Intake device for delivery of therapeutic agents to gastrointestinal tract

Abstract

The ingestible device may deliver a therapeutic agent directly to a desired tissue of the GI tract of a subject, such as submucosa, mucosa, and / or mucus of the GI tract, and methods of using the same. The ingestible device is capable of delivering therapeutic agents in a safe, efficient and reliable manner. The present disclosure also provides a pharmaceutical composition for use in a method of treating a disease or condition.

Description

Technical Field

[0001] The field of the present invention is ingestible devices capable of delivering dispensable substances, such as therapeutic agents, and related components, systems, and methods. Background Art

[0002] The gastrointestinal (GI) tract generally provides therapeutic media to an individual's body. Sometimes, it is desirable to distribute a therapeutic agent to the GI tract to treat a medical condition. Summary of the invention

[0003] The ingestible device is capable of delivering the therapeutic agent directly to the desired tissue of the GI tract of a subject, such as the submucosal layer, mucosa and / or mucus layer of the GI tract. The ingestible device is capable of delivering the therapeutic agent in a safe, effective and reliable manner. Also described are pharmaceutical compositions and methods of use for methods of treating human and animal diseases or conditions.

[0004] The ingestible device is configured to provide at least three different modes of direct delivery of the therapeutic agent to the GI tract of a subject, referred to herein as transepithelial delivery, epithelial delivery, and topical delivery. As used herein, direct delivery refers to a force-driven delivery mechanism.

[0005] Therefore, on the one hand, the trans-epithelial delivery of the therapeutic agent is delivered to the GI tract of the patient. The ingestible device can deliver the therapeutic agent directly across the epithelial cell layer of the mucosa of the GI tract to produce systemic (systemic) exposure of the therapeutic agent. The ingestible device can be configured to deliver the therapeutic agent directly across the epithelial cell layer of the mucosa of the GI tract and to the submucosal layer and / or to the mucosal region below the epithelial layer (e.g., to the lamina propria), where it can be used for systemic absorption. This can be particularly relevant when the oral bioavailability of the therapeutic agent is otherwise low. In some embodiments, the systemic exposure of the therapeutic agent is achieved by delivering the therapeutic agent across the epithelium to the submucosal layer of the small intestine (e.g., in the duodenum, jejunum, and / or ileum) and / or to the mucosal region below the epithelial layer (e.g., to the lamina propria). In further embodiments, transepithelial delivery delivers the therapeutic agent directly to the submucosal and / or mucosal regions beneath the epithelial layer of the GI tract (e.g., into the lamina propria) such that the percent systemic absorption for transepithelial delivery relative to intravenous or subcutaneous administration is at least about 10% (e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or more).

[0006] In another aspect, epithelial delivery of therapeutic agents to the GI tract is provided. The ingestible device can be configured to deliver the therapeutic agent directly into the mucus of the small or large intestine and / or onto the epithelial layer, but not across the epithelial layer of the mucosa, from which it can act locally, and in some cases away from the site of direct delivery. The device can be configured so that the therapeutic agent is delivered from the device with sufficient force to provide epithelial delivery, which force is lower than the force required for transepithelial delivery.

[0007] In yet another aspect, the ingestible device can provide for surface delivery of a therapeutic agent to the GI tract. The ingestible device is then configured to deliver the therapeutic agent into the lumen of the small or large intestine and / or to mucus or other surfaces of the GI tract facing the lumen, from which it can act topically, and in some cases remote from the site of delivery. In some embodiments, the device is configured such that the therapeutic agent is delivered from the device with sufficient force to allow for surface delivery of the therapeutic agent, which force is lower than that required for epithelial or transepithelial delivery.

[0008] Ingestible devices, whether configured for transepithelial, epithelial, or surface delivery, can have a streamlined and / or relatively simple mechanical design, be relatively small, and / or be inexpensive to manufacture. Generally speaking, the device protects a dispensable substance (e.g., a therapeutic agent or a pharmaceutical formulation comprising a therapeutic agent) until the device reaches a desired location in the subject. As an example, the device can be designed to deliver a dispensable substance to a desired location in the GI tract of a subject, and the device can be designed so that the dispensable substance does not experience components of the GI tract (e.g., acids, enzymes) before reaching the desired location in the GI tract. As another example, the device can be designed to deliver a dispensable substance so that the therapeutic properties of the dispensable substance do not change during delivery (e.g., the dispensable substance is a therapeutic agent that binds to its therapeutic target after delivery).

[0009] The described ingestible devices can deliver therapeutic agents directly to desired tissues of the GI tract of a subject (e.g., the submucosal layer, mucosa, and / or mucus layer of the GI tract), for example, to treat a particular class of diseases or a specific disease. Relatedly, methods of using the devices to deliver therapeutic agents to desired tissues of the GI tract, for example, to treat a particular class of diseases or a specific disease are disclosed. These disclosures also inherently provide disclosures of corresponding medical uses—i.e., disclosures of the listed therapeutic agents for use in methods of treating the listed classes of diseases or specific diseases by using the devices to deliver the listed therapeutic agents to desired tissues of the GI tract of a subject or patient.

[0010] On the other hand, the ingestible device includes a housing configured to hold a dispensable substance including a therapeutic agent. One or more openings in the housing are configured to allow the dispensable substance to move out of the housing. The ingestible device is configured to deliver the dispensable substance to the GI tract as a jet having a peak jet power of 3 to 8 watts and / or a peak jet velocity of 40 to 50 m / s and / or a peak jet force of 150 to 310 mN. The ingestible device may include a gas container in the housing, the gas container containing compressed gas. A piercer may be used to pierce a cylinder to release compressed gas from the gas container into the housing. In some designs, a piercer is not used.

[0011] In another aspect, the ingestible device includes a housing, an opening, and a gas container, as described above, further including a first piston and a second piston each longitudinally slidable within the housing, and a therapeutic agent in a storage reservoir formed by and located between the first piston, the second piston, and the housing. If a second piston is used, the second piston may include an internal breakaway cap having a breakaway portion that is embedded in a housing recess after being displaced by movement of the second piston. The storage reservoir may be formed by the inner wall of the housing itself, or by a separate element located in the housing.

[0012] In an embodiment including a piercer, a spring may apply a spring force to the piercer in a first direction toward the gas container, and a release member or trigger may hold the piercer in a fixed position relative to the spring force. In this case, a trigger support having a tapered surface may be held against the trigger by the spring, the tapered surface having an angle of 10 to 25 degrees. With or without the trigger support, the trigger may hold the arm of the piercer in a first position, wherein the arm holds the piercer in a fixed position relative to the spring force, and the arm may move to a second position in which the piercer is released and moves under the action of the spring force to pierce the gas container when the trigger partially or completely dissolves, degrades and / or erodes.

[0013] In any of the embodiments including a piercer, a separate piercer base or separate piercer flange may be used to hold the piercer in a fixed position until a threshold force is overcome, wherein when the trigger partially or completely dissolves, degrades, and / or erodes, the piercer is released and moves under the action of a spring force to pierce the gas container. Alternatively, a shear pin may be used to hold the piercer in a fixed position until the threshold force is reached by the force of the pressurized gas released from the gas container. A trigger crown is located between the trigger and the end of the housing to better allow for catastrophic single-step destruction of the trigger, thereby allowing the device to be actuated quickly and smoothly.

[0014] In the design without the piercer, the pin is screwed into the container cap. A first O-ring on the pin seals the gas container. A second O-ring on the container cap seals the device housing. A trigger housing containing a release member is attached to the device housing. The container cap is rotatable from a first position in which the gas container is substantially sealed to a second position in which the gas container is unsealed; the container cap is displaced from the gas container when the release member is released to release gas from the pressurized container.

[0015] In another design without a piercer, a seal or O-ring is displaced from the receiver to release the gas from the gas container.

[0016] The gas container used as the energy source of the device can be contained in any type of housing, canister, container, etc., in which the gas container has a breakable seal; a spring, a piston, and a piercer in the interior of the housing; a retainer; and a trigger exposed to the environment outside the housing. In a first state of the ingestible device: the trigger retains the retainer in a first position; the retainer retains the piercer in a first position, in which the piercer does not break the breakable seal of the gas container; and the interior of the ingestible device is configured to contain a dispensable substance without the dispensable substance being delivered from the ingestible device via the opening in the housing.

[0017] In the second state of the ingestible device: the trigger is partially or completely dissolved, degraded and / or eroded such that the trigger is unable to retain the retainer in its first position; and the retainer is unable to retain the piercer in its first position.

[0018] In the second state of the ingestible device: the spring applies a force to the piercer to move the piercer so that the piercer breaks the frangible seal of the gas container; releases gas from the gas container; the gas applies a force to the piston so that the piston applies a force to the dispensable substance; and the dispensable substance is delivered from the ingestible device through the opening in the housing.

[0019] The ingestible device may further include a seal between the piston and the housing, and / or a seal between the piercer and the housing.

[0020] The ingestible device may include: a housing configured to contain a dispensable substance in the interior of the housing, the dispensable substance including a therapeutic agent; a cylinder, a spring, and a piston in the interior of the housing; a seal between the piston and the housing; a piercer in the interior of the housing; a retainer; and a release member or trigger exposed to the environment outside the housing. A second seal between the retainer and the housing may also be used. The ingestible device may be a 00 size device. The release member or trigger may include an enteric material. The housing may include a first housing portion and a second housing portion, wherein the piston and the dispensable substance are located inside the first housing portion, and the spring and retainer are located inside the second housing portion. The opening of the ingestible device may be a nozzle, for example having a diameter of about 325 μm to 375 μm. The dispensable substance may be a solution or a suspension. One or more openings may be arranged radially around the ingestible device.

[0021] In some embodiments, at least one of the following is true: the ingestible device is configured to deliver the dispensable substance to tissue of the GI tract of the subject as a jet having a peak jet power of 3 watts to 8 watts, or in some embodiments, greater than 4.2 watts and less than 7.8 watts, or in some embodiments, greater than 5.0 watts and less than 6.3 watts; the ingestible device is configured to deliver the dispensable substance at a peak jet velocity of, in some embodiments, 28 meters per second to 44 meters per second; the ingestible device is configured to deliver the dispensable substance to tissue of the GI tract of the subject at a peak jet force of, in some embodiments, from 150 mN to 310 mN, or in some embodiments, from 150 mN to 310 mN. In some embodiments, the ingestible device is configured to deliver the dispensable substance as a jet having a jet stability length of at least 5 mm; the ingestible device is configured to provide an internal pressure of, in some embodiments, from 250 psig to 400 psig, or, in some embodiments, from 300 psig to 350 psig; and the ingestible device is configured to contain the dispensable substance with a peak fluid pressure of, in some embodiments, from 230 psig to 380 psig, and in some embodiments, from 280 psig to 330 psig.

[0022] Some embodiments may include one or more of the following: at least one component comprising a cyclic olefin polymer; the frangible seal is scored; the frangible seal has a varying thickness; and / or the gas container has a burst pressure of about 2,800 psig to about 4,500 psig, wherein the gas comprises at least one gas selected from the group consisting of: air, nitrogen, oxygen, carbon dioxide, hydrofluorocarbon gases, and noble gases, or mixtures thereof.

[0023] In some embodiments, the ingestible device further includes an element having a first state and a second state, in which the element at least partially covers the opening in the housing, and in the second state, the element does not cover the opening in the housing, wherein the ingestible device is configured such that, when the piston moves, the element moves from its first state to its second state. The element can move synchronously with the piston. When the piston moves a distance, the element can move the same distance. The ingestible device can also include a seal mechanically coupled to the piston and the element. The seal can be configured to cause movement of the piston to cause movement of the element. The element can be conformal to the inner radius of the housing.

[0024] In some embodiments, the ingestible device further comprises a covering over the opening in the housing. The covering is removable from the ingestible device. The covering may be configured to be removed from the housing due to pressure applied by the dispensable substance. The covering may comprise an enteric material. The covering may be partially or completely eroded or dissolved. The covering may be a film, foil, tape, plug or patch. In some embodiments, the covering has a burst pressure of up to about 440 psi.

[0025] The ingestible device may further include a second piston configured such that, when the first piston applies a force to the dispensable substance, the dispensable substance applies a force to the second piston to slide the second piston to expose the opening and the dispensable substance is forced to exit the ingestible device through the opening.

[0026] In some embodiments, the ingestible device further includes a removable cap secured to the ingestible device and configured such that, when the piston moves to apply a force to the dispensable substance, the dispensable substance applies a force to the cap to cause the cap to slide to expose the opening in the housing.

[0027] The ingestible device may also have an inflated membrane volume that covers the opening and is configured such that, when the piston moves to apply a force to the dispensable substance, the dispensable substance applies a force to the inflated membrane volume and the inflated membrane volume is compressed to expose the opening in the housing.

[0028] In one aspect, the present disclosure provides methods comprising delivering a dispensable substance to the GI tract of a subject using an ingestible device according to the present disclosure.

[0029] The details of one or more embodiments of the apparatus and method are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1A is a schematic cross-section of different regions of healthy intestinal tissue.

[0031] Figure 1B is corresponding to Figure 1A But for a schematic cross-sectional view of diseased intestinal tissue.

[0032] Figure 2 is a cross section of an ingestible device.

[0033] Figure 3 is a cross section of another ingestible device.

[0034] Figure 4 An exemplary process flow diagram for use with an ingestible device is shown wherein no pressure is applied to the dispensable substance prior to the subject swallowing the ingestible device.

[0035] Figures 5A-5C Another ingestible device is shown.

[0036] Figures 6A-6C Shows that with Figure 4 and ingestible devices of similar aspects to those shown in 5.

[0037] Figure 7-13 An ingestible device having multiple chambers for one or more dispensable substances is shown.

[0038] Figure 14-17 Another ingestible device is shown.

[0039] Fig.18 Shows Fig.16 Certain elements of an ingestible device.

[0040] Fig.19 and Fig. 20 Shows the status of the ingestible device.

[0041] Fig.21 and Fig. 22 Shows the status of the ingestible device.

[0042] Fig.23 and Fig.24 Shows the status of the ingestible device.

[0043] Figure 25-27 An ingestible device is shown.

[0044] Figure 28-30 Shows the status of the ingestible device.

[0045] Figure 31-34 Shows the status of the ingestible device.

[0046] Figure 35-40 Additional ingestible devices are shown.

[0047] Figures 41A-41C Aspects of an ingestible device are shown.

[0048] Figures 42A-47C Aspects of an ingestible device are shown.

[0049] Fig.48A and 48B Shows the status of the ingestible device.

[0050] Figures 49A-49E A second piston for use in an ingestible device is shown.

[0051] Fig.50A and 50B An exploded view of the ingestible device is shown.

[0052] Fig.51A and 51B An exploded view of the ingestible device is shown.

[0053] Figures 52A-52D A view of an ingestible device is shown.

[0054] Fig.53A and 53B A view of a portion of an ingestible device is shown.

[0055] Fig.54A and 54B A view of a portion of an ingestible device is shown.

[0056] Fig.55 A view of a portion of an ingestible device is shown.

[0057] Fig.56 is an exemplary graph of liquid pressure versus time for experiments run at various pressures and / or nozzle diameters.

[0058] Fig.57 is an exemplary graph of jet impact force versus time for experiments run at various pressures and / or nozzle diameters.

[0059] Fig.58 is an exemplary graph of jet power versus time for experiments run at various pressures and / or nozzle diameters.

[0060] Fig.59 is an exemplary graph of jet velocity versus time for experiments run at various pressures and / or nozzle diameters.

[0061] Fig.60 is an exemplary graph of liquid pressure versus time for experiments run at various pressures and / or nozzle diameters.

[0062] Fig.61is an exemplary graph of jet impact force versus time for experiments run at various pressures and / or nozzle diameters.

[0063] Fig.62 is an exemplary graph of jet power versus time for experiments run at various pressures and / or nozzle diameters.

[0064] Fig.63 is an exemplary graph of jet velocity versus time for experiments run at various pressures and / or nozzle diameters.

[0065] Fig.64 is an exemplary graph of liquid pressure versus delivered volume for experiments run at various pressures and / or nozzle diameters.

[0066] Fig.65 is an exemplary graph of jet impact force versus delivered volume for experiments run at various pressures and / or nozzle diameters.

[0067] Fig.66 is an exemplary graph of jet power versus delivered volume for experiments run at various pressures and / or nozzle diameters.

[0068] Fig.67 is an exemplary graph of jet velocity versus delivered volume for experiments run at various pressures and / or nozzle diameters.

[0069] Fig.68 is an exemplary graph of jet impact force versus time for an experiment run at 320 psi.

[0070] Fig.69 is an exemplary graph of jet impact force versus time for additional experiments run at 320 psi.

[0071] Fig.70 is an exemplary diagram of PGN-OB1 PK in pigs.

[0072] Fig.71 is an exemplary graph of bioavailability versus deployment time.

[0073] Fig.72A is an exemplary graph of jet impact force versus time for an experiment run at 320 psi.

[0074] Fig.72A is an exemplary graph of jet impact force versus time for an experiment run at 320 psi using a 14% Kollicoat nozzle cap.

[0075] Fig.72B is an exemplary graph of jet impact force versus time for an experiment run at 320 psi using a 20% Kollicoat nozzle cap.

[0076] Fig.73A and 73B A dispensable substance container and a piston are shown.

[0077] Figures 74A-74C An alternative trigger housing is shown.

[0078] Figures 75A-75D An alternative trigger support is shown.

[0079] Figures 76A-76F An alternative piercer design is shown.

[0080] Figures 77A-77D A separate piercer mount is shown.

[0081] Figures 78A-78F A separation piercer flange is shown.

[0082] Figure 78G1-78G4 Shows Figures 78A-78F Detail options for the piercer flange.

[0083] Figures 78H-78L Additional piercer flange designs are shown.

[0084] Figures 79A-79C A trigger with a shear pin is shown.

[0085] Figures 80A-80J The device is shown with a trigger crown.

[0086] Figures 81A-81F The device is shown with a gas container cap.

[0087] Figures 82A-82I A device having a piercer coupled to a gas container is shown.

[0088] Figures 83A-83E A device with a detachable cap is shown.

[0089] Figures 84A-84B An arrangement using a two-piece gas container is shown.

[0090] Fig.84C and 84D An apparatus is shown having a release member that retains the cylinder cap in sealing engagement with the gas container.

[0091] Figures 85A-85D A device is shown having a release member comprising an O-ring.

[0092] Figures 85E1-85E4 is a schematic diagram of the movement of the O-ring.

[0093] Fig.85FA graph showing the percentage of released gas versus time is shown.

[0094] Fig.86 is a graph of adalimumab plasma concentrations over time.

[0095] Fig.87 is a graph showing changes in semaglutide plasma concentration over time.

[0096] Fig.88 is a graph of the jet force varying with time.

[0097] Fig.89 is a graph of the jet impact force at 400 psi versus time.

[0098] Fig.90 is a graph of the jet impact force at 350 psi versus time.

[0099] Fig.91 is a graph of the jet impact force at 320 psi versus time.

[0100] Fig.92 is a graph of the jet impact force at 280 psi versus time.

[0101] Figure 93 is a graph of jet force versus time.

[0102] Fig.94 is a cross-sectional view of an ingestible device having external gas release capability or point-of-use gas release capability.

[0103] Fig.95 is located in the retainer Fig.94 A perspective view of an ingestible device.

[0104] Fig.96 Yes Fig.95 A partial cross-sectional view of an ingestible device is shown.

[0105] Fig.97 yes Fig.96 Cross-sectional view of an ingestible device during initial gas release.

[0106] Fig.98 yes Fig.94 and Fig.97 A cross-sectional view of an ingestible device, now shown after actuation is complete.

[0107] Fig.99 and Fig.100 An alternative second piston is shown that is configured to make filling of the drug module easier and provide a higher peak jet force.

[0108] Fig.100 and Fig.101 is a graph of trigger data.

[0109] Fig.101 and 102 is a graph showing the timing of piercer movement following dissolution or degradation of a self-releasing member or trigger. DETAILED DESCRIPTION OF THE INVENTION

[0111] definition

[0112] "Ingestible," as used herein with reference to a device, means that the device can be swallowed whole.

[0113] As used herein for any material, "distributable (of)" refers to any material that can be released from an ingestible device as disclosed herein or from a component (e.g., reservoir) of the device. For example, a distributable material can be a therapeutic agent disclosed herein and / or a formulation comprising a therapeutic agent disclosed herein. Distributable material can be a fluid, such as a liquid, a suspension, or a semisolid. In such an embodiment, the material can be converted into a fluid before being delivered from an ingestible device. In some embodiments, the therapeutic agent is a small molecule. In other embodiments, the therapeutic agent is a macromolecule, such as a biopharmaceutical. In some embodiments, the distributable material delivered as described herein is particularly suitable for treating diseases and disorders of the endodermal layer, for example, compared with subcutaneous or intravenous administration, it can be more effective in gut-associated lymphoid tissue (GALT) or liver systems. Distributable material can have a viscosity of at least about 0.5 centipoise (cP) to about 100 cP, 2 cP to about 50 cP, or about 5 cP to about 25 cP.

[0114] As used herein, the term "enteric" refers to a material that allows for transition to a desired location in the GI tract (e.g., through the stomach to the intestine) before dissolving / degrading / eroding due to exposure to certain conditions of the GI tract (e.g., pH, temperature, enzymes). Enteric materials can prevent the drug from being degraded by gastric juices and enzymes. In some embodiments, the enteric composition (e.g., when forming a coating (coating) on ​​the housing of an ingestible device) is selected from: a mixture of fats and fatty acids; shellac and shellac derivatives; and cellulose acetate phthalate. The enteric material can be an enteric polymer. Enteric polymers can remain insoluble in the stomach, but dissolve at a higher pH in the intestine (e.g., small intestine or large intestine), and are used to deliver the drug to the intestine. Examples include - Eudragit L100-55 mixture methacrylic copolymer); Evonik's Eudragit L 100-55 methacrylic copolymer, Eudragit L 30D-55 methacrylic copolymer (30%), Eudragit L 100 methacrylic copolymer, Eudragit L 12,5 methacrylic copolymer (12.5%), Eudragit S100 methacrylic copolymer, Eudragit S12,5 methacrylic copolymer (12.5%), Eudragit FS 30D methacrylic copolymer (30%); Kerry's SheffCoat ENT cellulose acetate phthalate, acrylate copolymer, HPMC-P; Eastman's CAP NF cellulose acetate phthalate; Sensient's PROTECT TM ENTERIC Shellac & Sodium Alginate.

[0115] In certain embodiments, enteric material dissolves in the small intestine and is suitable for small intestine release.The example of such enteric material includes but is not limited to cellulose derivatives, such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and RL100 (such as HP-55), malic acid-propane 1,2-diol, polyvinyl acetate phthalate, anionic polymers of methacrylic acid and methyl methacrylate, hydroxypropyl cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylate-methacrylic acid copolymer, styrene, maleic acid copolymer, shellac etc. Another suitable enteric material is the aqueous emulsion of ethyl acrylate methacrylic acid copolymer or hydroxypropyl methylcellulose acetate succinate (HPMAS).In some embodiments, enteric material dissolves in the large intestine and is suitable for colon release.The enteric material suitable for large intestine (such as colon) release is well known to those skilled in the art. In some embodiments, the degradation of the coating is microbially triggered, for example, bacteria in the colon enzymatically trigger the degradation of the coating. In some embodiments, the coating is a pH-dependent polymer that is insoluble at low pH but becomes increasingly soluble as the pH increases. In some embodiments, the coating is a polymethacrylate having a pH-dependent dissolution threshold of about pH 6.0 to about 7.0. Examples of suitable enteric materials include, but are not limited to, chitosan, alginates (e.g., as calcium salts), L (e.g. 100), S (e.g. S100), L (e.g. L-30D), FS (e.g. In some embodiments, the colon-specific degradation of enteric materials can be based on the presence of microorganisms that only reside in the colon, more particularly, biodegradable enzymes produced by these microorganisms. In general, such microorganisms are anaerobic bacteria, such as Bacteroides, Bifidobacteria, Enterobacteria, Eubacteria, Clostridia, Enterococci, and Ruminococcus, etc. These micro floras meet their energy needs by fermenting various types of substrates (such as polysaccharides, disaccharides, and trisaccharides, etc.) that are not digested in the small intestine. These polymers are stable in the environment of the stomach and small intestine. When reaching the colon, the polymer undergoes degradation caused by enzymes, or the decomposition of the polymer backbone causes a subsequent reduction in its molecular weight, thereby losing mechanical strength.

[0116] As used herein, the term "jet" refers to a collimated stream of fluid (e.g., liquid or suspension) that is stable and does not disintegrate into a spray. A jet can be formed by forcing a fluid (e.g., liquid or suspension) through an opening in an ingestible device. Typically, the jet remains in a stable form and is able to achieve its intended purpose by maintaining (e.g., for penetrating a surface) appropriate properties such as its diameter and / or velocity.

[0117] As used herein, "jet diameter" is the cross-sectional diameter of a jet at a given location.

[0118] As used herein, "average jet diameter" refers to the average cross-sectional diameter of the jet between the location where the jet is formed (e.g., the nozzle opening through which the dispensable substance is delivered from the ingestible device) and the location where the jet impacts the GI tissue of the subject.

[0119] As used herein, "jet stability length" refers to the distance from an opening of an ingestible device (eg, a nozzle opening) at which a dispensable substance delivered through the opening remains in the form of a jet.

[0120] As used herein, "jet velocity" is the average fluid velocity across a cross-section of a jet at a given point in time.

[0121] As used herein, "peak jet velocity" refers to the maximum jet velocity of a jet at the interface of a lumen and a lumen-facing surface of the GI tract. Generally speaking, peak jet velocity is reached upon initial delivery of a dispensable substance from an ingestible device.

[0122] As used herein, "minimum jet velocity" refers to the minimum velocity of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, the minimum jet velocity is reached at the end of delivery of the dispensable substance from the ingestible device.

[0123] As used herein, "mean jet velocity" and "average jet velocity" refer to the average velocity of the jet at the interface of the lumen and the lumen-facing surface of the GI tract determined over the time period for the ingestible device to deliver the dispensable substance.

[0124] As used herein, "peak jet power" refers to the maximum power of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, peak jet power is reached upon initial delivery of the dispensable substance from the ingestible device.

[0125] As used herein, "minimum jet power" refers to the minimum power of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, the minimum jet power is reached at the end of delivery of the dispensable substance from the ingestible device.

[0126] As used herein, "mean jet power" and "average jet power" refer to the average power of the jet at the interface of the lumen and the lumen-facing surface of the GI tract determined over the time that the ingestible device delivers the dispensable substance.

[0127] As used herein, "jet power during delivery" refers to the jet power at the interface of the lumen of a subject and the mucosa of the GI tract.

[0128] As used herein, "jet pressure" refers to the pressure of the jet at the interface of the lumen and the surface of the GI tract facing the lumen. As an example, the jet pressure can be the pressure of the jet measured at the intestinal wall. In some embodiments, the jet pressure is referred to herein as "impact pressure".

[0129] As used herein, "peak jet pressure" refers to the maximum pressure of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, peak jet pressure is reached upon initial delivery of the dispensable substance from the ingestible device.

[0130] As used herein, "minimum jet pressure" refers to the minimum pressure of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, the minimum jet pressure is reached at the end of delivery of the dispensable substance from the ingestible device.

[0131] As used herein, "mean jet pressure" and "average jet pressure" refer to the average pressure of the jet at the interface of the lumen and the lumen-facing surface of the GI tract determined over the time that the ingestible device delivers the dispensable substance.

[0132] As used herein, "jet force" refers to the force of a jet at the interface of a lumen and a lumen-facing surface of the GI tract. In some embodiments, the jet force is referred to herein as an "impact force."

[0133] As used herein, "peak jet force" refers to the maximum force of the jet at the interface of the lumen and the surface of the GI tract facing the lumen. Generally speaking, the peak jet force is reached when the dispensable material is initially delivered from the ingestible device. In some embodiments, the peak jet force is referred to as "impact force" herein.

[0134] As used herein, "minimum jet force" refers to the minimum force of a jet at the interface of a lumen of a subject and a mucosa of the GI tract. Generally speaking, the minimum jet force is reached at the end of delivery of the dispensable substance from the ingestible device.

[0135] As used herein, "mean jet force" and "average jet force" refer to the average pressure of the jet at the interface of the lumen and the lumen-facing surface of the GI tract determined over the time that the ingestible device delivers the dispensable substance.

[0136] As used herein, "fluid volume" refers to the volume of a dispensable substance contained in an ingestible device.

[0137] As used herein, "initial fluid volume" refers to the volume of the dispensable substance contained in the ingestible device just before the dispensable substance is delivered from the ingestible device.

[0138] As used herein, "final fluid volume" refers to the volume of the dispensable substance contained in the ingestible device just after delivery of the dispensable substance from the ingestible device is complete.

[0139] As used herein, "delivered fluid volume" refers to the volume of a dispensable substance delivered from an ingestible device. In some embodiments, the delivered fluid volume is less than the fluid volume.

[0140] As used herein, an "end circle" is the radius on the curve at the end of the housing of an ingestible device.

[0141] As used herein, "fluid pressure" refers to the pressure within a volume of a fluid.

[0142] As used herein, "peak fluid pressure" refers to the maximum pressure generated in a volume of fluid. Typically, the peak fluid pressure is reached upon initial delivery of the dispensable substance from the ingestible device. In some embodiments, the peak fluid pressure is referred to herein as "the internal pressure on the drug formulation in the device prior to release from the device."

