Self-expandable patch assembly for delivery of therapeutic agents to the intestinal wall - Patent Application 20070122997

Abstract

An embodiment of the present invention comprises: 1. A self-expanding patch assembly for intraluminal drug delivery, comprising: a flexible, inflatable patch having a water and gas impermeable wall defining an interior chamber and an array of piercing needles disposed on a surface thereof; one or more auxiliary gas-generating reaction chambers distinct from and in fluid communication with the inflatable patch, the reaction chambers being defined by flexible reaction chamber walls containing a water-sensitive gas-generating formulation, at least a portion of the reaction chamber walls having a water-permeable outer surface; and the patch assembly is configured such that each gas generating formulation or set thereof is retained within each auxiliary gas generating reaction chamber during expansion; A patch assembly is provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This invention claims the benefit of U.S. Patent Application No. 17 / 892,235, filed August 22, 2022, which is incorporated herein by reference in its entirety.

[0002] SUMMARY OF THE INVENTION Embodiments of the present disclosure relate to medical devices for automatic inflation activated by exposure to water. [Background technology]

[0003] Orally administered drug delivery to the intestinal wall is an area of ​​interest, particularly in the case of biologics (proteins, peptides, etc.) typically delivered parenterally, due to the potential for delivering therapeutic agents with relatively high bioavailability through increased blood flow, the potential for localized delivery of therapeutic agents to intestinal sites, and the ease of oral application to improve patient compliance. Pain-free, orally administered transintestinal patches can deliver therapeutic agents to the blood and allow for smooth, consistent, and safe penetration of therapeutic agents into the intestinal wall. This is particularly interesting for some therapeutic agents, including antibodies, proteins, and peptides, which currently cannot be delivered orally due to the sensitivity of these molecules to gastric pH, enzymatic digestion in the GI tract, the presence of mucus, and the low permeability across the intestinal wall due to the size and polarity of this group of molecules.

[0004] Although progress has been made in this field, several challenges remain to hinder development. Many technologies rely on enteric-coated capsules containing delivery devices that incorporate a piercing needle and a deployment mechanism with a therapeutic agent. One of the main challenges is the effectiveness of the piercing needle deployment, which is dependent on the control and influence of intestinal fluids.

[0005] A common approach involves releasing a capsule in intestinal fluids, followed by initiating a chemical reaction between a first and second reactant (e.g., citric acid and bicarbonate) to generate a gas (e.g., carbon dioxide). Typically, these reactants remain separate throughout the product's shelf life and early post-administration period, reacting only after the device is exposed to the intestinal environment. In this method, gas generation is delayed until after swallowing and deployment of the device in the intestine. Gas generation then actuates the penetrating needle into the intestinal lumen wall, where it can deliver a therapeutic agent.

[0006] There are several different methods for separating the first and second reactants, for example, using water-sensitive disintegrating separation means. U.S. Pat. No. 9,149,617 discloses a mechanism in which the liquid and the two reactants are kept in separate compartments. Exposure to intestinal fluid opens a separation means or valve. The two reactants, usually citric acid and bicarbonate, then mix with water, generating a gas such as carbon dioxide in an effervescent reaction. This gas then expands the inflatable patch, pushing the piercing needle into the intestinal wall. U.S. Pat. No. 9,492,396 discloses sodium bicarbonate at least partially coating the surface of a medication delivery element, which releases a gas that promotes unrolling of the stretched medication delivery element after exposure to intestinal fluid.

[0007] A further challenge relates to the conflicting material requirements for surfaces configured to constrain gas and accommodate balloon-like expansion while facilitating water absorption to deliver fluid to the foaming reactants. The use of prominent materials results in seams that have been found to allow gas to leak.

[0008] Deploying a pharmaceutically acceptable device with a gas-generating mechanism for inflating an expandable patch is a complex challenge because it involves conflicting objectives. The intestinal environment must drive the device to ensure that gas generation occurs at the desired time and location in the GI tract. At the same time, the device must be stable enough to withstand the moist environment during its useful life, to withstand the forces of gas expansion, and to maintain its durability during deployment in a lumen, particularly the intestine. Despite progress, there remains a need for improved gas-generating devices and methods for driving inflation and delivery of therapeutic agents across the intestinal lumen wall. Summary of the Invention

[0009] In a first aspect, a self-inflatable patch assembly (herein "patch assembly") for intraluminal (e.g., GI tract) drug delivery is provided, the self-inflatable patch assembly comprising a flexible, inflatable patch having a water- and gas-impermeable wall (the "inflatable patch wall") defining an interior chamber and an array of piercing needles disposed on its surface. In various embodiments, one or more auxiliary gas-generating reaction chambers are distinct from and in fluid communication with the inflatable patch, the reaction chambers being defined by flexible reaction chamber walls containing water-sensitive gas-generating formulations, the reaction chamber walls being configured to confine gas (i.e., substantially gas-impermeable) and having at least a portion of a water-permeable outer surface, and the patch assembly can be configured such that each gas-generating formulation (or set of formulations) is retained within each auxiliary gas-generating reaction chamber during inflation.

[0010] In another aspect, a self-inflatable patch assembly for intraluminal drug delivery includes: a flexible, inflatable patch having a water- and gas-impermeable wall defining an interior chamber and an array of piercing needles disposed on the interior chamber; and one or more auxiliary gas-generating reaction chambers distinct from the inflatable patch and in fluid communication with the inflatable patch, the reaction chambers being defined by flexible reaction chamber walls containing a water-sensitive gas-generating formulation, the reaction chamber walls being configured to contain gas, and the one or more auxiliary gas-generating reaction chambers having at least a portion with a water-permeable outer surface, wherein the patch assembly has a water-permeable resistance of 0.2 to 1.0 or 0.3 to 0.7 N / cm. 2 A self-expanding patch assembly is provided that is configured to apply a force per area of

[0011] In various embodiments, the patch assembly may be compressed and further contained within a swallowable enteric outer shell, where the patch assembly is configured for delivery of a therapeutic agent into the intestinal wall (e.g., the small intestinal wall).

[0012] In various embodiments, the water-sensitive gas-generating formulation can be a sustained-release gas-generating formulation. For example, the sustained-release gas-generating formulation can include a viscosity-enhancing agent.

[0013] In various embodiments, the gas-generating reaction chamber can be configured to generate a constant amount of gas for an extended period of time, for example, more than 30 minutes. In various embodiments, the water-sensitive gas-generating formulation is configured to generate gas that provides an inflatable patch pressure of greater than 3 psi when measured at 37° C. In various embodiments, the water-sensitive gas-generating formulation is configured to generate gas that provides an inflatable patch pressure of substantially constant pressure when measured at 37° C. for about 30 minutes. In various embodiments, the water-sensitive gas-generating formulation can be configured to generate gas that provides an inflatable patch pressure of greater than 2 psi when measured at 37° C. for about 30 minutes.

[0014] In various embodiments, one or more auxiliary gas-generating reaction chambers are in fluid communication with the inner chamber but separated from the inflatable patch by a formulation retainer. In various embodiments, one or more auxiliary gas-generating reaction chambers are in fluid communication with the inner chamber but separated from the inflatable patch by a water-permeable surface and contain a water-sensitive gas-generating formulation therein (not present in the inflatable patch).

[0015] In various embodiments, the patch assembly can be configured such that the combination of the interior chamber of the patch and each interior of the one or more auxiliary gas reaction chambers is configured to trap gas therein.

[0016] In various embodiments, the first and second reactants are contained within a single compartment.

[0017] In various embodiments, the gas-generating reaction chambers can be positioned along the periphery, periphery, or side of the inflatable patch. For example, there can be two or more gas-generating reaction chambers positioned along the periphery, periphery, or side of the inflatable patch. In another example, there can be three or more gas-generating reaction chambers positioned along the periphery, periphery, or side of the inflatable patch.

[0018] In various embodiments, the formulation retention portion may be positioned along the periphery, periphery, outer surface, or side of the expandable patch. The formulation retention portion may be designed to permit the passage of fluid while restricting the passage of water-sensitive gas-generating formulation, typically based on geometrical selection, although other methods may be envisioned.

[0019] In various embodiments, at least 50% of the exterior surface of the reaction chamber wall is water permeable, or preferably directionally permeable, ie, directionally permeable from the outside of the reaction chamber toward the interior volume.

[0020] In various embodiments, the piercing needle has a length of greater than 6.0 mm, or alternatively, 1.4 to 2.8 mm. In some embodiments, the piercing needle further comprises a therapeutic agent. In some embodiments, the inflatable patch comprises a fluid therapeutic agent operably coupled to the base of the piercing needle.

[0021] 28. The self-inflatable patch assembly of any one of claims 1 to 27, wherein the array of piercing needles is disposed on a first surface of the inflatable patch. For example, the first surface can be a plane of the inflatable patch in an uninflated, expanded state. In some embodiments, the array of piercing needles is disposed on the first surface of the inflatable patch, and the inflatable patch further includes an opposing wall having a surface without piercing needles.

[0022] In various embodiments, the expandable patch has a maximum dimension of less than 9 cm, e.g., 5.5 cm. In some embodiments, the expandable patch does not contain or include a gas-generating formulation. In some embodiments, the expandable patch does not include a water-permeable surface. In some embodiments, the expandable patch may be shaped or sized for contact with the inner circumference of a portion of the intestine.

[0023] In various embodiments, the compressed self-expanding patch assembly includes an auxiliary gas-generating reaction chamber disposed on the exterior surface of the compressed self-expanding patch.

[0024] In another aspect, a self-inflatable patch assembly is provided that includes a flexible, inflatable patch having a water- and gas-permeable wall ("inflatable patch wall") defining an interior chamber; and one or more auxiliary gas-generating reaction chambers distinct from and in fluid communication with the inflatable patch, the reaction chambers defined by flexible reaction chamber walls containing first and second reactants in a single compartment, the first and second reactants configured to foam upon exposure to water (e.g., in gas, liquid, or vapor form), the reaction chamber walls configured to be gas-confining (i.e., substantially gas-impermeable), and at least a portion of the auxiliary gas-generating reaction chambers having a water-permeable outer surface.

[0025] In various embodiments, the single compartment may be spaced from the expandable patch by a formulation retaining portion. In some embodiments of this aspect of the invention, the patch assembly further comprises an array of piercing needles disposed on the surface of the expandable patch.

[0026] The water-sensitive gas-generating formulation typically includes a first reactant that is a water-soluble organic acid (e.g., citric acid) and a second reactant that is an inorganic salt (e.g., alkali carbonate, alkali bicarbonate). In various embodiments of this aspect, the water-sensitive gas-generating formulation is configured for sustained release. For example, it may include a viscosity-enhancing agent. In another example, the water-sensitive gas-generating agent may include a disintegrant or super-disintegrant in the intragranular portion of the formulation. For example, the water-sensitive gas-generating formulation may include granules that include the first reactant, the second reactant, and the disintegrant or super-disintegrant. In another example, the water-sensitive gas-generating formulation may include a viscosity-enhancing agent that creates an extragranular portion. For example, a first water-soluble organic acid (e.g., citric acid), an inorganic salt (e.g., alkali carbonate, alkali bicarbonate), and a viscosity-enhancing agent may create the extragranular portion.

[0027] In various embodiments, the water-sensitive gas-generating formulation can be a single unit, such as a solid dosage form (e.g., a multi-layer tablet, a bi-layer tablet, a mini-tablet, or a micro-tablet). In some embodiments, the amount of the first reactant and the amount of the second reactant are less than 80% of the water-sensitive gas-generating formulation. In some embodiments, the first reactant and the second reactant are in anhydrous form. In some embodiments, the disintegrant is a sugar, such as sorbitol. In some embodiments, the gas-generating reaction chamber includes two or more water-permeable surfaces, for example, two or more opposing water-permeable surfaces.

[0028] In another aspect, a method for providing a self-expandable patch assembly for delivering a therapeutic agent into the intestinal wall of a subject, comprising: orally administering to the subject a device comprising a swallowable enteric coated outer shell and a self-expanding patch assembly, the patch assembly comprising a flexible, expandable patch having a water- and gas-impermeable wall ("expandable patch wall") defining an interior chamber and an array of piercing needles disposed on its surface, and an auxiliary gas-generating reaction chamber defined by a flexible reaction chamber wall containing a water-sensitive gas-generating formulation; the reaction chamber wall is configured to be gas-confining (i.e., substantially gas-impermeable) and has at least a portion of a water-permeable outer surface; exposing a water-sensitive gas-generating formulation to water through the water-permeable outer surfaces of the gas-generating reaction chambers, thereby creating a sustained release of gas that flows toward the inflatable patch while the formulation is retained within each auxiliary gas-generating reaction chamber; Optionally, further achieving gas equilibrium at constant pressure for a period of time. A method is provided, comprising:

[0029] In another aspect, a method for making a self-expandable patch assembly for delivering a therapeutic agent into the intestinal wall of a subject includes the steps of forming a sustained-release water-sensitive gas-generating formulation; providing upper and lower water- and gas-impermeable layers, a portion of the layers having a water-permeable surface; disposing the water-sensitive gas-generating formulation adjacent to the water-permeable surfaces; further providing a formulation retaining portion between the formulation and the expandable patch such that each gas-generating formulation can be retained within its respective auxiliary gas-generating reaction chamber; sealing a seam connecting the upper and lower layers to form the self-expandable patch; and folding or rolling the self-expandable patch assembly into a capsule such that a water-permeable surface can be maintained on the exterior surface of the self-expandable patch in a compressed state. A method is provided, comprising:

[0030] Aspects of the present disclosure are best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, under standard industry practice, various features are not drawn to scale. Dimensions of various features may be arbitrarily increased or decreased for clarity of discussion. Furthermore, the present disclosure may repeat reference numerals and / or letters in multiple instances. [Brief explanation of the drawings]

[0031] [Figure 1] FIG. 1 is a perspective view of an expanded self-expanding patch assembly. [Figure 2A-C] 1A-1D show schematic top, bottom, and cross-sectional views of a self-expanding patch assembly in an expanded, unexpanded configuration (e.g., after collapse of the outer shell) according to one or more embodiments. [Figure 3] 1 shows a schematic diagram of multiple gas generation chambers within the region of an inflatable patch according to one or more embodiments. [Figure 4] 1 shows a schematic diagram of a self-expanding patch assembly within a capsule in an expanded state and an expanded and inflated state. [Figure 5]1 shows a schematic diagram of a self-expandable patch assembly in a compressed state within the human intestine, according to one or more embodiments. [Figure 6] FIG. 1 shows a schematic diagram of an automatically inflatable drug delivery device for delivery of a therapeutic agent in the human intestine in an inflated state, according to one or more embodiments. [Figure 7A] FIG. 1 shows a schematic bottom view of a patch assembly in an expanded, inflated configuration, according to one or more embodiments. [Figure 7B] 1 shows a schematic top view of an expanded, inflated configuration of a self-inflatable patch according to one or more embodiments. [Figure 7C] FIG. 1 shows a side view of an expanded, unexpanded configuration of a self-expanding patch assembly before the gas-generating formulation begins to collapse, according to one or more embodiments. [Figure 8A] FIG. 10 shows a bottom view of the expanded, semi-expanded configuration of the self-expandable patch assembly after the reactants have initiated the gas-generating reaction, according to one or more embodiments. [Figure 8B] FIG. 10 shows a top view of a self-expanding patch assembly in an expanded, semi-expanded configuration after the reactants have initiated a gas-generating reaction, according to one or more embodiments. [Figure 8C] 1 shows a side view of an intestine including an expanded, semi-expanded configuration of a self-expandable patch according to one or more embodiments. [Figure 9A] FIG. 10 shows a bottom view of the expanded, inflated configuration of the self-expanding patch assembly after the reactants have undergone a gas-generating reaction, according to one or more embodiments. [Figure 9B] FIG. 10 shows a top view of the self-expanding patch assembly in an expanded, expanded configuration after the reactants have undergone a gas-generating reaction, according to one or more embodiments. [Figure 9C] 1 shows a side view of the intestine including the expanded and expanded configuration of the self-expandable patch assembly after the device has been deployed and the penetration needle has pierced the intestinal lumen wall. [Figure 10.11.12] 1A-1D are schematic diagrams of several configurations of gas generation chambers according to one or more embodiments. [Figure 13]1 illustrates one method of positioning a compressed gas-generating chamber and rolling and folding a self-expanding patch assembly into a capsule, according to one or more embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0032] In the following detailed description of aspects of the present invention, numerous specific details are set forth to provide a thorough understanding of the disclosed embodiments. However, it will be apparent to those skilled in the art that embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, techniques, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the embodiments of the present invention. Furthermore, to avoid unnecessary repetition of description, one or more components or acts described in one exemplary embodiment may be used or omitted from other exemplary embodiments, where applicable.

