Controlled gas release systems and uses thereof

Abstract

The present disclosure relates to a controlled gas release system comprising one or more enclosures defined by walls being substantially gas-impermeable and water-transferable, the one or more enclosures configured to house one or more gas-generating compositions and having a gas passageway for releasing generated gas, uses thereof and methods of using the same.

Description

[0001] CONTROLLED GAS RELEASE SYSTEMS AND USES THEREOF TECHNOLOGICAL FIELD

[0002] The present disclosure relates to controlled gas release compositions, controlled gas release systems, uses thereof, and methods for providing controlled gas release systems.

[0003] BACKGROUND

[0004] Controlled gas release systems are used in various applications, particularly in the field of oral pharmaceuticals. These systems typically produce gas through chemical reactions, often involving acids and carbonates. The generated gas can serve multiple purposes.

[0005] GENERAL DESCRIPTION

[0006] In accordance with some aspects, the present disclosure provides a controlled gas release system comprising:

[0007] one or more enclosures, each enclosure having walls that are substantially gas-impermeable and substantially water-transferable and comprising a gas passageway configured to direct generated gas out of the enclosure, the one or more enclosures being configured to house at least one gas-generating composition; said gas-generating composition comprising one or more of:

[0008] i. an immediate -release gas-generating composition; and

[0009] ii. an extended-release gas-generating composition comprising an extended-release component;

[0010] wherein each of the immediate -release gas-generating composition and the extended-release gas-generating compositions, independently comprises reactants that generate gas upon exposure to a fluid.

[0011] In accordance with some aspects, the present disclosure provides a controlled gas release system comprising:one or more enclosures, each enclosure having walls that are substantially gas-impermeable and substantially water-transferable and comprising a gas passageway configured to direct generated gas out of the enclosure, the one or more enclosures being configured to house at least one gas-generating composition; said gas-generating composition comprising one or more of:

[0012] i. an immediate -release gas-generating composition; and

[0013] ii. an extended-release gas-generating composition comprising an extended-release component;

[0014] wherein each of the immediate -release gas-generating composition and the extended-release gas-generating compositions, independently comprises a first reactant and a second reactant that generate gas upon exposure to a fluid.

[0015] In accordance with some aspects, the present disclosure provides a controlled gas release system comprising:

[0016] one or more enclosures defined by walls being substantially gas-impermeable and water-transferable, the one or more enclosures being configured to house one or more gasgenerating composition and having a gas passageway for releasing generated gas; said gasgenerating composition comprising one or more of:

[0017] i. an immediate-release gas-generating composition housed within the one or more enclosures; and

[0018] ii. an extended-release gas-generating composition comprising an extended-release component and housed within the one or more enclosures;

[0019] wherein each of the immediate -release gas-generating composition and the extended-release gas-generating compositions, independently comprises a first reactant and a second reactant that generate gas upon exposure to a fluid.

[0020] In accordance with some aspects, the present disclosure provides a controlled-release gas-generating bilayer tablet comprising:

[0021] (a) an immediate-release gas-generating layer comprising a first reactant and a second reactant which generate gas upon exposure to intestinal fluid, and(b) an extended-release gas-generating layer comprising an extended-release component and a first reactant and a second reactant which generate gas upon exposure to intestinal fluid.

[0022] In accordance with some aspects, the present disclosure provides an inflatable device comprising: (a) an inflatable member defining an internal volume; and (b) a controlled gas release system as described herein, wherein the controlled gas release system is in fluid communication with the inflatable member such that generated gas inflates the inflatable member.

[0023] In accordance with some aspects, the present disclosure provides a method of deploying an inflatable device, comprising: introducing the device comprising a controlled gas release system and an inflatable member as described herein into a subject; wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas and inflates the inflatable member.

[0024] In accordance with some aspects, the present disclosure provides a method of treating a disease in a subject in need thereof, comprising: introducing the device comprising a controlled gas release system and an inflatable member as described herein into a subject; wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas, inflates the inflatable member thereby delivering an active agent from the inflatable device into the subject.

[0025] In accordance with some aspects, the present disclosure provides use of a controlled gas release system as described herein, for inflating an auxiliary inflatable member.

[0026] In accordance with some aspects, the present disclosure provides use of the inflatable device as described herein for delivering an active agent to tissue.

[0027] BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of nonlimiting example only, with reference to the accompanying drawings, in which:

[0029] Figures 1A and IB show sectional views of a gas-generating system, in accordance with some exemplary embodiments of the present disclosure.Figures 2 A and 2B show sectional views of an inflatable device, in accordance with some exemplary embodiments of the present disclosure.

[0030] Figure 3 shows a sectional view of an inflatable device, in accordance with some exemplary embodiments of the present disclosure.

[0031] Figure 4 is a graph showing gas release profiles over time for different gas-generating systems, in accordance with some exemplary embodiments of the present disclosure. Figure 5 is a graph comparing various gas-generating compositions, in accordance with some exemplary embodiments of the present disclosure.

[0032] Figure 6 is a graph showing hardness measurements for different types of tablets.

[0033] Figure 7 is a graph showing gas release profiles over time for bilayer round tablets with various xanthan Gum levels (3%, 6%, 9%).

[0034] Figures 8A and 8B are histograms showing absorption capacity of membrane with different thickness with respect to membrane thickness (Figure 8A) and weight (Figure 8B) increase over time.

[0035] DETAILED DESCRIPTION OF EMBODIMENTS

[0036] The present invention relates to controlled gas-generating compositions and systems, configured to produce a defined gas-release profile upon exposure to an aqueous environment, characterized by an initial rapid gas generation phase followed by a sustained gas generation phase.

[0037] The gas-generating compositions, comprising an immediate-release (IR) gasgenerating composition and an extended-release (ER) gas-generating composition, are enclosed within a selectively permeable polymeric enclosure (e.g., a membrane-defined enclosure having walls) that permits ingress of water while substantially restricting egress of generated gas.

[0038] The permeability characteristics and thickness of the enclosure wall regulate the rate of water transfer into the enclosed compositions and thereby control the kinetics of gas generation and internal pressure development.The controlled gas-generating system is particularly suited for applications requiring mechanical actuation, wherein generated gas produces controlled pressure for activation, deployment, and / or inflation of a device. The system is especially useful in applications requiring both prompt gas availability and prolonged pressure maintenance, including medical devices, pharmaceutical dosage forms, and inflatable structures intended for deployment within a biological environment.

[0039] The inventors have recognized that combining an immediate-release gas-generating composition and an extended-release gas-generating composition within a selectively permeable enclosure enables generation of a tailored gas-release profile that cannot be achieved by either composition alone. In particular, an initial burst of gas may be used to rapidly activate or inflate a device, while continued gas generation over an extended period may be used to maintain pressure or force for a desired duration.

[0040] In other words, the immediate release composition is configured to produce gas relatively rapidly upon exposure to an aqueous environment, while the extended release composition is configured to produce gas over a more extended period of time. By combining these two compositions, the controlled gas release system can achieve a desired pressure profile that includes an initial burst followed by sustained gas production and / or sustained pressure maintenance.

[0041] Hence, the present disclosure provides a controlled-gas release system comprising: an immediate-release gas-generating composition comprising at least two reactants configured to generate gas upon exposure to an aqueous environment; and an extended-release gas-generating composition comprising an extended-release component and at least two reactants configured to generate gas upon exposure to an aqueous environment. In some examples, the reactants of the immediate-release gas -generating composition and the extended-release gas -generating composition are identical.

[0042] In some examples, one or more reactants of the immediate-release composition differ from one or more reactants of the extended-release composition.

[0043] The controlled gas release system achieves a specific gas / pressure profile by combining the immediate-release composition and the extended-release gas-generating composition inside (within) a suitable enclosure.In accordance with some aspects, the present disclosure provides a controlled gas release system comprising:

[0044] one or more enclosures configured to house at least one gas-generating composition; the gas-generating composition comprising one or more of:

[0045] i. an immediate -release gas-generating composition; and

[0046] ii. an extended-release gas-generating composition comprising an extended-release component;

[0047] wherein each of the immediate -release gas-generating composition and the extended-release gas-generating compositions, independently comprises reactants that generate gas upon exposure to an aqueous environment.

[0048] In some examples, each enclosure has / comprises walls that are substantially gas-impermeable while permitting controlled ingress of water (i.e., substantially water-transferable).

[0049] In some examples, the one or more enclosures comprise a gas passageway. In some examples, one or more enclosures comprise a gas passageway configured to direct generated gas out of the enclosure.

[0050] In accordance with some aspects, the present disclosure provides a controlled gas release system comprising:

[0051] one or more enclosures, each enclosure having walls that are substantially gas-impermeable and substantially water-transferable and comprises at least one gas passageway configured to direct generated gas out of the enclosure, the one or more enclosures being configured to house at least one gas-generating composition.

[0052] Each enclosure houses a gas-generating composition comprising at least two reactants configured to generate gas upon exposure to an aqueous environment.

[0053] In accordance with some aspects, the present disclosure provides a controlled gas release system comprising:

[0054] one or more enclosures, each enclosure having walls that are substantially gas-impermeable and substantially water-transferable and comprises at least one gas passageway configured to direct generated gas out of the enclosure, the one or moreenclosures being configured to house at least one gas-generating composition; said gasgenerating composition comprising one or more of:

[0055] i. an immediate -release gas-generating composition; and

[0056] ii. an extended-release gas-generating composition comprising an extended-release component;

[0057] wherein each of the immediate -release gas-generating composition and the extended-release gas-generating compositions, independently comprises reactants that generate gas upon exposure to an aqueous environment.

[0058] In accordance with some aspects, the present disclosure provides a controlled gas release system comprising:

[0059] one or more enclosures, each enclosure having walls that are substantially gas-impermeable and substantially water-transferable and comprising a gas passageway configured to direct generated gas out of the enclosure, the one or more enclosures being configured to house at least one gas-generating composition; said gas-generating composition comprising one or more of:

[0060] i. an immediate -release gas-generating composition; and

[0061] ii. an extended-release gas-generating composition comprising an extended-release component;

[0062] wherein each of the immediate -release gas-generating composition and the extended-release gas-generating compositions, independently comprises a first reactant and a second reactant that generate gas upon exposure to an aqueous environment.

[0063] In accordance with some aspects, the present disclosure provides a controlled gas release system comprising:

[0064] one or more enclosures defined by walls being substantially gas-impermeable and water-transferable, the one or more enclosures configured to house one or more gasgenerating compositions and having a gas passageway for releasing generated gas; said gas-generating composition comprising:

[0065] i. an immediate-release gas-generating composition housed within the one or more enclosures; andii. an extended-release gas-generating composition having an extended-release component and housed within the one or more enclosures; wherein each of the immediate-release gas-generating composition and the extended-release gas-generating composition comprises a first reactant and a second reactant which generate gas upon exposure to an aqueous environment.

[0066] As used herein, the term "controlled gas release system" refers to an assembly comprising (i) two or more gas-generating compositions, (ii) an enclosure configured to regulate water ingress and gas retention, and (iii) at least one gas passageway configured to permit directional release of generated gas.

[0067] The enclosure comprises walls that are substantially gas-impermeable while permitting controlled ingress of water.

[0068] In some examples, the enclosure further comprises a gas passageway configured to permit or direct generated gas out of the enclosure.

[0069] The system is configured such that, upon exposure to an aqueous environment, the gas-generating compositions collectively provide a gas-generation profile comprising an initial gas-generation phase and a sustained (extended) gas-generation phase.

[0070] In the controlled gas release system, the interaction between the enclosure, the immediate-release composition, and the extended-release composition enables generation of a controlled gas release profile. This system is designed to utilize the properties of the enclosure along with the distinct characteristics of the immediate-release composition and extended-release composition to manage the generation and release of gas in a precise manner.

[0071] The enclosure (also referred to herein as a membrane or enclosure wall, all terms having the same meaning) is an active structural component that cooperates with the gasgenerating compositions to define the pressure-time profile of the system.

[0072] The enclosure thickness and mechanical properties are selected such that, upon hydration and swelling, the enclosure maintains structural integrity and resists rupture under the internal pressure generated by the gas-generating composition. Accordingly, the enclosure cooperates with the gas-generating composition(s) to regulate exposure to an aqueous environment and to manage resulting pressure development.In some examples, the enclosure functions as a hydration-responsive, pressureregulating barrier.

[0073] In some examples, the enclosure is configured to regulate the kinetics of water ingress into the interior of the enclosure.

[0074] In some examples, the enclosure is configured to regulate retention and directional control of generated gas.

[0075] In some examples, the enclosure is configured to control initiation, rise, and maintenance of internal pressure.

[0076] By regulating both water ingress and gas retention, the enclosure cooperates with the immediate-release and extended-release gas-generating compositions to produce a tunable pressure profile comprising an initial gas-release phase and a sustained gas-release phase.

[0077] In some examples, the enclosure material exhibits a permeability profile in which water permeability exceeds gas permeability under operational conditions.

[0078] As used herein, the terms "water-transferable" or "water-transferable wall" or "water permeability" or "water ingress" refer to a property or functional characteristic of a wall structure or enclosure configuration that permits transfer of water from an external environment into an interior of the enclosure in liquid and / or vapor form, in an amount and at a rate sufficient to initiate and sustain the gas-generating reaction(s) of the composition housed within the enclosure.

[0079] Water transfer may occur by one or more mechanisms. In some examples, water transfer occurs by diffusion through polymeric material. In some examples, water transfer occurs by absorption and subsequent transport through the enclosure. In some examples, water transfer occurs by capillary transport. In some examples, water transfer occurs by vapor-phase humidity ingress. In some examples, water transfer occurs by transfer through defined openings or windows.

[0080] In some examples, the enclosure walls are configured to permit controlled ingress of water molecules from an external aqueous environment into the interior of the enclosure, thereby initiating the gas-generating reaction.The enclosure walls are further substantially gas-impermeable, such that generated gas is retained within the enclosure to enable internal pressure development.

[0081] As used herein, the term "substantially gas-impermeable" refer to a property or functional characteristic of a wall structure or enclosure configuration that restricts passage of gas to an extent sufficient to retain generated gas within the enclosure for at least a period required to achieve activation and / or inflation including during an initial pressure rise and sustained pressurization phase.

[0082] In some examples, the enclosure material is or comprises a polymer material. In some examples, the enclosure material consists essentially of a polymeric material.

[0083] In some embodiments, the enclosure comprises a hydrophilic or semi-hydrophilic polymer that permits selective permeation of water while substantially restricting permeation of generated gas.

[0084] In some examples, the polymeric enclosure material exhibits a gravimetric water absorption capacity of at least about 5% of the weight of the dry polymer membrane weight.

[0085] In some examples, the polymeric enclosure material exhibits a gravimetric water absorption capacity of at least about 5%, at times at least about 10%, at times at least about 20%, at times at least about 30%, at times at least about 40%, at times at least about 50%, at times at least about 60%, at times at least about 70%, at times at least about 80%, at times at least about 90%, at times at least about 95%, of the weight of the dry polymer material weight.

