Ingestible device for delivering fluid formulations to the gastrointestinal tract - Patent Application 20070233633

Abstract

A delivery assembly (300) for an ingestible device (200) for delivering a fluid formulation (317) into a GI tract lumen wall or surrounding tissue of a subject includes a housing (302), a piston, a needle (320), and a membrane (315). The housing (302) defines a chamber. The piston is movably disposed in the chamber. The needle (320) is coupled to the piston. The membrane is coupled to the piston, and the membrane and piston cooperate to define a reservoir (315a) for containing the fluid formulation.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 312,354, filed February 21, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Therapeutic agents, such as drugs, can be administered to subjects (patients) by ingestion or parenteral injection (e.g., subcutaneously, intramuscularly, or intravenously) to provide a desired therapeutic effect. However, these routes of administration have several drawbacks. For example, some therapeutic agents, such as molecules with large molecular weights (macromolecules), are not suitable for delivery by ingestion due to enzymatic degradation of these molecules in the gastrointestinal (GI) tract of the subject. Other types of therapeutic agents are poorly tolerated in the GI tract and have low systemic uptake. In the case of parenteral injections, subjects may experience pain and inconvenience that significantly impact compliance and quality of life.

[0003] To address these shortcomings, ingestible devices have been proposed for orally administering solid dosage forms of therapeutic agents to the luminal wall of the GI tract or surrounding tissue.However, solid dosage forms may be limited to relatively small dosage amounts (e.g., a few milligrams).Therefore, the use of solid dosage forms may be disadvantageous for treatment regimens that require higher dosage amounts, for example, for reasons of administration frequency, convenience, or cost.

[0004] Thus, there is a need for devices that can deliver a wide range of dosages of therapeutic agents and that can address one or more of the shortcomings associated with traditional oral and parenteral administration routes. Summary of the Invention [Problem to be solved by the invention]

[0005] Embodiments of the present disclosure generally relate to devices, assemblies, and methods for delivering a fluid formulation to the GI tract (e.g., the GI luminal wall or surrounding tissues) of a subject. The devices and assemblies are configured to deliver up to about 250 microliters (μL) or more of a fluid formulation, which may include up to about 75 milligrams (mg) or more of at least one therapeutic agent. In this manner, the disclosed devices, assemblies, and methods can enable efficient delivery of a wide range of dosages of a therapeutic agent for most treatment regimens. [Means for solving the problem]

[0006] In one aspect, a delivery assembly for an ingestible device for delivering a fluid formulation into a GI tract lumen wall or surrounding tissue of a subject includes a housing, a piston, a needle, and a membrane. The housing defines a chamber. The piston is movably disposed within the chamber. The needle is coupled to the piston. The membrane is coupled to the piston to cooperate with the piston to define a reservoir for containing the fluid formulation.

[0007] In another aspect, an ingestible device for delivering a fluid formulation into a GI luminal wall or surrounding tissue of a subject includes an expandable member and a delivery assembly coupled to and disposed within the expandable member. The delivery assembly includes a housing, a piston, a needle, a membrane, and a fluid formulation. The housing defines a chamber. The piston is movably disposed within the chamber. The needle is coupled to the piston. The membrane is coupled to the piston to cooperate with the piston to define a reservoir for containing the fluid formulation. The fluid formulation is disposed in the reservoir and includes at least one therapeutic agent.

[0008] In another aspect, the device includes a tissue penetrating member having an elongated portion and a tapered portion extending from the elongated portion to a distal end. The elongated portion defines a longitudinal opening extending therethrough. The tapered portion defines a slotted opening extending through a sidewall of the tapered portion to the longitudinal opening. The slotted opening is for ejecting a fluid formulation from the tissue penetrating member.

[0009] In another aspect, a method for delivering a fluid formulation into a GI luminal wall or surrounding tissue of a subject includes ingesting, by the subject, an ingestible device as described herein. The ingestible device includes an expandable member and a delivery assembly coupled to and disposed within the expandable member. The delivery assembly includes a housing, a piston, a needle, a membrane, and a fluid formulation. The housing defines a chamber. The piston is movably disposed within the chamber. The needle is coupled to the piston. The membrane is coupled to the piston to cooperate with the piston to define a reservoir for containing the fluid formulation. The fluid formulation is disposed in the reservoir and includes at least one therapeutic agent.

[0010] In another aspect, use of an ingestible device to deliver a fluid formulation into a GI luminal wall or surrounding tissue of a subject includes ingesting an ingestible device as described herein by a subject. The ingestible device includes an expandable member and a delivery assembly coupled to and disposed within the expandable member. The delivery assembly includes a housing, a piston, a needle, a membrane, and a fluid formulation. The housing defines a chamber. The piston is movably disposed within the chamber. The needle is coupled to the piston. The membrane is coupled to the piston to cooperate with the piston to define a reservoir for containing the fluid formulation. The fluid formulation is disposed in the reservoir and includes at least one therapeutic agent.

[0011] In another aspect, a method of preparing an ingestible device for delivering a therapeutic agent into the GI tract lumen wall or surrounding tissue of a subject includes loading a fluid formulation including a therapeutic agent into a delivery assembly as described herein.

[0012] In one or more embodiments of any of the aforementioned aspects, the expandable member comprises a balloon.

[0013] In one or more embodiments of any of the aforementioned aspects, the device further includes an ingestible housing, wherein the expandable member and the delivery assembly are disposed within the ingestible housing.

[0014] In one or more embodiments of any of the aforementioned aspects, the device further includes a plurality of reactants disposed within the expandable member to generate a gas pressure to inflate the expandable member within the GI lumen. In one or more embodiments, the generated gas pressure is applied against the membrane to move the piston axially relative to the housing.

[0015] In one or more embodiments of any of the aforementioned aspects, the piston further defines a needle cavity, and the needle is slidably coupled to the piston within the needle cavity.

[0016] In one or more embodiments of any of the aforementioned aspects, the delivery assembly further includes a seal coupled to the piston between the needle cavity and the reservoir defining a substantially fluid-tight seal therebetween.

[0017] In one or more embodiments of any of the aforementioned aspects, the needle includes a first end configured to penetrate the GI lumen wall and a second end configured to penetrate the seal in response to resistance applied to the needle from the GI lumen wall.

[0018] In one or more embodiments of any of the aforementioned aspects, the membrane is made of a flexible material such that the generated gas pressure causes the membrane to deform and expel the fluid formulation through the needle as the needle pierces the seal.

[0019] In one or more embodiments of any of the aforementioned aspects, the device is configured such that the first end of the needle penetrates the GI lumen wall before the second end of the needle penetrates the seal.

[0020] In one or more embodiments of any of the aforementioned aspects, the device is configured such that the first end of the needle penetrates the GI lumen wall at substantially the same time that the second end penetrates the seal.

[0021] In one or more embodiments of any of the aforementioned aspects, the needle is configured to penetrate into the peritoneum or peritoneal cavity of the subject to pierce the GI tract lumen wall and expel the fluid formulation therein.

[0022] In one or more embodiments of any of the aforementioned aspects, the membrane has a surface profile that is complementary to an inner surface profile of the piston that defines the reservoir.

[0023] In one or more embodiments of any of the preceding aspects, the reservoir defines a volume containing up to about 250 μL of fluid, in one or more embodiments, the reservoir defines a volume containing between about 50 μL and about 200 μL of liquid.

[0024] In one or more embodiments of any of the preceding aspects, the piston includes a fill port for filling the reservoir with the fluid formulation.

[0025] In one or more embodiments of any of the preceding aspects, the delivery assembly further includes a fluid formulation disposed in the reservoir, the fluid formulation including at least one therapeutic agent. In one or more embodiments of any of the preceding aspects, the at least one therapeutic agent is one or more selected from an immunosuppressant, a chemotherapeutic agent, a central nervous system (CNS) drug, an antidiabetic drug, an enzyme replacement therapy (ERT) drug, an antibody, a hormone, insulin, an incretin, or a combination thereof, or an oligonucleotide.

[0026] In one or more embodiments of any of the preceding aspects, the tissue-piercing member further comprises a tip coupled to or integrally formed with the tapered portion at the distal end, hi one or more embodiments, the tip comprises a material that is harder than a material of the tissue-piercing member.

[0027] In one or more embodiments, the device is ingestible.

[0028] The foregoing general description and the following detailed description are provided by way of example only and are intended to provide further explanation of the present disclosure as set forth in the claims, without limiting the scope of the disclosure or the claims. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following brief description of the drawings and detailed description of the present disclosure. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 is a block diagram illustrating one embodiment of a device for delivering a fluid formulation into the GI tract of a subject. [Diagram 2] FIG. 2 is a cross-sectional view of one embodiment of the device of FIG. [Diagram 3] FIG. 3 is a detailed view of a portion of the device of FIG. 2 including a delivery assembly. [Figure 4] FIG. 4 shows the device of FIG. 3 in a second state when it has reached a desired location within the GI tract for delivering a fluid formulation. [Diagram 5] FIG. 5 is a cross-sectional view taken along line 5-5 of FIG. [Figure 6] FIG. 6 illustrates a method of delivering a fluid formulation to the interior of the GI tract using the devices and assemblies of the present disclosure. [Figure 7] FIG. 7 illustrates a tissue penetrating (puncturing) member suitable for use in devices and assemblies of the present disclosure, such as the ingestible device of FIG. [Figure 8] FIG. 8 illustrates a tissue penetrating member suitable for use in devices and assemblies of the present disclosure, such as the ingestible device of FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Before describing the details of the devices, assemblies, and methods of the present disclosure, some conventions are provided for the convenience of the reader.