[0033] The inventors have discovered an expansion force and force per area sufficient to deliver the piercing needles to the associated layer for release of a therapeutic agent while keeping the gas-generating reaction chamber and / or the seams of the expandable patch intact. This force may be affected by a combination of factors, including the amount of gas-generating formulation, the volume of the internal volume of the self-inflatable patch assembly, and the structural integrity of the walls of the patch assembly. It should be recognized that the force per area may roughly correspond to the force per area applied to the base of the piercing needles or array thereof. Thus, in another aspect, similar to any of the embodiments of the self-inflatable patch assembly described herein, the self-inflatable patch assembly may have a force per area of ​​1.0 N / cm. 2 In some embodiments, the force per area is less than 0.9 N / cm 2 In some embodiments, the force per area may be less than 0.8 N / cm 2 In some embodiments, the force per area may be less than 0.7 N / cm 2 In some embodiments, the force per area may be less than 0.5 N / cm 2In some embodiments, the force per area may be less than 0.3 N / cm 2 In some embodiments, the force per area may be less than 0.1 N / cm 2 In some embodiments, the force per area may be greater than 0.09 N / cm. In some embodiments, the force per area may be greater than 0.15 N / cm. 2 In some embodiments, the force per area may be greater than 0.20 N / cm 2 In some embodiments, the force per area may be greater than 0.30 N / cm 2 In some embodiments, the force per area may be greater than 0.40 N / cm 2 In some embodiments, the force per area may be greater than 0.50 N / cm 2 In some embodiments, the force per area may be greater than 0.50 N / cm 2In any of the embodiments of the self-inflating patch assembly described herein, the sufficient amount of area force may be greater than 2 pounds per square inch (psi) when measured at 37° C. In any of the embodiments of the self-inflating patch assembly described herein, the sufficient amount of area force may be greater than 3 pounds per square inch (psi) when measured at 37° C. In any of the embodiments of the self-inflating patch assembly described herein, the sufficient amount of area force may be greater than 5 pounds per square inch (psi) when measured at 37° C. In any of the embodiments of the self-inflating patch assembly described herein, the sufficient amount of area force may be less than 5 pounds per square inch (psi) when measured at 37° C. In any of the embodiments of the self-inflating patch assembly described herein, the sufficient amount of area force may be less than 4 pounds per square inch (psi) when measured at 37° C. In any of the embodiments of the self-inflating patch assembly described herein, the amount of sufficient area force may be between 1 and 5 pounds per square inch (psi) when measured at 37° C. In any of the embodiments of the self-inflating patch assembly described herein, the amount of sufficient area force may be between 2 and 4 psi when measured at 37° C.

[0034] Embodiments of the present invention provide devices, systems, and methods of use for a self-inflatable patch assembly adapted to expand upon exposure to moisture, water, or fluids for application to the body, particularly the intestine. Under intestinal conditions, the self-inflatable patch assembly can expand and subsequently contact and apply pressure to at least a portion of the inner circumference of the intestine. The self-inflatable patch assembly includes a flexible, inflatable patch having a water- and gas-impermeable wall defining an interior chamber and a plurality of piercing needles disposed on its surface. The inflatable patch can be fluidly connected to one or more auxiliary gas-generating reaction chambers, each containing a gas-generating formulation. Each gas-generating reaction chamber is defined by a flexible reaction chamber wall containing a water-sensitive gas-generating formulation (e.g., a sustained-release formulation); the reaction chamber wall is configured to be gas-confining (substantially gas-impermeable) and have at least a portion of a water-permeable outer surface.

[0035] The patch assembly may be configured so that each gas-generating formulation can be retained within its respective auxiliary gas-generating reaction chamber. In some embodiments, each gas-generating formulation is configured to contact the inner surface of the gas-generating reaction chamber. In some embodiments, the gas-generating formulation can be disposed and / or maintained adjacent to (i.e., on) the water-permeable surface. In some embodiments, the gas-generating formulation can be prevented from migrating from the water-permeable surface, for example, by a formulation retaining portion adapted to allow fluid gas flow while retaining the gas-generating formulation within the gas-generating reaction chamber. For example, the formulation retaining portion may include a net-like sack or filter separating the gas-generating chamber from the inflatable patch so that the formulation can be retained within the gas-generating reaction chamber while allowing the free flow of gas. In some embodiments, water or fluid, other than that absorbed from the outside, may not be contained within the self-inflatable patch assembly to drive the effervescent reaction.

[0036] More specifically, embodiments of the present invention provide devices, systems, and methods of use of a self-inflatable patch assembly for delivery of a therapeutic agent into or through the wall of a lumen, for example, the wall of an intestinal lumen, wherein the self-inflatable patch assembly includes piercing needles on a water-impermeable surface of the inflatable patch, and the inflatable patch may be in fluid communication with one or more gas-generating reaction chambers containing a gas-generating formulation (e.g., a sustained-release gas-generating formulation), at least a portion of the surface of the gas-generating reaction chambers being water-permeable. Alternatively, the inflatable patch may be in fluid communication with one or more gas-generating reaction chambers containing a gas-generating formulation, and the gas-generating formulation may be disposed adjacent to an inner wall having a water-permeable surface.

[0037] As used herein, "expanded form" refers to a form that is, for example, uncompressed, unfolded, or uncoiled, and is prepared for placement within a swallowable enteric shell. The expanded form may or may not be expanded, depending on the context.

[0038] As used herein, "compressed form" is meant to refer to a state in which the drug is folded, rolled, or otherwise dimensionally reduced to fit into a smaller container, such as a swallowable enteric shell.

[0039] As used herein, unless otherwise specified, "gas-impermeable" or "gas-impermeable" refers to a material, membrane, or wall that impedes gas transmission by slowing, preventing, or limiting the escape or diffusion of a substantial amount of gas through its surface for a specified period of time. Typically, a "gas-impermeable" or "gas-impermeable" wall comprises a network of closely packed molecules or polymers that restricts the diffusion of gas molecules through its surface, effectively impeding, but not necessarily preventing, gas transmission. For example, a reaction chamber wall is configured to confine gas, and the selection of the wall material or membrane is guided by resistance, but gas permeability may be present and slow, or may depend on a combination of factors, including, but not limited to, material (e.g., polymer type) and width. Furthermore, while a reaction chamber wall is described as impermeable, this does not necessarily include a portion of the reaction chamber wall that has a water-permeable outer surface. In some embodiments, the permeable outer surface is directionally permeable to water in any form, including gas or liquid form, and is therefore gas-permeable. Furthermore, one skilled in the art will recognize that the quality of gas impermeable membranes in the GI tract can change over time, and while the reaction chamber walls are considered gas impermeable, this property can change over time in vivo and is meant to relate to characteristics at time = 0. When a water permeable portion absorbs water, this changes its physical characteristics, including but not limited to elasticity, thickness, gas permeability, etc.

[0040] As used herein, unless otherwise specified, a "water-impermeable" or "water-impermeable" surface, wall, or membrane prevents the passage of water molecules due to the tight arrangement of its polymer chains, which form a barrier that maintains a water-impermeable state.

[0041] As used herein, two reactants, or first and second reactants, are used interchangeably, which interact to foam and release gas in the presence of water.

[0042] As used herein, a "material" is a composition of matter from which parts, elements, components, etc. are made.

[0043] As used herein, expanded state has a meaning relating to the state of the device outside of the enteric outer shell, or in an uncompressed, unfolded, unrolled, or dimensionally reduced state.

[0044] As used herein, "sustained release" or "controlled release" are used interchangeably in reference to a formulation designed to gradually release, e.g., gas, over an extended period of time compared to the equivalent immediate release.

[0045] The term "lumen" as used herein refers to the interior space of a tubular structure. Examples of bodily lumens include arteries, veins, and tubular cavities within organs. In all cases, the lumen naturally contains water or fluid, or can be supplied with water or fluid.

[0046] The term "luminal wall" refers to the wall of a lumen, which includes the lumen, e.g., the lumens within the body, including the blood vessels and tissues that make up the lumen, the mucosa, the submucosa, the muscularis, the serosa, and all layers of the outer wall of the lumen from the inner periphery to the outer edge of the lumen.

[0047] 1 and 2, an inflatable patch assembly is illustrated. FIGS. 1A and 1B provide perspective views of an inflated self-inflatable patch assembly 10 (herein "patch assembly") according to one or more embodiments, and FIGS. 2A, 2B, and 2C show schematic top, bottom, and cross-sectional views of the self-inflatable patch assembly 10 in an expanded, uninflated configuration (e.g., after collapse of the outer shell) according to one or more embodiments. In FIG. 1, the patch assembly 10 is illustrated in its expanded configuration after release from a swallowable enteric-coated outer shell. The patch assembly 10 includes a flexible, inflatable patch 12 having a gas- and water-impermeable wall defining an interior chamber and a plurality of piercing needles disposed thereon. An auxiliary gas-generating reaction chamber 14 is defined by flexible reaction chamber walls that contain one or more water-sensitive gas-generating formulations 18, the reaction chamber walls being configured to be gas-confining (i.e., substantially gas-impermeable) and having at least a portion of a water-permeable outer surface. The patch assembly includes a plurality of gas-generating formulations 18, each of which is configured to be gas-confining (i.e., substantially gas-impermeable) and has a water-permeable outer surface. Alternatively, a set of gas-generating formulations may be retained in each auxiliary gas-generating reaction chamber 14 during inflation. For example, the formulation retaining portion 16 may be sized to restrict passage of the gas-generating formulation 18. The patch assembly 10 includes a formulation retaining portion 16 that divides the inflation chamber 12 and the reaction chamber 14. The inflation chamber 12 does not include a water-permeable surface. The interior chamber of the inflatable patch 12 and each interior of the one or more auxiliary gas reaction chambers 14 are configured to contain the gas within which inflation ultimately occurs. In some embodiments, despite the amount of pressure created within the gas-generating reaction chamber 14, substantial gas leakage from the self-inflatable patch does not occur during the first period. However, as time progresses, additional pressure is applied to the wall as gas continues to be generated, eventually reaching a pressure equilibrium. Gradual gas leakage may occur during the second period. In some embodiments, gas leakage drives the release of the self-inflatable patch from the intestinal wall.

[0048] In some embodiments, the water-sensitive gas-generating formulation 18 is a sustained-release gas-generating formulation. In some embodiments, the water-sensitive gas-generating formulation 18 is configured to generate gas that provides a pressure in the expandable patch 12 of greater than 2 psi, greater than 3 psi, or greater than 3.5 psi when measured at 37°C. In some embodiments, the water-sensitive gas-generating formulation 18 is configured to generate gas that provides a pressure in the expandable patch 12 of about 2-8, 2-6, or 2-5 psi when measured at 37°C. In some embodiments, the water-sensitive gas-generating formulation 18 is configured to generate gas that provides a substantially constant pressure in the expandable patch when measured for about 30 minutes at 37°C. In some embodiments, the water-sensitive gas-generating formulation 18 is configured to generate gas that provides a substantially constant pressure in the expandable patch of greater than 3.0 psi when measured for about 30 minutes at 37°C. In some embodiments, the sustained-release gas-generating formulation 18 includes a viscosity-enhancing agent. In some embodiments, the sustained-release gas generating formulation 18 includes first and second reactants configured to effervescent in the presence of water, hi some embodiments, the first and second reactants are contained within a single compartment.

[0049] Although three auxiliary gas-generating reaction chambers 14 are shown in FIG. 1 , any number of chambers may be provided in some embodiments. The inflatable patch 12 is spaced from each gas-generating reaction chamber 14 by a formulation-retaining portion 16. The formulation-retaining portion 16 is adapted to retain (i.e., not migrate from or remain adjacent to a water-permeable surface) a respective gas-generating formulation 18 within its respective auxiliary gas-generating reaction chamber 14. The formulation-retaining portion 16 (dashed line) is adapted to permit fluid-only flow, i.e., the flow of only gas and water. In some embodiments, three auxiliary gas-generating reaction chambers 14 are preferred. In some embodiments, the auxiliary gas-generating reaction chambers 14 are equally spaced from one another.

[0050] In some embodiments, the formulation holding portion is disposed along the periphery, periphery, outer surface, or side of the inflatable patch. In some embodiments, two or more formulation holding portions are disposed along the periphery, periphery, outer surface, or side of the inflatable patch. In some embodiments, three or more formulation holding portions are disposed along the periphery, periphery, outer surface, or side of the inflatable patch. In some embodiments, two to five formulation holding portions are disposed along the periphery, periphery, outer surface, or side of the inflatable patch. In some embodiments, the water-sensitive gas-generating formulation 18 is a sustained-release gas-generating formulation.

[0051] 2A, 2B, and 2C show schematic top (A), bottom (C), and cross-sectional (B) views of a self-inflatable patch assembly 10 in an expanded, uninflated configuration (e.g., after collapse of the outer shell) according to one or more embodiments. In the top view (A), multiple piercing needles 19 are disposed on the surface of a flexible, inflatable patch 12. The inflatable patch 12 and gas-generating reaction chamber 14 are configured to confine gas therein (e.g., be gas-impermeable), although a portion of the gas-generating reaction chamber 14 has a water-permeable outer surface 21. In FIG. 2B, the cross-sectional view shows an auxiliary gas-generating reaction chamber 14 defined by a flexible reaction chamber wall that contains a water-sensitive gas-generating formulation 18 in the patch's gas-generating reaction chamber 14. A formulation retainer 16 is spaced between the inflatable patch 12 and the gas-generating reaction chamber. While three are presented in this illustration, any number is possible in multiple embodiments. In Figure 2C, the bottom cross section is identical to the top cross section, but the multiple penetrating needles are absent. Rather, the bottom of the inflatable patch is configured to face the lumen or center of the intestine rather than the wall. Figures 2A, B, and C can be used to illustrate the components for fabrication. In Figure C, the bottom of the patch assembly can be prepared by providing a flexible, gas- and water-impermeable membrane while cutting a window for a water-permeable membrane. In some embodiments, at least 50% of the reaction chamber wall is water-permeable. In some embodiments, at least a portion of the reaction chamber wall is water-absorbent. Preferably, it is directionally permeable to water, whether the water is in vapor or liquid form. In this case, the water-permeable surface of the chamber wall can limit expansion so that the wall absorbs 20-100% by weight of the dry resin, as measured by equilibrium water content. For example, a portion of the water-permeable reaction chamber wall can be a hydrophilic membrane, such as a hydrophilic elastomer, e.g., hydrophilic polyurethane. The hydrophilic polyurethane can be a thermoplastic polyurethane.