[0086] In some examples, the enclosure comprises or is a polymeric material that may absorb water in an amount of about 10%, at times about 20%, at times about 30%, at times about 40%, at times about 50%, at times about 60%, at times about 70%, at times about 80%, at times about 90%, at times about 95%, of the weight of the dry polymer membrane weight.

[0087] In some examples, the enclosure comprises or is a polymeric material that may absorb water in an amount of about 90%, at times about 95%, at times about 100%, at times about 120% of the weight of the dry polymer membrane weight.

[0088] In some examples, the enclosure comprises or is a polymeric material that may absorb water in an amount of between about 5% and about 100%, at times between about20% and about 100%, at times between about 30% and about 100%, at times between about 40% and about 100%, at times between about 50% and about 100%, at times between about 60% and about 100%, at times between about 70% and about 100%, at times between about 80% and about 100%, at times between about 90% and about 100% of the weight of the dry polymer.

[0089] In some examples, the enclosure comprises or is a polymeric material that may absorb water in an amount of between about 80% and about 100%, of the weight of the dry polymer.

[0090] In some examples, the enclosure comprises or is a polymeric material that may absorb water in an amount of between about 5% and about 100%, at times between about 20% and about 100%, at times between about 20% and about 90%, at times between about 20% and about 80%, at times between about 20% and about 70%, at times between about 20% and about 60%, at times between about 20% and about 50%, of the weight of the dry polymer.

[0091] In some examples, the polymer absorbs at least about 80% or at least about 100% of its dry weight in water within 15-30 minutes of exposure.

[0092] Water absorption may be determined gravimetrically following exposure of a dried membrane sample to an aqueous environment under defined conditions. In some examples, exposure comprises immersion in liquid water at about 25 °C or about 37 °C for a defined time period. In other examples, exposure comprises incubation at high relative humidity, including about 90% or about 100% relative humidity, for a defined time period.

[0093] In some examples, the enclosure comprises or is a polymeric material that exhibits a thickness increase of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, or at least about 30% following immersion in an aqueous medium at 25 °C or 37°C for a defined time period, such as about 15 minutes or about 1 hour.

[0094] In some examples, the enclosure comprises or is a polymeric material that exhibits a thickness increase of at least 5%, at times at least 10%, at times at least 15%, at times at least 20%, at times at least 25%, at times at least 30% following immersion of the driedmaterial in an aqueous medium at 25°C or 37°C for a defined time period, such as about 15 minutes or about 1 hour.

[0095] In some examples, the enclosure retains at least about 80%, optionally at least about 90%, of internally generated gas or internal pressure (e.g., 3-5 psi) over a period of 30-60 minutes under operational conditions.

[0096] In some examples, the enclosure material exhibits a gas transmission rate (GTR) of less than about 1000 cm3 / m2 / day, optionally less than about 500 cm3 / m2 / day. GTR can be measured at standard conditions using conventional gas transmission test methods (e.g., ASTM D1434 or ISO 15105-1).

[0097] In some examples, the enclosure material exhibits a carbon dioxide permeability of less than about 200 Barrer, optionally less than about 100 Barrer, measured under dry-film conditions.

[0098] Under hydrated operational conditions, the enclosure retains at least about 80%, optionally at least about 90%, of internally generated pressure (e.g., 3-5 psi) over a period of about 30-60 minutes.

[0099] In some examples, water ingress is controlled at least in part by geometric parameters of the enclosure. In some examples, water ingress is controlled by the total water-permeable surface area. In some examples, water ingress is controlled by the dimensions of one or more exposure windows. In some examples, water ingress is controlled by the thickness of the enclosure walls.

[0100] In some examples, water ingress is controlled by one or more of total water-permeable surface area, dimensions of one or more exposure windows, thickness of the enclosure walls or any combination thereof.

[0101] In some examples, a water-permeable region forms part of the enclosure and may be localized to a defined region thereof. In certain embodiments, a water-permeable region may have dimensions of approximately 6 mm x 6 mm.

[0102] The size of the enclosure may be designed to accommodate the compositions described herein and / or any solid unit such as a bilayer tablet and provide sufficient surface area for water absorption and gas generation. In some cases, the enclosures may have asurface area of more than 800 mm2or between 800 to 1800 mm2. This surface area allows for efficient water absorption and gas generation.

[0103] In some examples, the total water-permeable surface area of the enclosure is greater than about 800 mm2, including greater than about 900 mm2, 1000 mm2, 1100 mm2, or 1200 mm2.

[0104] In some examples, the enclosure walls thickness is between about 15 pm and about 100 micrometers. In some examples, the enclosure walls thickness is between about 20 pm and about 90 pm. In some examples, the enclosure walls thickness is between about 20 pm and about 80 pm. In some examples, the enclosure walls thickness is between about 25 pm and about 80 pm. In some examples, the enclosure walls thickness is between about 40 pm and about 60 pm.

[0105] In some examples, upon ingress of water, the enclosure wall material absorbs water and undergoes swelling, resulting in an increase in effective thickness and / or alteration of polymer chain packing. This hydration-induced change may reduce effective gas mobility through the membrane and enhance retention of generated gas during activation and inflation.

[0106] In some examples, the enclosure may be formed from a single layer structure, a multilayer structure or a composite structure.

[0107] In some examples, the enclosure comprises a single layer.

[0108] In other examples, the enclosure comprises two or more layers, including two-layer or three -layer constructions.

[0109] In further examples, the enclosure comprises two-layers. In further examples, the enclosure comprises three-layers.

[0110] In multilayer embodiments, the layers may be formed from the same material or from different materials and may differ in one or more properties, including composition, thickness, permeability to water, permeability to gas, hydrophilicity, mechanical strength, elasticity, swelling behavior, surface treatment, or combinations thereof.

[0111] In some examples, one layer may be configured primarily to permit controlled water ingress, while another layer may be configured primarily to restrict gas permeation andenhance pressure retention. In other examples, the layers may collectively provide the desired balance of water transfer and gas retention.

[0112] Suitable materials include hydrophilic polymers, semi-hydrophilic polymers, thermoplastic elastomers, polyurethanes (including thermoplastic polyurethane (TPU)), polyureas, polyamides, polyesters, or combinations thereof.

[0113] In some examples, the enclosure is or comprises a hydrophilic polymer, a semi-hydrophilic polymer, a thermoplastic elastomer, a polyurethane, a polyurea, a polyamide, a polyester, or combinations thereof.

[0114] In some examples, the enclosure is or comprises a hydrophilic polymer. In some examples, the enclosure consists essentially of a hydrophilic polymer.

[0115] In some examples, the enclosure is or comprise a hydrophilic thermoplastic elastomer.

[0116] In some examples, the hydrophilic thermoplastic elastomer is a hydrophilic thermoplastic polyurethane (TPU). In some examples, the enclosure walls are or comprise a TPU. In some examples, the enclosure walls consist of TPU.

[0117] As used herein, the term "hydrophilic TPU" refers to a class of polymeric materials that combine the properties of thermoplasticity and hydrophilicity. These materials may be characterized by their ability to absorb water while maintaining structural integrity and mechanical properties. Upon water ingress, such materials may undergo swelling and changes in physical characteristics, including dimensional expansion and alterations in mechanical properties. Despite these hydration-induced changes, the material retains sufficient structural integrity to function as an enclosure wall and to maintain containment of generated gas during device operation.

[0118] In some examples, hydrophilic thermoplastic polyurethanes may be composed of alternating soft and hard segments, where the soft segments contribute to the material's flexibility and water absorption capabilities, while the hard segments provide mechanical strength and physical crosslinking.

[0119] The hydrophilic nature of these TPU may be attributed to the presence of polar groups, such as ether or ester linkages, in their molecular structure. These polar groups mayinteract with water molecules, thereby facilitating controlled water absorption by the enclosure walls.

[0120] In some examples, the degree of hydrophilicity may be tailored by adjusting the ratio of hydrophilic to hydrophobic components in the polymeric structure, enabling regulation of the rate at which water permeates the enclosure and initiates gas generation.

[0121] In some examples, hydrophilicity of the enclosure wall material may be assessed using surface characterization techniques, such as static or dynamic water contact angle measurements. Materials exhibiting lower water contact angles generally demonstrate increased affinity for water and may facilitate controlled ingress of water into the enclosure.

[0122] In some examples, hydrophilic TPU may exhibit water absorption. This water absorption property may allow these materials to function as selective barriers, permitting the passage of water molecules while restricting the flow of gases.

[0123] The water-absorbing property of the TPU allows for the ingress of fluid necessary to initiate the gas-generating reactions within the enclosures, while the gas-impermeable nature helps contain the generated gas.

[0124] Water absorption may be determined gravimetrically following immersion of the dried material in an aqueous medium at 25 °C or 37°C for a defined time period, such as about 15 minutes or about 1 hour, at times at least 80% of equilibrium water uptake occurs within 15 minutes.

[0125] In some examples, TPU may absorb water in an amount of at least 5%, at times at least about 20%, at times at least about 30%, at times at least about 40%, at times at least about 50%, at times at least about 60%, at times at least about 70%, at times at least about 80%, at times at least about 90%, at times at least about 95%, of the weight of the dry TPU.

[0126] In some examples, TPU may absorb water in an amount of about 10%, at times about 20%, at times about 30%, at times about 40%, at times about 50%, at times about 60%, at times about 70%, at times about 80%, at times about 90%, at times about 95%, of the weight of the dry TPU.

[0127] In some examples, TPU may absorb water in an amount of between about 5% and about 100%, at times between about 20% and about 100%, at times between about 30% and about 100%, at times between about 40% and about 100%, at times between about50% and about 100%, at times between about 60% and about 100%, at times between about 70% and about 100%, at times between about 80% and about 100%, at times between about 90% and about 100% of the weight of the dry TPU.

[0128] In some examples, TPU may absorb water in an amount of between about 5% and about 100%, at times between about 20% and about 100%, at times between about 20% and about 90%, at times between about 20% and about 80%, at times between about 20% and about 70%, at times between about 20% and about 60%, at times between about 20% and about 50%, of the weight of the dry TPU.

[0129] In some examples, TPU may increase in thickness following immersion of the dried material in an aqueous medium at 25 °C or 37 °C for a defined time period, such as about 15 minutes or about 1 hour.

[0130] In some examples, TPU may increase in thickness in at least 5%, at times at least 10%, at times at least 15%, at times at least 20%, at times at least 25%, at times at least 30% following immersion of the dried material in an aqueous medium at 25 °C or 37 °C for a defined time period, such as about 15 minutes or about 1 hour.

[0131] As shown in Figures 8A and 8B, a TPU membranes exhibited about a 20% increase in thickness, and about a 100% increase in weight within 15 minutes of direct water immersion, with no substantial additional change observed after 1 hour, indicating rapid attainment of swelling equilibrium.

[0132] In some examples, the enclosure walls comprising hydrophilic TPU has a thickness of between about 15 pm and about 100 micrometers.

[0133] In some examples, the enclosure walls comprising hydrophilic TPU has a thickness of between about 20 pm and about 90 pm. In some examples, the enclosure walls comprising hydrophilic TPU has a thickness of between about 20 pm and about 80 pm. In some examples, the enclosure walls comprising hydrophilic TPU has a thickness of between about 25 pm and about 80 pm. In some examples, the enclosure walls comprising hydrophilic TPU has a thickness of between about 40 pm and about 60 pm. In some examples, the enclosure walls comprising hydrophilic TPU has a thickness of between about 50 pm and about 80 pm.The enclosure further comprises a gas passageway configured to direct or permit controlled flow of generated gas from the interior of the enclosure to a downstream component.

[0134] As used herein, the term "gas passageway" refers to a structure or region configured to permit directional flow of generated gas out of the enclosure while substantially retaining the gas-generating composition(s) within the enclosure.

[0135] In some examples, the gas passageway comprises a discrete structural feature establishing fluid communication between the enclosure and the downstream component.

[0136] In some examples, the gas passageway is or comprises a lumen, port, conduit, channel, opening, or combinations thereof. In some examples, the gas passageway may be formed as an aperture, molded channel, bonded conduit, or integrated tubular structure.

[0137] In other embodiments, the gas passageway forms an integral part of the enclosure structure. In such embodiments, controlled gas release occurs through a defined region of the enclosure wall comprising a material selected or engineered to permit directional gas flow. The gas-permitting region may comprise a selectively permeable membrane portion, a microperforated region, a thinner wall section, a porous insert, or a material having a defined gas transmission rate sufficient to allow controlled release of generated gas while substantially retaining the gas-generating composition within the enclosure.

[0138] In each embodiment, the gas passageway permits outward passage of generated gas while its size, geometry, or material properties restrict passage of the gas-generating composition during a majority of the gas-generation process. In this manner, the gasgenerating composition is retained within the enclosure and maintained adjacent to the water-transferable enclosure wall.

[0139] The gas passageway specifically allows for gas passage, but its size and shape restrict passage of the compositions per se for a majority of the gas-generating process. In other words, the gas passageway specifically allows gas passage while retaining the position of the gas release composition within the enclosure for a majority of the gas-generating process. In this manner, the gas release compositions are maintained adjacent to the water-transferable enclosure wall.The design of the enclosures, including their material properties, dimensions, and gas passageway configuration, contributes to the controlled release of gas from the controlled gas release system.

[0140] As described herein, the system comprises an immediate gas release composition and an extended gas release composition.

[0141] The immediate -release composition and the extended-release composition may be housed together within a single enclosure forming a common compartment or housed within separate enclosures (or pockets).

[0142] In some examples, both the immediate-release composition and the extended-release composition are housed within a single enclosure forming a common compartment.

[0143] In other examples, the immediate -release composition and the extended-release composition are housed in separate enclosures (or pockets), each forming a discrete compartment in gas communication with a gas passageway.

[0144] In other examples, the immediate -release composition is housed within a first enclosure and the extended-release composition is housed within a second enclosure.

[0145] In further examples, one enclosure may house only the immediate-release composition while another enclosure houses both the immediate-release and extended-release compositions.

[0146] In still further examples, one enclosure may house only the extended-release composition while another enclosure houses both the immediate-release and extended-release compositions.

[0147] In configurations comprising multiple enclosures, gas generated from the respective enclosures may combine to produce a composite pressure-time profile.

[0148] In configurations comprising separate enclosures, water ingress into each enclosure may occur independently, such that gas generation within each enclosure proceeds according to the kinetics of the respective composition under the water-ingress conditions established by the enclosure. The combined gas output from the separate enclosures produces a composite pressure -time profile reflecting both the rapid initial contribution ofthe immediate-release composition and the sustained contribution of the extended-release composition.

[0149] The ratio of the immediate -release to extended-release compositions may be controlled to allow tailoring of a desired gas release profile, including an initial burst of gas followed by sustained release over a predetermined period. In this manner, the timing and intensity of the initial burst and the duration and rate of the subsequent release can be adjusted to meet application-specific performance requirements of the controlled gas release system, including maintaining a substantially constant internal pressure or force output over a defined period of time.

[0150] In some examples, the ratio between the immediate release composition and the extended release composition is between about 5:95 and about 95:5 by weight, based on the total mass of the gas-generating compositions.