[0031] As used in this disclosure, the terms "eg," "such as," "for example," "for an example," "for another example," "example of," "by way of example," and "etc." indicate that a list of one or more non-limiting example(s) is preceded or followed, and it is to be understood that other unlisted examples are within the scope of the disclosure.

[0032] As used herein, the singular terms "a," "an," and "the" may include plural references unless the context clearly dictates otherwise. Additionally, the singular terms "a," "an," and "the" do not mean "one and only one" unless expressly stated otherwise, but rather "one or more."

[0033] As used herein, a phrase in the form "A / B" or in the form "A and / or B" means (A), (B), or (A and B), and a phrase in the form "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).

[0034] The term "in one embodiment" or variations thereof (e.g., "in another embodiment" or "in one embodiment") is used herein to refer to use in one or more embodiments and does not in any way limit the scope of the disclosure to only the embodiments shown and / or described. Thus, components illustrated and / or described herein with respect to an embodiment can be omitted or used in another embodiment (e.g., another embodiment illustrated and described herein, or another embodiment within the scope of the disclosure but not illustrated and / or described herein).

[0035] As used herein, the term "component" refers to one item of a set of one or more items that collectively constitute the device, composition, or system under discussion. A component may be a solid, powder, gel, plasma, fluid, gas, or other configuration. For example, a device may include multiple solid components that are assembled together to constitute the device and may further include a fluid component disposed within the device. As another example, a composition may include a single component, or two or more components that are mixed together to make the composition. A composition may be in the form of a fluid, slurry, powder, or solid (e.g., in a compacted or combined form such as a tablet or microtablet). A device or system may include one or more compositions and / or one or more other components.

[0036] The term “design” or grammatical variations thereof (e.g., “designing” or “designed”), as used herein, refers to features that are intentionally built into a device based on, for example, estimates of tolerances (e.g., component tolerances and / or manufacturing tolerances) and estimates of the environmental conditions that are expected 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, or, if introduced into the body, physiology, body chemistry, biological composition). It is understood that different components, devices, compositions, or systems with identical designs may have different actual values ​​for these properties, since internal ambient pressure, external or internal mechanical pressure, stress from external or internal mechanical pressure, age or shelf life of the product, 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), actual tolerances and environmental conditions before and / or after delivery may affect the properties. Design also includes pre- or post-manufacturing changes or modifications.

[0037] The term "structured" or grammatical variations thereof (e.g., "structure" or "structuring"), as used herein, refers to a component, device, composition, or system that is produced according to a concept or design, or variations or modifications thereof (whether such variations or modifications occur before, during, or after production), regardless of whether such concept or design is described in writing.

[0038] As used herein, the term "body" refers to an animal body, unless the context clearly indicates otherwise.

[0039] As used herein, the term "subject" refers to a body to which an embodiment of the present disclosure is delivered or is intended to be delivered. For example, with respect to a human, a subject may be a patient receiving treatment from a medical professional. The terms "individual," "subject," and "patient" may be used interchangeably herein and refer to any individual animalia subject (e.g., bovine, canine, feline, equine, or human). In certain embodiments, the subject, individual, or patient is a human.

[0040] The term "fluid" as used herein refers to a liquid or gas, and includes water and humidity. The term "fluidic environment" as used herein refers to an environment in which one or more fluids are present.

[0041] The term "ingest" or grammatical variations thereof (e.g., "ingesting," "ingestion," or "ingested"), as used herein, refers to taking into the stomach, whether by swallowing or by other means of deposition into the stomach (e.g., deposition into the stomach by an endoscope or via a port).

[0042] The term "degrade" or grammatical variations thereof (e.g., "degrading," "degraded," "degradable," and "degradation"), as used herein, refers to weakening, partial degradation, or complete breakdown, such as by dissolution, chemical degradation (including biodegradation), breakdown, chemical modification, mechanical degradation, or disintegration, including, but not limited to, dissolving, crumbling, deformation, withering, or shrinking. The term "non-degradable" means that in the expected environment, at least for the expected period of time, degradation is minimal or within some acceptable design rate.

[0043] The term "degradation rate" or grammatical variations thereof (e.g., "rate of degradation"), as used herein, refers to the rate at which a material breaks down. The designed degradation rate of a material in certain embodiments can be defined by the rate at which the material is expected to degrade under the conditions (e.g., physiological conditions) expected at the target delivery site. The designed degradation time for certain embodiments can refer to the designed time to complete degradation or the designed time to partial degradation sufficient to achieve the design objective (e.g., breach). Thus, for example, the designed degradation time can be component specific and / or specific to the conditions expected at the target delivery site. The designed degradation time can be short or long and can be defined in terms of an approximate time, a maximum time, or a minimum time.

[0044] As used herein, the term "substantially" is used to describe and take into account small variations that may result, for example, from manufacturing or assembly processes. For example, when used with a numerical value, the term can refer to a variation in the numerical value of ±10% or less.

[0045] As used herein, the term "lumen" refers to the interior space of a tubular structure. Examples of lumens in the body include arteries, veins, lumens within organs, etc.

[0046] The term "lumen wall" means the wall of a lumen, and includes all layers of the lumen from the inner periphery to the outer periphery. For example, with respect to a lumen in the body, it includes the mucosa, submucosa, muscularis, serosa, the outer wall of the lumen, and the blood vessels and tissues that constitute it.

[0047] As used herein, the term "gastrointestinal tract" or "GI tract" refers to 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.

[0048] The term "GI lumen" generally refers to any lumen of the GI tract (eg, the lumen of the esophagus, stomach, small intestine, large intestine, colon), and the term "GI lumen wall" refers to the luminal wall of the GI lumen.

[0049] As used herein, the terms "comprising," "comprise," "comprises," "includes," and "including" are intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.

[0050] Referring generally to the drawings, disclosed herein are embodiments of devices, assemblies, and methods for delivering a fluid formulation to the luminal wall or surrounding tissues (e.g., the peritoneum or peritoneal cavity) of the GI tract of a subject. The devices are advantageously configured to substantially preserve one or more therapeutic agents in the fluid formulation within the GI lumen for delivery within the GI luminal wall or surrounding tissues. Delivery to the luminal wall or surrounding tissues may allow for systemic uptake of the one or more therapeutic agents in the fluid formulation. Additionally, the fluid form of the formulation may allow for delivery of a wide range of dosages of one or more therapeutic agents (e.g., up to about 75 mg or more) for most treatment regimens.

[0051] As described below, the disclosed devices and assemblies can deliver a variety of different types of therapeutic agents, including macromolecules that are not typically suitable for delivery by ingestion. In this manner, the disclosed devices, assemblies, and methods can address many of the shortcomings associated with traditional oral and parenteral routes of administration.

[0052] 1 illustrates in block diagram form an example of a device 100 in accordance with one or more embodiments of the present disclosure. The device 100 includes an enclosure 102, an optional outer coating 104, an expandable member 106, a release 108, and a delivery assembly 110. The delivery assembly 110 includes a housing 112, a membrane 114, a fluid formulation 116, a piston 118, and a needle 120.

[0053] According to a non-limiting example, the housing 102 (or optionally the housing 102 and / or the outer coating 104) can be degraded at a desired location within the subject's GI tract (e.g., stomach or small intestine) for delivery of the fluid formulation 116, as described in more detail below. In response to at least partial degradation of the housing 102 and / or the outer coating 104, the release means 108 is actuated to cause a chemical reaction within the expandable member 106 that results in the formation of a gas for inflating the expandable member 106, as described in more detail below. Expansion of the expandable member 106 within the GI lumen places the delivery assembly 110 in close proximity (e.g., adjacent or in contact with) the lumen wall. When the internal pressure generated by the gas within the expandable member 106 reaches a threshold value (e.g., upon expansion of the expandable member 106), the gas pressure applied to the membrane 114 moves the piston 118 relative to the housing 112, advancing the needle 120 toward the GI lumen wall. The GI lumen wall applies resistance to the needle 120, causing the piston 118 to move relative to the needle 120 such that the needle 120 pierces a seal in the piston 118 and the fluid formulation 116 flows into the needle 120. Once the seal is pierced, gas pressure applied against the membrane 114 causes the membrane 114 to expel the fluid formulation 116 through the needle 120 and into the GI lumen wall or surrounding tissue.

[0054] The housing 102 and optional outer coating 104, if provided, are configured to allow ingestion of the device 100 and temporarily protect the contents of the device 100 from degradation within one or more portions of the GI tract of a subject. The housing 102 can take a variety of different forms and shapes, such as a swallowable capsule (e.g., a size 00 capsule, a size 000 capsule, or other size capsule), or any other structure suitable for ingestion by a subject and capable of housing or containing one or more of the components of the device 100 (e.g., at least the expandable member 106, the release means 108, and the delivery assembly 110, as described below). In one or more embodiments, the housing 102 includes two or more sections that are coupled (e.g., press-fit) together to define the housing 102. For example, the housing 102 may be configured as a capsule that includes a first portion that at least partially overlaps a second portion in a press-fit arrangement to define the housing 102. The first and second portions may be releasably coupled to allow separation of the two portions. In one or more embodiments, the expandable member 106, the release means 108, and the delivery assembly 110 are each configured to be housed within the interior of the housing 102. The release means 108 may optionally be located outside the interior of the housing 102, such as on an exterior portion of the housing 102.