[0143] As used herein, "minimum fluid pressure" refers to the minimum pressure generated in a fluid volume. Typically, the minimum fluid pressure is reached at the end of delivery of the dispensable substance from the ingestible device.

[0144] As used herein, "fluid pressure during delivery" refers to the pressure in the volume of a fluid as the volume of the fluid decreases during the delivery process.

[0145] As used herein, "nozzle" refers to the passage between the fluid reservoir space and the external environment. Typically, in embodiments where a nozzle is used, the pressure in the fluid volume creates a high velocity flow of fluid through the nozzle to create a fluid jet at the opening of the nozzle through which the dispensable substance exits the ingestible device and enters the external environment of the ingestible device.

[0146] As used herein, "nozzle diameter" refers to the diameter of the opening of the nozzle at the opening of the nozzle through which the dispensable substance exits the ingestible device and enters the environment external to the ingestible device.

[0147] As used herein, "nozzle length" refers to the length of the opening of the nozzle.

[0148] As used herein, "nozzle stand-off distance" refers to the distance between: 1) the opening of the nozzle through which the dispensable substance exits the ingestible device and enters the external environment of the ingestible device; and 2) the interface between the lumen and the lumen-facing surface of the GI tract.

[0149] As used herein, the "internal pressure" of an ingestible device refers to the pressure applied to the dispensable material (e.g., a therapeutic agent or a formulation containing a therapeutic agent) contained in the ingestible device before the dispensable material is delivered from the ingestible device. In some embodiments, the internal pressure is provided by a driving force generator of the ingestible device. In certain embodiments, the internal pressure is greater than the fluid pressure. For example, this may be due to friction acting on the drive connector of the ingestible device, such as O-ring friction. This friction is referred to as "piston friction" in this article.

[0150] As used herein, "nozzle pressure" refers to the pressure of the dispensable substance at the nozzle opening measured at the surface facing the interior of the nozzle when the dispensable substance is delivered from the ingestible device. Generally speaking, for a given ingestible device at a given point in time, the nozzle pressure is approximately the same as the fluid pressure.

[0151] As used herein, "topical delivery" or "topical application" refers to a route of administration of a dispensable substance (e.g., a therapeutic agent or a pharmaceutical formulation containing a therapeutic agent) in which the dispensable substance is delivered to a localized area of ​​the body or the surface of a body part, regardless of the location of the effect; more particularly, topical administration of the dispensable substance includes releasing the dispensable substance into the lumen of the GI tract of a subject, the lumen-facing surface of the GI tract, the mucosa and / or lining of the gastrointestinal tract, including but not limited to surfaces, mucosa or linings containing one or more disease sites (e.g., gastrointestinal mucosal lesions). The effect of a topical delivery or topical application of a dispensable substance may be local to the site of topical application, or remote from the site of topical application (e.g., distal thereto).

[0152] As used herein, "epithelial delivery" or "epithelial administration" refers to a route of administration of a dispensable substance (e.g., a therapeutic agent or a pharmaceutical formulation containing a therapeutic agent) in which the dispensable substance is delivered directly into the mucus or onto the epithelium of the GI tract (e.g., the small intestine or large intestine) of a subject, but does not exceed the epithelial layer, from which the dispensable substance can act locally or peripherally. In some embodiments of epithelial delivery or epithelial administration, the therapeutic agent can move deeper into the GI tissue (i.e., through the epithelial layer) away from the direct delivery site, for example, by diffusion or active transport.

[0153] As used herein, "transepithelial delivery" or "transepithelial administration" refers to a route of administration of a dispensable substance (e.g., a therapeutic agent or a pharmaceutical formulation containing a therapeutic agent) wherein the dispensable substance is delivered directly to the submucosal layer of the GI tract of a subject through the epithelial layer of the mucosa of the GI tract; optionally, at least a portion of the dispensable substance is delivered directly across the epithelial layer to the mucosal region below the epithelial layer. In embodiments of transepithelial delivery in which a portion of the dispensable substance is delivered directly to the mucosal region below the epithelial layer, at least some (e.g., all) of the portion of the dispensable substance is delivered directly to the lamina propria. Once the therapeutic agent or pharmaceutical formulation containing the therapeutic agent is delivered directly across the epithelial layer of the GI tract, the therapeutic agent can be systemically exposed to the subject.

[0154] As used herein, "triggering" or "triggering event" or "actuation" refers to a change in the condition or position of a component that causes movement within the device, thereby causing the device to deliver a dispensable substance. A trigger or triggering component or element, also called a release component, is an element that provides or facilitates triggering.

[0155] As used herein, "about" means the disclosed number, plus or minus 10% of that number.

[0156] General Introduction

[0157] Figure 1A Schematically describe the different regions of healthy intestinal tissue presented in cross section. These regions include the lumen of the GI tract, the mucus of the GI tissue, the mucosa of the GI tissue, and the submucosa of the GI tissue. The mucosa of the GI tissue includes an epithelial layer and a lamina propria. The muscularis mucosa separates the mucosa from the submucosa. The muscularis extrema is located below the submucosa. Figure 1B The corresponding area of ​​diseased intestinal tissue presented in cross section is schematically depicted.

[0158] The ingestible devices described herein can deliver therapeutic agents via topical delivery (without direct delivery to mucus, mucosa, or submucosa), epithelial delivery (direct delivery to mucus or epithelium without direct delivery across the epithelial layer to the mucosa or submucosa), or transepithelial delivery (direct delivery to the submucosa and / or to a mucosal region beneath the epithelial layer (e.g., the lamina propria).

[0159] In general, the delivery form may depend on the design of the ingestible device and the parameters used with the device (e.g., internal pressure, fluid pressure, number of nozzles, nozzle design). Keeping other parameters constant, at relatively low fluid pressures and / or internal pressures, the therapeutic agent may be delivered surface, while higher fluid pressures and / or internal pressures may result in epithelial delivery, and still higher fluid pressures and / or internal pressures may result in transepithelial delivery. During transepithelial delivery, a bolus of the therapeutic agent initially contained in the dispensable substance may be formed within the submucosal layer and / or into a mucosal region (e.g., lamina propria) below the epithelial layer.

[0160] In some embodiments, the following is established. The ingestible device is designed to deliver dispensable substances, such as therapeutic agents or pharmaceutical formulations containing therapeutic agents, through the epithelial layer of the mucosa of the GI tract. In some embodiments, the dispensable substance is a solution formulation; optionally, a suspension. In some embodiments, the dispensable substance enters the submucosal layer of the small intestine and / or to the mucosal region (e.g., lamina propria) below the epithelial layer, where it can be absorbed by the whole body. After the patient swallows the device, it passes through the GI tract and eventually reaches the small intestine. The device includes a restraining mechanism, optionally a triggering mechanism (e.g., a degradable and / or erodible coating, such as an enteric coating, which partially or completely degrades and / or erodes when the device reaches the desired position in the GI tract). The desired position can be the small intestine or the large intestine. When the device is configured to be delivered across the epithelial GI tract to the submucosal layer and / or to the mucosal region (e.g., lamina propria) below the epithelial layer, the preferred position can be the small intestine. As the restraining element is removed, relative movement between certain components (e.g., sliding of components) occurs such that one or more openings in the ingestible device (e.g., in a compartment containing a dispensable substance (e.g., a reservoir, sometimes referred to herein as a "drug reservoir," "storage reservoir," or "substance reservoir")) align with one or more additional openings (e.g., one or more nozzles) in the ingestible device (e.g., in a housing). When the ingestible device is now in this open position, a force (e.g., generated by a force generator and / or transmitted by a drive coupling (e.g., a membrane or piston) forces the dispensable substance to exit the device from the drug reservoir via one or more openings (e.g., one or more nozzles). The dispensable substance is delivered as a jet of fluid (e.g., liquid) through the epithelial layer of the mucosa of the GI tract and directly into the submucosal layer and / or into the mucosal region below the epithelial layer (e.g., lamina propria) in the form of a single or multiple boluses. After the device is swallowed, the device travels through the GI tract (mouth, esophagus, stomach, duodenum, jejunum, ileum, cecum, and colon), ultimately exiting the GI tract via the anus.

[0161] Therefore, in general, the ingestible device disclosed herein provides the delivery of a therapeutic agent to the GI tract of a subject. On the one hand, the present disclosure relates to the trans-epithelial delivery of a dispensable substance (e.g., a therapeutic agent or a formulation comprising a therapeutic agent) to the GI tract of a subject. Accordingly, the present disclosure provides a kind of ingestible device, which can deliver a dispensable substance (e.g., a therapeutic agent or a formulation comprising a therapeutic agent) directly to the submucosal layer of the GI tract of the subject and / or to the mucosal region (e.g., lamina propria) below the epithelial layer, which can cause the therapeutic agent to be exposed to the whole body of the subject. In such an embodiment, the ingestible device is configured to deliver the dispensable substance directly across the epithelial cell layer of the mucosa of the GI tract and to the submucosal layer and / or to the mucosal region (e.g., lamina propria) below the epithelial layer, where the therapeutic agent so delivered can be used for systemic absorption. In some embodiments, systemic exposure of the therapeutic agent is achieved by delivering the dispensable substance transepithelially into the submucosal layer of the small intestine (e.g., in the duodenum, jejunum, and / or ileum) and / or into the mucosal region below the epithelial layer (e.g., lamina propria). In some further embodiments, transepithelial delivery delivers the dispensable substance directly into the submucosal layer of the GI tract and / or into the mucosal region below the epithelial layer (e.g., lamina propria) such that the percentage of systemic absorption of the therapeutic agent via transepithelial delivery relative to intravenous or subcutaneous administration is at least about 10% (e.g., at least about 15%, at least about 20%, at least about 25%, or more).

[0162] Direct delivery of therapeutic agents via transepithelial delivery to the submucosa and / or to mucosal regions beneath the epithelial layer (e.g., the lamina propria) may also or alternatively provide a therapeutic effect locally at the direct delivery site and / or remote from (e.g., distal to) the direct delivery site.

[0163] Transepithelial delivery can deliver a first portion of the dispensable substance directly to the submucosal layer of the GI tract and a second portion of the dispensable substance directly to the mucosa, all or other portions of which can be delivered directly to the lamina propria. In some embodiments, the second portion of the dispensable substance delivered to the mucosa (e.g., lamina propria) of the GI tract via transepithelial delivery can provide a therapeutic effect locally at the direct delivery site and / or distal to the direct delivery site (e.g., distal end thereof).

[0164] On the other hand, the present disclosure relates to the epithelial delivery of dispensable substances (e.g., therapeutic agents or formulations comprising therapeutic agents) to the GI tract of a subject. Accordingly, the present disclosure provides a kind of ingestible device, which is configured to deliver dispensable substances (e.g., therapeutic agents or formulations comprising therapeutic agents) directly to the mucus of the small intestine or large intestine, but not across the epithelial layer of the mucosa, from which it can provide a therapeutic effect locally and / or away from the direct delivery site (e.g., its distal end) at the direct delivery site. In some further embodiments, the ingestible device directly delivers the dispensable substance so that it contacts the surface of the mucosal epithelial cell layer facing the lumen, but as previously described, epithelial delivery does not directly deliver the dispensable substance across the epithelial layer of the mucosa. In some embodiments, the device is configured so that the dispensable substance is delivered from the device with enough force to provide epithelial delivery, and the force is lower than the force required for transepithelial delivery to the GI tract. In some further embodiments, epithelial delivery delivers the dispensable substance directly into the mucus of the GI tract such that the percentage of systemic absorption relative to the therapeutic agent delivered via the epithelium for intravenous or subcutaneous administration is greater than the percentage of surface delivery, but less than the percentage of transepithelial delivery. In other embodiments, epithelial delivery delivers the dispensable substance directly into the mucus of the GI tract such that the percentage of systemic absorption relative to the therapeutic agent delivered via the epithelium for intravenous or subcutaneous administration is about 0.5% to about 10% or greater (e.g., about 0.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, greater).

[0165] Accordingly, the present invention provides a new systemic delivery device and method for delivering therapeutic agents to the small intestinal mucosa and / or submucosal layer by jet injection. The current administration method of most macromolecular therapeutic agents is subcutaneous (SC), intramuscular (IM) or intravenous push (IV) injection for systemic circulation. The device and method described herein provide an alternative administration route of current injectable drugs, which can bring greater convenience and compliance because they minimize or avoid the challenges of arrangement coordination, patient compliance and compliance challenges, pain and discomfort associated with traditional administration routes.

[0166] Furthermore, by providing higher concentrations of therapeutic agents in GI tissues, the devices and methods described herein are particularly well suited for treating diseases and disorders of the endoderm, including the liver.

[0167] In some embodiments of epithelial delivery, therapeutic agents delivered directly to the mucus of the GI tract via epithelial delivery may undergo active or passive transport or diffusion across the epithelial layer. Once across the epithelial layer, the therapeutic agent may provide a therapeutic effect locally at the site of direct delivery and / or remotely from the site of direct delivery (e.g., distally thereof). In some embodiments, the therapeutic agent binds to a therapeutic target present in the GI epithelial layer, or induces other pharmacodynamic effects locally at the site of delivery or remotely from the site of delivery via immune cells or tissues (e.g., dendritic cells, lymphocytes, mucosa-associated lymphoid tissue) in the GI tract.

[0168] In yet another aspect, the present disclosure relates to surface delivery of a dispensable substance (e.g., a therapeutic agent or a formulation comprising a therapeutic agent) to the GI tract of a subject. Accordingly, the present disclosure provides an ingestible device configured to deliver a dispensable substance (e.g., a therapeutic agent or a formulation comprising a therapeutic agent) into the lumen of the small or large intestine and / or to mucus or other surfaces of the GI tract facing the lumen (e.g., a diseased surface), from which it can provide a therapeutic effect locally at the delivery site and / or away from the delivery site (e.g., its distal end). In some embodiments, the device is configured so that the dispensable substance is delivered from the device with sufficient force to deliver the dispensable substance surface-wise, and the force is lower than the force required for epithelial or transepithelial delivery to the GI tract. In some embodiments, surface delivery to the GI tract results in reduced systemic absorption of the therapeutic agent compared to transepithelial delivery to the GI tract, intravenous or subcutaneous delivery.

[0169] In some further embodiments, topical delivery delivers the dispensable substance into the lumen and / or onto mucus or other surfaces of the GI tract facing the lumen such that the percentage systemic absorption of the topically delivered therapeutic agent relative to intravenous or subcutaneous administration is less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%. In some embodiments, topical delivery to the GI tract results in negligible or no systemic absorption of the therapeutic agent compared to transepithelial delivery to the GI tract, intravenous or subcutaneous delivery.

[0170] The surface-delivered dispensable material may spread on the mucus or other surface of the GI tract that faces the lumen, thereby coating the surface of the GI tract at and / or away from the delivery site (e.g., its distal end). In some embodiments, upon or after the surface delivery of the dispensable material, the therapeutic agent may undergo transport (e.g., diffusion) from the mucus surface into the mucus, and optionally, active or passive transport or diffusion across the epithelial layer of the mucosa.

[0171] The mucus and / or epithelial layer of the mucosa can be destroyed or even missing, such as in patients with diseases or conditions of the GI tract. In such embodiments, the dispensable material surface delivery to the GI tract of the patient can provide the dispensable material to be delivered directly to the surface of the GI tract facing the lumen, such as mucosal tissue exposed by the destruction and / or lack (for example, due to a disease or condition, both the mucus layer and / or the epithelial layer are completely or partially missing or damaged in the part of the GI). For example, in some embodiments, the dispensable material surface delivery to the GI tract of the patient can provide the surface delivery to one or more lesions of the GI tract. In some embodiments, the disease or condition is inflammatory bowel disease. In some further embodiments, the inflammatory bowel disease is ulcerative colitis. In some other embodiments, the inflammatory bowel disease is Crohn's disease.

[0172] Accordingly, the present invention provides a new systemic delivery device and method for delivering therapeutic agents to the small intestinal mucosa and / or submucosal layer by jet injection. The current method of administration of most macromolecular therapeutic agents is subcutaneous (SC), intramuscular (IM) or intravenous push (IV) injection for systemic circulation. The device and method described herein provide an alternative route of administration for current injection drugs, which can bring greater convenience and compliance because they minimize or avoid the challenges of arrangement coordination, patient compliance and compliance challenges, pain and discomfort associated with traditional routes of administration.

[0173] Furthermore, by providing higher concentrations of therapeutic agents in GI tissues, the devices and methods described herein are particularly well suited for treating diseases and disorders of the endoderm, including the liver.

[0174] Device Description

[0175] generally

[0176] In general, the ingestible device is suitable for being swallowed by the patient and passing through the GI tract of the patient safely and effectively. Generally, the device can be in the shape of a capsule, a pill or any other swallowable form that can be consumed orally by the subject. In some embodiments, the ingestible device can be swallowed voluntarily under medical supervision or in a home use environment before subsequent intake with guidance. Generally, the ingestible device is intended for a single subject, single use. The ingestible device can have a sufficiently high density so that the ingestible device sinks into the human gastric juice, for example, the unfilled ingestible device can have a density greater than 1.01g / cm3. The ingestible device can have a maximum size that allows the ingestible device to pass through the GI tract of ordinary people. In some embodiments, the ingestible device is configured to prevent rolling in the small intestine of the people. For example, the ingestible device has sufficient length so that it will not roll in the small intestine of the people before, during or after the dispensable material is released. Generally, the ingestible device is configured to deliver a sufficient amount of therapeutic agents contained in the dispensable material to be effectively used for its intended purpose. Generally, the patient contact portion (e.g., outer surface) of the ingestible device and the dispensable material contact portion are biocompatible. Preferably, the device can withstand indirect bite forces without damaging the shell or causing leakage. As an example, when accommodating dispensable materials, the ingestible device can withstand a bite force of at least about 60 Newtons (N). Typically, unless otherwise intended (see discussion below), the components of the ingestible device can withstand exposure to the expected pH range in the human GI tract without significant functional loss, significant structural damage or significant leakage. As an example, in some embodiments, the ingestible device can withstand being immersed in a fluid environment of pH 1.5 ± 0.5 for at least about 24 hours without significant functional loss, significant structural damage or significant leakage. In general, the ingestible device can maintain an external fluid barrier between the inside of the ingestible device and the GI tract of the subject during transportation by it. Typically, the ingestible device can withstand the external fluid pressure to which it is exposed during use without significant functional loss, significant structural damage or significant leakage. As an example, in some embodiments, the ingestible device does not experience significant loss of function, significant structural damage, or significant leakage when exposed to a sustained pressure of at least about 2 psig for at least about 24 hours and / or when exposed to a transient pressure of at least about 5 psig for at least about 1 minute.

[0177] In general, the ingestible devices disclosed herein include the following features.

[0178] shell

[0179] In some embodiments, the ingestible device includes a shell configured to maintain its mechanical integrity during the use of the ingestible device. In some embodiments, the shell has a first part and a second part. In some further embodiments, the shell has a first actuating member on the shell and a second actuating member in the shell. In some embodiments, the storage reservoir is located in the shell, wherein the storage reservoir is configured to store dispensable substances. In some embodiments, the shell has an opening that is fluidly connected to the storage reservoir. In some embodiments, the ingestible device adopts an electrolytic mechanism to produce one or more openings in the ingestible device, wherein the substance can be distributed through the opening, as described in WO2019178071. For example, the shell can include an external electrolytic circuit (electrolytically erodible surface on the outside of the device), whereby the surrounding gastric fluid is an electrolyte that completes the electrolytic circuit between the anode and the cathode. By sufficient bias voltage (e.g., 1.5-15 volts, e.g., 3-5 volts), the anode will be electrolytically eroded or dissolved, so that an opening is produced in the shell within the desired time interval. In some embodiments, one or more openings produced by the electrolysis mechanism are connected to one or more nozzles, thereby allowing trans-epithelial, epithelial or surface delivery as described herein. In some embodiments, the ingestible device includes an enteric coating on the shell. In certain embodiments, the enteric coating only covers certain areas of the shell. The shell can be designed to withstand the chemical and mechanical environment of the GI tract (for example, the influence of muscle contraction force and concentrated hydrochloric acid in the stomach). The range of materials that can be used for the shell is very wide. Examples of these materials include, but are not limited to: thermoplastics, fluoropolymers (such as fluorinated ethylene propylene (FEP) and perfluoroalkoxy (PFA)), elastomers, stainless steel and glass that meet the biocompatibility specifications of ISO 10993 and USP Class VI; and any other suitable materials and combinations thereof. In certain embodiments, these materials may further include: a liquid silicone rubber material (such as a NuSil®) having a hardness level of 10 to 90 measured using a durometer; TM Manufactured by MED-4942 TM ), soft biocompatible polymeric materials such as, but not limited to, polyvinyl chloride (PVC), polyethersulfone (PE), polyethylene (PE), polyurethane (PU), or polytetrafluoroethylene (PTFE), and rigid polymeric materials coated with soft or flexible biocompatible materials (e.g., poly(methyl methacrylate) (PMMA) materials coated with silicone polymers). Using different materials for different components can allow for the functionalization of certain surfaces to interact with proteins, antibodies, and other biomarkers. For example, in an ingestible device, As a material for movable parts, to reduce friction between these parts. Other example materials can include other materials commonly used in micro-manufacturing, such as polydimethylsiloxane (PDMS), borosilicate glass and / or silicon. Although specific materials can be referred to as used to construct the device for illustrative purposes herein, the listed materials are not intended to be restrictive, and those skilled in the art can easily transform the device into any number of different materials without affecting the overall operation or function of the device. In some embodiments, the shell of the ingestible device can be made of a type of plastic (such as a photosensitive acrylic polymer material or an inert polycarbonate material). The shell can also be formed using materials that can be sterilized by chemicals. In some embodiments, the wall of the shell can have a thickness of, for example, about 0.5 millimeters to about 1 millimeter. In some embodiments, in addition to biocompatibility, the material of the shell is also non-ferrous and non-magnetic. Such materials include various plastics (such as PVC or polycarbonate). Optionally, the shell can include metal-based materials, such as alloys, stainless steel or substantially pure metals. Such materials can be sterilized without affecting the mechanical work of the ingestible device or the outer surface of the ingestible device. In some embodiments, metal-based materials are compatible with dispensable substances during long-term storage duration. Various stainless steel alloys meet these standards, including SAE grades 303, 304, 304L, 316, 316L, 440. Taking into account nickel content, purity and / or traceability, in some embodiments, stainless steel grades are approved for use as surgical implant materials, such as ASTM grades F138, F1314, F1586, F2229 or F2581. The walls of the shell of the ingestible device are usually thick enough to withstand the internal and external pressures to which they are exposed without significant functional loss, significant structural damage or significant leakage. In general, the wall of the shell is ideally as thin as possible to enhance the volume that can be used to accommodate dispensable substances. As an example, in some embodiments, the wall is about 0.05mm to about 0.5mm thick (for example, if made of metal-based materials such as stainless steel) or about 0.1 to about 1mm thick (for example, if made of plastics such as polycarbonate). In general, the housing is made of a material having a coefficient of thermal expansion that is low enough so that the device does not deform significantly at temperatures encountered during transport and storage or in the GI tract. In some embodiments, the walls of the housing are made of an electrolytically erodible surface as described in WO2019178071. For example, in some embodiments, the housing includes an electrolytically erodible valve that is coupled to a nozzle for exposing a liquid volume to its surroundings. The exposed metal anode material as the valve may include a metal alloy or substantially pure metal that is acceptable for human ingestion in terms of the amount of electrolysis during the opening of the valve, taking into account its biocompatibility.It may be desirable to have the metal thickness in the valve region be small (e.g., to reduce the time and amount of current used to open the valve). For example, the metal portion of the drug container may be 0.025 mm thick on a diameter that matches or slightly exceeds the diameter of the attached nozzle (e.g., 0.60 mm). In general, the thickness of the metal in the valve region may be in the range of 0.002 mm to 0.200 mm.

[0180] The housing of the ingestible device can be assembled from multiple modules. For example, in some embodiments, the housing is assembled from two modules. In such an embodiment, one of the modules can accommodate dispensable substances ("drug module"), and another module can accommodate a driving force generator and a drive coupling ("drive module"). Typically, the drug module includes a housing portion with a suitable size, shape and material as discussed herein. Typically, the housing portion is sterilized, and the dispensable substance is then arranged in the housing under aseptic conditions. Optionally, a sterile seal (such as a sterile foil seal) is incorporated into the drug module. The components of the drug module (such as housing portion, driving force generator, drive coupling) are assembled in a clean environment. Subsequently, the drug module and the drive module are combined to form an ingestible device. Representative examples of modules, their individual components and their combinations for forming an ingestible device are provided elsewhere herein.

[0181] Typically, the size and shape of the ingestible device is designed for relatively safe and efficient movement and intended use within the GI tract of a subject. In certain embodiments, the ingestible device is a capsule having an industry standard size. For example, in some embodiments, the ingestible device is configured as a 00 capsule or a 000 capsule.

[0182] In certain embodiments, the housing of the ingestible device has a length of at least about 20 mm (e.g., at least about 21 mm, at least about 22 mm, at least about 23 mm) and / or at most about 28 mm (e.g., at most about 27 mm, at most about 26 mm).

[0183] In some embodiments, the housing of the ingestible device has a diameter of at least about 7 mm (e.g., at least about 7.5 mm, at least about 8 mm, at least about 8.5 mm, at least about 9 mm, at least about 9.5 mm) and / or at most about 12 mm (e.g., at most about 11.5 mm, at most about 11 mm, at most about 10.5 mm, at most about 10 mm, at most about 9.5 mm, at most about 9 mm).

[0184] In certain embodiments, the housing of the ingestible device has an aspect ratio (ratio of length to width) of at least about 0.75 (e.g., at least about 1) and / or at most about 4 (e.g., at most about 3, at most about 2). In some embodiments, the housing of the ingestible device has an aspect ratio of about 0.75 to 4 (e.g., about 1 to about 3, about 1 to about 2). For example, in some embodiments, the housing aspect ratio is about 1.5:1 (length:diameter). In some other embodiments, the housing aspect ratio is about 2:1 (length:diameter).

[0185] In certain embodiments, the housing of the ingestible device has a wall thickness of at least about 0.05 mm (e.g., at least about 0.5 mm, at least about 0.6 mm, at least about 0.7 mm) and / or at most about 1 mm (e.g., at most about 0.9 mm, at most about 0.8 mm). In certain embodiments, the ingestible device has a wall thickness of about 0.05 mm to about 0.5 mm. In some embodiments, the ingestible device has a wall thickness of about 0.1 mm to about 1 mm. In certain embodiments, the wall thickness of one area of ​​the housing of the ingestible device may be different from the wall thickness of a different area of ​​the housing of the ingestible device.

[0186] In some embodiments, the housing of the ingestible device has a splined or spherical end circle. In certain embodiments, the ingestible device has an end circle of about 1 mm to about 2 mm (e.g., about 1.5 mm). In some embodiments, the ingestible device has an end circle of about 4 mm to about 4.5 mm (e.g., about 4.25 mm). In certain embodiments, the ingestible device has an end circle of about 4.9 to about 5 mm (e.g., about 4.95 mm). In some embodiments, the ingestible device has an end circle of about 5.4 mm to about 5.6 mm (e.g., about 5.5 mm).

[0187] In certain embodiments, the housing of the ingestible device has an internal volume of at least about 700 μL (e.g., at least about 750 μL, at least about 800 μL, at least about 850 μL) and / or at most about 1700 μL (e.g., at most about 1650 μL, at most about 1600 μL, at most about 1500 μL, at most about 1400 μL, at most about 1300 μL, at most about 1200 μL).

[0188] In one exemplary embodiment, the housing of the ingestible device has a diameter of about 11 mm, a length of about 26 mm, a wall thickness of about 0.8 mm, an end circle of about 1.5 mm, and an internal volume of about 1685 μL.

[0189] In another exemplary embodiment, the housing of the ingestible device has a diameter of about 11 mm, a length of about 26 mm, a wall thickness of about 0.8 mm, an end rounding (spherical) of about 5.5 mm, and an internal volume of about 1475 μL.

[0190] In a further exemplary embodiment, the housing of the ingestible device has a diameter of about 9.9 mm, a length of about 26 mm, a wall thickness of about 0.8 mm, an end circle of about 1.5 mm, and an internal volume of about 1315 μL.

[0191] In yet another exemplary embodiment, the housing of the ingestible device has a diameter of about 9.9 mm, a length of about 26 mm, a wall thickness of about 0.8 mm, an end rounding (spherical) of about 4.95 mm, and an internal volume of about 1177 μL.

[0192] In a further exemplary embodiment, the housing of the ingestible device has a diameter of about 8.5 mm, a length of about 23.3 mm, a wall thickness of about 0.7 mm, an end circle of about 1.5 mm, and an internal volume of about 861 μL.

[0193] In yet a further exemplary embodiment, the housing of the ingestible device has a diameter of about 8.5 mm, a length of about 23.3 mm, a wall thickness of about 0.7 mm, an end rounding (spherical) of about 4.25 mm, and an internal volume of about 773 μL.

[0194] In yet a further exemplary embodiment, the housing of the ingestible device has a diameter of about 8.5 mm, a length of about 23.3 mm, a wall thickness of about 0.7 mm, a splined end circle, and an internal volume of about 820 μL.

[0195] In some embodiments, the ingestible device is 00 size.

[0196] Fluid volume

[0197] Ingestible devices include a fluid volume that holds dispensable substances (e.g., liquids, suspensions). In some embodiments, the fluid volume is completely disposed within the housing. Alternatively, the fluid volume can be limited by a storage reservoir. Such a storage reservoir can be a component prepared separately from the housing. In such a storage reservoir, the dispensable substance can be disposed in the storage reservoir before the storage reservoir is associated with the ingestible device.

