivery of RTJH23 and other incretin dosage forms to humans, for example, for weight disorders, weight management, or the treatment of other metabolic conditions.

[0250] Example 5 - Oral delivery of anti-interleukin (IL-12 and / or IL-23 targeting) antibody formulations to dogs A preliminary pharmacokinetic (PK) study was conducted in dogs to evaluate the oral delivery of ustekinumab biosimira (CT-P43, manufactured by Celltrion, Inc.) of STELARA® in liquid form using one embodiment of the ingestible device described herein (i.e., an embodiment of the ingestible device 100 configured to deliver a fluid dosage form), compared to a subcutaneous (SC) administered control. After an overnight fast, seven awake dogs were orally administered and swallowed one device each, while the SC control included three awake dogs, each receiving an 18 mg dose of CT-P43 via SC injection. Each ingestible device contained an 18 mg dose of CT-P43 in liquid form. One dog was excluded from the study after vomiting the device following oral administration.

[0251] The gastrointestinal passage and deployment of the orally administered device were tracked by fluoroscopy to determine the time of drug administration (t = 0). Serum samples were collected at intervals including 4 hours, 12 hours, and 24 hours after administration, as well as daily from day 2 to day 12, and on days 14, 16, 18, 21, 23, and 27, using a validated and qualified ELISA. Four of the six devices successfully delivered ustekinumab, and both the oral and SC dosing regimens showed no clinically significant findings throughout the study and were well tolerated by all dogs. The mean results are shown in Figure 37, and the mean PK parameters are summarized in Table 4 below.

Table 4

[0252] As shown in Figure 37 and Table 4, oral administration of ustekinumab via an ingestible device (“RaniPill Oral”) resulted in a mean PK profile similar to that of the SC control (“SC Injection”), but with relatively higher bioavailability, higher C max , and shorter t max than the SC control. These results support the use of the ingestible devices described herein for oral delivery of ustekinumab and other anti-interleukin antibodies to humans for the treatment of, for example, moderate to severe plaque psoriasis, psoriatic arthritis, moderate to severe Crohn's disease, and moderate to severe ulcerative colitis.

[0253] The foregoing description of various embodiments has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise forms disclosed. Many modifications, variations, and improvements will be apparent to those skilled in the art of medicine. For example, embodiments of the device can be sized and otherwise adapted for various pediatric and neonatal applications as well as various veterinary applications. Also, those skilled in the art can recognize or confirm, using only routine experimentation, numerous equivalents to the specific devices and methods described herein. Such equivalents are considered to be within the scope of this disclosure.

[0254] While the present invention has been described and illustrated with reference to specific embodiments, these descriptions and illustrations are not intended to limit the invention. It is clearly understood that various modifications can be made and equivalent components can be replaced within embodiments without departing from the true spirit and scope of the disclosure. Furthermore, components, characteristics, or actions from one embodiment can be readily recombined or replaced with one or more components, characteristics, or actions from other embodiments to form numerous additional embodiments within the scope of the invention. Moreover, elements shown or described as being combined with other elements may exist as independent elements in various embodiments. Furthermore, with respect to any positive description of elements, characteristics, components, features, actions, steps, etc., embodiments of the invention specifically assume the exclusion of such elements, values, characteristics, components, features, actions, steps, etc. Illustrations are not necessarily drawn to a constant scale. There may be distinctions between artistic representations in the disclosure and actual apparatus due to variability such as manufacturing processes. Other embodiments of the disclosure not specifically illustrated may exist. The specification and drawings should be considered illustrative, not limiting. Modifications can be made to suit specific circumstances, materials, substance compositions, methods, or processes to fit the purposes, intent, and scope of this disclosure. All such modifications are intended to be within the scope of this disclosure. While the methods disclosed herein have been described with reference to specific operations performed in a particular order, it can be understood that these operations can be combined, subdivided, or rearranged to form equivalent methods without departing from the instructions of this disclosure. Thus, unless specifically indicated herein, the order and grouping of operations are not limitations of this disclosure.