[0055] In one or more embodiments, the housing 102 can degrade under certain conditions. Additionally, different portions of the housing 102 can be configured to degrade under different conditions or at different degradation rates depending on the target site in the GI tract for delivery of the fluid formulation 116. For example, some or all of the housing 102 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 within 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 target site in the GI tract for delivery of the fluid formulation 116).

[0056] An optional outer coating 104 optionally covers some or all of the housing 102. The outer coating 104 may include a single layer or multiple layers. The various layers may be formed of the same material or a combination of different materials. In one or more embodiments, the outer coating 104 may degrade under certain conditions, as described above with reference to the housing 102. One example of an outer coating 104 is an enteric coating, such as an enteric coating that degrades at a predetermined rate in water and / or an enteric coating that degrades when exposed to a solution having a pH level above a certain threshold or within a certain range. Another example of an outer coating 104 is a protective coating (e.g., a wax), such as a coating that protects a portion of the outer surface of the housing 102 from contact with fluids or tissues (e.g., bodily tissues or fluids).

[0057] In one or more embodiments, degradation of the housing 102 and / or outer coating 104 allows fluids (e.g., gastric or intestinal fluids) to enter the interior of the housing 102 / outer coating 104 and activate the release means 108. Alternatively, the release means 108 may be located on an exterior portion of the housing 102, and degradation of the outer coating 104 may expose the release means 108 to a surface of the housing 102 to facilitate activation of the release means 108. Alternatively, the release means 108 may be located in a portion of the housing 102 that is not exposed to the outer coating 104, and the release means 108 may be structured to degrade at a different rate than the housing 102 and / or under different conditions within the GI tract.

[0058] The housing 102 and / or the outer coating 104 may define one or more degradation regions for localized degradation of the housing 102 and / or the outer coating 104, for example, to enable controlled degradation and detachment of the housing 102. For example, the outer coating 104 may be selectively applied only to certain regions of the housing 102 (e.g., ends of the housing 102) to expose selected portions of the housing 102 (e.g., a mid-portion of the housing 102 between the ends), thereby defining regions of the housing 102 that can degrade at a faster rate and / or degrade faster than other regions of the housing 102. This controlled degradation of the housing 102 allows for more consistent detachment of the housing 102 to enable delivery of the fluid formulation 116 from the delivery assembly 110 into the GI lumen wall.

[0059] The expandable member 106 is a flexible, adjustable structure. In one or more embodiments, the expandable member 106 is configured to expand from a collapsed state (e.g., folded, rolled, flattened) to an expanded state within a desired location of the GI lumen for delivery of the fluid formulation 116. The expandable member 106 may have a variety of different shapes, sizes, and configurations for temporary storage in the housing 102 and deployment within the lumen of the subject's GI tract. The expandable member 106 may be configured as a balloon, a bellows / accordion structure, or any other structure that is adjustable from a collapsed state to an expanded state.

[0060] The expandable member 106 defines an interior volume for containing various components of the device 100. For example, the expandable member 106 can include (e.g., contain) one or more reactants that are temporarily separated from one another within the interior volume. The interior volume is configured to facilitate a chemical reaction caused by mixing the reactants together (e.g., in response to actuation of the release means 108) to form a gas that causes expansion of the expandable member 106. The expandable member 106 can further include structure for contracting the expandable member 106 upon delivery of the fluid formulation 116 to facilitate excretion of the expandable member 106 from the subject. The expandable member 106 is configured to stretch a prescribed amount without perforating upon expansion.

[0061] The expandable member 106 can be formed from one or more materials. Examples of suitable materials for the expandable member 106 include hydroxypropyl methylcellulose (HPMC), polyvinyl acetate (PVA), lactide, glycolide, lactic acid, glycolic acid, per-dioxanone, trimethylene carbonate, caprolactone, and mixtures and copolymers thereof. The expandable member 106 can include one or more layers of material. The expandable member 106 can be a monolithic structure. In other embodiments, the expandable member 106 can be composed of one or more sections that are joined together (e.g., sealed or sutured).

[0062] The release means 108 is a chemical, mechanical, electrical, electromechanical, electrochemical, chemical-mechanical, or electromechanical-chemical structure. The release means 108 is a structure that causes expansion of the expandable member 106 upon actuation of the release means 108. In one or more embodiments, the release means 108 is configured to be actuated (e.g., degrade, release, move, open) in response to conditions in the GI tract. For example, the release means 108 may be configured to degrade in water such that the release means 108 degrades upon contact with fluid in the GI tract. As another example, the release means 108 may be configured to degrade above a particular pH level or within a range of pH levels associated with a location in the GI tract (e.g., stomach pH, ​​intestinal pH). In these and other embodiments, the release means 108 may be made from a biodegradable material, such as an enteric material.

[0063] Additionally or alternatively, the release means 108 may be configured as a latch, clip, cover, plug, coating, or any other structure that moves, opens, or otherwise releases in response to conditions within the GI tract. The release means 108 may be comprised of a single material or combination of materials. In embodiments in which multiple components are included in the release means 108, the components may be co-located (e.g., coaxial) or may be physically separated from one another.

[0064] The delivery assembly 110 has a chemical, mechanical, electrical, electromechanical, electrochemical, chemical-mechanical, or electromechanical structure. In one or more embodiments, the delivery assembly 110 can include a housing 112, a membrane 114, a fluid formulation 116, a piston 118, and a needle 120. In other embodiments, the delivery assembly 110 can include a housing 112, a membrane 114, a fluid formulation 116, and a piston 118 without including a needle 120. In these embodiments, the delivery assembly 110 can be structured to deliver the fluid formulation 116 as a fluid jet through a nozzle or opening in the housing 112 with sufficient velocity for the fluid jet to penetrate the GI lumen wall to deliver the fluid formulation 116.

[0065] The delivery assembly 110 is a structure coupled to and disposed (partially or entirely) on the expandable member 106. In response to expansion of the expandable member 106, the delivery assembly 110 is further configured to deliver a fluid formulation 116 into the GI lumen wall or into the surrounding tissue. The device 100 can include one or more delivery assemblies 110 coupled to the expandable member 106 to enable delivery of one or more fluid formulations.

[0066] The housing 112 is coupled to the expandable member 106 and configured to be disposed (partially or entirely) therein. The housing 112 defines one or more chambers for movably receiving the piston 118 and needle 120, or a piston without a needle. The housing 112 is configured to allow gas pressure from within the expandable member 106 to be applied against the membrane 114 to axially move the piston 118 and needle 120 relative to the housing 112. The housing 112 can include one or more components. In embodiments in which multiple components are included in the housing 112, the components may be co-located or physically separated from one another.

[0067] The membrane 114 is a flexible structure. The membrane 114 is coupled to the piston 118. The membrane 114 and the piston 118 cooperate to define a reservoir for containing the fluid formulation 116. The reservoir may define a volume for containing up to about 250 μL or more of fluid, including 250 μL of fluid. The reservoir may define a volume for containing about 50 μL to about 200 μL of fluid, including 50 μL to 250 μL of fluid, for example, 50 μL, 100 μL, 150 μL, or 200 μL of fluid, or any value therebetween, or may include 200 μL or 250 μL of fluid, or any value therebetween. The membrane 114 is further configured to expel the fluid formulation 116 from the reservoir into the needle 120 in response to pressure applied against an exterior surface of the membrane 114 (e.g., by gas generated within the expandable member 106).

[0068] The membrane 114 may have any suitable shape, such as cylindrical, ellipsoidal, spherical, cubic, or other shapes. The membrane 114 may be formed from or may include a flexible or pliable material to allow deformation of the membrane 114 (e.g., bending / flexing under pressure) to expel the fluid formulation 116. Examples of suitable materials for the membrane 114 include polymeric materials (e.g., polyethylene terephthalate (PET)) or other flexible materials with sufficiently low moisture and gas permeability for use with the fluid formulation 116. The membrane 114 can be formed from a single material or a combination of materials. Additionally, the membrane 114 may include one or more layers of material. The membrane 114 may be a monolithic structure. In other embodiments, the membrane 114 may be comprised of multiple sections that are joined together (e.g., sealed or sewn) to define the membrane 114. The membrane 114 may include one or more components. In embodiments in which multiple components are included in membrane 114, the multiple components may be co-located or may be physically separated from one another.