[0052] The water-sensitive gas-generating formulation 18 can be prepared by granulating the first and second reactants with a disintegrant (e.g., a superdisintegrant), followed by combining with an additional granular viscosity agent. The final formulation can then be pressed, for example, into a tablet and placed in the bottom layer in an area adjacent to the water-permeable membrane. The top layer can be prepared in the same manner as the bottom layer by adding an array of permeable membranes containing therapeutic agents to the surface of the swellable patch. The two layers (top and bottom) surrounding the tablet can then be welded along the perimeter, and the formulation retainer 16 can be added, for example, by welding or fusing the top and bottom membranes together.

[0053] FIG. 3 illustrates another configuration of the present invention in which multiple gas-generating reaction chambers 314 are surrounded by an inflatable patch 312 and a formulation-retaining portion 316 is disposed along the periphery, periphery, outer surface, or side of one or more of the gas-generating reaction chambers 314. In one embodiment, there are two gas-generating chambers 314, although more or fewer are possible. The multiple gas-generating chambers 314 are dispersed within the general area of ​​the inflatable patch 312, but they are separated by formulation-retaining portions 316 configured to allow the passage of fluid while limiting the passage of water-sensitive gas-generating formulation 318. A water-absorbing portion 321 forms part of the gas-generating reaction chamber 314 and is bounded by a substantially airtight seam 324 where two materials, a water-permeable membrane and a water-impermeable membrane, meet. The two membranes are made from substantially the same chemicals so that they are hermetically welded together. In some embodiments, the relatively airtight seam 324 connects any two of the following: the reaction chamber wall, the inflatable patch wall, or the water-permeable outer surface of the reaction chamber wall. In some embodiments, a portion of the water-permeable outer surface of the reaction chamber wall contacts the water-impermeable wall at the relatively airtight seam 324.

[0054] The formulation retainer 316 is adapted to allow fluid gas flow while ensuring that the gas generating formulation 318 remains adjacent to the bibulous surface 321 (membrane or film).

[0055] The formulation retaining portion 316 is disposed between the expandable patch 312 and the gas-generating reaction chamber 314. The formulation retaining portion 316 is adapted to allow the passage of gas while preventing the passage of the water-sensitive gas-generating formulation 318. In some embodiments, the formulation retaining portion 316 is adapted to allow directional gas flow. In some embodiments, the directional flow occurs naturally based on equilibrium science. In this manner, water transferred from the outside to the inside of the reaction chamber 314 further interacts with the water-sensitive gas-generating formulation 318 to generate gas that drives the expansion of the expandable patch 312. Gas freely passes through the formulation retaining portion, but the formulation retaining portion does not allow the passage of the water-sensitive gas-generating formulation 318, thereby continuously reacting and generating gas for a period of time. In some embodiments, the formulation retaining portion 316 includes a formulation retaining portion 316 adapted to maintain the gas-generating formulation 318 in the gas-generating reaction chamber 314.

[0056] 4, 5, and 6, the self-inflating patch assembly 10 is disposed within a swallowable enteric outer shell. FIG. 4 illustrates the sequence of events from before administration to after administration to a subject. In one or more embodiments of the present invention, the self-inflating patch assembly is contained within, or configured to be contained within, a swallowable enteric outer shell 220 (i.e., having a flexible wall) by being rolled or folded. For example, prior to administration, the self-inflating patch assembly is in a compressed state (e.g., folded or rolled) and disposed within the swallowable enteric outer shell. Note that the auxiliary gas-generating reaction chamber 414 is disposed outside the compressed state. In this manner, gas generation can occur immediately after a portion of the enteric outer shell collapses, and early gas generation can contribute to expansion due to the unfolded or unrolled state.

[0057] The self-inflating patch assembly 410 further includes one or more gas-generating reaction chambers 414. The gas-generating reaction chambers 414 define an interior volume and are bounded by reaction chamber walls including a water-permeable portion. The gas-generating reaction chambers 414 also contain a water-sensitive gas-generating formulation 418 (e.g., a solid dosage form) including first and second reactants that effervescently effervescently effervescently evolve in the presence of water to generate gas upon exposure to water molecules (liquid or vapor form). As used herein, a solid dosage form in the context of a water-sensitive gas-generating formulation is meant to include tablets, such as compressed or molded tablets. In some embodiments, powders or granules are excluded.

[0058] While the walls of both the inflatable patch 412 and the gas-generating reaction chamber 414 are configured to confine gas therein, i.e., be gas-impermeable, the walls of the gas-generating reaction chamber 414 provide at least a portion of an exterior surface configured to deliver water molecules therethrough, whether in liquid or solid form, so that water on the exterior or surface of the walls migrates into the interior volume of the reaction chamber 414. In some embodiments, at least a portion of the exterior surface is water-absorbent. In some embodiments, the reaction chamber walls are water-permeable. The self-inflatable patch assembly 410 is configured such that, in a compressed state, the gas-generating chamber is exposed to the exterior. While many different folding and rolling approaches are possible, at least one gas-generating chamber wall may be on the exterior of the device in its compressed or folded / rolled state, providing early exposure to water.

[0059] In FIG. 5 , the self-inflatable patch assembly 200 includes an outer shell 220, e.g., a swallowable, enteric-coated outer shell 220. The outer shell 220 is configured to resist disintegration in the gastric environment until it reaches the subject's small intestine, where it dissolves in the small intestine wall 202 in the presence of intestinal fluids, exposing the self-inflatable patch assembly 210. Typically, the outer shell 220 is pH-sensitive and may be configured to dissolve within 15 minutes (e.g., within 10 or 5 minutes). In some applications, the self-inflatable patch assembly 210 is biodegradable along the gastrointestinal tract. In some applications, the self-inflatable patch assembly 210 and all of its components, except for the piercing needle configured to pierce tissue, are biodegradable or comprise materials that safely pass through the remainder of the gastrointestinal tract without sharp or rigid elements. Typically, the outer shell 220 has a length of at least 5 mm, no more than 30 mm, and / or between 5 and 30 mm. Typically, the outer shell 220 has a diameter of 3 mm to 6 mm, or 4 mm to 5 mm. The self-inflatable patch assembly 210 has a compressed shape when disposed within the outer shell 220. The self-inflatable patch assembly 210 comprises an inflatable patch 412 having an upper surface 428 and a lower surface 434, each having an inflatable patch wall 203, which is gas- and water-impermeable and includes penetration needles 419 on the upper surface 428 configured to face the intestinal lumen wall 423 in its expanded form prior to penetration. After expansion, by applying a sufficient degree of pressure through the generation of a certain amount of gas, the upper surface 428 of the inflatable patch 412 establishes contact with the intestinal wall 423 and remains there until the penetration needles 428 deposit a therapeutic agent. Typically, one or more penetration needles 419 penetrate the intestinal wall 423 to release an active agent without releasing the therapeutic agent in the lumen itself.

[0060] The expandable patch 412 is operatively coupled to the gas-generating chamber 414, which is folded to form a compressed outer surface of the self-inflatable patch assembly 210 directly beneath the outer shell 220, as illustrated in FIG. 4. In this manner, after the outer shell 220 begins to degrade, the gas-generating chamber 414 may become exposed to intestinal fluids and begin gas generation via a chemical reaction between the two reactants, as discussed in FIGS. 7A, 7B, and 7C. The shape and dimensions of the expandable patch 412 in its gas-expanded state are such that it does not contact the entire circumference of the intestinal lumen wall 423 of the small intestine wall 202. The self-inflatable patch assembly 200 typically remains axially stationary in the small intestine for a release period that allows for release of the active agent, even under small intestine wall contraction, with the penetration needle 419 within the intestinal wall 202. After delivery of the active agent, the self-inflatable patch assembly 210 continues through the GI tract and is eventually expelled from the body. The effectiveness of the expandable patch 212 is generally not affected by peristalsis (muscle contractions in the intestines) and does not inhibit the passage of liquids or food through the intestines.

[0061] 6, after collapse of the enteric outer shell, the self-inflatable patch assembly is in an expanded state, but in an uninflated or partially inflated state. The walls of the inflatable patch 412 are flexible and substantially impermeable to gas and water. The inflatable patch 412 is configured to expand upon receiving gas from within the interior volume or from an adjacent gas-generating reaction chamber 414. No portion of the inflatable patch 412 is adapted to absorb water.

[0062] 7-9, the self-inflatable patch assembly 10 is fluid-sensitive and includes a surface configured to expand after absorbing water (or vapor) 20 from a surrounding area, such as the intestinal tract (i.e., on the surface of the gas-generating reaction chamber). Absorption of water proximal to the water-sensitive gas-generating formulation causes the formulation to generate gas 22, which then results in directional gas flow 30 from the gas-generating chamber to the empty inflatable patch via a fluid-only passageway having a formulation retention portion 16 configured to maintain the formulation in the gas-generating reaction chamber. In some embodiments, the inflatable patch 12 further includes one or more piercing needles 19 configured to deliver a therapeutic agent to the surface of the luminal wall when gas pressure is applied to deliver the therapeutic agent through the surface of the luminal wall upon inflation of the inflatable patch 12.

[0063] The gas-driven inflation mechanism is illustrated in detail. In Figures 7A, 7B, and 7C, the outer shell 220 has collapsed within the small intestinal lumen to expose the self-inflatable patch assembly 10. The self-inflatable patch assembly 10 is an automated GI fluid drug delivery device capable of delivering one or more therapeutic agents in solid or fluid form following expansion of the inflatable patch. The exposed self-inflatable patch assembly 10 assumes an unconstrained shape, and the self-inflatable patch assembly 10 expands by being unfolded and / or unrolled in response to being unconstrained by the outer shell, e.g., a coating or capsule, a coating over a capsule, or a capsule over a coating.

[0064] The self-inflatable patch assembly 10 includes an inflatable patch 12 and a gas-generating reaction chamber 14, which houses the gas-generating reaction chamber. The therapeutic agent in a solid formulation may form part of the piercing needles 19 on the surface of the inflatable patch (a solid within the piercing needles). Alternatively, the therapeutic agent may be in the form of a fluid (e.g., a liquid) contained within the inflatable patch 12. The self-inflatable patch assembly 10 may include an inflatable patch 12, a gas-generating chamber 14 having a seam surrounding a window with a water-absorbent surface 15 and containing a gas-generating formulation 18, a formulation holding section 17 such that gas is in fluid communication between the gas-generating formulation 18 and the inflatable patch 12, and a formulation holding section 16. Note that along the formulation holding section connecting the gas-generating chamber 14 to the inflatable patch 12, an airtight seam exists at the transition between the water-permeable surface 15 and the remainder of the chamber 14. The gas-generating reaction chamber 14 is now exposed to the intestinal fluids and includes a water- or particularly vapor-permeable surface 15 bordered by seams and a water- and gas-impermeable frame, which begins to absorb water, moisture, or vapor from the intestinal fluids, thereby activating the gas-generating formulation 18 contained within the generating reaction chamber 14. While the illustration shows a circular chamber wall surrounding the formulation, other shapes, such as square or rectangular, are possible.

[0065] 8A, 8B, and 8C, a reaction between two reactants contained within gas-generating formulation 18 begins to generate gas, ultimately causing gas flow toward expandable patch 12 and driving expansion, but the first and second major axes (diameters of the circles in the figures) of expandable patch 12 do not increase. FIG. 7C illustrates a thickened portion of expandable patch 12. This expansion drives unfolding at the intestinal lumen wall 23 illustrated in FIG. 7C. Expandable patch 12 has upper (intestinal wall-contacting) surface 28 and lower (intestinal lumen-facing) surface 34 facing generally opposite directions, and an array of multiple or piercing needles (e.g., microneedles) 19 operably coupled to or disposed on flexible upper surface 28. The gas-generating chamber 14 is water- or vapor-permeable at least on its surface and has an inward permeability toward the interior volume of the gas-generating chamber 14, continually absorbing water (e.g., vapor) so that sufficient gas is generated to flow through the formulation retaining portion 16, continue to expand, and apply pressure to the piercing member 26, which is configured with a tip to pierce the intestinal lumen wall 23. The unique shape and size of the gas-generating formulation allows it to be retained by a retention feature within the gas-generating chamber, which allows the free flow of gas toward the inflatable patch.

[0066] 9A, 9B, and 9C, even with the self-inflatable patch assembly in its fully expanded configuration, the inner periphery of the small intestine is not completely in contact with the inflatable patch 12 (i.e., it does not encompass the total internal volume of the lumen at any particular location), allowing food and liquid to pass through the remainder of the small intestine, as illustrated in FIG. 8C. Furthermore, the force applied to the wall is generated from inside the device without an opposing lumen wall force. Typically, the inflatable patch 12 has elastomeric characteristics, such as a plastic material (e.g., thermoplastic polyurethane or silicone). Preferably, the surface of the inflatable patch 12 does not stretch and forms a substantially flat surface with a height variation of about 5 mm, 4 mm, 3 mm, or 2 mm.

[0067] In one aspect, a self-inflatable patch assembly is provided, comprising: an inflatable patch having an inflatable patch wall defining an interior volume, the wall being flexible and impermeable to gas and water; and three or more gas-generating reaction chambers, each chamber fluidly connected to the inflatable patch via a dedicated fluid passageway. The gas-generating reaction chambers may be defined by reaction chamber walls that contain an interior volume and a water-sensitive gas-generating formulation (e.g., a solid dosage form or a single unit) containing two reactants; the reaction chamber walls are configured to confine gas (e.g., have a degree of gas impermeability, and at least a portion of the exterior surface is water-permeable or delivers water molecules therethrough). In some embodiments, the gas-generating reaction chamber may be a single compartment containing the two reactants. In some embodiments, the gas-generating reaction chamber comprises at least a portion of a water-permeable exterior surface. For example, the portion may comprise at least 50%. In some embodiments, the gas-generating reaction chamber comprises two or more opposing water-permeable surfaces. In some embodiments, the gas-generating reaction chambers may be disposed along the periphery, periphery, outer surface, or side of the inflatable patch. In some embodiments, the self-inflatable comprises two or more gas-generating reaction chambers. In some embodiments, the self-inflatable comprises three or more gas-generating reaction chambers. In some embodiments, the self-inflatable comprises three gas-generating reaction chambers. In some embodiments, the self-inflatable comprises four gas-generating reaction chambers. In some embodiments, the water-sensitive gas-generating formulation may be a solid dosage form. In some embodiments, the water-sensitive gas-generating formulation may be a single unit. In some embodiments, the self-inflatable patch assembly may be configured to minimize substantial gas leakage from the collective interior volume. In some embodiments, the pressure generated in the gas-generating reaction chambers does not cause substantial gas leakage from the self-inflatable patch. However, in some embodiments, the gas-generating reaction chambers may be configured to intentionally release gas after a period of time, for example, via a water-permeable outer surface.In some embodiments, the gas-generating reaction chamber may be configured to release gas as the pressure increases or reaches equilibrium, and thus in some embodiments, the self-expandable patch assembly may be configured such that the pressure decreases after a period of time, such that the self-expandable patch assembly subsequently detaches from the lumen wall, such as the intestinal wall.

