Intake device for delivery of therapeutic agents to gastrointestinal tract

Abstract

The present invention relates to ingestible devices for delivery of therapeutic agents to the gastrointestinal tract. The ingestible device may deliver a therapeutic agent directly to a desired tissue of the GI tract of a subject, such as a submucosal, mucosal, and / or mucous layer of the GI tract, and methods of using the same. The ingestible device can deliver the therapeutic agent in a safe, efficient and reliable manner. The disclosure also provides a pharmaceutical composition for use in a method of treating a disease or condition in a subject in need thereof.

Description

[0001] This application is a continuation-in-part of patent application number 202080096177.X, filed December 11, 2020, having a priority date of: December 13, 2019, entitled “Ingestible Device for Delivery of Therapeutic Agent to the Gastrointestinal Tract.”

[0002] Cross Reference to Related Applications

[0003] This application claims priority under 35 U.S.C. § 119 to U.S.S.N. 62 / 948,082, filed December 13, 2019, and entitled “Ingestible Device for Delivery of Therapeutic Agent to the Gastrointestinal Tract”; U.S.S.N. 63 / 027,427, filed May 20, 2020, and entitled “Ingestible Device for Delivery of Therapeutic Agent to the Gastrointestinal Tract”; and U.S.S.N. 63 / 086,630, filed October 2, 2020, and entitled “Ingestible Device for Delivery of Therapeutic Agent to the Gastrointestinal Tract.” The entire disclosure of each of these applications is incorporated herein by reference. TECHNICAL FIELD

[0004] The present disclosure relates generally to ingestible devices capable of delivering dispensable substances, such as therapeutic agents, and related components, systems, and methods. BACKGROUND

[0005] The gastrointestinal (GI) tract generally provides a therapeutic medium for an individual’s body. At times, it is desirable to dispense therapeutic agents to the GI tract to treat medical conditions. SUMMARY

[0006] The present disclosure provides ingestible devices that can deliver therapeutic agents directly to desired tissues of the GI tract of a subject, such as the submucosa, mucosa, and / or mucous layer of the GI tract, and methods of using the same. The ingestible devices can deliver therapeutic agents in a safe, effective, and reliable manner. The present disclosure also provides pharmaceutical compositions for use in methods of treating a disease or condition in a subject in need thereof.

[0007] The ingestible devices of the present disclosure are configured to provide at least three different modes of direct delivery of a therapeutic agent to the GI tract of a subject, referred to herein as trans-epithelial delivery, epithelial delivery, and topical delivery. As used herein, direct delivery refers to a force-driven delivery mechanism.

[0008] Accordingly, in one aspect, the present disclosure relates to trans-epithelial delivery of a therapeutic agent to the GI tract of a subject. Accordingly, the present disclosure provides an ingestible device that can directly deliver a therapeutic agent across an epithelial cell layer of the mucosa of the GI tract of a subject to produce systemic exposure of the therapeutic agent to the subject. In such embodiments, the ingestible device is configured to directly deliver the therapeutic agent across an epithelial cell layer of the mucosa and into the submucosa and / or into the mucosal region below the epithelial layer (e.g., into the lamina propria) of the GI tract, where it can be available for systemic absorption. This can be particularly relevant when the oral bioavailability of the therapeutic agent is otherwise low. In some embodiments, systemic exposure of the therapeutic agent is achieved by trans-epithelial delivery of the therapeutic agent into the submucosa and / or into the mucosal region below the epithelial layer (e.g., into the lamina propria) of the small intestine (e.g., in the duodenum, jejunum, and / or ileum). In further embodiments, trans-epithelial delivery directly delivers the therapeutic agent into the submucosa and / or into the mucosal region below the epithelial layer (e.g., into the lamina propria) of the GI tract such that the percentage of systemic absorption for trans-epithelial 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).

[0009] Without wishing to be bound by theory, it is believed that trans-epithelial delivery into the submucosa and / or into the mucosal region below the epithelial layer (e.g., into the lamina propria) of the GI tract is achieved by using appropriate values for one or more performance parameters associated with an ingestible device configured for such use. Such performance parameters include, for example, internal pressure of the ingestible device, peak fluid pressure of the ingestible device, nozzle pressure of the ingestible device, peak jet power of a dispensable substance (e.g., a drug formulation containing a therapeutic agent) delivered from the ingestible device, peak jet velocity of a dispensable substance (e.g., a drug formulation containing a therapeutic agent) delivered from the ingestible device, peak jet pressure of a dispensable substance (e.g., a drug formulation containing a therapeutic agent) delivered from the ingestible device, peak jet force of a dispensable substance (e.g., a drug formulation containing a therapeutic agent) delivered from the ingestible device, peak jet stability length of a dispensable substance (e.g., a drug formulation containing a therapeutic agent) delivered from the ingestible device, nozzle shape, nozzle length, and nozzle diameter.

[0010] In another aspect, the present disclosure relates to epithelial delivery of a therapeutic agent to a subject's GI tract. Accordingly, the present disclosure provides an ingestible device configured to deliver a therapeutic agent directly into the mucus and / or onto the epithelial layer of the small or large intestine, but not beyond the epithelial layer of the mucosa, from which it can act locally, and in some cases distally from the site of direct delivery. In some embodiments, the device is configured such that the therapeutic agent is delivered from the device with sufficient force to provide epithelial delivery, the force being lower than that required for trans-epithelial delivery.

[0011] In yet another aspect, the present disclosure relates to local delivery of a therapeutic agent to a subject's GI tract. Accordingly, the present disclosure provides an ingestible device configured to deliver a therapeutic agent into the lumen and / or onto the mucus or other surface of the GI tract facing the lumen of the small or large intestine, from which it can act locally, and in some cases distally 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 provide local delivery of the therapeutic agent, the force being lower than that required for epithelial or trans-epithelial delivery.

[0012] Ingestible devices, whether configured for trans-epithelial, epithelial, or local delivery, can have a streamlined and / or relatively simple mechanical design, be relatively small and / or inexpensive to manufacture. In general, the devices protect the dispensable substance (e.g., therapeutic agent or pharmaceutical formulation comprising a therapeutic agent) until the device reaches the desired location in the subject. As one example, the device can be designed to deliver the dispensable substance to a desired location in the GI tract of a subject, and the device can be designed such that the dispensable substance does not experience components of the GI tract (e.g., acid, enzymes) prior to reaching the desired location in the GI tract. As another example, the device can be designed to deliver the dispensable substance such 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).

[0013] The present disclosure provides ingestible devices that can deliver a therapeutic agent directly to a desired tissue of a subject's GI tract (e.g., submucosal, mucosal, and / or mucus layer of the GI tract), e.g., to treat a particular class of disease or a particular disease. Relatedly, methods of using the devices to deliver a therapeutic agent to a desired tissue of the GI tract, e.g., to treat a particular class of disease or a particular disease, are disclosed. These disclosures also inherently provide disclosures of corresponding medical uses - i.e., disclosures of listed therapeutic agents for use in methods of treating listed classes of disease or particular diseases by using the listed therapeutic agents to deliver the listed therapeutic agents to a desired tissue of a subject's GI tract using the devices.

[0014] In an aspect, the present disclosure provides an ingestible device comprising: a housing comprising an interior and an opening; a gas cylinder in the interior of the housing, the gas cylinder having a breakable seal; a spring in the interior of the housing; a piston in the interior of the housing; a perforator in the interior of the housing; a retainer; and a trigger exposed to an environment external to the housing. In a first state of the ingestible device: the trigger holds the retainer in a first position; the retainer holds the perforator in a first position in which the perforator does not break the breakable seal of the gas cylinder; 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.

[0015] In some embodiments, in a second state of the ingestible device: the trigger is at least partially dissolved, degraded, and / or eroded such that the trigger is unable to hold the retainer in its first position; and the retainer is unable to hold the perforator in its first position.

[0016] In some embodiments, in a second state of the ingestible device: the spring exerts a force on the perforator to move the perforator such that the perforator breaks the breakable seal of the gas cylinder; a gas is released from the gas cylinder; the gas exerts a force on the piston such that the piston exerts a force on the dispensable substance; and the dispensable substance is delivered from the ingestible device via the opening in the housing.

[0017] The ingestible device can further comprise a seal between the piston and the housing, and / or a seal between the perforator and the housing.

[0018] In an aspect, the present disclosure provides an ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent in an interior of the housing; a gas cylinder in the interior of the housing; a spring in the interior of the housing; a piston in the interior of the housing; a seal between the piston and the housing; a perforator in the interior of the housing; a retainer; and a trigger exposed to an environment external to the housing.

[0019] In an aspect, the present disclosure provides an ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent in an interior of the housing; a gas cylinder in the interior of the housing; a spring in the interior of the housing; a piston in the interior of the housing; a perforator in the interior of the housing; a retainer; a seal between the retainer and the housing; and a trigger exposed to an environment external to the housing.

[0020] In an aspect, the present disclosure provides an ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent in an interior of the housing; a gas cartridge in the interior of the housing; a spring in the interior of the housing; a piston in the interior of the housing; a first seal between the piston and the housing; a perforator in the interior of the housing; a retainer; a second seal between the retainer and the housing; and a trigger exposed to an environment outside of the housing.

[0021] The ingestible device can be a 00 size device.

[0022] The trigger can comprise an enteric material.

[0023] The housing can comprise first and second housing portions, wherein the piston and the dispensable substance are in an interior of the first housing portion and the spring and the retainer are in an interior of the second housing portion.

[0024] The opening of the ingestible device can be a nozzle, e.g., a nozzle having a diameter of about 325 pm to 375 pm.

[0025] In some embodiments, at least one of the following is true: the ingestible device is configured for trans-epithelial delivery of the dispensable object to a GI tract of a subject; the ingestible device is configured for epithelial delivery of the dispensable object to a GI tract of a subject; and the ingestible device is configured for local delivery of the dispensable object to a GI tract of a subject.

[0026] The ingestible device can further comprise the dispensable substance. In some embodiments, the dispensable substance is a solution or a suspension.

[0027] In some embodiments, at least one of the following is true: the ingestible device is configured to deliver the dispensable substance as a jet stream having a peak jet power of about 1 Watt to about 3 Watts to tissue of a GI tract of a subject; the ingestible device is configured to deliver the dispensable substance at a peak jet velocity of about 25 meters / second to about 45 meters / second; the ingestible device is configured to deliver the dispensable substance to tissue of a GI tract of a subject at a peak jet pressure of about 100 psig to about 250 psig; the ingestible device is configured to deliver the dispensable substance to tissue of a GI tract of a subject at a peak jet force of about 0.09 N to about 0.15 N; the ingestible device is configured to deliver the dispensable substance as a jet stream having a jet stabilization length of at least about 0.5 millimeters; the ingestible device is configured to provide an internal pressure of about 225 psig to about 425 psig; and the ingestible device is configured to contain the dispensable substance at a peak fluid pressure of about 200 psig to about 400 psig.

[0028] In some embodiments, at least one component of the ingestible device comprises a cyclic olefin polymer.

[0029] In some embodiments, the frangible seal is scored.

[0030] In some embodiments, the frangible seal has a varying thickness.

[0031] In some embodiments, the gas cylinder has a burst pressure of about 2,800 psig to about 4,500 psig.

[0032] In some embodiments, the gas cylinder contains at least one gas selected from the group consisting of air, nitrogen, oxygen, carbon dioxide, hydrofluorocarbon gas, and noble gas.

[0033] In some embodiments, the ingestible device further comprises an element having a first state in which the element at least partially covers the opening in the housing and a second state in which 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 in synchronization with the piston. The element can move the same distance as the piston moves when the piston moves a distance. The ingestible device can further comprise 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.

[0034] In some embodiments, the ingestible device further comprises a covering over the opening in the housing. The covering can be removable from the ingestible device. The covering can be configured to be removed from the housing due to pressure exerted by the dispensable substance. The covering can comprise an enteric material. The covering can be a film, a foil, a band, a plug, or a patch. The covering has a burst pressure of at most 420 psig.

[0035] In some embodiments, the ingestible device further comprises a second piston configured such that, when the first piston exerts a force on the dispensable substance, the dispensable substance exerts a force on the second piston to cause the second piston to slide to expose the opening and the dispensable substance is forced to exit the ingestible device via the opening.

[0036] In some embodiments, the ingestible device further comprises a removable cap secured to the ingestible device and configured such that, when the piston moves to exert a force on the dispensable substance, the dispensable substance exerts a force on the cap to cause the cap to slide to expose the opening in the housing.

[0037] In some embodiments, the ingestible device further comprises an inflated membrane volume covering the opening and configured such that, when the piston moves to exert a force on the dispensable substance, the dispensable substance exerts a force on the inflated membrane volume and the inflated membrane volume is compressed to expose the opening in the housing.

[0038] In an aspect, the present disclosure provides methods comprising delivering a dispensable substance to a subject's GI tract using an ingestible device according to the present disclosure.

[0039] The details of one or more embodiments of the devices and methods 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 DRAWINGS

[0040] Figure 1A is a schematic cross-section of a different region of healthy intestinal tissue.

[0041] Figure 1B is a schematic cross-section of intestinal tissue corresponding to Figure 1A but diseased.

[0042] Figure 2 is a cross-section of an ingestible device.

[0043] Figure 3 is a cross-section of an ingestible device.

[0044] Figure 4 An exemplary process flow diagram using an ingestible device is shown, in which pressure is not applied to the dispensable substance prior to the subject ingesting the ingestible device.

[0045] Figures 5A-5C An ingestible device is shown having aspects similar to those shown in Figure 4 .

[0046] Figures 6A-6C An ingestible device is shown having aspects similar to those shown in Figure 4 and 5.

[0047] Figures 7-13 An ingestible device is shown having multiple chambers for one or more dispensable substances.

[0048] Figures 14-17 An ingestible device is shown.

[0049] Figure 18 Certain elements of the ingestible device of Figure 19 are shown.

[0050] Figure 19 and 20A state of the ingestible device is shown.

[0051] Figure 21 and 22 A state of the ingestible device is shown.

[0052] Figure 23 and 24 A state of the ingestible device is shown.

[0053] Figures 25-27 A state of the ingestible device is shown.

[0054] Figures 28-30 A state of the ingestible device is shown.

[0055] Figures 31-34 A state of the ingestible device is shown.

[0056] Figures 35-40 A state of the ingestible device is shown.

[0057] Figures 41A-41C A state of the ingestible device is shown.

[0058] Figures 42A-47C A state of the ingestible device is shown.

[0059] Figure 48 and 49 A state of the ingestible device is shown.

[0060] Figure 50A and 50B An exploded view of the ingestible device is shown.

[0061] Figure 51A and 51B An exploded view of the ingestible device is shown.

[0062] Figures 52A-52D A view of the ingestible device is shown.

[0063] Figure 53A and 53B A view of a portion of the ingestible device is shown.

[0064] Figure 54A and 54B A view of a portion of the ingestible device is shown.

[0065] Figure 55 A view of a portion of the ingestible device is shown. DETAILED DESCRIPTION

[0066] INCORPORATED BY REFERENCE

[0067] The present application incorporates by reference in its entirety the following patent applications: U.S.S.N. 62 / 769,496, filed November 19, 2018, and entitled “Ingestible Device With High Pressure Substance Delivery to the Gastrointestinal Tract”; U.S.S.N. 62 / 818,731, filed March 14, 2019, and entitled “Ingestible Device With High Pressure Substance Delivery to the Gastrointestinal Tract”; U.S.S.N. 62 / 819,513, filed March 15, 2019, and entitled “Ingestible Device With High Pressure Substance Delivery to the Gastrointestinal Tract”; and U.S.S.N. 62 / 932,459, filed November 7, 2019, and entitled “Ingestible Device and Method of Use to Deliver Therapeutic Agent to the Gastrointestinal Tract”.

[0068] DEFINITIONS

[0069] “ingestible”, as used herein with respect to a device, means that the device can be swallowed whole.