Claims

1. A payload delivery module for an ingestible device, wherein the payload delivery module is The piston, including the internal components, A hollow needle coupled to the piston, A membrane coupled to the piston is provided to define a reservoir inside the aforementioned interior, A fluid dosage form disposed within the reservoir, comprising at least one therapeutic agent, A payload delivery module comprising: a valve coupled to the piston for controlling the flow of the fluid dosage form from the reservoir to the needle.

2. A payload delivery module for an ingestible device, wherein the payload delivery module is The piston, including the internal components, A hollow needle coupled to the piston, A plunger movably coupled to the piston to define a reservoir inside the aforementioned interior, A fluid dosage form disposed within the reservoir, comprising at least one therapeutic agent, A payload delivery module comprising: a valve coupled to the piston for controlling the flow of the fluid dosage form from the reservoir to the needle.

3. A payload delivery module for an ingestible device, wherein the payload delivery module is A piston including a base and an elongated section, A cartridge including a container, A payload delivery module comprising a solid dosage form disposed within the container, the solid dosage form containing at least one therapeutic agent.

4. A payload delivery module for an ingestible device, wherein the payload delivery module is A piston including an internal needle port and a filling port, A membrane coupled to the piston defines a reservoir inside for containing a fluid dosage form, A payload delivery module comprising a valve coupled to the piston between the membrane and the needle port.

5. A payload delivery module for an ingestible device, wherein the payload delivery module is A piston including an internal needle port and a filling port, A plunger movably coupled to the piston defines a reservoir inside for containing a fluid dosage form, A payload delivery module comprising a valve coupled to the piston between the plunger and the needle port.

6. The payload delivery module according to any one of claims 1 to 5, wherein the piston is configured to be releasably coupled to the housing and movably disposed within the housing.

7. The payload delivery module according to any one of claims 1, 2, 4, and 5, wherein the valve is configured to control the flow of the fluid dosage form from the reservoir to the needle in response to the axial movement of the module relative to the housing.

8. The payload delivery module according to any one of claims 1 to 5, wherein the piston includes a lateral wall defining a release feature for releasably coupling the piston to a housing.

9. The payload delivery module according to claim 8, wherein the release feature is defined by the outer surface of the piston.

10. The payload delivery module according to claim 8 or 9, wherein the release feature includes a press-fit feature.

11. The payload delivery module according to any one of claims 1, 2, 4, and 5, wherein the valve comprises a seal coupled to the piston so as to contain the fluid dosage form in the reservoir.

12. The payload delivery module according to claim 11, wherein the valve further comprises a puncture member coupled to the piston adjacent to the seal, the puncture member being configured to move relative to the piston to penetrate the seal.

13. The payload delivery module according to claim 12, wherein the puncture member is configured to create a substantially liquid-tight seal with the piston when it penetrates the seal.

14. The payload delivery module according to claim 11, wherein the valve further comprises a base protruding from the outer surface of the piston and a tip coupled to the base.

15. The payload delivery module according to claim 14, wherein the base is integrated with the piston.

16. The payload delivery module according to claim 14 or 15, wherein the base is configured to deform so that the tip moves relative to the piston and penetrates the seal.

17. The payload delivery module according to any one of claims 1, 2, 4, and 5, wherein the valve comprises a base protruding from the outer surface of the piston and a plug adjacent to the base and releasably coupled to the piston.

18. The payload delivery module according to claim 17, wherein the plug creates a substantially liquid-tight seal between the membrane and the needle and the piston in order to contain the fluid dosage form in the reservoir.

19. The payload delivery module according to claim 17 or 18, wherein the base is configured to deform in such a way that it releases the plug from the piston and allows the fluid dosage form to flow into the needle.

20. The payload delivery module according to claim 1 or 4, wherein the membrane includes a flexible material that allows the membrane to deform when the valve opens due to pressure applied to the outer surface of the membrane.