[0198] Dispensable substances

[0199] The device may include one or more dispensable substances, each dispensable substance including one or more therapeutic agents and / or one or more pharmaceutical formulations including one or more therapeutic agents.

[0200] nozzle

[0201] In some embodiments, the ingestible device includes one or more nozzles that are fluidly connected to one or more openings in the ingestible device. The nozzle is configured so that when the dispensable material is delivered from the ingestible device, the dispensable material passes through the nozzle. Generally speaking, the nozzle can have any desired size and shape suitable for the delivery of the desired type of the dispensable material from the ingestible device. In certain embodiments, the nozzle has a shape and / or size suitable for transepithelial delivery, epithelial delivery or surface delivery. In some embodiments, the ingestible device includes more than one nozzle. In some embodiments, the ingestible device includes 2 nozzles to 50 nozzles. In certain embodiments, the ingestible device includes 2 nozzles, 3 nozzles, 4 nozzles, 5 nozzles, 6 nozzles, 7 nozzles, 8 nozzles, 10 nozzles, 20 nozzles, 30 nozzles, 36 nozzles, 40 nozzles, 50 nozzles). In some embodiments, the nozzles are arranged around the perimeter of the device at uniform intervals (optionally in pairs if an even number of nozzles are used).

[0202] Restraint mechanism

[0203] In some embodiments, the ingestible device includes a restraining mechanism. Typically, the restraining mechanism has: a first state, wherein it is configured to prevent the dispensable material from leaving the ingestible device through the opening, and a second state, wherein it is configured so that it does not prevent the dispensable material from leaving the ingestible device through the opening. The restraining mechanism can be configured to switch from its first state to its second state when it is exposed to a triggering condition. The restraining mechanism can be provided by one or more restraining elements. The restraining element can have: a first state, wherein it is configured to prevent the dispensable material from leaving the ingestible device through the opening, and a second state, wherein it is configured to allow the dispensable material to leave the ingestible device through the opening. The restraining element can be configured to switch from the first state to the second state when the restraining element is exposed to a triggering condition. In some embodiments, the restraining element includes a first type of restraining element and a second type of restraining element different from the first type of restraining element. The first type of restraining element can be configured to switch to its second state before the second type of restraining element switches to its second state. In some embodiments, the constraining element comprises a cap, a pin, a band, a plug, a pin, a buckle, a clip, a flange, a rivet, an annulus, a torus, a ring, a wafer, a cylinder, an asymmetric shape such as a partial annulus, a partial torus, a partial ring, a partial wafer, a partial cylinder, or any combination thereof (e.g., two partial torus). Optionally, the constraining element can have a filled interior (e.g., no holes). Optionally, the constraining element can have a variable thickness (e.g., a central region thinner than an edge). In some embodiments, the constraining element comprises a plasticizer such as triethyl citrate (TEC). In some embodiments, the constraining element comprises a degradable and / or erodible material, such as an enteric material. The enteric material can be degradable and / or erodible in the small intestine of the GI tract, or can be degradable and / or erodible in the large intestine (e.g., colon) of the GI tract. In some embodiments, the restraining mechanism can be a mechanism that prevents the dispensable material from being delivered from the ingestible device even when the driving force generator (or optionally the driving coupling) applies an internal force. For example, such a restraint can be an element (e.g., a pin, a band, a plug) in an opening (e.g., a nozzle opening) through which the dispensable material can be delivered from the ingestible device. Such a restraining element can be formed of a material that degrades and / or erodes, for example, as described above.

[0204] Generally speaking, the restraining mechanism comprises a material that will lose a sufficient degree of its mechanical strength at the desired location to cause the ingestible device to deliver the dispensable substance. The material may experience a loss of mechanical strength for any suitable mechanism or combination of mechanisms, including, for example, moisture ingress, solubility, swelling, leaching, erosion, and / or the like.

[0205] In some embodiments, the restraining mechanism comprises a degradable and / or erodible material such as a water-soluble material, optionally with one or more coatings of one or more enteric materials. The degradable and / or erodible material is designed to lose its mechanical strength in the presence of moisture (e.g., liquid or "biological fluid" present in the GI tract).

[0206] Typically, enteric materials erode after being swallowed, for example in the small intestine or in the large intestine. In some embodiments, the degradable and / or erodible material is coated with an enteric material that limits the amount of moisture or fluid that reaches the degradable and / or erodible material, whereby the degradable and / or erodible material is able to resist the trigger load, for example at a pH of 1.1 for at least two hours. In certain embodiments, the enteric material decomposes to release the trigger load after exposure to a pH of 1.1 for two hours followed by exposure to a pH of 6.8 for 10, 20, 30, 40, 50, 60 or more minutes.

[0207] The enteric material can be in the form of one or more coatings (e.g., one or more spray coatings and / or one or more dip coatings) of varying coating weights on a degradable and / or erodible material (e.g., a water-soluble material). For example, in some embodiments, the coating weight can be 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or more compared to the weight of the degradable and / or erodible material. In general, the coating weight is selected as desired, for example, based on the intended use of the ingestible device. For example, the coating weight can be selected to select a desired location and / or time for allowing the degradable and / or erodible material to degrade and / or erode to a sufficient degree to trigger delivery of the dispensable substance from the ingestible device.

[0208] Desirably, the degradable and / or erodible material is strong enough to resist the trigger load when dry, but is also capable of weakening sufficiently to release the trigger load when the degradable and / or erodible material is exposed to an aqueous environment for a desired period of time (such as, for example, at least 5, 10, 30, 60, 120, or at least 160 minutes).

[0209] In some embodiments, the trigger mechanism has a density of about 1 g / cm3 to about 3 grams / cm3 (eg, about 1.3 g / cm3 to about 2 g / cm3).

[0210] In certain embodiments, the trigger mechanism is about 1 mm to about 5 mm thick (eg, about 1 mm to about 2 mm thick).

[0211] In some embodiments, the coating of enteric material has a density of about 0.5 mg / cm2 to 20 mg / cm2 (e.g., about 2 mg / cm2 to about 6 mg / cm2).

[0212] The example of degradable and / or erodible material includes polyethylene glycol (PEG) and isomalt (Isolmalt). In some embodiments, degradable and / or erodible material includes one or more diluents / fillers, one or more binding agents, and / or one or more disintegrants. The example of diluent / filler includes lactose, starch, mannitol, microcrystalline cellulose, carboxymethyl cellulose and dicalcium phosphate. The example of binding agent includes polyvidone, hypromellose, hydroxypropyl cellulose, copolyvidone and microcrystalline cellulose. The example of disintegrant includes cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose (SD-711), sodium starch glycolate and low-substituted hydroxypropyl cellulose. Optionally, degradable and / or erodible material can include lubricant such as magnesium stearate.

[0213] As an example, the degradable and / or erodible material includes starch (e.g., StarTab grade from Colorcon, Starch 1500 grade from Colorcon), microcrystalline cellulose (e.g., Vivapur 102 grade from JRS Pharma), croscarmellose sodium (e.g., Ac-di-sol SD-711 grade from FMC Biopolymer), and magnesium stearate (e.g., Ligamed MF-2-V grade from Giusto Faravelli), and optionally further includes talc (e.g., PSD<75 μm grade from Acros), enteric methacrylate polymer (e.g., FL30D-55 grade from Evonik), and HPMC polymer sub coat (e.g., Opadry 03K19229 grade from Colorcon). As an example, the degradable and / or erodible material may include starch 1500 (e.g., 49.6% w / w), microcrystalline cellulose 102 starch (e.g., 49.6% w / w); and crosslinked sodium carboxymethylcellulose SD-711 (e.g., 0.5% w / w); and magnesium stearate (e.g., 0.26% w / w). As a further example, the degradable and / or erodible material may include Startab (e.g., 49.6% w / w), microcrystalline cellulose 102 starch (e.g., 49.6% w / w); and crosslinked sodium carboxymethylcellulose SD-711 (e.g., 0.5% w / w); and magnesium stearate (e.g., 0.26% w / w). As another example, the degradable and / or erodible material may include starch 1500 (e.g., 48.9% w / w), microcrystalline cellulose 102 starch (e.g., 48.9% w / w); cross-linked sodium carboxymethylcellulose SD-711 (e.g., 2% w / w); and magnesium stearate (e.g., 0.26% w / w). As a further example, the degradable and / or erodible material may include Startab (e.g., 49.6% w / w), microcrystalline cellulose 102 starch (e.g., 49.6% w / w); cross-linked sodium carboxymethylcellulose SD-711 (e.g., 2% w / w); and magnesium stearate (e.g., 0.26% w / w). As another example, the degradable and / or erodible material may include dicalcium phosphate (e.g., 48.9% w / w), microcrystalline cellulose 102 starch (e.g., 48.9% w / w); cross-linked sodium carboxymethylcellulose SD-711 (e.g., 2% w / w); and magnesium stearate (e.g., 0.25% w / w). As a further example, the degradable and / or erodible material may include dicalcium phosphate (e.g., 33.25% w / w), microcrystalline cellulose 102 starch (e.g., 33.25% w / w); mannitol (e.g., 33.25% w / w); and magnesium stearate (e.g., 0.25% w / w).

[0214] Examples of enteric materials coated on degradable and / or erodible materials include: sprayed Eudragit FL30D-55 (e.g., 12 mg / cm2 Eudragit FL 30D-55 sprayed directly on a water-soluble material); dipped Eudragit L 100D-55 (e.g., 4 mg / cm2 Eudragit L 100D-55 dipped onto an HPMC capsule cap); and sprayed Eudragit FL 30D-55 (e.g., 9 mg / cm2 Eudragit FL 30D-55 sprayed directly on a water-soluble material; 6 mg / cm2 Eudragit FL 30D-55 sprayed directly on a water-soluble material).

[0215] In some embodiments, the entire release member comprises 80%, 85%, 90%, 95% or more enteric material (eg, the release member is made entirely of Eudragit 100 or another enteric material).

[0216] Release, actuation or triggering mechanism

[0217] In some embodiments, the ingestible device includes a trigger mechanism, which is configured to cause the dispensable material in the fluid volume to be released under one or more trigger conditions. If a trigger mechanism is used, the trigger mechanism starts the driving force generator. The trigger mechanism can be combined with mechanical features such as a constraint mechanism. As an example, one or more constraint elements degrade and / or erode in the presence of certain GI tract conditions (e.g., pH is greater than 5), thereby triggering a driving force generator, such as a compression spring. As another example, a spring can have a piercing element, which pierces a cylinder with compressed gas, and the gas released thereby acts as a force applied to the dispensable material. In certain embodiments, the trigger mechanism is combined with electrical features. For example, an enteric coating degrades and / or erodes in the presence of certain GI tract conditions (e.g., pH is greater than 5), thereby exposing the conductor to intestinal fluid, and intestinal fluid acts as a liquid conductor to trigger the driving force generator. In some embodiments, the trigger condition relates to the conditions of the GI tract, such as temperature, pH, the presence and time of one or more enzymes. In some more specific embodiments, the condition of the GI tract is a pH greater than 5. In certain embodiments, the trigger mechanism is configured such that the release mechanism is triggered autonomously (eg, due to degradation, dissolution, and / or erosion of the restraining mechanism caused by conditions in the GI tract).

[0218] The constraining element may include one or more small molecule therapeutic agents, for example, one or more small molecule therapeutic agents as disclosed herein. In certain embodiments, the small molecule therapeutic agent contained in the constraining mechanism may be the same as the therapeutic agent contained in the dispensable substance. The small molecule therapeutic agent contained in the constraining mechanism may be different from the therapeutic agent contained in the dispensable substance. The constraining mechanism may include a plurality of small molecule therapeutic agents, wherein the dispensable substance contains the same therapeutic agent. In certain embodiments, the dispensable substance includes a therapeutic agent capable of treating a certain condition, and the small molecule therapeutic agent included in the constraining element is capable of treating the same condition. In some embodiments, the dispensable substance includes a therapeutic agent capable of treating a certain condition, and the small molecule therapeutic agent included in the constraining element is capable of treating different conditions. In certain embodiments, the dispensable substance includes a therapeutic agent capable of treating a certain condition, and the small molecule therapeutic agent included in the constraining element is capable of treating the same condition and at least one different condition. In some embodiments, the small molecule therapeutic agent included in the constraining element is capable of treating a certain condition, and the dispensable substance includes a therapeutic agent capable of treating at least one different condition. Other combinations are possible.

[0219] Generally speaking, the initial gas pressure within the cylinder (the gas pressure before the cylinder is implemented as a force generator) is suitable to provide the desired internal pressure. Typically, the initial gas pressure in the cylinder is at least about 500 psig (e.g., at least about 600 psig, at least about 700 psig, at least about 750 psig, at least about 800 psig, at least about 850 psig, at least about 900 psig) and / or at most about 1,200 psig (e.g., at most about 1,100 psig, at most about 1,000 psig, at most about 950 psig, at most about 900 psig). In some embodiments, the initial gas pressure within the cylinder is about 500 psig to about 1,200 psig (e.g., about 600 psig to about 1,100 psig, about 700 psig to about 1,000 psig, about 750 psig to about 950 psig, about 800 psig to about 950 psig, about 850 psig to about 950 psig).

[0220] The burst pressure of the cylinder (the minimum pressure at which the cylinder bursts) is generally based on the desired initial gas pressure within the cylinder. For the initial gas pressures mentioned in the previous paragraph, the burst pressure of the cylinder may be at least about 2,800 psig to 4500 psig.

[0221] Typically, the gas in the gas container or cylinder can be a single gas or a mixture of two or more gases. Exemplary gases include air, nitrogen, oxygen, carbon dioxide, hydrofluorocarbon gases, and rare gases (e.g., helium, neon, argon, krypton, xenon). In some embodiments, the gas in the cylinder is a gas mixture including helium (e.g., a nitrogen / helium mixture, an argon / helium mixture). Optionally, such a gas mixture includes up to about 5% helium. The presence of helium in the gas mixture can allow the cylinder to be checked for leaks based on the presence of helium adjacent to the outside of the cylinder.

[0222] In general, the gas container can be made of any suitable and / or desired material. Examples include metals, plastics and / or composite materials. In some embodiments, the gas container is made of stainless steel or galvanized steel. In certain embodiments, the gas container can be made of the following materials: itself prepared by a process including stretching, stamping, machining, casting, molding and / or the like (e.g., deep drawing from a metal sheet (plate)). In some embodiments, the gas container can be made of ceramics, alloys, aluminum and / or titanium.

[0223] In some embodiments, the gas container includes a breakable seal (e.g., a film or a diaphragm), which is broken via an element (e.g., a piercer) when the gas container is used as a force generator, as described in more detail below. Typically, the breakable seal is a part of the end cap of the gas container. The end cap and / or the breakable seal can be formed by one or more of the materials mentioned in the previous paragraph. Breaking the breakable seal can involve, for example, tearing a part of the breakable seal and / or piercing a part of the breakable seal. More generally, breaking the breakable seal is intended to change the seal in a manner that the breakable seal is no longer able to restrict the gas in the gas container. In general, the breakable seal is made of a material having at least the following area: it is relatively thin and / or is configured to (e.g., scored) break. Optionally, the entire barrier is relatively thin. As an example, the barrier may have a relatively thin periphery with a relatively thick portion within the periphery (eg, a central portion) such that when an element (eg, a piercer) applies an appropriate force, the relatively thin portion of the frangible seal breaks.

[0224] As another example, the barrier may have an inner (e.g., central) portion surrounded by a scored portion such that when an element (e.g., a piercer) applies an appropriate force, the scored portion of the breakable seal breaks. In some embodiments, the breakable seal has a substantially constant thickness and has a portion configured (e.g., scored) to break when an element (e.g., a piercer) applies an appropriate force. In general, such scores can be configured as desired. As an example, the scores can be configured as a series of parallel lines. As another example, the scores can be configured as a grid (grid). As a further example, the scores can be configured as a plurality of points (e.g., equidistant points).

[0225] In some embodiments, the element (e.g., piercer) has a contact point on the frangible seal. Optionally, the contact points are concentrated in a relatively small local area. For example, the piercer can be a needle or a thin rod element cut at an angle to initially produce a single point contact. Relative to the frangible seal, the point of initial contact can be on the center or off-center. Letting the initial contact point off-center relative to the frangible seal can cause the force applied by the element (e.g., piercer) to decrease. In the embodiment where the modified (e.g., scored) area of ​​the frangible seal is off-center, placing the element (e.g., piercer) off-center means that at the contact point of the element (e.g., piercer) with the frangible seal, the contact point is closer to the modification (e.g., thinner scored area) of the frangible seal. In certain embodiments where the modified (e.g., scored) area of ​​the frangible seal is a circle, the element (e.g., piercer) can be configured so that its contact point with the frangible seal is close to a point on the circle. Generally speaking, the closer the contact point is to the modified region of the frangible seal, the lower the force of the element (eg, piercer) used to rupture the frangible seal.

[0226] In order to produce a relatively rapid release, the modified (e.g., scored) portion of the frangible seal is desirably broken over a substantially large portion of the modified region (e.g., the diameter of the circle when the modified region is a scored region formed as a circle). In some embodiments, the closer the contact point is to the center of the scored circle, the more likely the seal is to break over the entire circumference of the scored circle. In such embodiments, it is typically desirable to have the contact point of the element (e.g., piercer) close to the circle, but not on it. Optionally, the contact point can be moved inward to obtain a rapid release property. Optionally, a wider footprint for initial contact of the element (e.g., piercer) can be implemented in some embodiments. For example, the contact point can be an arcuate sector disposed near the circular score of the frangible seal. This can cause the frangible seal to break over a larger sector of the scored region, which can produce faster gas escape.

[0227] In some embodiments, before the gas container is used as a force generator, the element (e.g., piercer) is not in contact with the frangible seal. In certain embodiments, before the gas container is used as a force generator, the element (e.g., piercer) may be in contact with the frangible seal so that the element (e.g., piercer) applies a relatively low pressure to the frangible seal. The pressure may be, for example, at least about 1 Newton (e.g., at least about 2 Newtons, at least about 3 Newtons, at least about 4 Newtons, at least about 5 Newtons) and / or at most about 15 Newtons.

[0228] Typically, in order to release the gas in the gas container from the gas container, an element (such as a piercer) applies a relatively high pressure to the frangible seal. The relatively high pressure can be, for example, at least about 5 Newtons (such as at least 8 Newtons, at least about 10 Newtons, at least about 15 Newtons) and / or at most about 40 Newtons (such as at most about 35 Newtons, at most about 30 Newtons, at most about 25 Newtons). In some embodiments, the relatively high pressure can be about 5 Newtons to about 35 Newtons. Examples of gas containers (including those with end caps and / or frangible seals) are, for example, disclosed in US2017 / 0258583.

[0229] In some embodiments, the element (e.g., piercer) is coupled to an actuator in the actuator assembly. In some embodiments, the actuator assembly has a total length of less than about 2, 5, or 10 mm. The actuator can be provided in the form of a spring (e.g., a wave spring), such as a spring with a compression length less than about 2.5 to 5 mm and a stroke length less than about 0.3 to 0.8 mm.

[0230] In some embodiments, the element (e.g., piercer) is moved relatively quickly when a relatively high force is applied to the breakable seal. In certain embodiments, the element (e.g., piercer) is moved relatively slowly when a relatively high force is applied to the breakable seal. In some embodiments, using a lower element (e.g., piercer) movement speed allows a lower force to be used to break the breakable seal compared to the force used to break the breakable seal when the element (e.g., piercer) is moved at a higher speed.

[0231] The element (e.g., piercer) may be movable relative to the gas container, or the gas container may be movable relative to the element (e.g., piercer). For example, the gas container may be coupled to an actuator that causes the gas container to move.

[0232] In some embodiments of any of the devices or methods described herein, release of the therapeutic agent is triggered by one or more of: a pH in the jejunum of about 6.1 to about 7.2, a pH in the mid-small intestine of about 7.0 to about 7.8, a pH in the ileum of about 7.0 to about 8.0, a pH in the right colon of about 5.7 to about 7.0, a pH in the middle colon of about 5.7 to about 7.4, or a pH in the left colon of about 6.3 to about 7.7, e.g., about 7.0.

[0233] Driving force generator

[0234] The driving force generator is configured to provide the necessary force to the dispensable material so that when the restraining mechanism is removed, the dispensable material is delivered from the ingestible device as required. The driving force generator can apply force using different mechanisms, including, for example, compressed gas, gas generated by a chemical reaction, a spring, a liquid-gas mixture, an impact plunger, a sudden expansion caused by a controlled exothermic reaction, and the like. When the driving force generator is a spring, the spring may have one or more of the following properties: the outer diameter of the spring is smaller than the inner diameter of the ingestible device; the compressed length of the spring is minimized to leave more space for the dispensable material; the spring is conical in shape, and the physical length of the spring is potentially reduced; the free length of the spring is maximized and greater than the free length of the inner cavity of the ingestible device to ensure that an acceptable driving pressure is provided throughout the delivery time step; and the spring rate is large enough to provide an acceptable pressure of the dispensable material from the beginning of delivery until the end. Examples of springs include parallel springs, wave springs, and conical springs. Examples of chemical reactants include airbag inflators, hydrogen batteries (e.g., Varta hydrogen batteries), sodium bicarbonate, and acids (e.g., seltzer and water, seltzer, and GI tract fluids on an ingestible device). Examples of compressed gases include gases loaded into an ingestible device, and containers (e.g., cylinders) of compressed gases. In some embodiments, the compressed gas is a gas container from Picocyl LLC of Gordon, Colorado, USA. Exemplary cylinders are disclosed, for example, in US2017-0258583. An example of a liquid-gas mixture is liquid nitrogen / HFA (hexafluoroacetone) / propane. An example of an impact plunger is a two-phase spring / plunger. Other examples of driving force generators include wax actuators, heat generated by electricity (a mechanism based on the Peltier effect), and mechanical puncture of the tissue delivered later.

[0235] Drive connector

[0236] In general, the driving force coupling transfers force from the driving force generator to the dispensable material. The example of the driving coupling includes a piston and a film. The example of the film includes an air bag (balloon) and an elastomeric material. An example of a piston is an O-ring sealed piston. In some embodiments, the piston is provided by a gas container (e.g., with an additional O-ring or a custom shell). In some embodiments, the driving coupling is a vein, such as a rotary vein. In certain embodiments, the driving coupling is a double piston configured to offset the impact of the cap. In certain embodiments, the driving coupling is a folding bag, such as a folding foil bag. In some embodiments, the driving coupling is a folding bellows (bellows). In some embodiments, the driving force generator is also used as a driving coupling. For example, the gas container may not be fixed in a fixed position so that when actuated, the gas container moves longitudinally to remove the drug payload from the device.

[0237] Storage Repository

[0238] The ingestible device may include a storage reservoir configured to store a dispensable substance. The storage reservoir may be disposed entirely within the housing. The ingestible device may be provided with or without a dispensable substance in the storage reservoir.

[0239] Figure 2 200, which includes a housing 202, a fluid volume 204 containing a dispensable substance, a nozzle 206 having a nozzle opening 208, a restraining mechanism 210, a trigger mechanism 212, a driving force generator 214, and a drive coupling 216. During use, the ingestible device 200 is swallowed by a subject and passes through the GI tract. At the appropriate location, the trigger mechanism 212 is triggered, thereby allowing the driving force generator to apply pressure to the drive coupling 216, which then applies pressure to the fluid volume so that at least some of the dispensable substance is delivered out of the fluid volume 204, through the nozzle 206, and exits the device 200 via the nozzle opening 208. In some embodiments, the internal pressure is applied even before the trigger mechanism 212 is triggered. As an example, at the appropriate location, the trigger mechanism 212 is triggered, thereby allowing the drive coupling 216 to apply pressure to the fluid volume 204. In certain embodiments, the internal pressure is not applied until the trigger mechanism 212 is triggered.

[0240] Devices for transepithelial delivery

[0241] Figure 3A cross-sectional view of a representative ingestible device 400 for transepithelial delivery is shown schematically illustrating certain parameters and functional components of the device 400. These include a drive force generator 42 that applies a force (generating an internal pressure) to a drive coupling 44. The drive coupling 44 transmits the force from the force generator 42 to a fluid volume 46 containing a dispensable substance (e.g., a liquid, a suspension). The force applied to the fluid volume 46 by the drive coupling 44 generates a pressure (fluid pressure) in the fluid volume 46. The pressure in the fluid volume 46 generates a high velocity flow through an open nozzle 48 to generate a jet 50 of fluid at a nozzle outlet 52 having a nozzle diameter 72 and the nozzle has a nozzle length 74.

[0242] During transepithelial delivery, the fluid jet 50 has a jet stabilization length 54 that is sufficient for the fluid jet 50 to travel across the nozzle standoff distance 56 to reach the interface of the lumen of the GI tract and the lumen-facing surface of the GI tract. Ultimately, the fluid (e.g., liquid, suspension) impacts the mucosal layer of the GI tract (e.g., epithelial layer and any mucus that may be present on the epithelial layer) as a stable fluid stream with little to no breakup into a spray and is deposited in the submucosal and / or mucosal tissue 58. That is, between the nozzle outlet 52 and the impact site at the mucosa, the jet 50 has a jet diameter 76 that can vary in the manner discussed above with respect to the average jet diameter.

[0243] Fluid volume 46 experiences peak fluid pressure 60, which generates fluid jet 50, which exits device 40 at peak jet velocity and impacts the lumen of the GI tract and the interface of the lumen-facing surface of the GI tract at peak jet power, peak jet pressure, and peak jet force. Those of ordinary skill in the art recognize that these three parameters are interrelated.

[0244] The pressure in the fluid volume 46 decreases during delivery, causing the fluid pressure to change during delivery 70, as does the jet power, jet force, and jet pressure. The fluid pressure during delivery 70 maintains the fluid jet 50 at sufficient jet impact force during delivery to continue delivering the fluid (including the dispensable substance of one or more therapeutic agents) from the fluid volume 46 into the submucosal and / or mucosal tissue 58. The surrounding tissue can then absorb the delivered therapeutic agent for systemic delivery of the therapeutic agent.

[0245] Even before the subject swallows the ingestible device, the drive coupling 44 transmits the force from the force generator 42 to the fluid volume 46. The drive coupling 44 is prevented from moving by a restraining mechanism 80 (e.g., a selectively degradable and / or selectively eroded pin or plug) until movement of the drive coupling is triggered by a triggering mechanism, and / or the opening becomes open.

[0246] Figure 4An exemplary process flow chart 400 using an ingestible device is shown, wherein no pressure is applied to the dispensable material before the subject swallows the ingestible device. The process begins at step 402, when the patient swallows the ingestible device. In step 404, a trigger condition (e.g., pH, pH change, presence of certain enzymes, concentration of certain enzymes) is met in the GI tract, thereby triggering the driving force generator. In step 406, the driving force mechanism applies pressure to the dispensable material, resulting in a jet of the dispensable material being delivered from the ingestible device for each opening. In step 408, the jet has a sufficient jet stability length for the jet to impact the GI tissue of the subject. In step 410, the peak jet power of the jet is sufficient to achieve transepithelial delivery of the therapeutic agent contained in the dispensable material. In step 412, the fluid pressure of the dispensable material decreases during delivery, but is sufficient to cause the peak jet power to continue to be sufficient to achieve transepithelial delivery of the therapeutic agent contained in the dispensable material.

[0247] Figures 5A-5C A view of an assembled ingestible device 500, an exploded view of an ingestible device, and aspects of the assembly process of an ingestible device are shown respectively. The ingestible device 500 includes a nozzle 502, a gas container 504, a piston 506, a seal 508, a piercing pin 510, and a piercer 512. A removable cap 514 may be fixed on a portion of the ingestible device 500 and removed before swallowing. The ingestible device 500 may be used for transepithelial delivery. The ingestible device 500 is configured so that when the subject swallows the ingestible device 500, the dispensable substance 516 maintained in the device is not under pressure. The ingestible device has two housing parts, a primary (first, primary) container 518 and a secondary (second, secondary) container 520. The primary container 518 including a fluid volume for accommodating a dispensable substance may be formed by a cyclic olefin copolymer (COC), such as molded COC. The primary container 518 includes a nozzle 502 having a nozzle opening. In some embodiments, the nozzle length is approximately equal to the primary container wall thickness. In some embodiments, the nozzle length is 0.5 mm to 0.7 mm, or in some embodiments 0.6 mm. The ingestible device also includes a covering 522 over the nozzle opening, a spring 524, a gas container 504 with a breakable seal, a piston 506 (e.g., made of COC), a piercer 512, and an O-ring 526. The nozzle covering 522 can be an integral nozzle cap for gastric protection and can soften after the ingestible device 500 is ingested, such as by gastric fluids, so that the covering 522 dissolves / degrades and exposes the nozzle 502. In some embodiments, the O-ring 526 can be lubricated. Similarly, any O-ring or piston (including Figures 48A-49B The second piston) is lubricated.

[0248] The ingestible device 500 also includes a collar-shaped trigger element 528 as a trigger mechanism. Figure 5B The trigger element 528 is shown as a collar shape, but other shapes can be used. Generally speaking, the trigger element 528 can have any appropriate shape. The example of the shape of the trigger element includes a complete ring, a ring divided into two parts. In some embodiments, the trigger element includes two or more sectors of the ring, wherein there is a gap between the sectors. This will increase the surface exposure of the surface to the environment (such as water environment) to promote degradation. The ring can have an outer diameter of about 5.5 to 8mm or about 6.85mm and an inner diameter of about 2.4 to 4.2mm or about 3.25mm, and a maximum height or thickness of about 1 to 2mm or about 1.45mm.