[0068] In another aspect, a self-inflatable patch assembly is provided that includes: an inflatable patch having an inflatable patch wall defining an interior volume, the wall being flexible and impermeable to gas and water; one or more gas-generating reaction chambers fluidly connected to the inflatable patch but spaced apart by a formulation-retaining portion, the one or more gas-generating reaction chambers being defined by reaction chamber walls containing a single compartment containing two reactants that generate gas upon exposure to water (the reaction chamber walls are configured to confine gas therein (e.g., gas impermeable) and have at least a portion of an outer surface configured to allow water molecules to pass therethrough (e.g., water permeable); and a formulation-retaining portion disposed between the inflatable patch and the gas-generating reaction chamber. In some embodiments, the gas-generating reaction chamber may be a single compartment containing the two reactants. In some embodiments, the gas-generating reaction chamber includes at least a portion of its outer surface that may be water permeable. For example, the portion may include at least 50%. In some embodiments, the gas-generating reaction chamber comprises two or more opposing water-permeable surfaces. In some embodiments, the gas-generating reaction chambers may be disposed along the periphery, periphery, or sides of the inflatable patch. In some embodiments, the self-inflatable comprises two or more gas-generating reaction chambers. In some embodiments, the self-inflatable comprises three or more gas-generating reaction chambers. In some embodiments, the self-inflatable comprises three gas-generating reaction chambers. In some embodiments, the self-inflatable comprises four gas-generating reaction chambers. In some embodiments, the water-sensitive gas-generating formulation may be a solid dosage form. In some embodiments, the water-sensitive gas-generating formulation may be a single unit. In some embodiments, the self-inflatable patch assembly may be configured to minimize substantial gas leakage from the collective interior volume.

[0069] In another aspect, a self-inflatable patch assembly is provided, comprising: an inflatable patch having an inflatable patch wall defining an interior volume, the wall being flexible and impermeable to gas and water; one or more gas-generating reaction chambers fluidly connected to the inflatable patch via a fluid-only passageway, the chambers being defined by reaction chamber walls containing an interior volume and a water-sensitive gas-generating formulation, the walls having a water-permeable surface on at least 50% of their outer wall surface; and a formulation retainer disposed between the inflatable patch and the gas-generating reaction chamber, the formulation retainer adapted to allow the passage of gas while preventing the passage of the water-sensitive gas-generating formulation. In some embodiments, the gas-generating reaction chamber may be a single compartment containing two reactants. In some embodiments, the gas-generating reaction chamber comprises at least a portion of its exterior surface that may be water-permeable. For example, the portion may comprise at least 50%. In some embodiments, the gas-generating reaction chamber comprises two or more opposing water-permeable surfaces. In some embodiments, the gas-generating reaction chambers may be positioned along the periphery, periphery, outer surface, or side of the inflatable patch. In some embodiments, the self-inflatable patch includes two or more gas-generating reaction chambers. In some embodiments, the self-inflatable patch includes three or more gas-generating reaction chambers. In some embodiments, the self-inflatable patch includes three gas-generating reaction chambers. In some embodiments, the self-inflatable patch includes four gas-generating reaction chambers. In some embodiments, the water-sensitive gas-generating formulation may be a solid dosage form. In some embodiments, the water-sensitive gas-generating formulation may be a single unit. In some embodiments, the self-inflatable patch assembly may be configured to minimize substantial gas leakage from the collective interior volume.

[0070] In another aspect, a self-inflatable patch assembly is provided that includes: an inflatable patch having an inflatable patch wall defining an interior volume, said wall being flexible and impermeable to gas and water; one or more gas-generating reaction chambers in fluid communication with the inflatable patch via a formulation retainer, said chambers comprising: The gas-generating reaction chamber is defined by walls defining an interior volume containing a water-sensitive gas-generating formulation including two reactants, the walls being at least partially water-permeable; wherein the inflatable patch walls, the chamber walls, and their connections are adapted to minimize substantial gas leakage from the interior volume. In some embodiments, the device includes a formulation retainer disposed between the inflatable patch and the gas-generating reaction chamber, which may be adapted to allow only fluid passage and prevent the water-sensitive gas-generating formulation from leaking. In some embodiments, the gas-generating reaction chamber may be a single compartment containing the two reactants. In some embodiments, the gas-generating reaction chamber includes at least a portion of a water-permeable outer surface. For example, the portion may include at least 50%. In some embodiments, the gas-generating reaction chamber includes two or more opposing water-permeable surfaces. In some embodiments, the gas-generating reaction chamber may be disposed along the periphery, periphery, outer surface, or side of the inflatable patch. In some embodiments, the self-inflatable device includes two or more gas-generating reaction chambers. In some embodiments, the self-inflatable patch assembly includes three or more gas-generating reaction chambers. In some embodiments, the self-inflatable patch assembly includes three gas-generating reaction chambers. In some embodiments, the self-inflatable patch assembly includes four gas-generating reaction chambers. In some embodiments, the water-sensitive gas-generating formulation may be a solid dosage form. In some embodiments, the water-sensitive gas-generating formulation may be a single unit. In some embodiments, the self-inflatable patch assembly may be configured to minimize substantial gas leakage from the collective interior volume. In some embodiments, the self-inflatable patch assembly may be configured to minimize substantial gas leakage from the collective interior volume during a first period of time, while providing gas release from the collective interior volume during a subsequent period of time. This subsequent period of time is after a portion of the water-absorbing surface has absorbed a certain amount of water. This process is based on a change in characteristics that occurs during the water-absorbing process.

[0071] While Figures 10-12 disclose multiple configurations for the one or more gas-generating reaction chambers 14, inflatable patch 12, formulation holding portion, and gas-generating reaction formulation 18, additional configurations are contemplated. In some embodiments, such as Figures 10, 11, and 12, the gas-generating reaction chambers extend outward from a central inflatable patch. In some embodiments, the self-inflatable patch assembly may include one or more gas-generating reaction chambers located on the periphery, periphery, outer surface, or side of the inflatable patch. In some embodiments described herein, the self-inflatable patch assembly may include two or more gas-generating reaction chambers extending radially from the inflatable patch.

[0072] In any of the embodiments described herein, the self-inflatable patch assembly can include an array of gas-generating reaction chambers. In some embodiments, the self-inflatable patch assembly includes approximately 2-5 or 2-4 gas-generating reaction chambers. The number of gas-generating reaction chambers can be selected to ensure that the chambers and patch remain intact despite the buildup of gas pressure in the shared internal volume of the inflatable patch and the gas-generating chambers. The inclusion of multiple gas-generating chambers allows for more gradual forces over time, which contributes to the structural integrity of the patch.

[0073] For example, in Figure 10, two gas-generating chambers 14 are illustrated, each operably connected to an inflatable patch 12 by a formulation retaining portion 16. Note that along the formulation retaining portion that separates the gas-generating chambers 14 from the inflatable patch 12, there is an airtight seam at the transition between the water-permeable surface 15 and the remainder of the chamber 14. According to the inventors, one of the challenges to obtaining an effective gas generating system with minimal gas leakage despite increased pressure may be identifying materials that are compatible with welding at the seams where the transition occurs.

[0074] In yet another embodiment, Figures 11 and 12 illustrate gas generating members arranged in series (e.g., see 14) or in parallel (e.g., see 14). It should be understood that any collection of gas generating chambers including multiple gas generating formulations arranged adjacent to a water-absorbing membrane may be contemplated as illustrated by the figures, and that the formulations or walls contained within the interior volume of the gas generating chamber by a formulation retainer.

[0075] FIG. 11 also illustrates various single-unit and multi-unit gas-generating formulations 780. The first and second reactants may be formulated in a single unit or in multiple units within the interior volume of the gas-generating chamber 14. As shown in FIG. 11, the gas-generating formulation 18 consists of two portions separated into different compartments of the gas-generating chamber. The first portion is contained in a first compartment having gas-generating formulation 18A, and the second portion is contained in a second compartment having gas-generating formulation 18B. The compartments may be separated by a conduit 16. One portion (formulation 18A) may contain a first reactant, such as potassium bicarbonate, that relies on exposure to intestinal fluids for disintegration, while the other portion (formulation 18B) contains a second reactant, such as citric acid, that relies on exposure to intestinal fluids for disintegration, which reacts with the disintegrated first reactant to generate a gas, such as CO2. This may add some stability during the shelf life, when it may be expected that water vapor from humidity may affect the functionality of the reaction.

[0076] In various embodiments of the self-inflatable patch assemblies described herein, the self-inflatable patch assembly includes an inflatable patch. In some embodiments, the inflatable patch wall can be defined by a wall that defines an interior volume (e.g., a maximum interior volume). In some embodiments, the inflatable patch can be configured to receive and maintain a fluid (e.g., a gas) therein. In some embodiments, the inflatable patch wall can be flexible. The term flexible refers to flexibility or the ability to be easily bent, folded, or rolled, as shown in FIG. 13, which illustrates the position of the compressed gas-generating chamber and one method of rolling and folding the self-inflatable patch assembly into a capsule, according to one or more embodiments.

[0077] In some embodiments, the expandable patch walls may be impermeable to gas and water. In some embodiments, the expandable patch includes expandable patch walls defining an interior volume, said walls being flexible and impermeable to gas and water. The expandable patch may be configured to prevent water ingress while simultaneously preventing gas escape from the interior volume. In some embodiments, the expandable patch does not include any portion that may be capable of absorbing water. In other words, none of the walls of the expandable patch have water-absorbing properties. In some embodiments, the expandable patch may be configured to contain gas generated by the gas-generating reaction chamber. In some embodiments, the containment of gas received from the gas-generating reaction chamber may be based on shape and / or material, as described below. In some embodiments, the gas-generating reaction chamber and / or gas-generating formulation are contained outside the interior volume of the expandable patch.

[0078] In some embodiments, the inflatable patch wall has limited elasticity or stretching. In some embodiments, the inflatable patch wall is characterized by being made of a material that does not easily change its shape or expand when subjected to pressure or force. In other words, the wall deforms or expands in response to applied pressure or volume change based on its flexibility. For example, the inflatable patch wall may include a polymer, a substantially non-compliant polymer, polyethylene, PET, or polyimide.

[0079] As used herein, the first and second major axes are the largest and second largest dimensions of the inflatable patch. Typically, the first and second major axes change in size minimally as the inflatable patch expands from a compressed state to a gas-expanded state. Typically, only the third major axis, i.e., the expansion in one direction of the patch width, increases in size, as shown in Figures 7C, 8C, and 9.

[0080] In various embodiments of the self-expanding patch assembly described herein, the self-expanding patch assembly can be used for drug delivery. In this case, the expandable patch can be flexible to transition from a compressed state to an expanded state, or vice versa. In some embodiments, the compressed state can be folded or rolled to be further contained within a swallowable outer shell. In the folded or rolled state, the gas-generating reaction chamber can be exposed to fluid and disposed on the outer surface to drive the transition to the expanded state via gas generation. Prior to adding the outer shell, the expandable patch can be folded and / or rolled to an appropriate size (e.g., a size suitable for disposable use in a 00 or 000 size capsule). In some embodiments, the expandable patch can be folded or rolled such that upon capsule collapse (or at least partial collapse), the expandable patch can be only partially exposed to GI fluids.

[0081] In some embodiments, the expansion of the gas drives the unfolding or rolling back and positioning adjacent the inner circumference of the small intestinal lumen, and subsequent penetration of the penetration needle. This limited elasticity or extensibility may play a role in ensuring that the generated gas can exert pressure (e.g., gradual expansion pressure) on the surface of the intestine, rather than continuously stretching the inflatable patch until it erupts.

[0082] In some embodiments, the expandable patch may have at least one surface operably connected to one or more tissue-piercing needles configured to deliver a therapeutic agent through the intestinal wall. As used herein, "through the intestinal wall" refers to penetrating or relating to penetrating the intestinal tissue for delivery within the wall layer. Typically, the expandable patch is not connected in any way to the outer shell. Ideally, when the expandable patch begins to expand, the outer shell is no longer substantially intact. The piercing needles are configured to deliver the therapeutic agent in liquid or solid form. When providing a therapeutic agent in liquid form, the piercing needles act to deliver the therapeutic agent liquid from a therapeutic agent reservoir. When providing a therapeutic agent in solid form, the piercing needles may be, for example, a solid formulation of the therapeutic agent, including biodegradable microneedles, for disintegration, dissolution, or detachment and release within the intestinal tissue, i.e., the intestinal wall.

[0083] In some embodiments, the expandable patch includes a portion of its surface operably coupled to an array of piercing needles configured to deliver a therapeutic agent. 2 Each needle contains an array of about 20 to about 250 penetrating needles.

[0084] In some embodiments, the expandable patch may be shaped to include two relatively flat surfaces or planes facing in opposite directions.

[0085] In some embodiments, the inflatable patch does not include a first or second reactant that generates gas within its interior volume.

[0086] In some embodiments, the inflatable patch may have a cross-sectional circular shape (e.g., a disk shape). However, additional shapes are possible, including, but not limited to, square, rectangular, triangular, etc. cross-sectional shapes. The cross-sectional shape may include rounded or sharp edge corners. In some examples, the inflatable patch may be in the shape of a circle with two relatively flat surfaces. In some embodiments, the inflatable patch may have upper and lower surfaces facing in opposite directions, with the lower surface configured to open in a manner facing the intestinal lumen and the upper surface configured to open in a manner facing the intestinal lumen wall.

[0087] In some embodiments, the expandable patch can be configured to be a gas-expanding expandable patch sized to contact only a portion of the inner circumference of the intestinal wall. Stated another way, the expandable patch in its expanded state can be sized to allow the passage of GI fluids or other GI contents. Thus, in some embodiments, the expandable patch can be configured to apply a gas driving force to the needle array. In some embodiments, the expandable patch can be configured to apply a gas driving force to the needle array without any contributing pressure provided by the opposing intestinal wall. Thus, in some embodiments, the gas pressurizes the expandable patch, causing it to expand to its expanded state. The expandable patch can be shaped with an upper surface and a lower surface such that pressure within the expandable patch aligns the upper surface of the expandable patch with the tissue at the delivery site. In this manner, orientation of the patch occurs.

[0088] In some embodiments, the expandable patch can be inflated by gas pressure, which drives the expansion of the expandable patch walls of the patch to a gas-expanded state. In other embodiments, the expandable patch can be configured to expand from a compressed state to an expanded state by gas. In some embodiments, the expandable patch can be fluidly connected to one or more gas-generating reaction chambers, either directly or via a dedicated fluid passageway. As used herein, fluid communication refers to allowing a gas gradient to allow fluid (e.g., gas) flow from the gas-generating reaction chambers or those chambers into the expandable patch during the initial stages of gas generation, but eventually, the gas flow reaches equilibrium and the gas pressure can be maintained.