[0070] "Distributable" as used herein in reference to any substance means any substance that can be released from an ingestible device or from a component (e.g., reservoir) of the device as disclosed herein. For example, a distributable substance can be a therapeutic agent as disclosed herein, and / or a formulation including a therapeutic agent as disclosed herein. A distributable substance can be a fluid, e.g., a liquid, a suspension, or a semi-solid. For example, a distributable substance can be a liquid in the form of a solution, e.g., an aqueous solution. In some embodiments, the substance is non-fluid, e.g., a solid, when placed in an ingestible device. In such embodiments, the substance can be converted to a fluid prior to delivery from the ingestible device. In some embodiments, the therapeutic agent is a small molecule. In other embodiments, the therapeutic agent is a large molecule, e.g., a biologic. Non-limiting examples of biologics include antibodies (including monoclonal antibodies), proteins (including fusion proteins), peptides (including cyclic peptides), cells (including stem cells), and nucleic acids (including inhibitory nucleic acids, antisense nucleic acids, siRNA, ribozymes). In some embodiments, a distributable substance is a pharmaceutical formulation including a therapeutic agent and a liquid carrier. In some embodiments, a pharmaceutical formulation including a therapeutic agent and a liquid carrier is a solution formulation. In other embodiments, a pharmaceutical formulation including a therapeutic agent and a liquid carrier is a suspension formulation or an emulsion formulation. In some embodiments, a distributable substance delivered as described herein is particularly suitable for treating diseases and disorders of the endoderm, e.g., it can be more effective in the gut-associated lymphoid tissue (GALT) or the liver system than subcutaneous or intravenous administration. In general, the viscosity of a distributable substance can be suitably selected. In some embodiments, a distributable substance has a viscosity of at least about 0.5 centipoise (cP) (e.g., at least about 0.8 cP, at least about 1 cP, at least about 2 cP, at least about 3 cP, at least about 4 cP, at least about 5 cP, at least about 10 cP, at least about 15 cP, at least about 25 cP, at least about 50 cP) and / or at most about 100 cP (e.g., at most about 75 cP, at most about 65 cP, at most about 50 cP, at most about 25 cP, at most about 20 cP, at most about 10 cP at most about 9 cP, at most about 8 cP, at most about 7 cP). In certain embodiments, a distributable substance has a viscosity of about 0.5 cP to about 10 cP (e.g., about 0.8 cP to about 9 cP, about 0.8 cP to about 8 cP). In some embodiments, a distributable substance has a viscosity of about 0.5 cP to about 100 cP (e.g., about 1 cP to about 100 cP, about 1 cP to about 50 cP, about 1 cP to about 25 cP, about 1 cP to about 20 cP, about 1 cP to about 15 cP, about 1 cP to about 10 cP, about 5 cP to about 100 cP, about 10 cP to about 100 cP, about 25 cP to about 100 cP, about 25 cP to about 75 cP, about 25 cP to about 50 cP).

[0071] As used herein, the term“enteric” refers to a material that allows transition into the GI tract to a desired location (e.g., from the stomach to the intestine) before dissolving / degrading / eroding due to exposure to certain conditions (e.g., pH, temperature, enzymes) of the GI tract. Enteric materials can prevent degradation of the drug by gastric fluids and enzymes. In some embodiments, the enteric composition (e.g., when forming a coating (a layer) on the shell of an ingestible device) is selected from the group consisting of: a mixture of fats and fatty acids; shellac and shellac derivatives; and cellulose acetate phthalate. The enteric material can be an enteric polymer. In some embodiments, the enteric polymer can remain insoluble in the stomach, but dissolves at the higher pH of the intestine (e.g., small intestine or large intestine), and is used to deliver the drug to the intestine. Examples include: Opadry Enteric 91 series polyvinyl acetate phthalate by Colorcon, Opadry Enteric 94 series methacrylic acid by Colorcon, Opadry Enteric 95 series methacrylic acid by Colorcon, Sureteric PVAP (polyvinyl acetate phthalate) by Colorcon, Nutrateric ethyl cellulose Evonik Acryl-EZE (Colorcon & Evonik collaboration - Eudragit L 100-55 mixture methacrylic acid copolymer); Eudragit L 100-55 methacrylic acid copolymer by Evonik, Eudragit L 30D-55 methacrylic acid copolymer (30%) by Evonik, Eudragit L 100 methacrylic acid copolymer by Evonik, Eudragit L 12,5 methacrylic acid copolymer (12.5%) by Evonik, Eudragit S 100 methacrylic acid copolymer by Evonik, Eudragit S 12,5 methacrylic acid copolymer (12.5%) by Evonik, Eudragit FS 30D methacrylic acid copolymer (30%) by Evonik; SheffCoat ENT cellulose acetate phthalate, acrylate copolymer, HPMC-P by Kerry, C-A-P NF cellulose acetate phthalate by Eastman; PROTECT TMENTERIC CHIC AND SODIUM ALGINATE. In certain embodiments, the enteric material dissolves in the small intestine and is suitable for small intestinal release. Examples of such enteric materials include, but are not limited to, cellulose derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and Eudragit® RL100 (e.g., Eudragit® 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, methacrylic acid ester-methacrylic acid copolymer, styrene, maleic acid copolymer, shellac, and the like. Other suitable enteric materials are aqueous emulsions of ethyl acrylate methacrylic acid copolymer or hydroxypropyl methylcellulose acetate succinate (HPMAS). (See, e.g., U.S. Patent No. 5,591,433). In some embodiments, the enteric material dissolves in the large intestine and is suitable for colonic release. Enteric materials suitable for large intestinal (e.g., colonic) release are known to those of skill in the art. In some embodiments, degradation of the coating is microbially triggered, e.g., bacterial enzymes in the colon enzymatically trigger degradation of the coating (see, e.g., Archana et al., Int. J. Pharm. Sci. Res. 1(5): 40-47 (2016); and Sethi et al., Int. J. Pharm. Sci. Res. 3(9): 2989-3000 (2012)). In some embodiments, the coating is a pH-dependent polymer that is insoluble at low pH but becomes increasingly soluble as pH increases. In some embodiments, the coating is a polymethacrylate with a pH-dependent solubility threshold of about pH 6.0 to about 7.0. Examples of suitable enteric materials include, but are not limited to, chitosan, alginate (e.g., as a calcium salt), L (e.g. 100), S (e.g. S100), L (e.g. L-30D), FS (e.g. FS 30D), hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, and cellulose acetate phtalate. In some embodiments, the enteric material is a material described in US 10,226,430; Sethi et al., Int. J. Pharm. Sci. Res. 3(9): 2989-3000 (2012); or Archana et al., Int. J. Pharm. Sci. Res. 1(5): 40-47 (2016), each of which is incorporated by reference in its entirety. In some embodiments, the colon-specific degradation of the enteric material can be based on the presence of microorganisms that reside only in the colon, more particularly, biodegradable enzymes produced by these microorganisms. Generally, such microorganisms are anaerobic bacteria, such as Bacteroides, Bifidobacteria, Enterobacteria, Eubacteria, Clostridia, Enterococci, and Ruminococcus, among others. These micro floras meet their energy requirements by fermenting various types of substrates (e.g., polysaccharides, disaccharides, and trisaccharides, among others) that are not digested in the small intestine. These polymers are stable in the environment of the stomach and small intestine. Upon reaching the colon, the polymers undergo degradation by enzymes, or the breakdown of the polymer backbone results in a subsequent decrease in their molecular weight, thereby losing mechanical strength.

[0072] The term "jet stream" as used herein refers to a collimated stream of fluid (e.g., liquid or suspension) that is stable without disintegrating into a spray. A jet stream can be formed by forcing a fluid (e.g., liquid or suspension) through an opening in an ingestible device. Generally, a jet stream maintains a stable form and is able to achieve its intended purpose by maintaining appropriate properties such as its diameter and / or velocity (e.g., for penetrating a surface).

[0073] As used herein, "jet diameter" refers to the cross-sectional diameter of a jet stream at a given location.

[0074] As used herein, "average jet diameter" refers to the average cross-sectional diameter of a jet stream between the location at which the jet stream is formed (e.g., from a nozzle opening through which a dispensable substance is delivered from an ingestible device) and the location at which the jet stream impacts a subject's GI tissue.

[0075] As used herein, "jet stability length" refers to the distance from an opening (e.g., a nozzle opening) of an ingestible device at which a dispensable substance delivered through the opening maintains a form of a jet stream.

[0076] As used herein, "jet velocity" is the average fluid velocity across the cross section of the jet at a given point in time.

[0077] As used herein, "peak jet velocity" refers to the maximum jet velocity of the jet at the interface of the lumen and the surface of the GI tract facing the lumen. Generally, peak jet velocity is reached at the initial delivery of the dispensable substance from the ingestible device.

[0078] As used herein, "minimum jet velocity" refers to the minimum velocity of the jet at the interface of the lumen and the surface of the GI tract facing the lumen. Generally, minimum jet velocity is reached at the end of the delivery of the dispensable substance from the ingestible device.

[0079] 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 surface of the GI tract facing the lumen determined over the time of delivery of the dispensable substance by the ingestible device.

[0080] As used herein, "peak jet power" refers to the maximum power of the jet at the interface of the lumen and the surface of the GI tract facing the lumen. Generally, peak jet power is reached at the initial delivery of the dispensable substance from the ingestible device.

[0081] As used herein, "minimum jet power" refers to the minimum power of the jet at the interface of the lumen and the surface of the GI tract facing the lumen. Generally, minimum jet power is reached at the end of the delivery of the dispensable substance from the ingestible device.

[0082] 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 surface of the GI tract facing the lumen determined over the time of delivery of the dispensable substance by the ingestible device.

[0083] As used herein, "jet power during delivery" refers to the jet power at the interface of the lumen and the mucosa of the GI tract of the subject.

[0084] 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 one 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".

[0085] As used herein, "peak jet pressure" refers to the maximum pressure of the jet at the interface of the lumen and the surface of the GI tract facing the lumen. Generally, peak jet pressure is reached at the initial delivery of the dispensable substance from the ingestible device.

[0086] As used herein, "minimum ejection pressure" refers to the minimum pressure of the ejection stream at the interface of the lumen and the GI tract-facing surface of the lumen. Generally, the minimum ejection pressure is reached at the end of delivery of the dispensable substance from the ingestible device.

[0087] As used herein, "mean ejection pressure" and "average ejection pressure" refer to the average pressure of the ejection stream at the interface of the lumen and the GI tract-facing surface of the lumen determined over the time the ingestible device delivers the dispensable substance.

[0088] As used herein, "ejection force" refers to the force of the ejection stream at the interface of the lumen and the GI tract-facing surface of the lumen. In some embodiments, the ejection force is referred to herein as "impact force."

[0089] As used herein, "peak ejection force" refers to the maximum force of the ejection stream at the interface of the lumen and the GI tract-facing surface of the lumen. Generally, the peak ejection force is reached at the initial delivery of the dispensable substance from the ingestible device. In some embodiments, the peak ejection force is referred to herein as "impact force."

[0090] As used herein, "minimum ejection force" refers to the minimum force of the ejection stream at the interface of the lumen and the mucosa of the GI tract of the subject. Generally, the minimum ejection force is reached at the end of delivery of the dispensable substance from the ingestible device.

[0091] As used herein, "mean ejection force" and "average ejection force" refer to the average pressure of the ejection stream at the interface of the lumen and the GI tract-facing surface of the lumen determined over the time the ingestible device delivers the dispensable substance.

[0092] As used herein, "fluid volume" refers to the volume of the dispensable substance contained in the ingestible device.

[0093] As used herein, "initial fluid volume" refers to the volume of the dispensable substance contained in the ingestible device immediately prior to delivery of the dispensable substance from the ingestible device.

[0094] As used herein, "final fluid volume" refers to the volume of the dispensable substance contained in the ingestible device immediately after the end of delivery of the dispensable substance from the ingestible device.

[0095] As used herein, "delivery fluid volume" refers to the volume of the dispensable substance delivered from the ingestible device. In some embodiments, the delivery fluid volume is less than the fluid volume.

[0096] As used herein, "end circle" is the radius on the curve at the end of the housing of the ingestible device.

[0097] As used herein, "fluid pressure" refers to the pressure in the fluid volume.

[0098] As used herein, "peak fluid pressure" refers to the maximum pressure generated in a fluid volume. Typically, the peak fluid pressure is reached at the initial delivery of dispensable substance from an 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."

[0099] 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 the delivery of dispensable substance from an ingestible device.

[0100] As used herein, "fluid pressure during delivery" refers to the pressure in a fluid volume as the fluid volume decreases during the course of delivery.

[0101] As used herein, "nozzle" refers to a passageway between a fluid reservoir space and the environment outside. Typically, in embodiments in which a nozzle is used, the pressure in the fluid volume generates a high velocity flow of fluid through the nozzle to create a jet stream of fluid at the opening of the nozzle through which the dispensable substance exits the ingestible device and enters the environment outside the ingestible device.

[0102] As used herein, "nozzle diameter" refers to the diameter of the opening of the nozzle at which the dispensable substance exits the ingestible device and enters the environment outside the ingestible device.

[0103] As used herein, "nozzle length" refers to the length of the opening of the nozzle.

[0104] 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 environment outside the ingestible device; and 2) the interface between the lumen and the surface of the GI tract facing the lumen.

[0105] As used herein, "internal pressure" of an ingestible device refers to the pressure exerted to the dispensable substance (e.g., a therapeutic agent or a formulation containing a therapeutic agent) contained in the ingestible device prior to the delivery of the dispensable substance from the ingestible device. In some embodiments, the internal pressure is provided by the drive force generator of the ingestible device. In certain embodiments, the internal pressure is greater than the fluid pressure. For example, this can be due to friction acting on the drive coupling of the ingestible device, such as O-ring friction. This friction is referred to herein as "piston friction."

[0106] As used herein, "nozzle pressure" refers to the pressure of the dispensable substance at the nozzle opening as measured at a surface facing the interior of the nozzle when dispensing the dispensable substance from the ingestible device. Generally, for a given ingestible device at a given point in time, the nozzle pressure is approximately the same as the fluid pressure.

[0107] As used herein, "local delivery" or "local 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 to a local region of the body or to the surface of a body part, regardless of the location of the effect; more particularly, local administration of a dispensable substance includes release of the dispensable substance to the lumen of the GI tract, the surface of the GI tract facing the lumen, the mucosa, and / or the lining of the gastrointestinal tract of a subject, including but not limited to the surface, mucosa, or lining containing one or more disease sites (e.g., a gastrointestinal mucosal lesion). The effect of local delivery or local administration of a dispensable substance can be local at the site of local administration, or remote from the site of local administration (e.g., distal thereto).

[0108] 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 the large intestine) of a subject, but does not cross 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) distal from the site of direct delivery, e.g., by diffusion or active transport.

[0109] As used herein, "trans-epithelial delivery" or "trans-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 through the epithelial layer of the mucosa of the GI tract to the submucosal layer of the GI tract of a subject; optionally, at least a portion of the dispensable substance is delivered directly beyond the epithelial layer to the mucosal region beneath the epithelial layer. In embodiments of trans-epithelial delivery in which a portion of the dispensable substance is delivered directly to the mucosal region beneath the epithelial layer, at least some (e.g., all) of that portion of the dispensable substance is delivered directly to the lamina propria. Once the therapeutic agent or pharmaceutical formulation containing a therapeutic agent is delivered directly beyond the epithelial layer of the GI tract, the therapeutic agent can be exposed systemically to the subject.

[0110] OVERVIEW

[0111] Figure 1ADifferent regions of healthy intestinal tissue are schematically depicted in cross-section. These regions include the lumen of the GI tract, 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 the epithelial layer and the lamina propria. The muscularis mucosa separates the mucosa from the submucosa. The muscularis externa is located beneath the submucosa. Figure 1B Corresponding regions of diseased intestinal tissue are schematically depicted in cross-section.

[0112] The ingestible devices described herein can deliver the therapeutic agent via local delivery (not directly to the mucus, mucosa, or submucosa), epithelial delivery (directly to the mucus or epithelium without direct delivery past the epithelial layer to the mucosa or submucosa), or trans-epithelial delivery (directly to the submucosa and / or into the mucosal region beneath the epithelial layer (e.g., the lamina propria).

[0113] Generally, the mode of delivery can 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 pressure and / or internal pressure, the therapeutic agent can be delivered locally, while higher fluid pressure and / or internal pressure can result in epithelial delivery, and still higher fluid pressure and / or internal pressure can result in trans-epithelial delivery. During trans-epithelial delivery, a bolus of the therapeutic agent initially contained in the dispensable substance can form within the submucosa and / or into the mucosal region beneath the epithelial layer (e.g., the lamina propria).