[0151] In some examples, the ratio between the immediate release composition and the extended release composition is between about 10:90 and about 90:10. In some examples, the ratio between the immediate release composition and the extended release composition is between about 20:80 and about 80:20. In some examples, the ratio between the immediate release composition and the extended release composition is between about 25:75 and about 75:25. In some examples, the ratio between the immediate release composition and the extended release composition is between about 35:65 and about 65:35. In some examples, the ratio between the immediate release composition and the extended release composition is between about 45:55 and about 55:45. In some examples, the ratio between the immediate release composition and the extended release composition is about 50:50. In some examples, the ratio between the immediate release composition and the extended release composition is about 1:1.

[0152] As described herein, each of the immediate-release composition and the extended-release composition comprises at least two components configured to react to generate gas, denoted herein at times as reactants.

[0153] The reactants may comprise components of an effervescent system. In the present system, the effervescent reaction may be regulated by the enclosure architecture, the relative proportions of the immediate -release and extended-release compositions, and / orthe physical configuration of the gas-generating elements within the enclosure to produce a defined pressure-time profile.

[0154] The at least one first reactant and at least one second reactant in the immediate-release composition may be the same as or different from the corresponding reactant(s) in the extended-release composition.

[0155] In some examples, one or more reactants present in the immediate-release composition are chemically identical to those present in the extended-release composition. In other examples, one or more reactants differ between the immediate -release and extended-release compositions.

[0156] In some examples, the gas-generating composition comprises at least one acid component and at least one basic component capable of reacting to generate gas. The acid component may comprise one or more distinct acid reactants, and the basic component may comprise one or more distinct basic reactants. Thus, a given composition (including the immediate-release or extended-release composition) may comprise two or more acid reactants, two or more basic reactants, or combinations thereof.

[0157] The acid and / or basic components may be distributed between intragranular and extragranular fractions to modulate gas-generation kinetics. A first portion of an acid or base may be incorporated into an intragranular fraction, while a second portion of the same or a different acid or base may be incorporated into an extragranular fraction. The acid present in the intragranular fraction may be chemically identical to or different from the acid present in the extragranular fraction. Likewise, the base present in the intragranular fraction may be chemically identical to or different from the base present in the extragranular fraction.

[0158] In some examples, both acid and base components are present in each of the intragranular and extragranular fractions. In other embodiments, one component may be primarily intragranular while the other is primarily extragranular. The relative proportions of acid and base within the respective fractions may be selected to control the rate and extent of gas generation upon exposure to aqueous fluid.

[0159] In some examples, a first portion of the acid component and a first portion of the basic component may be incorporated into an intragranular fraction.In some examples, a second portion of the acid component and / or a second portion of the basic component may be incorporated into an extragranular fraction.

[0160] In some examples, both the acid and the basic components are present in each of the intragranular and extragranular fractions.

[0161] In some examples, one of the components (e.g., the acid component) may be primarily intragranular while the other component (e.g., the basic component) is primarily extragranular.

[0162] In some examples, the relative proportions of acid and base in the intragranular and extragranular fractions may be adjusted to control the rate and extent of gas generation upon exposure to aqueous fluid.

[0163] As used herein, the term "intragranular" refers to components that are incorporated into a granulated fraction prior to final blending and compression, such that the components are contained within granules formed during a granulation process before formation of the final solid gas-generating unit. The granulation process may comprise dry granulation, including roller compaction (e.g., ribbon formation followed by milling) or slugging (e.g., formation of large compacts followed by milling), wet granulation, or combinations thereof. Granulation may be used to increase particle density, improve flowability, and enhance compressibility prior to final tableting.

[0164] As used herein, the term “extragranular” refers to components that are added after formation of the granulated (intragranular) fraction and blended externally with the granules prior to final compression, such that the components are not incorporated within the interior of the granules but are distributed between or around the granules.

[0165] Due to their spatial localization within or outside the granules, intragranular and extragranular components may exhibit different accessibility to aqueous fluid upon exposure, thereby influencing gas-generation kinetics.

[0166] In some examples, the reactants are maintained in physical separation within the enclosure prior to exposure to fluid, for example in separate compartments or by means of coatings or barriers. Upon fluid ingress, dissolution of the separating barrier or diffusion of fluid enables the components to react and generate gas.

[0167] In some examples, the first reactant is or comprises an acid.In some examples, the first reactant is or comprises a weak acid.

[0168] As used herein, a "weak acid" refers to an acid that only partially dissociates in aqueous solution under standard conditions. Specifically, a weak acid is an acid that only partially dissociates (ionizes) in water, establishing an equilibrium between the undissociated acid and its ions (i.e., it has a finite acid dissociation constant (Ka) and typically a pKa greater than about 0, often in the range of -3-10 depending on the compound and definition used). As a result, at a given concentration, a weak acid produces fewer hydrogen ions (H+) than a strong acid, which (by contrast) dissociates essentially completely.

[0169] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises an acid component in an amount of between about 10% and about 80% by weight of the total composition.

[0170] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises an acid component in an amount of between about 10% and about 60% by weight of the total composition.

[0171] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises an acid component in an amount of between about 10% and about 50% by weight of the total composition.

[0172] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises an acid component in an amount of between about 20% and about 50% by weight of the total composition.

[0173] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises an acid component in an amount of between about 25% and about 50% by weight of the total composition.

[0174] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises an acid component in an amount of between about 25% and about 40% by weight of the total composition.

[0175] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises an acid component in an amount of between about 30% and about 40% by weight of the total composition.In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises an acid component in an amount of between about 30% and about 35% by weight of the total composition.

[0176] The stated weight percentages of the acid component refer to the total amount of acid present in the respective composition, including any portions distributed between intragranular and extragranular fractions. In examples in which the acid component is present in both intragranular and extragranular fractions, the recited percentage may represent the combined total of the acid across such fractions. In examples in which the acid component is present primarily or exclusively in only one of the intragranular or extragranular fractions, the recited percentage may correspond to the amount present in that fraction.

[0177] In some examples, the first reactant comprises one or more acids capable of participating in an effervescent reaction with a carbonate or bicarbonate to generate gas upon exposure to an aqueous fluid.

[0178] In some examples, the first reactant may be present as the free acid or as a pharmaceutically acceptable derivative.

[0179] In some examples, the first reactant is encapsulated, coated, granulated, or otherwise processed to modify dissolution and / or reaction kinetics and thereby adjust an initial burst release and / or an extended-release profile of gas generation.

[0180] In some examples, the first reactant is or comprises one or more acids selected from succinic acid, tartaric acid, adipic acid, acetic acid, lactic acid, citric acid, fumaric acid, malic acid, gluconic acid, glucono-delta-lactone, ascorbic acid, aspartic acid, glutamic acid, phosphoric acid, carbonic acid, benzoic acid, sorbic acid, and combinations thereof.

[0181] In some examples, the first reactant is one or more of a succinic acid, a tartaric acid, an adipic acid, an acetic acid, a lactic acid, a citric acid and combination thereof.

[0182] In some examples, the first reactant is present in an anhydrous form, a hydrated form, a crystalline form, an amorphous form, or combinations thereof.

[0183] In some examples, the first reactant is citric acid.In some examples, the citric acid may be provided in in anhydrous form, monohydrate form, or in coated, surface-treated, or modified forms thereof.

[0184] In some examples, the citric acid is provided as citrcoat N.

[0185] In some examples, the citric acid is anhydrous citric acid. In some examples, the citric acid is citric acid monohydrate.

[0186] In some examples, the first reactant is present in a salt form of the acid. In some examples, the salt is a pharmaceutically acceptable salt.

[0187] In some examples, the salt comprises a counterion selected from sodium, potassium, calcium, magnesium, ammonium, tromethamine, meglumine, lysine, arginine, choline, and combinations thereof.

[0188] In some examples, the salt is sodium, magnesium, or calcium.

[0189] In some examples, the second reactant is or comprises a base. In some examples, the second reactant is or comprises a base component.

[0190] In some examples, the second reactant is or comprises a basic salt.

[0191] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises a base component in an amount of between about 10% and about 80% by weight of the total composition.

[0192] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises a base component in an amount of between about 10% and about 60% by weight of the total composition.

[0193] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises a base component in an amount of between about 10% and about 50% by weight of the total composition.

[0194] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises a base component in an amount of between about 20% and about 50% by weight of the total composition.In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises a base component in an amount of between about 25% and about 45% by weight of the total composition.

[0195] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises a base component in an amount of between about 25% and about 40% by weight of the total composition.

[0196] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises a base component in an amount of between about 30% and about 40% by weight of the total composition.

[0197] In some examples, each one of the immediate -release gas-generating composition and the extended-release composition comprises a base component in an amount of between about 30% and about 35% by weight of the total composition.

[0198] The stated weight percentages of the base component refer to the total amount of base present in the respective composition, including any portions distributed between intragranular and extragranular fractions. In examples in which the base component is present in both intragranular and extragranular fractions, the recited percentage may represent the combined total amount of base across such fractions. In examples in which the base component is present primarily or exclusively in only one of the intragranular or extragranular fractions, the recited percentage may correspond to the amount present in that fraction.

[0199] The base component present in the intragranular fraction may be chemically identical to or different from the base component present in the extragranular fraction. A first portion of a base component may be incorporated into the intragranular fraction, and a second portion of the same or a different base component may be incorporated into the extragranular fraction, thereby modulating gas-generation kinetics.

[0200] As used herein, a "basic salt" refers to a salt that exhibits alkaline behaviour in the presence of water, including by producing a solution having a pH greater than 7 and / or by neutralizing an acid reactant.In some examples, the second reactant is selected such that, upon reaction with the first reactant, a gas is generated. In some examples, the gas comprises carbon dioxide (CO2).

[0201] In some examples, the second reactant is or comprises a carbonate and / or bicarbonate salt.

[0202] In some examples, the carbonate salt is one or more of an alkali metal carbonate, an alkaline earth metal carbonate, and an alkaline earth metal bicarbonate.

[0203] In some examples, the carbonate and / or bicarbonate salt comprises one or more of an alkali metal carbonate, an alkali metal bicarbonate, an alkaline earth metal carbonate, ammonium carbonate, ammonium bicarbonate, sodium sesquicarbonate or combinations thereof.

[0204] In some examples, the carbonate and / or bicarbonate salt comprises one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, ammonium bicarbonate, sodium sesquicarbonate, or combinations thereof.

[0205] In some examples, the carbonate salt is one or more of a sodium carbonate, a potassium carbonate, a sodium bicarbonate, a potassium bicarbonate, a calcium carbonate, or any combinations thereof.

[0206] In some examples, the carbonate or bicarbonate component may be provided as a compressible excipient such as EfferSoda®.

[0207] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, and a base component in an amount of between about 10% and about 80% by weight of the total composition.

[0208] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, and a base component in an amount of between about 10% and about 60% by weight of the total composition.In some examples, each one of the immediate -release gas-generating composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 50%, and a base component in an amount of between about 10% and about 50% by weight of the total composition.

[0209] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, and a base component in an amount of between about 20% and about 50% by weight of the total composition.

[0210] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 25% and about 45%, and a base component in an amount of between about 25% and about 45% by weight of the total composition.

[0211] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 25% and about 40%, and a base component in an amount of between about 25% and about 40% by weight of the total composition.

[0212] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, and a base component in an amount of between about 30% and about 40% by weight of the total composition.

[0213] The stated weight percentages of the acid component and the base component refer to the total amounts present in each one of the immediate -release gas-generating composition and the extended-release gas-generating composition, including any portions distributed between intragranular and extragranular fractions. In embodiments in which the acid and / or base components are present in both intragranular and extragranular fractions, the recited percentages may represent the combined total amounts across such fractions. In embodiments in which the acid or base component is present primarily or exclusively in only one of the intragranular or extragranular fractions, the recited percentage may correspond to the amount present in that fraction.The acid component present in the intragranular fraction may be chemically identical to or different from the acid component present in the extragranular fraction in each one of the immediate -release gas-generating composition and the extended-release gas-generating composition. Likewise, the base component present in the intragranular fraction may be chemically identical to or different from the base component present in the extragranular fraction.

[0214] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas -generating composition comprises citric acid anhydrous in an amount of between about 10% and about 80%, and sodium bicarbonate in an amount of between about 10% and about 80% by weight of the total composition.

[0215] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas -generating composition comprises citric acid anhydrous in an amount of between about 10% and about 60%, and sodium bicarbonate in an amount of between about 10% and about 60% by weight of the total composition.

[0216] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas -generating composition comprises citric acid anhydrous in an amount of between about 10% and about 50%, and sodium bicarbonate in an amount of between about 10% and about 50% by weight of the total composition.

[0217] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas -generating composition comprises citric acid anhydrous in an amount of between about 20% and about 50%, and sodium bicarbonate in an amount of between about 20% and about 50% by weight of the total composition.

[0218] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 25% and about 45%, and a base component in an amount of between about 25% and about 45% by weight of the total composition.

[0219] In some examples, each one of the immediate -release gas-generating composition and the extended-release gas -generating composition comprises citric acid anhydrous in an amount of between about 25% and about 40%, and sodium bicarbonate in an amount of between about 25% and about 40% by weight of the total composition.As described herein, the extended-release gas-generating composition comprises at least one extended-release component.

[0220] As used herein, an "extended-release component" refers to a component that retards and / or controls the rate of gas generation and / or gas release.

[0221] The extended-release component may retard gas generation by any suitable mechanism, including matrix formation, viscosity increase, reduced water mobility, diffusion limitation, coating-based delay, or combinations thereof.

[0222] In some examples, the extended-release component may retard gas generation by matrix formation. In some examples, the extended-release component may retard gas generation by viscosity increase. In some examples, the extended-release component may retard gas generation by reducing water mobility. In some examples, the extended-release component may retard gas generation by limiting diffusion. In some examples, the extended-release component may retard gas generation by delaying coating-based.

[0223] In some examples, the extended-release component forms a gel-like matrix when hydrated, which slows the diffusion of the reactants and controls the rate of gas generation. As described herein, this controlled release may allow for sustained gas generation over an extended period, complementing the initial rapid gas generation from the immediate-release gas-generating layer.

[0224] In some examples, the extended-release component may be incorporated into the intragranular fraction, the extragranular fraction, or both.

[0225] In some examples, the extended-release component is incorporated into the intragranular fraction of the gas-generating composition. In some examples, the extended-release component is incorporated into the extragranular fraction of the gas-generating composition. As described herein, upon exposure to an aqueous environment, the component hydrates and forms a gel layer that modulates water ingress and diffusion of reactants, thereby extending the duration of gas generation.

[0226] It should be noted that the retardation / control is relative to the immediate-release composition. Such retardation may occur by modulating water mobility within the composition, delaying activation of the acid-base reaction, limiting water penetration, controlling dissolution or diffusion of reactive components, forming a hydrated matrix,altering erosion characteristics, or combinations thereof, thereby extending carbon dioxide generation over time.