[0089] In some embodiments, the expandable patch may be in fluid communication with an adjacent, but outwardly disposed, distinct gas-generating reaction chamber having different properties than the expandable patch, hi some embodiments, the expandable patch may be in fluid communication with one or more gas-generating reaction chambers via dedicated fluid passageways.

[0090] In some embodiments, the inflatable patch may be configured to be in fluid communication with an array of dedicated fluid passageways, each in fluid communication with a gas-generating reaction chamber. In some embodiments, the inflatable patch may be in fluid communication with more than two gas-generating reaction chambers via dedicated fluid passageways per chamber. In some embodiments, the inflatable patch may be in fluid communication with three gas-generating reaction chambers via dedicated fluid passageways per chamber. For clarity, despite the fluid communication, the inflatable patch and the auxiliary gas-generating reaction chamber differ in that they are separated by a formulation retaining portion, in the nature of their surfaces, in the case of the reaction chamber, a portion of the surface being water-permeable, and in terms of containing the gas-generating formulation.

[0091] In some embodiments, the inflatable patch includes a substantially flat surface. For example, in some embodiments, the inflatable patch includes first and second major surfaces, preferably of similar or equivalent size. In any of the embodiments of the self-inflatable patch assemblies described herein, the inflatable patch includes a substantially flat surface even in an expanded state. In this manner, the flat surface can be configured to press against the intestinal wall (IW) in a relatively uniform manner upon expansion of the inflatable patch, thereby applying a consistent force to the array of piercing needles. In some examples, the array of piercing needles can be oriented in a single plane. In some examples, the array of piercing needles can be oriented in opposite directions.

[0092] In any of the embodiments of the self-inflatable patch assembly described herein, the inflatable patch has upper and lower surfaces facing generally opposite directions, where the upper surface can be configured to open (from the compressed state to the expanded state) in a manner that faces the intestinal wall. In any of the embodiments of the self-inflatable patch assembly described herein, the inflatable patch has upper and lower surfaces that, when expanded, contact a portion of the inner periphery of the intestine (e.g., the small intestine), allowing contact with the intestinal wall but allowing the passage of solids or fluids through the intestinal lumen. In this way, instead of the inflatable patch increasing in volume to occlude the entire cross-section of the lumen, a portion of the intestinal lumen can be opened for the passage of food and liquids. In this way, the inflatable patch adheres to the intestinal lumen wall without impeding the passage of food and liquids. In any of the embodiments of the self-inflatable patch assembly described herein, the inflatable patch can be sized to accommodate various interpopulation anatomies, such as by contacting only a partial inner periphery of the intestinal wall. In any of the embodiments of the self-expandable patch assemblies described herein, the expandable patch may be configured to accommodate various intestinal contraction states or peristatic forces, such as by contacting only a partial perimeter of the intestinal wall.

[0093] In any of the embodiments of the self-expandable patch assembly described herein, the expandable patch applies an internally generated force to penetrate the intestinal wall without relying on a contributing force provided by the opposing intestinal wall.

[0094] In any of the embodiments, the expandable patch has a maximum longitudinal dimension that can be less than about 9 cm, less than 8 cm, less than 7 cm, less than about 6 cm, less than about 5.5 cm, or less than about 5 cm.

[0095] In any of the embodiments, the expandable patch may be molded to form an internal volume. In any of the embodiments, the expandable patch may be molded to form an internal volume of less than 30 mL. In any of the embodiments of the self-inflating patch assemblies described herein, the expandable patch may be molded to form an internal volume of less than 20 mL. In any of the embodiments of the self-inflating patch assemblies described herein, the expandable patch may be molded to form an internal volume of less than 10 mL. In any of the embodiments of the self-inflating patch assemblies described herein, the expandable patch may be molded to form an internal volume of less than 8 mL. In any of the embodiments of the self-inflating patch assemblies described herein, the expandable patch may be molded to form an internal volume of between 4 and 10 mL. In any of the embodiments of the self-inflating patch assemblies described herein, the expandable patch may be molded to form an internal volume of between 5 and 10 mL. In any of the embodiments of the self-inflating patch assemblies described herein, the expandable patch may be molded to form an internal volume of between 6 and 10 mL. In any of the embodiments of the self-inflating patch assemblies described herein, the expandable patch may be molded to form an internal volume of between 4 and 9 mL. In any of the embodiments of the self-inflating patch assembly described herein, the inflatable patch can be molded to form an internal volume of 5 mL to 9 mL. In any of the embodiments of the self-inflating patch assembly described herein, the inflatable patch can be molded to form an internal volume of 5 mL to 8 mL. In any of the embodiments of the self-inflating patch assembly described herein, the inflatable patch can be molded to form an internal volume of 5 mL to 7 mL.

[0096] In any of the embodiments of the self-inflatable patch assemblies described herein, the inflatable patch includes an upper surface having multiple layers. A portion of the inflatable patch (e.g., the upper surface) can be configured with pressure-equalizing properties that improve contact between the surface of the inflatable patch and the intestinal wall to evenly deliver a therapeutic agent (e.g., a tissue-piercing needle) over a selected area. In any of the embodiments of the self-inflatable patch assemblies described herein, the inflatable patch has multiple layers, including a first layer and a second layer secured together in a fixed position. In any of the embodiments of the self-inflatable patch assemblies described herein, the inflatable patch has one or more layers to provide a structure that minimizes or prevents stretching of another layer or other layers. For example, the inflatable patch can include a first layer of an elastic polymer, a second layer of nylon mesh, and a third layer of an elastic polymer.

[0097] In any of the embodiments of the self-inflatable patch assembly described herein, the inflatable patch may be substantially impermeable to liquids or gases. It is understood that the term impermeability in this context may be relatively variable depending on environmental changes, particularly the gradual application of gas pressure to the inflatable patch. For example, gas may be slowly released from the inflatable patch when the gas pressure reaches a certain threshold. However, this system relies on the inflatable patch to deploy adjacent to the intestinal lumen wall and constrain the gas to achieve the desired shape and volume for penetrating the penetration needle into the intestinal wall. For example, the inflatable patch may be shaped or sized to contact the inner circumference of a portion of the intestine.

[0098] Various materials are described herein as relevant for manufacturing the inflatable patch. In any embodiment, the inflatable patch includes a water-impermeable surface and does not have a portion with a water-absorbent surface. For example, the inflatable patch may be a polymer that is substantially impermeable to liquids or gases, such as a thermoplastic elastomer (TPE), which may include, for example, thermoplastic polyurethane (TPU); polyurethane (PU), or polyethylene (PE). More specifically, examples include, but are not limited to, poly(ether urethane) selected from TECOflex® EG-80A, Tecoflex® EG-85A, TECOflex® EG-93A, or ChronoThan™ T75A, T75B, T75C, or T75D polyurethanes. In some embodiments, a coating may be included on the outer surface of the inflatable patch. The membrane thickness may be less than 40 cm, less than 30 cm, or less than 400 μm. The membrane thickness may be less than 300 μm. The membrane thickness may be less than 200 μm. In some instances, the expandable patch further comprises a slow or gradually dissolving deflation valve configured to release gas at the end of the period, or alternatively, the gas-generating reaction is complete and no further gas is generated.

[0099] Examples of permeation members suitable for the present disclosure are described in U.S. Patent Application No. 17 / 562,899, entitled "Controlled release formulations and methods of targeted drug delivery within the small intestine," filed December 27, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0100] In any of the embodiments of the self-inflatable patch assembly described herein, the self-inflatable patch assembly includes at least one piercing needle. In any of the embodiments, the self-inflatable patch assembly includes a 1 cm 2In one embodiment, the self-expanding patch assembly includes an array of needles having about 50 to 250 needles per cm. 2 The tissue-piercing needles may include an array of approximately 100-150 penetrating needles per needle. In some embodiments, the tissue-piercing needles have a base configured to receive a force and a penetrating tip. In some embodiments, the tissue-piercing needles have sufficient hardness or mechanical strength to be advanced into the intestinal wall by applying a force to the tissue-piercing needle or its base. In some embodiments, the tissue-piercing needles may be elongated members having a base at one end and a tapered, sharp, or honed tip at the other end, and may be straight or curved. Other shapes, such as pyramidal or conical, are also contemplated.

[0101] As used herein, "penetrating" is meant to include any disruption in at least one region of the mucosa or submucosa or muscularis mucosae barrier of the small intestine after deployment intraluminally within a subject, for example.

[0102] In any of the embodiments of the self-inflatable patch assembly described herein, the self-inflatable patch assembly includes a tissue-piercing needle having a length of 0.02 to 6.0 mm, or 0.5 to 2.8 mm. In some embodiments, the piercing needle extends from the surface of the inflatable patch and has a length of 1.4 to 2.8 mm. In some embodiments, the piercing needle extends from the surface of the inflatable patch and has a length of 1.4 to 2.0 mm. In some embodiments, the piercing needle extending from the surface of the inflatable patch has a length of 1.4 to 1.7 mm. In other embodiments, the tissue-piercing needle may have a length of about 20 to 1000 μm.

[0103] In some applications, the average density of all needles on the surface on which they are attached is between 2 and 6 needles / mm 2 , for example, 4 lines / mm 2 Alternatively or additionally, in some applications, each of the dispensing needles 1250 may be positioned within 1 mm of at least one adjacent dispensing needle.

[0104] In some embodiments, the tissue-piercing needle has sufficient rigidity to be advanced into the intestinal wall (i.e., soft tissue) by applying a force to the tissue-piercing needle or its base. In any embodiment of the self-inflatable patch assemblies described herein, at least a portion of the penetrating needle is removably coupled to the inflatable patch. In any embodiment of the self-inflatable patch assemblies described herein, at least a portion of the penetrating needle is configured to penetrate the mucosa, submucosa, fascia, or serosa.

[0105] The self-inflatable patch assembly can be inflated by gas generated in the auxiliary gas-generating chamber when the gas-generating formulation, specifically the first and second reactants, are exposed to water (e.g., intestinal fluids) through the water-permeable surface. The water can be in any form, whether vapor or liquid. In some embodiments, water or fluid is not present in the gas-generating chamber or the inflatable patch unless it enters through the water-permeable surface, which naturally allows it to undergo expansion. In some embodiments, the auxiliary gas-generating reaction chamber can be defined by a flexible reaction chamber wall containing the water-sensitive gas-generating formulation; the reaction chamber wall is gas-impermeable and has at least a water-permeable outer surface. In this context, the water-permeable outer surface can be adapted to allow water molecules in gaseous or liquid state to pass through. In some embodiments, the wall having a water-permeable outer surface may not be completely gas-impermeable, but the wall can be adapted to contain gas despite increased pressure within the internal chamber.

[0106] In some embodiments, the flexible reaction chamber wall is adapted to be rolled or folded into a compressed state to facilitate packaging within a swallowable enteric outer shell, hi some embodiments, the auxiliary gas-generating reaction chamber may be disposed on the outer surface of the self-expanding patch in a compressed state.

[0107] The auxiliary gas-generating chamber may be in fluid communication with the interior chamber of the inflatable patch, while being separated or divided by a formulation-retaining portion. The formulation-retaining portion may be configured to retain the formulation within the auxiliary gas-generating reaction chamber. In this manner, the formulation-retaining portion prevents migration from the water-permeable surface and / or maintains the formulation adjacent to the water-permeable surface.

[0108] In some embodiments, the formulation-retaining portion functions as a fluid passageway, possessing structural components or features that selectively permit fluid passage or flow (e.g., liquids or gases, including humidity) while effectively preventing the passage of solid particles. This is achieved, for example, by a design featuring controlled pore sizes that collectively facilitate fluid passage and confine or obstruct solid entities (e.g., of minimal size). In some embodiments, the formulation-retaining fluid passageway may be a conduit or channel defined within a structure engineered to allow unimpeded flow of fluid due to its low viscosity. The formulation-retaining fluid passageway may be designed with dimensions that ensure selective permeability, facilitating fluid transmission while effectively preventing the passage of solid entities due to geometric constraints, by preventing the passage of solid particles above a certain threshold.

[0109] In some embodiments, one or more auxiliary gas-generating reaction chambers are fluidly connected to the inflatable patch via dedicated fluid passages or formulation holders. The chambers are defined by chamber walls containing an internal volume and a water-sensitive gas-generating formulation including first and second reactants. In some embodiments, the gas-generating reaction chamber defines a single compartment or chamber containing both the first and second reactants. In some embodiments, the single compartment does not contain a fluid or liquid. The two reactants combine with water to generate gas. The reaction chamber walls are, on the one hand, gas-impermeable or configured to trap gas therein, and, on the other hand, at least partially water-permeable to deliver water molecules therein, whether liquid or vapor. In some embodiments, the gas-generating reaction chamber can be configured to be compressed and expanded (e.g., by rolling or folding). In some embodiments, the gas-generating reaction chamber remains intact on the surface of the compressed patch assembly. In some embodiments, the chamber walls include a water-permeable surface that is at least 50%, at least 60%, or at least 70% of the outer wall surface. In some embodiments, the gas-generating reaction chamber comprises two or more opposing water-permeable surfaces.

[0110] In some embodiments, the gas-generating reaction chambers may be positioned along the periphery, periphery, or side of the inflatable patch. For example, two or more gas-generating reaction chambers may be positioned along the periphery, periphery, or side of the inflatable patch. In another embodiment, three or more gas-generating reaction chambers may be positioned along the periphery, periphery, outer surface, or side of the inflatable patch. In another embodiment, two to five gas-generating reaction chambers may be positioned along the periphery, periphery, outer surface, or side of the inflatable patch.

[0111] In some embodiments, the gas generating reaction chamber is 800 mm 2 Super, 900mm 2 Super, 10000mm 2 Super, 1100mm 2 Over 1200mm 2In other embodiments, the gas generating reaction chamber may have a surface area of ​​800 to 1800 mm 2 In other embodiments, the gas generating reaction chamber may have a surface area of ​​1200 to 1350 mm 2 may have a surface area of

[0112] In any of the embodiments described herein, the multiple gas-generating reaction chambers are configured to provide different initiation times and / or rates of gas generation. For example, the chambers may be coated with a layer that delays water absorption and therefore the onset of gas generation. Alternatively, each chamber may contain a gas-generating formulation formulated to release gas at different times and / or rates.

[0113] In any of the embodiments described herein, the one or more gas-generating reaction chambers are configured to generate gas such that the patch can be deployed and / or attached to the intestinal wall within about 10 minutes.

[0114] In some embodiments, the one or more gas-generating reaction chambers include a fluid-only passageway disposed between the gas-generating reaction chamber and the inflatable patch to facilitate a gas flow path between the interior volume of the gas-generating reaction chamber and the interior volume of the one or more inflatable patches.

[0115] According to the inventors, one of the challenges encountered during development was finding biocompatible materials relevant to creating both a water-absorbent surface or membrane and a water-impermeable surface or membrane, each of which meets a very different set of functional requirements but does not result in gas leakage at the seam (i.e., welded seam) despite the stress of releasing (increased internal gas pressure) and the presence of fluid in the intestinal lumen. This transition can be located radially between the gas-generating reaction chamber and the inflatable patch. Thus, in any of the embodiments of the self-inflatable drug delivery device described herein, the fluid-only passageway includes a seam configured to minimize gas leakage. In some embodiments, the seam is configured to maintain integrity despite applied pressure. Thus, in any of the embodiments of the self-inflatable drug delivery device described herein, the fluid-only passageway includes a seam of two compatible membranes, for example, by hot melt.