[0069] Fluid formulation 116 is a formulation that includes one or more components, where the formulation is intended for a therapeutic, diagnostic, or other biological purpose. Fluid formulation 116 is in a fluid form, such as a liquid, a slurry, a gel, a suspension (including a colloidal suspension), a gas, a powder, or any combination thereof. Fluid formulation 116 includes one or more components that include one or more therapeutic agents, such as proteins, peptides, polypeptides, antibodies, drugs (e.g., one or more selected from immunosuppressants (e.g., adalimumab), chemotherapeutic drugs, central nervous system (CNS) drugs (e.g., anti-Parkinson's drugs, anti-emetic drugs), anti-diabetic drugs (e.g., metformin), enzyme replacement therapy (ERT) drugs, hormones (e.g., parathyroid hormone (PTH), follicle stimulating hormone (FSH), and analogs thereof), and the like. ), insulin, incretins or combinations thereof (e.g., GLP-1, GLP-2, GIP, glucagon, PYY, and analogs thereof), oligonucleotides (e.g., antisense oligonucleotides (ASO), RNA interference (RNAi), aptamer RNA), DNA or SiRNA transcripts, cells, cytotoxic agents, vaccines or other prophylactic agents, nutritional supplements, vasodilators or vasoconstrictors, delivery enhancers, retardants, excipients, diagnostic agents, or cosmetic enhancements. The fluid formulation 116 may contain a therapeutically effective amount of one or more therapeutic agents, as well as appropriate amounts of other ingredients (e.g., excipients) to achieve a desired therapeutic effect in a subject.

[0070] The piston 118 is movably (e.g., slidably) disposed in the housing 112. The piston 118 includes one or more cavities that cooperate with the membrane 114 to define a reservoir for holding the fluid preparation 116. The piston 118 is further configured to interface with the needle 120 such that the needle 120 is movable relative to the piston 118 to selectively control the flow of the fluid preparation 116 from the reservoir to the needle 120. The piston 118 is further configured to advance the needle 120 into the GI lumen wall or into the surrounding tissue in response to sufficient pressure being applied to the piston 118 (e.g., via gas pressure applied to the membrane 114). In embodiments in which multiple components are included in the piston 118, the components may be co-located or physically separated from one another.

[0071] The needle 120 is coupled to the piston 118 and is configured to penetrate the GI lumen wall or surrounding tissue. The needle 120 can have a length sufficient to penetrate the GI lumen wall or surrounding tissue of the subject to a desired depth. For example, the needle 120 can have a length sufficient to penetrate the GI lumen wall and through the GI lumen wall into the peritoneum or peritoneal cavity of the subject to expel the fluid formulation 116 therein. In one or more embodiments, the needle 120 is movable relative to the piston 118. In other embodiments, the needle 120 is fixed relative to the piston 118. The needle 120 includes a channel for receiving the fluid formulation 116 from the reservoir and an opening for expelling the fluid formulation 116 into the GI lumen wall or surrounding tissue.

[0072] The needle 120 may be at least partially degradable or may be fully degradable so that the needle 120 can degrade within the GI lumen or surrounding tissue upon delivery of the fluid formulation 116. Suitable materials for the needle 120 include, for example, polyethylene oxide (PEO), magnesium, polymeric materials, or other materials or combinations of materials. The needle 120 may include one or more components. In embodiments in which multiple components are included in the needle 120, the components may be co-located or physically separated from one another. In other embodiments, the needle 120 may be substantially non-degradable or may include substantially non-degradable portions. In any embodiment, particularly in embodiments in which the needle 120 is substantially non-degradable, the delivery assembly 110 may include a return spring or other biasing structure to allow retraction of the needle 120 from the GI lumen wall within the housing 112 to prevent injury to the subject.

[0073] One or more components of the device 100 (e.g., the housing 102, the outer coating 104, the expandable member 106, the release means 108, the delivery assembly 110) may be formed from or otherwise include one or more biodegradable materials to facilitate degradation of such components, e.g., to allow passage through the remainder of the subject's intestinal tract following delivery of the fluid formulation 116. Examples of biodegradable materials suitable for use with various components of the device 100 include, for example, hydroxypropyl methylcellulose (HPMC), polyvinyl acetate (PVA), lactide, glycolide, lactic acid, glycolic acid, per-dioxanone, trimethylene carbonate, caprolactone, and mixtures and copolymers thereof.

[0074] The above description is an overview of ingestible device 100. The following description, with reference to Figures 2-8, relates to examples of various features and aspects of device 100. These examples are intended to be illustrative of device 100, but are not intended to be limiting of device 100.

[0075] 2, a cross-sectional view of device 200 (one embodiment of device 100) is illustrated in an unfolded and / or unrolled state. Device 200 is illustrated without housing 102 and / or any outer coating 104. However, it should be understood that device 200 may be folded, rolled, and / or otherwise manipulated to be disposed within housing 102 (optionally with outer coating 104) to enable ingestion and subsequent delivery of device 200 into the GI tract.

[0076] The device 200 includes an expandable member in the form of a balloon 202 (an embodiment of the expandable member 106), a deflation valve 212, a reactant reservoir 214 containing a first reactant 215, a release means 216 (an embodiment of the release means 108), a second reactant 217, and a delivery assembly 300 (an embodiment of the delivery assembly 110).

[0077] Referring again to FIG. 2, the balloon 202 includes an inflator portion 204, a deflator portion 205, a lower portion 206, and an elongated portion 210 extending between the inflator portion 204 and the deflator portion 205. The lower portion 206 extends downwardly (in the orientation shown in FIG. 2) between the inflator portion 204 and the deflator portion 205. The various portions of the balloon 202 cooperatively define an interior 202a for housing the various components of the device 200. As described below, the balloon 202 is configured to expand at a desired location within the lumen of the GI tract (e.g., stomach, intestines) in response to the formation of a gas from a chemical reaction between a first reactant 215 and a second reactant 217 within the interior 202a. In this manner, the balloon 202 can facilitate delivery of the fluid formulation 317 from the delivery assembly 300 into the GI lumen wall or into the surrounding tissue.

[0078] The balloon 202 has a size and shape to occupy a space within the GI lumen upon inflation of the balloon 202 and enable delivery of the fluid formulation 317 into the GI lumen wall. For example, upon inflation of the balloon 202, the outer periphery of the balloon 202 (e.g., the outer periphery of the lower portion 206 and the elongated portion 210) presses against the surface of the lumen wall. The pressure exerted by the balloon 202 is sufficient to temporarily hold the balloon 202 against the lumen wall for delivery of the fluid formulation 317. Depending on the inner circumference of the lumen delivery site, the lower portion 206 may remain partially folded or may fully expand when the balloon 202 is inflated. For example, if the lumen is relatively large and there is no obstruction resisting the expansion of the balloon 202, the balloon 202 will assume a fully inflated configuration with the lower portion 206 fully expanded (as shown in FIG. 2). However, if the lumen is relatively small and the inner lumen circumference is smaller than the maximum size of the fully expanded balloon 202, the lower portion 206 will remain partially folded. In this manner, the balloon 202 can self-adjust to the size of the GI lumen to hold the balloon 202 in position for delivery of the fluid formulation 317, and the same balloon 202 can be used for a wide range of lumen sizes (e.g., different inner circumferences).

[0079] The deflation valve 212 is configured to cause deflation of the balloon 202 upon completion of delivery of the fluid formulation 317 into the GI lumen wall or surrounding tissue. In this manner, the deflation valve 212 can facilitate passage of the balloon 202 through the remainder of the GI tract and out the subject's anus. In the illustrated embodiment, the deflation valve 212 is configured as a degradable plug that temporarily covers an opening leading to the interior 202a. The degradable plug can be structured to degrade upon contact with fluids (e.g., bodily fluids) in the GI tract, thereby allowing gas contained in the interior 202a to exit through the opening. For example, the deflation valve 212 can be formed from or include an enteric material. The balloon 202 can include an optional flap 228 that can temporarily cover the deflation valve 212 to prevent premature activation (e.g., degradation) of the deflation valve 212 until the balloon 202 is inflated. For example, the flaps 228 can be temporarily held (e.g., glued, tacked, or otherwise held) in a folded position 228' about the flap fold axis 228a. Inflation of the balloon 202 can cause the flaps 228 to deploy from the folded position 228' to expose the deflation valve 212 and allow fluid within the GI tract to reach and cause the deflation valve 212 to disintegrate, thereby providing an opening for gas to escape to allow deflation.

[0080] Although the deflation valve 212 is shown disposed at the deflator portion 205, the deflation valve 212 may be disposed elsewhere on the expandable member 202 in other embodiments. Additionally, the balloon 202 may include multiple deflation valves 212. The deflation valve 212 may be configured differently than in the embodiment shown in FIG. 2. For example, in other embodiments, the deflation valve 212 may be configured as a dissolvable and / or movable cover disposed over an opening in the balloon 202. In these embodiments, dissolving and / or moving the cover away from the opening allows gas to exit the interior 202a through the opening, thereby enabling deflation.

[0081] The reactant reservoir 214 is disposed within the interior 202a and is structured to hold a first reactant 215 within the reactant reservoir 214 and temporarily prevent the first reactant 215 from contacting a second reactant 217 that is separately disposed within the interior 202a. The first reactant 215 may be, for example, citric acid. The second reactant 217 may be, for example, a carbonate such as potassium bicarbonate. In other embodiments, the first reactant 215 and the second reactant 217 may be other types of reactants (e.g., an acid and a base) that, when mixed, result in the formation of a gas sufficient to inflate the balloon 202. The second reactant 217 is shown disposed within the interior 202a of the inflator portion 204 near the first reactant 215. In other embodiments, the first reactant 215 and the second reactant 217 may be included in other regions of the balloon 202 so long as they are temporarily separated from one another.