[0227] In some examples, the extended-release component is configured to retard activation of the gas-generating reactants upon exposure to an aqueous environment, including by delaying interaction between reactive components, thereby extending carbon dioxide generation over time

[0228] The amount of the extended release component may be adjusted based on tablet size, geometry, and desired release kinetics.

[0229] In some examples, the extended-release gas-generating composition comprises between about 1% and about 30% of the extended release component out of total weight of the extended-release composition.

[0230] In some examples, the extended-release gas-generating composition comprises between about 1% and about 20% of the extended release component out of total weight of the extended-release composition.

[0231] In some examples, the extended-release gas-generating composition comprises between about 1% and about 15% of the extended release component out of total weight of the extended-release composition.

[0232] In some examples, the extended-release gas-generating composition comprises between about 3% and about 12% of the extended release component out of total weight of the extended-release composition.

[0233] In some examples, the extended-release gas-generating composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% of the extended release component out of the total weight of the extended-release composition.

[0234] In some examples, the extended-release gas-generating composition comprises about 3% of the extended release component out of the total weight of the extended-release composition.In some examples, the extended-release gas-generating composition comprises about 6% of the extended release component out of the total weight of the extended-release composition.

[0235] In some examples, the extended-release gas-generating composition comprises about 9% of the extended release component out of the total weight of the extended-release composition.

[0236] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0237] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and an extended-release component in an amount of between about 3% and about 12% by weight of the total composition.

[0238] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0239] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and an extended-release component in an amount of between about 3% and about 12% by weight of the total composition.

[0240] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0241] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and an extended-release component in an amount of between about 3% and about 12% by weight of the total composition.In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 25% and about 45%, a base component in an amount of between about 25% and about 45% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0242] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 25% and about 45%, a base component in an amount of between about 25% and about 45% and an extended-release component in an amount of between about 3% and about 12% by weight of the total composition.

[0243] In some examples, the extended-release gas-generating composition comprises between about 30% and about 45% citric acid anhydrous, between about 30% and about 45% sodium bicarbonate and between about 1% and about 15% extended-release component, by weight of the total composition.

[0244] In some examples, the extended-release gas-generating composition comprises between about 30% and about 45% citric acid anhydrous, between about 30% and about 45% sodium bicarbonate and between about 3% and about 10% extended-release component, by weight of the total composition.

[0245] In some examples, the extended-release gas-generating composition comprises between about 30% and about 45% citric acid anhydrous, between about 30% and about 45% sodium bicarbonate and between about 5% and about 10% extended-release component, by weight of the total composition.

[0246] In some examples, reactive components of the gas-generating composition, such as an acid component and a carbonate or bicarbonate component, are maintained in physical separation within the enclosure prior to exposure to an aqueous environment, for example in separate compartments or by means of coatings or barriers. Upon aqueous ingress, dissolution of the separating barrier or diffusion of fluid enables the components to react and generate gas.

[0247] In some examples, the extended-release component comprises one or more polymers, polysaccharides, waxes, lipids, coating agents, encapsulants, or combinations thereof.In some examples, the extended-release component comprises one or more hydrophilic film-forming or matrix-forming polymers capable of increasing viscosity and / or forming a hydrated gel structure upon exposure to an aqueous environment.

[0248] Such polymers may modulate water mobility within the composition, delay interaction between reactive components, and thereby control the rate of gas generation.

[0249] In some examples, the extended-release component comprises one or more releasemodulating polymers selected from hydrophilic matrix-forming polymers, natural polysaccharides, and hydrophobic release-retarding materials.

[0250] In some examples, the hydrophilic polymer is or comprises povidone, copovidone, polyvinyl alcohol, hydrophilic polyacrylamide derivatives, proteins, gelatin, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose and sodium carboxymethylcellulose (NaCMC), polyethylene oxide (PEO), alginate, carrageenan, chitosan, starch, xanthan gum, amino-methacrylate copolymers, polyvinyl alcohol-polyethylene glycol graft copolymers, and combinations thereof.

[0251] In some examples, the extended-release component is or comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene oxide (PEO), and carboxymethylcellulose sodium (NaCMC), one or more natural polysaccharides selected from xanthan gum, guar gum, alginate, and pectin, one or more hydrophobic releaseretarding materials selected from ethylcellulose and waxes, or combinations thereof.

[0252] In some examples, the extended-release component may be selected from a group consisting of acetan, dextran, alginate, hyaluronic acid, pullulan, xanthan gum, gellan gum, levan, curdlan, cellulose, chitosan, mauran, and schizophyllan.

[0253] In some examples, the extended-release component is xanthan gum or a derivative thereof.

[0254] As used herein, "xanthan gum derivatives” include chemically modified forms of xanthan gum that retain the ability to absorb water and form a hydrated matrix, including crosslinked, partially depolymerized, acetylated, or otherwise substituted xanthan materials.

[0255] In some examples, the extended-release component is or comprises xanthan gum.Xanthan gum is a hydrophilic, high-molecular-weight polysaccharide capable of forming a hydrated gel network upon exposure to moisture. Upon contact with an aqueous environment, xanthan gum absorbs water and undergoes polymer chain relaxation, resulting in rapid gel formation and increased local viscosity within the composition.

[0256] In certain embodiments, xanthan gum functions to modulate water mobility within the gas-generating composition. Without being bound by theory, upon exposure to moisture the polymer chains begin to relax as they adsorb water molecules. This hydration process may involve diffusion of water into the polymer network and formation of a viscous or gel-like matrix that regulates water penetration into the reactive regions of the composition, delays interaction between the reactants, spatially separates reactive domains, and mitigates rapid initial gas generation (“burst effect”).

[0257] In some embodiments, xanthan gum exhibits a critical relative humidity threshold at which moisture uptake increases significantly. At room temperature, this threshold may occur at approximately 60-70% relative humidity. Below approximately 50% RH, xanthan gum may remain relatively stable as a dry powder. Above approximately 65% RH, polymer chain relaxation and capillary condensation within tablet pores may occur, accelerating moisture absorption and initiating gel formation.

[0258] Upon hydration, xanthan gum may form a three-dimensional hydrogel-like network. Swelling of the polymer involves diffusion of water and relaxation of polymer chains, resulting in controlled water distribution within the composition. The swelling behavior and kinetics may be influenced by polymer concentration, network density, and spatial configuration within the enclosure.

[0259] In some embodiments, xanthan gum is present in an amount sufficient to form a continuous hydrated matrix within the extended-release composition. In some examples, the xanthan gum is present in an amount sufficient to form a continuous hydrated matrix within the extended-release composition to extend gas generation relative to an immediate-release formulation lacking the polymer. Xanthan gum content may be adjusted based on tablet size, geometry, and desired release kinetics.In some examples, the extended-release gas-generating composition comprises xanthan gum in an amount of between about 1% and about 15% of the total weight of the extended-release composition, including each value within the specified range.

[0260] In some examples, the extended-release gas-generating composition comprises xanthan gum in an amount of about 1% to about 12% of the total weight of the extended-release composition.

[0261] In some examples, the extended-release gas-generating composition comprises xanthan gum in an amount of about 3% to about 12% of the total weight of the extended-release composition.

[0262] In some examples, the xanthan gum may be present in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% of the total weight of the extended-release composition.

[0263] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and xanthan gum in an amount of between about 1% and about 15% by weight of the total composition.

[0264] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and xanthan gum in an amount of between about 3% and about 12% by weight of the total composition.

[0265] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and xanthan gum in an amount of between about 1% and about 15% by weight of the total composition.

[0266] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and xanthan gum in an amount of between about 3% and about 12% by weight of the total composition.In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and xanthan gum in an amount of between about 1% and about 15% by weight of the total composition.

[0267] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and xanthan gum in an amount of between about 3% and about 12% by weight of the total composition.

[0268] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and xanthan gum in an amount of between about 1% and about 15% by weight of the total composition.

[0269] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and xanthan gum in an amount of between about 3% and about 12% by weight of the total composition.

[0270] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, a base component in an amount of between about 30% and about 40% and xanthan gum in an amount of between about 1% and about 15% by weight of the total composition.

[0271] In some examples, the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, a base component in an amount of between about 30% and about 40% and xanthan gum in an amount of between about 3% and about 12% by weight of the total composition.

[0272] In some examples, the extended-release gas-generating composition comprises between about 30% and about 45% citric acid anhydrous, between about 30% and about 45% sodium bicarbonate and between about 1% and about 15% xanthan gum, by weight of the total composition.

[0273] In some examples, the extended-release gas-generating composition comprises between about 30% and about 45% citric acid anhydrous, between about 30% and about45% sodium bicarbonate and between about 3% and about 12% xanthan gum by weight of the total composition.

[0274] In some examples, the extended-release gas-generating composition comprises between about 30% and about 45% citric acid anhydrous, between about 30% and about 45% sodium bicarbonate and between about 5% and about 12% xanthan gum, by weight of the total composition.

[0275] In some examples, the extended-release gas-generating composition comprises about 30% to 45% citric acid anhydrous, about 30% to 45% sodium bicarbonate, about 3% to 12% xanthan gum, by weight of the total composition.

[0276] In addition to the first and second reactants, the immediate-release gas-generating composition may include other components such as excipients, fillers, binders, and lubricants. A filler may be included to provide bulk and improve compressibility. In some examples, the filler is present in an amount of about 10% to about 35% by weight of the composition.

[0277] In some examples, the filler is an alpha-lactose-monohydrate. In some examples, the filler is Starlac®. Starlac®, a co-processed excipient comprising corn starch and lactose.

[0278] In some examples the excipient s added to allow flowability. In some examples, the excipient is silicon dioxide.

[0279] A lubricant may be added to reduce friction during compression and ejection. In some examples, the lubricant is one or more of stearic acid, polyethylene glycol, glycerol derivatives or stearates, such as magnesium stearate or sodium stearyl fumarate, L-leucine, SLS, calcium stearate, sucrose fatty acid esters, and talc. In certain examples, magnesium stearate is used as a lubricant in an amount of about 0.1% to about 0.25%, 0.03% to about 0.2%, or 0.05% to about 0.15%, by weight of the composition.

[0280] The combination of immediate -release and extended-release compositions in the controlled gas release system resulted in a controlled gas release profile that may be advantageous for applications requiring both rapid initial inflation and sustained pressure maintenance.

[0281] In some examples, the immediate -release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, and a base componentin an amount of between about 10% and about 80% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0282] In some examples, the immediate -release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, and a base component in an amount of between about 10% and about 60% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0283] In some examples, the immediate -release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, and a base component in an amount of between about 20% and about 50% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0284] In some examples, the immediate -release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0285] In some examples, the immediate -release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of betweenabout 30% and about 45% and an extended-release component in an amount of between about 3% and about 12% by weight of the total composition.

[0286] In some examples, the immediate -release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, and a base component in an amount of between about 30% and about 40% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, a base component in an amount of between about 30% and about 40% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0287] In the immediate -release layer, a quick initial burst of gas generation. The extended-release layer, containing the extended-release component such as xanthan gum, provides a more controlled and sustained gas generation over time. As the extended-release layer hydrates, it forms a gel-like matrix that slows the diffusion of the reactants, resulting in a prolonged gas generation profile.

[0288] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, and a base component in an amount of between about 10% and about 80% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and an extended-release component in an amount of between about 1 % and about 15% by weight of the total composition.

[0289] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, and a base component in an amountof between about 10% and about 60% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and an extended-release component in an amount of between about 1 % and about 15% by weight of the total composition.

[0290] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, and a base component in an amount of between about 20% and about 50% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and an extended-release component in an amount of between about 1 % and about 15% by weight of the total composition.

[0291] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition.

[0292] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU andwherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 3% and about 12% by weight of the total composition.

[0293] In such aspects, the extended-release component is xanthan gum.

[0294] The gas-generating composition housed within the enclosure may be provided in various physical configurations and structural arrangements.

[0295] In some examples, the gas-generating compositions form a single blended gasgenerating composition.

[0296] In some examples, the gas-generating compositions form a heterogeneous monolithic structure in which intermediate release and extended release compositions are dispersed within a single solid body.

[0297] In some examples, at least two distinct gas-generating compositions are provided. In other words, the at least two gas-generating compositions are arranged as at least two distinct gas-generating compositions.

[0298] In some examples, the at least two gas-generating compositions are arranged in a multilayer structure.

[0299] In some examples, the at least two gas-generating compositions are arranged in two or more distinct layers.

[0300] In other examples, the at least two gas-generating compositions are arranged in a bilayer configuration.

[0301] In other examples, the at least two gas-generating compositions are arranged in a layered configuration.

[0302] In other examples, the at least two gas-generating compositions are arranged in a core-shell or zoned configuration.The gas-generating composition, whether provided as a single blended composition or as multiple distinct compositions arranged in any of the structural configurations described herein, may be provided in various solid physical forms. In some examples, the solid physical form is one or more of a mini-tablet, or other compressed or molded solid body.

[0303] The gas-generating composition, whether provided as a single blended composition or as multiple distinct compositions arranged in any of the structural configurations described herein, may be provided in various solid physical forms.

[0304] In other examples, at least two gas-generating compositions are arranged within a solid gas-generating unit.

[0305] In other examples, at least two gas-generating compositions are arranged within a semi-solid gas-generating unit.

[0306] In some examples, the gas-generating composition is provided as a tablet or minitablet.

[0307] In other examples, the composition may be provided as a compressed or molded solid body of suitable size and geometry for placement within the enclosure.

[0308] In some examples, the composition is provided as a tablet or mini-tablet.

[0309] In other examples, the composition may be provided as one or more compressed or molded solid bodies of suitable size and geometry for placement within the enclosure.

[0310] In further examples, the composition may be provided in particulate form, including granules, pellets, beads, spheroids, coated particles, or multiparticulate blends, optionally retained within the enclosure.

[0311] In still further examples, the composition may be provided as a powder, molded compact, extrudate, porous body, plug, wafer, film, disc, capsule fill, or combinations thereof.

[0312] In some examples, the gas-generating composition is provided as one or more discrete solid units, such as tablets or mini-tablets.

[0313] In some examples, the gas-generating composition may be provided as a discrete solid unit.In some examples, the gas-generating composition may be provided as a tablet. In some examples, the gas-generating composition may be provided as a mini-tablet. In some examples, the gas-generating composition may be provided as a plurality of particulate units.

[0314] In some examples, the gas-generating composition may be provided as granules, pellets, beads, or coated particles, optionally retained within the enclosure.

[0315] The gas release profile of the solid unit dose, such as a bilayer tablet, may be characterized by pressure measurements over time. In some cases, the gas-generating system may be fluidly connected to an auxiliary inflatable member via a gas passageway. The pressure within this auxiliary inflatable member may be measured to determine the gas release profile.

[0316] The gas-generating system may be configured to provide a gas release profile that reaches maximum pressure within about 10-15 minutes and extends for more than 60 minutes. This profile combines the rapid initial gas generation from the immediate-release layer with the sustained gas generation from the extended-release layer.