[0114] In some embodiments, the following holds true. The ingestible device is designed to deliver a dispensable substance, e.g., a therapeutic agent or a drug formulation containing a therapeutic agent, through the epithelial layer of the mucosa of the Gl 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 into the mucosal region below the epithelial layer (e.g., the lamina propria), where it can be systemically absorbed. After the patient swallows the device, it travels through the Gl 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, e.g., an enteric coating, that partially or completely degrades and / or erodes when the device reaches a desired location in the Gl tract). The desired location can be the small intestine or the large intestine. When the device is configured for trans-epithelial Gl tract delivery into the submucosal layer and / or into the mucosal region below the epithelial layer (e.g., the lamina propria), the preferred location can be the small intestine. As the restraining element is removed, relative motion (e.g., sliding of components) between certain components occurs such that one or more openings in the ingestible device (e.g., in a compartment (e.g., reservoir, sometimes referred to herein as a "drug reservoir," "storage reservoir," or "substance reservoir") that houses the dispensable substance) aligns with one or more additional openings (e.g., one or more nozzles) in the ingestible device (e.g., in the 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 a piston)) forces the dispensable substance out of the device via the one or more openings (e.g., one or more nozzles) from the drug reservoir. The dispensable substance is delivered as a jet stream of fluid (e.g., liquid) in a single or multiple bolus form through the epithelial layer of the mucosa of the Gl tract and directly into the submucosal layer and / or into the mucosal region below the epithelial layer (e.g., the lamina propria). After swallowing the device, the device travels through the Gl tract (mouth, esophagus, stomach, duodenum, jejunum, ileum, cecum, and colon), eventually exiting the Gl tract via the anus.

[0115] Accordingly, in general, the ingestible devices disclosed herein provide for the delivery of a therapeutic agent to the GI tract of a subject. In one aspect, the 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 disclosure provides an ingestible device that can deliver a dispensable substance (e.g., a therapeutic agent or a formulation comprising a therapeutic agent) directly to the submucosa of the GI tract of a subject and / or into the mucosal region beneath the epithelial layer (e.g., the lamina propria), which can result in systemic exposure of the therapeutic agent to the subject. In such embodiments, the ingestible device is configured to deliver the dispensable substance directly across the epithelial cell layer of the mucosa of the GI tract and into the submucosa and / or into the mucosal region beneath the epithelial layer (e.g., the lamina propria), where the therapeutic agent so delivered can be available for systemic absorption. In some embodiments, systemic exposure of the therapeutic agent is achieved by trans-epithelial delivery of the dispensable substance into the submucosa and / or into the mucosal region beneath the epithelial layer (e.g., the lamina propria) of the small intestine (e.g., in the duodenum, jejunum, and / or ileum). In some further embodiments, the trans-epithelial delivery delivers the dispensable substance directly into the submucosa and / or into the mucosal region beneath the epithelial layer (e.g., the lamina propria) of the GI tract such that the percentage of systemic absorption of the therapeutic agent via trans-epithelial 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).

[0116] In some embodiments, the direct delivery of the therapeutic agent via trans- epithelial delivery into the submucosa and / or into the mucosal region beneath the epithelial layer (e.g., the lamina propria) can also or alternatively provide a therapeutic effect locally at the site of direct delivery and / or distally from the site of direct delivery (e.g., distal thereto).

[0117] In some embodiments, the trans-epithelial delivery can deliver a first portion of the dispensable substance directly to the submucosa 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., the lamina propria) of the GI tract via trans-epithelial delivery can provide a therapeutic effect locally at the site of direct delivery and / or distally from the site of direct delivery (e.g., distal thereto).

[0118] In another aspect, the present disclosure relates to the epithelial delivery of a dispensable substance (e.g., a therapeutic agent or a formulation comprising a therapeutic agent) to a subject's GI tract. 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) directly into the mucus of the small or large intestine, but not across the epithelial layer of the mucosa, from which it can provide a therapeutic effect locally at the site of direct delivery and / or distal to the site of direct delivery (e.g., distal thereto). In some further embodiments, the ingestible device delivers the dispensable substance directly such that it contacts the surface of the mucosal epithelial cell layer facing the lumen, but as previously described, epithelial delivery does not deliver the dispensable substance across the epithelial layer of the mucosa. In some embodiments, the device is configured such that the dispensable substance is delivered from the device with sufficient force to provide epithelial delivery, the force being lower than that required for trans-epithelial delivery to the GI tract. In some further embodiments, the epithelial delivery delivers the dispensable substance directly into the mucus of the GI tract such that the percent of systemic absorption of the therapeutic agent via epithelial delivery relative to intravenous or subcutaneous administration is greater than the percent of local delivery, but less than the percent of trans-epithelial delivery. In other embodiments, the epithelial delivery delivers the dispensable substance directly into the mucus of the GI tract such that the percent of systemic absorption of the therapeutic agent via epithelial delivery relative to 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).

[0119] In some embodiments of epithelial delivery, the therapeutic agent delivered via epithelial delivery directly into the mucus of the GI tract can undergo active or passive transport or diffusion across the epithelial layer. Once across the epithelial layer, the therapeutic agent can provide a therapeutic effect locally at the site of direct delivery and / or distal to the site of direct delivery (e.g., distal thereto). In some embodiments, the therapeutic agent binds to a therapeutic target present in the GI epithelial layer, or elicits other pharmacodynamic effects locally at the site of delivery or distal to the site of delivery via immune cells or tissues in the GI tract (e.g., dendritic cells, lymphocytes, mucosa-associated lymphoid tissue).

[0120] In yet another aspect, the present disclosure relates to the local 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 intestine or large intestine and / or onto mucus or other surfaces of the GI tract (e.g., diseased surfaces) facing the lumen, from which it can provide a therapeutic effect locally at the site of delivery and / or distal to the site of delivery (e.g., distal thereto). In some embodiments, the device is configured such that the dispensable substance is delivered therefrom with sufficient force to locally deliver the dispensable substance, the force being lower than that required for epithelial or trans-epithelial delivery to the GI tract. In some embodiments, local delivery to the GI tract results in reduced systemic absorption of the therapeutic agent as compared to trans-epithelial delivery to the GI tract, intravenous, or subcutaneous delivery.

[0121] In some further embodiments, local 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 percent systemic absorption of the therapeutic agent via local delivery 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% relative to intravenous or subcutaneous administration. In some embodiments, local delivery to the GI tract results in negligible or no systemic absorption of the therapeutic agent as compared to trans-epithelial delivery to the GI tract, intravenous, or subcutaneous delivery.

[0122] In some embodiments, the locally delivered dispensable substance can spread over the mucus or other surfaces of the GI tract facing the lumen, thereby coating the surfaces of the GI tract at the site of delivery and / or distal to the site of delivery (e.g., distal thereto). In some embodiments, upon or following local delivery of the dispensable substance, the therapeutic agent can 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.

[0123] In some embodiments, the mucus and / or the epithelial layer of the mucosa can be disrupted or even missing, for example in a patient having a disease or disorder of the GI tract. In such embodiments, local delivery of the dispensable substance to the GI tract of the patient can provide for direct delivery of the dispensable substance to the surfaces of the GI tract facing the lumen, e.g., mucosal tissue exposed by the disruption and / or missing (e.g., both the mucus layer and / or the epithelial layer are completely or partially missing or compromised in portions of the GI due to the disease or disorder). For example, in some embodiments, local delivery of the dispensable substance to the GI tract of the patient can provide for local delivery to one or more lesions of the GI tract. In some embodiments, the disease or disorder 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.

[0124] Accordingly, this article provides novel systemic delivery devices and methods for delivering therapeutic agents to the small intestinal mucosa and / or submucosa via jet injection. Current administration methods for most macromolecular therapeutic agents target systemic circulation via subcutaneous (SC), intramuscular (IM), or intravenous (IV) bolus injection. The devices and methods described herein provide alternative routes of administration for currently injectable medicines, leading to greater convenience and adherence as they minimize or avoid the logistical challenges, patient adherence and dependence challenges, pain, and discomfort associated with traditional administration routes.

[0125] Furthermore, by providing high concentrations of therapeutic agents in GI tissues, the devices and methods described herein are particularly well-suited for treating diseases and conditions of the endoderm (including the liver).

[0126] DEVICES

[0127] overall

[0128] Generally, ingestible devices are designed to be swallowed by a patient and to pass safely and effectively through the patient's gastric tract. Typically, the device may be in the form of a capsule, pill, or any other swallowable form that can be orally consumed by the subject. In some embodiments, the ingestible device may be swallowed voluntarily under medical supervision or in a home use setting, with guidance provided prior to subsequent ingestion. Typically, ingestible devices are intended for single-use by a single subject. The ingestible device may have a sufficiently high density to sink into the gastric juices; for example, an unfilled ingestible device may have a density greater than 1.01 g / cm³. 3The ingestible device can have a maximum size that allows the ingestible device to pass through the GI tract of an average human. In some embodiments, the ingestible device is configured to prevent tumbling in the small intestine of a human. For example, the ingestible device has sufficient length such that it does not tumble in the small intestine of a human before, during, or after release of the dispensable substance. Generally, the ingestible device is configured to deliver a sufficient amount of a therapeutic agent contained in the dispensable substance to be effective for its intended purpose. In general, the patient-contacting portions (e.g., outer surfaces) and the dispensable substance-contacting portions of the ingestible device are biocompatible. Preferably, the device can withstand indirect biting forces without damage to the housing or causing a leak. As one example, the ingestible device can withstand a biting force of at least about 60 Newtons (N) when containing the dispensable substance. Generally, unless otherwise intended (see discussion below), the components of the ingestible device can withstand exposure to the pH range expected in the GI tract of a human without significant loss of function, significant structural damage, or significant leakage. As one example, in some embodiments, the ingestible device can withstand immersion in a fluid environment at pH 1.5 ± 0.5 for at least about 24 hours without significant loss of function, significant structural damage, or significant leakage. In general, the ingestible device can maintain an external fluid barrier between the interior of the ingestible device and the GI tract of a subject during transit therethrough. Generally, the ingestible device can withstand external fluid pressures to which it is exposed during use without significant loss of function, significant structural damage, or significant leakage. As one 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.

[0129] In general, the ingestible devices disclosed herein include the following features.

[0130] Housing

[0131] In some embodiments, the ingestible device includes a housing configured to maintain its mechanical integrity during use of the ingestible device. In some embodiments, the housing has a first portion and a second portion. In some further embodiments, the housing has a first actuation component on the housing and a second actuation component within the housing. In some embodiments, a storage reservoir is located within the housing, wherein the storage reservoir is configured to store a dispensable substance. In some embodiments, the housing has an opening in fluid communication with the storage reservoir. In some embodiments, the ingestible device employs an electrolytic mechanism to create one or more openings in the ingestible device through which a substance can be dispensed, as described in PCT Application No. PCT / US2019 / 021814, published as WO2019178071 and incorporated by reference herein. For example, the housing can include an external electrolytic circuit (electrolytically erodible surfaces on the exterior of the device), whereby the surrounding gastric fluid is the electrolyte completing the electrolytic circuit between the anode and the cathode. With a sufficient bias voltage (e.g., 1.5-15 volts, e.g., 3-5 volts), the anode will erode or dissolve electrolytically, thus creating an opening in the housing over a desired time interval. In some embodiments, the one or more openings created by the electrolytic mechanism are coupled to one or more nozzles, allowing trans-epithelial, epithelial, or local delivery as described herein. In some embodiments, the ingestible device includes an enteric coating on the housing. In certain embodiments, the enteric coating covers only certain regions of the housing. The housing can be designed to withstand the chemical and mechanical environment of the GI tract (e.g., the effects of muscle contraction forces and concentrated hydrochloric acid in the stomach). A wide range of materials can be used for the housing. Examples of these materials include, but are not limited to: thermoplastics, fluoropolymers, 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 can further include: liquid silicone rubber materials having a hardness level of 10 to 90 as determined using a durometer (e.g., NuSil MED-4942, manufactured by NuSil Technology LLC, Carpinteria, CA), soft biocompatible polymeric materials such as, but not limited to, polyvinyl chloride (PVC), polyether sulfone (PE), polyethylene (PE), polyurethane (PU), or polytetrafluoroethylene (PTFE), and rigid polymeric materials coated with a soft or pliable biocompatible material (e.g., poly(methyl methacrylate) (PMMA) material coated with a silicone polymer). The use of different materials for different components can enable functionalization of certain surfaces to interact with proteins, antibodies, and other biomarkers. For example, the ingestible device can use TM Manufacture of MED-4942 TM ), soft biocompatible polymeric materials such as, but not limited to, polyvinyl chloride (PVC), polyether sulfone (PE), polyethylene (PE), polyurethane (PU), or polytetrafluoroethylene (PTFE), and rigid polymeric materials coated with a soft or pliable biocompatible material (e.g., poly(methyl methacrylate) (PMMA) material coated with a silicone polymer). The use of different materials for different components can enable functionalization of certain surfaces to interact with proteins, antibodies, and other biomarkers. For example, the ingestible device can use As a material for movable components to reduce friction between these components. Other example materials can include other materials commonly used in microfabrication, such as polydimethylsiloxane (PDMS), borosilicate glass, and / or silicon. Although specific materials can be referred to herein for purposes of illustration for constructing the device, the materials listed are not intended to be limiting, and one of skill in the art can readily adapt the device to use any number of different materials without affecting the overall operation or function of the device. In some embodiments, the housing of the ingestible device can be fabricated from one type of plastic, such as a light-sensitive acrylic polymer material or an inert polycarbonate material. The housing can also be formed using a material that can be sterilized by chemicals. In some embodiments, the walls of the housing can have a thickness of, for example, about 0.5 millimeters to about 1 millimeter. In some embodiments, the material from which the housing is fabricated is non-ferrous and non-magnetic, in addition to being biocompatible. Such materials include various plastics, such as PVC or polycarbonate. Optionally, the housing can include a metal-based material, such as an alloy, stainless steel, or a substantially pure metal. Such materials can be sterilized without affecting the mechanical workings of the ingestible device or the exterior surface of the ingestible device. In some embodiments, the metal-based material is compatible with the dispensable substance for long-term storage durations. Various stainless steel alloys meet these criteria, including SAE grades 303, 304, 304L, 316, 316L, 440. In some embodiments, stainless steel grades are approved for use as surgical implant materials, such as ASTM grades F138, F1314, F1586, F2229, or F2581, taking into account nickel content, purity, and / or traceability. The walls of the housing of the ingestible device are typically thick enough to withstand the internal and external pressures to which they are exposed without significant loss of function, significant structural damage, or significant leakage. In general, the walls of the housing are ideally as thin as possible to enhance the volume available for containing the dispensable substance. As one example, in some embodiments, the walls are about 0.05 mm to about 0.5 mm thick (e.g., if made from a metal-based material such as stainless steel) or about 0.1 to about 1 mm thick (e.g., if made from a plastic such as polycarbonate). In general, the housing is made from a material having a coefficient of thermal expansion that is low enough so that the device does not significantly deform at temperatures encountered during shipping and storage or within the GI tract. In some embodiments, the walls of the housing are made from an electrolytically erodible surface as described in PCT / US2019 / 021814 (published as WO2019178071). For example, in some embodiments, the housing includes an electrolytically erodible valve coupled to a nozzle for exposing a volume of liquid to its surroundings. The exposed metal anode material of the valve can include a metal alloy or a substantially pure metal that is acceptable for human ingestion in terms of biocompatibility, in terms of the amount that is electrolyzed during opening of the valve.It can be desirable to have a small thickness of metal in the valve region (e.g., to reduce the time and amount of current used to open the valve). For example, the metal portion of the drug container can be 0.025 mm thick at a diameter that matches or slightly exceeds the diameter of the coupled nozzle (e.g., 0.60 mm). Generally, the thickness of the metal in the valve region can range from 0.002 mm to 0.200 mm.