[0082] The reactant reservoir 214 defines an interior volume for containing the first reactant 215. The reactant reservoir 214 can take a variety of different forms and shapes, such as a balloon or other structure. The reactant reservoir 214 is in selective fluid communication with the interior 202a via a reactant conduit 218 and a release means 216. The release means 216 is coupled to the reactant conduit 218 such that upon actuation (e.g., decomposition) of the release means 216, the first reactant 215 can exit the reactant reservoir 214 through the reactant conduit 218 to the interior 202a. For example, the release means 216 can be in the form of a degradable plug that blocks the interior of the reactant conduit 218 to temporarily prevent the first reactant 215 from entering the interior 202a. For example, when fluid in the GI tract contacts the release means 216 (upon decomposition of the housing 102 and / or outer coating 104), the release means 216 then decomposes allowing the reactant conduit 218 to discharge the first reactant 215 into the interior 202a.

[0083] In other embodiments, the device 200 includes a clip, band, or other structure for holding a portion of the balloon 202 to temporarily define separate chambers within the interior 202a for separately housing the first reactant 215 and the second reactant 217, respectively. For example, a portion of the balloon 202 can be clamped or compressed with a degradable clip or band to temporarily define multiple separate chambers within the interior 202a. The multiple chambers can be substantially sealed together to substantially prevent the first reactant 215 and the second reactant 217 from mixing. The clip or band can be positioned on an outer portion of the balloon 202 such that exposure to fluids within the GI tract (e.g., upon degradation of the housing 102 and / or the outer coating 104) causes the clip or band to degrade and then be released from the balloon 202. When the clip or band or similar structure is released from the balloon 202, the separate chambers are no longer substantially sealed together, allowing the first reactant 215 to mix with the second reactant 217 within the interior 202a.

[0084] Combining first reactant 215 with second reactant 217 within interior 202a causes a chemical reaction to occur forming a gas (e.g., CO2) that expands balloon 202 to an inflated state within the GI lumen and substantially aligns elongated portion 210 with a surface of the GI lumen wall. The substantial alignment of elongated portion 210 with the GI lumen wall advantageously helps to facilitate delivery of fluid formulation 317 from delivery assembly 300 into the GI lumen wall or surrounding tissue.

[0085] 2, delivery assembly 300 is coupled to balloon 202 and at least partially disposed within interior 202a. Delivery assembly 300 is shown to include housing 302 (an embodiment of housing 112), membrane 315 (an embodiment of membrane 114), fluid formulation 317 (an embodiment of fluid formulation 116), piston 319 (an embodiment of piston 118), and needle 320 (an embodiment of needle 120). Membrane 315 and piston 319 cooperatively define a reservoir 315a for containing fluid formulation 317.

[0086] As described below, gas pressurizing the balloon 202 can pass through an opening in the housing 302 and apply pressure against the membrane 315 of the piston 319. When the gas pressure reaches a threshold (e.g., when the balloon 202 is fully or partially inflated within the GI lumen), the pressure causes the piston 319 and needle 320 to move relative to the housing 302 toward the GI lumen wall. In response to resistance applied to the needle 320 by the GI lumen wall, the piston 318 moves axially relative to the needle 320, causing the needle 320 to pierce a seal in the piston 319, thereby allowing the fluid formulation 317 to flow from the reservoir 315a to the needle 320. Upon piercing the seal, the gas pressure causes the needle 320 to advance further into the GI lumen wall or into the surrounding tissue. The gas pressure also causes the membrane 315 to expel the fluid formulation 317 from the reservoir 315a through the needle 320 and into the GI lumen wall or into the surrounding tissue.

[0087] 3, a detailed view of a portion of device 200 is shown including a delivery assembly 300. As shown in FIG. 3, delivery assembly 300 includes housing 302, needle seal 304, release means 306, reservoir seal 307, membrane 315, fluid formulation 317, piston 319, needle 320, piston seal retainer 321, and piston seal 323. In the illustrated embodiment, needle 320 is collectively defined by needle sleeve 322, tissue penetrating member 324, and seal piercing member 326. In other embodiments, needle 320 may be a monolithic structure including needle sleeve 322, tissue penetrating member 324, and seal piercing member 326.

[0088] The housing 302 includes a peripheral housing wall 302a that defines a piston chamber 302a′ and a needle chamber 302a″. The piston 319 is movably (e.g., slidably) disposed in the piston chamber 302a′. A portion of the needle 320 (e.g., tissue penetrating member 324) is disposed in the needle chamber 302a″. In the orientation shown in FIG. 3, the needle chamber 302a″ extends from an upper end of the piston chamber 302a′. The housing 302 is configured to be coupled (e.g., heat sealed, glued) to the balloon 202 (e.g., elongated portion 210 shown in FIG. 3) along the peripheral housing wall 302a at a transition between the piston chamber 302a′ and the needle chamber 302a″. In the assembled state, a portion of the peripheral housing wall 302a above the piston chamber 302a′ extends outwardly from the elongated portion 210 of the balloon 202 to position the needle chamber 302a″ adjacent to the GI lumen wall. The piston chamber 302a' and the needle chamber 302a'' each have a substantially cylindrical shape and cooperate to define a longitudinal axis 302ab along which the piston 319 and the needle 320 move axially. However, it should be understood that the piston chamber 302a' and the needle chamber 302a'' may have different shapes other than cylindrical (e.g., ovoid, spherical) according to other embodiments. The housing 302 may further define one or more vent ports to act as pressure relief for the piston chamber 302a' or the balloon interior 202a during or after axial movement of the piston 319 relative to the housing 302. The vent ports may be configured to allow selective fluid communication between the piston chamber 302a' and the balloon interior 202a and the GI lumen environment outside the device 200.

[0089] The needle seal 304 is coupled (e.g., glued) to the peripheral housing wall 302a'' at an upper end of the needle chamber 302a'' to substantially prevent fluid within the GI tract from entering the needle chamber 302a'' until the needle 320 (e.g., tissue-piercing member 324) penetrates the needle seal 304. The needle seal 304 may be formed from a penetrable material (e.g., aluminum foil) to allow the needle 320 to penetrate the needle seal 304. In this manner, the needle seal 304 and the peripheral housing wall 302a may cooperate to define a substantially sterile environment within the interior of the needle chamber 302a'' for containing the needle 320 prior to delivery of the fluid formulation 317 into the GI lumen wall or into the surrounding tissue.

[0090] The release means 306 (e.g., actuator, trigger) is coupled (e.g., press-fit, snap-fit, adhesively) or integrally formed with the housing 302 within the piston chamber 302a'. As shown in FIG. 3, the release means 306 is coupled to the inner surface of the housing peripheral wall 302a within the piston chamber 302a'. As described below, the release means 306 is configured to interface with the piston 319 to substantially prevent forward movement of the piston 319 and needle 320 until sufficient pressure is generated by gas within the interior 202a of the balloon 202. For example, FIG. 5 illustrates a cross-sectional view of the release means 306 taken along line 5-5 of FIG. 3. As shown in FIG. 5, the release means 306 has a substantially circular cross-sectional shape and includes one or more fingers 306a extending radially inward toward the longitudinal axis 302ab. Each of the fingers 306a extends radially inward in a cantilevered manner from a circumferential end of the release means 306 to a free end adjacent the piston 319. As described below, the fingers 306a are structured to interface with a protrusion 319c of the piston 319 through interference (e.g., overlap) to substantially prevent the needle 320 from penetrating the needle seal 304 until sufficient pressure is generated within the interior 202a. When a threshold level of internal gas pressure is reached (e.g., upon full or partial inflation of the balloon 202), the protrusion 319c breaks the interference with the fingers 306a by moving the fingers 306a away from the piston 319, thereby allowing the piston 319 to move axially along the longitudinal axis 302ab toward the needle seal 304 such that the tissue penetrating member 324 penetrates the needle seal 304.

[0091] According to other embodiments, the release mechanism can be defined by a detachable connection between the piston 319 and the housing 302. For example, the delivery assembly 300 can include a rear cover coupled to the housing 302. The rear cover can include one or more snap features that interface with complementary features on the piston 319 to temporarily hold the piston 319 against the housing 302 until sufficient pressure is generated by gas within the interior 202a of the balloon 202.

[0092] In another embodiment, the rear cover may have a flexible (e.g., breakable) connection with the piston 319 that may be configured to break away in response to a threshold gas pressure generated within the interior 202a to allow axial movement of the piston 319 relative to the housing 302.

[0093] The piston 319 is movably (e.g., slidably) coupled to the housing 302. In the unactuated state shown in FIG. 3, the piston 319 is disposed in a piston chamber 302a'. The piston 319 includes a piston circumferential wall 319a that defines a fluid cavity 319a' and a needle cavity 319a''. As described below, the membrane 315 is coupled to the piston 319 such that the membrane 315 surrounds the fluid cavity 319a' and defines a reservoir 315a for containing the fluid formulation 317 therein. The piston 319 is structured to move axially relative to the housing 302 in response to a threshold gas pressure applied against an outer surface of the membrane 315. The piston circumferential wall 319a further defines a fill port 319a''' for filling the reservoir 315a with the fluid formulation 317.