[0317] In some examples, the controlled gas release system may exhibit the following gas release profile when measured in a pressure -resistant model:

[0318] 1. 0-5 minutes: Rapid increase in pressure due to the immediate-release layer

[0319] 2. 5-15 minutes: Continued pressure increase, reaching maximum pressure

[0320] 3. 15-60+ minutes: Sustained pressure with gradual decline due to the extended-release layer

[0321] The specific gas release profile may vary depending on the composition and configuration of the bilayer tablet. Factors that may influence the gas release profile include:

[0322] 1. Ratio of immediate -release to extended-release layers

[0323] 2. Type and amount of acid and base used

[0324] 3. Type and amount of extended-release component

[0325] 4. Total weight of the bilayer tablet5. Tablet layer porosivity

[0326] 6. Membrane water absorption and %RH

[0327] 7. Contact between tablet and membrane

[0328] Various arrangements of the immediate-release and extended-release layers within the bilayer tablet are possible such as side-by-side, stacked, or matrix arrangements. In some implementations, the gas release profile may be tailored for specific applications by adjusting the composition and configuration of the bilayer tablet. For instance, a higher proportion of the immediate-release layer may result in a more rapid initial gas generation, while a greater amount of extended-release component may prolong the duration of gas generation.

[0329] Figure 1A shows a sectional view of an exemplary controlled gas release system 100 comprising an enclosure 106 defined by a wall 118. The enclosure 106 contains a gas release tablet 108 and further comprises a gas passage 116 configured to provide fluid communication between an interior of enclosure 106 and an exterior environment.

[0330] As described herein, the exterior environment may be ambient air, a closed container volume, a headspace of a package, or another surrounding atmosphere or environment in fluid communication with the gas passage 116.

[0331] In some examples, the system 100 may comprise more than one enclosure.

[0332] In some examples, the system 100 comprises two gas-generating compositions. Figure IB shows a sectional view of an exemplary controlled gas release system 100 comprising an enclosure 106 defined by a wall 118. The enclosure 106 comprises two different gas release tablets 108a and 108b and further comprises a gas passage 116 configured to provide fluid communication between an interior of enclosure 106 and an exterior environment.

[0333] As described herein, the exterior environment may be ambient air, a closed container volume, a headspace of a package, or another surrounding atmosphere or environment in fluid communication with the gas passage 116.

[0334] The selected physical configuration may be optimized to balance surface area, membrane contact, and internal void volume within the enclosure.In some examples, spatial arrangement of discrete units of the gas-generating composition within the enclosure is designed to promote controlled and reproducible contact between the composition and the water-transferable enclosure wall, thereby enabling predictable hydration kinetics and gas evolution dynamics over time. Parameters such as unit size, number of units, packing density, and positioning relative to the enclosure wall may be adjusted to achieve a desired pressure-time profile.

[0335] These configurations represent alternative structural implementations of the gasgenerating composition within the enclosure. The selected configuration including orientation, porosity, spatial distribution, and contact with the enclosure wall may influence water access to the reactive components, gas evolution dynamics, and the resulting pressure -time profile, in combination with the permeability characteristics of the enclosure.

[0336] In some embodiments, the enclosure may contain a mixture of immediate-release tablets and extended-release tablets distributed within the enclosure.

[0337] In certain embodiments, the gas-generating composition is provided in the form of multiple mini-tablets housed within the enclosure. In certain embodiments, multiple minitablets are housed within the enclosure with spacing there between, creating internal void volume. Such spacing may influence the distribution of water upon ingress, local activation timing, and composite gas generation behavior.

[0338] Figure 6 is a bar graph showing hardness measurements (in Newtons) for different oval gas-generating tablet configurations. The y-axis represents hardness in Newtons, ranging from 0 to approximately 16 N. The x-axis presents three tablet configurations: immediate-release, extended -release comprising 3% xanthan gum (3% XG), and bilayer tablets comprising a 50:50 IR:ER configuration with 3% xanthan gum (BL 50:503% XG).

[0339] The IR tablets exhibit average hardness values of approximately 11-12 N. The extended-release 3% XG tablets exhibit slightly higher hardness values of approximately 12-13 N. The bilayer (50:50) tablets exhibit lower hardness values of approximately 9-10 N, indicating a modest reduction in mechanical strength relative to the monolithic immediate-release and extended-release tablets.

[0340] In some embodiments, the enclosure may contain a mixture of immediate-release tablets and extended-release tablets distributed within the enclosure.The tablet or the minitablet may have different shapes selected based on several factors such as ease of manufacture, stability, dissolution properties, and suitability for the intended application. These formats may facilitate the precise delivery and containment of the compositions within the enclosure, potentially ensuring consistent performance and stability during storage.

[0341] In some examples, the tablet or the minitablet has one or more of an oval shape, a round shape, an oblong shape, a diamond shape, a triangle shape, a square shape, a rectangle shape, a teardrop shape, a heart-shaped shape, a hexagonal shape, an octagonal shape, a crescent shape, or a torus-shape.

[0342] The tablet or the minitablet may have different weights or size to facilitate the containment of the compositions within the enclosure, and controlled release of gas at the desired rate while ensuring consistent performance.

[0343] In some examples, the compositions are in the form of minitablets having a weight of between about 20 mg and about 40 mg.

[0344] In some examples, the compositions are in the form of minitablets having a weight of about 30 mg.

[0345] In some examples, the compositions are in the form of tablets having a weight of between about 60 mg and about 90 mg. In some examples, the compositions are in the form of tablet having a weight of between about 65 mg and about 90 mg. In some examples, the compositions are in the form of tablets having a weight of between about 70 mg and about 90 mg. In some examples, the compositions are in the form of tablets having a weight of between about 70 mg and about 85 mg. In some examples, the compositions are in the form of tablets having a weight of between about 70 mg and about 80 mg.

[0346] In some examples, the compositions are in the form of oval tablets having a weight of between about 60 mg and about 90 mg. In some examples, the compositions are in the form of oval tablet having a weight of between about 65 mg and about 90 mg. In some examples, the compositions are in the form of oval tablets having a weight of between about 70 mg and about 90 mg. In some examples, the compositions are in the form of oval tablets having a weight of between about 70 mg and about 85 mg. In some examples, thecompositions are in the form of oval tablets having a weight of between about 70 mg and about 80 mg.

[0347] In some examples, the compositions are in the form of oval tablet having a weight of between about 72 mg and about 79 mg.

[0348] In some examples, the compositions are in the form of round tablet. In some examples, the compositions are in the form of round tablet having a weight of between about 50 mg and about 150 mg. In some examples, the compositions are in the form of round tablet having a weight of between about 80 mg and about 120 mg.

[0349] In some examples, the compositions are in the form of round tablet having a weight of about 50 mg. In some examples, the compositions are in the form of round tablet having a weight of about 80 mg. In some examples, the compositions are in the form of round tablet having a weight of about 100 mg.

[0350] In some examples, the compositions are in the form of round tablet having a diameter of between about 3 mm and about 10 mm. In some examples, the compositions are in the form of round tablet having a diameter of between about 4 mm and about 8 mm. In some examples, the compositions are in the form of round tablet having a diameter of about 3 mm. In some examples, the compositions are in the form of round tablet having a diameter of about 5 mm. In some examples, the compositions are in the form of round tablet having a diameter of about 6 mm. In some examples, the compositions are in the form of round tablet having a diameter of about 8 mm.

[0351] In certain embodiments, the gas-generating composition is provided in the form of bilayer tablet.

[0352] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, and a base component in an amount of between about 10% and about 80% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of betweenabout 10% and about 80%, a base component in an amount of between about 10% and about 80% and an extended-release component in an amount of between about 1 % and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition, and the at least one extended-release gas-generating composition are in the form of tablet.

[0353] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, and a base component in an amount of between about 10% and about 60% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and an extended-release component in an amount of between about 1 % and about 15% by weight of the total composition, and wherein the at least one immediate-release gas-generating composition, and the at least one extended-release gas-generating composition are in the form of tablet.

[0354] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, and a base component in an amount of between about 20% and about 50% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and an extended-release component in an amount of between about 1 % and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition, and the at least one extended-release gas-generating composition are in the form of tablet.In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition, and the at least one extended-release gas-generating composition are in the form of tablet.

[0355] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 3% and about 12% by weight of the total composition and wherein the at least one immediate-release gas-generating composition, and the at least one extended-release gas-generating composition are in the form of tablet.

[0356] In some aspects which may be considered as embodiments of the disclosure, a controlled release system comprises at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gas-generating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate -release gas-generating composition comprises an acid componentin an amount of between about 30% and about 40%, and a base component in an amount of between about 30% and about 40% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, a base component in an amount of between about 30% and about 40% and an extended-release component in an amount of between about 1 % and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition, and the at least one extended-release gas-generating composition are in the form of tablet.

[0357] In such aspects, the extended-release component is xanthan gum. In such aspects, the tablet may be a bilayer tablet.

[0358] In another aspect, the present disclosure provides a controlled-release gas-generating bilayer tablet configured for controlled generation of gas. The bilayer tablet comprises two layers, including an immediate-release gas-generating layer and an extended-release gasgenerating layer.

[0359] In operation, namely in the wetted condition, the immediate-release layer is configured to generate gas relatively rapidly, and the extended-release layer is configured to generate gas over a longer period of time, thereby providing a gas-generation profile that is controlled over time.

[0360] The specific configuration of the layers may be selected based on the desired gas generation profile and manufacturing considerations. For example, a side-by-side arrangement may provide a more rapid initial gas generation, while a core-shell structure with the extended-release layer surrounding the immediate -release gas-generating layer may result in a more gradual onset of gas generation.

[0361] The bilayer tablet configuration may be optimized to achieve the desired balance between immediate gas generation and sustained release over time. Factors such as layer thickness, composition, and arrangement may be adjusted to tailor the gas generation profile for specific applications.

[0362] In some examples, the layers may be separate and arranged side-by-side.In some examples, the layers may be stacked one on top of the other. In some examples, the extended-release gas-generating layer may be the first layer and the immediate-release layer may be on top of the first layer.

[0363] In some examples, one layer of the two layers may surround the other, creating a core-shell structure.

[0364] In some examples, one layer is placed between two portions of the other layer ("sandwich").

[0365] In some examples, one layer may be dispersed as small portions within the other layer ("a matrix -type structure").

[0366] The bilayer tablet is housed within an enclosure as described herein.

[0367] The controlled gas release system and components described herein employ pharmaceutically acceptable components. As used herein, the term "pharmaceutically acceptable components" may refer to substances that are approved by regulatory agencies for use in pharmaceutical compositions, are generally recognized as safe for human consumption, and are compatible with the other ingredients in the composition. This may include components that are disintegrable and / or absorbable within the gastrointestinal tract and / or capable of passing through the gastrointestinal system without causing harm or undue side effects. In some examples, pharmaceutically acceptable components may comply with guidelines set forth by regulatory bodies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). These components may include, but are not limited to, excipients, binders, disintegrants, lubricants, and other additives that meet established safety and efficacy standards for pharmaceutical use.

[0368] In some examples, the system may further comprise an outer coating. The outer coating may be configured to modulate exposure of the enclosure to physiological fluids.

[0369] In some examples, the outer coating is configured to prevent exposure of the enclosure and gas-generating compositions to gastric contents during gastric transit. In such examples, the enclosure and associated gas-generating components are fully encapsulated while in the stomach, thereby preventing premature hydration and gas generation.The encapsulating material may comprise an enteric coating or an enteric capsule that remains substantially intact under gastric pH conditions and dissolves upon reaching the higher pH environment of the small intestine. Dissolution of the enteric material exposes the enclosure to intestinal luminal fluid, thereby permitting controlled water ingress and activation of the gas-generating composition.

[0370] In another aspect, the present disclosure provides an enteric capsule comprising a controlled gas release system as described herein.

[0371] In a further aspect, the present disclosure provides an enteric capsule comprising a controlled gas release system, the controlled gas release system including an enclosure and a bilayer gas-generating tablet disposed within the enclosure, wherein the bilayer gasgenerating tablet comprises an immediate-release gas-generating layer and an extended-release gas-generating layer.

[0372] The enteric capsule, when present, functions as an outer delivery vehicle and is distinct from the enclosure that regulates water ingress and gas retention.

[0373] It should be noted that in some examples, the tablet, such as the bilayer tablet, does not include an active pharmaceutical ingredient. It should be further noted that the tablet is designed specifically for controlling gas generation through the interaction of its components when exposed to certain conditions, such as aqueous environment.

[0374] The combination of immediate -release and extended-release layers in a single bilayer tablet, along with the optional enclosure and enteric capsule, provides a system for generating gas in a controlled manner over time. This gas generation may be useful for various applications where controlled gas release is desired, as is the case for oral inflatable patched for delivery of biologies in solid needles to intestinal tissue.

[0375] The immediate -release gas-generating layer comprises a first reactant and a second reactant which generate gas upon exposure to aqueous environment. In some examples, the first reactant may be an acid selected from the group consisting of succinic acid, tartaric acid, adipic acid, and citric acid. The second reactant may be a base, such as sodium bicarbonate.

[0376] In some examples, the immediate -release gas-generating layer may comprise citric acid as the first reactant and sodium bicarbonate / sodium carbonate as the second reactant.These components may be formulated to react rapidly upon membrane exposure to aqueous environment, generating gas quickly.

[0377] The gas-generating system may be configured to provide a gas release profile that reaches maximum pressure within about 10-15 minutes and extends for more than 60 minutes. This profile combines the rapid initial gas generation from the immediate-release layer with the sustained gas generation from the extended-release layer.

[0378] In some examples, the controlled gas release system is configured to generate gas to provide a pressure of at least about 2 psi, at times at least about 3 psi, or at times at least about 3.5 psi as measured in a flat force test.

[0379] In some examples, the system is configured to maintain a pressure of at least about 3.5 psi within about 10-15 minutes following exposure to an aqueous environment and deployment of the system. In some examples, the system is configured to reach a pressure of at least about 3.5 psi for a duration of greater than 60 minutes. It was suggested that this pressure generation capability ensures sufficient and sustained force for various applications of the controlled gas release system.

[0380] This controlled release pattern is shown in the gas release profiles shown in Figure 4, demonstrating that different compositions and / or configurations result in varying gas generation patterns over time. Specifically, Figure 4 illustrates example pressure profiles (psi) over time (sec) generated by different gas-generating compositions: an immediate release (IR) composition (solid line) exhibits a rapid rise to a peak pressure followed by a gradual decline, an extended-release (ER) composition (dotted line) exhibits a delayed rise and a lower initial rate of pressure increase, with pressure being maintained over a longer time period, whereas a combined composition including extended-release and immediate-release components at an ER:IR ratio of about 50:50 (dashed line) exhibits an intermediate profile, providing an initial pressure increase earlier than the ER composition while maintaining pressure longer than the control composition.

[0381] In certain embodiments, the gas-generating composition is provided in the form of multiple discrete elements (e.g., mini-tablets) positioned within the enclosure, such that there may be loose or non-compressive contact between the enclosure membrane and the gas-generating elements and void volume around the elements. In such embodiments,water distribution, hydration kinetics, and gas flow dynamics may differ from a configuration using a single compressed tablet, and the resulting pressure-time profile may reflect the combined influence of composition, ratio, and spatial configuration within the enclosure. In this manner, adjusting the ratio of immediate-release to extended-release components and / or the physical configuration of the gas-generating elements within the enclosure may be used to tailor the initial burst timing and intensity and the duration of pressure maintenance to meet a desired performance requirement.