21. The payload delivery module according to claim 1 or 4, wherein the film comprises a metallized film or a coating.

22. The payload delivery module according to claim 2 or 5, wherein the plunger is configured to move relative to the piston when the valve opens in response to pressure applied to the outer surface of the plunger.

23. The payload delivery module according to any one of claims 1, 2, 4, or 5, wherein the reservoir defines a volume for accommodating a maximum of approximately 250 μl of fluid.

24. The payload delivery module according to claim 23, wherein the reservoir defines a volume for containing about 50 to 200 μl of fluid.

25. The payload delivery module according to claim 1 or 4, wherein the needle has a critical length in the range of about 3.5 to 12 mm such that the needle passes through the GI lumen wall and delivers the fluid dosage form into the peritoneal cavity.

26. The payload delivery module according to claim 1 or 4, wherein the needle has a critical length in the range of about 1.5 to 3 mm so that the needle delivers the fluid dosage form into the layer of the GI lumen wall.

27. The payload delivery module according to claim 1 or 4, wherein the needle comprises a biodegradable material that enables the decomposition of at least a portion of the needle within the GI lumen wall or surrounding tissue.

28. The payload delivery module according to claim 27, wherein the needle comprises a body and a tip coupled to the body, the body being formed from a first material and the tip being formed from a second material, the second material having a hardness greater than that of the first material.

29. The payload delivery module according to any one of claims 1 to 5, further comprising a cover releasably coupled to the piston.

30. The payload delivery module according to claim 29, wherein the cover defines a portion of the housing for holding the payload delivery module.

31. The payload delivery module according to claim 3, wherein the solid dosage form is formed as a needle structure or housed in a needle structure.

32. The payload delivery module according to claim 31, wherein the elongated section of the piston is configured to discharge the needle structure from the container as a projectile into the GI lumen wall or surrounding tissue.

33. The payload delivery module according to any one of claims 1 to 3, wherein the at least one therapeutic agent is one or more selected from small molecules, peptides, polypeptides, proteins, hormones, antibodies, or nucleic acids.

34. The payload delivery module according to any one of claims 1 to 3, wherein the at least one therapeutic agent is one or more selected from immunosuppressants, chemotherapeutic agents, central nervous system (CNS) agents, antidiabetic agents, enzyme replacement therapy (ERT) agents, anti-infective agents, C-type natriuretic peptide (CNP), programmed cell death ligand 1 (PD-L1) protein, monoclonal antibodies, anticoagulants, blood coagulation factors, insulin, incretins or combinations thereof, or oligonucleotides.

35. The at least one therapeutic agent comprises an antisense oligonucleotide (ASO) which is optionally MALAT1, one or more blood coagulation factors or their mimics selected from factor VIII, factor IX, or factor X, an anti-PCSK9 antibody, an optionally TNF-α inhibitor antibody which comprises adalimumab or its analogue, and an anti-interleukin antibody which optionally targets interleukin 4 and interleukin 13 (e.g., dupilumab or its analogue), or interleukin 1 A payload delivery module according to any one of claims 1 to 3, comprising one or more therapeutic agents selected from: an anti-interleukin antibody targeting at least one of interleukin 2 or interleukin 23 (e.g., ustekinumab or an analog thereof), or targeting interleukin 2; parathyroid hormone (PTH) or an analog thereof; amylin or an analog thereof; and one or more incretins or their mimics, optionally selected from GLP-1, GLP-2, GIP, PYY, or glucagon receptor agonists.

36. A delivery assembly for an ingestible device, wherein the delivery assembly is Housing and A delivery assembly comprising a payload delivery module according to any one of claims 1 to 35, coupled to the housing.

37. The delivery assembly according to claim 36, wherein the housing comprises a proximal end, a distal end, a piston chamber located between the proximal end and the distal end, and a housing release feature, the proximal end including a first opening for receiving force internally, and the distal end including a second opening for discharging the dosage form.