[0249] The ingestible device 500 may include two modules: a drug module and a drive module. For example, Figure 5C Shown are separate component modules 530 (drug module) and 532 (drive module) which are assembled to form the ingestible device 500.

[0250] Figures 6A-6CA view of an assembled ingestible device 600, an exploded view of the ingestible device 600, and a view of aspects of the assembly process of the ingestible device 600 are shown respectively. The ingestible device 600 can be used for transepithelial delivery or for other forms of delivery as discussed elsewhere herein as appropriate. The ingestible device 600 includes a nozzle 602, a gas container 604, a piston 606, a seal 608, a piercing pin 610, and a piercer 612. A removable cap 614 can be fixed on a portion of the ingestible device 600 and removed before swallowing. The ingestible device is configured so that when the subject swallows the ingestible device, the dispensable substance 616 in the device is not under pressure. The ingestible device has two housing parts, a primary container 618 and a secondary container 620. The primary container 618 including a fluid volume for accommodating a dispensable substance can be formed of a cyclic olefin copolymer (COC), such as molded COC, or any other suitable material as disclosed elsewhere herein. The primary container 618 includes a nozzle 602 having a nozzle opening. In some embodiments, the nozzle length is approximately equal to the primary container wall thickness. In some embodiments, the nozzle length is 0.5 mm to 0.7 mm, or in some embodiments, 0.6 mm. The ingestible device 600 also includes a cover 622 over the nozzle opening, a spring 624, a gas container 604 with a frangible seal 608, a piston 606 (e.g., made of COC, or another suitable material), a two-part piercer, and an O-ring 626. The ingestible device also includes a collar-shaped trigger element 628 as a trigger mechanism, which can be made of any suitable material as discussed elsewhere herein. Although Figures 6A-6C The trigger element 628 is depicted as being collar-shaped, but other shapes may be used as disclosed elsewhere herein.

[0251] Figures 6A-6C The device shown in has an enhanced piston stabilization length 634 (eg, approximately 2 mm). Figures 6A-6C The device shown in has a metal spring slider 636, which enhances space efficiency. Figures 6A-6C The device shown in has a piercer slide 638 (e.g., a metal piercer slide) that bottoms out on the spring housing during assembly. This can enhance space efficiency. Figures 6A-6C In the device shown in , the two-part piercer reduces (eg removes) tolerances from the spacing between the piercer and the gas container when manufacturing the trigger element. Figures 6A-6C In the device shown in , the piercer seal 640 (e.g., an O-ring) has a relatively small diameter, which can enhance stability and / or reduce the resistance accumulated along its travel length. Figures 6A-6CIn the device shown in , the spring 624 has a tapered end coil 642, which can enhance the maximum force potential. In some embodiments, a wave spring can be used. Figures 6A-6C A hermetic seal 644 (eg, ultrasonic welding) is shown. Figures 6A-6C Gas container retention feature 646 is also shown.

[0252] In addition, the ingestible device includes a removable cap 614, which is removed (e.g., by a user) before the ingestible device is swallowed. When the subject swallows the device 600, the trigger element 628 prevents the dispensable material 616 in the fluid volume from being under pressure by keeping the spring 624 and the piercer 612 in place. When the device reaches the appropriate position in the GI tract, the trigger element 628 at least partially erodes, degrades and / or dissolves (e.g., due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), and the trigger element 628 is no longer sufficient to suppress the pressure from the spring 624. In some embodiments, the trigger element 628 at least partially erodes, degrades and / or dissolves in the presence of water. In such an embodiment, the trigger element may include a covering of a film of a material that is preferentially degraded due to, for example, pH changes and / or the presence of an enzyme. The spring 624 forces the piercing pin 610 of the piercer 612 to enter the frangible seal 608, thereby causing the frangible seal to break. This causes the gas under elevated pressure to leave the gas container 604, thereby causing the elevated pressure to press against the piston 606 and apply pressure to the fluid volume 616. This causes the cover 622 of the nozzle opening, which is made of a relatively low mechanical strength material (e.g., foil or film), to break, so that the dispensable substance is delivered from the nozzle opening in the form of a jet. In certain embodiments, the cover 622 of the nozzle opening is made of a material that erodes, degrades, and / or dissolves in the presence of, for example, water or elevated pH (e.g., an enteric strip or a strip of water-soluble polymer material). The cover may be partially or completely displaced from the capsule upon actuation of the trigger element. This results in transepithelial delivery of the therapeutic agent contained in the dispensable substance.

[0253] Figure 6C Aspects of the assembly process of the ingestible device are shown, such as individual component modules 630 and 632, which are assembled to form the ingestible device 600. Figure 6CThe main container in combination with the cap and nozzle cover is shown to which a dispensable substance is added, followed by the piston. This can be done in a sterile environment or other environment suitable for drug filling and independent of the environment in which the mechanical drive assembly is constructed. The other housing portion and its components are assembled in a clean environment, wherein the piercer is maintained in a fixed position by a trigger element. The gas container 604 is maintained in a fixed position by the components of the assembly, the components including an assembly housing, the assembly housing including features for positioning the gas container in the correct position in the assembled ingestible device. The positioning and installation of the gas container can be assisted by forming mounting features (e.g., flanges) that are integral with the gas container components.

[0254] Figure 7-13 Various views of an ingestible device 700 and / or aspects of an ingestible device 700 are shown. Notably, the delivery mechanism of the ingestible device 700 is shown as having a substantially similar design to the device shown in FIG. 5 , although more generally, Figure 7-13 The ingestible device 700 depicted in may have a delivery mechanism as described elsewhere herein.

[0255] Ingestible device 700 includes gas container 716, union 708, O-ring 732, enteric trigger 726, piercer 720, spring 724, spring retaining cup 722, retaining element 728, drug housing 704, drive housing 706, and piercer retainer 724.

[0256] The ingestible device 700 has two chambers 710a, 710b, each of which contains a dispensable substance. The chambers are separated by a partition 705 (e.g., a rib) (which prevents the dispensable substance in one chamber from entering another chamber, such as from 710a to 710b and vice versa). In addition, the ingestible device 700 includes a face seal 707 that seals the partition. The ingestible device also has two pistons 718a, 718b, one for each chamber. Each chamber 710a, 710b has at least a nozzle 702 for delivering the dispensable substance from the chamber to the outside of the ingestible device 700. In general, the dispensable substance in a chamber, such as chamber 710a, may be the same or different from the dispensable substance in another chamber, such as chamber 710b. Although shown as having two chambers 710a, 710b, the present disclosure is not limited in this sense. More generally, the ingestible device 700 may have as many chambers as desired (e.g., 2 chambers, 3 chambers, 4 chambers, 5 chambers, 6 chambers, 7 chambers, 8 chambers, 9 chambers, 10 chambers, more than 10 chambers). Generally, each chamber 710a, 710b will have a corresponding piston 718a, 718b, and there will be a partition 705 between adjacent chambers. In some embodiments, each chamber has the same internal volume. In certain embodiments, different chambers may have different volumes. Combinations of such embodiments are also possible.

[0257] The ingestible device may include an element 712 (e.g., a cover) having a first state in which the element 712 at least partially covers the nozzle opening of the nozzle 702 in the housing 704 and a second state in which the element 712 does not cover the nozzle opening in the housing 704, wherein the ingestible device 700 is configured so that when the driving force coupling (e.g., pistons 718a, 718b) moves, the element 712 moves from its first state to its second state. In certain embodiments, the element 712 is conformal to the inner radius of the housing 704, is flexible and / or includes a cylindrical portion. In some embodiments, the element 712 is removable from the ingestible device 700 (e.g., when the element 712 is in its second state, the element 712 is removed from the ingestible device). Such a removable element 712 may be, for example, a cap. Optionally, the movement of the element 712 may be synchronized with the driving force coupling, such as pistons 718a, 718b. In some embodiments, when the driving force coupling moves a distance, the element 712 moves the same distance. The ingestible device may include a seal 718 (e.g., an O-ring) that mechanically couples (e.g., seals) the drive force coupler and the element 712. Using this arrangement, the seal 718 may be configured to cause movement of the drive force coupler to cause movement of the element 712.

[0258] Figure 14-18An ingestible device 1400 is shown containing a dispensable substance that is not under pressure when the subject swallows the ingestible device. Fig.14 In FIG. 1 , the jet opening 1402 is shown as being covered, and in FIG. Fig.15 The mid-jet opening 1402 is not covered.

[0259] Fig.16 and 17 Ingestible device 1400 is shown in more detail. Ingestible device 1400 has housing portions 1404 and 1406 connected by union 1408 and having a fluid volume 1410 containing a dispensable substance, an opening 1402, and a fluidic cover 1412 such as a cylindrical sleeve (made of a flexible material that can conform to the inner radius of housing 1406 that slides to open or seal opening 1402), a spring 1414, a gas container 1416, a piston 1418, a piercer 1420, and an O-ring 1432. Gas container 1416 is retained by retaining element 1428. Seal 1430 forms a gas seal between piercer 1420 and housing 1404. Spring retaining cup 1422 retains spring-loaded piercer 1420. The piercer retainer 1424 holds the piercer 1420 in a fixed position together with the enteric trigger 1426, which holds the piercer retainer in a fixed position until it dissolves and serves as a trigger mechanism. When the device 1400 is swallowed by the subject, the enteric trigger 1426 prevents the dispensable material in the fluid volume 1410 from being under pressure by holding the spring 1414 and the piercer 1420 in a fixed position. When the device 1400 reaches the appropriate position in the GI tract, the enteric trigger 1426 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the piercing pin retainer 1424 is no longer sufficient to inhibit the pressure from the spring 1414. The spring 1414 forces the piercer 1420 into the gas container 1416, thereby piercing the gas container 1416 and causing the gas under elevated pressure to leave the container 1416. This causes the gas container 1416 to press against the piston 1418 and apply pressure to the fluid volume 1410. The piston provides friction to slide the jet cover 1412 open, thereby exposing the jet opening 1402, so that the dispensable substance is delivered in the form of a jet from the jet opening 1402. This results in transepithelial delivery of the therapeutic agent contained in the dispensable substance. Fig.17 An embodiment of the ingestible device 1400 is shown in which the jet cover 1412 is slid open to expose the jet opening 1402.

[0260] Typically, the ingestible device 1400 is used for transepithelial delivery. However, the ingestible device 1400 can be used for epithelial delivery or surface delivery. Appropriate parameters for different types of delivery are provided elsewhere herein.

[0261] In some embodiments, the housing of the ingestible device 1400 has a diameter of about 9.5 mm to about 10.5 mm (e.g., about 9.8 mm to about 10 mm), a length of about 23 mm to about 26.5 mm (e.g., about 23.3 mm to about 26.1 mm), a wall thickness of about 0.4 mm to about 0.6 mm (e.g., about 0.5 mm), a fluid volume of about 425 μL to about 600 μL (e.g., about 450 μL to about 585 μL), and / or a gas volume of about 150 μL to about 175 μL (e.g., about 160 μL) in the gas container 1416. In some embodiments, the housing of the ingestible device 1400 has a diameter of 9.9 mm, or in some embodiments the housing of the ingestible device 1400 has a diameter of 8.5 mm. In some embodiments, the length of the ingestible device is 23.3 mm (dimension 00), or in some embodiments the length of the ingestible device is 26 mm (dimension 000). In some embodiments, the dispensable substance includes an initial fluid volume of 420 μL. Fig.18 An ingestible device 1400 is shown wherein the jet cover 1412 is conformal to the radius of the ingestible device 1400. Figure 35-40 An exemplary size 00 device is also provided.

[0262] Fig.19 and 20Ingestible device 1900 is shown in its closed and open states, respectively. Ingestible device 1900 contains a dispensable substance that is not under pressure when a subject swallows the ingestible device. Ingestible device 1900 has: housing portions 1904 and 1906 connected by union 1908 and having a fluid volume 1910 containing the dispensable substance, a spring 1914, a gas container 1916, a piston 1918, a piercer 1920, and an O-ring 1932. Gas container 1916 is retained by retaining element 1928. Seal 1930 forms a gas seal between piercer 1920 and housing 1906. Spring retaining cup 1922 retains spring-loaded piercer 1920. The piercer retainer 1924 holds the piercer 1920 in a fixed position together with the enteric trigger 1926, which holds the piercer retainer in a fixed position and serves as a trigger mechanism until it dissolves. When the device 1900 is swallowed by a subject, the enteric trigger 1926 prevents the dispensable material in the fluid volume 1910 from being under pressure by holding the spring 1914 and the piercer 1920 in a fixed position. When the device 1900 reaches the appropriate position in the GI tract, the enteric trigger 1926 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the piercer retainer 1924 is no longer sufficient to inhibit the pressure from the spring 1914. The spring 1914 forces the piercer 1920 into the gas container 1916, thereby piercing the gas container 1916 and causing the gas under elevated pressure to leave the container 1916. This causes gas container 1916 to press against piston 1918 and apply pressure to fluid volume 1910. The piston provides friction to cause cap 1934 to open / deploy, allowing the dispensable substance to be delivered from volume 1910. This results in the release of the therapeutic agent into the GI tract of the subject.

[0263] In some embodiments, the housing of the ingestible device 1900 has a diameter of about 10 mm to about 12 mm, a length of about 23 mm to about 26.5 mm, a wall thickness of about 0.4 mm to about 0.6 mm, a fluid volume of about 565 μL to about 630 μL, and / or a gas volume in the gas container 1916 of about 150 μL to about 175 μL. The housing 1900 can have a diameter of 8.5 mm or 9.9 mm and a length of 23.3 mm (size 00) or 26 mm (size 000). In some embodiments, the length of the ingestible device 1900 is 23.3 mm (size 00), or in some embodiments, 26 mm (size 000). In some embodiments, for example, for a size 000 device, the dispensable substance includes an initial fluid volume of about 420 μL, and in some embodiments, for a size 00 device, the dispensable substance includes an initial fluid volume of about 180 μL to about 280 μL.

[0264] Generally speaking, ingestible device 1900 is used for topical delivery.

[0265] Fig.21 and 22 Ingestible device 2100 is shown in its closed and open states, respectively. Ingestible device 2100 contains a dispensable substance that is not under pressure when a subject swallows the ingestible device. Ingestible device 2100 has: housing portions 2104 and 2106 connected by union 2108 and having a fluid volume 2110 containing a dispensable substance, a spring 2114, a gas container 2116, a piston 2118, a piercer 2120, and an O-ring 2132. Gas container 2116 is retained by retaining element 2128. Seal 2130 forms a gas seal between piercer 2120 and housing 2106. Spring retaining cup 2122 retains spring-loaded piercer 2120. The piercer holder 2124 holds the piercer 2120 in a fixed position together with the enteric trigger 2126, which holds the piercer holder in a fixed position and serves as a trigger mechanism until it dissolves. When the device 2100 is swallowed by a subject, the enteric trigger 2126 prevents the dispensable material in the fluid volume 2110 from being under pressure by holding the spring 2114 and the piercer 2120 in a fixed position. When the device 2100 reaches the appropriate position in the GI tract, the enteric trigger 2126 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the piercer holder 2124 is no longer sufficient to inhibit the pressure from the spring 2114. The spring 2114 forces the piercer 2120 into the gas container 2116, thereby piercing the gas container 2116 and causing the gas under elevated pressure to leave the container 2116. This causes the gas container 2116 to press against the piston 2118 and apply pressure to the fluid volume 2110. The piston provides friction to cause the cap 2134 to open / deploy, allowing the dispensable substance to be delivered from the volume 2110. This results in delivery (e.g., surface delivery) of the therapeutic agent contained in the dispensable substance.

[0266] In some embodiments, the housing of the ingestible device 2100 has a diameter of about 10 mm to about 12 mm (e.g., about 11.3 mm to about 11.5 mm), a length of about 23 mm to about 26.5 mm (e.g., about 23.3 mm to about 26.3 mm), a wall thickness of about 0.4 mm to about 0.6 mm (e.g., about 0.5 mm), a fluid volume of about 565 μL to about 630 μL (e.g., about 574 μL to about 623 μL), and / or a gas volume in the cylinder 2116 of about 150 μL to about 175 μL (e.g., about 160 μL). In some embodiments, the housing of the ingestible device 2100 has a diameter of 9.9 mm, or in some embodiments, a diameter of 8.5 mm. In some embodiments, the length of the ingestible device is 23.3 mm (size 00), or in some embodiments, 26 mm (size 000). In some embodiments, for example, for a size 000 device, the dispensable substance comprises an initial fluid volume of about 420 μL, and in some embodiments, for a size 00 device, the dispensable substance comprises an initial fluid volume of about 180 μL to about 280 μL.

[0267] Fig.23 and 24Ingestible device 2300 is shown in its closed and open states, respectively. Ingestible device 2300 contains a dispensable substance that is not under pressure when a subject swallows the ingestible device. Ingestible device 2300 has: housing portions 2304 and 2306 connected by union 2308 and having a fluid volume 2310 containing a dispensable substance, a spring 2314, a gas container 2316, a piston 2318, a piercer 2320, and an O-ring 2332. Gas container 2316 is retained by retaining element 2328. Seal 2330 forms a gas seal between piercer 2320 and housing 2306. Spring retaining cup 2322 retains spring-loaded piercer 2320. The piercer retainer 2324 holds the piercer 2320 in a fixed position together with the enteric trigger 2326, which holds the piercer retainer in a fixed position and serves as a trigger mechanism until it dissolves. When the device 2300 is swallowed by the subject, the enteric trigger 2326 prevents the dispensable material in the fluid volume 2310 from being under pressure by holding the spring 2314 and the piercer 2320 in a fixed position. When the device 2300 reaches the appropriate position in the GI tract, the enteric trigger 2326 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the piercer retainer 2324 is no longer sufficient to inhibit the pressure from the spring 2314. The spring 2314 forces the piercer 2320 into the gas container 2316, thereby piercing the gas container 2316 and causing the gas under elevated pressure to leave the container 2316. This causes the gas container 2316 to press against the piston 2318 and apply pressure to the fluid volume 2310. The piston provides friction to cause the cap 2334 to open / deploy, so that the dispensable substance is delivered from the volume 2310. This results in delivery (e.g., surface delivery) of the therapeutic agent contained in the dispensable substance.

[0268] The ingestible device in the figure can have a diameter of about 8 mm to about 11 mm, a length of about 23 mm to about 26.5 mm, a wall thickness of about 0.4 mm to about 0.6 mm, a fluid volume of about 230 μL to about 355 μL, and / or a gas volume in the gas container 2316 of about 150 μL to about 175 μL.

[0269] Fig.25An embodiment of an ingestible device 2500 is shown, which contains a dispensable substance that is not under pressure when the subject swallows the ingestible device. The ingestible device 2500 has: a housing portion 2504 and 2506 connected by a union 2508 and having a fluid volume 2510 containing the dispensable substance, a spring 2514, a piston 2518, a spring retaining pin 2536, and an O-ring 2532. After the housing portion 2504 is filled with the dispensable substance (e.g., a liquid containing a drug), a cap 2538 containing the dispensable substance seals into the dispensable substance (e.g., a liquid containing a drug). The seal 2530 forms a gas seal between the spring retaining pin 2536 and the housing portion 2506. The spring retaining cup 2522 retains the spring retaining pin 2536. The pin holder 2540 holds the spring holding pin 2536 in a fixed position together with the enteric trigger 2526, which holds the pin holder in a fixed position until it dissolves and serves as a trigger mechanism. When the device 2500 is swallowed by the subject, the enteric trigger 2526 prevents the dispensable material in the fluid volume 2510 from being under pressure by holding the spring 2514 and the spring holding pin 2536 in a fixed position. When the device 2500 reaches the appropriate position in the GI tract, the enteric trigger 2526 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the pin holder 2540 is no longer sufficient to inhibit the spring holding pin 2536, thereby releasing the spring 2514. The spring 2514 pushes the piston 2518, so that the piston 2518 applies pressure to the fluid volume 2510. The piston provides friction to cause the cap 2534 to open / deploy, so that the dispensable material is delivered from the volume 2510. This results in delivery of the therapeutic agent away from the dispensable mass (eg, surface delivery).

[0270] Fig.26 and 27 Ingestible device 2600 is shown in its closed and open states, respectively. Ingestible device 2600 is configured similarly to ingestible device 2500 and has housing components 2604 and 2606 that have a smaller profile than the housing components of ingestible device 2500. Fluid volume 2610 of ingestible device 2600 may have a smaller capacity than fluid volume 2510 of ingestible device 2500.

[0271] Fig.28An embodiment of an ingestible device 2800 is shown, which contains a dispensable substance that is not under pressure when the subject swallows the ingestible device. The ingestible device 2800 has: a housing portion 2804 and 2806 connected by a union 2808 and having a fluid volume 2810 containing the dispensable substance, a spring 2814, a piston 2818, a spring retaining pin 2836, and an O-ring 2832. After the housing portion 2804 is filled with the dispensable substance (e.g., a liquid containing a drug), a cap 2838 containing the dispensable substance is sealed into the dispensable substance (e.g., a liquid containing a drug). The seal 2830 forms an airtight seal between the spring retaining pin 2836 and the housing 2806. The spring retaining cup 2822 retains the spring retaining pin 2836. The pin holder 2840 holds the spring holding pin 2836 in a fixed position together with the enteric trigger 2826, which holds the pin holder in a fixed position until it dissolves and serves as a trigger mechanism. When the device 2800 is swallowed by the subject, the enteric trigger 2826 prevents the dispensable material in the fluid volume 2810 from being under pressure by holding the spring 2814 and the spring holding pin 2836 in a fixed position. When the device 2800 reaches the appropriate position in the GI tract, the enteric trigger 2826 degrades and / or dissolves (e.g., due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the pin holder 2840 is no longer sufficient to inhibit the spring holding pin 2836, thereby releasing the spring 2814. The spring 2814 pushes the piston 2818, so that the piston 2818 applies pressure to the fluid volume 2810. The piston provides friction to cause the cap 2834 to open / deploy, so that the dispensable material is delivered from the volume 2810. This results in delivery (eg, surface delivery) of the therapeutic agent contained in the dispensable substance.

[0272] Fig.29A An external view of an embodiment of an ingestible device 2800 is shown, and Fig.29B An exterior view of housing component 2804 holding a fluid volume 2810 is shown.

[0273] Fig.30 An embodiment of the ingestible device 2800 is shown with the cap 2834 opened / deployed.

[0274] Fig.31An embodiment of an ingestible device 3100 is shown, which contains a dispensable substance that is not under pressure when the subject swallows the ingestible device. The ingestible device 3100 has: housing portions 3104 and 3106 and a fluid volume 3110 containing the dispensable substance, a piston 3118, a wave spring 3142, and an O-ring 3132. After the housing portion 3104 is filled with the dispensable substance (e.g., a liquid containing a drug), a cap 3138 containing the dispensable substance seals into the dispensable substance (e.g., a liquid containing a drug). The seal 3130 forms a gas seal between the switch 3146 and the housing 3106. The spring retaining cup 3122 retains the wave spring 3142. The pin retainer 3140 holds the switch 3146 in a fixed position together with the enteric trigger 3126, which holds the pin retainer in a fixed position until it dissolves and serves as a trigger mechanism. When the device 3100 is swallowed by a subject, the enteric trigger 3126 prevents the dispensable substance in the fluid volume 3110 from being under pressure by holding the wave spring 3142 and the switch 3146 in a fixed position. When the device 3100 reaches the appropriate position in the GI tract, the enteric trigger 3126 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the pin holder 3140 is no longer sufficient to restrain the wave spring 3142 and releases the switch 3146. The switch 3146 completes the circuit with the gas cell 3144, which begins to produce gas. As pressure builds, the piston 3118 slides along the track and closes the circuit via the conductive O-ring 3132. When the track ends at a defined travel distance, the circuit is disconnected to stop the production of gas by the gas cell 3144. The piston 3118 applies pressure to the fluid volume 3110 and provides friction to cause the cap 3134 to open / deploy, so that the dispensable substance is delivered from the volume 3110. This results in the delivery (eg, surface delivery) of the therapeutic agent contained in the dispensable substance.

[0275] Fig.32A An external view of an embodiment of an ingestible device 3100 is shown, and Fig.32B An exterior view of housing component 3104 holding fluid volume 3110 is shown.

[0276] Fig.33 Another view of an embodiment of the ingestible device 3100 is shown.

[0277] Fig.34 An embodiment of the ingestible device 3100 is shown with the cap 3134 opened / deployed.

[0278] In some embodiments, the length of the ingestible device can be reduced to achieve an altered 00 standardized length, such as a length of approximately 23.3 mm, while maintaining the same diameter as the standard size 000. The reduced length of the ingestible device can result in a reduced volume available for the dispensable substance. Adjusting one or more dimensions of the gas container within the ingestible device and / or changing the position of the piston can be used to increase the volume available for the dispensable substance while maintaining a threshold dispensable substance volume and / or pressure provided by the gas container for the ingestible device. In some embodiments, the length of the ingestible device is 23.3 mm (size 00), or in some embodiments, 26 mm (size 000). Reference is made herein to Figure 35-40 Example implementations are described.

[0279] Fig.35An embodiment of an ingestible device 3500 for epithelial delivery is shown, wherein the length of the ingestible device is reduced to achieve a modified size 00 submucosal device, and it contains a dispensable substance that is not under pressure when the subject swallows the ingestible device. The ingestible device 3500 has: housing portions 3504 and 3506 connected by a union 3508 and having a fluid volume 3510 containing the dispensable substance, a spring 3514, a gas container 3516, a piston 3518, a piercer 3520, and an O-ring 3532. In some embodiments, there may be a gap between the inner housing portions (3504 and 3506) and the union 3508, for example, a gap of about 50 microns. The gas container 3516 is retained by a retaining element 3528. A seal 3530 forms a gas seal between the piercer 3520 and the housing 3506. A spring retaining cup 3522 retains the spring-loaded piercer 3520. The piercer retainer 3524 holds the piercer 3520 in a fixed position together with the enteric trigger 3526, which holds the piercer retainer in a fixed position until it dissolves and serves as a trigger mechanism. When the device 3500 is swallowed by the subject, the enteric trigger 3526 prevents the dispensable material in the fluid volume 3510 from being under pressure by holding the spring 3514 and the piercer 3520 in a fixed position. When the device 3500 reaches the appropriate position in the GI tract, the enteric trigger 3526 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the piercer retainer 3524 is no longer sufficient to inhibit the pressure from the spring 3514. The spring 3514 forces the piercer 3520 into the gas container 3516, thereby piercing the gas container 3516 and causing 3534 under elevated pressure to leave the gas container 3516. This causes the gas container 3516 to press against the piston 3518 and apply pressure to the fluid volume 3510. The piston provides friction to cause the cap 3534 to open / deploy, causing the dispensable substance to be delivered from the volume 3510. This results in epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0280] In some embodiments, the ingestible device 3500 can hold a dispensable substance volume of about 250 μL to about 350 μL, can have an expansion volume of about 230 μL to about 260 μL, and can have a gas container fill volume of about 140 μL to about 150 μL.

[0281] In some embodiments, one or more adjustments to the piston length and / or gas container size may be varied for an ingestible device, such as ingestible device 3500. Figure 36-40 Depicted reference Fig.35 Various variations of the ingestible device structures are described with respect to piston length and / or gas container size.

[0282] Fig.36 An embodiment of an ingestible device 3600 is shown in which the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and a reduced piston length. Fig.36 As shown, the ingestible device 3600 includes a piston 3618, a gas container 3616, and a fluid volume 3610. In some embodiments, the ingestible device 3600 can hold a dispensable substance volume of 300 μL to about 350 μL, can have an expansion volume of about 350 μL to about 380 μL, and can have a gas container fill volume of about 35 μL to about 45 μL. In some embodiments, a 280 PSIG fill pressure of the gas container corresponds to an actuation pressure volume of about 70-80 μL. In some embodiments, a 240 PSIG fill pressure of the gas container corresponds to an actuation pressure volume of about 90-100 μL.

[0283] Fig.37 An embodiment of an ingestible device 3700 is shown in which the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and the piston length is reduced. In some embodiments, the length of the ingestible device 3700 is 23.3 mm (size 00), or in some embodiments, 26 mm (size 000). Fig.37 As shown, the ingestible device 3700 includes a piston 3718, a gas container 3716, and a fluid volume 3710. In some embodiments, the ingestible device 3700 can hold a dispensable substance volume of 300 μL to about 350 μL, can have an expansion volume of about 320 μL to about 380 μL, and can have a gas container fill volume of about 65 μL to about 85 μL. A 280 PSIG fill pressure of the gas container corresponds to an actuation pressure volume of about 140-150 μL. A 240 PSIG fill pressure of the gas container corresponds to an actuation pressure volume of about 170-190 μL.

[0284] Fig.38 An embodiment of an ingestible device 3800 is shown in which the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and the piston length is reduced. In some embodiments, the length of the ingestible device 3800 is 23.3 mm (size 00), or in some embodiments, 26 mm (size 000). Fig.38As shown, the ingestible device 3800 includes a piston 3818, a gas container 3816, and a fluid volume 3810. In some embodiments, the ingestible device 3800 can hold a dispensable substance volume of 300 μL to about 350 μL, can have an expansion volume of about 300 μL to about 320 μL, and can have a gas container fill volume of about 35 μL to about 45 μL. The piston shape of the piston 3818 can result in a residual dispensable substance volume of about 80 μL within the dispensable substance housing (out of a total of 335 μL delivered) after delivery.