[0132] In some embodiments, the housing of the ingestible device is assembled from multiple modules. For example, in some embodiments, the housing is assembled from two modules. In such embodiments, one of the modules can house the dispensable substance ("drug module") and the other module can house the drive force generator and drive coupling ("drive module"). Typically, the drug module includes a housing portion having appropriate dimensions, shape, and material as discussed herein. Generally, the housing portion is sterilized and the dispensable substance is subsequently disposed within the housing under aseptic conditions. Optionally, aseptic seals (e.g., aseptic foil seals) are incorporated into the drug module. The components of the drug module (e.g., the housing portion, the drive force generator, the drive coupling) are assembled in a clean environment. The drug module and the drive module are then combined to form the ingestible device. Representative examples of the modules, their individual components, and their combinations for forming the ingestible device are provided elsewhere herein.

[0133] Generally, the ingestible device is sized and shaped for relatively safe and effective 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.

[0134] 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).

[0135] 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).

[0136] 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).

[0137] 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, a region of the housing of the ingestible device can have a different wall thickness than a different region of the housing of the ingestible device.

[0138] In some embodiments, the housing of the ingestible device has a spline-shaped or spherical end round. In certain embodiments, the ingestible device has an end round of about 1 mm to about 2 mm (e.g., about 1.5 mm). In some embodiments, the ingestible device has an end round of about 4 mm to about 4.5 mm (e.g., about 4.25 mm). In certain embodiments, the ingestible device has an end round of about 4.9 to about 5 mm (e.g., about 4.95 mm). In some embodiments, the ingestible device has an end round of about 5.4 mm to about 5.6 mm (e.g., about 5.5 mm).

[0139] 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).

[0140] 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 round of about 1.5 mm, and an internal volume of about 1685 μL.

[0141] 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 round (spherical) of about 5.5 mm, and an internal volume of about 1475 μί.

[0142] 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 round of about 1.5 mm, and an internal volume of about 1315 μί.

[0143] 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 round (spherical) of about 4.95 mm, and an internal volume of about 1177 μί.

[0144] 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 round of about 1.5 mm, and an internal volume of about 861 μί.

[0145] 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 round (spherical) of about 4.25 mm, and an internal volume of about 773 μί.

[0146] 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, a spline-shaped end round, and an internal volume of about 820 μί.

[0147] Fluid volume

[0148] The ingestible device includes a fluid volume containing a dispensable substance (e.g., a liquid, a suspension). In some embodiments, the fluid volume is disposed entirely within the housing. Optionally, the fluid volume can be defined by a storage reservoir. Such a storage reservoir can be a component that can be fabricated separately from the housing. In such a storage reservoir, the dispensable substance can be disposed in the storage reservoir prior to associating the storage reservoir with the ingestible device.

[0149] Dispensable substance

[0150] The device can include one or more dispensable substances, each dispensable substance including one or more therapeutic agents and / or one or more drug formulations including one or more therapeutic agents.

[0151] Nozzle

[0152] In some embodiments, the ingestible device includes one or more nozzles in fluid communication with one or more openings in the ingestible device. The nozzles are configured such that the dispensable substance passes through the nozzles when the dispensable substance is delivered from the ingestible device. Generally, the nozzles can have any desired size and shape suitable for the desired type of delivery of the dispensable substance from the ingestible device. In certain embodiments, the nozzles have a shape and / or size suitable for trans-epithelial delivery, epithelial delivery, or topical delivery. In some embodiments, the ingestible device includes more than one nozzle. For example, the ingestible device can include, e.g., up to 50 nozzles (e.g., up to 40 nozzles, up to 35 nozzles, up to 30 nozzles, up to 25 nozzles, up to 20 nozzles, up to 15 nozzles, 10 nozzles). In some embodiments, the ingestible device includes from 2 nozzles to 50 nozzles. In certain embodiments, the ingestible device includes 2 nozzles, three nozzles, four nozzles, five nozzles, six nozzles, seven nozzles, eight nozzles, 10 nozzles, 20 nozzles, 30 nozzles, 36 nozzles, 40 nozzles, 50 nozzles). In some embodiments, the nozzles are arranged at uniform intervals (optionally in pairs if an even number of nozzles are used) around the circumference of the device.

[0153] Restraint mechanism

[0154] In some embodiments, the ingestible device includes a restraining mechanism. Generally, the restraining mechanism has a first state in which it is configured to prevent dispensable substance from exiting the ingestible device through the opening, and a second state in which it is configured to allow dispensable substance to exit the ingestible device through the opening. The restraining mechanism can be configured to transition 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 elements can have a first state in which they are configured to prevent dispensable substance from exiting the ingestible device through the opening, and a second state in which they are configured to allow dispensable substance to exit the ingestible device through the opening. The restraining elements can be configured to transition from the first state to the second state when the restraining elements are exposed to a triggering condition. In some embodiments, the restraining elements include a first type of restraining element and a second type of restraining element that is different from the first type of restraining element. The first type of restraining element can be configured to transition to its second state before the second type of restraining element transitions to its second state. In some embodiments, the restraining elements include a cap, a pin, a band, a plug, a peg, a clasp, 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 tori). Optionally, the restraining elements can have a filled interior (e.g., no holes). Optionally, the restraining elements can have a varying thickness (e.g., a center region that is thinner than the edges). In some embodiments, the restraining elements include a plasticizer such as triethyl citrate (TEC). In some embodiments, the restraining elements include 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 dispensable substance from being delivered from the ingestible device even when the internal force is applied by the driving force generator (or, optionally, the driving coupler). 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 dispensable substance can be delivered from the ingestible device. Such a restraining element can be formed of, for example, a degradable and / or erodible material as described above.

[0155] Generally, the restraining mechanism includes a material that will lose a sufficient degree of its mechanical strength at a desired location to cause the ingestible device to deliver dispensable substance. The material can undergo a loss of mechanical strength for any appropriate mechanism or combination of mechanisms, including, for example, moisture ingress, solubility, swelling, leaching, erosion, and / or the like.

[0156] In some embodiments, the constraining mechanism comprises a degradable and / or erodible material, such as a water-soluble material, optionally with one or more coatings of an enteric material. The degradable and / or erodible material is designed to lose its mechanical strength in the presence of moisture (e.g., liquid present in the GI tract).

[0157] Generally, the enteric material erodes after being ingested, 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 for at least two hours at a pH of 1.1. In certain embodiments, the enteric material disintegrates 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.

[0158] 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) on the degradable and / or erodible material (e.g., water-soluble material) in varying coating weights. For example, in some embodiments, the coating weight can be 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or greater, compared to the weight of the degradable and / or erodible material. Generally, 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 location and / or time at which it is desirable for the degradable and / or erodible material to degrade and / or erode to a sufficient degree to trigger dispensing of the dispensable substance from the ingestible device.

[0159] Desirably, the degradable and / or erodible material is strong enough to resist the trigger load when dry, but is also able to weaken sufficiently to release the trigger load when the degradable and / or erodible material is exposed to a water-containing environment for a desired period of time (e.g., at least two minutes, such as at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, or at least 160 minutes).

[0160] In some embodiments, the trigger mechanism has a density of about 1 g / cm 3 to about 3 grams / cm 3 (e.g., about 1.3 g / cm 3 to about 2 g / cm 3 ).

[0161] In certain embodiments, the trigger mechanism is about 1 mm to about 5 mm thick (e.g., about 1 mm to about 2 mm thick).

[0162] In some embodiments, the coating of enteric material has a density of about 0.5 mg / cm 2 to 20 mg / cm 2 (e.g., about 2 mg / cm 2 to about 6 mg / cm 2 ).

[0163] Examples of degradable and / or erodible materials include polyethylene glycol (PEG) and Isolmalt. In some embodiments, the degradable and / or erodible material includes one or more diluents / fillers, one or more binders, and / or one or more disintegrants. Examples of diluents / fillers include lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and dicalcium phosphate. Examples of binders include povidone, hypromellose, hydroxypropyl cellulose, copovidone, and microcrystalline cellulose. Examples of disintegrants include crospovidone, croscarmellose sodium (Ac-Di-Sol® SD-711), sodium starch glycolate, and low-substituted hydroxypropyl cellulose. Optionally, the degradable and / or erodible material can include a lubricant such as magnesium stearate.

[0164] 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 pm grade from Acros), enteric methacrylate polymer (e.g., Eudragit® 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 can include Starch 1500 (e.g., 49.6% w / w), microcrystalline cellulose 102 starch (e.g., 49.6% w / w); and croscarmellose sodium 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 can include Startab (e.g., 49.6% w / w), microcrystalline cellulose 102 starch (e.g., 49.6% w / w); and croscarmellose sodium 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 can include Starch 1500 (e.g., 48.9% w / w), microcrystalline cellulose 102 starch (e.g., 48.9% w / w); croscarmellose sodium 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 can include Startab (e.g., 49.6% w / w), microcrystalline cellulose 102 starch (e.g., 49.6% w / w); croscarmellose sodium 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 can include dicalcium phosphate (e.g., 48.9% w / w), microcrystalline cellulose 102 starch (e.g., 48.9% w / w); croscarmellose sodium 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 can 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).

[0165] Examples of enteric materials coated on degradable and / or erodible materials include: spray coated Eudragit FL 30D-55 (e.g., 12 mg / cm 2 of Eudragit FL 30D-55 directly sprayed on water-soluble material); dip coated Eudragit L 100D-55 (e.g., 4 mg / cm 2 of Eudragit L 100D-55 dip coated onto HPMC capsule cap); and spray coated Eudragit FL 30D-55 (e.g., 9 mg / cm 2 of Eudragit FL 30D-55 directly sprayed on water-soluble material); 6 mg / cm 2 of Eudragit FL 30D-55 directly sprayed on water-soluble material).

[0166] Trigger mechanism

[0167] In some embodiments, the ingestible device includes a trigger mechanism. In some embodiments, the trigger mechanism is configured to cause the dispensable substance within the fluid volume to be released under one or more trigger conditions. In some embodiments, the trigger mechanism initiates the drive force generator. In some embodiments, the trigger mechanism incorporates a mechanical feature such as a restraining mechanism. As one example, one or more restraining elements degrade and / or erode in the presence of certain GI tract conditions (e.g., pH greater than 5), thereby triggering the drive force generator, e.g., a compressed spring. As another example, the spring can have a piercing element that pierces a cylinder having compressed gas, whereby the released gas acts as the force applied to the dispensable substance. In certain embodiments, the trigger mechanism incorporates an electrical feature. For example, an enteric coating degrades and / or erodes in the presence of certain GI tract conditions (e.g., pH greater than 5), thereby exposing a conductor to the intestinal fluid, which acts as a liquid conductor to trigger the drive force generator. In some embodiments, the trigger condition relates to a condition of the GI tract. In some embodiments, the condition of the GI tract includes at least one condition selected from the group consisting of temperature, pH, presence of one or more enzymes, and time. In some more particular 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 autonomously triggered (e.g., due to degradation, dissolution, and / or erosion of the restraining mechanism by conditions in the GI tract).

[0168] In some embodiments, the constraining element can include one or more small molecule therapeutic agents, e.g., one or more small molecule therapeutic agents as disclosed herein. In certain embodiments, the small molecule therapeutic agent contained in the constraining mechanism can be the same as the therapeutic agent contained in the dispensable substance. In some embodiments, the small molecule therapeutic agent contained in the constraining mechanism can be different than the therapeutic agent contained in the dispensable substance. In certain embodiments, the constraining mechanism includes multiple small molecule therapeutic agents, and the dispensable substance contains the same therapeutic agent. In some embodiments, the constraining mechanism includes multiple small molecule therapeutic agents, and the dispensable substance contains one or more different therapeutic agents. 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 a different condition. 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.

[0169] Generally, the initial gas pressure within the gas cylinder (the gas pressure prior to implementation of the gas cylinder as a force generator) is adapted to provide the desired internal pressure. Typically, the initial gas pressure in the gas 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 gas cylinder is from about 500 psig to about 1,200 psig (e.g., from about 600 psig to about 1,100 psig, from about 700 psig to about 1,000 psig, from about 750 psig to about 950 psig, from about 800 psig to about 950 psig, from about 850 psig to about 950 psig).

[0170] The burst pressure of a cylinder (the minimum pressure at which a cylinder will burst) is generally based on the desired initial gas pressure within the cylinder. For the initial gas pressures mentioned in the preceding paragraph, the burst pressure of a cylinder can be at least about 2,800 psig (e.g., at least about 2,900 psig, at least about 3,000 psig, at least about 3,100 psig, at least about 3,200 psig, at least about 3,300 psig, at least about 3,400 psig, at least about 3,500 psig, at least about 3,600 psig) and / or at most about 4,500 psig (e.g., at most about 4,400 psig, at most about 4,300 psig, at most about 4,200 psig, at most about 4,100 psig, at most about 4,000 psig, at most about 3,900 psig, at most about 3,800 psig). In some embodiments, the burst pressure of a cylinder is about 2,800 psig to about 4,500 psig (e.g., about 2,900 psig to about 4,400 psig, about 3,000 psig to about 4,300 psig, about 3,100 psig to about 4,200 psig, about 3,200 psig to about 4,100 psig, about 3,100 psig to about 4,000 psig, about 3,200 psig to about 3,900 psig, about 3,300 psig to about 3,800 psig, about 3,400 psig to about 3,800 psig, about 3,500 psig to about 3,800 psig, about 3,600 psig to about 3,800 psig, about 3,700 psig to about 3,800 psig).

[0171] Generally, the gas within a 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 noble gases (e.g., helium, neon, argon, krypton, xenon). In some embodiments, the gas within a 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 a gas mixture can allow for the inspection of a cylinder for leaks based on the presence of helium adjacent to the exterior of the cylinder.

[0172] Generally, a cylinder can be made of any appropriate and / or desired material. Examples include metals, plastics, and / or composites. In some embodiments, a cylinder is made of stainless steel or galvanized steel. In certain embodiments, a cylinder can be made of a material that is itself produced by a process including drawing, stamping, machining, casting, molding, and / or the like (e.g., deep drawing from a sheet of metal). In some embodiments, a cylinder can be made of ceramic, alloys, aluminum, and / or titanium.

[0173] In some embodiments, the gas cylinder includes a frangible seal (e.g., a membrane) that is fractured via an element (e.g., a perforator) when the gas cylinder is used as a force generator, as described in greater detail below. Typically, the frangible seal is part of an end cap of the gas cylinder. The end cap and / or the frangible seal can be formed of one or more of the materials mentioned in the preceding paragraph. Fracturing the frangible seal can involve, for example, tearing a portion of the frangible seal and / or puncturing a portion of the frangible seal. More generally, fracturing the frangible seal is intended to change the seal in a manner such that the seal can no longer restrict the gas within the gas cylinder. In general, the frangible seal is made of a material that has at least a region that is relatively thin and / or configured (e.g., scored) to fracture. Optionally, the entire barrier is relatively thin. As one example, the barrier can have a relatively thin outer perimeter with a relatively thick portion within the outer perimeter (e.g., a central portion) such that the relatively thin portion of the frangible seal fractures when an element (e.g., a perforator) applies an appropriate force. As another example, the barrier can have an inner (e.g., central) portion that is surrounded by a scored portion such that the scored portion of the frangible seal fractures when an element (e.g., a perforator) applies an appropriate force. In some embodiments, the frangible seal has a substantially constant thickness and has a portion configured (e.g., scored) to fracture when an element (e.g., a perforator) applies an appropriate force. In general, such scoring can be configured as desired. As one example, the scoring can be configured as a series of parallel lines. As another example, the scoring can be configured as a grid (ruling). As a further example, the scoring can be configured as a plurality of dots (e.g., equidistant dots).

[0174] In some embodiments, the element (e.g., a puncturer) has a point of contact on the frangible seal. Optionally, the point of contact is concentrated in a relatively small local area. For example, the puncturer can be a needle or a thin rod element that is cut at an angle to initially create a single point of contact. The point of initial contact can be on center or off center with respect to the frangible seal. Having the point of initial contact off center with respect to the frangible seal can result in a reduction in the force exerted by the element (e.g., puncturer). In embodiments where the modified (e.g., scored) region of the frangible seal is off center, placing the element (e.g., puncturer) off center means that, at the point of contact of the element (e.g., puncturer) with the frangible seal, the point of contact is closer to the modified (e.g., thinner scored) region of the frangible seal. In certain embodiments where the modified (e.g., scored) region of the frangible seal is circular, the element (e.g., puncturer) can be configured such that its point of contact with the frangible seal is near a point on the circle. In general, the closer the point of contact is to the modified region of the frangible seal, the lower the force of the element (e.g., puncturer) to break the frangible seal. To produce a relatively fast release, the modified (e.g., scored) portion of the frangible seal desirably breaks over substantially the entire modified region (e.g., the diameter of the circle when the modified region is a scored region shaped as a circle). In some embodiments, the closer the point of contact 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 point of contact of the element (e.g., puncturer) near the circle, but not on it. Optionally, the point of contact can be moved inward to obtain fast release properties. Optionally, a wider footprint for the initial contact of the element (e.g., puncturer) can be implemented in some embodiments. For example, the point of contact can be an arc-shaped sector positioned 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 result in faster gas escape.