38. The delivery assembly according to claim 37, wherein the housing further comprises a body and a cover coupled to the body, the body including the second opening and the piston chamber, and the cover including the first opening and the housing release feature.

39. The delivery assembly according to claim 37 or 38, wherein the piston is disposed within the piston chamber and is releasably coupled to the housing release feature.

40. The delivery assembly according to any one of claims 37 to 39, further comprising a seal coupled to the housing at the second opening.

41. The delivery assembly according to any one of claims 37 to 40, wherein the housing further comprises a vent channel for discharging gas.

42. The delivery assembly according to any one of claims 37 to 41, wherein the force is gas pressure.

43. The delivery assembly according to claim 42, wherein the housing release feature is configured to release the piston in response to a threshold gas pressure applied to the module through the first opening, the threshold gas pressure being about 10 to 40 psi.

44. The delivery assembly according to any one of claims 37 to 43, wherein the housing release feature is located on the side wall of the housing.

45. The delivery assembly according to any one of claims 37 to 44, wherein the housing release feature includes a press-fit feature.

46. The delivery assembly according to any one of claims 37 to 45, wherein the housing release feature extends circumferentially around the housing.

47. If the payload delivery module includes the fluid dosage form, the delivery assembly according to any one of claims 37 to 46, wherein the module is configured to move axially within the piston chamber to insert the hollow needle through the second opening into the GI lumen wall or surrounding tissue, and in response to the force received through the first opening, discharge the fluid dosage form through the hollow needle into the GI lumen wall or surrounding tissue.

48. The delivery assembly according to claim 47, wherein the fluid dosage form is discharged from the reservoir when the valve opens in response to sufficient axial movement of the module relative to the housing.

49. The delivery assembly according to claim 47 or 48, wherein the fluid dosage form is discharged through the hollow needle after the hollow needle has penetrated the GI lumen wall or the surrounding tissue.

50. If the payload delivery module includes the solid dosage form, the cartridge is coupled to the housing and the piston is configured to move axially within the piston chamber in response to the force received through the first opening to discharge the solid dosage form from the container as a projectile into the GI lumen wall or surrounding tissue, according to any one of claims 37 to 46.

51. A device that can be ingested, Expandable components, An ingestable device comprising a delivery assembly according to any one of claims 36 to 50, coupled to the expandable member.

52. The ingestionable device according to claim 51, further comprising a gas generation mechanism coupled to the expandable member.

53. The ingestible device according to claim 52, wherein the gas generation mechanism is configured to generate gas to expand the expandable member at a location within the target GI tube, thereby oriented and positioning the delivery assembly with respect to the GI lumen wall.

54. The ingestible device according to claim 53, wherein the location is the small intestine of the subject.

55. The ingestible device according to any one of claims 52 to 54, wherein the gas generation mechanism comprises a plurality of reactants that are separated from each other by decomposable release.

56. An ingestible device according to any one of claims 51 to 55, wherein, upon expansion of the expandable member, the delivery assembly is configured to deliver the dosage form through the GI lumen wall into the peritoneum or peritoneal cavity of the target for systemic uptake of the at least one therapeutic agent.

57. An ingestible device according to any one of claims 51 to 55, wherein, upon expansion of the expandable member, the delivery assembly is configured to deliver the dosage form into the layer of the GI lumen wall for systemic uptake of the at least one therapeutic agent.

58. The ingestible device according to any one of claims 51 to 57, wherein the expandable member includes a balloon.

59. The ingestible device according to any one of claims 51 to 58, further comprising an ingestible enclosure, wherein the expandable member and the delivery assembly are disposed within the ingestible enclosure.

60. The ingestible device according to claim 59, wherein the ingestible enclosure includes a biodegradable material that enables the decomposition of at least a portion of the ingestible enclosure within the GI tube.

61. The ingestible device according to claim 59 or 60, further comprising a coating disposed on at least a portion of the ingestible enclosure, wherein the coating is configured to decompose at a selected pH within the GI tube.