[0285] Fig.39 An embodiment of an ingestible device 3900 is shown in which the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and a modified gas container diameter. The length of the ingestible device 3900 is 23.3 mm (size 00), or in some embodiments, 26 mm (size 000). Fig.39 As shown, the ingestible device 3900 includes a piston 3918, a gas container 3916, and a fluid volume 3910. In some embodiments, the ingestible device 3900 can hold a dispensable substance volume of 300 μL to about 350 μL, can have an expansion volume of about 250 μL to about 290 μL, and can have a gas container fill volume of about 70 μL to about 80 μL. The piston shape of the piston 19166 can result in a residual dispensable substance volume of about 70-90 μL (e.g., about 80 μL) out of the total amount of dispensable substance volume delivered within the housing after delivery.

[0286] Fig.40 An embodiment of an ingestible device 4000 is shown in which the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and a modified gas container diameter. The length of the ingestible device 4000 is 23.3 mm (size 00), or in some embodiments, 26 mm (size 000). Fig.40 As shown, the ingestible device 4000 includes a piston 4018, a gas container 4016 and a fluid volume 4010.

[0287] In some embodiments, the ingestible device 4000 can hold a dispensable material volume of 300 μL to about 350 μL (e.g., about 332 μL), can have an expansion volume of about 220 μL to about 270 μL (e.g., about 240 μL), and can have a cylinder fill volume of about 125 μL to about 145 μL (e.g., about 138 μL). In some embodiments, a 240 PSI drive pressure of the cylinder corresponds to a fill pressure of about 650-710 PSI (e.g., 684 PSI). In some embodiments, a 280 PSI fill pressure of the cylinder corresponds to a drive pressure of about 770-830 PSI (e.g., about 798 PSI). In some embodiments, a 320 PSI drive pressure of the cylinder corresponds to a fill pressure of about 880-940 PSI (e.g., 912 PSI). Table 1 below provides other cylinder fill pressures.

[0288] Table 1: Cylinder filling pressure

[0289]

[0290] exist Figures 41A-41C In the embodiment of the present invention, the nozzle opening 4102 can be covered by a covering (including a member such as a patch 4104) that forms a barrier between the dispensable substance 4112 held in the housing 4110 and the external environment of the ingestible device. The patch 4104 can be formed by a material that is a degradable material, an erodible material, and a soluble material. The patch can be a barrier film composed of various materials such as polyethylene (PE), polypropylene, cyclic olefin copolymer (COC), cyclic olefin polymer (COP), polycarbonate, polyvinyl chloride (PVC), polyurethane, etc. The patch can be a multilayer film, for example, two or more layers of the same or different materials to enhance barrier properties. The multilayer structure of the patch 4104 can include, for example, PE / ethylene-vinyl alcohol copolymer (EVOH), ethylene-vinyl acetate (EVA) / EVOH / EVA, EVA / polyvinylidene chloride (PVDC) / EV, etc. The multilayer structure of the patch can include a metal layer.

[0291] The patch 4104 can have a variety of shaped profiles such as circular, rectangular, polygonal, or asymmetrical profiles. As shown in FIG. 41 , the patch can be fixed off-center 4106 above the nozzle opening 4102 on the outer surface of the ingestible device so that the force of the jet discharged through the nozzle opening 4102 (e.g., by pressurized release of the dispensable substance) can preferentially move the patch away from the direction of the formed jet.

[0292] The patch 4104 may be loosely secured over the nozzle opening (eg, using an adhesive or another pressure-sensitive method, or using static suction). The adhesive for securing the patch may be used on the surface around the nozzle, but not directly on the nozzle.

[0293] Film, coating, foil, band etc. can be arranged on the patch fixed on the nozzle opening, and can be made up of soluble materials such as enteric materials, so that during the operation (carrying, handling), storage and intake of the ingestible device, the film, coating, foil or band will keep the patch in a fixed position above the nozzle opening. In one example, band 4108 is made up of dissolvable materials when entering the body. Film or band can be made up of water-soluble materials such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) or gelatin. Film or band 4108 can be made up of materials including pH-dependent solubility, such as being made up of polymethacrylate or including polymethacrylate, so that the material is more stable under acidic conditions such as pH 1-4, and wherein the dissolution rate increases when the material is exposed to higher pH such as pH 5-7.

[0294] The band covering the nozzle opening can be composed of a heat shrink material that heat shrinks to the housing so that it provides a nozzle cover. An example of a heat shrink material is polyethylene terephthalate (PET). Other examples of heat shrink materials include polyolefins, polyethylene, LDPE, PTFE, FEP and COC. Generally speaking, such heat shrink materials do not work by being dissolved. On the contrary, it is broken (e.g., pierced) by the pressure applied to the heat shrink material by the dispensable material. Such heat shrink tape can have a thickness of, for example, about 5 μm to about 100 μm.

[0295] In general, the covering (e.g., film, coating, foil, tape) of the nozzle opening can be scored, for example, so that the seal is more easily broken when needed. Typically, such scoring can be configured as needed. As an example, the scoring can be configured as a series of parallel lines. As another example, the scoring can be configured as a grid (grid). As a further example, the scoring can be configured as a plurality of points (e.g., equidistant points). In some embodiments of the scored seal, the seal is composed of LDPE, for example, LDPE with a thickness of 20 μm to 75 μm (e.g., 25 μm, 50 μm). For example, a seal composed of LDPE can be scored with stripes or a grid or a plurality of points, and the LDPE has a thickness of 25 μm or 50 μm.

[0296] In some embodiments, the covering (e.g., a coating, film, tape, or patch) has a minimum burst pressure. In some embodiments, for example, the minimum burst pressure is less than 420, 220, 110 psig. Typically, the minimum burst pressure is greater than 5 psig (e.g., greater than 10 psig, greater than 25 psig, greater than 50 psig, greater than 80 psig).

[0297] The following coating or film can be applied on the nozzle opening 4102: it can be dissolved / degraded or otherwise become unstable after the ingestion of the ingestible device. In some embodiments, the coating or film is hydrophobic. The coating or film can be structurally weakened by drilling / scratching, such as using laser drilling, and / or can be composed of materials weakened based on the environment around the material, such as enteric materials in the body. In one example, laser microslicing technology such as grinding / polishing process can be used to thin the coating or film to reduce the coating or film thickness. The coating or film of enteric material can be applied on the nozzle opening 4102 and on a part of the outer surface of the ingestible device. The final thickness of the applied coating or film can be controlled by machining / polishing process such as centerless grinding or grinding. The coating or film can be further processed with a laser to drill, score, and / or punch holes to a part of the coating or film so that the coating or film is mechanically weakened.

[0298] Figures 42A-47C Embodiments of patches, coatings, films, foils, and / or bands that can be secured to or in contact with a nozzle opening are depicted. Although such embodiments are shown in these figures, the present disclosure is not limited in this sense. In some embodiments, a combination of more than one (e.g., more than two, more than three) of such methods of covering the nozzle opening may be used in a given ingestible device. Further, variations of the methods disclosed herein are available as long as they generally conform to the relevant functions, for example, providing a barrier between a dispensable substance (e.g., a liquid containing a drug) held within a drug housing and the external environment of the ingestible device.

[0299] like Fig.42A and 42B As shown, the nozzle opening 4202 may be covered by a covering (comprising a member 4248, such as a patch, film, foil, tape, etc.) that forms a barrier between a fluid volume 4210 including a dispensable substance (e.g., a liquid containing a drug) held within the housing and an environment external to the ingestible device. Certain embodiments including nozzle covering members formed of films, foils, patches, tapes, etc., such as those described in U.S. Pat. No. 11,007,356 B2 Fig.17 , 18 , 19A-N discuss and optionally apply to Fig.42A and 42B .

[0300] The internal pressure from the pressurized dispensable substance (e.g., during the release of the pressurized dispensable substance) can cause the dispensable substance to pierce the covering member or partially peel off / detach the covering member from the outer surface of the ingestible device to allow the formation of a jet 4262 containing the dispensable substance. The covering member 4248 can be composed of various materials such as PE, PP, PVC, cellulose acetate, hot blocking films, etc. In some embodiments, the covering member can be composed of materials that are intended to be insoluble in gastric media, but can be decomposed in the small intestine based on pH (e.g., enteric materials) or one or more enzymes such as one or more pancreatic enzymes (e.g., lipid-based materials). The covering member 4248 can be composed of materials that can be hydrated and / or softened without significant dissolution when exposed to gastric media. The covering member 4248 in this embodiment and other embodiments described herein can be composed of a gas permeable membrane (e.g., it may help to degas during the filling process of the ingestible device). The covering member can be applied, for example, from a reel in a post-molding operation.

[0301] The covering member 4248 can be a thin shrink-fit film or adhesive label component applied to the outer surface of the ingestible device to cover the nozzle opening. In certain embodiments, the film or adhesive label can be a thin barrier, such as a barrier having a thickness of 20 μm to 40 μm (e.g., 25 μm to 35 μm, 30 μm).

[0302] The covering member 4248 can be an outer band applied to cover the nozzle opening 4202. In certain embodiments, the band can be, for example, 100 μm to 200 μm (e.g., 125 μm to 175 μm, e.g., 150 μm) thick. Optionally, the band can be composed of a material soluble in the gastric medium, such as gelatin, HPMC, or other material, or can be composed of an enteric material.

[0303] In some embodiments, covering member 4248 can be a partial film or covering, such as an external cap, applied to the exterior of the ingestible device to cover nozzle opening 4202. The cap can be, for example, 100 μm to 200 μm (e.g., 125 μm to 175 μm, such as 150 μm) thick and / or cover less than the entire exterior of the ingestible device.

[0304] like Fig.43A and 43BAs shown in FIG. 4 , a covering member 4348, such as a patch, film, foil, tape, coating, etc., that forms a barrier between a fluid volume 4310 including a dispensable substance (e.g., a liquid containing a drug) held within a housing 4304 and an environment external to the ingestible device can be applied and / or secured to an inner surface 4364 of the ingestible device. In some embodiments, the covering member 4348 is a thin film that is applied to the inner surface of the primary container 4304 of the ingestible device (e.g., during a molding process) to cover the nozzle opening 4302. Internal pressure from the pressurized dispensable substance (e.g., during pressurized dispensable substance) can cause the dispensable substance to pierce the covering member or partially peel / detach the covering member from the outer surface of the ingestible device to allow formation of a jet 4362 containing the dispensable substance. The covering member 4348 can be composed of various materials, such as a COC-based film, such as a COC+LLDPE laminate, etc. In some embodiments, the covering member 4348 can be composed of a material that is intended to be insoluble in the gastric medium, but can be decomposed in the small intestine based on pH (e.g., enteric materials) and / or one or more enzymes such as one or more pancreatic enzymes (e.g., lipid-based materials). The covering member 4348 can be composed of a material that is hydrated and / or softened without significant dissolution when exposed to the gastric medium. The covering member 4348 in this embodiment and other embodiments described herein can be composed of a gas permeable membrane (e.g., which may help degas during the filling process of the ingestible device). The covering member 4348 can be applied to the inner surface 4364 of the ingestible device, for example, using a molding process (e.g., based on in-mold labeling or blow molding). The covering member can be, for example, 20 μm to 40 μm (e.g., 25 μm to 35 μm, 30 μm) thick. In some embodiments, the covering member can be applied / fixed without an adhesive, such as molded bonding.

[0305] like Fig.44A and Fig.44BAs shown, the covering member can be a feature, such as a molded feature 4466, formed on the inner end of the nozzle opening 4402 (or adjacent thereto) and forming a barrier between the fluid volume 4410 including the dispensable substance (e.g., liquid containing a drug) retained within the housing 4404 and the environment outside the ingestible device. Internal pressure from the pressurized dispensable substance (e.g., during release of the pressurized dispensable substance) can cause the dispensable substance to pierce the covering member 4466, causing the covering member to completely or partially peel / detach from the outer surface of the ingestible device to allow the formation of a jet 4464 containing the dispensable substance. The covering member can be composed of various materials, such as COC-based films such as COC+LLDPE laminates, etc. In some embodiments, the covering member 4466 can be composed of a material that is intended to be insoluble in the gastric medium, but can be broken down in the small intestine based on pH (e.g., enteric materials) and / or one or more enzymes such as one or more pancreatic enzymes (e.g., lipid-based materials). The covering member 4466 can be composed of a material that can hydrate and / or soften without significantly dissolving when exposed to gastric media.

[0306] like Fig.45A and 45B As shown, the cover member 4548 can be a cover member tethered 4568 to the ingestible device, for example, to an exterior portion of the housing 4504. The cover member 4548 can be formed of a flexible material, such as an elastomeric material. Internal pressure from the pressurized dispensable substance (e.g., during release of the pressurized dispensable substance) can cause the dispensable substance to disengage / displace a portion or all of the cover member from the nozzle opening 4502 of the ingestible device to allow a jet 4562 containing the dispensable substance to be formed.

[0307] like Fig.46A and 46B As shown, the covering member can be a plug 4650, such as an elastomeric plug, that can block the nozzle opening 4602 from the outer surface of the ingestible device. The plug can be tethered to the housing component 4604 of the ingestible device to prevent the released plug from being dispersed into the body. The plug 4650 can be formed of a biodegradable material so that the plug is processed by the body. (For example, during the release of the pressurized dispensable substance) The internal pressure from the pressurized dispensable substance can cause the dispensable substance to disengage / displace the plug 4650 from the nozzle opening of the ingestible device to allow the formation of a jet 4662 containing the dispensable substance.

[0308] like Figures 47A-47CAs shown, the nozzle opening 4702 can be blocked by a plug 4750 formed by applying a liquid-filled gel from an external device 4770 of the ingestible device (e.g., via a nozzle or a rotating mandrel). The liquid-filled gel can harden prior to the dispensable substance filling process to provide the plug 4750. The gel can be composed of a material that is substantially insoluble in the gastric medium / dispensable substance, but can be broken down in the pH of the small intestine (e.g., enteric materials) and / or one or more enzymes such as one or more pancreatic enzymes (e.g., lipid-based materials). The internal pressure from the pressurized dispensable substance (e.g., during the release of the pressurized dispensable substance) can cause the dispensable substance to displace the gel from the nozzle opening 4702 of the ingestible device to allow the formation of a jet 4762 containing the dispensable substance.

[0309] Fig.48A 48 and B depict an embodiment of an ingestible device 4800 utilizing an internal piston. The ingestible device 4800 contains a dispensable substance that is not under pressure when the subject swallows the ingestible device. Fig.48A , nozzle 4802 is shown as being covered, while in Fig.48B 4802 is uncovered. The ingestible device 4800 has housing portions 4804 and 4806 connected by a union 4808 and having a fluid volume 4810 containing a dispensable substance, a spring 4814, a gas container 4816, a first piston 4818a and a second piston 4818b, a piercer 4820, and an O-ring 4832. The piercer 4820 is held in a fixed position by an enteric trigger 4826 that dissolves and acts as a trigger mechanism. When the device 4800 is swallowed by a subject, the enteric trigger 4826 prevents the dispensable substance in the fluid volume 4810 from being under pressure by holding the spring 4814 and the piercer 4820 in a fixed position. When the device 4800 reaches the appropriate location in the GI tract, a triggering event occurs, for example, the enteric trigger 4826 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), causing the spring 4814 to force the piercer 4820 into the gas container 4816, thereby piercing the gas container 4816 and causing the gas under elevated pressure to leave the gas container 4816. This causes the gas container 4816 to press against the first piston 4818a and apply pressure to the fluid volume 4810. The pressurized fluid volume 4810 applies pressure to the second piston 4818b, causing the second piston 4818b to slide and expose the nozzle 4802, causing the dispensable substance to be delivered from the nozzle 4802 in the form of a jet. Fig.48AThe second piston 4818b shown in FIG. 4 and B includes an extension that may, for example, help guide the second piston away from a vent or opening in the housing. However, as described herein, XX is not a requirement for the second piston. This can result in transepithelial and / or epithelial delivery of a therapeutic agent contained in the dispensable substance.

[0310] Figures 49A-49E The design of the second piston 4919bA-4918bE is shown, which is used as a jet cover to prevent the dispensable material from leaking from the opening before the triggering event. When the device reaches the appropriate position in the GI tract, the triggering event occurs, for example, the enteric trigger degrades and / or dissolves (for example, due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the spring forces the piercer to enter the cylinder, thereby piercing the cylinder and causing the gas under the increased pressure to leave the cylinder. The triggering event causes the cylinder to press against the piston and apply pressure to the fluid volume. The pressurized fluid volume 4910 applies pressure to the second piston 4918bA-4918bE, causing the second piston 4918bA-4918bE to slide and expose the nozzle 4902, so that the dispensable material is delivered from the nozzle 4902 in the form of a jet. This can result in the trans-epithelial and / or epithelial delivery of the therapeutic agent contained in the dispensable material. The second piston 4918bA-4918bE can have a diameter (DD) equal to or slightly larger (e.g., 5-15% larger) than the inner diameter of the housing. For a 000 size device, the second piston can have a diameter of approximately 8.5 to 9.0 mm. The second piston 4918bA-4918bE can have a thickness (TT) of 0.6 mm to 1.2 mm, with a preferred thickness of approximately 1.0 mm. The durometer range of the second piston 4918bA-4918bE can be 60A to 85A, with a preferred durometer of approximately 70A. In other embodiments, the opening in the drug module is not disposed on a curved surface of the drug module. Figures 49A-49E These are illustrated by showing "nozzle heights" of 11.9 mm and 11.3 mm, where the 11.3 mm height is the clear space for the curved surface of the drug module and results in a better seal and subsequent jet formation for transepithelial delivery (see Fig.49B ).

[0311] In other embodiments, one or more vents can be introduced into the drug module to allow air between the second piston and the drug module to escape, thereby allowing the second piston 4918bA-4918bE to slide more easily without resistance from trapped air. The second piston 4918bA-4918bE can be shaped to increase the surface area of ​​the portion of the piston that contacts the interior of the drug module, i.e., the flange 4920 of the second piston 4918bA-4918bE can be sized equal to or larger than the opening to ensure that the opening is sealed. This is particularly useful in Fig.49D and 49Eshown in the figure, where the edge of the piston is larger than Fig.49C The first piston 4918a may be physically coupled to the second pistons 4918bA-4918bE via one or more couplings (eg, via foldable arms). Figures 49A-49E The design of the device shown in the figure can be similar to that described above in other aspects. Fig.48A and 48B The same as in.

[0312] A plug / cap may be secured over the nozzle opening, wherein the plug / cap is further connected to the piercer component of the ingestible device via a connector and a collar component. Fig.50A and 50B One embodiment of an ingestible device 5000 including a plug / cap assembly is shown. The ingestible device 5000 includes: a nozzle opening 5002, a drug container 5004, a drive housing 5006, an o-ring 5032, a retaining element 5028, a piercer 5020, a gas seal 5030, a trigger element 5026, a trigger support 5024, a spring 5014, a gas container 5016, a union 5008, and a piston 5018. The ingestible device 5000 optionally includes a nozzle cap 5048.

[0313] The plug / cap assembly can be a single formed piece, for example, comprised of a plastic material, and externally mounted to the ingestible device such that the plug 5050 covers the nozzle opening 5002 on the ingestible device 5000. The plug / cap assembly can further include a connector 5052 that connects the plug / cap assembly to a collar 5054 component that can be attached to the top of the piercer 5020 and the exterior of the trigger element 5026 such that when the piercer is released, for example, after the trigger element 5026 dissolves / degrades, the collar component 5054 is pulled down by the piercer 5020, and the plug / cap 5050 is pulled away from the nozzle opening 5002 by movement of the collar 5054. In some embodiments, the plug / cap 5050 is pulled away from the nozzle opening 5002 by movement of the collar 5054 in a direction parallel to the length of the ingestible device 5000, for example, along the exterior surface of the ingestible device. The plug / cap 5050 is pulled away from the nozzle opening 5002 by movement of the ring 5054 in a direction outward (e.g., normal or oblique) from the outer surface of the ingestible device 5000.

[0314] The band may be secured over one or more nozzle openings, wherein the band is further connected to a piercer component of the ingestible device via a connector and loop component. Fig.51A and 51BOne embodiment of an ingestible device 5100 including a belt assembly is shown. The ingestible device 5100 includes: a nozzle opening 5102, a drug container 5104, a drive housing 5106, an o-ring 5132, a retaining element 5128, a piercer 5120, a gas seal 5130, a trigger element 5126, a trigger support 5124, a spring 5114, a gas container 5116, a union 5108, and a piston 5118. The ingestible device 5100 optionally includes a nozzle cover 5148.

[0315] The band assembly can be a single formed piece, composed, for example, of a plastic material, including the band 5156, the connector 5152, and the loop member 5154. The band assembly can alternatively be a multi-piece assembly composed of: the band 5156, which is placed around the ingestible device 5100 during the filling process; and the connector / loop assembly, which is secured to the band 5156 and the piercer member 5120. The band assembly can be connected to the piercer 5120 by the loop member 5154, which can be attached to the top of the piercer member and the exterior of the trigger element 5126, so that when the piercer is released, for example, after the trigger element 5126 dissolves / degrades, the loop member 5154 is pulled down by the piercer 5120, and the band 5156 is pulled away from the nozzle opening 5102 (e.g., along the length of the ingestible device 5100) to expose the nozzle opening 5102 by the movement of the loop 5154, followed by or simultaneously delivering the dispensable substance through the nozzle opening 5102.

[0316] like Figures 52A-52D As shown, the ingestible device 5200 includes a sliding cover 5248. The sliding cover 5248 can be a single formed piece, such as a sleeve composed of a plastic material, and is externally mounted to the ingestible device 5200 such that a portion of the sliding cover covers the nozzle opening 5202 on the ingestible device 5200. The sliding cover 5248 can be attached to the top of the piercer component 5220 and the exterior of the trigger element 5226 such that when the piercer is released, such as after the trigger element 5226 dissolves / degrades, the sliding cover 5248 is pulled down by the piercer 5220, and the sliding cover 5248 is pulled away from the nozzle opening 5202 by the movement of the piercer 5220. The sliding cover 5248 can be pulled away from the nozzle opening 5202 by the movement of the sliding cover in a direction parallel to the length of the ingestible device 5200, such as along the outer surface of the ingestible device, before or simultaneously delivering the dispensable substance in the fluid volume 5210 through the nozzle opening 5202. In some embodiments, the sliding cover 5248 is mounted internally to the ingestible device 5200 such that a portion of the sliding cover covers the nozzle opening 5202 on the ingestible device 5200. The internal sliding cover can be attached to the piercer member 5220 or the piston 5218.

[0317] like Fig.53Aand 53B The ingestible device 5300 shown in the embodiment includes a cap 5334, which is fixed on one end of the ingestible device 5300 and partially encloses the volume 5310. A seal 5358, such as an overmolded elastomer-based seal, can be used to seal the dispensable material in the volume 5310 while the cap 5334 is fixed on the end of the ingestible device 5300 and prevent the dispensing of the dispensable material. The seal 5358 can additionally prevent the cap 5334 from moving before the delivery of the dispensable material. When the device 5300 is swallowed by the subject, the enteric trigger prevents the dispensable material in the fluid volume from being under pressure by keeping the spring and the piercer in a fixed position. When the device reaches the appropriate position in the GI tract, the enteric trigger degrades and / or dissolves (e.g., due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the spring forces the piercer to enter the gas container, thereby piercing the gas container and causing the gas under elevated pressure to leave the container. This causes the gas container to press against the piston and apply pressure to the fluid volume. The pressurized fluid volume applies pressure to the cap and causes the cap to slide open and expose the nozzle, so that the dispensable substance is delivered from the nozzle in the form of a jet. This can result in trans-epithelial and / or epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0318] like Fig.54A and 54B As shown, the ingestible device 5400 includes an inflatable membrane volume 5460, such as a gas balloon or the like, which is positioned within the volume 5410 including the dispensable substance and is arranged to seal the nozzle opening 5402 when the inflatable volume 5460 is inflated. In some embodiments, the inflatable membrane volume 5460 may conform to one or more contours, such as the inner curvature, of the ingestible device housing 5404. The inflatable membrane volume 5460 may be composed of a balloon and / or a soft material, such as a low durometer elastomer. When the device 5400 is swallowed by the subject, the enteric trigger prevents the dispensable substance in the fluid volume from being under pressure by keeping the spring and the piercer in a fixed position. When the device reaches the appropriate position in the GI tract, the enteric trigger degrades and / or dissolves (e.g., due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the spring forces the piercer to enter the gas container, thereby piercing the gas container and causing the gas under elevated pressure to leave the container. This causes the gas container to press against the piston and apply pressure to the fluid volume. The pressurized fluid volume applies pressure to the inflatable membrane volume 5460 and causes the inflatable membrane volume to deflate or otherwise reposition to expose the nozzle opening 5402, so that the dispensable substance is delivered from the nozzle in the form of a jet. This can result in transepithelial and / or epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0319] Fig.55 The ingestible device in does not include a covering member. For example, the nozzle opening 5502 can be exposed so that when the ingestible device 5500 is swallowed / inserted, the air gap and / or surface tension effects in the nozzle opening 5502 can prevent or prevent the gastric medium from damaging the internal components or dispensable material (e.g., a liquid containing a drug) within the ingestible device. In other words, through the movement of the ingestible device within the gastric region, a differential force can be generated between the external intestinal force / pressure and the internal force of the dispensable material in the volume of the ingestible device. The surface tension of the dispensable material within the volume 5510 of the ingestible device can be higher than the surrounding environment, such as the external intestinal force / pressure, within the gastric region of the body, so that a significant percentage of the dispensable material is retained within the volume of the ingestible device until the delivery point of the dispensable material, such as until the piston 5518 applies pressure to the volume 5510 to force the dispensable material retained in the volume 5510 out of the nozzle opening 5502. In one example, at least 75% of the dispensable substance (e.g., at least 85%, at least 95% of the dispensable substance) is retained within the volume of the ingestible device until the dispensable substance is delivered to a point in the body within the stomach region.

[0320] like Fig.73A and 73B As shown, the draft angle of the medication module 7000 (exaggerated for illustration) can be about 0.05 degrees to 0.25 degrees or about 0.10 to 0.15 degrees. A draft angle of less than about 0.25 degrees generally allows for an improved seal between the piston 7002 or piston o-ring 7004 and the medication module housing 7000. The medication module 7000 may include one or more vent holes 7006, which are generally located on or near a relatively flat portion of the medication module 7000. In Figures 49A-49E In the Figures, these are shown as "nozzle heights" of 11.9 mm and 11.3 mm, where the 11.3 mm height is the clear space of the curved surface of the drug module, i.e., at the bottom of the drug module or below the dome of the drug module, and results in better sealing, better opening gap and subsequent jet formation for transepithelial delivery.

[0321] like Fig.73B As shown, the draft angle of the piston 7002 can match the draft angle of the drug module, for example, about 0.15 degrees. The piston O-ring cross-section can be about 0.50mm to 0.70mm, or about 0.60mm. The piston O-ring has a nominal compression of about 14.5% to about 22.0%. For example, the O-ring compression can be about 16.5% at the beginning of the piston stroke and about 20.0% at the end of the stroke. The O-ring groove width can be about 0.80mm to 0.90mm, or about 0.85mm.

[0322] Steering Figures 74A-74C, the trigger housing 7400 includes two to six ribs 7402, such as five ribs, which improve spring alignment and positioning. In this case, the piercer 7404 includes an O-ring 7406, the width of the groove of the O-ring 7406 is about 0.90mm to 0.95mm, and the nominal compression is about 16.5% to about 22.0%. For example, the O-ring compression can be about 20.0% at the beginning of the piercer stroke and about 18.7% at the end of the stroke.

[0323] The trigger support 7500A, 7500B or 7500C can be angled to improve the triggering of the device. Fig.75B As shown in , with an angle of 0 degrees (i.e., as Fig.75A Introducing a 15 degree angle to the trigger support improves the trigger degradation of the release member compared to a trigger support that is flat as in FIG. Fig.75C As shown, a trigger support having an angle of 30 degrees or more may not be able to resist the force of the spring, resulting in premature triggering or insufficient "shelf life". Therefore, the trigger support can be at an angle of about 10 degrees to 25 degrees, or about 15 degrees to 20 degrees. The spring that applies force to the piercer to move the piercer to break the frangible seal of the gas container typically generates a force of between about 28N to 44N, or about 34N to 38N, and can have a wire diameter of 0.85mm to 0.95mm or 0.90mm. The above angles are relative to Fig.75D The angles are measured relative to the flat top surface of the housing as shown, that is, the angles are measured relative to a plane perpendicular to the central longitudinal axis of the device and perpendicular to the direction of movement of the piercer.

[0324] refer to Figures 76A-76F , the piercer 7600 can be incorporated into the cartridge 7602. More specifically, as Fig.76A and 76B As shown, the release member is designed as a wedge or other shape, whereby during assembly it forces the snap arm 7604 of the piercer onto the washer 7606. When the release member degrades, the snap arm closes, thereby releasing from the washer and allowing the piercer to be actuated. Alternatively, as Fig.76C and 76D As shown, the release member is held between the circular post 7608 and the radial snap arm 7610 extending from the trigger housing. When the release member degrades, the radial snap arm 7610 extends outward, thereby releasing from the piercer and allowing the piercer to be actuated.