[0175] In some embodiments, the element (e.g., puncturer) does not contact the frangible seal until the cylinder is used as a force generator. In certain embodiments, the element (e.g., puncturer) can contact the frangible seal before the cylinder is used as a force generator such that the element (e.g., puncturer) exerts a relatively low pressure on the frangible seal. The pressure can 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 (e.g., at most about 14 Newtons, at most about 13 Newtons, at most about 12 Newtons, at most about 11 Newtons, at most about 10 Newtons). In some embodiments, the pressure is about 1 Newton to about 15 Newtons.

[0176] Typically, to cause gas in a gas cylinder to be released from the gas cylinder, an element (e.g., a piercer) applies a relatively high pressure to the frangible seal. The relatively high pressure can be, for example, at least about 5 Newtons (e.g., at least 8 Newtons, at least about 10 Newtons, at least about 15 Newtons) and / or at most about 40 Newtons (e.g., 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.

[0177] Examples of gas cylinders (including those having end caps and / or frangible seals) are disclosed, for example, in US 2017 / 0258583, the entire disclosure of which is incorporated herein by reference.

[0178] In some embodiments, the element (e.g., a piercer) is coupled to an actuator in an actuator assembly. In some embodiments, the actuator assembly has a total length that is less than about 10 mm (e.g., less than about 9 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, less than about 5 mm, less than about 4 mm, less than about 3 mm, less than about 2 mm). In some embodiments, the actuator is a spring (e.g., a wave spring). In some embodiments, the spring has a compression length that is less than about 5 mm, less than about 4 mm, less than about 3.5 mm, less than about 3 mm, less than about 2.5 mm). In some embodiments, the spring has a travel length that is less than about 0.8 mm (e.g., less than about 0.7 mm, less than about 0.6 mm, less than about 0.5 mm, less than about 0.4 mm, less than about 0.3 mm).

[0179] In some embodiments, the element (e.g., a piercer) is moved relatively quickly when a relatively high force is applied to the frangible seal. In certain embodiments, the element (e.g., a piercer) is moved relatively slowly when a relatively high force is applied to the frangible seal. In some embodiments, to break the frangible seal, using a lower element (e.g., piercer) movement speed allows a lower force to be used compared to a force used to break the frangible seal when the element (e.g., piercer) is moved at a higher speed.

[0180] In some embodiments, the element (e.g., a piercer) is moved relative to the gas cylinder. In certain embodiments, the gas cylinder is moved relative to the element (e.g., a piercer). For example, the gas cylinder can be coupled to an actuator that causes the gas cylinder to move.

[0181] 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 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, e.g., about 7.0.

[0182] Drive force generator

[0183] The drive force generator is configured to provide the necessary force to the dispensable substance so that the dispensable substance is delivered from the ingestible device as needed when the restraining mechanism is removed. The drive force generator can exert the force using different mechanisms including, for example, compressed gas, gas generated by a chemical reaction, a spring, a liquid-gas mixture, an impact plunger, sudden expansion caused by a controlled exothermic reaction, and the like. When the drive force generator is a spring, the spring can 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 substance; the spring is conical in shape, potentially reducing the physical length of the spring; the free length of the spring is maximized and larger than the free length of the inner lumen 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 for the dispensable substance from the beginning until the end of the delivery. Examples of springs include parallel springs, wave springs, and conical springs. Examples of chemical reactants include airbag inflators, hydrogen cells (e.g., Varta hydrogen cells), sodium bicarbonate, and acid (e.g., seltzer and water on the ingestible device, seltzer and GI tract fluid). Examples of compressed gas include gas loaded within the ingestible device, and a container of compressed gas (e.g., a gas cylinder). In some embodiments, the compressed gas is a gas cylinder from Picocyl. Exemplary gas cylinders are disclosed, for example, in US 2017-0258583, which is incorporated herein by reference. One example of a liquid-gas mixture is liquid nitrogen / HFA (hexafluoroacetone) / propane. One example of an impact plunger is a two-phase spring / plunger. Other examples of drive force generators include a wax actuator, heat generated from electricity (a mechanism based on the Peltier effect), and mechanical puncturing of tissue followed by delivery.

[0184] Drive coupling

[0185] Generally, the driving force coupler transmits force from the driving force generator to the dispensable substance. Examples of driving couplers include pistons and membranes. Examples of membranes include balloons and elastomeric materials. One example of a piston is an O-ring sealed piston. In some embodiments, the piston is provided by a gas cylinder (e.g., with an additional O-ring or custom housing). In some embodiments, the driving coupler is a vein, e.g., a rotating vein. In certain embodiments, the driving coupler is a dual piston configured to counteract cap impact. In certain embodiments, the driving coupler is a folded pouch, e.g., a folded foil pouch. In some embodiments, the driving coupler is a folded bellows.

[0186] storage reservoir

[0187] In some embodiments, the ingestible device includes a storage reservoir configured to store the dispensable substance. In some embodiments, the storage reservoir stores the dispensable substance. In some embodiments, the storage reservoir is disposed entirely within the housing.

[0188] Figure 2 is a schematic view of an ingestible device 200, including a housing 202, a fluid volume 204 containing a dispensable substance, a nozzle 206 having a nozzle opening 208, a restraining mechanism 210, a triggering mechanism 212, a driving force generator 214, and a driving coupler 216. During use, the ingestible device 200 is swallowed by a subject and passes through the Gl tract. At an appropriate location, the triggering mechanism 212 is triggered, allowing the driving force generator to apply pressure to the driving coupler 216, which then applies pressure to the fluid volume, such that at least some of the dispensable substance is delivered out of the fluid volume 204, through the nozzle 206, and out of the device 200 via the nozzle opening 208. In some embodiments, internal pressure is applied even before the triggering mechanism 212 is triggered. As an example, at an appropriate location, the triggering mechanism 212 is triggered, allowing the driving coupler 216 to apply pressure to the fluid volume 204. In certain embodiments, internal pressure is not applied until the triggering mechanism 212 is triggered.

[0189] Devices for trans-epithelial delivery

[0190] Generally, trans-epithelial delivery can be achieved at any desired location within the Gl tract of a subject. In some embodiments, trans-epithelial delivery is achieved in the small intestine of a subject, e.g., in the duodenum, jejunum, and / or ileum. In certain embodiments, trans-epithelial delivery is achieved in the large intestine of a subject, e.g., the cecum or colon.

[0191] Generally, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having a peak jet power of at least about 1 Watt (e.g., at least about 1.1 Watt, at least about 1.2 Watt, at least about 1.3 Watt, at least about 1.4 Watt, at least about 1.5 Watt, at least about 1.6 Watt, at least about 1.7 Watt, at least about 1.8 Watt) and / or at most about 3 Watt (e.g., at most about 2.9 Watt, at most about 2.8 Watt, at most about 2.7 Watt, at most about 2.6 Watt, at most about 2.5 Watt, at most about 2.4 Watt, at most about 2.3 Watt, at most about 2.2 Watt, at most about 2.1 Watt). In some embodiments, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having a peak jet power of about 1 Watt to about 3 Watt (e.g., about 1.3 Watt to about 2.8 Watt, about 1.5 Watt to about 2.5 Watt).

[0192] Generally, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having a minimum jet power of at least about 0.1 W (e.g., at least about 0.2 W, at least about 0.3 W) and / or at most about 0.6 W (e.g., at most about 0.5 W, at most about 0.4 W). In some embodiments, the device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having a minimum jet power of about 0.1 W to about 0.6 W (e.g., about 0.2 W to about 0.5 W, about 0.3 W to about 0.4 W).

[0193] Generally, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having an average jet power of at least about 0.5 W (e.g., about 0.8 W, about 1 W) and / or at most about 2 W (e.g., at most about 1.7 W, at most about 1.5 W). In some embodiments, devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having an average jet power of about 0.5 W to about 2 W (e.g., about 0.8 W to about 1.7 W, about 1 W to about 1.5 W). Generally, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having a peak jet pressure of at least about 100 psig (e.g., at least about 110 psig, at least about 120 psig, at least about 130 psig, at least about 140 psig, at least about 150 psig, at least about 160 psig, at least about 170 psig, at least about 180 psig, at least about 190 psig) and / or at most about 250 psig (e.g., at most about 240 psig, at most about 230 psig, at most about 220 psig, at most about 210 psig). In certain embodiments, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having a peak jet pressure of about 100 psig to about 250 psig (e.g., about 140 psig to about 225 psig, about 180 psig to about 205 psig).

[0194] Generally, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having a minimum jet pressure of at least about 30 psig (e.g., at least about 40 psig, at least about 50 psig) and / or at most about 80 psig (e.g., at most about 70 psig, at most about 60 psig). In some embodiments, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having a minimum jet pressure of about 30 psig to about 80 psig (e.g., about 40 psig to about 70 psig, about 50 psig to about 60 psig).

[0195] Generally, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having an average jet pressure of 60 psig (e.g., at least about 80 psig, at least about 100 psig) and / or at most about 160 psig (e.g., at most about 140 psig, at most about 120 psig). In some embodiments, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having an average jet pressure of about 60 psig to about 160 psig (e.g., about 80 psig to about 140 psig, about 100 psig to about 120 psig).

[0196] Generally, the ingestible device for trans-epithelial delivery is configured to deliver a jet stream of dispensable substance having a peak jet force of at least about 0.09 Newtons (N) (e.g., at least about 0.1 N, at least about 0.11 N, at least about 0.12 N, at least about 0.13 N) and / or at most about 0.15 N (e.g., at most about 0.14 N). In some embodiments, the ingestible device for trans-epithelial delivery is configured to deliver a jet stream of dispensable substance having a peak jet force of about 0.09 N to about 0.15 N (e.g., about 0.1 N to about 0.14 N, about 0.11 N to about 0.14 N).

[0197] Generally, the ingestible device for trans-epithelial delivery is configured to deliver a jet stream of dispensable substance having a minimum jet force of at least about 0.01 N (e.g., at least about 0.02 N, at least about 0.03 N) and / or at most about 0.06 N (e.g., at most about 0.05 N, at most about 0.04 N). In some embodiments, the ingestible device for trans-epithelial delivery is configured to deliver a jet stream of dispensable substance having a minimum jet force of about 0.01 N to about 0.06 N (e.g., about 0.02 N to about 0.05 N, about 0.03 N to about 0.04 N).

[0198] Generally, the ingestible device for trans-epithelial delivery is configured to deliver a jet stream of dispensable substance having an average jet force of at least about 0.05 N (e.g., at least about 0.06 N, at least about 0.07 N) and / or at most about 0.1 N (e.g., at most about 0.09 N, at most about 0.08 N). In some embodiments, the ingestible device for trans-epithelial delivery is configured to deliver a jet stream of dispensable substance having an average jet force of about 0.05 N to about 0.1 N (e.g., about 0.06 N to about 0.09 N, about 0.07 N to about 0.08 N).

[0199] Generally, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having a peak jet velocity of at least about 25 meters / second (m / s) (e.g., at least about 26 m / s, at least about 27 m / s, at least about 28 m / s, at least about 29 m / s, at least about 30 m / s, at least about 31 m / s, at least about 32 m / s, at least about 34 m / s, at least about 35 m / s, at least about 36 m / s) and / or at most about 45 m / s (e.g., at most about 44 m / s, at most about 43 m / s, at most about 42 m / s, at most about 41 m / s, at most about 40 m / s, at most about 39 m / s, at most about 38 m / s, at most about 37 m / s). In some embodiments, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having a peak jet velocity of about 25 m / s to about 45 m / s (e.g., about 30 m / s to about 42 m / s, about 34 m / s to about 39 m / s, about 36.5 m / s).

[0200] Generally, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having a minimum jet velocity of at least about 15 m / s (e.g., at least about 16 m / s, at least about 17 m / s) and / or at most about 22 m / s (e.g., at most about 21 m / s, at most about 20 m / s). In some embodiments, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having a minimum jet velocity of about 15 m / s to about 22 m / s (e.g., about 16 m / s to about 21 m / s, about 17 m / s to about 20 m / s).

[0201] Generally, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having an average jet velocity of at least about 20 m / s (e.g., at least about 25 m / s) and / or at most about 35 m / s (e.g., at most about 30 m / s). In some embodiments, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having an average jet velocity of about 20 m / s to about 30 m / s (e.g., about 20 m / s, about 21 m / s, about 22 m / s, about 23 m / s, about 24 m / s, about 25 m / s, about 26 m / s, about 27 m / s, about 28 m / s about 29 m / s, about 30 m / s). In certain embodiments, the ingestible device for trans-epithelial delivery is configured to deliver a jet of dispensable substance having an average jet velocity of about 25 m / s to about 35 m / s (e.g., about 25 m / s, about 26 m / s, about 27 m / s, about 28 m / s, about 29 m / s, about 30 m / s, about 31 m / s, about 32 m / s, about 33 m / s about 34 m / s, about 35 m / s).

[0202] Generally, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having a jet stable length of at least about 0.5 millimeters (mm) (e.g., at least about 1 mm, at least about 1.5 mm, at least about 2 mm, at least about 2.5 mm, at least about 3 mm, at least about 3.5 mm, at least about 4 mm, at least about 4.5 mm, at least about 5 mm) and / or at most about 20 mm (e.g., at most about 15 mm, at most about 10 mm). In certain embodiments, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having a jet stable length of about 0.5 mm to about 20 mm (e.g., about 2 mm to about 20 mm, about 5 mm to about 20 mm).

[0203] In some embodiments, ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having a jet diameter of at least about 0.1 mm (e.g., at least about 0.2 mm, at least about 0.3 mm, at least about 0.4 mm) and / or at most about 2 mm (e.g., at most about 1.5 mm, at most about 1 mm, at most about 0.9 mm, at most about 0.8 mm, at most 0.7 mm, at most about 0.6 mm, at most about 0.5 mm). For example, such ingestible devices for trans-epithelial delivery are configured to deliver a jet stream of dispensable substance having a jet diameter of about 0.1 mm to about 2 mm (e.g., about 0.2 mm to about 0.5 mm, about 0.3 mm to about 0.4 mm, about 0.3 mm to about 0.5 mm, about 0.35 mm).

[0204] Generally, ingestible devices for trans-epithelial delivery are configured to provide an internal pressure of at least about 225 psig (e.g., at least about 235 psig, at least about 245 psig, at least about 255 psig, at least about 265 psig, at least about 275 psig, at least about 285 psig, at least about 295 psig, at least about 305 psig, at least about 315 psig) and / or at most about 425 psig (e.g., at most about 400 psig, at most about 390 psig, at most about 380 psig, at most about 375 psig, at most about 370 psig, at most about 360 psig, at most about 350 psig, at most about 340 psig, at most about 330 psig). In certain embodiments, ingestible devices for trans-epithelial delivery are configured to provide an internal pressure of about 225 psig to about 400 psig (e.g., about 250 psig to about 375 psig, about 300 psig to about 340 psig).

[0205] Generally, the ingestible device for trans-epithelial delivery is configured to have a nozzle pressure of at least about 150 psig (e.g., at least about 175 psig, at least about 200 psig, at least about 210 psig, at least about 220 psig, at least about 225 psig, at least about 230 psig, at least about 240 psig, at least about 250 psig, at least about 260 psig, at least about 270 psig, at least about 275 psig, at least about 280 psig, at least about 290 psig, at least about 300 psig, at least about 325 psig) and / or at most about 400 psig (e.g., at most about 375 psig, at most about 365 psig, at most about 355 psig, at most about 350 psig, at most about 345 psig, at most about 335 psig, at most about 325 psig, at most about 315 psig, at most about 305 psig). In certain embodiments, the ingestible device for trans-epithelial delivery is configured to have a nozzle pressure encompassed by any of the endpoints mentioned in the preceding sentence (e.g., about 150 psig to about 400 psig).