62. The ingestible device according to any one of claims 59 to 61, wherein the ingestible enclosure is a swallowable capsule of size 00 or size 000.

63. A method for preparing an ingestible device for delivering a therapeutic agent into the luminal wall or surrounding tissue of a target GI, the method comprising filling a dosage form containing the therapeutic agent into a payload delivery module according to any one of claims 1 to 35.

64. A method for delivering a therapeutic agent into the luminal wall or surrounding tissue of a subject in need of the therapeutic agent, wherein the method comprises the subject ingesting an ingestible device according to any one of claims 51 to 62, wherein at least one therapeutic agent is present in a therapeutically effective dose, and further optionally, at least one therapeutic agent is present in liquid form.

65. An ingestible device according to any one of claims 51 to 62 for use in delivering the therapeutic drug into the GI lumen wall or surrounding tissue of a subject requiring the therapeutic drug.

66. A modular delivery assembly for an ingestible device for delivering a dosage form into the luminal wall or surrounding tissue of a target GI, wherein the delivery assembly comprises: It comprises a housing having a proximal end, a distal end, and an interior located between the proximal end and the distal end, The proximal end includes a first opening for receiving force internally, The distal end includes a second opening for discharging the dosage form, The interior of the receptacle is configured to receive a module selected from a first payload delivery module containing a fluid dosage form and a second payload delivery module containing a solid dosage form. A modular delivery assembly wherein the housing further comprises release features for releasably coupling the module to the housing.

67. The modular delivery assembly according to claim 66, wherein the first payload delivery module has a first delivery mode, and the second payload delivery module has a second delivery mode different from the first delivery mode.

68. The modular delivery assembly according to claim 67, wherein the first delivery mode includes inserting a hollow needle into the GI lumen wall or surrounding tissue, and discharging the fluid dosage form into the GI lumen wall or surrounding tissue through the hollow needle.

69. The modular delivery assembly according to claim 67 or 68, wherein the second delivery mode includes discharging the solid dosage form as a projectile from the second payload delivery module into the GI lumen wall or surrounding tissue.

70. A delivery assembly for an ingestible device, wherein the delivery assembly is A housing comprising a proximal end, a distal end, a piston chamber located between the proximal and distal ends, and a release feature, wherein the proximal end includes a first opening for receiving force internally, and the distal end includes a second opening for discharging the dosage form, A payload delivery module disposed within the housing comprises a payload delivery module including a piston and a dosage form containing at least one therapeutic agent, A delivery assembly in which the piston is releasably coupled to the release feature and configured to move axially within the piston chamber between the proximal and distal ends in response to the force discharging the dosage form from the housing.

71. A device that can be ingested, Expandable components, A delivery assembly coupled to the expandable member, comprising a delivery assembly including a fluid dosage form containing at least one therapeutic agent, The expandable member is configured to expand within the target GI tube to position the delivery assembly relative to the GI lumen wall. An ingestible device wherein, upon expansion of the expandable member, the delivery assembly is configured to deliver the fluid dosage form through the GI lumen wall into the peritoneum or peritoneal cavity of the target for systemic uptake of the at least one therapeutic agent.

72. A device that can be ingested, Housing and A piston is movably disposed within the housing, A hollow needle coupled to the piston, A fluid dosage form disposed within the housing, comprising at least one therapeutic agent, An ingestionable device comprising a force generation mechanism operably coupled to the piston.

73. The device according to claim 72, wherein the hollow needle has a critical length in the range of about 3.5 to 12 mm, such that when the device is taken, the hollow needle is configured to deliver the fluid dosage form through the GI lumen wall into the peritoneal cavity of the subject for systemic uptake of the at least one therapeutic agent.

74. The device according to claim 72, wherein the hollow needle has a critical length in the range of about 1.5 to 3 mm, such that when the device is taken, the hollow needle is configured to deliver the fluid dosage form into the layer of the GI lumen wall for systemic uptake of the at least one therapeutic agent.

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