[0325] like Figures 77A-77DAs shown, the trigger housing 7700 may include a separate piercer base 7702 or 7710, which is designed to improve the actuation of the device by piercing the cylinder. When the release member degrades, the separate piercer base 7702 or 7710 holds the piercer in a fixed position until a threshold force is overcome, and the threshold force is, for example, a threshold force of about 8N to 30N or 16N to 30N or a corresponding force applied by the piercer spring, after which the piercer extends undisturbed and pierces the frangible seal of the cylinder. The separate piercer base 7702 or 7710 is designed to ensure that the piercer moves with a single, rapid motion after the release member is partially or completely degraded. The separate piercer base can be made of any material with appropriate properties to hold the piercer until the threshold force is overcome. For example, the separate piercer base can be made of metal, alloy, plastic, filler or a combination thereof. The separate piercer base can include two or more arms. The radial arm 7704 on the outside of the split piercer base 7702 extends above the top of the spring, as shown in FIG. Fig.77A and 77B As shown, the detachable piercer base 7710 has an internal hook arm 7712.

[0326] like Figures 78A-78D As shown, the trigger housing includes a separate piercer flange 7800, which is designed to improve the actuation of the device by piercing the cylinder, whereby once the release member is degraded, the separate piercer flange holds the piercer in a fixed position until a threshold force is overcome, the threshold force being, for example, a threshold force of about 20Nn to 30N or a corresponding force applied by a piercer spring. Thereafter, the piercer extends undisturbed and pierces the frangible seal of the cylinder. The separate piercer flange is designed to ensure that the piercer moves in a single, rapid motion after the release member is partially or completely degraded. The separate piercer flange can be made of any material with appropriate properties to hold the piercer until the threshold force is overcome. For example, the separate piercer flange can be made of metal, alloy or plastic. The separate piercer flange can include a straight, J-shaped, L-shaped or V-end-shaped foot 7802, such as Figure 78B1 , 78B2 As shown in Figure 78B3 and 78B4, the threshold force of the flange is increased. Fig.78C and 78D As shown, if a breakaway piercer flange 7800 is used, the breakaway piercer flange 7800 can be formed as a flat template and bent into a circular shape.

[0327] Figure 78E , 78F and 78G1-G4 show a separate piercer flange 7800 that rests on an internal rib of the trigger housing and has a protrusion that projects radially inward to engage the piercer. Figures 78H-78LAs shown, during assembly, the separate piercer flange arm will not deform outward. In this embodiment, the flange arm is preferably made of plastic. The flange arm may include one or both of an interference rib or a snap ring, such as Figure 78H shown.

[0328] exist Fig.79A , 79B In the example of 79C, the trigger housing includes two or more shear pins 7900, which hold the piercer in a fixed position until a threshold force is overcome, such as a threshold force of about 20NN to 30N or a corresponding force applied by the piercer spring, after which the piercer extends undisturbed and pierces the frangible seal of the cylinder. The diameter of the shear pins 7900 can be in the range of about 0.6mm to 1.2mm.

[0329] exist Figures 80A-80F In an embodiment of the invention, the trigger housing includes a trigger crown 8000. The crown allows for increased or more uniform hydration of the release member. The crown may include one or more ribs or other features for applying concentrated pressure on the release member, which helps to prevent catastrophic failure of the release member. In addition, the crown provides space for debris from the release member to disperse, thereby preventing any moving parts on the device (such as the trigger support) from being blocked.

[0330] The release component can be designed to have greater strength and / or reduced degradation when it interacts with the ribs of the crown, for example, by providing a denser or stronger release component formulation at the rib contact site. The release component can include an enteric material (e.g., a polymethacrylate-based copolymer (e.g., Eudragit)) at the rib contact site.

[0331] exist Figures 80G-80J In the design of the trigger housing, two or more balls 8002 are displaced when the release member is partially or completely degraded. More specifically, when the release member is degraded, the ball groove 8010 moves downward, allowing the ball 8002 to move radially, thereby releasing the nut. Once the nut 8014 is released, the nut and the piercer travel longitudinally and break the frangible seal of the gas container.

[0332] exist Figures 81A-81C In an embodiment, the trigger housing does not include a spring. Instead, the container cap 8100 is locked to the gas container, thereby preventing the release of the pressurized gas. The screwed-in pin 8102 and pin O-ring 8104 are assembled to the container cap 8100. After the gas container is pressurized, the container cap is attached to the gas container and rotated (e.g., 90 degrees) to lock it in a fixed position, such as Fig.81CAs shown. A second O-ring 8106 is mounted on the container cap, and both the release member and the gas container assembly are inserted into the trigger housing. The cap is turned again (e.g., 90 degrees) to unlock it, and now the gas pressure from the gas container pushes the container cap against the release member. After the device is applied, the release member is introduced into the biological fluid, where it dissolves or degrades at a predetermined anatomical position according to physiological conditions (e.g., pH) in the biological fluid. When the release member dissolves or degrades, the container cap is displaced from the gas container, and the gas is released from the pressurized container, thereby actuating the device. Therefore, in this design, no spring and piercer are used.

[0333] See also Fig.81E and 81F , the trigger housing may include one or more ribs 8110 or other features for applying concentrated pressure on the release member, which helps to contribute to catastrophic failure of the release member. In this case, the gas from the gas container applies a force to the release member, which also helps to clear the release member or fragments of the release member from the trigger housing. The trigger housing optionally includes an opening or "window" that allows for increased or more uniform hydration of the release member.

[0334] The trigger housing may include one or more ribs or other features for applying concentrated pressure on the release member, which helps to prevent catastrophic failure of the release member. In addition, the trigger housing may provide space for debris from the release member to disperse, thereby preventing any moving parts on the device (such as the cylinder cap) from being blocked.

[0335] In another embodiment, similar to Figures 81A-81F In the device shown in , the trigger housing does not include a spring, but instead uses a piercer to seal the cylinder - the two parts are connected by a press fit, as shown in Figures 82A-82I As shown. The piercer may include an O-ring 8200 to improve the seal. The piercer destroys the frangible seal or diaphragm of the gas container. After the piercer is coupled to the cylinder, the trigger housing or drive module housing is connected to the drug module housing. Similar to the device shown in Figures 81-81F, the release component helps maintain the seal between the piercer and the cylinder. In the presence of biological fluids, when the release component dissolves or degrades, the piercer is displaced from the cylinder and the gas is released from the pressurized cylinder, thereby actuating the device.

[0336] and Figures 81A-81F Similar to the devices shown in 82A-82I, in Figures 83A-83EIn the design of the trigger housing, the spring is not included, but a piercer or piercer-like plug 8300 is used to seal the cylinder - the two components are connected by a sliding valve 8302. The shape and position of the release component puts the erosion surface under tension to accelerate the structural failure or degradation of the release component, thereby actuating the device. In another embodiment, the device includes a second piston 8304 for blocking the opening, wherein the second piston includes an internal split cap 8306. As shown in FIG. Fig.83C and 83D As shown, the detachable portion is embedded in the housing recess after it is displaced by the drive piston. The drug payload can flow through the channel in the housing and out of the opening. Alternatively, as Fig.49A and 49B As shown, the second piston 8304 can be moved to expose the opening and the split cap can be used as a vent.

[0337] Fig.84A and 84B The device shown in is similar to the device shown in 81A-81F and 82A-82I, however, the device includes a second piston 8400, which blocks one or more openings until the device is actuated. In addition, the gas container 8402 has a first portion 8404, which is sealed with a second portion 8406. When the release member is weakened, the two parts separate, allowing the gas to escape. The total volume of the cylinder can be reduced to about 80-100 μL, and the drug volume can be increased to 500-600 μL. In this embodiment, the spring and piercer are also not used.

[0338] and Fig.84A and Fig.84B similar, Fig.84C and Fig.84D The device shown in has a gas container 8402 sealed with a second portion such as an end cap 8406. The end cap 8406 may or may not include an inner O-ring on a portion of the end cap that extends into the opening of the gas container, and an outer O-ring that slidably seals the end cap against the inner wall of the trigger housing. The end cap 8406 is maintained in a sealed position against the opening of the gas container by a release member. The end cap 8406 prevents gas from escaping from the gas container (when the release member is intact). When the release member partially or completely erodes, degrades, ruptures and / or dissolves, the end cap is pushed away from the gas container, allowing gas to escape, thereby actuating the device. As shown, a piercer and spring are not used. In some embodiments, the device does not include a release member such as Fig.84D , and in other embodiments, has a second piston as shown in Fig.84A and 84BIn some embodiments, the trigger housing includes an opening or "window" that allows for increased or more uniform hydration of the release member and for degraded material from the release member to migrate out of the housing.

[0339] In some embodiments, such as FIG. 85A to FIG. 8 5E, an O-ring is used to seal the gas container, and the release mechanism uses one or more O-rings 8500 in the receiver 8502, such as Figures 85E1-85E4 As shown, one or more O-rings 8500 are displaced from the gas pathway. Fig.85F Test results for a displaced O-ring used to seal a pressurized gas container are shown. At pressures of 250 psi or higher (1.72 MPa), approximately 35% of the gas is released within 35 milliseconds.

[0340] Fig.85B An ingestible device 8510 is shown having a gas container having a first or bulbous portion 8512, a sealing plate 8514 connected to the neck or narrow end of the bulbous portion 8512, and a septum or seal 8516 on the sealing plate 8514 that can be pierced by a piercer 8518. The piercer 8518 can have a length of about 2-3 mm or about 2.4 to 2.6 mm measured from the top of the shield (which bottoms out against the trigger housing). In the present design, the piercer parameters are shown in Table 2 below.

[0341]

[0342] After relaxation

[0343]

[0344] Therefore, the spring may exert a force of about 35 to 45N.

[0345] In some cases, the gas container is filled with a liquefied gas such as difluoromethane (R-32, CH2F2) or argon. Liquefied gases have advantages over non-liquefied gases. For example, difluoromethane allows for a smaller cylinder volume than non-liquefied gases, while liquefied gases provide a more consistent gas pressure throughout the piston stroke. Argon has the advantage of being less sensitive to temperature changes than difluoromethane.

[0346] like Figures 94-98As shown, the ingestible device 9400 can be designed to provide a two-step gas release. In this design, in the first step, gas is released from the gas container by manually breaking or puncturing the seal of the gas container using an external element or tool before the device is ingested, while also sealing the gas released from the piston to prevent the device from being actually actuated. In the second step, after the device is ingested, the release component dissolves, allowing components within the device to move, thereby allowing the gas to act on the piston and actuate the device. The second step can be performed in a factory for manufacturing and assembly purposes, or at the point of use, that is, immediately before the device is ingested.

[0347] The device 9400 includes a first housing 9401 attached to a second housing 9403. A release member 9402 is located inside the second housing 9403. A piercer 9404 is slidably positioned between the release member 9402 and a seal 9412, which is located on a gas container 9416 that includes a compressed gas. An O-ring 9406 provides a sliding seal between the piercer 9404 and the second housing 9403. An O-ring 9410 provides a sliding seal between the first piston 9408 and the first housing 9401. An O-ring 9422 provides a sliding seal between the second piston 9420 and the first housing 9401. A dispensable substance (e.g., a liquid) 9425 is contained in a reservoir formed between the first piston and the second piston and located within the cylindrical side wall of the first housing.

[0348] refer to Fig.95 and Fig.96 In the example of point-of-use gas release, the device 9400 is placed in a holder 9500 which prevents the device from moving as a plunger 9502 is manually pressed against the release member 9402. This causes the release member 9402 and the piercer 9404 to move along Fig.96 9412. The plunger 9502 can slide through a damping sleeve or element in the retainer 9500 to reduce the recoil movement caused by the release of compressed gas.

[0349] like Fig.97 As shown by the arrow in FIG. 1 , the compressed gas is released into the second housing 9403, pushing the piercer 9404 and the release member 9402 back to Fig.94 9404. The compressed gas is confined within the second housing 9403 by the O-ring 9406. The device is then ingested. After ingestion, the release member partially or completely erodes, degrades, ruptures and / or dissolves. The piercer 9404 is then moved along ( Fig.96 This allows the compressed gas to flow out of the second housing 9403 and exert force on the first piston 9408. Fig.97 and Fig.98 As shown, the first piston 9408 applies pressure to the dispensable substance, which moves the second piston 9420 (if used) from its original position to Fig.98 The extended position is shown. The dispensable substance is ejected from the nozzle or opening in the first housing 9401.

[0350] Fig.99 and Fig.100 An alternative second piston is shown, which is configured to make filling the drug module easier and provide a higher jet force, which can allow the use of a lower gas pressure (e.g., 320 psi). The dimensions shown are representative examples. As shown, the second piston has a periphery 10002, which has a flat top surface, a flat vertical edge, and an angled lower surface. The inner portion or dome 10004 is a spherical shell.

[0351] Devices for transepithelial delivery

[0352] In general, transepithelial delivery can be achieved at any desired location within the GI tract of a subject. In some embodiments, transepithelial delivery is achieved in the small intestine of a subject, such as in the duodenum, jejunum, and / or ileum. In certain embodiments, transepithelial delivery is achieved in the large intestine (e.g., cecum or colon) of a subject.

[0353] Transepithelial delivery can be achieved using any of the ingestible devices described above for transepithelial delivery. In such embodiments, the relevant parameters are typically modified accordingly. Typically, such modifications involve modifying the values ​​of the relevant parameters. The following paragraphs provide examples.

[0354] Generally speaking, the ingestible device for transepithelial delivery is configured to deliver a jet of a dispensable substance, and in some embodiments, the jet has a peak jet power of 6 watts to 17 watts, or, in some embodiments, the jet has a peak jet power of greater than 6.6 watts to 11 watts, or, in some embodiments, the jet has a peak jet power of greater than 6.6 watts and less than 9 watts.

[0355] Typically, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable material having a peak jet pressure of about 2 psig (e.g., about 2.5 psig, about 3 psig, about 3.5 psig, about 4 psig) and / or at most about 10 psig (e.g., at most about 8 psig, at most about 6 psig, at most about 5 psig). In some embodiments, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable material having a peak jet pressure of about 2 psig to about 10 psig (e.g., about 2.5 psig to about 8 psig, about 3 psig to about 6 psig, about 3.5 psig to about 5 psig, about 4 psig to about 5 psig).

[0356] Generally speaking, the ingestible device for transepithelial delivery is configured to deliver a jet of a dispensable substance, wherein in some embodiments, the jet has a peak jet force of 0.2N to 0.6N, or, in some embodiments, the jet has a peak jet force of greater than 0.26N to 0.4N, or, in some embodiments, the jet has a peak jet force from 0.28N to 0.32N.

[0357] Generally speaking, ingestible devices for transepithelial delivery are configured to deliver a jet of a dispensable substance: at a minimum jet velocity of at least about 2 m / s (e.g., at least about 3 m / s, at least about 4 m / s, at least about 5 m / s) and / or at most about 20 m / s (e.g., at most about 15 m / s, at most about 10 m / s, at most about 8 m / s), or at a peak jet velocity of 45 meters per second to 60 meters per second.

[0358] Generally speaking, ingestible devices for transepithelial delivery are configured to provide an internal pressure, in some embodiments, between 280 psig and 400 psig, or in some embodiments, between 320 psig and 350 psig.

[0359] Generally, ingestible devices for transepithelial delivery are configured to provide a nozzle pressure of about 3.62 psig to about 21.76 psig (e.g., about 3.62 psig to about 18.13 psig, about 3.62 psig to about 14.50 psig, about 3.62 psig to about 10.88 psig, about 3.62 psig to about 7.25 psig, about 4.35 psig to about 7.25 psig, about 4.35 psig).

[0360] Typically, ingestible devices for transepithelial delivery are configured to contain a dispensable substance at a peak fluid pressure, in some embodiments, at a peak fluid pressure of 270 psig to 390 psig, and in some embodiments, at a peak fluid pressure of 310 psig to 340 psig.

[0361] Generally speaking, an ingestible device for transepithelial delivery is configured to deliver at least about 50% (e.g., at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%) of the dispensable substance directly from the ingestible device to the mucus.

[0362] Devices for surface delivery

[0363] Typically, surface delivery can be achieved at any desired location within the GI tract of a subject. In some embodiments, surface delivery is achieved in the small intestine of a subject, such as in the duodenum, jejunum, and / or ileum. In certain embodiments, surface delivery is achieved in the large intestine (e.g., cecum, ascending colon, transverse colon, or descending colon) of a subject.

[0364] Generally speaking, the ingestible device for topical delivery is configured to provide an internal pressure, in some embodiments, an internal pressure of 5 psig to 350 psig, or in some embodiments, an internal pressure of 5 psig to 100 psig, or in some embodiments, an internal pressure of 5 psig to 50 psig. Unlike the ingestible device for transepithelial delivery, the ingestible device for topical delivery does not generate a high-speed jet intended to penetrate the epithelial layer of the gastrointestinal tract; therefore, it generally has a lower internal pressure and / or larger and / or more numerous openings.

[0365] Generally, ingestible devices for topical delivery include an initial fluid volume of about 50 μL to about 800 μL (eg, about 100 μL to about 600 μL, about 200 μL to about 400 μL).

[0366] Generally speaking, an ingestible device for topical delivery is configured to deliver at least about 50% (e.g., at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%) of the dispensable substance from the ingestible device into the lumen of the GI tract.

[0367] In certain embodiments, the ingestible device for topical delivery is configured as disclosed above in the discussion of transepithelial delivery, but has a relatively large number of openings and a relatively large opening diameter so that the performance properties for topical delivery (discussed above) can be achieved. As an example, in some embodiments, the ingestible device for topical delivery has 2 nozzles to 10 nozzles. Each nozzle can have a diameter of about 0.5 mm to about 3 mm (e.g., about 1 mm to about 2.5 mm, about 2 to 2.5 mm).

[0368] Delivery of therapeutic agents

[0369] Provided herein is an ingestible device and method for delivering therapeutic agents to the intestinal lumen, mucus, mucosa and / or submucosal layer by surface, epithelial or transepithelial administration to the GI tract of a subject. The current method of administration for most macromolecular therapeutics or small molecule therapeutics with poor oral bioavailability is subcutaneous (SC), intramuscular (IM) or push intravenous (IV) injection targeting systemic circulation. Devices and methods described herein provide alternative routes of administration for current injection drugs, which can bring greater convenience and compliance because they minimize or avoid challenges in arrangement coordination, patient compliance and compliance challenges, pain and discomfort associated with traditional routes of administration.

[0370] In some embodiments of any of the devices or methods described herein:

[0371] The therapeutic agent is released at a location in the small intestine of the subject. In some embodiments of any of the devices or methods described herein, the location is in the proximal portion of the small intestine (e.g., the duodenum or jejunum);

[0372] The location is in the distal portion of the small intestine (e.g., the jejunum or ileum). In some embodiments of the devices or methods described herein, the therapeutic agent is released at a location in the large intestine of the subject. In some embodiments of any of the devices or methods described herein, the location is in the proximal portion of the large intestine (e.g., the cecum, ascending colon, or transverse colon); and / or

[0373] The location is in the distal portion of the large intestine (eg, the transverse colon or descending colon).

[0374] Furthermore, by providing higher concentrations of therapeutic agents in GI tissues, the devices and methods described herein are particularly well suited for treating diseases and disorders of the endoderm, including the liver.

[0375] In some embodiments of any of the devices or methods described herein:

[0376] Release of the therapeutic agent is triggered by one or more of: a pH in the jejunum of about 6.1 to about 7.2, a pH in the mid-small intestine of about 7.0 to about 7.8, a pH in the ileum of about 7.0 to about 8.0, a pH in the right colon of about 5.7 to about 7.0, a pH in the mid-colon of about 5.7 to about 7.4, or a pH in the left colon of about 6.3 to about 7.7;

[0377] Release of the therapeutic agent is triggered by degradation of a release component located in the device;

[0378] Release of the therapeutic agent is dependent on enzyme activity at or near that location;

[0379] The composition comprises a plurality of electrodes comprising a coating, and the release of the therapeutic agent is triggered by an electrical signal from the electrodes, the electrical signal being generated by the interaction of the coating with the intended release site of the therapeutic agent;

[0380] The release of the therapeutic agent is triggered by a remote electromagnetic signal. In some embodiments of any of the devices or methods described herein, the release of the therapeutic agent is triggered by generating a gas in the composition in an amount sufficient to expel the therapeutic agent; and / or

[0381] Release of the therapeutic agent is triggered by an electromagnetic signal generated within the device according to a predetermined drug release profile.

[0382] Therapeutic agents for delivery

[0383] The therapeutic agent suitable for the devices and methods described herein includes small molecules and macromolecules. In some embodiments, the therapeutic agent is a macromolecule. Examples of macromolecules include, but are not limited to, biopharmaceuticals, proteins (including fusion proteins), peptides (including cyclic peptides), protein-drug conjugates, cells (including stem cells) and nucleic acids (such as inhibitory nucleic acids, antisense nucleic acids, siRNA, ribozymes, etc.). In some embodiments, the therapeutic agent is a macromolecule with a molecular weight of at least about 60 kilodaltons (kDa), or about 60kDa to about 200kDa, about 60kDa to about 175kDa, or about 60kDa to about 150kDa.

[0384] In some other embodiments, the therapeutic agent has a molecular weight of at least about 20 kDa, at least about 30 kDa, at least about 40 kDa, or at least about 50 kDa, or about 20 kDa to about 200 kDa, about 20 kDa to about 175 kDa, or about 20 kDa to about 150 kDa.

[0385] In some embodiments, the therapeutic agent is a molecule such as a protein or peptide having a molecular weight greater than about 1.5 kDa and less than about 20 kDa, less than about 30 kDa, less than about 40 kDa, less than about 50 kDa, or less than about 60 kDa. In some other embodiments, the therapeutic agent has a molecular weight of about 5 kDa to about 10 kDa, 20 kDa, 30 kDa, 40 kDa, or 50 kDa. In some embodiments, the therapeutic agent is a molecule with a molecular weight of about 5 kDa to about 10 kDa, such as about 6 kDa. In some embodiments, the therapeutic agent is a protein or peptide. In some embodiments, the therapeutic agent is a protein-drug conjugate. In some embodiments, the therapeutic agent is insulin.

[0386] In some embodiments, the therapeutic agent is a small molecule. As used herein, a "small molecule" is a compound having a molecular weight of about 50Da to about 1500Da, about 60Da to about 1500Da, about 500Da to about 1000Da, or not more than about 1500Da, such as about 1000Da, about 750Da, or about 500Da, typically an organic compound. In some embodiments, the therapeutic agent is a small molecule having a molecular weight of about 50Da to about 1500Da. In some embodiments, the therapeutic agent is a small molecule having a molecular weight of about 150Da to about 1500Da.

[0387] In some embodiments, the therapeutic agent is a non-small molecule. Exemplary non-small molecule therapeutic agents for use in the devices and methods provided herein include, but are not limited to, abatacept, teriparatide, eculizumab, emicizumab, pegfilgrastim, semaglutide, dulaglutide, sargramostim, ustekinumab, secukinumab, tocilizumab, Vedolizumab, natalizumab, interferon beta-1a, denosumab, alirocumab, evolocumab, adalimumab, etanercept, golimumab, trastuzumab, pembrolizumab, pertuzumab, ARO-HBV, glatiramer acetate LY-3321367, cetuximab Ipilimumab Daratumumab Albumin-bound paclitaxel tanezumab, LY-2510924, LCAR-B38M, PF-004518600, TAK-079, PF-06730512, LY-3076226, NOV-13, FAZ-053, LY-3375880, PF-06823859, CNGB3 gene therapy, mosunetuzumab, RG-6147, scAAV / JeT-GAN-based gene therapy, ranibizumab, cofetuzumab pelidotin, SHR-A1201, TAK-671, A-004 (AAV2 / 5-hRKp.RPGR) gene therapy, NG-HER2 antibody-drug conjugate, TAK-164, RG-7861, JNJ-61186372, PF-05206388, NJH-395, PF-05230907, BIIB-059, PF-06688992, ianalumab, TAK-573, PF-06755347, CD200R mAb agonists, cetrelimab, ligelizumab, PF-06801591, JNJ-64407564, polatuzumab vedotin, PF-06817024, NOV-12, BIIB-054, CTL-119, JNJ-61178104, spartalizumab, RNACART123, LY-3300054, PD-1mAb agonists, CART-EGFRvIII, NOV-10, TQJ-230, PF-06863135, PCA-062, JNJ-64041757, CNTO-2476, tiragolumab, PF-0694686 0, elgemtumab, LY-3415244, LKA-651, RG-6109, ECF-843, JNJ-61610588, AAV8-RLBP1 gene therapy, LAG-525, MOR-106, BTLA agonist mAb, AMV-564, JNJ-64041809, MBG-453, CGF-166, brolucizumab, NOV-9, CJM-112, tesidolumab, NIZ-985, MCS-110, BHQ-880, NOV-8, CLR-325, XmAb-13676, huMesoCART, NZV-930, CGM-097, NOV-7, and certolizumab pegol); and biosimilars thereof; and glycosylation variants thereof. Additional exemplary drugs for delivery using any of the devices or methods described herein include those listed in Table 3. .

[0388] Table 3

[0389]

[0390]

[0391]

[0392] a Capsule quantity assumes drug reservoir of approximately 400 μL

[0393] sq: subcutaneous

[0394] IFU: Instructions for Use

[0395] IU: International Unit

[0396] In some embodiments, the therapeutic agent is a small molecule. Exemplary small molecule therapeutic agents for use in the devices and methods provided herein include, but are not limited to, glasdegib maleate, ibuprofen + paracetamol combination, PF-06873600, LY-3200882, PF-06952229, PF-06821497, LY-3405105, LY-3372689, LY-3023414, enzastaurin, SY-008, taladegib, crenigacestat, merestinib, LY-3214996, ralimetinib, gruniset alunisertib), TBA-7371, LY-3381916, LY-2874455, erdafitinib, pimodivir, aprocitentan, JNJ-56136379, BMS-986177, lazertinib, JNJ-64619178, JNJ-55308942, AL-034, JNJ-67670187, JNJ-64264681, JNJ-64417184, JNJ-3534, JNJ-64991524 、JNJ-64140284、pimodivir + oseltamivir combination、JNJ-61803534、ipatasertib dihydrochloride、fenebrutinib、RG-6171、belvarafenib、RG-6174、alpelisib、asciminib、leniolisib、clofazimine、siremadlin、capmatinib、PBF -509, LNP-023, UNR-844, ganaplacide, cipargamin, adriforant, LYS-006, QCC-374, MAK-683, LCL-161, BLZ-945, LOU-064, VPM-087, WNT-974, totrombopag, hydroxychloroquine + trametinib combination, LTT-462, NOV-11, LSZ-102, allosteric inhibitor of SHP2 phosphatase, mocravimod dihydrochloride, BCL-201,mivavotinib, DSM-265, sapanisertib, TAK-931, TAK-906, alisertib, TAK-580, pediatric azilsartan formulation, TAK-418, and vonoprazan fumarate + aspirin combination.

[0397] In some embodiments, the therapeutic agent is a monoclonal antibody (mAb). In some embodiments, the mAb is an anti-interleukin-17A (anti-IL-17A) mAb. In some embodiments, the mAb is an anti-interleukin-17A (anti-IL-17A) mAb, which can be used to treat inflammatory conditions and / or autoimmune diseases, including, but not limited to, rheumatoid arthritis, plaque psoriasis, active psoriatic arthritis, and ankylosing spondylitis. An exemplary anti-IL-17A mAb is ixekizumab See, e.g., Genovese et al., Arthritis & Rheumatology, 66.7:1693-1704 (2014). In some embodiments, the mAb is a selective mAb for angiopoietin 2 (Ang2). An exemplary mAb selective for Ang2 is LY3127804. In some embodiments, the mAb is a PD-1 receptor agonist mAb, such as peresolimab (LY3462817), which can be used to treat inflammatory conditions and / or autoimmune diseases.

[0398] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a glucagon-like peptide 1 (GLP-1) receptor agonist. The GLP-1 pathway has been indicated in the treatment of other metabolic diseases such as type 2 diabetes (T2DM) or obesity. In some embodiments, the GLP-1 receptor agonist is a peptide or a small molecule. In some embodiments, the GLP-1 receptor agonist is formulated with a carrier or delivery agent, which can be a salt of a medium-chain fatty acid derivative.

[0399] Exemplary GLP-1 receptor agonists for delivery using any of the devices or methods described herein include those listed in Table 4A.

[0400] Table 4A: GLP-1 receptor agonists suitable for delivery via ingestible devices for treating the listed diseases and conditions:

[0401]

[0402]

[0403] Table 4B GLP-1

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417] As yet another further example, in some embodiments, the surface of the ingestible device is very smooth. However, in certain embodiments, the outer surface of the ingestible device has a non-zero roughness. In such embodiments, allowing the outer surface of the ingestible device to have a non-zero roughness can result in a relatively desired passage of the ingestible device through the GI tract of the subject. As an example, an ingestible device having an outer surface with a non-zero roughness can pass through one or more regions of the GI tract in a relatively slow manner. In some embodiments, the ingestible device may have an outer surface with a non-zero roughness, which may include, for example, one or more regions with grooves. When the ingestible device is disposed in an appropriate region of the GI tract, the outer surface with a non-zero roughness may, for example, allow more time and opportunity to deliver one or more dispensable substances. Such a device can be used for delivery as needed, including, for example, transepithelial delivery, epithelial delivery, or surface delivery. Typically, the parameters for such delivery are similar to those described elsewhere herein.