[0206] Generally, the ingestible device for trans-epithelial delivery is configured to contain a dispensable substance at a peak fluid pressure of at least about 150 psig (e.g., at least about 175 psig, at least about 200 psig, at least about 210 psig, at least about 220 psig, at least about 225 psig, at least about 230 psig, at least about 240 psig, at least about 250 psig, at least about 260 psig, at least about 270 psig, at least about 275 psig, at least about 280 psig, at least about 290 psig, at least about 300 psig, at least about 325 psig) and / or at most about 400 psig (e.g., at most about 375 psig, at most about 365 psig, at most about 355 psig, at most about 350 psig, at most about 345 psig, at most about 335 psig, at most about 325 psig, at most about 315 psig, at most about 305 psig). In certain embodiments, the ingestible device for trans-epithelial delivery is configured to contain a dispensable substance at a peak fluid pressure having any of the endpoints mentioned in the preceding sentence (e.g., about 150 psig to about 400 psig).

[0207] Generally, the ingestible device for trans-epithelial delivery is configured to contain a dispensable substance at a minimum fluid pressure of at least about 50 psig (e.g., at least about 60 psig, at least about 70 psig) and / or at most about 100 psig (e.g., at most about 90 psig, at most about 80 psig). In some embodiments, the ingestible device for trans-epithelial delivery is configured to contain a dispensable substance at a minimum fluid pressure of about 50 psig to about 100 psig (e.g., about 60 psig to about 90 psig, about 70 psig to about 80 psig).

[0208] Generally, the ingestible device for trans-epithelial delivery is configured to have a piston friction of at least about 1 N (e.g., at least about 2 N, at least about 3 N) and / or at most about 20 N (e.g., at most about 15 N, at most about 12 N). In certain embodiments, the ingestible device for trans-epithelial delivery is configured to have a piston friction of 1 N to 20 N (e.g., 2 N to 15 N, about 3 N to about 12 N).

[0209] Generally, the ingestible device for trans-epithelial delivery contains a dispensable substance at an initial fluid volume of at least about 50 microliters (pL) (e.g., at least about 100 pL, at least about 150 pL, at least about 200 pL, at least about 250 pL) and / or at most about 800 pL (e.g., at most about 700 pL, at most about 600 pL, at most about 500 pL, at most about 400 pL). In some embodiments, the ingestible device for trans-epithelial delivery contains a dispensable substance at an initial fluid volume of about 50 pL to about 800 pL (e.g., about 100 pL to about 600 pL, about 200 pL to about 400 pL).

[0210] Generally, the ingestible device for trans-epithelial delivery is configured to provide a delivery fluid volume of a dispensable substance of at least about 50 microliters (pL) (e.g., at least about 100 pL, at least about 150 pL, at least about 200 pL, at least about 250 pL) and / or at most about 800 pL (e.g., at most about 700 pL, at most about 600 pL, at most about 500 pL, at most about 400 pL). In some embodiments, the ingestible device for trans-epithelial delivery has a fluid volume of a dispensable substance of about 50 pL to about 800 pL (e.g., about 50 pL to about 500 pL, about 100 pL to about 450 pL, about 100 pL to about 600 pL, about 200 pL to about 400 pL, about 250 pL to about 400 pL, about 300 pL to about 400 pL).

[0211] Generally, the ingestible device for trans-epithelial delivery accommodates dispensable substance in a final fluid volume of at most about 100 microliters (mL) (e.g., at least about 90 mL, at least about 80 mL, at least about 70 mL, at least about 60 mL) and / or at most at least 5 mL (e.g., at most about 10 mL, at most about 20 mL, at most about 30 mL, at most about 40 mL). In some embodiments, the ingestible device for trans-epithelial delivery accommodates dispensable substance in a fluid volume of about 30 mL to about 70 mL (e.g., about 40 mL to about 60 mL, about 45 mL to about 55 mL). Generally, the ingestible device for trans-epithelial 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 submucosa and / or mucosa (e.g., into the lamina propria).

[0212] Generally, ingestible devices for trans-epithelial delivery have at least 1 opening for delivery of a dispensable substance (e.g., at least 2 openings for delivery of a dispensable substance, at least 3 openings for delivery of a dispensable substance, at least 4 openings for delivery of a dispensable substance) and / or at most about 8 openings for delivery of a dispensable substance (e.g., at most 7 openings for delivery of a dispensable substance, at most 6 openings for delivery of a dispensable substance, at most 5 openings for delivery of a dispensable substance, at most 4 openings for delivery of a dispensable substance). In certain embodiments, ingestible devices for trans-epithelial delivery have from 1 to 8 openings for delivery of a dispensable substance (e.g., from 2 to 4 openings for delivery of a dispensable substance, 2 openings for delivery of a dispensable substance). In some embodiments, ingestible devices for trans-epithelial delivery have one or more nozzles, each having a nozzle opening for delivery of a dispensable substance. In such embodiments, the ingestible device can have at least 1 nozzle (e.g., at least 2 nozzles, at least 3 nozzles, at least 4 nozzles) and / or at most 8 nozzles (e.g., at most 7 nozzles, at most 6 nozzles, at most 5 nozzles, at most 4 nozzles). For example, the ingestible device can have from 1 to 8 nozzles (e.g., from 1 to 5 nozzles, from 2 to 4 nozzles, 2 nozzles). In embodiments in which the ingestible device for trans-epithelial delivery includes one or more nozzles, each nozzle can have a nozzle length of at least about 0.2 mm (e.g., at least about 0.5 mm, at least about 0.7 mm, at least about 1 mm, at least about 2 mm, at least about 3 mm) and / or at most about 5 mm (e.g., at most about 4 mm). In some embodiments, each nozzle can have a nozzle length of from about 0.2 mm to about 5 mm. In embodiments in which the ingestible device for trans-epithelial delivery includes one or more nozzles, each nozzle can have a nozzle diameter of at least about 0.1 mm (e.g., at least about 0.2 mm, at least about 0.3 mm) and / or at most about 2 mm (e.g., at most about 1 mm, at most about 0.8 mm, at most about 0.5 mm, at most about 0.4 mm). In some embodiments, each nozzle can have a nozzle diameter of from about 0.1 mm to about 2 mm (e.g., from about 0.1 mm to about 1 mm, from about 0.15 mm to about 0.5 mm, from about 0.2 mm to about 0.8 mm, from about 0.25 mm to about 0.45 mm, from about 0.3 mm to about 0.4 mm, from about 0.3 mm to about 0.5 mm, from about 0.34 mm to about 0.36 mm, about 0.35 mm).

[0213] Generally, ingestible devices for trans-epithelial delivery are configured to provide a delivery fluid volume of at least about 20 microliters (mL) (e.g., at least about 25 mL, at least about mL, at least about 50 mL, at least about 75 mL, at least about 100 mL) and / or at most about 800 mL (e.g., at most about 700 mL, at most about 600 mL, at most about 500 mL, at most about 400 mL, at most about 300 mL) per opening (e.g., per nozzle) for delivering a dispensable substance. In some embodiments, ingestible devices for trans-epithelial delivery are configured to provide a delivery fluid volume of about 25 mL to about 400 mL (e.g., about 25 mL to about 300 mL, about 100 mL to about 300 mL) per opening (e.g., per nozzle) for delivering a dispensable substance.

[0214] In one example, an ingestible device having a nozzle with a nozzle diameter of 0.35 mm diameter and containing a dispensable substance at a peak fluid pressure of 150 psig can deliver a jet stream of the dispensable substance at an average jet velocity of about 20 m / s and at an average jet impact pressure of about 29 psig.

[0215] In another example, an ingestible device having a nozzle pressure of 300 psig can deliver a dispensable substance at an average jet velocity of about 27 m / s and at an average jet impact pressure of about 58 psig. In some embodiments, such an arrangement results in perforation of the intestinal wall.

[0216] In another example, an ingestible device having a nozzle with a nozzle diameter of 0.35 mm diameter and containing a dispensable substance at a peak fluid pressure of 320 psig can deliver a jet stream of the dispensable substance at an average jet velocity of about 28 m / s and at an average jet impact pressure of about 62.4 psig.

[0217] Figure 3 A cross-sectional view of a representative ingestible device 400 for trans- epithelial delivery is shown, which schematically illustrates certain parameters and acting components of the device 400. These include a drive force generator 42, which applies a force (creating 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 by the drive coupling 44 to the fluid volume 46 creates a pressure (fluid pressure) in the fluid volume 46. The pressure in the fluid volume 46 creates a high velocity flow through an open nozzle 48 to create a jet stream 50 of the fluid at a nozzle exit 52 having a nozzle diameter 72 and the nozzle has a nozzle length 74.

[0218] During trans-epithelial delivery, the fluid jet stream 50 has a jet stabilization length 54 sufficient for the fluid jet stream 50 to travel across the nozzle separation distance 56 to reach the interface of the lumen of the GI tract and the surface of the GI tract facing the lumen. Ultimately, the fluid (e.g., liquid, suspension) impacts the mucosal layer (e.g., epithelial layer and any mucus that can be present on the epithelial layer) of the GI tract as a stabilized fluid stream and is almost not broken up into a spray and is deposited in the submucosal layer and / or mucosal tissue 58. That is, between the nozzle exit 52 and the impact site at the mucosa, the jet stream 50 has a jet diameter 76 that can vary in the manner discussed above with respect to the average jet diameter.

[0219] The fluid volume 46 experiences a peak fluid pressure 60 that generates the fluid jet stream 50 that exits the device 40 at a peak jet velocity and impacts the interface of the lumen of the GI tract and the surface of the GI tract facing the lumen at a peak jet power, a peak jet pressure, and a peak jet force. One of ordinary skill in the art recognizes that these three parameters are interrelated.

[0220] The pressure in the fluid volume 46 decreases during delivery such that the fluid pressure during the delivery 70, and so too the jet power, jet force, and jet pressure, varies. The fluid pressure during the delivery 70 maintains the fluid jet stream 50 during the delivery at a sufficient jet impact force to continue to deliver the fluid (including the dispensable substance of one or more therapeutic agents) from the fluid volume 46 into the submucosal layer and / or mucosal tissue 58. The surrounding tissue can then absorb the delivered therapeutic agents for systemic delivery of the therapeutic agents.

[0221] Even before the subject swallows the ingestible device, the drive coupling 44 transmits 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 erodible pin or plug) until the movement of the drive coupling is triggered by a triggering mechanism, and / or the opening becomes open.

[0222] Figure 4An exemplary process flow diagram 400 is shown using an ingestible device in which pressure is not applied to the dispensable substance prior to ingestion by the subject. The process begins at step 402 when the patient ingests the ingestible device. In step 404, a trigger condition is met in the GI tract (e.g., pH, change in pH, presence of certain enzymes, concentration of certain enzymes), triggering the drive force generator. In step 406, the drive force mechanism applies pressure to the dispensable substance, resulting in a jet stream of the dispensable substance being delivered from the ingestible device for each opening. In step 408, the jet stream has a sufficient jet stabilization length for the jet stream to impact the subject's GI tissue. In step 410, the peak jet power of the jet stream is sufficient to enable trans-epithelial delivery of a therapeutic agent contained in the dispensable substance. In step 412, the fluid pressure of the dispensable substance decreases during delivery, but is sufficient such that the peak jet power continues to be sufficient to enable trans-epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0223] Figures 5A-5CViews of an assembled ingestible device 500, exploded views of the ingestible device, and aspects of the assembly process of the ingestible device are shown. The ingestible device 500 includes a nozzle 502, a gas cylinder 504, a piston 506, a seal 508, a piercing pin 510, and a perforator 512. A removable cap 514 can be secured over a portion of the ingestible device 500 and removed prior to ingestion. The ingestible device 500 can be used for delivery across an epithelium. The ingestible device 500 is configured such that when a subject ingests the ingestible device 500, the dispensable substance 516 held within the device is not under pressure. The ingestible device has two housing portions, a primary (first) container 518 and a secondary (second) container 520. The primary container 518, which includes a fluid volume containing a dispensable substance, can be formed of 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. Exemplary nozzle lengths include about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, and about 1.0 mm. In some embodiments, the nozzle length is about 0.7 mm. The ingestible device also includes a cover 522 over the nozzle opening, a spring 524, a gas cylinder 504 having a frangible seal, a piston 506 (e.g., made of COC), a perforator 512, and an O-ring 526. The nozzle cover 522 can be an integral nozzle cap for gastric protection and can soften after the ingestible device 500 is ingested, e.g., ingested by gastric fluid, such that the cover 522 dissolves / degrades and exposes the nozzle 502. In some embodiments, the O-ring 526 can be lubricated. Similarly, any O-rings disclosed elsewhere herein can optionally be lubricated.

[0224] The ingestible device 500 also includes a collar-shaped trigger element 528 as a trigger mechanism. Although Figure 5B The trigger element 528 is depicted as a collar shape, but other shapes can be used. In general, the trigger element 528 can have any appropriate shape. Examples of shapes of the trigger element include a full circular ring, a circular ring split into two pieces. In some embodiments, the trigger element includes two or more sectors of a circular ring with a gap between the sectors. In some embodiments, such a design can increase surface exposure to the environment (e.g., a water environment) to facilitate degradation. For example, Figure 5C Assemblies of two separate pieces of a collar, e.g., individual component modules 530 and 532, are shown, which are assembled to form the ingestible device 500.

[0225] Figures 6A-6CViews of an assembled ingestible device 600, an exploded view of the ingestible device 600, and views of aspects of the assembly process of the ingestible device 600 are shown. The ingestible device 600 can be used for trans-epithelial delivery or for other forms of delivery as discussed elsewhere herein as appropriate. The ingestible device 600 includes a nozzle 602, a gas cylinder 604, a piston 606, a seal 608, a piercing pin 610, and a perforator 612. A removable cap 614 can be secured over a portion of the ingestible device 600 and removed prior to ingestion. The ingestible device is configured such that the dispensable substance 616 in the device is not under pressure when the ingestible device is ingested by a subject. The ingestible device has two housing portions, a primary container 618 and a secondary container 620. The primary container 618, which includes a fluid volume containing a dispensable substance, can be formed of 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 about equal to the primary container wall thickness. Exemplary nozzle lengths include about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, and about 1.0 mm. In some embodiments, the nozzle length is about 0.7 mm. The ingestible device 600 also includes a cover 622 over the nozzle opening, a spring 624, a gas cylinder 604 having a frangible seal 608, a piston 606 (e.g., made of COC, or another suitable material), a two-part perforator, 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 the trigger element 628 is depicted as collar-shaped, other shapes can be used as disclosed elsewhere herein. Figures 6A-6C The trigger element 628 is depicted as collar-shaped, but other shapes can be used as disclosed elsewhere herein.

[0226] Figures 6A-6C The device shown in FIG. 6C has an enhanced piston stabilization length 634 (e.g., about 2 mm). Figures 6A-6C The device shown in FIG. 6D has a metal spring slider 636, which can enhance space efficiency. Figures 6A-6C The device shown in FIG. 6E has a perforator slider 638 (e.g., a metal perforator slider), which bottoms out on the spring housing during assembly. This can enhance space efficiency. In the device shown in FIG. 6E, the two-part perforator reduces (e.g., removes) the tolerance from the perforator to gas cylinder spacing when the trigger element is manufactured. Figures 6A-6C The device shown in FIG. 6E has a perforator slider 638 (e.g., a metal perforator slider), which bottoms out on the spring housing during assembly. This can enhance space efficiency. In the device shown in FIG. 6E, the two-part perforator reduces (e.g., removes) the tolerance from the perforator to gas cylinder spacing when the trigger element is manufactured. Figures 6A-6C The device shown in FIG. 6E has a perforator slider 638 (e.g., a metal perforator slider), which bottoms out on the spring housing during assembly. This can enhance space efficiency. In the device shown in FIG. 6E, the two-part perforator reduces (e.g., removes) the tolerance from the perforator to gas cylinder spacing when the trigger element is manufactured. Figures 6A-6CIn the device shown in FIG. 6A, 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 (e.g., an ultrasonic weld) is shown. Figure 6C A gas bottle retention feature 646 is also shown.