[0382] Figure 5 illustrates additional example pressure profiles (psi) over time (sec) for gasgenerating compositions formed in an oval geometry. An immediate release composition (solid line) exhibits a rapid rise to a relatively high peak pressure followed by a decline, an extended-release (ER) composition (doted line) exhibits a slower pressure increase and a lower peak pressure, with pressure being generated and maintained over a longer period of time, whereas an ER:IR bilayer oval composition (dash line) provides both a relatively rapid initial pressure increase and prolonged pressure maintenance, exhibiting a pressure profile that differs from either the control or the ER composition alone.

[0383] In some examples, by selecting a bilayer configuration and / or by adjusting the relative amounts of extended release and IR regions, the timing and magnitude of an initial pressure burst and the duration of sustained pressure generation may be tailored for a desired application.

[0384] In accordance with some aspects, the present disclosure provides a process for preparing an immediate-release (IR) gas-generating composition, the process comprising:

[0385] (a) dry blending at least one acid component and at least one basic component to form a first powder mixture; (b) subjecting the first powder mixture to dry granulation by compressing the mixture into slugs or sheets, optionally using roller compaction; (c) milling and / or sizing the slugs or sheets to form intragr anular granules; (d) blending the intragranular granules with an extragranular fraction comprising a second portion of the acid component and / or a second portion of the basic component; and (e) compressing the blended material into a solid gas-generating unit.

[0386] In certain examples, the acid component comprises citric acid and the basic component comprises sodium bicarbonate. In some embodiments, the dry granulation isperformed at a compression force sufficient to form cohesive slugs, which are subsequently milled to a defined particle size prior to final compression.

[0387] In accordance with some aspects, the present disclosure provides a process for preparing an extended-release (ER) gas-generating composition, the process comprising:

[0388] (a) dry blending at least one acid component and at least one basic component to form a first powder mixture; (b) subjecting the first powder mixture to dry granulation by compressing the mixture into slugs or sheets, optionally using roller compaction; (c) milling and / or sizing the slugs or sheets to form intragr anular granules; (d) blending the intragranular granules with an extragranular fraction comprising a second portion of the acid component and / or a second portion of the basic component and a controlled release component; and (e) compressing the blended material into a solid gas-generating unit.

[0389] In certain examples, the controlled release component comprises xanthan gum. In some embodiments, the controlled release component is incorporated primarily into the extragranular fraction to modulate water ingress and extend gas-generation duration.

[0390] The controlled-release gas -generating bilayer tablet generates gas upon exposure to aqueous environment through the reaction between the first reactant (acid) and the second reactant (base) in both the immediate -release and extended-release layers. When the membrane (denoted herein as enclosure or enclosure walls') comes into contact with an aqueous environment and the solid gas-generating unit (e.g., a tablet) is exposed to humidity and / or water, water enters the tablet primarily through its exposed surface and is transported inward via capillary uptake and diffusion through the porous matrix. Dissolution of the acid and base components then occurs within the hydrated regions of the matrix, resulting in generation of carbon dioxide gas.

[0391] Upon administration, the controlled gas release system may be exposed to physiological environments within the body. In some examples, the controlled gas release system may be positioned within a confined physiological space. In some examples, controlled gas release system may be positioned within a localized biological compartment. In some examples, controlled gas release system may be positioned within a tissue pocket. In some examples, controlled gas release system may be positioned within a mucosalcavity. In such configurations, the system may be at least partially encapsulated by surrounding tissue and / or retained within a defined pocket.

[0392] Exposure sufficient to initiate gas generation may occur through contact with bodily fluids, contact with moist biological tissue, and / or exposure to water vapor or localized humidity present in mucus or surrounding tissue.

[0393] In some examples, the controlled gas release system is configured to be in contact with bodily fluids.

[0394] As used herein, the term “bodily fluids” refers to aqueous physiological fluids present within or on the body, including but not limited to saliva, gastric fluid, intestinal fluid, mucus, and other fluid environments associated with moist biological tissues.

[0395] In some examples, bodily fluid is or comprises saliva.

[0396] In some examples, bodily fluid is or comprises gastrointestinal fluid.

[0397] In some examples, bodily fluid is or comprises small intestinal fluid.

[0398] In some examples, bodily fluid is or comprises colonic fluid.

[0399] In some examples, activation occurs upon exposure to intestinal fluid within the lumen of the small intestine. Contact with luminal fluid and / or localized humidity present within the intestinal lumen may be sufficient to initiate gas generation.

[0400] In some examples, the system is configured for activation within the small intestine. Where an enteric coating or capsule is present, the enteric material may remain substantially intact under gastric pH conditions and dissolve upon reaching the higher pH environment of the small intestine, thereby exposing the enclosure to intestinal fluid. Following such exposure, water ingress is regulated by the cooperative interaction of the water-transferable enclosure wall and one or more structural elements of the gas-generating unit, including matrix composition, porosity, and / or layer configuration, thereby initiating hydration of the gas-generating composition.

[0401] Although the system may encounter gastric fluid during transit through the stomach, in some embodiments the enclosure and / or enteric coating are configured such that substantial gas generation and pressure development occur primarily upon exposure tointestinal fluid. This may be particularly advantageous in embodiments configured to inflate, deploy, or press against the intestinal wall.

[0402] The gas generated may comprise carbon dioxide (CO2), produced by reaction of at least one acid component and at least one basic component within the gas-generating composition. CO2 is generally regarded as physiologically acceptable in the quantities generated by the system.

[0403] Upon exposure to intestinal fluid, the hydrophilic enclosure wall (e.g., TPU) absorbs water and undergoes hydration-induced swelling. Water permeates through the enclosure wall and contacts the gas-generating unit housed therein. In embodiments comprising a bilayer gas-generating unit, the immediate-release (IR) layer reacts relatively rapidly upon hydration, generating an initial increase in internal pressure. The extended-release (ER) layer simultaneously begins to hydrate. Where a release-modifying polymer such as xanthan gum is present, the polymer hydrates and forms a gel matrix that modulates water diffusion to the acid and basic components, thereby extending gas generation over time.

[0404] The combination of (i) controlled water ingress through the enclosure wall and (ii) structural differentiation between IR and ER compositions provides a tunable gasgeneration profile characterized by an initial pressure increase followed by sustained gas production. The generated gas may be retained within the enclosure due to the gas-impermeable properties of the enclosure wall. In embodiments including a gas passageway, generated gas may be directed to an inflatable member or other device component.

[0405] The coordinated interaction between the enclosure properties and the spatially organized gas-generating composition enables controlled activation under physiological conditions and permits tailoring of the pressure -time profile by adjusting composition, structural configuration, and enclosure characteristics.

[0406] This controlled and tunable pressure -generation capability provides functional advantages in systems requiring predictable inflation, deployment, or sustained pressurization.

[0407] Hence, the system may be applicable to a variety of applications in which generated gas is used to inflate and / or pressurize an inflatable member, deploy and / or actuate a structure, and / or maintain pressure and / or an inflated configuration for a desired duration.In some examples, such applications include medical devices, pharmaceutical dosage forms, and other deployable or inflatable structures.

[0408] In some examples, the controlled gas release system is operably coupled to an inflatable member.

[0409] In accordance with some aspects, the present disclosure provides an inflatable device comprising an inflatable member and a controlled gas release system in fluid communication with the inflatable member, wherein the controlled gas release system is configured to generate gas upon exposure to an aqueous environment and to direct the generated gas into the inflatable member to cause inflation thereof. The inflatable device may be denoted as times as patch.

[0410] In accordance with some other aspects, the present disclosure provides an inflatable device comprising: (i) an inflatable member; and (ii) a controlled gas release system operably coupled to the inflatable member, the controlled gas release system comprising at least one enclosure having walls that are substantially gas-impermeable and water-transferable and housing at least one gas-generating composition, the enclosure further comprising a gas passageway configured to direct generated gas into the inflatable member, wherein, upon exposure to an aqueous environment, the gas-generating composition generates gas that inflates the inflatable member.

[0411] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, and a base component in an amount of between about 10% and about 80% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition.In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, and a base component in an amount of between about 10% and about 60% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition

[0412] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, and a base component in an amount of between about 20% and about 50% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition.

[0413] Figures 2A-2B illustrate sectional views of an inflatable device in line with some examples.

[0414] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generatingcomposition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition

[0415] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, and a base component in an amount of between about 30% and about 40% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, a base component in an amount of between about 30% and about 40% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate-release gas-generating composition

[0416] Figure 2A shows an inflatable device 200. The device 200 comprises an inflatable member 202 and a controlled gas release system 206 operably coupled thereto. The controlled gas release system 206 is configured to generate gas and to direct the generated gas into the inflatable member 202 to cause inflation thereof.

[0417] In the illustrated embodiment, the controlled gas release system 206 comprises a single enclosure housing at least two gas-generating compositions, shown as a first gasgenerating composition 220 and a second gas-generating composition 222. The first and second gas-generating compositions may correspond, for example, to an immediate-release gas-generating composition and an extended-release gas-generating composition, respectively.

[0418] The enclosure of the controlled gas release system 206 may comprise a wall that is substantially gas-impermeable and water- transfer able, as described herein, and may furthercomprise a gas passageway establishing fluid communication between the interior of the enclosure and the inflatable member 202.

[0419] Upon exposure to an aqueous environment, the gas-generating compositions 220 and 222 generate gas, which is directed into the inflatable member 202, thereby inflating the inflatable member.

[0420] The inflatable member 202 is shown in an inflated or inflatable configuration and defines an internal volume configured to receive generated gas from the controlled gas release system 206.

[0421] Figure 2B shows a sectional view of an inflatable device 200 according to certain embodiments of the present disclosure.

[0422] The device 200 comprises an inflatable member 202 and a controlled gas release system comprising a first enclosure 206a and a second enclosure 206b disposed in fluid communication with the inflatable member 202.

[0423] In the illustrated embodiment, a first gas-generating composition 220 is housed within a first enclosure 206, and a second gas-generating composition 222 is housed within a second enclosure 206. The first and second gas-generating compositions may correspond, for example, to an immediate-release gas-generating composition and an extended-release gas-generating composition, respectively.

[0424] Each enclosure 206 may comprise walls that are substantially gas-impermeable and water-transferable, and each enclosure may further comprise a gas passageway configured to direct generated gas into the inflatable member 202.

[0425] Upon exposure to an aqueous environment, the gas-generating compositions 220 and 222 generate gas independently within their respective enclosures. The generated gas from both enclosures is directed into the inflatable member 202, producing a composite pressuretime profile that inflates the inflatable member.

[0426] As used herein, the term ‘ inflatable member’ refers to a structure defining an internal volume and configured to undergo expansion upon introduction of a gas.In some examples, the inflatable member is in a non-inflated or collapsed state prior to deployment and expands upon receiving gas generated by the controlled gas release system.

[0427] The inflatable member may transition from a first configuration (e.g., compact, folded, deflated, or reduced-volume state) to a second configuration (e.g., expanded, pressurized, or deployed state). Inflation may result in an increase in volume, pressure, surface area, shape change, mechanical force output, or combinations thereof.

[0428] The inflatable member may comprise an elastic, semi-elastic, flexible, compliant, or deformable material capable of expanding upon gas introduction.

[0429] In some embodiments, the inflatable member carries one or more delivery needles. In some examples, the system is used in connection with an auto-inflatable patch, an ingestible or capsule -based device, a catheter-delivered device, an endoluminal device, a wound dressing or bandage, a wearable or skin-contact article, an expandable reservoir, a pressure-actuated actuator, an occlusion device, an anchoring device, a stent-delivery aid, a diagnostic or sensing device, or combinations thereof, wherein the system is configured to inflate and / or pressurize an inflatable member and / or to provide a sustained pressure over a desired duration. In some examples, the system is configured to provide a sustained pressure for at least about 2 minutes, at least about 5 minutes, at least about 7 minutes, at least about 10 minutes.

[0430] In some examples, the system is configured to provide a sustained pressure for between about 2 minutes and about 20 minutes.

[0431] In some examples, the system is configured to provide a sustained pressure for between about 7 minutes and about 10 minutes. In some examples, the system further comprises one or more protrusions and / or tissue-engaging features selected from microneedles, drug-delivery needles, microprotrusions, microelectrodes, anchors, barbs, and combinations thereof.

[0432] In some examples, the system may be used with an inflatable member.

[0433] In some examples, the system may be used with an auto-inflatable patch.

[0434] In some examples, the system may be used with a capsule-based device.In some examples, the system may be used with an inflatable member comprising one or more protrusions.

[0435] In some examples, the system may be used with an auto-inflatable patch or capsulebased device comprising an inflatable member and one or more protrusions.

[0436] In some examples, the one or more protrusions is or comprises microneedles or drugdelivery needles.

[0437] Examples of relevant applications are further disclosed in PCT / IB2023 / 058358. A larger passageway may be formed during the manufacturing process of the enclosure, and prior to physically retaining the gas-generating compositions therein to form the gas passageway.

[0438] In some examples, a larger passage is formed connecting between the enclosure and the target inflatable, the gas release compositions are positioned within the enclosure, and opposing sides of the larger passageway are welded together to physically retain the gas release compositions.

[0439] In accordance with some aspects, the present disclosure provides an inflatable device comprising:

[0440] (i) an inflatable member; and (ii) a controlled gas release system as described herein, operably coupled to the inflatable member and configured to inflate the inflatable member upon exposure to an aqueous environment, wherein the inflatable member comprises one or more protrusions disposed on a surface thereof.

[0441] In some embodiments, the inflatable device is configured as an auto-inflatable device, including an auto-inflatable patch or capsule-based device.

[0442] In some embodiments, the one or more protrusions comprise microneedles.

[0443] In some embodiments, the one or more protrusions comprise drug-delivery needles. In some embodiments, inflation of the inflatable member applies force to a base of the one or more protrusions, thereby facilitating penetration of tissue.

[0444] In some embodiments, the device is configured for deployment within a gastrointestinal environment.Figure 3 illustrates a sectional view of an inflatable device. The device 200 comprises an inflatable member 202 defining an internal volume 204. The inflatable member 202 is configured to receive gas and expand upon accumulation of gas within the internal volume 204.

[0445] A controlled gas release system includes an enclosure 206 containing a gasgenerating composition 208. The enclosure 206 comprises a wall 218 and a gas passage 216.

[0446] Gas generated within the enclosure 206 is directed through gas passage 216 into the internal volume 204 of the inflatable member 202.

[0447] The device comprises a composition retainer 214.

[0448] The inflatable member 202 further comprises a plurality of protrusions 212 disposed on an outer surface thereof. Protrusions 212 may comprise microneedles or drug -delivery needles.

[0449] In some embodiments, the protrusions 212 retain a composition 104 comprising an active agent. The composition 104 may be coated onto, embedded within, or contained inside the protrusions 212 for delivery into tissue upon inflation-induced penetration.