[0094] After filling the reservoir 315a (partially or completely), the fill port 319a''' is substantially fluidly sealed, for example, by heat staking the peripheral housing wall 302a to substantially close the fill port 319a'''. In other embodiments, a separate seal (e.g., silicone or aluminum foil) may be bonded to the peripheral housing wall 302a at the fill port 319a'''. In other embodiments, the fill port 319a''' may include a septum (e.g., a silicone septum) such that the fill port 319a''' is self-sealing after filling the reservoir 315a with the fluid formulation 317.

[0095] In either case, the reservoir 315a can be filled with the fluid formulation 317 before the piston 319 is coupled to the housing 302 and balloon 202. This can advantageously provide flexibility for aseptic assembly of the device 200. For example, a vacuum can be drawn on the reservoir 315a through the fill port 319a''' in a sterile environment to substantially evacuate the reservoir 315a before the piston 319 is assembled to the housing 302 and balloon 202. The evacuated reservoir 315a can then be filled with the fluid formulation 317 through the fill port 319a''' in a sterile environment before assembly with the housing 302 and balloon 202.

[0096] 3, the piston peripheral wall 319a further defines a stop feature 319b extending from an inner surface of the piston peripheral wall 319a toward the longitudinal axis 302ab within the needle cavity 319a''. The stop feature 319b is configured to interface with a complementary feature on the needle 320 (illustrated in FIG. 3 as protrusion 326c) to limit axial movement of the piston 319 relative to the needle 320, as will be described in more detail below with reference to FIG. 4.

[0097] The piston peripheral wall 319a further defines a protrusion 319c extending from an outer surface of the piston peripheral wall 319a at an upper portion of the needle cavity 319a''. In the unactuated state shown in FIG. 3, the protrusion 319c is disposed adjacent to and below the plurality of fingers 306a of the release means 306. As discussed above with respect to FIG. 5, the protrusion 319c interfaces with the plurality of fingers 306a to substantially prevent advancement of the needle 320 through the needle seal 304 until an internal pressure generated by gas within the interior 202a reaches a threshold pressure. For example, the threshold pressure may be associated with a fully inflated state of the balloon 202 within the GI lumen to ensure substantial alignment of the elongated portion 210 with the GI lumen wall prior to advancement of the needle 320 from the housing 302.

[0098] The reservoir seal 307 is bonded (e.g., glued) to an inner surface of the piston peripheral wall 319a to define a substantially fluid-tight seal between the fluid cavity 319a' and the needle cavity 319a". In this manner, the reservoir seal 307 substantially prevents the fluid formulation 317 from entering the needle cavity 319a" until the needle 320 penetrates the reservoir seal 307. The reservoir seal 307 may be formed from a pierceable material, such as aluminum foil.

[0099] The piston seal 323 is coupled to an outer portion of the piston wall 319a by a piston seal retainer 321. The piston seal retainer 321 is coupled (e.g., glued, snap-fit) to an upper portion of the piston wall 319a to retain the piston seal 323 against the piston 319. In other embodiments, the piston seal 323 can be integrally molded (e.g., insert molded) or otherwise coupled to the peripheral side of the piston 319. The piston seal 323 is configured to engage an inner surface of the housing wall 302a to form a substantially fluid-tight seal between the piston 319 and the housing wall 302a within the piston chamber 302a'. The piston seal 323 is further configured to allow relative axial movement between the piston 319 and the housing 302. The piston 319 may be formed from a polymeric material (e.g., acrylonitrile butadiene styrene (ABS)) or other material or combination of materials. The piston seal 323 may be formed from silicone or other suitable material.

[0100] Referring again to FIG. 3, the membrane 315 is coupled to the piston 319 and defines a reservoir 315a. For example, the membrane 315 may be coupled to the piston 319 by heat sealing, ultrasonic welding, gluing, or other means. In the illustrated embodiment, the membrane 315 is coupled to an inner surface of the piston peripheral wall 319a, which defines a fluid cavity 319a'. The membrane 315 extends circumferentially around the piston 319 to surround the fluid cavity 319a'. In this manner, the membrane 315, the piston peripheral wall 319a, and the reservoir seal 307 cooperate to contain the fluid formulation 317 within the reservoir 315a. The reservoir 315a may define a volume for containing up to about 250 μL or more of fluid, as described above with reference to FIG. 1. For example, the reservoir 315a may define a volume to contain between about 50 μL and about 200 μL of fluid, including between 50 μL and 250 μL of fluid, such as 50 μL, 100 μL, 150 μL, or 200 μL of fluid, or any value therebetween. As described below, the membrane 315 is configured (e.g., bends, flexes, contracts) in response to gas pressure (due to reaction of the first reactant 215 and the second reactant 217) generated within the balloon 202 to expel the fluid formulation 317 from the reservoir 315a to the needle 320. The membrane 315 may have a surface shape that is complementary to the inner surface shape of the piston 319 that defines the fluid cavity 319a′ in a relaxed state (i.e., when the reservoir 315a is not filled with the fluid formulation 317). For example, the membrane 315 may be vacuum formed using the fluid cavity 319a' as a mold to form the membrane 315 such that the membrane 315 substantially mimics the inner surface shape of the fluid cavity 319a'. In this manner, the membrane 315 may be sufficiently deformed to expel a significant amount of the fluid formulation 317 from the reservoir 315a. Furthermore, such a complementary shape of the membrane 315 may help facilitate sufficient expulsion of the reservoir 315a for subsequent filling with the fluid formulation 317 during assembly.The membrane 315 may be formed from a flexible polymeric material (e.g., polyethylene terephthalate (PET)) or other flexible material or combination of materials that have sufficiently low moisture and gas permeability for use with the fluid formulation 317.

[0101] Needle 320 is movably (e.g., slidably) coupled to piston 319 and disposed within needle cavity 319a''. In the embodiment shown in FIG. 3, needle 320 is collectively defined by needle sleeve 322, tissue penetrating member 324, and seal piercing member 326. In other embodiments, needle 320 is a unitary structure including needle sleeve 322, tissue penetrating member 324, and seal piercing member 326.

[0102] The needle sleeve 322 couples the tissue-piercing member 324 to the seal-piercing member 326. Additionally, the needle sleeve 322 functions to movably couple the needle 320 to the piston 319 within the needle cavity 319a''. In the illustrated embodiment, the needle sleeve 322 has a hollow cylindrical shape defining a needle sleeve first end 322a and an opposing needle sleeve second end 322b. An outer surface of the needle sleeve 322 engages an inner surface of the piston peripheral wall 319a within the needle cavity 319a'' to define a substantially fluid-tight seal therebetween. In this manner, the needle sleeve 322 can help prevent the fluid formulation 317 from passing through the needle cavity 319a'' between the needle 320 and the piston peripheral wall 319a such that a substantial amount of the fluid formulation 317 is directed from the reservoir 315a through the needle 320. The needle sleeve 322 is further configured to allow relative axial movement between the piston 319 and the needle 320 along the longitudinal axis 302ab. The needle sleeve 322 may be formed, for example, from silicone or other suitable material.

[0103] The tissue penetrating member 324 is coupled (e.g., press-fit, glued) to the needle sleeve 322 at the needle sleeve first end 322a. The tissue penetrating member 324 extends outwardly from the needle sleeve 322. The tissue penetrating member 324 includes a tapered portion 324a (e.g., a pointed tip) configured to penetrate the needle seal 304 and penetrate the GI lumen wall in response to sufficient axial movement of the piston 319. The tissue penetrating member 324 may have a length sufficient to penetrate the GI lumen wall and penetrate into the peritoneum or peritoneal cavity of a subject for delivery of the fluid formulation 317 thereto. The free end (e.g., the pointed tip) of the tapered portion 324a defines a first end of the needle 320. The tapered portion 324a defines a needle opening 324a' extending through the tapered portion 324a for ejecting the fluid formulation 317 into the GI lumen wall or into surrounding tissue. The tissue penetrating member 324 further includes an elongated portion 324b extending from the tapered portion 324a. The elongated portion 324b may be coupled to the tapered portion 324a or may be integrally formed therewith. A portion of the elongated portion 324b is disposed in the needle sleeve 322 at the needle sleeve first end 322a. The elongated portion 324b defines a first needle channel 324b' that extends from the needle opening 324a' to the opposite end of the elongated portion 324b.

[0104] In other embodiments, the tissue penetrating member 324 includes a side opening (e.g., a slotted opening) for discharging the fluid formulation 317 into the GI lumen wall or into the surrounding tissue. For example, referring to FIGS. 7-8, another example of a tissue penetrating member 724 (one embodiment of the tissue penetrating member 324) is shown. As shown in FIGS. 7-8, the tissue penetrating member 724 includes a tapered portion 724a (e.g., cone-shaped) that extends from an elongated portion 724b to a distal or tip end. The tapered portion 724a includes a slotted opening 724a' that extends through a side wall of the tapered portion 724a to an interior channel 724b' of the elongated portion 724b. The slotted opening 724a' is defined by a recess that extends laterally through a side wall of the tapered portion 724a and leads to a through hole that extends into the interior channel 724b'. The slotted opening 724a' is offset from the central axis and tip of the tissue-piercing member 724 to avoid blockage of the slotted opening 724a' by bodily tissue or fluids that may accumulate as the tissue-piercing member 724 penetrates the GI lumen wall or surrounding tissue.