[0227] In addition, the ingestible device includes a removable cap 614, which is removed (e.g., by a user) prior to the ingestible device being swallowed. When the device 600 is swallowed by a subject, the trigger element 628 prevents the dispensable substance 616 in the fluid volume from being under pressure by holding the spring 624 and the perforator 612 in place. When the device reaches an appropriate location in the GI tract, the trigger element 628 at least partially erodes, degrades, and / or dissolves (e.g., due to pH, a change in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), and the trigger element 628 is no longer sufficient to inhibit 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 embodiments, the trigger element can include a covering of a thin film of material that degrades preferentially due to, e.g., a change in pH and / or the presence of enzymes. The spring 624 forces the piercing pin 610 of the perforator 612 into the frangible seal 608, causing the frangible seal to break. This causes the gas, which is under elevated pressure, to exit the gas bottle 604, causing the elevated pressure to push against the piston 606 and apply pressure to the fluid volume 616. This causes the covering 622 of the nozzle opening, which is made of a relatively low mechanical strength material (e.g., a foil or a film), to break, such that the dispensable substance is delivered from the nozzle opening in the form of a jet stream. In certain embodiments, the covering 622 of the nozzle opening is made of a material that erodes, degrades, and / or dissolves in the presence of, e.g., water or an elevated pH (e.g., an enteric band or a band of a water-soluble polymeric material). The covering can be partially or completely displaced from the capsule upon actuation of the trigger element. This results in trans-epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0228] Figure 6C Aspects of the assembly process of the ingestible device are shown, e.g., separate component modules 630 and 632, which are assembled to form the ingestible device 600. Figures 7-13A primary container depicted in combination with a cap and nozzle cover is added with a dispensable substance, followed by the addition of a piston. This can be done in a sterile or other environment suitable for drug filling and independent of the environment in which the mechanical drive assembly is built. Another housing portion and its components are assembled in a clean environment, with the perforator held in place by a trigger element. The gas cylinder 604 is held in place by components of the assembly, including an assembly housing that includes features for positioning the gas cylinder in the correct location in the assembled ingestible device. Positioning and mounting of the gas cylinder can be aided by mounting features, such as flanges, that are integral with the gas cylinder components.

[0229] Figures 7-13 Various views of the ingestible device 700 and / or aspects of the ingestible device 700 are shown. It is apparent that the delivery mechanism of the ingestible device 700 is shown to have a design substantially similar to the device shown in FIG. 5, although more generally, Figures 14-18 The ingestible device 700 depicted in FIG. 6 can have a delivery mechanism as described elsewhere herein.

[0230] The ingestible device 700 includes a gas cylinder 716, a union 708, an O-ring 732, an enteric trigger 726, a perforator 720, a spring 724, a spring retention cup 722, a retention element 728, a drug housing 704, a drive housing 706, and a perforator retainer 724.

[0231] The ingestible device 700 has two chambers 710a, 710b, each containing a dispensable substance. The chambers are separated by a partition 705, such as a rib, that prevents the dispensable substance in one chamber from entering the other 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 one chamber, such as chamber 710a, can be the same or different from the dispensable substance in the other chamber, such as chamber 710b. While shown as having two chambers 710a, 710b, the present disclosure is not limited in this regard. More generally, the ingestible device 700 can 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). In general, 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 can have different volumes. Combinations of such embodiments are also possible.

[0232] In some embodiments, the disclosure provides an ingestible device comprising an element 712 (e.g., a covering) having a first state in which the element 712 at least partially covers a nozzle opening of a nozzle 702 in a 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 such that, when a driving force coupler (e.g., a piston 718a, 718b) moves, the element 712 moves from its first state to its second state. In certain embodiments, the element 712 is conformal to an inner radius of the housing 704, is flexible, and / or comprises a cylindrical portion. In some embodiments, the element 712 is removable from the ingestible device 700 (e.g., the element 712 is removed from the ingestible device when the element 712 is in its second state). Such a removable element 712 can be, for example, a cap. Optionally, the element 712 moves synchronously with the driving force coupler, e.g., the piston 718a, 718b. In some embodiments, the element 712 moves the same distance when the driving force coupler moves a distance. The ingestible device can comprise a seal 718 (e.g., an O-ring) that is mechanically coupled (e.g., sealed) to the driving force coupler and the element 712. Using this arrangement, the seal 718 can be configured to cause movement of the driving force coupler to cause movement of the element 712.

[0233] Figure 14 An ingestible device 1400 is shown that contains a dispensable substance that is not under pressure when the subject swallows the ingestible device. In Figure 15 the ejection opening 1402 is depicted as being covered, and in Figure 16 the ejection opening 1402 is not covered.

[0234] Figure 17 and 17An ingestible device 1400 is shown in greater detail. The ingestible device 1400 has a housing portion 1404 and 1406 connected by a union 1408 and has a fluid volume 1410 containing a dispensable substance, an ejection stream covering 1412, e.g., a cylindrical sleeve (made of a flexible material that can conform to the inner radius of the housing 1406 that slides to open or seal the opening 1402), a spring 1414, a gas cartridge 1416, a piston 1418, a puncturer 1420, and an O-ring 1432. The gas cartridge 1416 is held by a holding element 1428. A seal 1430 forms a gas seal between the puncturer 1420 and the housing 1404. A spring retention cup 1422 retains the spring-loaded puncturer 1420. The puncturer retainer 1424, along with an enteric trigger 1426, retains the puncturer 1420 in place, the enteric trigger 1426 retaining the puncturer retainer in place until it dissolves and acts as a trigger mechanism. When the device 1400 is swallowed by a subject, the enteric trigger 1426 prevents the dispensable substance in the fluid volume 1410 from being under pressure by retaining the spring 1414 and the puncturer 1420 in place. When the device 1400 reaches the appropriate location in the GI tract, the enteric trigger 1426 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes), such that the puncture pin retainer 1424 is no longer sufficient to contain the pressure from the spring 1414. The spring 1414 forces the puncturer 1420 into the gas cartridge 1416, thereby puncturing the gas cartridge 1416 and causing gas under elevated pressure to exit the gas cartridge 1416. This causes the gas cartridge 1416 to press against the piston 1418 and apply pressure to the fluid volume 1410. The piston provides friction to slide the ejection stream covering 1412 open, thereby exposing the ejection opening 1402, such that the dispensable substance is delivered out of the ejection opening 1402 in the form of an ejection stream. This results in trans-epithelial delivery of a therapeutic agent contained in the dispensable substance. Figure 18 An embodiment of the ingestible device 1400 is shown in which the ejection stream covering 1412 is slid open to expose the ejection opening 1402.

[0235] Typically, the ingestible device 1400 is used for trans-epithelial delivery. However, the ingestible device 1400 can be used for epithelial delivery or local delivery. Appropriate parameters for different types of delivery are provided elsewhere herein.

[0236] In some embodiments, the housing of 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 in gas cylinder 1416 of about 150 μL to about 175 μL (e.g., about 160 μL). Figure 19 Ingestible device 1400 is shown with the jet stream covering 1412 conformal to the radius of ingestible device 1400.

[0237] Figure 21 and 20 Ingestible device 1900 is shown in its closed and open states, respectively. Ingestible device 1900 contains dispensable substance that is not under pressure when the subject swallows the ingestible device. Ingestible device 1900 has housing portions 1904 and 1906 connected by union 1908 and has fluid volume 1910 containing dispensable substance, spring 1914, gas cylinder 1916, piston 1918, perforator 1920, and O-ring 1932. Gas cylinder 1916 is held by retaining element 1928. Seal 1930 forms a gas seal between perforator 1920 and housing 1906. Spring retention cup 1922 retains spring-loaded perforator 1920. Perforator retainer 1924, along with enteric trigger 1926, retains perforator 1920 in place until it dissolves and acts as a trigger mechanism. When device 1900 is swallowed by a subject, enteric trigger 1926 prevents the dispensable substance in fluid volume 1910 from being under pressure by retaining spring 1914 and perforator 1920 in place. When device 1900 reaches the appropriate location in the GI tract, enteric trigger 1926 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes) so that perforator retainer 1924 is no longer sufficient to contain the pressure from spring 1914. Spring 1914 forces perforator 1920 into gas cylinder 1916, thereby puncturing gas cylinder 1916 and causing gas under elevated pressure to exit gas cylinder 1916. This causes gas cylinder 1916 to press against piston 1918 and apply pressure to fluid volume 1910. The piston provides friction to cause cap 1934 to open / unfold so that dispensable substance is delivered out of volume 1910. This results in the therapeutic agent being released into the subject's GI tract.

[0238] In some embodiments, the housing of ingestible device 1900 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 gas cylinder 1916 of about 150 μL to about 175 μL (e.g., about 160 μL).

[0239] In general, ingestible device 1900 is used for local delivery.

[0240] Figure 23 and 22 Ingestible device 2100 is shown in its closed and open states, respectively. Ingestible device 2100 contains dispensable substance that is not under pressure when the subject swallows the ingestible device. Ingestible device 2100 has housing portions 2104 and 2106 connected by a union 2108 and has a fluid volume 2110 containing dispensable substance, a spring 2114, a gas cylinder 2116, a piston 2118, a puncturer 2120, and an O-ring 2132. Gas cylinder 2116 is held by a retaining element 2128. A seal 2130 forms a gas seal between puncturer 2120 and housing 2106. A spring retention cup 2122 retains spring-loaded puncturer 2120. Puncturer retainer 2124, along with enteric trigger 2126, retains puncturer 2120 in place until it dissolves and acts as a trigger mechanism. When device 2100 is swallowed by a subject, enteric trigger 2126 prevents dispensable substance in fluid volume 2110 from being under pressure by retaining spring 2114 and puncturer 2120 in place. When device 2100 reaches the appropriate location in the GI tract, enteric trigger 2126 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes), such that puncturer retainer 2124 is no longer sufficient to contain the pressure from spring 2114. Spring 2114 forces puncturer 2120 into gas cylinder 2116, thereby puncturing gas cylinder 2116 and causing gas under elevated pressure to exit gas cylinder 2116. This causes gas cylinder 2116 to press against piston 2118 and apply pressure to fluid volume 2110. The piston provides friction to cause cap 2134 to open / unfold, such that dispensable substance is delivered out of volume 2110. This results in delivery (e.g., local delivery) of a therapeutic agent contained in the dispensable substance.

[0241] In some embodiments, the housing of 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 gas cylinder 2116 of about 150 μL to about 175 μL (e.g., about 160 μL).

[0242] Figure 25 and 24 Ingestible device 2300 is shown in its closed and open states, respectively. Ingestible device 2300 contains dispensable substance that is not under pressure when the subject swallows the ingestible device. Ingestible device 2300 has housing portions 2304 and 2306 connected by union 2308 and has fluid volume 2310 containing dispensable substance, spring 2314, gas cylinder 2316, piston 2318, perforator 2320, and O-ring 2332. Gas cylinder 2316 is held by retaining element 2328. Seal 2330 forms a gas seal between perforator 2320 and housing 2306. Spring retention cup 2322 retains spring-loaded perforator 2320. Perforator retainer 2324, along with enteric trigger 2326, retains perforator 2320 in place until it dissolves and acts as a trigger mechanism. When device 2300 is swallowed by a subject, enteric trigger 2326 prevents the dispensable substance in fluid volume 2310 from being under pressure by retaining spring 2314 and perforator 2320 in place. When device 2300 reaches the appropriate location in the GI tract, enteric trigger 2326 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes) such that perforator retainer 2324 is no longer sufficient to contain the pressure from spring 2314. Spring 2314 forces perforator 2320 into gas cylinder 2316, thereby puncturing gas cylinder 2316 and causing gas under elevated pressure to exit gas cylinder 2316. This causes gas cylinder 2316 to press against piston 2318 and apply pressure to fluid volume 2310. The piston provides friction to cause cap 2334 to open / unfold, such that dispensable substance is delivered out of volume 2310. This results in delivery (e.g., local delivery) of a therapeutic agent contained in the dispensable substance.

[0243] In some embodiments, the housing of ingestible device 2300 has a diameter of about 8 mm to about 11 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 26.3 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 230 μL to about 355 μL (e.g., about 235 μL to about 349 μL), and / or a gas volume in gas cylinder 2316 of about 150 μL to about 175 μL (e.g., about 160 μL).

[0244] Figure 26 An embodiment of ingestible device 2500 is shown, which contains dispensable substance that is not under pressure when the subject swallows the ingestible device. Ingestible device 2500 has housing portions 2504 and 2506 connected by a union 2508 and has a fluid volume 2510 containing dispensable substance, a spring 2514, a piston 2518, a spring retention pin 2536, and an O-ring 2532. After housing portion 2504 is filled with dispensable substance (e.g., a liquid containing a drug), a cap 2538 containing dispensable substance (e.g., a liquid containing a drug) is sealed into the dispensable substance (e.g., a liquid containing a drug). A seal 2530 forms a gas seal between spring retention pin 2536 and housing portion 2506. A spring retention cup 2522 retains spring retention pin 2536. Pin retainer 2540 retains spring retention pin 2536 in place with an enteric trigger 2526 that retains the pin retainer in place until it dissolves and acts as a trigger mechanism. When device 2500 is swallowed by a subject, enteric trigger 2526 prevents the dispensable substance in fluid volume 2510 from being under pressure by retaining spring 2514 and spring retention pin 2536 in place. When device 2500 reaches the appropriate location in the GI tract, enteric trigger 2526 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes), such that pin retainer 2540 is no longer sufficient to restrain spring retention pin 2536, thereby releasing spring 2514. Spring 2514 pushes against piston 2518, such that piston 2518 exerts pressure on fluid volume 2510. The piston provides friction to cause cap 2534 to open / unfold, such that dispensable substance is delivered out of volume 2510. This results in delivery (e.g., local delivery) of therapeutic agent out of the dispensable substance.

[0245] In some embodiments, the housing of ingestible device 2500 has a diameter of about 8 mm to about 11 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 395 μL to about 570 μL (e.g., about 403 μL to about 559 μL).

[0246] Figure 28 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 can have a smaller capacity than fluid volume 2510 of ingestible device 2500.

[0247] In some embodiments, the housing of ingestible device 2600 has a diameter of about 8 mm to about 11 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 395 μL to about 570 μL (e.g., about 403 μL to about 559 μL).

[0248] Figure 29AAn embodiment of ingestible device 2800 is shown, which contains dispensable substance that is not under pressure when the subject swallows the ingestible device. Ingestible device 2800 has: housing portions 2804 and 2806 connected by a union 2808 and has a fluid volume 2810 containing dispensable substance, a spring 2814, a piston 2818, a spring retention pin 2836, and an O-ring 2832. After housing portion 2804 is filled with dispensable substance (e.g., a liquid containing a drug), a cap 2838 containing dispensable substance (e.g., a liquid containing a drug) is sealed into the dispensable substance. A seal 2830 forms a gas seal between spring retention pin 2836 and housing 2806. A spring retention cup 2822 retains spring retention pin 2836. Pin retainer 2840 retains spring retention pin 2836 in place with an enteric trigger 2826 that retains the pin retainer in place until it dissolves and acts as a trigger mechanism. When device 2800 is swallowed by a subject, enteric trigger 2826 prevents the dispensable substance in fluid volume 2810 from being under pressure by retaining spring 2814 and spring retention pin 2836 in place. When device 2800 reaches the appropriate location in the GI tract, enteric trigger 2826 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes), such that pin retainer 2840 is no longer sufficient to restrain spring retention pin 2836, thereby releasing spring 2814. Spring 2814 pushes against piston 2818, such that piston 2818 exerts pressure on fluid volume 2810. The piston provides friction to cause cap 2834 to open / unfold, such that dispensable substance is delivered out of volume 2810. This results in delivery (e.g., local delivery) of a therapeutic agent contained in the dispensable substance.

[0249] In some embodiments, the housing of ingestible device 2800 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 25.2 mm to about 26.2 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 790 μL to about 870 μL (e.g., about 802 μL to about 855 μL).

[0250] Figure 29B An external view of an embodiment of ingestible device 2800 is shown, and Figure 30 An external view of housing portion 2804, which retains fluid volume 2810, is shown.