[0116] In any of the embodiments described herein, one or more gas-generating reaction chambers include a water-absorbent surface. In some embodiments, gas leakage can be minimized by a relatively airtight seam at the interface between the water-absorbent membrane and the water-impermeable membrane. In some embodiments, gas leakage can be minimized by a relatively airtight seam between the water-absorbent window and the water-impermeable frame surrounding the window.

[0117] In some embodiments, the gas-generating reaction chamber can be configured to provide sufficient gas to the inflatable patch for a period of time sufficient to advance at least one tissue-piercing needle through the intestinal wall.

[0118] While effervescent formulations are known in the art, storing water-sensitive gas generating formulations at ambient temperatures adjacent to water-absorbent surfaces presents unique challenges.

[0119] In any of the embodiments described herein, the self-inflatable drug delivery device includes two or more gas-generating reaction chambers.

[0120] In any of the embodiments described herein, the self-inflatable drug delivery device includes a gas generation chamber configured to generate a consistent amount of gas over an extended period of time, e.g., the patch assembly can reach equilibrium between generated gas and leaked gas such that air pressure can be maintained.

[0121] In any of the embodiments described herein, the self-inflatable drug delivery device includes a gas generation chamber configured to generate a consistent amount of gas for an extended period of time greater than 30 minutes.

[0122] In any of the embodiments described herein, the self-inflatable drug delivery device includes a gas-generating chamber having a thickness of 15-100 μm, or about 20-90 μm, or about 20-80 μm, or about 25-80 μm. In any of the embodiments described herein, the self-inflatable drug delivery device includes a gas-generating chamber having a thickness of 350 mm. 2 Over 350-550mm 2 , or approximately 400-500 mm 2 The gas generation chamber may have a surface area of ​​.

[0123] Any resilient and biocompatible material may be used in constructing the chamber walls. In some instances, the material may not be resorbable. In some instances, the material may be resorbable. In any of the embodiments described herein, the chamber walls may be constructed or coated to promote adhesion between the gas-generating formulation and the chamber walls.

[0124] The shape of the chamber can be of various shapes and configurations, so long as it provides a sealed shape to contain the generated gas with the lumen contracted at the outlet.

[0125] Any of the embodiments of the self-inflatable patch assembly described herein includes a gas-generating reaction chamber having a chamber wall. Any of the embodiments of the self-inflatable patch assembly described herein includes a gas-generating reaction chamber in fluid communication with the inflatable patch via a dedicated fluid passageway. As used herein, "fluidly connected" in this context means including a fluid passageway that allows free flow of gas within the interior volume of the gas-generating chamber toward the inflatable patch. Any of the embodiments of the self-inflatable patch assembly described herein includes a gas-generating chamber in which a surface of the gas-generating reaction chamber may not be connected to a tissue-piercing needle.

[0126] In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating reaction chamber wall can be configured to limit the degree of expansion while promoting a driving force for the transport of water, preferably water vapor. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating reaction chamber wall defines an interior volume that contains gas. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating reaction chamber wall can be made of a material configured to be substantially gas impermeable.

[0127] In some embodiments, the present invention provides a self-expanding patch assembly including at least a portion of a chamber wall configured to facilitate water transport. The water transport can be in the form of liquid or gas (vapor). In preferred embodiments, the water transport can be in the form of gas (vapor). Water is typically readily available for absorption into intestinal fluids after the outer shell can be at least partially degraded. The membrane can be somewhat gas impermeable, but water absorption can result in a gelling effect, providing properties different from the starting membrane such that the polarity of gases, such as water vapor, allows for a degree of transmission through the membrane.

[0128] In some embodiments, the present invention provides a self-expanding patch assembly, wherein at least a portion of the chamber wall can be a water-absorbent or hydrophilic surface. In preferred embodiments, the chamber wall further comprises a water- and gas-impermeable surface.

[0129] In any of the embodiments of the self-inflatable patch assembly described herein, the chamber walls can be configured to define an interior volume that accommodates and restrains gas, the chamber walls being configured to be water absorbent while limiting the degree and rate of swelling.

[0130] In any of the embodiments of the self-expanding patch assembly described herein, the chamber wall thickness may be less than 100 μm, less than 80 μm, less than 70 μm, less than 60 μm, or less than 50 μm. In some embodiments, the chamber wall thickness may be between 20 and 100 μm. In some embodiments, the chamber wall thickness may be between 25 and 80 μm. In some embodiments, the chamber wall thickness may be between 25 and 50 μm.

[0131] In any of the embodiments of the self-inflating patch assembly described herein, the chamber wall is between 300 and 600 mm 2 In some embodiments, the chamber wall has a surface area of ​​400 to 500 mm 2 It has a surface area of

[0132] In any of the embodiments of the self-inflating patch assembly described herein, the thickness of the chamber wall facilitates the passage of water in vapor or liquid form through the membrane. In some embodiments, the thickness of the chamber wall allows water in gas form to pass through the membrane. In some embodiments, the thickness of the chamber wall allows water in liquid form to pass through the membrane.

[0133] In any of the embodiments of the self-inflatable patch assemblies described herein, the chamber walls may be configured such that gas can be generated and constrained to form an outward gas flow from the chamber toward the target inflatable patch over a period of time. Typically, this is optimized by selection of the optimal shape and size for forming the chamber or housing and associated materials that constrain the gas.

[0134] In preferred embodiments of the self-inflatable patch assemblies described herein, the chamber walls may comprise any one or more materials, membranes, or films that promote any one, preferably more than one, and most preferably all of the following characteristics: high flexibility and abrasion resistance to contain and drive gas flow; resistance to dissolution in intestinal fluids over a period of time; flexibility; biocompatibility and biostability; and compatibility with other plastics to provide dedicated fluid passageways or airtight seams in the inflatable walls.

[0135] In some embodiments of the self-inflatable patch assemblies described herein, the chamber wall may include a hydrophilic membrane. As used herein, a hydrophilic membrane is a non-porous film that breathes via osmotic potential by absorbing and desorbing vapor molecules, then transporting the molecules to the back side. Water vapor molecules are first absorbed on the outer surface of the chamber wall facing the intestinal lumen, where the vapor concentration is higher than inside the chamber. The vapor molecules occupy the free volume between the polymer chains and move across the membrane without chemically interacting with the polymer, leaving the polymer intact and largely unaffected. Essentially, the amorphous regions function like intermolecular pores, allowing the passage of water vapor while substantially preventing the penetration of liquid water. Upon reaching the other side, the water vapor is desorbed into the interior volume surrounding the gas-generating reaction chamber due to interaction with the gas-generating formulation. Note that conventional polymers and rubbers typically used in inflatable patch assemblies lack the polar groups necessary to activate the hydrophilic mechanism for water transport. For example, some contemplated hydrophilic polymers, such as polyvinyl alcohol (PVA), polyvinylpyrrolidone, and the like, and polyethylene oxide (PEO), dissolve or swell in water, resulting in poor flexibility and abrasion resistance.

[0136] In any of the embodiments of the self-inflatable patch assembly described herein, the chamber wall comprises a hydrophilic membrane having a Shore hardness of between 70A and 65D. In a preferred embodiment, the hydrophilic membrane has a Shore hardness of about 83A.

[0137] In any of the embodiments of the self-inflatable patch assembly described herein, the hydrophilic membrane of the chamber wall may be a hydrophilic elastomer.

[0138] In any of the embodiments of the self-expanding patch assembly described herein, the chamber wall may be a hydrophilic membrane with a limited degree of swelling such that the material absorbs an equilibrium water content of 20% to 100% of the weight of the dry resin, as measured by equilibrium water content.

[0139] In any of the embodiments of the self-inflatable patch assembly described herein, the hydrophilic membrane of the chamber wall may be made from a hydrophilic elastomer. In preferred embodiments, the hydrophilic elastomer may be made at least in part from a thermoplastic polyurethane, a hydrophilic polyester, or a hydrophilic polyamide.

[0140] In any of the embodiments of the self-inflating patch assembly described herein, the hydrophilic elastomer of the chamber wall has a limited degree of swelling such that the material absorbs an equilibrium water content of 20% to 100% of the weight of the dry resin. In some embodiments, the hydrophilic elastomer may be a multiblock poly(ether urethane) or a silicone poly(ether urethane). In some embodiments, the hydrophilic elastomer may be a multiblock poly(ether urethane). In some embodiments, the multiblock poly(ether urethane) may be water-swellable and include poly(ethylene oxide).

[0141] In any of the embodiments of the self-inflating patch assembly described herein, the chamber wall can be an aliphatic hydrophilic polyether-based resin (i.e., in the polyurethane backbone), such as, but not limited to, a thermoplastic polyurethane with ionomeric groups, such as carboxylic acid or urea, that promote water absorption in the elastomer. Particularly preferred hydrophilic polyurethanes are those that absorb water after contact with aqueous media but with very little swelling, about 20-100%. In some examples, commercially available thermoplastic polyurethanes with hydrophilic properties suitable for the present invention are provided, including, but not limited to, Tecophilic™ thermoplastic polyurethanes such as Tecophilic™ HP-60D-20, Tecophilic™ HP-60D-35, Tecophilic™ HP-60D-60, or Tecophilic™ HP-93A-100 (Lubrizol Advanced Materials, Inc.); HydroThane™ thermoplastic polyurethane (AdvanSource Biomaterials Corp.); Quadraphilic™ thermoplastic polyurethane (Biomerics, LLC), HydroMed™ (AdvanSource Biomaterials Corp.); or Dryflex™ (HEXPOL TPE); or PurSil™ (Pak Chromical Ltd.). It should be recognized that a variety of different polymers, such as polyethylene oxide, can be modified with sufficient hydrophilic groups to enhance hydrophilicity and absorb water, thereby allowing water to be delivered through the chamber membrane or wall.

[0142] In any of the embodiments of the self-inflating patch assembly described herein, the thermoplastic polyurethane has a Shore durometer value of about 70 A to about 65 D. The particular material and its thickness and wall area can be selected to achieve a particular moisture absorption profile, i.e., water permeation rate.

[0143] As used herein, a seam may be used to describe the boundary of two membranes, films, or materials. In this context, the membranes, films, or materials may be the same or different. In some instances, different materials making up the seam present additional challenges in ensuring a hermetic (i.e., substantially airtight) seal.

[0144] One of the challenges in developing the present invention relates to the requirement for sealed (i.e., airtight) seams even under increasing air pressure driven by the gas-generating reaction chamber. Accordingly, in any of the embodiments of the self-inflatable patch assembly described herein, the chamber wall and the gas-generating reaction chamber are configured to include substantially sealed seams that secure the air pressure formulation within the interior volume of the gas-generating reaction chamber as well as the inflatable compartment. In any of the embodiments of the self-inflatable patch assembly described herein, the inflatable patch and / or the gas-generating reaction chamber can be configured to prevent substantial gas leakage. This can be by, for example, using compatible materials and applying specific heat to weld the seams.

[0145] In any of the embodiments of the self-inflatable patch assembly described herein, the chamber wall includes a first major surface and a second major surface that are substantially symmetrical. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating reaction chamber has a substantially flat shape with a first major surface and a second major surface, each having a water-impermeable frame portion with a water-permeable window in the center of the frame. Because different materials are typically used for the frame and window portion, the term window seam is used herein to represent the window boundary or the interface of two membranes, films, or materials. Thus, in any of the embodiments of the self-inflatable patch assembly described herein, the window seam is configured to minimize or prevent substantial gas leakage from the self-inflatable patch assembly. In any of the embodiments of the self-inflatable patch assemblies described herein, the gas-generating reaction chamber of the formulation contained therein is configured to generate a controlled amount of pressure to minimize substantial gas leakage from the self-inflatable patch assembly. For example, the selection of materials, the amount of gas, and / or the pressure exerted on the wall by the gas from the gas-generating reaction chamber may be such that the pressure does not cause the seams to open.

[0146] Additionally, the number of gas-generating chambers in the self-inflating patch assemblies described herein can be selected to minimize the risk of gas leakage at seams. In any of the embodiments of the self-inflating patch assemblies described herein, there are two or more gas-generating reaction chambers. In any of the embodiments of the self-inflating patch assemblies described herein, there are three or more gas-generating reaction chambers. In any of the embodiments of the self-inflating patch assemblies described herein, there are between two and six gas-generating reaction chambers.

[0147] In any of the embodiments of the self-expanding patch assembly described herein, the chamber wall may be additionally coated with or mixed with additional excipients to promote stability or adjust water absorption characteristics, where stability refers to consistent performance in the GI track despite exposure to water in liquid and vapor form prior to exposure to water in the GI track, such as during shelf life or manufacturing.

[0148] In any of the embodiments of the self-inflatable patch assembly described herein; the chamber wall can be conformed with a relatively airtight seam at the transition to the gas-generating reaction chamber wall.

[0149] In another aspect, a sustained-release gas generating chamber for prolonged gas generation in the presence of water is provided, the chamber being defined by a flexible reaction chamber wall containing in a single compartment a water-sensitive gas generating formulation comprising first and second reactants that foam in the presence of water, the reaction chamber wall being gas-impermeable and having at least a portion of a water-permeable exterior surface.

[0150] In some embodiments, the slow-release gas-generating chamber comprises a first and second reactant in a single unit. In some embodiments, the slow-release gas-generating chamber comprises a slow-release gas-generating formulation.

[0151] In some embodiments, the sustained-release gas generating chamber comprises a water-sensitive gas generating formulation configured to generate gas such that the inflatable patch pressure is greater than 2 psi, greater than 3 psi, greater than 3.5 psi, greater than 5 psi, greater than 7 psi, or greater than 10 psi when measured at 37° C. In some embodiments, the sustained-release gas generating chamber comprises a water-sensitive gas generating formulation configured to generate gas such that the inflatable patch pressure is greater than 2 psi, greater than 3 psi, or greater than 3.5 psi when measured at 37° C. In some embodiments, the sustained-release gas generating chamber comprises a water-sensitive gas generating formulation configured to generate gas such that the inflatable patch pressure is greater than about 2-8, 2-6, or 2-5 psi when measured at 37° C. In some embodiments, the sustained-release gas generating chamber comprises a water-sensitive gas generating formulation configured to generate gas such that the inflatable patch pressure is substantially constant when measured at 37° C. for about 30 minutes.

[0152] In some embodiments, the sustained-release gas-generating chamber contains a sustained-release gas-generating formulation with a viscosity-enhancing agent. In some embodiments, the single unit may be a solid dosage form, such as a multi-layer tablet, a bi-layer tablet, a mini-tablet, or a micro-tablet. In some embodiments, the amount of the first reactant and the amount of the second reactant may be less than 80% of the water-sensitive gas-generating formulation. In some embodiments, the first reactant may be a water-soluble organic acid (e.g., citric acid), and the second reactant may be an inorganic salt (e.g., alkali carbonate, alkali bicarbonate). In some embodiments, the sustained-release gas-generating chamber contains a water-sensitive gas-generating formulation further comprising a disintegrant and a viscosity-enhancing agent.