[0105] The recess of the slotted opening 724a' extending laterally through the sidewall of the tapered section 724a can advantageously serve to direct the fluid formulation substantially longitudinally (represented in FIG. 8 by directional arrow 726) through the tissue penetrating member 724, thereby avoiding significant alteration of the flow path through the interior channel 724b'. In this manner, the fluid formulation can be efficiently ejected via the tissue penetrating member 724 and into the GI lumen wall or surrounding tissue.

[0106] 7-8, tissue penetrating member 724 further includes a tip 725 coupled (e.g., glued) or integrally formed (e.g., insert molded) with tapered portion 724a. Tip 725 defines an outermost distal end of tissue penetrating member 724. Tip 725 is configured to penetrate the GI lumen wall or surrounding tissue. Tip 725 may be formed from a material that is harder than the material of tissue penetrating member 724. For example, tip 725 may be formed from or include magnesium, metal, or other material or combination of materials.

[0107] The tissue penetrating member 324, 724 may be at least partially or completely degradable such that at least a portion of the tissue penetrating member 324, 724 may substantially degrade within the GI lumen wall (or elsewhere within the GI tract) upon delivery of the fluid formulation 317. For example, the tissue penetrating member 324, 724 may be formed from or include polyethylene oxide (PEO), magnesium, or other degradable material or combination of materials.

[0108] Referring again to FIG. 3, the seal piercing member 326 is coupled (e.g., press-fit, glued) to the needle sleeve 322. In the illustrated embodiment, the seal piercing member 326 is configured as a substantially cylindrical member having a generally elongated configuration, although other shapes and configurations are contemplated according to other embodiments. The seal piercing member 326 extends from a seal piercing member first end 326a to an opposing seal piercing member second end 326b. The seal piercing member second end 326b defines a second end of the needle 320 opposite the first end. The seal piercing member first end 326a is coupled (e.g., press-fit, glued) to the needle sleeve 322 at the needle sleeve second end 322b. The seal piercing member 326 extends outwardly from the needle sleeve second end 322b and terminates at the seal piercing member second end 326b. The seal piercing member second end 326b has a tapered shape (e.g., a pointed end) configured to pierce the reservoir seal 307 in response to relative movement between the piston 319 and the needle 320. The seal piercing member 326 further defines a protrusion 326c extending outwardly (e.g., radially) from its outer surface. As described above and below, the protrusion 326c functions as a complementary feature to interface with the stop element 319b to limit axial movement of the piston 319 relative to the needle 320. The seal piercing member 326 further defines a second needle channel 326a' for directing the fluid formulation 317 from the reservoir 315a to the first needle channel 324b' of the tissue piercing member 324. The second needle channel 326a' extends longitudinally along the longitudinal axis 302ab from the seal piercing member first end 326a to the seal piercing member second end 326b. The seal piercing member 326 can be formed, for example, from a polymeric material.

[0109] Referring to FIG. 4, a portion of the device 200 including the delivery assembly 300 is illustrated in an actuated state after the device 200 reaches a desired location in the GI tract (e.g., stomach or small intestine) to deliver the fluid formulation 317. As shown in FIG. 6, the balloon 202 is inflated by gas generated within the interior 202a such that the elongated portion 210 is substantially aligned with a surface of the GI lumen wall. The gas generated within the interior 202a applies pressure (indicated by unidirectional arrow 330) against the outer surface of the membrane 315 through the rear opening of the housing 302. When the gas pressure reaches a threshold value (e.g., a pressure associated with a fully inflated or partially inflated state of the balloon 202), the protrusion 319c overcomes the interference with the release means 306. As a result, the piston 319 moves axially relative to the housing 302 along the longitudinal axis 302ab toward the GI lumen wall such that the first end (e.g., tapered portion 324a) of the needle 320 advances through the needle seal 304 and into contact with the GI lumen wall.

[0110] When there is sufficient resistance from the GI luminal wall acting on the needle 320, the gas pressure applied to the membrane 315 causes the piston 319 to move axially relative to the needle 320 along the longitudinal axis 302ab toward the GI luminal wall. For example, the device 200 may be configured such that the piston 319 moves relative to the needle 320 when the needle 320 initiates contact with the GI luminal wall to generate sufficient resistance with the luminal wall. In other embodiments, the device 200 may be configured such that the piston 319 moves relative to the needle 320 when the needle 320 penetrates the GI luminal wall to a particular depth to generate sufficient resistance between the piston 319 and the needle sleeve 322. This may be accomplished, for example, by selecting a material for the piston 319 and / or the needle sleeve 322 to have a sufficient coefficient of friction to control the relative movement between the piston 319 and the needle 320. In either case, the fluid formulation 317 remains in the reservoir 315a until the second end of the needle 320 (e.g., seal piercing member second end 326b) penetrates the reservoir seal 307 while gas pressure of the balloon 202 is applied against the membrane 315. In this embodiment, the delivery assembly 300 allows for sequential timing between penetrating the GI luminal wall and expelling the fluid formulation 317, substantially avoiding expelling the fluid formulation 317 into the luminal environment and ensuring delivery of the fluid formulation 317 to the GI luminal wall or surrounding tissue (e.g., the peritoneum or peritoneal cavity).

[0111] Sufficient movement of the piston 319 relative to the needle 320 results in the second end of the needle 320 penetrating the reservoir seal 307, allowing the fluid formulation 317 to flow from the reservoir 315a into the second needle channel 326a'. The piston 319 is permitted to move axially relative to the needle 320 until the stop element 319b engages the protrusion 326c. Upon engagement between the stop element 319b and the protrusion 326c, gas pressure applied against the membrane 315 moves the piston 319 and the needle 320 axially relative to the housing 302 along the longitudinal axis 302ab such that the needle 320 further penetrates the GI lumen wall or surrounding tissue.

[0112] Furthermore, upon piercing the reservoir seal 307, gas pressure applied against the membrane 315 causes the membrane 315 to deform inwardly against the piston 319 toward the needle 320, expelling the fluid formulation 317 from the reservoir 315a toward the needle 320. As a result, the fluid formulation 317 is directed through the second needle channel 326a', the first needle channel 324b', and the needle opening 324a' into the GI lumen wall or surrounding tissue. In this manner, one or more therapeutic agents contained in the fluid formulation 317 may be delivered into the bloodstream of a subject for systemic delivery.

[0113] Upon completion of delivery of the fluid formulation 317, one or more components of the needle 320 (e.g., tissue penetrating member 324) may then disintegrate within the GI lumen wall or other areas within the GI lumen along with one or more additional components of the device 200 (e.g., housing 302, membrane 315, piston 319). In embodiments in which the needle 320 is substantially non-disintegrating, the device 200 is structured to retract the tissue penetrating member 324 from the GI lumen wall into the housing 302 after delivery of the fluid formulation 317 is completed. For example, the device 200 includes a return spring or other biasing feature to retract the needle 320 into the housing 302 after delivery of the fluid formulation 317. In any of these embodiments, the deflation valve 212 releases a substantial amount of gas contained within the interior 202a to significantly deflate the balloon 202 and then permit the device 200 to pass through the remainder of the GI tract and out the subject's anus.

[0114] 6, a method 600 of delivering a fluid formulation 116 to a subject's GI tract using the device 500 is shown. In a first step, the subject ingests the device 100 (e.g., by swallowing the device 100) (step 501), which results in the housing 102 and / or outer coating 104 being at least partially (or completely) degraded when the device 100 reaches a desired location in the GI tract for delivery of the fluid formulation 116 (step 502). In response to the degradation of the housing 102 and / or outer coating 104, the release means 108 is actuated to expand the expandable member 106 within the GI lumen (step 503). Expansion of the expandable member 106 within the GI lumen positions the delivery assembly 110 in proximity to the GI lumen wall (step 504). When the gas pressure within the expandable member 106 reaches a threshold value, the gas pressure is applied against the membrane 114, moving the piston 118 relative to the housing 112 and advancing the needle 120 toward the GI lumen wall (step 505). The GI lumen wall applies resistance to the needle 120, moving the piston 118 axially relative to the needle 120, forcing the needle 120 to pierce a seal in the piston 118 and allowing the fluid formulation 116 to be expelled into the needle 120 (step 506). In this manner, the device 100 can release one or more therapeutic agents contained in the fluid formulation 116 into the bloodstream of the subject for systemic delivery.

[0115] 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 form disclosed. Many modifications, variations, and improvements will be apparent to those skilled in the art. For example, the device embodiments can be sized and otherwise adapted for various pediatric and neonatal applications, as well as various veterinary applications. Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific devices and methods described herein. Such equivalents are deemed to be within the scope of the present disclosure.