[0418] As yet another further example, although various embodiments of ingestible devices having one or more nozzles and ingestible devices in which the outlet of the nozzle is flush with the outer surface of the ingestible device have been described, the present disclosure is not limited to such embodiments. For example, an ingestible device having one or more nozzles may be configured so that the nozzle outlet extends outward from one or more regions of the outer surface of the ingestible device. In some embodiments in which the ingestible device includes one or more nozzles extending outward from one or more regions of the outer surface of the device, the nozzle is disposed on the major axis of the device. In another embodiment in which the ingestible device includes one or more nozzles extending outward from one or more regions of the outer surface of the device, the nozzle is disposed on the radial axis of the device. Such an arrangement may allow for enhanced alignment with the surface of the GI tract, for example, the one or more nozzles are closer to the mucosal tissue of the GI tract. More generally, any ingestible device having one or more nozzles described herein may be configured so that one or more of the nozzles extend outward from one or more regions of the outer surface of the ingestible device.

[0419] As an additional example, although certain capsule shapes have been disclosed, the present disclosure is not limited to such shapes. For example, in some embodiments, the diameter of the capsule adjacent one end is significantly different from (e.g., significantly smaller than) the diameter of the capsule adjacent the opposite end of the capsule. An example of such a capsule is a drop-shaped capsule. In certain embodiments, the capsule has a shape described in this paragraph, which can allow the capsule to be relatively closer to the mucus of the GI tract (and, as a result, relatively closer to the epithelial layer of the GI tract).

[0420] As another example, in some embodiments, the density of the ingestible device is lower than the fluid present in one or more (e.g., all) regions of the GI tract of interest in using the ingestible device to deliver one or more dispensable substances. Such an ingestible device can be passed through one or more regions of the GI tract in a relatively predictable manner, which can enhance the ability to deliver one or more dispensable substances to one or more desired locations in a relatively controlled and / or predictable manner. In some cases, the density of the ingestible device is lower than the fluid present in one or more (e.g., all) regions of the GI tract of interest in using the ingestible device to deliver one or more dispensable substances, which can be referred to as having no buoyancy.

[0421] As another example, although certain examples of embodiments of a seal for the nozzle outlet (e.g., a foil seal) have been described, the present disclosure is not limited to such seals. More generally, the seal for the nozzle outlet can have any shape and be formed of any material that resists crushing until it is needed. In addition, the seal for the nozzle outlet can be in the interior of the device (e.g., on the surface of the drug reservoir), whereby the nozzle inlet is sealed. In some embodiments, the seal for the nozzle outlet can be made of ethyl cellulose (e.g., EthoCel) or polyvinyl acetate (e.g., BASF Coating Polymers). ) is formed. In certain embodiments, the seal may be in the form of a film, for example, having a thickness of about 10 μm to about 50 μm (e.g., about 20 μm to about 40 μm, for example, about 30 μm). In some embodiments, the seal for the nozzle outlet may be formed by a coating covering some or all of the outer surface of the capsule material (including the nozzle outlet to be sealed). Such a coating may be a single-layer coating or a multi-layer coating. Materials that can be used in a single-layer coating include cyclic olefin copolymers (COC), polytetrafluoroethylene (PTFE), thermopolymers, and cellulose acetate. The thickness of such a single layer can be, for example, about 25 μm to about 200 μm (e.g., about 35 μm, about 75 μm, about 140 μm, about 200 μm). In some embodiments, the coating is a 140 μm COC single layer. COC can be commercially available from, for example, TekniPlex. In certain embodiments, the coating is a 75 μm PTFE single layer. In some embodiments, the coating is a 200 μm PTFE single layer. In certain embodiments, the coating is a 35 μm cellulose acetate monolayer. In some embodiments, the coating is a 75 μm cellulose acetate monolayer. Cellulose acetate can be commercially available from, for example, Agar Scientific. Multilayer coatings can be formed, for example, by a layer of COC and a polymer layer (e.g., polychlorotrifluoroethylene (PCTFE)) and a tie layer therebetween. Such multilayer coatings can have a thickness of about 25 μm to about 75 μm (e.g., about 50 μm). For example, a multilayer coating is formed by a layer of COC (e.g., 20 μm), a tie layer (e.g., 16 μm), and a layer of polychlorotrifluoroethylene (e.g., 15 μm). An example of such a commercially available multilayer material is Tekniflex CTA160 (TekniPlex). As described above, in some embodiments, the seal for the nozzle can be a polyolefin material, for example, having a thickness of about 40 μm to about 60 μm (e.g., about 50 μm). As an example, the commercially available polyolefin Trans-Pharma TRA-150 (Tanscendia). In certain embodiments, the seal can be composed of LDPE, for example, having a thickness of about 10 μm to about 100 μm (e.g., about 20 μm to about 80 μm, about 25 μm, about 50 μm, about 100 μm). An example of a commercial supplier of such LDPE is Goodfellows. In some embodiments, the seal for the nozzle can be composed of polyethylene terephthalate (PET), for example, having a thickness of about 5 μm to about 15 μm (e.g., about 13 μm), such as available from Nordsen Medical, Salem, NH, USA.

[0422] In certain embodiments, the seal for the nozzle can be composed of PTFE, for example, having a thickness of about 50 μm to about 250 μm (e.g., about 75 μm, about 75 μm), for example, available from RS Components. In certain embodiments, the seal for the nozzle can be composed of fluorinated ethylene propylene (FEP) or nylon (e.g., nylon 12). In some embodiments, the seal for the nozzle can be formed of metal (e.g., metal foil). An example of such a metal is aluminum, such as household aluminum foil. In some embodiments, the film containing the metal can have a multilayer structure.

[0423] In some embodiments, one or more components of the ingestible device may include one or more starch-based polymers, such as one or more thermoplastic starch polymers. In some embodiments, the starch-based polymer may be starch as is or a polymer having a high starch content selected from greater than 70% starch, greater than 80% starch, or greater than 90% starch. Examples of molecules in starch include amylose and amylopectin. In some embodiments, the starch-based polymer may be generally fully biodegradable. In some embodiments, the starch-based polymer may be corn starch, such as Cornpack. Starch-based non-polymers may be decomposable. In some cases, starch-based polymers may be relatively stable and relatively inert in solid dosage forms.

[0424] In some embodiments, one or more of the components of the ingestible device may include one or more cellulose-based polymers.

[0425] In some embodiments, one or more components of the ingestible device include one or more biodegradable polymers.

[0426] As a further example, in some embodiments, the formulation is deposited in the submucosa and / or mucosa of the small intestine of a subject (e.g., into the lamina propria). In some embodiments, the formulation is deposited in the submucosa and / or mucosa of the duodenum of a subject (e.g., into the lamina propria). In some embodiments, the formulation is deposited in the submucosa and / or mucosa of the jejunum or ileum of a subject (e.g., into the lamina propria).

[0427] As another example, the first portion of the drug formulation released from the device is deposited in the submucosal layer, and the second portion is deposited in the mucosa (e.g., lamina propria), and / or released into the lumen, and may subsequently adhere to the mucus of the gastrointestinal tract. In some embodiments, the first portion of the drug formulation deposited in the submucosal layer contains at least about 99% of the total drug formulation released from the device, wherein % is w / w%, w / v%, or v / v% of the drug formulation. In other embodiments, the first portion of the drug formulation deposited in the submucosal layer contains at least about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of the drug formulation, wherein % is w / w%, w / v%, or v / v% of the drug formulation. In yet other embodiments, the first portion of the drug formulation deposited into the submucosal layer contains at least about 45%, at least about 40%, at least about 35%, at least about 30%, at least about 25%, at least about 20%, at least about 15%, at least about 10%, or at least about 5% of the drug formulation, wherein % is w / w %, w / v % or v / v % of the drug formulation.

[0428] As a further example, the formulation is topically delivered to the small intestine, duodenum or jejunum of a subject. In some embodiments, the formulation is topically delivered to the ileum of a subject. Topical delivery of the formulation to the small intestine can be used to treat ileal Crohn's disease.

[0429] As another example, in some embodiments, the formulation is topically delivered to the large intestine, cecum, colon, or rectum of a subject.Topical delivery of the formulation to the large intestine can be used to treat inflammatory bowel disease (IBD), wherein the IBD is Crohn's disease or ulcerative colitis.

[0430] Release of the therapeutic agent can be triggered by one or more of: a pH in the jejunum of about 6.1 to about 7.2, a pH in the middle small intestine of about 7.0 to about 7.8, a pH in the ileum of about 7.0 to about 8.0, a pH in the right colon of about 5.7 to about 7.0, a pH in the middle colon of about 5.7 to about 7.4, or a pH in the left colon of about 6.3 to about 7.7, e.g., about 7.0.

[0431] The release of the therapeutic agent can be triggered by degradation of a release component located in the device and can depend on enzyme activity at or near that location. In some embodiments of any of the devices or methods described herein:

[0432] The composition includes a plurality of electrodes including a coating, and the release of the therapeutic agent is triggered by an electrical signal from the electrode, which is generated by the interaction of the coating with the intended release site of the therapeutic agent; the release of the therapeutic agent is triggered by a remote electromagnetic signal; the release of the therapeutic agent is triggered by the generation of a gas in the composition in an amount sufficient to expel the therapeutic agent; and / or the release of the therapeutic agent is triggered by an electromagnetic signal generated within the device according to a predetermined drug release profile.

[0433] As a further example, the ingestible device includes one or more safety mechanisms, for example to reduce / eliminate the possibility of accumulating undesirably high pressure within the ingestible device. Such a safety mechanism can, for example, be configured as a disc that opens (e.g., explodes) when the pressure within the ingestible device reaches or exceeds a certain value. Optionally, the safety mechanism can be configured as a valve that opens when the pressure within the ingestible device reaches or exceeds a certain value. In some embodiments, the safety mechanism can be configured as one or more groove channels (e.g., in the inner wall of the device).

[0434] refer to Figure 56-72B and the table below, which describe several additional ingestible device embodiments in more detail.

[0435] Example 1 - Modeling Device Performance

[0436] In this example, modeling is used to determine performance parameters of an ingestible device for delivering a dispensable substance.

[0437] Model

[0438] For a given point in dose delivery, the driving pressure is related to the volume of liquid delivered and the resulting increase in gas volume, via the equation of state for adiabatic expansion.

[0439] The velocity through the orifice (or nozzle) (e.g., peak jet velocity, mean jet velocity, or minimum jet velocity) is in turn given by the driving pressure. This is a steady-state approximation, where transient effects of fluid acceleration / deceleration are neglected. In other words, the gas expands very quickly, allowing almost no time for heat transfer / thermal equilibrium with the surroundings. Therefore, the process is considered adiabatic (no energy loss).

[0440] For an adiabatic process, the pressure P and volume V of the gas are related as follows, assuming that the fluid (liquid) pressure is equal to the gas pressure (frictionless piston).

[0441]

[0442] Where P is pressure, V is volume, and γ is the specific heat ratio.

[0443] The pipe shear stress is given by the Darcy-Weisbach equation:

[0444]

[0445] Where ρ is the density of the liquid, L is the nozzle length, υ o is the velocity through the nozzle orifice, d o is the diameter of the nozzle orifice and f is the Darcy friction factor for pipe flow.

[0446] The friction factor for a rough pipe is given by:

[0447]

[0448] Where ∈ is the pipe surface roughness and Re is the Reynolds number of the fluid.

[0449] Haaland proposed the following explicit approximation, which differs from Colebrook by less than 2%:

[0450]

[0451]

[0452] Therefore, the pipeline pressure is:

[0453]

[0454] If Re is unknown, this explicit approximation requires an iterative solution.

[0455] Assume that the pipe outlet and inlet losses are given by:

[0456]

[0457]

[0458] Therefore, the total pressure drop across the orifice is:

[0459]

[0460] Among them C entry is the flow coefficient at the inlet, C exit is the flow coefficient at the outlet.

[0461] The total flow is:

[0462]

[0463] where Q is the volume flow rate through a single orifice.

[0464] Taking piston friction into account, the liquid delivery pressure through the orifice is related to the gas pressure as follows. The force balance on the piston is given by:

[0465]

[0466] Applying the steady-state assumption yields:

[0467]

[0468] Rearrange it and the result is:

[0469]

[0470] The jet impact force is given by the rate of change of the jet momentum at the impact surface:

[0471] F=dp / dt=d(mv) / dt=v(dm / dt)+m(dv / dt),

[0472] Where p is momentum, v is velocity, and m is mass.

[0473] Assuming that the jet velocity is constant at a given time step, D v The / dt term becomes zero, giving:

[0474] F=V(dm / dt),or F=velocity*mass flow rate

[0475] F=density*area*velocity^2

[0476] F=1 / 4*pi*density*diameter^2*velocity^2

[0477] It has been demonstrated that jet power correlates with needle-free penetration and dispersion:

[0478] Power=1 / 8*pi*density*diameter^2*velocity^3

[0479] Example 2 - Modeling Device Performance

[0480] In this example, modeling was used to determine the performance parameters of different ingestible device configurations for delivering a dispensable substance. The model was the same as described in Example 1.

[0481] Device and fluid properties

[0482] Number of nozzles = 2

[0483] Nozzle throat geometry = round, sharp-edged orifice

[0484] Piston diameter = 7mm

[0485] Piston friction force = 3.7N

[0486] Friction pressure loss = 14 psig

[0487] Dispensable substance (fluid) = water

[0488] Fluid density = 1,000 kg / m 3

[0489] Fluid viscosity = 1 centipoise

[0490] Specific heat capacity ratio (air) ratio = 1.4

[0491] Initial dose volume of dispensable material = 300 μL

[0492] Initial gas volume = 400 μL

[0493] Using these different ingestible device configurations, modeling yielded the results shown in Table 5. Note that liquid pressure is the same as fluid pressure.

[0494] Table 5

[0495]

[0496]

[0497] Example 3 - Fluidics Measurement

[0498] High-speed video was used to measure the jet parameters of the dispensable material (water) delivered from the device with different nozzle diameters and nozzle lengths. The parameters of the device were the same as those listed in Example 2 above. The receiving medium (external environment) was air with gelatin (4% gelatin solution) located 5 mm from the nozzle outlet. The nozzle was made of machined aluminum. The nozzle shape was a round, sharp-edged orifice.

[0499] The results are shown in the last two columns of Table 6. The first eight columns of Table 6 provide nozzle data based on the modeling (see Table 5 above).

[0500] Table 6

[0501]

[0502] The experimental peak force values ​​showed some agreement with those from modeling. The experimental dose delivery times also showed good correlation with those from modeling.

[0503] The ability of the nozzle in Table 6 to deliver dispensable material to gelatin was also studied. Under an air pressure of 320 PSIG, the power of the high-speed liquid jet of the 0.1 mm diameter nozzle and its ability to penetrate transparent glue were significantly reduced compared to the nozzle of 0.35 mm diameter. Reducing the air pressure to below 320 PSIG further reduced the jet power and extended the dose delivery time. For a nozzle with a diameter of 0.1 mm and a length of 0.25, there was no penetration into the gelatin under an air pressure of 34 PSIG.

[0504] It appears from Examples 2 and 3 that peak jet power is a particularly important parameter in determining whether an ingestible device is capable of providing transepithelial delivery of a dispensable substance. For example, using a relatively small nozzle diameter but a relatively high peak jet velocity, a relatively high peak jet force can be achieved, but the peak jet power may be insufficient to achieve transepithelial delivery of a dispensable substance. It is believed that the combination of a high peak jet pressure and a relatively large nozzle diameter (with a corresponding relatively large jet diameter) is involved in successfully providing transepithelial delivery.

[0505] Example 4 - Performance Evaluation of an Ingestible Multi-Nozzle Jet Delivery Device in Beagle Dogs and Female Yorkshire Pigs

[0506] introduce

[0507] Studies were conducted using a molded ingestible device designed and constructed for jet delivery to the GI tract. The ingestible device operates by triggering the release of a laminar flow of fluid with sufficient energy to deposit the drug payload into the gastrointestinal tissue, initiated by the disintegration of the trigger module at the desired location. After deposition, the drug can be absorbed into the systemic circulation. In this example, the performance of each iteration of the ingestible device in both ex vivo tissue and in vivo animal studies is described, including, among others, intestinal trigger location confirmation, nozzle cover performance, jet parameter characterization, and submucosal injection pharmacokinetics.

[0508] Fluoroscopic confirmation of deployment and position in beagle dogs

[0509] Beagles have GI motility similar to that of humans, and administration of ingestible devices to canines is relatively easy compared to other animals. In this study, 10 of 12 ingestible devices were successfully deployed in the small intestine as confirmed by C-arm imaging of the iohexol payload. The overall trigger time was consistent across groups, with the 25% enteric trigger (i.e., 25% enteric coating weight—see Example 5 below) having an average deployment of 1 hour 8 minutes ± 5 minutes after gastric emptying, approximately 14 minutes faster than the 30% enteric trigger.

[0510] Comparison of ex vivo tissue deposition and GI anatomy in dogs, pigs, and humans.

[0511] Benchtop studies of ex vivo intestinal tissue ink deposition suggest that the canine model is not an ideal model for drug distribution in gastric tissue. Ingestible devices with black India ink were encapsulated with porcine or canine jejunal tissue in a humid chamber at room temperature. A small amount of fluid was then added to the tissue to assist in triggering the device through degradation of the trigger. Less injection volume was observed in beagle dog gastric tissue compared to porcine or human tissue.

[0512] Comparisons of gastrointestinal anatomy and physiology between pigs, dogs, and humans are provided below in Tables 7 and 8. The Yucatan minipig model was determined to provide a viable animal model for evaluating injected gastrointestinal tissues. However, due to the different gastric retention times observed in pigs (0.9 hours to 20 days) (see Table 5), as well as differences in gastric anatomy compared to dogs and humans, semi-autonomous ingestible devices with uncoated triggers were placed in the duodenum by endoscopy in some studies.

[0513] In terminal necropsy trials in pigs, different gas and water pockets in the small intestine between animals suggest that different motility and enlarged intestinal diameter may affect submucosal injection efficiency in the pig model. In humans, the literature also suggests that there are variations in water pockets in the small intestine. After ingestion of water, fluid is distributed throughout the small intestine in fluid pockets that are variable in both volume and number. Therefore, it may be preferable to trigger the ingestible device in the proximal portion of the small intestine, where fluid and gas variations are less.

[0514] Table 7 - Comparison of physiological conditions

[0515]

[0516] Table 8 - Comparison of GI anatomy and motility

[0517]

[0518] *Small intestine length %

[0519] Ingestible Device Injection and Pharmacokinetics in a Porcine Model

[0520] To evaluate the injection efficiency of the ingestible jet delivery device, a semi-autonomous device with an uncoated trigger was administered by endoscopic placement (ID) of the duodenum and released into the proximal small intestine of female Yucatan pigs. In the first study (Q19), the device was filled with PGN-001 (a variant of adalimumab) and included a nozzle cover to prevent premature drug loss. The nozzle cover consisted of 40% RTV (room temperature vulcanized silicone, commercially available under the trade name Permatex 81730) and 60% mineral oil, applied using a dip coater before filling with 0.415 mL of PGN-001.

[0521] result

[0522] First, in the ex vivo platform testing, the nozzle cover was found not to interfere with tissue drug deposition. Second, in the in vivo portion of the study, 7 of 12 animals achieved 44% bioavailability of PGN-001 (see Tables 8 and Fig.70 ). The variability in oral bioavailability from animal to animal ranged from 6-44% (N=6; mean 15%) and appeared to be a function of one or more of trigger time, differences in GI motility, presence of pockets, intestinal distension due to gas, or changes in device efficiency or function. In addition, it should be noted that the device with 350 PSI initial gas pressure showed higher bioavailability compared to the 320 PSI device, which is consistent with the results described in Examples 2 and 3. For example, it was observed that the quality of the O-ring seal improved device performance, as demonstrated in subsequent studies (Q28) where the device produced up to 62% bioavailability in vivo.

[0523] In the Q30 study, additional updates were performed to the ingestible device assembly process to further improve device efficiency. Ex vivo tissue testing prior to in vivo studies showed consistent tissue ink deposition. In addition, the ingestible device was pre-soaked in simulated gastric fluid for up to 13 minutes to pre-hydrate the trigger prior to small intestine administration. Eight of the 13 animals showed detectable drug in the blood, and earlier triggering (≤2 hours) was associated with higher bioavailability. A mean bioavailability of 25% was observed in animals with a trigger time (T1) ≤2 hours (N=7), while a trigger time of 72 hours post-dose produced a bioavailability of only 1.2% (N=1). See Tables 9 and 10 and Fig.86 and 87 .

[0524] Table 9 - Device Characteristics Across In Vivo Studies

[0525]

[0526] Table 10 - Submucosal injection PK results

[0527]

[0528] Monoclonal Antibody Pharmacokinetics in a Porcine Model Using an External Trigger Device

[0529] Similar pig studies as described above were repeated using an external trigger device. Fig.80A The triggering mechanism described is similar; however, the device is coupled to an endoscope, which is used to mechanically displace the ball, thereby actuating the device.

[0530] Similar to the preclinical experiments above, this study was conducted using a molded ingestible device designed and constructed for jet delivery to the GI tract. The ingestible device operates by triggering the release of a laminar fluid with sufficient energy to deposit the drug payload into the gastrointestinal tissue, initiated by triggering the device at the desired location, in this study using an endoscope. After deposition, the drug can be absorbed into the systemic circulation.

[0531] External triggering studies were performed using adalimumab, a TNF inhibitor that specifically binds to TNF and neutralizes the biological function of TNF by blocking the interaction of TNF with both TNFR1 and TNFR2 receptors. The device was filled with ~56 mg BT-001 (a variant of adalimumab), was administered by intraduodenal (ID) endoscopic placement and was externally triggered in the proximal small intestine of female Yucatan pigs. Serum was collected 0-96 hours after dosing and compared with the average IV control of four different studies, and the dose was adjusted according to body weight.

[0532] result

[0533] Nine of nine devices (9 / 9) were successfully advanced through the pyloric sphincter and triggered in the proximal small intestine via endoscopic placement. All nine animals showed detectable drug levels up to 96 hours after dosing ( Fig.86 ) and had a mean oral bioavailability of 51 / 4%±24% (CV: 46%), ranging from 10%-90% compared to the IV control. No overt clinical signs were observed in the animals before or after dosing for up to 10 days.

[0534] in conclusion

[0535] This study demonstrated that oral administration of an oral systemic device has the potential to achieve an average of 51% and up to 90% bioavailability of the adalimumab variants in animals.

[0536] Peptide Pharmacokinetics in a Porcine Model Using an External Trigger Device

[0537] The above externally triggered studies were also conducted using semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist that stimulates insulin secretion and inhibits glucagon release. Devices filled with ~0.96 mg of semaglutide were administered via intraduodenal (ID) endoscopic placement and externally triggered in the proximal small intestine of female Yucatan pigs. Plasma samples were then collected from 0 to 240 hours after dosing. Systemic concentrations of semaglutide were measured using LC-MS-MS to evaluate the PK of semaglutide administered via ID with the OBDS device ( Fig.87Animals 1003-ID; 1004-ID; 1005-ID; 1009-ID; 10053-ID and 1055-ID) and IV controls ( Fig.87 Compared with animal 1015-IV).

[0538] result

[0539] Seven of eight devices (7 / 8) were successfully advanced through the pyloric sphincter and triggered in the proximal small intestine via endoscopic placement. One animal had a procedural error and was excluded from PK analysis. All seven animals showed detectable drug levels up to 10 days after dosing ( Fig.87 ) and had a mean oral bioavailability of 37%±15% (CV: 40%), ranging from 19%-60% compared to IV controls. No overt clinical signs were observed in the animals before or after dosing for up to 10 days.

[0540] in conclusion

[0541] The study showed that the oral administration of the OBDS device has the potential to achieve an average bioavailability of 37% and up to 60% of the GLP-1 receptor agonist in animals. This is more than the currently available oral tablets. An order of magnitude higher, The estimated bioavailability in human trials was less than 1%.

[0542] Summarize

[0543] These results indicate that the ingestible delivery system can deliver monoclonal antibodies (e.g., adalimumab) at bioavailability levels close to those estimated in human trials for the subcutaneous route of administration (64% compared to IV at a 40 mg biweekly dose), and deliver peptides (e.g., semaglutide) at average bioavailability levels of 37% and up to 60%. With increasing dosing frequency and dose per device, the ingestible devices described herein may provide a new, non-invasive route of administration that may lead to improved patient compliance and compliance.

[0544] Example 5 - Preclinical Ingestible Device Characterization

[0545] The preclinical ingestible device used in Example 4 was tested to characterize the resulting fluidic parameters. These results were compared to the model fluidic parameters described in Examples 1-3.

[0546] Mathematical Modeling of Dose Delivery: Preclinical Devices

[0547] Modeling for determining performance parameters of preclinical ingestible devices is described in Example 1. A summary of device inputs for different preclinical devices (e.g., 320 PSI vs. 350 PSI devices) is provided below, along with test equipment parameters and empirically derived factors (e.g., empirical loss coefficients obtained from tuning to experimental outputs).

[0548] Preclinical 320PSI, 2x0.35 mm nozzles

[0549]

[0550]

[0551]

[0552] The empirical factor used to adjust the inlet loss coefficient is 0.35

[0553] Export loss coefficient 1.00

[0554] For the above device characteristics and parameters (eg, a 320 PSI preclinical device with two 0.35 x 0.60 mm nozzles), modeling yielded Tables 11 and Figures 56-67 The results shown in , a device delivering 400 μl of liquid, with a peak liquid pressure of 315 PSI (liquid pressure is the same as fluid pressure), a peak velocity of 55 m / s, and an average velocity of 38 m / s. The ingestible device can produce a liquid laminar jet with a peak jet impact force of 288 mN and a peak jet power of 7.9 W. The total delivery time was modeled as 50.6 ms.

[0555]

[0556] Preclinical 350PSI, 2x0.35 mm nozzles

[0557]

[0558]

[0559] The empirical factor used to adjust the inlet loss coefficient is 0.35

[0560] Export loss coefficient 1.00

[0561] For the above device characteristics and parameters (e.g., a 350 PSI preclinical device with two 0.35×0.60 mm nozzles), modeling produces Tables 12 and Figures 56-67The results shown in , a device delivering 400 μl of liquid, with a peak liquid pressure of 345 PSI (liquid pressure is the same as fluid pressure), a peak velocity of 57 m / s, and an average velocity of 44 m / s. The ingestible device can produce a liquid laminar jet with a peak jet impact force of 316 mN and a peak jet power of 9.1 W. The total delivery time was modeled as 48.3 ms.

[0562]

[0563] As described in Examples 2 and 3, relatively large nozzle diameters (and correspondingly relatively large jet diameters) can significantly increase jet power. The following are device and jet parameters for a 320 PSI ingestible device with a 2x0.40 mm nozzle and a 2x0.50 mm nozzle.

[0564] Preclinical 320PSI, 2x0.40 mm nozzles and 320PSI, 2x0.50 mm nozzles

[0565]

[0566]

[0567] The empirical factor used to adjust the inlet loss coefficient is 0.35

[0568] Export loss coefficient 1.00

[0569] For the above device characteristics and parameters (e.g., 320 PSI preclinical device with two 0.40 x 0.60 mm nozzles and 320 PSI preclinical device with two 0.50 x 0.60 mm nozzles), the modeling results are shown in Tables 13 and 14, respectively. Figures 56-67 .

[0570] The 320 PSI device with two 0.40 mm diameter nozzles delivered 400 μl of liquid with a peak liquid pressure of 315 PSI (liquid pressure is the same as fluid pressure), a peak velocity of 55 m / s, and an average velocity of 42 m / s. The ingestible device can produce a liquid laminar jet with a peak jet impact force of 381 mN and a peak jet power of 10.5 W. The total delivery time was modeled as 38.5 ms. See Tables 13 and Figures 56-67 .

[0571] The 320 PSI device with two 0.50 mm diameter nozzles delivered 400 μl of liquid with a peak liquid pressure of 315 PSI (liquid pressure is the same as fluid pressure), a peak velocity of 56 m / s, and an average velocity of 43 m / s. The ingestible device can produce a liquid laminar jet with a peak jet impact force of 605 mN and a peak jet power of 16.8 W. The total delivery time was modeled as 24.4 ms. See Tables 14 and Figures 56-67 .

[0572]

[0573]

[0574] Fluidics performance of preclinical devices

[0575] In this section, results of engineering testing conducted on an ingestible device manufactured for preclinical studies are provided. The devices tested were made of plastic parts (e.g., polycarbonate) connected with UV adhesive. The trigger element included an enteric coating (e.g., Acryl-EZE at 35% weight gain), and in some cases, the trigger element was uncoated to facilitate faster triggering during testing. The gas container was nominally filled with 15.7 mg, producing an actuation pressure of approximately 320 PSI. Additional testing was performed on a device with a nominal gas container fill of 17.2 mg, which produced an actuation pressure of approximately 350 PSI. In this round of testing, the device did not include a nozzle cover, which is envisioned here in the final device to seal the nozzle during storage and gastric transit and to shift after triggering to allow jet delivery. However, testing performed with a jet cover will be described in a subsequent section of this article.

[0576] Jet Rig Method

[0577] The following is a summary of the jet force rig method used to measure jet performance:

[0578] 1. Set the device on the fluidic table

[0579] a. Obtain the gelatin test sample and set it onto the fluidic table at a standoff distance of 5 mm from the device nozzle outlet; the test should be started within 5 minutes of removing the gelatin sample from the refrigerator.

[0580] b. Ensure that the force sensor of the fluidic force table is located at a standoff distance of 5 mm from the nozzle outlet of the device.