[0153] In some embodiments, in the sustained-release gas-generating chamber, the water-soluble organic acid (e.g., citric acid) and / or inorganic salt (e.g., alkali carbonate, bicarbonate) are in anhydrous form. In some embodiments, the water-soluble organic acid (e.g., citric acid), inorganic salt (e.g., alkali carbonate, bicarbonate), and disintegrant form granules. In some embodiments, the first reactant may be a water-soluble organic acid (e.g., citric acid), and the second reactant may be an inorganic salt (e.g., alkali carbonate, bicarbonate). In some embodiments, the water-sensitive gas-generating formulation comprises granules comprising a first reactant, a second reactant, and a disintegrant or super-disintegrant. In some embodiments, the water-sensitive gas-generating formulation comprises a viscosity-enhancing agent that creates an extragranular portion. In some embodiments, the water-soluble organic acid (e.g., citric acid), inorganic salt (e.g., alkali carbonate, bicarbonate), and viscosity-enhancing agent create an extragranular portion.

[0154] In some embodiments, the sustained release gas generation chamber comprises a gas generation reaction chamber comprising two or more water permeable surfaces. In some embodiments, the sustained release gas generation chamber comprises two or more opposing water permeable surfaces.

[0155] In some embodiments described herein, the self-inflatable patch assembly includes a water-sensitive gas-generating formulation disposed in one or more gas-generating reaction chambers. As used herein, reference to a gas-generating formulation refers to a water-sensitive gas-generating formulation including two reactants that react in the presence of water to generate a gas. Thus, in any of the embodiments described herein, the self-inflatable patch assembly includes a gas-generating formulation configured to generate a gas upon exposure to water (liquid or vapor form). In any of the embodiments described herein, the gas-generating formulation includes a first and a second reactant. In any of the embodiments described herein, the first and second reactants are configured to generate a gas upon exposure to water in liquid or gas form. In any of the embodiments described herein, the gas-generating formulation includes a first reactant that is an organic acid component and a second reactant that is a carbonate component.

[0156] In some embodiments, the first and second reactants may be contained in a single compartment. In some embodiments, the water-sensitive gas-generating formulation may be a single unit containing two reactants. In some embodiments, the water-sensitive gas-generating formulation may be in a solid dosage form. For example, the solid dosage form may be a multi-layer tablet, a bi-layer tablet, a mini-tablet, or a micro-tablet.

[0157] In any of the embodiments described herein, the organic acid component may be citric acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, adipic acid, sodium bisulfate, succinic anhydride, monosodium phosphate (NaH2PO(4)), disodium dihydrogen diphosphate (NaH2PO(7)), and mixtures thereof. In any of the embodiments described herein, the carbonate component may be sodium carbonate (NaHCO3), sodium bicarbonate (Na2CO3), sodium calcium bicarbonate (Ca(HCO3)2), sodium citrate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate (CaCO3), and mixtures thereof. In any of the embodiments described herein, the carbonate may be sodium bicarbonate. In some embodiments, the organic acid component may be citric acid.

[0158] In some embodiments, the water-soluble organic acid (e.g., citric acid), inorganic salt (e.g., alkali carbonate, alkali bicarbonate), and disintegrant (e.g., superdisintegrant) form granules. In some embodiments, the inorganic salt and / or water-soluble organic acid may be in anhydrous form. In some embodiments, the disintegrant (e.g., superdisintegrant) may be a sugar such as sorbitol. In some embodiments, the water-sensitive gas-generating formulation comprises a disintegrant (e.g., superdisintegrant) and a viscosity-enhancing agent.

[0159] In some embodiments, the gas-generating formulation may be a sustained-release gas-generating formulation or effervescent. In some embodiments, the gas-generating formulation may include a viscosity-enhancing agent. As used herein, a viscosity-enhancing agent increases the viscosity of a composition comprising a first and second reactant. Viscosity-enhancing agents suitable for use in this embodiment of the present invention include, but are not limited to, cellulose derivatives (including, but not limited to, hydroxyethyl cellulose, carboxymethyl cellulose or salts thereof, hypromellose, etc.), polyvinylpyrrolidone (PVP) (preferably those having a molecular weight of about 10,000 to about 350,000, as well as mixtures comprising one or more grades or molecular weights of PVP), carrageenan, guar gum, alginates, carbomer, polyethylene glycol, polyvinyl alcohol, xanthan gum, etc. In certain preferred embodiments, xanthan gum may be used as a viscosity-enhancing agent.

[0160] For example, the viscosity enhancing agent may be extragranular, while the disintegrant (e.g., superdisintegrant) may be intragranular. In some embodiments, the amount of the first and second reactants may be less than 80% of a single unit of the water-sensitive gas-generating formulation. In some embodiments, the water-sensitive gas-generating formulation may be a solid disposed adjacent to (e.g., in contact with) a water-permeable portion of the wall of the gas-generating reaction chamber. For example, the solid may be disposed adjacent to (e.g., in contact with) at least two opposing surfaces of the water-permeable wall. In some embodiments, the solid water-sensitive gas-generating formulation may be a multi-layer tablet, bi-layer tablet, mini-tablet, or micro-tablet containing two reactants. In some embodiments, the bi-layer tablet includes a first layer containing a viscosity enhancing agent and a second layer without the viscosity enhancing agent. In some embodiments, the solid water-sensitive gas-generating formulation may be configured to generate a consistent amount of gas over an extended period of time. In some embodiments, the extended period of time may be greater than 30 minutes. In some embodiments, the solid water-sensitive gas-generating formulation includes a viscosity enhancing agent.

[0161] In some embodiments, the water-sensitive gas-generating formulation may be in an amount sufficient to generate gas to provide an inflatable patch pressure of about 2-5 psi when measured at 37° C. For example, the water-sensitive gas-generating formulation may be in an amount sufficient to generate gas to provide an inflatable patch with a substantially constant pressure when measured for about 30 minutes at 37° C. after exposing the gas-generating reaction chamber to water, intestinal fluid, or a model thereof.

[0162] In any of the embodiments described herein, the self-inflatable patch assembly includes a gas generating formulation that can have an acid:bicarbonate molar ratio of about 1:2 to 1:4. In any of the embodiments, the self-inflatable patch assembly includes a gas generating formulation that can have an acid:bicarbonate molar ratio of 1:2, 1:3, or 1:4. In any of the embodiments, the self-inflatable patch assembly includes a gas generating formulation that can have a citric acid:sodium bicarbonate molar ratio of about 1:2 to 1:4. In any of the embodiments, the self-inflatable patch assembly includes a gas generating formulation that can have a citric acid:sodium bicarbonate molar ratio of 1:2. In any of the embodiments, the self-inflatable patch assembly includes a gas generating formulation that can have a citric acid:sodium bicarbonate molar ratio of 1:3. In any of the embodiments, the self-inflatable patch assembly includes a gas generating formulation that can have a citric acid:sodium bicarbonate molar ratio of 1:4.

[0163] In any of the embodiments described herein, the self-inflating patch assembly includes a gas-generating formulation having a first and a second reactant. In some embodiments, the amount of the first and second reactants may be less than 80% by weight of the excipients in the gas-generating formulation. In some embodiments, the amount of the first and second reactants may be less than 70% by weight of the excipients in the gas-generating formulation. In some embodiments, the amount of the first and second reactants may be less than 65% by weight of the excipients in the gas-generating formulation. In some embodiments, the amount of the first and second reactants may be greater than about 35% by weight of the excipients in the gas-generating formulation. In some embodiments, the amount of the first and second reactants may be greater than about 50% by weight of the excipients in the gas-generating formulation. In some embodiments, the amount of the first and second reactants may be between about 35-70% by weight of the excipients in the gas-generating formulation.

[0164] In any of the embodiments of the self-inflating patch assembly described herein, the self-inflating patch assembly includes a gas-generating formulation including a first reactant in an amount less than 40% by weight of the excipients in the gas-generating formulation. In any of the embodiments of the self-inflating patch assembly described herein, the gas-generating formulation may include a second reactant in an amount less than 40% by weight of the excipients in the gas-generating formulation. In any of the embodiments of the self-inflating patch assembly described herein, the gas-generating formulation includes a filler in a proportion of about 20-35% of the total reactants (e.g., first and second reactants) making up the gas-generating formulation, or about 25% of the total reactants.

[0165] In any of the embodiments described herein, the self-expanding patch assembly includes a gas-generating formulation containing additional excipients. The excipients should be carefully selected so that they do not interfere, but rather promote gradual gas release upon exposure to water (e.g., in gas or liquid form), are stable despite some humidity in typical environments, and promote sustained gas release over time. The gradual release of gas contributes to a constant pressure over a period of time. Relevant excipients used in the preparation of gas-generating formulations can include the following: polymers, sugars, fillers, lubricants, superdisintegrants, polymers, and binders. Typical fillers can include, for example, lactose, microcrystalline cellulose, starch, and mannitol. Exemplary disintegrants (e.g., superdisintegrants) can include croscarmellose sodium, primogel, L-HPC, polyplasdone XL-10, crospovidone, plasdone XL, SSG primogel, LHPC, croscarmellose sodium, carboxymethylcellulose calcium, microcrystalline cellulose, alginic acid, alginates (e.g., sodium alginate, potassium alginate, or calcium alginate), sodium starch glycolate, starch, and mixtures thereof.

[0166] Further selection and structure (e.g., layers) of excipients can be configured to generate an acidic local environment during the disintegration process, for example, with an additional outer layer of acid. In some embodiments, an acid can be used to increase the acidity of the local environment during effervescence. In some examples, an outer coating or layer can be included to promote storage stability due to the nature of the hygroscopic chamber wall containing the gas-generating formulation. In some examples, an outer coating or layer can be included to promote storage stability due to the nature of the hygroscopic chamber wall containing the gas-generating formulation. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation can include any one or more of the following: sugar, bicarbonate, citric acid, and PVP.

[0167] In any of the embodiments described herein, the self-inflatable patch assembly includes a gas-generating formulation that can be in any of a number of different typical single-unit forms, including, but not limited to, multi-layer tablets, bi-layer tablets, microparticles, thin films, mini-tablets, micro-tablets, and granules. In any of the embodiments described herein, the self-inflatable patch assembly includes a gas-generating formulation that can be in any of a number of different typical multi-unit forms that can be held by a formulation holder, including, but not limited to, granules, pellets, microparticles, powders, mini-tablets, micro-tablets, and granules. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may preferably be in the form of multiple single-unit micro-tablets or mini-tablets. Typically, micro-tablets have a diameter of approximately 1.0 to 1.7 mm. Typically, mini-tablets have a diameter of approximately 1.8 to 3.5 mm. When granules, pellets, microparticles, or powders are used, a formulation holder can be used.

[0168] In any of the embodiments described herein, the self-expandable patch assembly includes a gas-generating formulation, which may be a film or layer, within the gas-generating chamber. If it is a film or layer, a formulation retention portion may not be necessary, and the film or layer on the inner surface of the gas-generating chamber may be sufficient to retain the formulation within the gas-generating chamber.

[0169] In some embodiments, the single unit may be coated. In some instances, the single unit may have an additional layer on the inner gas-generating reaction chamber wall. If granulation is employed, intragranular or extragranular superdisintegrants may be present. In some embodiments, the single unit may have some degree of porosity. In some embodiments, the gas-generating formulation has a true density of about 500-2500 mg / ml. In some embodiments, the gas-generating formulation has a true density of about 1500-1900 mg / ml. In some embodiments, the gas-generating formulation has a true density of about 1600-1700 mg / ml.

[0170] The shape of the single unit can be selected from any typical shape, including, for example, a core, a rod, an oval, a circle, a square, a rectangle, or a triangle. In any of the embodiments of the self-inflating patch assembly described herein, the gas-generating formulation has a shape that maximizes the surface area to volume ratio, for example, a ring shape.

[0171] In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation can include a plurality of single units (e.g., mini-tablets). In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation can include a plurality of single units (e.g., mini-tablets), each containing either the first or second reactant. In any of the embodiments of the self-inflatable patch assembly described herein, the first and second reactants are contained within the interior volume of the chamber by multiple or single members. In any of the embodiments of the self-inflatable patch assembly described herein, the first and second reactants are contained within the interior volume of the chamber by multiple members. In any of the embodiments of the self-inflatable patch assembly described herein, the first and second reactants are contained within the interior volume of the chamber by a single member. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation can include an array of single units, each containing either the first or second reactant, wherein the array of units, each containing either the first or second reactant, is contained within a common gas-generating reaction chamber. In any of the embodiments of the self-expanding patch assembly described herein, the gas-generating formulation may include a number of single unit tablets, each containing either a first or second reactant, and the array of tablets, each containing either a first or second reactant, may be contained within separate gas-generating reaction chambers.

[0172] In any of the embodiments of the self-inflating patch assemblies described herein, the gas-generating formulation can have a total mass of greater than 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 70 mg. In any of the embodiments of the self-inflating patch assemblies described herein, the gas-generating formulation can have a total mass of less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, or less than 90 mg. In any of the embodiments of the self-inflating patch assemblies described herein, the gas-generating formulation can have a total mass of 1-250 mg, 1-200 mg, 1-150 mg, 1-150 mg, 50-150 mg, or 70-100 mg per device. The total mass can be comprised of one or more individual formulations, including, for example, a single at least partial layer or multiple tablets on the gas-generating inner wall.

[0173] In any of the embodiments of the self-expanding patch assembly described herein, the gas-generating formulation can be manufactured in a single-pot or multi-pot process. The formulation can be prepared by dry or wet granulation (e.g., in ethanol). The formulation can be a homogenous mixture and / or can include multiple layers for sustained gas release or additional storage stability.

[0174] In any of the embodiments of the self-inflating patch assembly described herein, the gas-generating formulation may be configured to foam, i.e., release carbon dioxide, and completely disintegrate or decompose over a period of about 60 minutes. In any of the embodiments of the self-inflating patch assembly described herein, the gas-generating formulation may be configured to foam and completely disintegrate or decompose over a period of about 90 minutes. In any of the embodiments of the self-inflating patch assembly described herein, the gas-generating formulation may be configured to foam and completely disintegrate or decompose over a period of about 120 minutes.

[0175] In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient quantity of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for a period of time to apply a sufficient penetration force, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into an adjacent soft tissue wall. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient quantity of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 10 minutes to apply a force of greater than 1 pound per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into an adjacent soft tissue wall.

[0176] In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for a period of time to apply a sufficient penetration force, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into an adjacent soft tissue wall. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 30 minutes to apply a force of more than 1 pound per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into an adjacent soft tissue wall. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 30 minutes to apply a force of more than 2 pounds per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into an adjacent soft tissue wall. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient quantity of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 30 minutes to apply greater than 3 pounds per square inch as measured at 37° C., in order to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient quantity of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 30 minutes to apply approximately 3.5 pounds per square inch as measured at 37° C., in order to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue.

[0177] In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 45 minutes to apply more than 2 pounds per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 45 minutes to apply more than 3 pounds per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 45 minutes to apply about 3.5 pounds per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue.

[0178] In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 60 minutes to apply more than 2 pounds per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 60 minutes to apply more than 3 pounds per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 60 minutes to apply about 3.5 pounds per square inch, as measured at 37° C., to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue.