[0450] As used herein, the term "composition retainer" may refer to a physical barrier or structure within the enclosure configured to maintain the gas release composition within the enclosure during activation and gas generation. This retainer may prevent or restrict movement of the composition while allowing generated gas to pass through. The composition retainer may take various forms, such as a mesh, screen, welded contact between two membranes or other suitable structure that can hold the composition in place while permitting gas flow.

[0451] In some examples, the inflatable member having drug delivery needles on a surface thereof, obtain a psi of at least 3 as early as possible and maintains a psi of at least 3 psi for an extended period of time.

[0452] In another aspect, the present disclosure provides a drug delivery system comprising: (i) an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member; and (ii) a controlled gas release system in fluid communication with the inflatable member, the controlled gas release system comprising an enclosure defining aninterior volume and containing one or more gas release composition, the enclosure including a water-transferable, gas-impermeable membrane portion configured to permit transfer of water into the enclosure to activate the gas release composition, and a gas passage configured to direct gas generated within the enclosure into the inflatable member to inflate the inflatable member, wherein inflation of the inflatable member applies a force to a base of the delivery needles to facilitate penetration of tissue.

[0453] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, and a base component in an amount of between about 10% and about 80% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition.

[0454] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, and a base component in an amount of between about 10% and about 60% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 60%, a base component in an amount of between about 10% and about 60% and an extended-release component inan amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition.

[0455] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, and a base component in an amount of between about 20% and about 50% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition.

[0456] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition.In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 3% and about 12% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition.

[0457] In some aspects which may be considered as embodiments of the disclosure, an inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, and a base component in an amount of between about 30% and about 40% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, a base component in an amount of between about 30% and about 40% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition.

[0458] In some examples, the gas release composition comprises an immediate -release gasgenerating composition and an extended-release gas-generating composition. In some examples, the system is configured to reach an internal pressure within the inflatablemember of at least about 3 psi within a predetermined time after exposure to an aqueous environment and to maintain a pressure of at least about 3 psi for a predetermined duration.

[0459] Interestingly, the controlled-release formulation, representing the combined immediate-release and extended-release compositions, demonstrates attainment of the desired pressure (psi) early and maintenance of the desired pressure for an extended period of time, thereby facilitating penetration by the needles and delivery of an active agent, for example an active agent disposed on and / or within the delivery needles and / or delivered from an active agent reservoir in fluid communication with the delivery needles.

[0460] The present disclosure is not limited to any specific active agent. In some examples, the active agent comprises a small molecule drug, a peptide, a protein, a polynucleotide, a vaccine antigen, an antibody or antigen-binding fragment thereof, a hormone, an enzyme, a cytokine, a growth factor, or combinations thereof.

[0461] In some examples, antibodies include monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and antigen-binding fragments (for example Fab, scFv, or Fc-containing fragments), including antibodies against inflammatory targets, infectious disease targets, or oncology targets.

[0462] In some examples, nucleic acid-based active agents include DNA, RNA, mRNA, siRNA, antisense oligonucleotides, aptamers, gene -editing reagents, and combinations thereof.

[0463] In some examples, the active agent is formulated as a salt, prodrug, ester, hydrate, polymorph, amorphous form, or combinations thereof.

[0464] In some examples, the active agent may be delivered into the intestinal walls via the action of the needles.

[0465] In some examples, the inflatable device is for use in delivering an active agent to tissue.

[0466] In accordance with some other aspects, the present disclosure provides a method of deploying an inflatable device, comprising: introducing an inflatable device into a subject; wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas and inflates the inflatable member.In some aspects which may be considered as embodiments of the disclosure, a method of deploying an inflatable device comprises introducing an inflatable device into a subject, wherein the inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, and a base component in an amount of between about 10% and about 80% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 10% and about 80%, a base component in an amount of between about 10% and about 80% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition, wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas and inflates the inflatable member.

[0467] In some aspects which may be considered as embodiments of the disclosure, a method of deploying an inflatable device comprises introducing an inflatable device into a subject, wherein the inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, and a base component in an amount of between about 20% and about 50% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 20% and about 50%, a base component in an amount of between about 20% and about 50% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition, wherein, upon exposure to an aqueousenvironment within the subject, the controlled gas release system generates gas and inflates the inflatable member.

[0468] In some aspects which may be considered as embodiments of the disclosure, a method of deploying an inflatable device comprises introducing an inflatable device into a subject, wherein the inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition, wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas and inflates the inflatable member.

[0469] In some aspects which may be considered as embodiments of the disclosure, a method of deploying an inflatable device comprises introducing an inflatable device into a subject, wherein the inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, and a base component in an amount of between about 30% and about 45% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 45%, a base component in an amount of between about 30% and about 45% and an extended-release component inan amount of between about 3% and about 12% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition, wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas and inflates the inflatable member.

[0470] In some aspects which may be considered as embodiments of the disclosure, a method of deploying an inflatable device comprises introducing an inflatable device into a subject, wherein the inflatable device comprises an inflatable member having a plurality of delivery needles disposed on a surface of the inflatable member, at least one enclosure, at least one immediate-release gas-generating composition, at least one extended-release gasgenerating composition and at least one gas passageway, wherein the enclosure is or comprises hydrophilic TPU and wherein the immediate-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, and a base component in an amount of between about 30% and about 40% by weight of the total composition and the extended-release gas-generating composition comprises an acid component in an amount of between about 30% and about 40%, a base component in an amount of between about 30% and about 40% and an extended-release component in an amount of between about 1% and about 15% by weight of the total composition and wherein the at least one immediate -release gas-generating composition, and the at least one extended-release gas-generating composition, wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas and inflates the inflatable member.

[0471] As described herein by deploying the inflatable device within the subject, treatment may be initiated upon activation of the controlled gas release system. Upon exposure to an aqueous environment, the gas-generating compositions produce gas that inflates the inflatable member, thereby causing mechanical deployment of the device. In examples in which the inflatable member comprises delivery needles, inflation of the inflatable member applies force sufficient to cause penetration of tissue and delivery of an active agent contained within or carried by the device.

[0472] Accordingly, treatment may be initiated in situ without external mechanical actuation, relying instead on physiologically triggered gas generation. The timing of treatment initiation may be governed by the exposure of the controlled gas release systemto aqueous fluid, thereby enabling location-specific activation, controlled deployment, and delivery of the active agent to a target tissue.

[0473] Hence, in accordance with some aspects, the present disclosure the inflatable device for use in treating a disease in a subject in need thereof.

[0474] In accordance with some other aspects, the present disclosure provides a method of treating a disease in a subject, comprising administering to the subject an inflatable device comprising an inflatable member and a controlled gas release system as defined herein, wherein gas generated by the controlled gas release system inflates the inflatable member and causes delivery of an active agent from the device to the subject.

[0475] In accordance with some further aspects, the present disclosure provides a method of treating a disease in a subject, comprising administering to the subject an inflatable device comprising: (i) an inflatable member defining an internal volume and carrying one or more delivery needles; and (ii) a controlled gas release system in fluid communication with the inflatable member, the controlled gas release system comprising an enclosure containing an immediate -release gas-generating composition and an extended-release gas-generating composition; wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas that inflates the inflatable member; wherein by inflation of the inflatable member, penetration of tissue by the one or more delivery needles; and an active agent is delivered from the device into the tissue to treat the disease.

[0476] As used herein, the term "treat", "treating", or "treatment" refers to any intervention that provides a therapeutic, prophylactic, palliative, diagnostic-supportive, or diseasemodifying benefit to a subject. Treatment may include one of more of preventing or reducing the risk of disease onset, delaying disease progression, reducing severity, frequency, or duration of symptoms, stabilizing a condition, promoting remission, improving a measurable clinical parameter and delivering an active agent for local or systemic effect

[0477] As used herein, the term "disease" includes any pathological condition, disorder, injury, infection, inflammatory condition, metabolic condition, autoimmune condition, neoplastic condition, degenerative condition, or other abnormal physiological state that may benefit from delivery of an active agent.The therapeutic outcome may depend on the nature of the active agent incorporated within the device. The active agent may be selected based on the disease or condition to be treated.

[0478] In some embodiments, the active agent is delivered locally to tissue penetrated by one or more delivery needles carried by the inflatable member. In other embodiments, the active agent may be delivered systemically following tissue penetration.

[0479] In accordance with some other aspects, the present disclosure relates to use of a controlled gas release system for inflating an auxiliary inflatable member.

[0480] In accordance with some other aspect, the present disclosure relates to a use of the inflatable device for delivering an active agent to tissue.

[0481] As used herein, the term "substantially” refers to a condition that is largely, but not necessarily wholly or perfectly, as specified. The term encompasses variations, tolerances, or minor deviations that do not materially affect the function, performance, or intended result of the referenced element or feature.

[0482] For example, "substantially impermeable" may permit limited permeation that does not materially alter the intended gas retention function, and “substantially retains” may allow minimal escape that does not significantly impact system performance.

[0483] Features of any of the examples or embodiments outlined above may be combined to create additional examples or embodiments without losing the intended effect. It should be understood that the description of an embodiment or example provided above is by way of example only, and various modifications could be made by one skilled in the art. Furthermore, one skilled in the art will recognize that numerous further modifications and combinations of various aspects are possible. Accordingly, the described aspects are intended to encompass all such alterations, modifications, and variations that fall within the scope of the appended claims.

[0484] The term "about" as used herein indicates values that may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% higher or lower than the value referred to, the deviation range including integer values, and, if applicable, non-integer values as well, constituting a continuous range. In some embodiments, the term "about" refers to ± 10 %.The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0485] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0486] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of’ “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0487] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within thelist of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0488] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0489] It should be noted that various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging / ranges between" a first indicate number and a second indicate number and "ranging / ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals there between.As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0490] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0491] Various embodiments and aspects of the present invention as delineated herein above and as claimed in the claims section below find experimental support in the following examples.

[0492] Disclosed and described, it is to be understood that this invention is not limited to the particular examples, methods steps, and compositions disclosed herein as such methods steps and compositions may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

[0493] The following examples are representative of techniques employed by the inventors in carrying out aspects of the present invention. It should be appreciated that while these techniques are exemplary of preferred embodiments for the practice of the invention, those of skill in the art, in light of the present disclosure, will recognize that numerous modifications can be made without departing from the spirit and intended scope of the invention.NON-LIMITING EXAMPLES

[0494] The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention.

[0495] Example 1: Preparation of Immediate Release (IR) gas-generating tablet

[0496] For the production of IR tablets, slugs were produced by dry granulation of citric acid anhydrous (Sigma), EfferSoda® (SPI pharma) and Starlac® and Avicel and subsequent compressing into approximately 1 g slugs having slug power. The slugs were then milled and sieved through a 600-micron sieve (28 mesh) resulting in uniform granules.

[0497] The granules were mixed with an extra granular mixture of sodium bicarbonate (Fisher) per tablet and citric acid anhydrous per tablet (Sigma) to produce granules surrounded by extra granular mixture. Magnesium stearate per tablet (0.2%, pre mesh 300 micron) was added as a lubricant and the composition was compressed into oval tablets, each having tablet power. The composition of each ingredient and the relative weight per immediate release tablet are summarized in Table 1.

[0498] Table 1: Immediate release (IR) composition per tablet

[0499]

[0500]

[0501] (Total relative weight % of carbonate in the immediate release tablet weight: 37.4%.). The IR gas-generating tablets are structured to effervesce when exposed to water.

[0502] Example 2: Preparation of Extended Release (ER) gas-generating tablet

[0503] For the production of ER gas-generating tablets, slugs were produced by dry granulation of 3 citric acid anhydrous (Sigma), EfferSoda® (SPI pharma) and Starlac® and avicel and compressing into slugs having slug power of. The slugs were subsequently milled at and sieved through a 600-micron sieve (28 mesh) to produce granules.

[0504] The resulting granules were mixed with sodium bicarbonate (Fisher), citric acid anhydrous (Sigma), and xanthan gum as an extended-release agent to form the surrounding extra granular portion. Additionally, magnesium stearate (0.2%, pre mesh 300 micron) was added as a lubricant before compressing into oval tablets, each having tablet power of [kg / cm2, kg 5, 40, sec, 900]. The composition and relative weight per unit are summarized in Table 2.

[0505] Table 2: Extended-release composition per tablet

[0506]

[0507]

[0508] (*Total relative weight % of carbonate in the extended-release tablet weight: 26.3%.). The ER gas-generating tablet is configured to effervesce and generate gas when exposed to water.

[0509] Example 3: Preparation of a combined IR-ER bilayer tablet

[0510] Bilayer tablets comprising an immediate-release (IR) gas-generating composition and an extended-release (ER) gas-generating composition were prepared in various geometries and dosages.

[0511] Three configurations were prepared:

[0512] 1. Mini-tablets (MT) (-30-40 mg)

[0513] 2. Oval tablets (-75-85 mg)

[0514] 3. Round tablets (90-110 mg)

[0515] Each configuration comprised an IR layer and an ER layer in approximately equal proportions (about 50:50 by weight), unless otherwise indicated. The IR gas-generating composition is as described in Example 1 and the ER gas-generating composition is as described in Example 2, aside of the Xanthan gum which was added as described below. The amount of xanthan gum (XG) present in the ER composition was adjusted based on tablet mass and geometry.

[0516] • For mini-tablets (-30 mg) and oval tablets (-80 mg), about 3 wt% xanthan gum (relative to total ER composition) was added.

[0517] For round tablets (-100 mg), about 3-12 wt% xanthan gum were added.The extended-release (ER) composition was first introduced into the die cavity and subjected to a pre -compression at approximately 900 kg to form a first layer. The immediate-release (IR) composition, which is comparatively more porous, was subsequently added on top of the ER layer, and the combined layers were subjected to final compression at approximately 900 kg to form a bilayer tablet comprising an ER layer and an IR layer in approximately equal proportions.

[0518] Example 4: Preparation of IR, ER and IR / ER bilayer-controlled gas release systems To evaluate the gas-generating system, a gas-generating tablet (e.g., IR-, ER-, or a combined IR / ER bilayer) was encapsulated into gas impermeable and surface water-transferable thermoplastic polyurethane (TPU) membrane (denoted herein also as "enclosure").

[0519] The membrane was sealed along its perimeter (e.g., by thermal welding) to form a closed chamber containing the gas-generating tablet while allowing water permeation through the membrane surface.

[0520] The enclosure was fluidically connected via a gas passageway to an inflatable chamber equipped with a pressure monitoring system. The gas-generating tablet was maintained in close proximity to the water-transferable TPU membrane using a retentive element to ensure controlled and reproducible membrane contact. For testing, the assembled patch containing a single gas-generating system was connected to a pressure monitor. The encapsulated gas -generating unit was then immersed in buffer solution maintained at 37 °C to simulate physiological conditions. Pressure development within the inflatable chamber was continuously recorded over time.