[0581] 2. Start HSV camera recording

[0582] 3. Fill the preclinical prototype mount with tap water to start the device triggering process. Observe the device triggering. Follow the fluidic force table operating procedures to record the following data:

[0583] a. Jet impact force curve

[0584] b. Peak force (from force curve)

[0585] c. Time to peak force (from force curve)

[0586] d. Jet delivery time (from force curve)

[0587] e. Jet Penetration Depth, Width, and Bolus Initiation Point in Gelatin Test Samples

[0588] 4. Once the device activation is complete, close the HSV camera and save the captured video.

[0589] Jet Rig Results

[0590] The jet performance curve results are summarized in Table 15. Note that these values ​​are derived from the original force curves. Examples of the original force curves compared to the modeled force curves are shown in Figures 68-69 .

[0591] Table 15 - Summary of Jet Performance Profile Metrics

[0592]

[0593]

[0594] Testing with nozzle cap

[0595] This section provides results from fluidic force bench testing of preclinical ingestible devices with nozzle caps. The same fluidic force bench described above was used to measure the fluidic characteristics of devices with nozzle caps. Cyclic olefin copolymer (COC) drug containers were dip coated with formulations with 14% or 20% Kollicoat MAE 100P in 97% IPA and then cured to evaporate the IPA and leave a 100% Kollicoat MAE 100P nozzle cap coating. The 320 PSI device with nozzle cap produced reproducible drug delivery times of ~55 mm (N=4) with similar fluidic forces to the device without nozzle cap. See Fig.72A and B. For the 20% Kollicoat covering, longer conditioning (3 hours vs. 30 minutes) produced a force profile closer to baseline. Conditioning was performed to simulate retention of the device in the human gastrointestinal tract.

[0596] Testing with a second piston as a nozzle cap

[0597] This section provides the results of a fluidic force bench test of an ingestible device with a mechanical nozzle cover (e.g., a second piston as shown in FIG. 49). The same fluidic force bench described above was used to measure the fluidic characteristics of the device incorporating the second piston "D" in FIG. 49, and the fluidic force was measured over time. Fig.88 As shown, the average jet force of eight devices produced a uniform jet force curve (the standard deviation of the peak force was calculated to be ˜33.4 mN), the peak jet force was all over 200 mN, and the average peak force was 292.4 mN. All eight devices had an internal pressure of 350 psi and incorporated a second piston D to block both openings before triggering. One device was excluded from the analysis because its total deployment time was approximately 30 ms, which was a significant anomaly.

[0598] Tests at different viscosities

[0599] This section provides results from fluidic bench testing of ingestible devices with varying viscosity payloads. The same fluidic bench described above was used to measure the fluidic characteristics of devices delivering 50 cP liquid formulations with water (1 cP). See Table 16 and Figure 93.

[0600] Table 16-50cP formulation observation results

[0601] capsule Viscosity observe water 1 Uniform jet formed by two nozzles 1 50 Uniform jet formed by two nozzles 2 50 Uniform jet formed by two nozzles 3 50 Uniform jet formed by two nozzles 4 50 Uniform jet formed by two nozzles

[0602] As shown in Figure 93, the 50 cP jet curve (average of four 50 cP devices in Table 16) is similar to water, although the force is slightly lower, but still has a peak force of over 200 mN.

[0603] Recalibrated model results

[0604] Additional fluidic force bench testing (as described above) was performed to measure the force and average peak force of the device without the nozzle cover at internal pressures (or "driving pressures") of 280, 320, 350, and 400 psi. The average delivery time was also measured. See Tables 17 and Figures 89-92 .

[0605] Table 17 - Summary of Results for Peak Force and Jet Delivery Time

[0606] Internal pressure (psi) Average peak jet force (mN) Average jet delivery time (ms) 280 196 60.0 320 225 60.3 350 251 56.6 400 282 52.7

[0607] Using the jet force bench data shown in Table 18, the device performance model described in Examples 1 and 2 was recalibrated, and the calculation results of peak jet power, peak jet force, and average jet velocity at different internal pressures and viscosities are provided in Table 18 below. Figures 89-92In , the predicted fluidic force and delivery time are shown using the smooth thick lines, while the noisier thin lines show the experimental results summarized in Table 17. Recalibration involves adjusting the "entry loss coefficient" in the model (between 0 and 1) to best fit the results of the experimental fluidic force bench.

[0608] Table 18 - Device performance at different viscosities using updated model calibration

[0609]

[0610]

[0611] Example 6 - Trigger Development and Testing

[0612] The uncoated trigger formulation was further characterized and developed to meet targets for strength, disintegration rate and disintegration consistency:

[0613] Strength: The trigger material (ie, the shaped constraining element referred to herein as a "tablet") requires a tensile strength of ~≥1.0 MPa (calculated using a portion diameter approximation to take the center hole into account) and low friability required for subsequent use in a coating mechanism.

[0614] Rapid disintegration: Rapid disintegration of the uncoated tablets is required in 9 ml pH 6.5 FASSIF 37°C (no stirring) when tested in a spring loaded apparatus. As used herein, disintegration may be used interchangeably with degradation or erosion.

[0615] Consistent Disintegration: Uncoated tablets provide consistent disintegration between batches and after storage for up to 6 months.

[0616] Different uncoated trigger (i.e., tablet) formulations were created and tested for breaking force, disintegration time, friability, and dimensional stability. The restraining element (tablet) was made with a 7.6 kN compression force (284 MPa) to a height of 1.45 mm. A faster disintegration rate was observed (e.g., the average trigger time was reduced from [1 minute 43 seconds] to [0 minutes 48 seconds]), as well as a reduction in tablet mass (56.0 mg vs 42.2 mg) and a small decrease in the ratio of mass to exposed surface area (54.9 mg / cm2 vs 49.4 mg / cm2). Examples of trigger materials and their corresponding breaking force, disintegration time, and friability assessments are provided in Table 19 below.

[0617] Table 19 - Uncoated Trigger Formulations: Breaking Force, Disintegration Time and Friability

[0618]

[0619] Preferred uncoated trigger formulations include C1-A (StarTab + MCC 102 + Ac-di-Sol + Mg S), C1-E (StarTab + MCC 102 + Ac-di-Sol + Mg S + crospovidone), C2-B (StarTab + MCC 102 + Ac-di-Sol + Mg S + crospovidone + cross-linking + starch), C2-D (StarTab + MCC 102 + Ac-di-Sol + Mg S + crospovidone + mannitol) and C2-F (StarTab + MCC 102 + Ac-di-Sol + Mg S + Explotab). The trigger formulation can also include an enteric material (e.g., Opadry 5% w / g + Acryl-EZE 35% w / g) coated on the outside of the trigger formulation provided in Table 19. The enteric material can be coated at different weights (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% and values ​​therebetween) depending on the desired triggering site in the gastrointestinal tract.

[0620] Organization Trigger Modification-Test Results

[0621] Tested by puncturing the gas tank as expected Fig.75A -The ability of the angle support shown in D to actuate the device (i.e., the gas container diaphragm failed in a catastrophic event, resulting in a rapid piston movement). When five 15 degree angle supports were tested using high force springs (approximately 35-45N) and shorter piercers (approximately 2.55mm reference surface length), all five devices actuated immediately after the release member dissolved, and there were no slow or two-stage pistons (i.e., the piston moved too slowly or unevenly to produce a liquid jet). This is in Fig.101 , which shows the time to piercer movement after the release member or "trigger" dissolves or degrades. Suspected slow or two-stage pistons are marked with an asterisk. Devices without angled supports are slower to actuate and result in some slow or two-stage pistons. Fig.101 In the figure, "TS" means the trigger support, "High Force" refers to the force of the spring, and "Hand Tight" and "100Nmm" refer to the force applied to tighten the trigger support to the release part.

[0622] Also tested by puncturing the gas tank as expected Fig.78A - Capability of the split piercer flange actuation device shown in -L (i.e. the gas container diaphragm fails in a catastrophic event, resulting in a rapid movement of the piston). See Fig.102. All five devices with a separate piercer flange actuated immediately after the release member dissolved; however, the piston of one of the devices was suspected to be slow. Video imaging showed a possible gas leak at the glue joint, which suggested that the cause of the slow piston was unrelated to the trigger. The "Standard Device" does not have a separate piercer flange. As described above, "High Force" refers to the force of the spring (about 35-45N), and "Short Tip" refers to the piercer size (about 2.55mm reference surface length). "Rev D" refers to the design of the separate piercer flange.

[0623] Based on the additional testing and new data discussed above, the following observations can be made:

[0624] Generally speaking, an ingestible device for transepithelial delivery is configured to deliver a jet of a dispensable substance having one or more of the following:

[0625] A peak jet power of about 3 watts to about 8 watts, or about 4.2 watts to about 7.8 watts, or about 4.6 watts to about 7.0 watts, or about 5.0 watts to about 6.3 watts;

[0626] The minimum jet power is about 1.7 W to about 0.8 W (e.g., about 1.5 W to about 0.9 W, or about 1.3 W to about 1.0 W);

[0627] The average jet power is at least about 1.9 W (e.g., about 2.2 W, about 2.4 W) and / or at most about 3.8 W (e.g., at most about 3.5 W, at most about 3.1 W);

[0628] A peak jet force of about 150 mN to about 310 mN, or about 195 mN to about 285 mN, or about 215 mN to about 250 mN;

[0629] A minimum jet force of about 63 mN to about 102 mN (e.g., about 70 mN to about 92 mN, or about 76 mN to about 86 mN);

[0630] An average jet force of about 110 mN to about 172 mN (e.g., about 118 mN to about 162 mN, about 126 mN to about 158 ​​mN);

[0631] A peak jet velocity of about 43 meters per second to about 55 meters per second, or about 45 meters per second to about 53 meters per second, or about 47 meters per second to about 51 meters per second;

[0632] An average jet velocity of about 32 m / s to about 42 m / s (e.g., about 33 m / s, about 34 m / s, about 35 m / s, about 36 m / s, about 37 m / s, about 38 m / s, about 39 m / s, about 40 m / s, about 41 m / s);

[0633] The jet stability length is at least about 5 mm, or about 5-15 mm, or about 5-10 mm, or about 5-8 mm;

[0634] The jet diameter is from about 0.25 mm to about 0.40 mm, or in some embodiments, from about 0.30 mm to about 0.35 mm, or in some embodiments, about 0.35 mm;

[0635] The internal pressure is, in some embodiments, from about 250 psi to about 400 psi, or from about 280 psi to about 370 psi, or from about 300 psi to about 350 psi;

[0636] Peak fluid pressure of 280 psi to 320 psi or 290 psi to 310 psi; and / or

[0637] The inlet loss coefficient is from about 0.50 to about 0.90, or from about 0.60 to about 0.80, or about 0.70.

[0638] In one instance, an ingestible device having two nozzles, each having a nozzle diameter of 0.35 mm in diameter, a nozzle length of 0.60 mm, and including 1 cP of dispensable substance at a peak fluid pressure of 308 psi, can deliver a jet of dispensable substance at a peak jet velocity of about 49 m / s, a peak jet impact pressure of about 342 psi, and a peak jet power of about 5.5 watts, with a total delivery time of about 58 milliseconds (ms).

[0639] In another example, an ingestible device having two nozzles, each having a nozzle diameter of 0.35 mm in diameter, a nozzle length of 0.60 mm, and including 1 cP of dispensable substance at a peak fluid pressure of 268 psi, can deliver a jet of dispensable substance at a peak jet velocity of about 45 m / s, a peak jet impact pressure of about 298 psi, and a peak jet power of about 4.5 watts, with a total delivery time of about 62 milliseconds (ms).

[0640] In another example, an ingestible device having two nozzles, each having a nozzle diameter of 0.35 mm in diameter, a nozzle length of 0.60 mm, and including 50 cP of dispensable substance at a peak fluid pressure of 308 psi, can deliver a jet of dispensable substance at a peak jet velocity of about 47 m / s, a peak jet impact pressure of about 323 psi, and a peak jet power of about 5.0 watts, with a total delivery time of about 60 milliseconds (ms).

[0641] In another example, an ingestible device having two nozzles, each having a nozzle diameter of 0.35 mm in diameter, a nozzle length of 0.60 mm, and including 50 cP of dispensable substance at a peak fluid pressure of 338 psi, can deliver a jet of dispensable substance at a peak jet velocity of about 50 m / s, a peak jet impact pressure of about 355 psi, and a peak jet power of about 5.8 watts, with a total delivery time of about 57 milliseconds (ms).

[0642] A number of embodiments have been described. However, various modifications may be made without departing from the spirit and scope of the present disclosure. Accordingly, other embodiments are within the scope of the following claims.

[0643] U.S. National Phase Only: Incorporation by Reference

[0644] The following patent applications are incorporated by reference. The references to each of these applications in U.S. Provisional Application No. 63 / 321,537 are also incorporated herein by reference.

[0645] WO2020106704;

[0646] 62 / 948,082;

[0647] 63 / 027,427;

[0648] 63 / 086,630;

[0649] 63 / 321,537;

[0650] WO2021119482;

[0651] WO2022034041;

[0652] WO2022033949;

[0653] WO2019178071;

[0654] US2017 / 0258583.

Claims

1. An ingestible device comprising: a housing configured to contain a dispensable substance, the dispensable substance comprising a therapeutic agent; and one or more openings in the housing configured to allow the dispensable substance to move out of the housing; Wherein the ingestible device is configured to deliver the dispensable substance to the GI tract as a jet having a peak jet power of 3 watts to 8 watts.

2. An ingestible device according to claim 1, wherein the peak jet power is 4.2 to 7.8 watts.

3. An ingestible device according to claim 1, wherein the peak jet power is 5.0 to 6.3 watts.

4. An ingestible device according to claim 1 or 2, wherein the ingestible device is configured to provide a peak jet force of 150mN to 310mN.

5. An ingestible device according to claim 4, wherein the ingestible device is configured to provide a peak jet force of 195mN to 285mN.

6. The ingestible device of any one of claims 1-4, wherein the ingestible device is configured to provide an internal pressure of 250 psig to 400 psig.

7. An ingestible device according to claim 6, wherein the ingestible device is configured to provide an internal pressure of 300 psig to about 350 psig.

8. An ingestible device according to any one of claims 1-7, wherein the ingestible device is configured to contain the dispensable substance at a peak fluid pressure of 230 psig to 380 psig.

9. An ingestible device according to claim 8, wherein the ingestible device is configured to accommodate the dispensable substance having a peak fluid pressure of 280 psig to 330 psig.

10. The ingestible device of any one of claims 1-9, wherein the ingestible device is configured to deliver the dispensable substance directly into the subbasal membrane layer of the GI tract of a patient.

11. The ingestible device of any one of claims 1-9, wherein the ingestible device is configured to deliver the dispensable substance directly into the submucosal layer of the GI tract of a patient.

12. The ingestible device of any one of claims 1-11, wherein the ingestible device is configured to deliver the dispensable substance at a peak jet velocity of 45 m / s to 60 m / s.

13. An ingestible device according to any one of claims 1-12, wherein the device is configured to release a volume of 50 microliters to 200 microliters of dispensable substance per opening.

14. The ingestible device of any one of claims 1-12, further comprising a dispensable substance in the housing, wherein the dispensable substance comprises a liquid.

15. The ingestible device of claim 14, wherein the dispensable substance further comprises a therapeutic agent.

16. The ingestible device of claim 14, wherein the dispensable substance comprises a solution or a suspension.

17. The ingestible device of claim 1, wherein the ingestible device is configured to deliver the dispensable substance to tissue of the GI tract as a jet having a peak jet power of 4.2 watts to 7.8 watts, and the ingestible device is configured to provide an internal pressure of 280 psig to 350 psig.

18. The ingestible device of any one of claims 1-17, further comprising: a storage reservoir in the housing; a dispensable substance in said storage reservoir; openings in the housing connected to the storage reservoir, each opening extending through a side wall of the housing; and A gas container is provided in the housing, the gas container containing compressed gas.

19. The ingestible device of claim 18, further comprising a trigger component that triggers the release of the compressed gas from the gas container after the ingestible device is ingested.

20. The ingestible device of claim 19, wherein the trigger component comprises an enteric material that partially or completely erodes, degrades and / or dissolves upon ingestion to allow the piercer to pierce the gas container.

21. An ingestible device according to claim 18 or 19, further comprising a sliding piston in the housing located between the gas container and the storage reservoir.

22. The ingestible device of any one of claims 1-20, wherein the ingestible device is configured to deliver the dispensable substance at an average jet velocity of about 28 m / s to about 44 m / s.

23. The ingestible device of any one of claims 1-21, wherein one or more of the openings has a nozzle having a diameter of 0.2 to 2 mm.

24. An ingestible device comprising: a housing configured to contain a dispensable substance, the dispensable substance comprising a therapeutic agent; and an opening in the housing configured to allow the dispensable substance to move out of the housing; Wherein the ingestible device is configured to deliver the dispensable substance at a peak jet velocity of 30 m / s to 60 m / s.

25. The ingestible device of claim 24, wherein the ingestible device is configured to deliver the dispensable substance at a peak jet velocity of 40 m / s to 50 m / s.

26. The ingestible device of claim 24 or 25, wherein the ingestible device is configured to deliver the dispensable substance to the GI tract as a jet having a peak jet power of 3 Watts to 8 Watts.

27. The ingestible device of claim 26, wherein the ingestible device is configured to deliver the dispensable substance to the GI tract as a jet having a peak jet power of 4.2 to 7.8 Watts.

28. The ingestible device of claim 26 or 27, wherein the ingestible device is configured to deliver the dispensable substance to the GI tract as a jet having a peak jet power of 5.0 to 6.3 Watts.

29. The ingestible device of any one of claims 24-28, wherein the ingestible device is configured to provide a peak jet force of 150 mN to 310 mN.

30. The ingestible device of claim 29, wherein the ingestible device is configured to provide a peak jet force of 195 mN to 285 mN.

31. The ingestible device of any one of claims 24-30, wherein the ingestible device is configured to provide an internal pressure of 250 psig to 400 psig.

32. The ingestible device of any one of claims 31 , wherein the ingestible device is configured to provide an internal pressure of 300 psig to 350 psig.

33. An ingestible device according to any one of claims 24-31, wherein the ingestible device is configured to contain the dispensable substance at a peak fluid pressure of 230 psig to 380 psig.

34. An ingestible device according to claim 33, wherein the ingestible device is configured to contain the dispensable substance having a peak fluid pressure of 280 psig to 330 psig.

35. The ingestible device of any one of claims 24-34, wherein the ingestible device is configured to deliver the dispensable substance directly into the subbasal membrane layer of the patient's GI tract.

36. The ingestible device of any one of claims 24-34, wherein the ingestible device is configured to deliver the dispensable substance directly into the submucosal layer of the GI tract.

37. An ingestible device according to any one of claims 24-36, wherein the device is configured to release a volume of 50 microliters to 200 microliters of dispensable substance per opening.

38. The ingestible device of any one of claims 24-37, further comprising a dispensable substance in the housing, wherein the dispensable substance comprises a liquid.

39. An ingestible device according to claim 38, wherein the dispensable substance further includes a therapeutic agent.

40. The ingestible device of claim 39, wherein the dispensable substance comprises a solution or a suspension.

41. The ingestible device of claim 24, wherein the ingestible device is configured to deliver the dispensable substance to tissue of the GI tract as a jet having a peak jet power of 4.2 watts to 7.8 watts, and the ingestible device is configured to provide an internal pressure of 280 psig to 350 psig.

42. The ingestible device of any one of claims 24-41, further comprising: a storage reservoir in the housing; a dispensable substance in said storage reservoir; openings in the housing connected to the storage reservoir, each opening extending through a side wall of the housing; and A gas container is provided in the housing, the gas container containing compressed gas.

43. The ingestible device of claim 42, further comprising a trigger component that triggers the release of the compressed gas from the gas container after the ingestible device is ingested.

44. An ingestible device according to claim 43, wherein the trigger component includes an enteric material that partially or completely erodes, degrades and / or dissolves after being ingested to allow the piercer to pierce the gas container.

45. The ingestible device of any one of claims 42-44, further comprising a sliding piston in the housing between the gas container and the storage reservoir.

46. ​​An ingestible device according to any one of claims 42-45, wherein one or more of the openings has a nozzle having a diameter of 0.2 to 0.5 mm.

47. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; said opening in said housing being connected to said storage reservoir; a first piston longitudinally slidable within the housing; a second piston longitudinally slidable within the housing; and The storage reservoir is located between the first piston and the second piston.

48. The ingestible device of claim 47, further comprising a gas container in the housing, the gas container containing compressed gas, and the first piston being located between the gas container and the storage reservoir.

49. An ingestible device according to claim 48, wherein the second piston is movable from a first position where the second piston closes the opening to a second position where the second piston is displaced from the opening.

50. The ingestible device of claim 48, further comprising: A piercer, a spring and a trigger, wherein the piercer is configured to pierce the gas container to release compressed gas from the gas container into the housing, the spring applies an elastic force to the piercer in a first direction toward the gas container, and the trigger keeps the piercer in a fixed position relative to the elastic force.

51. The ingestible device of claim 50, further comprising a trigger support having a conical surface held against a complementary surface of the trigger by the spring, the conical surface having an angle of 10 to 25 degrees.

52. An ingestible device according to any one of claims 47-51, wherein the storage reservoir has cylindrical side walls that converge toward the opening at a draft angle of 0.3 to 0.1 degrees.

53. An ingestible device according to any one of claims 47-52, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

54. An ingestible device comprising: a storage reservoir in the housing; one or more openings through a side wall of the housing leading to the storage reservoir; a gas container in said housing; a piercer configured to pierce the gas container to release compressed gas from the gas container into the housing; a spring that applies a spring force to the piercer in a first direction toward the gas container, and a trigger that holds the piercer in a fixed position relative to the spring force; and A trigger support having a tapered surface held against the trigger by the spring, the tapered surface having an angle of 10 to 25 degrees.

55. The ingestible device of claim 54, further comprising a first piston longitudinally slidable within the housing, a second piston longitudinally slidable within the housing, and a storage reservoir between the first piston and the second piston.

56. An ingestible device according to claim 54 or 55, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

57. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. a piercer configured to pierce the gas container to release compressed gas from the gas container into the housing; a spring that applies elastic force to the piercer; The piercer has an arm; and A trigger holds the arm of the piercer in a first position, wherein the arm holds the piercer in a fixed position relative to the elastic force, and the arm is movable to a second position when the trigger partially or completely dissolves, degrades and / or erodes, wherein the piercer is released and moves under the action of the elastic force to pierce the gas container.

58. An ingestible device according to claim 57, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

59. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. a piercer configured to pierce the gas container to release compressed gas from the gas container into the housing; a spring that applies elastic force to the piercer; and A trigger that holds a radial snap arm in a first position, wherein the radial snap arm holds the piercer in a fixed position relative to the elastic force, and when the trigger is partially or completely dissolved, degraded and / or eroded, the radial snap arm can be radially moved to a second position, wherein the piercer is released and moves under the action of the elastic force to pierce the gas container.

60. An ingestible device according to claim 59, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

61. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. a piercer configured to pierce the gas container to release compressed gas from the gas container into the housing; a spring that applies elastic force to the piercer; a trigger that holds the piercer in a fixed position relative to the spring force; and A detachable piercer base holds the piercer in a fixed position until a threshold force is overcome, wherein when the trigger partially or completely dissolves, degrades and / or erodes, the piercer is released and moves under the action of a spring force to pierce the gas container.

62. An ingestible device according to claim 61, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

63. An ingestible device according to claim 61 or 62, wherein the detachable piercer base comprises two or more arms.

64. An ingestible device according to claim 61 or 62, wherein the detachable piercer base includes an outer radial arm extending above the end of the spring.

65. An ingestible device according to claim 61 or 62, wherein the detachable piercer base includes an internal hook arm.

66. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. a piercer configured to pierce the gas container to release compressed gas from the gas container into the housing; a spring that applies elastic force to the piercer; a trigger that holds the piercer in a fixed position relative to the spring force; and A breakaway piercer flange holds the piercer in a fixed position until a threshold force is overcome, wherein when the trigger partially or completely dissolves, degrades and / or erodes, the piercer is released and moves under the action of a spring force to pierce the gas container.

67. An ingestible device according to claim 66, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

68. An ingestible device according to claim 66 or 67, wherein the breakaway piercer flange has a protrusion that projects radially inward to engage the piercer.

69. An ingestible device according to claim 68, wherein the protrusion extends below one end of the spring.

70. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. a piercer configured to pierce the gas container to release the compressed gas from the gas container into the housing; a spring that applies elastic force to the piercer; a trigger that holds the piercer in a fixed position relative to the spring force; and When the trigger partially or completely dissolves, degrades and / or erodes, it moves under the action of elastic force to pierce the gas container.

71. An ingestible device according to claim 70, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

72. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. a piercer configured to pierce the gas container to release compressed gas from the gas container into the housing; a spring that applies elastic force to the piercer; a trigger that holds the piercer in a fixed position relative to the spring force; a trigger crown located between the trigger and the end of the housing; and The trigger is configured to partially or completely dissolve, degrade and / or erode to release the piercer to move under the action of the spring force to pierce the gas container.

73. An ingestible device according to claim 72, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

74. The ingestible device of claim 72 or 73, further comprising one or more ribs located on the trigger crown to apply concentrated pressure on the trigger.

75. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. a piercer configured to pierce the gas container to release compressed gas from the gas container into the housing; a spring that applies elastic force to the piercer; a trigger that holds the piercer in a fixed position relative to the spring force, the trigger being attached to the ball groove; a nut inside the ball groove that secures the ball relative to the inner surface of the sleeve; and The ball groove is movable from a first position in which the ball retains the piercer from movement to a second position in which the ball moves radially out of the ball groove to allow movement of the piercer.

76. An ingestible device according to claim 75, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

77. An ingestible device comprising: a storage reservoir in the device housing; one or more openings in the housing of the device; Gas containers containing compressed gas; a pin that screws into the container cap; a first O-ring on the pin that seals the gas container; a second O-ring on the container cap that seals the device housing; a trigger housing attached to the device housing; a release member in the trigger housing; The container cap is rotatable from a first position where the gas container is substantially sealed to a second position where the gas container is unsealed; wherein the container cap is displaced from the gas container to release gas from the gas container when the release member is released.

78. The ingestible device of claim 77, having no spring and no piercer.

79. An ingestible device according to claim 77 or 78, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

80. The ingestible device of any one of claims 77 to 79, further comprising one or more elements in the trigger housing configured to apply concentrated pressure on the release component to cause catastrophic failure of the release component.

81. An ingestible device according to claim 80, wherein the one or more elements include ribs.

82. The ingestible device of any one of claims 77 to 81 , further comprising an opening in the trigger housing.

83. The ingestible device of any one of claims 77 to 82, wherein the container cap includes a tool accessory to allow the pin to be rotated by a tool.

84. An ingestible device according to any one of claims 77 to 83, wherein after ingestion, the release component partially or completely dissolves, degrades and / or erodes, thereby allowing the container cap to move longitudinally in the trigger housing, releasing the compressed gas to act on the piston in the device housing.

85. An ingestible device comprising: a storage reservoir in the housing; one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. Release components; a first piston and a second piston in the housing, the second piston blocking the opening; and The second piston includes an inner split cap having a split portion which is inserted into the housing recess after being displaced by movement of the second piston.

86. An ingestible device according to claim 85, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

87. An ingestible device comprising: one or more openings in the housing; a gas container in said housing; a receiver having one or more O-rings sealing the gas container; Gas containers containing compressed gas; Release components; Wherein actuation of the release member allows the one or more O-rings to be displaced to release gas from the gas container.

88. An ingestible device according to claim 87, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

89. An ingestible device comprising: one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. a piercer between the gas container and the release member; a piston slidable within the housing; a reservoir of dispensable substance between the piston and the opening; The release member and the piercer are movable by an external element to pierce a seal on the gas container; The device is configured to prevent compressed gas from acting on the piston after the seal is pierced until the release member trigger partially or completely dissolves, degrades, ruptures and / or erodes.

90. The ingestible device of claim 89, further comprising a retainer for retaining the ingestible device, and wherein the external element comprises a plunger insertable through the retainer.

91. The ingestible device of claim 89, further comprising a second piston, the dispensable substance reservoir being located between the piston and the second piston.

92. An ingestible device according to claim 90 or claim 91, wherein the opening in the shell is radially connected to extend through the side wall of the shell.

93. An ingestible device according to any one of claims 89-92, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

94. An ingestible device comprising: one or more openings in the housing; A gas container is provided in the housing, the gas container containing compressed gas. an end cap held in engagement with the gas container by a release member; Wherein actuation of the release member allows the end cap to be displaced to release gas from the gas container to actuate the device.

95. The ingestible device of claim 94 which is spring-less and piercer-less.

96. An ingestible device according to claim 94, wherein the end cap has an inner O-ring on a portion of the end cap extending into the opening of the gas container, and an outer O-ring that slidably seals the end cap against the inner wall of the housing.

97. An ingestible device according to claim 95 or 96, further comprising a first piston in the housing, located between the gas container and the opening.

98. The ingestible device of claim 97, further comprising a second piston and a reservoir of a dispensable substance located in the housing, the reservoir being located between the first piston and the second piston.

99. An ingestible device according to claim 97 or 98, wherein the housing includes a first portion and a second portion, wherein the first piston is in the first portion and the release member and the end cap are in the second portion.

100. The ingestible device of claim 99, wherein the second shell has an opening.

101. An ingestible device according to any of claims 94-100, having one or more of the peak jet power; peak jet force; internal pressure; peak fluid pressure; peak jet velocity; and / or dispensable material volume of claims 2-13.

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