[0179] In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 60 minutes to apply 1 to 5 pounds per square inch, as measured at 37°C, to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 60 minutes to apply 1 to more than 4 pounds per square inch, as measured at 37°C, to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 60 minutes to apply approximately 2 to 4 pounds per square inch, as measured at 37°C, to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue. In any of the embodiments of the self-inflatable patch assembly described herein, the gas-generating formulation may be configured to generate a sufficient amount of gas within the interior volume of the inflatable patch to expand the outer wall of the inflatable patch for at least 60 minutes to apply approximately 3 to 4 pounds per square inch as measured at 37°C in order to advance at least a portion of the plurality of tissue-piercing needles into the wall of adjacent soft tissue.

[0180] Effervescent granules are typically manufactured under low-humidity conditions. Care should be taken to ensure that all equipment does not contain traces of water or moisture, as this can destroy the effervescent reactant mixture. A water-soluble lubricant can be included as a final step before compression into tablets. Strict humidity control may be required in all manufacturing areas [25°C, less than 30% relative humidity (RH)]. All packaging used to store effervescent tablets should protect the tablets from external shear and trap little or no air, as moisture present in trapped air can lead to physical and / or chemical degradation of the tablet (Altomare et al., 1997).

[0181] In any of the embodiments described herein, the self-inflatable patch assembly includes a dedicated fluid passageway. As used herein, a dedicated fluid passageway includes any suitable passageway adapted to allow gas generated in the gas-generating reaction chamber to pass through the inflatable patch while preventing the passage of the gas-generating formulation, which must be maintained adjacent to the water-permeable surface. In some embodiments, the dedicated fluid passageway may be operatively associated with a dosage form retaining element configured to retain a solid dosage form along with the reaction chamber.

[0182] In any of the embodiments of the self-inflatable patch assembly described herein, a fluid-only passageway may be disposed between the gas-generating reaction chamber and the inflatable patch to facilitate a gas flow path between the interior volume of the gas-generating reaction chamber and the interior volume of the one or more inflatable patches. In any of the embodiments of the self-inflatable patch assembly described herein, the one or more gas-generating reaction chambers may be fluidly connected to the inflatable patch via one or more fluid-only passageways configured to connect between the one or more gas-generating reaction chambers and the inflatable patch.

[0183] In some embodiments, one or more fluid-dedicated passageways are disposed along the periphery, periphery, exterior, or side of the inflatable patch. For example, there may be two or more or three or more fluid-dedicated passageways disposed along the periphery, periphery, exterior, or side of the inflatable patch. For example, there may be two to five fluid-dedicated passageways disposed along the periphery, periphery, exterior, or side of the inflatable patch.

[0184] In any of the embodiments of the self-inflatable drug delivery device described herein, the fluid-only passageway may include a valve in the interior volume to facilitate the direction of gas flow from the gas-generating reaction chamber toward the inflatable patch.

[0185] In any of the embodiments described herein, the self-expanding patch assembly can include an outer shell, such as a swallowable enteric outer shell, that contains or compresses the assembly. In some embodiments, the outer shell initially surrounds the self-expanding patch assembly prior to release in the intestine.

[0186] In any of the embodiments described herein, the self-inflatable patch assembly may include a swallowable enteric-coated outer shell sized to accommodate the self-inflatable patch assembly while being swallowed and passing through the intestinal tract. Examples of relevant sizes include, but are not limited to, a 00-size capsule (e.g., 00 elongated) or a 000-size capsule. The outer shell defines an interior volume for accommodating the self-inflatable patch assembly (i.e., the gas-generating reaction chamber(s) and the inflatable patch(es)). The outer shell may include a coating or capsule, a coating on a capsule, or a capsule on a coating. Degradation of the outer shell may be complete or partial and may occur in stages. For example, the outer shell may include seams, perforations, or similar features to accelerate degradation or promote early and complete exposure of the drug delivery device to intestinal fluids.

[0187] The self-expanding patch assembly may be housed in a swallowable enteric-coated outer shell, which may degrade in whole or in part at, above, or below a design threshold, e.g., at a pH level above 5.5. Breakdown of the outer shell due to its degradation initiates a gas-generating process within the gas-generating chamber, culminating in the potential for the therapeutic agent in liquid form to be extruded from the expandable patch or disintegrate, or to be deposited through a penetration needle into the lumen wall of a GI tract, such as the small intestine, where the agent may be deposited through the penetration needle. The swallowable enteric-coated outer shell may have at least a portion (e.g., a coating or capsule portion) made from various biocompatible polymers known in the art, including various enteric polymers, that protect the outer shell from degradation in the stomach and degrade in response to the pH in the intestinal tract. For example, selective degradation may be initiated upon exposure to a pH above about 5.5-6.0, which corresponds to pH levels commonly found in the intestinal tract.

[0188] As used herein, the terms "drug," "active agent," "therapeutic agent," "therapeutic agent," or "medication" may be used interchangeably and include small molecules, biologics (antibodies, proteins, and peptides), diagnostic agents, or active pharmaceutical ingredients used to treat or diagnose patients. These may refer to any agent that has a therapeutic effect and / or a desired biological and / or pharmacological effect when administered. Generally, a therapeutic agent may refer to multiple therapeutic agents. Examples of therapeutic agents that may be suitable for use include, but are not limited to, chemotherapeutic agents, interferons, antibodies, antibiotics, growth hormones, parathyroid hormones, glucose regulators, insulin compounds, incretin hormones, GLP-1 compounds, or exenatide, antivirals, protease inhibitors, or anticonvulsant compounds, or other therapeutic agents that are chemically degraded or have limited permeability when released within the intestinal lumen of the gastrointestinal tract. In various embodiments of any of the presented aspects, the therapeutic agent is a peptide sequence, protein, enzyme, polysaccharide or polynucleotide, amino acid, nucleotide, carbohydrate, sugar, lipid, nucleoprotein, glycoprotein, lipoprotein, steroid, etc., commonly found in cells and tissues, whether naturally occurring or artificially created (by synthetic or recombinant methods). Specific classes of biologics include, but are not limited to, enzymes, receptors, neurotransmitters, hormones, cytokines, cell response regulators such as growth factors and chemotactic factors, antibodies, vaccines, haptens, toxins, interferons, ribozymes, antisense agents, plasmids, DNA, and RNA.

[0189] In any of the embodiments of the self-expanding patch assembly described herein, the therapeutic agent may be, for example, a digestive polypeptide, such as pancreatic polypeptide and / or the glycopeptide metformin. The bioactive may be, for example, a DPP4 inhibitor, such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, dutogliptin, and / or berberine lopeol. The bioactive may be, for example, a sodium / glucose cotransporter 2 (SGLT2) inhibitor, such as dapagliflozin, empagliflozin, canagliflosin, tofogliflosin, sergliflosin, remogliflosin, ertogliflosin, and / or sotagliflosin. Bioactive agents include, for example, GLP-1 analogs, such as incretins (e.g., semaglutide, glucagon-like peptide-1 (GLP-1), GLP-1 analogs, exenatide, albiglutide, taspoglutide, or gastric inhibitory polypeptide (GIP)), efpeglenatide, exenatide, liraglutide, pramlintide, GnRH, and analogs such as abarelix, cetrorelix, degarelix, ganirelix, elagolix / relugolix, KLH-2109, and / or ASP-1707. Bioactive agents may also be proteins that bind to selective transforming growth factor-β superfamily ligands, such as luspatercept. Bioactive agents may also be proteins that block abnormal signaling between cells in the pulmonary vasculature, such as sotatercept. Bioactive agents may also be anti-interleukin-13 (IL-13) monoclonal antibodies, such as sendakimab. The bioactive agent may be other monoclonal antibodies such as Evinacumab, Ocrelizumab, Emicizumab, Dupilumab, Sarilumab, Isatuximab, Sutimlimab, Lanadelumab, etc. The bioactive agent may be a selective inhibitor of TLR 7 / 8 such as Affymetran.For example, the therapeutic agent may be a glucagon-like peptide 1 receptor agonist or a glucagon receptor agonist.Examples of the therapeutic agent include but are not limited to mazudutide, tirzepatide, caglilintide, semaglutide, pembidutide, retatortide, efinopeglutide, bimagrumab or combinations thereof.The therapeutic agent may treat growth hormone deficiency, such as somatotropin and lonapegsomatropin.Exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide.

[0190] In any of the embodiments of the self-expandable patch assembly described herein, the therapeutic agents may be more than two different therapeutic agents that benefit from similarly timed delivery through the intestinal wall.

[0191] In any of the embodiments of the self-expanding patch assembly described herein, the therapeutic agent may be a biomolecule (protein, peptide, etc.) or a biomaterial (e.g., cell) that is chemically degraded by GI fluids (e.g., small intestinal fluids) within the GI tract if not delivered to the luminal wall of the GI tract. Such biomolecules may include various biologics, including one or more of proteins, antibodies, polypeptides, and other molecules produced by cells or other biological processes.

[0192] In any of the embodiments of the self-expanding patch assemblies described herein, the therapeutic agent may be in an amount that provides a desired therapeutic effect at a lower amount than would provide the corresponding effect if the agent were delivered orally without being encapsulated in an ingestible formulation. In some embodiments of any of the presented aspects, the therapeutic agent may be a combination of therapeutic agents. In some embodiments of any of the presented aspects, the therapeutic agent may be chemically or enzymatically degraded, have limited permeability, or have adverse effects on the subject if released and washed away into the lumen of the gastrointestinal tract. In some embodiments of any of the presented aspects, the therapeutic agent comprises a polypeptide that is chemically degraded or has limited permeability in the GI tract, and the agent is delivered into the wall of the small intestine without minimizing or losing binding affinity or specificity for the target binding site.

[0193] In any of the embodiments of the self-inflatable patch assembly described herein, the therapeutic agent forms part of the solid permeation member. In any of the embodiments of the self-inflatable patch assembly described herein, the therapeutic agent is in a fluid or other non-solid form that is contained in a reservoir within the inflatable patch and advanced into the intestinal wall through one or more hollow needles or other syringes by applying a gas force to the reservoir in a liquid dosage form or other non-solid form. As used herein, fluid refers to fluid properties and can be in the form of a gas, liquid, colloidal suspension, gel slurry, nanopowder, or powder.

[0194] As used herein, water impermeable refers to a structure that is substantially impermeable to fluid water, such that essentially no water or drugs are absorbed through the wall structure over a period of time.

[0195] It should be understood that the term "gas impermeable" is a relative term. The compartment or chamber, and particularly its walls, must provide a sufficient barrier to prevent substantial escape of gas in order to maintain the desired pressure within the compartment or chamber. However, there is some tolerance for gas escape due to the varying degrees of gas pressure exerted on the walls, which are continually generating gas and continuously absorbing water from the internal volume.

[0196] It should be understood that the term "stable" is a relative term. Stable devices and formulations are desired to be stable for the desired shelf life of the packaged device assembly. The specific properties required for this goal depend on the length of the desired shelf life, the amount of vapor-donating liquid placed in the package prior to sealing the package from the environment, and the conditions under which the product will be stored.

[0197] As used herein, the terms "substantially" and "about" are used to describe and explain insignificant variations. For example, when used in connection with a numerical value, the terms can represent a variation in value of ±10% or less, such as ±5% or less, ±4% or less, ±3% or less, ±2% or less, ±1% or less, ±0.5% or less, ±0.1% or less, or ±0.05% or less.

[0198] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural equivalents unless the context clearly dictates otherwise. Thus, for example, reference to "a disintegrant" may include a mixture of two or more disintegrants.

[0199] Furthermore, in some cases, amounts, ratios, and other numerical values ​​may be expressed herein in range format. As used herein, a range of numerical values ​​includes any number within that range, or any subrange, provided that the minimum and maximum numbers within that range fall within that range. Ranges may be expressed herein as from one particular value and / or to another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. It is further understood that the endpoints of each range are significant both in relation to the other endpoint and independently of the other endpoint. For example, if "1 to 6" is disclosed and "2 to 4" is disclosed, then "4 to 6" is also disclosed. It is also understood that there are multiple values ​​disclosed herein, and that each value is herein disclosed as "approximately" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that whenever a range is described within this application, every integer within that range is contemplated as an embodiment of the invention, and vice versa. For example, when a list of units is provided, ranges between the units provided are also contemplated.

Claims

1. An auto-inflatable patch assembly for delivering drugs into a lumen, i. A flexible and expandable patch having a water and gas impermeable wall, defining an internal chamber and an array of through-needles arranged on its surface, ii. One or more auxiliary gas generation reaction chambers, distinct from and in fluid communication with the expandable patch, wherein each reaction chamber is defined by a flexible reaction chamber wall containing a water-sensitive gas generation formulation, the reaction chamber wall is configured to restrain the gas, and at least a portion of it has a water-permeable outer surface. Includes, The patch assembly is such that each gas-generating formulation or set is held within each auxiliary gas-generating reaction chamber during expansion. Patch assembly.

2. The self-inflatable patch assembly according to claim 1, wherein the patch assembly is compressed and further housed in a swallowable enteric-coated outer shell.

3. The self-inflatable patch assembly according to claim 1, wherein the water-sensitive gas generating preparation is a sustained-release gas generating preparation.

4. The self-inflatable patch assembly according to claim 1, wherein the water-sensitive gas generating formulation is configured to generate a gas that provides an inflatable patch pressure greater than 3 psi when measured at 37°C.

5. The auto-inflatable patch assembly according to claim 1, wherein one or more auxiliary gas generation reaction chambers are in fluid communication with the internal chamber but are separated from the expansion patch by a formulation holding section.

6. The self-inflatable patch assembly according to claim 1, wherein the patch assembly is configured such that the combination of the internal chamber of the patch and the internal chambers of one or more auxiliary gas generation reaction chambers contains a gas.

7. The self-inflatable patch assembly according to claim 1, wherein the water-sensitive gas generating formulation comprises a first reactant and a second reactant contained within a single compartment.

8. The auto-inflatable patch assembly according to claim 1, wherein one or more auxiliary gas generation reaction chambers are arranged along the outer periphery, periphery, or side of the inflatable patch.

9. The auto-inflatable patch assembly according to claim 1, wherein the one or more auxiliary gas generation reaction chambers include three or more gas generation reaction chambers arranged along the outer circumference, periphery, or sides of the inflatable patch.

10. The autoinflatable patch assembly according to claim 5, wherein the formulation holding portion is arranged along the outer circumference, periphery, outer surface, or side of each of the one or more gas generation reaction chambers.

11. The auto-inflatable patch assembly according to claim 1, wherein each of the one or more auxiliary gas generation reaction chambers is configured to generate a constant amount of gas over a long period of time.

12. The self-inflatable patch assembly according to claim 1, wherein the reaction chamber wall is directionally permeable.

13. The self-inflatable patch assembly according to claim 1, wherein the internal chamber of the inflatable patch does not have a water-permeable surface.

14. An autoinflatable patch assembly comprising: a flexible and inflatable patch having water and gas impermeable walls defining an internal chamber; and one or more auxiliary gas generation reaction chambers, distinct from the inflatable patch and in fluid communication with the internal chamber of the inflatable patch, each of the reaction chambers being defined by flexible reaction chamber walls containing first and second reactants in a single compartment, the first and second reactants being configured to foam when exposed to water, and the reaction chamber walls being configured to contain gases, and at least a portion of which having a water-permeable outer surface.

15. The auto-inflatable patch assembly according to claim 1 or 14, wherein one or more auxiliary gas generation reaction chambers extend radially from the inflatable patch.

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