[0116] Although the present disclosure has been described and illustrated with reference to specific embodiments thereof, these descriptions and illustrations are not intended to limit the present disclosure. It can be clearly understood that various changes can be made within the embodiments and equivalent components can be substituted without departing from the true spirit and scope of the present disclosure as defined by the appended claims. Also, components, properties, or acts from one embodiment can be easily recombined or substituted with one or more components, properties, or acts from other embodiments to form numerous additional embodiments within the scope of the present invention. Furthermore, a component illustrated or described as being combined with other components can exist as a single component in various embodiments. Furthermore, when a component, property, component, feature, step, etc. is positively described, the embodiment of the present invention specifically contemplates excluding that component, value, property, component, feature, step, etc. The illustrations are not necessarily drawn to scale. There may be a distinction between the artistic depictions in the present disclosure and the actual device due to variables in the manufacturing process, etc. There may be other embodiments of the present disclosure that are not specifically illustrated. The present specification and drawings are considered to be illustrative and not restrictive. Modifications may be made to adapt a particular situation, material, composition of matter, method, or process to the objective, spirit, and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto. Although the methods disclosed herein have been described with reference to certain operations performed in a particular order, it will be understood that these operations can be combined, further divided, or reordered to form equivalent methods without departing from the teachings of the present disclosure. Thus, unless specifically indicated herein, the order and grouping of operations are not limitations of the present disclosure.

Claims

1. 1. A delivery assembly for an ingestible device for delivering a fluid formulation into a GI tract lumen wall or surrounding tissue of a subject, comprising: a housing defining a chamber; a piston movably disposed within the chamber; a needle coupled to the piston; a membrane coupled to the piston to cooperate with the piston to define a reservoir for containing the fluid formulation.

2. The delivery assembly of claim 1 , wherein the piston defines a needle cavity, and the needle is slidably coupled to the piston at the needle cavity.

3. The delivery assembly of claim 2 , further comprising a seal coupled to the piston between the needle cavity and the reservoir defining a substantially fluid-tight seal therebetween.

4. 4. The delivery assembly of claim 3, wherein the needle includes a first end configured to penetrate the GI lumen wall and a second end configured to penetrate the seal in response to resistance applied to the needle from the GI lumen wall.

5. 2. The delivery assembly of claim 1, wherein the needle is configured to penetrate through the GI tract lumen wall into the peritoneum or peritoneal cavity of the subject and expel the fluid formulation therein.

6. The delivery assembly of claim 1 , wherein the membrane has a surface profile complementary to an inner surface profile of the piston that defines the reservoir.

7. The delivery assembly of claim 1 , wherein the reservoir defines a volume containing up to about 250 μL of fluid.

8. The delivery assembly of claim 1 , wherein the reservoir defines a volume containing from about 50 μL to about 200 μL of fluid.

9. The delivery assembly of claim 1 , wherein the housing is coupled to an expandable member and configured to be disposed within the expandable member.

10. The delivery assembly of claim 1 , wherein the piston is configured to move relative to the housing in response to pressure applied against the membrane to advance the needle into the GI lumen wall.

11. The delivery assembly of claim 1 , wherein the membrane is made of a flexible material that allows deformation of the membrane by pressure applied to an exterior surface of the membrane to expel the fluid formulation from the reservoir into the needle.

12. The delivery assembly of claim 1 , wherein the piston includes a fill port for filling the reservoir with the fluid formulation.

13. The delivery assembly of claim 1 , further comprising a fluid formulation disposed within the reservoir, the fluid formulation comprising at least one therapeutic agent.

14. 14. The delivery assembly of claim 13, wherein the at least one therapeutic agent is one or more selected from an immunosuppressant, a chemotherapeutic agent, a central nervous system (CNS) drug, an antidiabetic drug, an enzyme replacement therapy (ERT) drug, an antibody, a hormone, insulin, an incretin or a combination thereof, or an oligonucleotide.

15. 1. An ingestible device for delivering a fluid formulation into a GI tract lumen wall or surrounding tissue of a subject, comprising: An expandable member; coupled to the expandable member and disposed within the expandable member; a housing defining a chamber; a piston movably disposed within the chamber; a needle coupled to the piston; a membrane coupled to the piston to cooperate with the piston to define a reservoir; a fluid formulation disposed in the reservoir, the fluid formulation including at least one therapeutic agent; and a delivery assembly comprising the fluid formulation.

16. The device of claim 15 , wherein the expandable member comprises a balloon.

17. The device of claim 15 , further comprising an ingestible housing, the expandable member and the delivery assembly disposed within the ingestible housing.

18. 16. The device of claim 15, further comprising a plurality of reactants disposed on the expandable member to generate a gas pressure that causes the expandable member to inflate within the GI lumen.

19. 20. The device of claim 18, wherein the generated gas pressure is applied against the membrane to move the piston axially relative to the housing.

20. 20. The device of claim 18, wherein the piston further defines a needle cavity, the needle being slidably coupled to the piston in the needle cavity.

21. 21. The device of claim 20, wherein the delivery assembly further includes a seal coupled to the piston between the needle cavity and the reservoir defining a substantially fluid-tight seal therebetween.

22. 22. The device of claim 21, wherein the needle includes a first end configured to penetrate the GI lumen wall and a second end configured to penetrate the seal in response to resistance applied to the needle from the GI lumen wall.

23. 23. The device of claim 22, wherein the membrane is made of a flexible material such that the generated gas pressure causes the membrane to deform and expel the fluid formulation through the needle as the needle penetrates the seal.

24. 23. The device of claim 22, wherein the first end of the needle is configured to pierce the GI lumen wall before the second end of the needle pierces the seal.

25. 23. The device of claim 22, wherein the first end of the needle is configured to pierce the GI lumen wall at substantially the same time that the second end pierces the seal.

26. 16. The device of claim 15, wherein the needle is configured to penetrate through the GI tract lumen wall into the peritoneum or peritoneal cavity of a subject and expel the fluid formulation therein.

27. The device of claim 15 , wherein the membrane has a surface profile complementary to an inner surface profile of the piston that defines the reservoir.

28. The device of claim 15 , wherein the reservoir defines a volume containing up to about 250 μL of fluid.

29. The device of claim 15, wherein the reservoir defines a volume containing from about 50 μL to about 200 μL of fluid.

30. The device of claim 15 , wherein the piston includes a fill port for filling the reservoir with the fluid formulation.

31. 16. The device of claim 15, wherein the at least one therapeutic agent is one or more of an immunosuppressant, a chemotherapeutic agent, a central nervous system (CNS) drug, an antidiabetic drug, an enzyme replacement therapy (ERT) drug, an antibody, a hormone, insulin, an incretin or a combination thereof, or an oligonucleotide.

32. a tissue penetrating member having an elongated portion and a tapered portion extending from the elongated portion to a distal end; the elongated portion defines a longitudinal opening extending therethrough; the tapered portion defines a slotted opening extending through a sidewall of the tapered portion to the longitudinal opening; The slotted opening is for expelling the fluid formulation from the tissue penetrating member.

33. 33. The device of claim 32, wherein the tissue penetrating member further comprises a tip coupled to or integrally formed with the tapered section at the distal end.

34. 34. The device of claim 33, wherein the tip is made of a material that is harder than a material of the tissue penetrating member.

35. 32. A method of delivering a fluid formulation into the GI tract lumen wall or surrounding tissue of a subject in need thereof, comprising ingesting by the subject the ingestible device of any one of claims 15 to 31.

36. 32. Use of the ingestible device of any one of claims 15 to 31 for delivery of a fluid formulation comprising a therapeutic agent into the GI tract lumen wall or surrounding tissue of a subject in need thereof.

37. 15. A method of preparing an ingestible device for delivering a therapeutic agent into the GI tract lumen wall or surrounding tissue of a subject, comprising loading the delivery assembly of any one of claims 1 to 14 with a fluid formulation comprising the therapeutic agent.

38. 1. A delivery assembly for use in an ingestible device for delivering a fluid formulation to the GI tract of a subject, comprising: a housing defining a chamber; a piston movably disposed in the chamber; a needle coupled to the piston; a membrane coupled to the piston to cooperate with the piston to define a reservoir for containing the fluid formulation.

39. 1. A device for delivering a fluid formulation to the GI tract of a subject, comprising: An expandable member; coupled to the expandable member and disposed on the expandable member; a housing defining a chamber; a piston movably disposed in the chamber; a needle coupled to the piston; a membrane coupled to the piston to cooperate with the piston to define a reservoir for containing the fluid formulation.

40. 1. A method for delivering a fluid formulation to the GI tract of a subject, comprising ingesting a device; The device includes an expandable member and a delivery assembly coupled to and disposed on the expandable member; the delivery assembly includes a housing defining a chamber, a piston movably disposed in the chamber and defining a needle cavity, a needle coupled to the piston and disposed in the needle cavity, a membrane coupled to the piston to cooperate with the piston to define a reservoir for containing the fluid formulation, and a seal coupled to the piston to define a substantially fluid-tight seal between the needle cavity and the reservoir; gas is generated within the expandable member to expand the expandable member within the GI lumen and position the delivery assembly adjacent to a wall of the GI lumen; The gas pressure is applied against the membrane to advance the needle out of the housing and toward the GI lumen wall; the piston moves relative to the needle to pierce the seal in response to resistance applied to the needle from the GI lumen wall and to allow the fluid formulation to flow from the reservoir to the needle; Upon penetrating the seal, the gas pressure causes the membrane to expel the fluid formulation from the reservoir, through the needle, and into the GI lumen wall or surrounding tissue.

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