[0521] A gas impermeable and surface water-transferable enclosure or multiple enclosure s having a gas-passageway and housing an IR gas-generating tablet is denoted herein after an IR controlled gas release system. Respectively, a gas impermeable and surface water-transferable enclosure or multiple enclosures having a gas-passageway and housing an ER gas-generating tablet is denoted herein after an ER controlled gas release system. Following the same rational, a gas-generating system which comprises enclosure or multiple enclosure that house a combination of IR and ER gas-generating tablets either inthe same enclosure or each of the IR or ER generating tablets in different enclosures, or a bilayer tablet is denoted herein after a controlled release gas-generating system.

[0522] Example 5: Gas release profile of ER, IR, and controlled release-controlled gas release systems comprising minitablets (MT)

[0523] Determining the gas release profile of the ER and IR controlled gas release systems (the controlled release system is a combination of IR and ER) was performed in a patch model using the gas-generating systems as described in Example 4, each connected to an inflatable member, in this case an inflatable patch. Absorption of water / buffer (e.g. water vapors, H2O(g)) in the proximity of the gas-generating tablet initiated the gas-generating reaction and subsequently caused a directional gas flow from the enclosure through the gas passageway into the inflatable patch, while the gas -generating tablet is maintained within the enclosure by the retentive element. The inflatable member / patch is configured to inflate and retain the gas upon gas flow therein.

[0524] The gas release profile was determined in a pressure resistant patch model. Gas-generating systems include two enclosures, each housing a 30 mg minitablet (MT). The mini-tablet may be an immediate-release (IR), extended-release (ER), or controlled-release bilayer (e.g., IR / ER) tablet. Each of the gas-generating systems were connected to an inflatable member / patch were immersed separately in ml2of 10 mM pH 6.5 Phosphate-Buffered Saline (PBS), as described in Table 3.

[0525] The gas release profile (average PSI / sec) was measured by an IR gas-generating system served as a control. The results (average, mean) of the gas release profiles are presented in Figure 4, IR gas-generating system, ER gas-generating system, ER:IR at a ratio of 50:50 ER to IR gas-generating system.

[0526] Table 3: PBS lO mMpH 6.5

[0527] <

[0528]

[0529] As can be seen in Figure 4, the controlled gas-generating system produced peak pressure of about 3.7 psi at about 1250 seconds, while the ER gas-generating system produced a lower peak pressure of about a 2.9 psi at a delayed timepoint of about 2070 sec. The IR gas-generating system, produced peak pressure of about a 4 psi at about 930 sec. The decline in gas pressure from the peak value of the controlled gas-generating system was a more moderate decline than the IR gas-generating system, yet steeper than the ER gasgenerating system.

[0530] Example 6: gas release profile of ER, IR, and ER:IR controlled gas release systems comprising oval tablets

[0531] The gas release profile of the ER, IR, ER:IR gas-generating systems comprising an ~80 mg oval ER, IR, and bilayer ER:IR at a ratio of 50:50 tablets respectively was evaluated as described in Example 5. Briefly, the above-mentioned gas-generating systems comprising the respective 80 mg oval tablet were immersed separately 10 mM pH 6.5 PBS (Table 3). The gas release profile (average PSI / sec) was measured by a testing apparatus. An IR gasgenerating system (78 mg oval tablet) served as a control. ER:IR at a ratio of 50:50 gasgenerating system (79 mg oval tablet) was evaluated. An ER gas-generating 79 mg oval tablet was evaluated.

[0532] The results of the gas release profiles are presented in Figure 5, IR gas-generating system, ER gas-generating system, and ER:IR at a ratio of 50:50 gas-generating system.

[0533] As can be seen in Figure 5, the ER:IR (at a ratio of 50:50 ER to IR) gas-generating system produced peak pressure of about a 5.5 PSI at about 1150 to about 1210 sec, while the ER gas-generating system produced a lower peak pressure of about a 2.54 PSI later point of about 1470 to about 1480 sec. The IR gas-generating system, which served as a control, produced peak pressure of about a 5.9 PSI at a much earlier time point compared with the ER:IR of about 600 sec.

[0534] The decline in gas pressure from the peak value of the ER:IR gas-generating system was a more moderate decline than the control (e.g., IR gas-generating system), yet steeper than the ER gas-generating system.

[0535] In conclusion the ER:IR gas-generating system provided pressure values (PSI) which are closer to the ones provided by the IR gas-generating systems and higher than the pressurevalues provided by the ER gas-generating systems. Moreover, the gas release profile as evaluated showed that the ER:IR gas-generating systems were able to maintain gas pressure greater than 3.5 PSI for a longer period than the IR gas-generating systems.

[0536] Example 7: Gas release profile of ER, IR, and ER:IR controlled gas release systems comprising oval tablets

[0537] The gas release profile of the ER, IR, ER:IR gas-generating systems comprising an ~80 mg oval ER, IR, and bilayer ER:IR at a ratio of 50:50 tablets respectively was evaluated for the second time as described in examples 5 and 6. Briefly, the above-mentioned gasgenerating systems comprising the respective 80 mg oval tablet were immersed separately 10 mM pH 6.5 PBS (table 3). The gas release profile (average PSI / sec) was measured by a testing apparatus. Three IR gas-generating systems (oval tablets) served as a control, each comprising a 75mg, 76 mg, or 78 mg IR oval tablet. Three ER:IR at a ratio of 50:50 gasgenerating systems (oval tablets) were evaluated, each comprising a 72 mg, 76 mg, or a 79 mg bilayer oval tablet. An ER gas-generating systems (duplicate) each comprising a 79 mg ER oval tablet and an ER gas-generating system comprising a 78 mg ER oval tablet were evaluated.

[0538] The results of the gas release profiles are similar to the ones in Figure 3.

[0539] Example 8: Hardness measurements

[0540] Oval gas-generating tablets (4.5 x 8 mm) having a target weight of 80 mg were tested using a Kremers HC 6.2 tablet hardness testers. Monolithic immediate-release (IR) tablets, monolithic extended-release (ER) tablets (comprising 3% controlled-release element), and bilayer tablets comprising an IR layer and a ER layer in a 50:50 weight ratio were produced as described at Example 4. Tablets (final blend) were compressed at a compression force of approximately 900 kg.

[0541] Mechanical strength (hardness) of the resulting tablets was evaluated. As shown in Figure 6, no significant difference in hardness was observed between the monolithic IR tablets and the monolithic ER tablets. The bilayer tablets exhibited a slight decrease in hardness relative to the monolithic tablets, while maintaining acceptable mechanical integrity for handling and use.Example 9: Pressure measurements of round tablet with various xanthan Gum levels The gas release profile of various gas-generating tablet formulation was evaluated using a pressure -resistant patch model, and the pressure (psi) profile was recorded over time. As can be seen in Figure 7, bilayer IR:ER tablets (50:50) (3%, 6%, 9% XG) showing different pressure profile, supporting xanthan gum as the key factor for controlled / tunable behaviour. The bilayer tablet containing 3% xanthan gum achieved peak pressures with a broader peak and slower decline. Increasing xanthan gum content to 6% and 9% progressively reduced the maximum pressure and prolonged the pressure maintenance phase. These results demonstrate that gas release kinetics and peak pressure can be modulated by tablet architecture, formulation and controlled element concentration in the tablet.

[0542] Example 10: Characterization of enclosure (membrane)

[0543] Water absorption via hydrophilic membrane for activation of the gas-generating element is a critical parameter for patch functionality, affecting inflation onset, inflation time and penetration power. The impact of membrane type and width on water absorption capacity was evaluated using TPU membranes differing in their width (1.5 mil and 3 mil).

[0544] As shown in Figures 8A and 8B, both membranes show rapid (within 15 min) water absorption and membrane expansion (width and area) upon water exposure but to different extents.

[0545] As shown in Figures 8A and 8B, 3 mil membrane exhibits 100% weight increase, 22% width increase, and 44% increase in x-y dimension after 15 min in water. While 1.5 mil shows 120-130% weight increase, 20% width increase, and 44% increase in x-y dimension. Meaning that both membranes reach similar 3D dimensions but with different contents of water (1.5 mil membrane had more water content / absorption capacity). Water ingress is rapid and shows limited absorption capacity depending on testing conditions (%RH). Exposure to 100% humidity for 24 hr shows lower water absorption (30%) resulting lower expansion (10% width and 21% X-Y area).

Claims

CLAIMS:

1. A controlled gas release system comprising:one or more enclosures defined by walls being substantially gas-impermeable and water-transferable, the one or more enclosures configured to house one or more gas-generating compositions and having a gas passageway for releasing generated gas; said gas-generating composition comprising one or more of:

1. an immediate-release gas-generating composition housed within the one or more enclosures; andii. an extended-release gas-generating composition having an extended-release component and housed within the one or more enclosures;wherein each of the immediate-release gas-generating composition and the extended-release gas-generating composition comprises a first reactant and a second reactant which generate gas upon exposure to an aqueous environment.

2. The controlled gas release system of claim 1, wherein the immediate -release and extended-release compositions are housed within a single enclosure.

3. The controlled gas release system of claim 1, wherein the immediate-release composition is housed within a first enclosure and the extended-release composition is housed within a second enclosure.

4. The controlled gas release system of claim 1, wherein the immediate-release composition is housed within a first enclosure and both the immediate-release composition and the extended-release composition are housed within a second enclosure.

5. The controlled gas release system of claim 1, wherein the extended -release composition is housed within a first enclosure and both the immediate-release composition and the extended-release composition are housed within a second enclosure.

6. The controlled gas release system of any one of the preceding claims, wherein the gas passageway comprises a lumen, port, conduit, or channel.

7. The controlled gas release system of any one of the preceding claims, wherein the ratio between the immediate -release gas-generating composition and the extended-release gas-generating composition is between about 20:80 and about 80:20.

8. The controlled gas release system of any one of the preceding claims, wherein the ratio between the immediate -release gas-generating composition and the extended-release gas-generating composition is between about 35:65 and about 65:35.

9. The controlled gas release system of any one of the preceding claims, wherein the ratio between the immediate -release gas-generating composition and the extended-release gas-generating composition is between about 45:55 and about 55:45.

10. The controlled gas release system of any one of the preceding claims, wherein the enclosure comprise a hydrophilic polymer.

11. The controlled gas release system of claim 10, wherein the hydrophilic polymer is capable of absorbing water in an amount of at least about 20% of a weight of dry polymer.

12. The controlled gas release system of claim 10 or 11, wherein the hydrophilic polymer is or comprises hydrophilic thermoplastic polyurethane (TPU).

13. The controlled gas release system of any one of the preceding claims, wherein the enclosure exhibits a gas permeability coefficient of less than 200 Barrer for carbon dioxide at 25°C.

14. The controlled gas release system of any one of the preceding claims, wherein the enclosure exhibits a water absorption capacity of at least 80% of its dry weight.

15. The controlled gas release system of any one of the preceding claims, wherein the immediate-release gas-generating composition comprises a first reactant in an amount of between about 20% and about 50% by weight of the total composition and a second reactant in an amount of between about 20% and about 50% by weight of the total composition.

16. The controlled gas release system of any one of the preceding claims, wherein the extended -release gas-generating composition comprises a first reactant in an amount of between about 20% and about 50% by weight of the total composition and a second reactant in an amount of between about 20% and about 50% by weight of the total composition.

17. The controlled gas release system of any one of the preceding claims, wherein the first reactant is a weak acid.

18. The controlled gas release system of claim 17, wherein the first reactant is selected from a group consisting of succinic acid, tartaric acid, adipic acid, acetic acid, lactic acid, and citric acid.

19. The controlled gas release system of claim 18, wherein the first reactant is anhydrous citric acid.

20. The controlled gas release system of any one of the preceding claims, wherein the second reactant is carbonate salt.

21. The controlled gas release system of any one of the preceding claims, wherein the extended-release component is selected from a group consisting of acetan, dextran, alginate, hyaluronic acid, pullulan, xanthan gum, gellan gum, levan, curdlan, cellulose, chitosan, mauran, and schizophyllan.

22. The controlled gas release system of any one of the preceding claims, wherein the extended-release component is xanthan gum or a derivative thereof.

23. The controlled gas release system of claim 22, wherein the xanthan gum is in an amount of between 3% and 12% by weight of the extended-release gas-generating composition.

24. The controlled gas release system of any one of the proceeding claims, wherein each of the one or more enclosures houses an immediate -release gas-generating composition or an extended-release gas-generating composition as individual tablets.

25. The controlled gas release system of any one of the proceeding claims, wherein each of the one or more enclosures house both an immediate gas-generating composition and an extended gas-generating composition as individual tablets or a bilayer single tablet.

26. The controlled gas release system of any one of the proceeding claims, wherein the immediate gas-generating composition and the extended gas-generating composition form a bilayer tablet.

27. The controlled gas release system of any one of the proceeding claims, wherein the enclosure walls define an inner volume which is operably in fluid communication with an inner volume of an inflatable member via a passageway, said passageway configured to retain the formulation within the enclosure.

28. The controlled gas release system of any one of the proceeding claims, further comprising an enteric outer layer.

29. An inflatable device comprising: an inflatable member defining an internal volume; and a controlled gas release system according to any one of claims 1 to 28, wherein the controlled gas release system is in fluid communication with the inflatable member such that generated gas inflates the inflatable member.

30. The inflatable device of claim 29, wherein inflation of the inflatable member occurs within a biological environment.

31. The inflatable device of claim 29 or 30, wherein the inflatable member comprises one or more protrusions disposed on a surface thereof.

32. The inflatable device of claim 31, wherein the one or more protrusions comprise microneedles.

33. The inflatable device of claim 31 or 32, wherein the one or more protrusions comprise hollow drug-delivery needles.

34. The inflatable device of any one of the proceeding claims, wherein inflation of the inflatable member applies force to a base of the one or more protrusions to facilitate penetration of tissue.

35. The inflatable device of any one of claims 31 to 34, wherein the one or more protrusions retain a composition comprising an active agent.

36. The inflatable device of claim 35, wherein the active agent is coated onto the protrusions.

37. The inflatable device of claim 34, wherein the active agent is embedded within the protrusions.

38. The inflatable device of any one of the proceeding claims, wherein the device is configured as a capsule -based device for administration to the gastrointestinal tract.

39. The inflatable device of any one of the proceeding claims, for use in delivering an active agent to tissue.

40. The inflatable device of any one of the proceeding claims, for use in treating a disease in a subject in need thereof.

41. A method of deploying an inflatable device, comprising introducing the inflatable device of any one of claims 29 to 38 into a subject; wherein, upon exposure to an aqueous environment within the subject, the controlled gas release system generates gas and inflates the inflatable member.

42. Use of a controlled gas release system of any one or more of claims 1 to 28, for inflating an auxiliary inflatable member.

43. The use of claim 42 wherein the auxiliary inflatable member is in fluid communication with the gas passageway of the controlled gas release system.

44. The use of claim 42 or 43, wherein the auxiliary inflatable member extends from or is attached to the gas passageway.

45. Use of the inflatable device of any one of claims 29 to 38 for delivering an active agent to tissue.

46. Use of the inflatable device of any one of claims 29 to 38 for treating a disease in a subject in need thereof.

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