[0251] Figure 31 An embodiment of ingestible device 2800 is shown, in which cap 2834 is opened / unfolded.

[0252] Figure 32A An embodiment of ingestible device 3100 is shown, which contains dispensable substance that is not under pressure when the subject swallows the ingestible device. Ingestible device 3100 has: housing portions 3104 and 3106 and fluid volume 3110 containing dispensable substance, piston 3118, wave spring 3142, and O-ring 3132. After housing portion 3104 is filled with dispensable substance (e.g., a liquid containing a drug), cap 3138 containing dispensable substance (e.g., a liquid containing a drug) is sealed in. Seal 3130 forms a gas seal between switch 3146 and housing 3106. Spring retention cup 3122 retains wave spring 3142. Pin retainer 3140, along with enteric trigger 3126, retains switch 3146 in place, which retains pin retainer 3140 in place and acts as a trigger mechanism until it dissolves. When device 3100 is swallowed by a subject, enteric trigger 3126 prevents dispensable substance in fluid volume 3110 from being under pressure by retaining wave spring 3142 and switch 3146 in place. When device 3100 reaches the appropriate location in the GI tract, enteric trigger 3126 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes), such that pin retainer 3140 is no longer sufficient to restrain wave spring 3142, and switch 3146 is released. Switch 3146, along with gas cell 3144, completes a circuit, which gas cell 3144 begins to generate gas. As pressure builds, piston 3118 slides along the track and closes the circuit via conductive O-ring 3132. The circuit is broken when the track ends at a defined travel distance to stop the generation of gas by gas cell 3144. Piston 3118 applies pressure to fluid volume 3110 and provides friction to cause cap 3134 to open / unfold, such that dispensable substance is delivered out of volume 3110. This results in the delivery (e.g., local delivery) of a therapeutic agent contained in the dispensable substance.

[0253] In some embodiments, the housing of ingestible device 3100 has a diameter of about 10 mm to about 12 mm (e.g., about 11 mm to about 11.5 mm), a length of about 23 mm to about 26.5 mm (e.g., about 25.2 mm to about 26.2 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 880 μL to about 940 μL (e.g., about 890 μL to about 930 μL).

[0254] Figure 32B An external view of an embodiment of ingestible device 3100 is shown, and Figure 33An external view of the housing component 3104 holding the fluid volume 3110 is shown.

[0255] Figure 34 Another view of an embodiment of the ingestible device 3100 is shown.

[0256] Figures 35-40 An embodiment of the ingestible device 3100 is shown with the cap 3134 open / unfolded.

[0257] In some embodiments, the length of the ingestible device can be reduced to achieve a modified 00 standardized length, such as a length of approximately 23.3 mm, while maintaining the same diameter as the standard size 00. The reduced length of the ingestible device can result in a reduced volume available for dispensable substance. Adjusting one or more dimensions of the gas cylinder within the ingestible device and / or changing the position of the piston can be used to increase the volume available for dispensable substance while maintaining a threshold volume and / or pressure of dispensable substance provided by the gas cylinder for the ingestible device. Reference is made herein to Figure 35 Example embodiments are described.

[0258] Figures 36-40One embodiment of an ingestible device 3500 for epithelial delivery is shown, wherein the length of the ingestible device is reduced to achieve a changed size submucosal device, and which houses a dispensable substance that is not under pressure when the ingestible device is swallowed by a subject. The ingestible device 3500 has a housing portion 3504 and 3506 connected by a union 3508 and has a fluid volume 3510 that houses a dispensable substance, a spring 3514, a gas cylinder 3516, a piston 3518, a puncturer 3520, and an O-ring 3532. The gas cylinder 3516 is held by a holding element 3528. A seal 3530 forms a gas seal between the puncturer 3520 and the housing 3506. A spring retention cup 3522 retains the spring loaded puncturer 3520. The puncturer retainer 3524, along with an enteric trigger 3526, retains the puncturer 3520 in place, which retains the puncturer retainer in place until it dissolves and acts as a trigger mechanism. When the device 3500 is swallowed by a subject, the enteric trigger 3526 prevents the dispensable substance in the fluid volume 3510 from being under pressure by retaining the spring 3514 and the puncturer 3520 in place. When the device 3500 reaches the appropriate location in the GI tract, the enteric trigger 3526 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes), such that the puncturer retainer 3524 is no longer sufficient to contain the pressure from the spring 3514. The spring 3514 forces the puncturer 3520 into the gas cylinder 3516, thereby puncturing the gas cylinder 3516 and causing the gas 3534 under elevated pressure to exit the gas cylinder 3516. This causes the gas cylinder 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 / unfold, such that the dispensable substance is delivered out of the volume 3510. This results in epithelial delivery of a therapeutic agent contained in the dispensable substance.

[0259] In some embodiments, the ingestible device 3500 can hold a dispensable substance volume of about 250 μL to about 350 μL (e.g., about 267 μL), can have an expansion volume of about 230 μL to about 260 μL (e.g., about 243 μL), and can have a gas cylinder fill volume of about 140 μL to about 150 μL (e.g., about 160 μL).

[0260] In some embodiments, one or more adjustments to the piston length and / or gas cylinder dimensions can be varied for an ingestible device, such as ingestible device 3500. Figure 35 Variations to the piston length and / or gas cylinder dimensions of the ingestible device structures described are depicted with reference to Figure 36 Variations to the piston length and / or gas cylinder dimensions of the ingestible device structures described are depicted with reference to

[0261] Figure 36One embodiment of ingestible device 3600 is shown, where the length of the ingestible device is reduced to achieve a changed size 00 submucosal device and the piston length is reduced. As Figure 37 In embodiments depicted in FIGS. 36A-36B, ingestible device 3600 includes piston 3618, gas cylinder 3616, and fluid volume 3610. In some embodiments, ingestible device 3600 can hold a dispensable substance volume of 300 μΐ^ to about 350 μΐ^ (e.g., about 322 μΐ^), can have an inflation volume of about 350 μΐ^ to about 380 μΐ^ (e.g., about 372 μΐ^), and can have a gas cylinder fill volume of about 35 μΐ^ to about 45 μΐ^ (e.g., about 40 μΐ^). In some embodiments, a 280 PSIG fill pressure of the gas cylinder corresponds to a drive pressure volume of about 70-80 μΐ^ (e.g., about 75 μΐ^). In some embodiments, a 240 PSIG fill pressure of the gas cylinder corresponds to a drive pressure volume of about 90-100 μΐ^ (e.g., about 95 μΐ^).

[0262] Figure 37 One embodiment of ingestible device 3700 is shown, where the length of the ingestible device is reduced to achieve a changed size 00 submucosal device and the piston length is reduced. As Figure 38 In embodiments depicted in FIGS. 37A-37B, ingestible device 3700 includes piston 3718, gas cylinder 3716, and fluid volume 3710. In some embodiments, ingestible device 3700 can hold a dispensable substance volume of 300 μΐ^ to about 350 μΐ^ (e.g., about 332 μΐ^), can have an inflation volume of about 320 μΐ^ to about 380 μΐ^ (e.g., about 336 μΐ^), and can have a gas cylinder fill volume of about 65 μΐ^ to about 85 μΐ^ (e.g., about 75 μΐ^). In some embodiments, a 280 PSIG fill pressure of the gas cylinder corresponds to a drive pressure volume of about 140-150 μΐ^ (e.g., about 145 μΐ^). In some embodiments, a 240 PSIG fill pressure of the gas cylinder corresponds to a drive pressure volume of about 170-190 μΐ^ (e.g., about 180 μΐ^).

[0263] Figure 38 One embodiment of ingestible device 3800 is shown, where the length of the ingestible device is reduced to achieve a changed size 00 submucosal device and the piston length is reduced. As Figure 39The ingestible device 3800, as depicted, includes a piston 3818, a gas cylinder 3816, and a fluid volume 3810. In some embodiments, the ingestible device 3800 can hold a dispensable substance volume of 300 μΐ, to about 350 μΐ, (e.g., about 335 μΐ,), can have an inflation volume of about 300 μΐ, to about 320 μΐ, (e.g., about 306 μΐ,), and can have a gas cylinder fill volume of about 35 μΐ, to about 45 μΐ, (e.g., about 40 μΐ,). The piston shape of the piston 3818 can result in a residual dispensable substance volume of about 80 μΐ, of the total amount of dispensable substance volume within the housing after delivery (out of the total 335 μΐ, delivered).

[0264] Figure 39 An embodiment of an ingestible device 3900 is shown, in which the length of the ingestible device is reduced to achieve a changed size 00 submucosal device and the gas cylinder diameter is changed. As Figure 40 The ingestible device 3900, as depicted, includes a piston 3918, a gas cylinder 3916, and a fluid volume 3910. In some embodiments, the ingestible device 3900 can hold a dispensable substance volume of 300 μΐ, to about 350 μΐ, (e.g., about 335 μΐ,), can have an inflation volume of about 250 μΐ, to about 290 μΐ, (e.g., about 271 μΐ,), and can have a gas cylinder fill volume of about 70 μΐ, to about 80 μΐ, (e.g., about 75 μΐ,). The piston shape of the piston 19166 can result in a residual dispensable substance volume of about 70-90 μΐ, (e.g., about 80 μΐ,) of the total amount of dispensable substance volume within the housing after delivery.

[0265] Figure 40 An embodiment of an ingestible device 4000 is shown, in which the length of the ingestible device is reduced to achieve a changed size 00 submucosal device and the gas cylinder diameter is changed. As Figures 41A-41C The ingestible device 4000, as depicted, includes a piston 4018, a gas cylinder 4016, and a fluid volume 4010. In some embodiments, the ingestible device 4000 can hold a dispensable substance volume of 300 μΐ, to about 350 μΐ, (e.g., about 332 μΐ,), can have an inflation volume of about 220 μΐ, to about 270 μΐ, (e.g., about 240 μΐ,), and can have a gas cylinder fill volume of about 125 μΐ, to about 145 μΐ, (e.g., about 138 μΐ,). In some embodiments, a 240 PSIG drive pressure of the gas cylinder corresponds to a fill pressure of about 780-800 PSIG (e.g., 792.7 PSIG). In some embodiments, a 280 PSIG fill pressure of the gas cylinder corresponds to a drive pressure of about 910-930 PSIG (e.g., about 925 PSIG). In some embodiments, a 320 PSIG drive pressure of the gas cylinder corresponds to a fill pressure of about 1040-1060 PSIG (e.g., 1057 PSIG).

[0266] In some implementations, the puncture force required to puncture the gas cylinder can be reduced, allowing the use of shorter / lower force springs and / or shorter / stiffer springs.

[0267] In some implementation schemes, such as Figures 42A-47C As depicted, the nozzle opening 4102 may be covered by a covering (including components such as a patch 4104) that forms a barrier between the dispensable material 4112 held within the housing 4110 and the external environment of the ingestible device. The patch 4104 may be formed of a material that is biodegradable, erosive, or soluble. The patch may 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 may be a multilayer film, for example, two or more layers of the same or different materials, to enhance the barrier properties. The multilayer structure of the patch 4104 may include, for example, PE / ethylene-vinyl alcohol copolymer (EVOH), ethylene-vinyl acetate (EVA) / EVOH / EVA, EVA / polyvinylidene chloride (PVDC) / EV, etc. In some embodiments, the multilayer structure of the patch may include a metal layer.

[0268] The patch 4104 may have various shape profiles, such as circular, rectangular, polygonal, or asymmetrical profiles. In some embodiments, as depicted in FIG41, the patch may be fixed off-center 4106 to a nozzle opening 4102 on the outer surface of the ingestible device, such that the force of the jet stream discharged through the nozzle opening 4102 (e.g., by pressurized release of the dispensable substance) preferentially moves the patch away from the direction of the formed jet stream.

[0269] The patch 4104 can be loosely attached to the nozzle opening (e.g., using an adhesive or other pressure-sensitive method, or using static attraction). The adhesive for securing the patch can be applied to the surface around the nozzle, but not directly to the nozzle.

[0270] In some embodiments, a film, coating, foil, tape, etc. can be disposed on a patch that is secured over the nozzle opening and can be composed of a dissolvable material, e.g., an enteric material, such that the film, coating, foil, or tape holds the patch in place over the nozzle opening during handling, storage, and ingestion of the ingestible device. In one example, the tape 4108 is composed of a material that is dissolvable upon entering the body. The film or tape can be composed of a water-soluble material, e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or gelatin. The film or tape 4108 can be composed of a material that includes pH-dependent solubility, e.g., composed of or including polymethacrylate, such that the material is more stable under acidic conditions, e.g., pH 1-4, and wherein the rate of dissolution increases when the material is exposed to higher pH, e.g., pH 5-7.

[0271] In some embodiments, a tape covering the nozzle opening can be composed of a heat-shrink material that heat shrinks to the outer shell such that it provides a nozzle covering. One example of a heat-shrink material is polyethylene terephthalate (PET). Additional examples of heat-shrink materials include polyolefins, polyethylene, LDPE, PTFE, FEP, and COC. Generally, such heat-shrink materials do not function by being dissolved. Rather, they are broken (e.g., punctured) by the pressure of the dispensable material being applied to the heat-shrink material. Such heat-shrink tapes can have a thickness of, e.g., about 5 pm to about 100 pm (e.g., about 5 pm to about 50 pm, about 10 pm, about 12 pm, about 15 pm, about 50 pm). Specific examples include heat-shrink PET with a thickness of about 12 pm (e.g., medical film), heat-shrink polyolefin with a thickness of about 15 pm (e.g., shipping packaging film), and heat-shrink polyethylene with a thickness of about 50 pm (e.g., shipping packaging film).

[0272] Generally, the covering of the nozzle opening (e.g., film, coating, foil, tape) can be scored, e.g., to make the seal easier to break when desired. Generally, such scoring can be configured as desired. As one example, the scoring can be configured as a series of parallel lines. As another example, the scoring can be configured as a grid (ruling). As a further example, the scoring can be configured as a plurality of dots (e.g., equidistant dots). In some embodiments of a scored seal, the seal is composed of LDPE, e.g., LDPE having a thickness of 20 pm to 75 pm (e.g., 25 pm, 50 pm). For example, a seal composed of LDPE can be scored with a stripe or grid or plurality of dots, and the LDPE has a thickness of 25 pm or 50 pm.

[0273] In some embodiments, the covering (e.g., coating, film, tape, or patch) has a minimum burst pressure. In some embodiments, for example, the minimum burst pressure is less than 420 psig, 410 psig, 400 psig, 390 psig, 380 psig, 370 psig, 360 psig, 350 psig, 340 psig, 330 psig, 320 psig, 310 psig, 300 psig, 290 psig, 280 psig, 270 psig, 260 psig, 250 psig, 240 psig, 230 psig, 220 psig, 210 psig, 200 psig, 190 psig, 180 psig, 170 psig, 160 psig, 150 psig, 140 psig, 130 psig, 120 psig, 110 psig, 100 psig, 90 psig, 80 psig, 70 psig, 60 psig, 50 psig, 40 psig, 30 psig, or 20 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). For example, in certain embodiments, the burst pressure can range from 5 psig to any of the minimum burst pressures mentioned earlier in this paragraph.

[0274] In some embodiments, a coating or film can be applied over the nozzle opening 4102 that is dissolvable / degradable or otherwise becomes unstable upon 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, for example, using a laser, and / or can be composed of a material that weakens based on the environment around the material, for example, an enteric material within the body. In one example, the coating or film can be thinned using a laser microslicing technique, for example, a milling / polishing process, to reduce the coating or film thickness. In some embodiments, a coating or film of an enteric material can be applied over the nozzle opening 4102 as well as over a portion of the outer surface of the ingestible device. A machining / polishing process, for example, centerless grinding or lapping, can be utilized to control the final thickness of the applied coating or film. The coating or film can be further processed using a laser to drill, scratch, and / or punch a portion of the coating or film to mechanically weaken the coating or film.

[0275] Figure 42AEmbodiments of patches, coatings, films, foils, and / or bands that can be affixed to or in contact with a nozzle opening are depicted. While such embodiments are depicted in these figures, the present disclosure is not limited in this regard. In some embodiments, more than one (e.g., more than two, more than three) combination of such methods of covering a nozzle opening can be used in a given ingestible device. Further, variations of the methods disclosed herein are available so long as they generally conform to the relevant functionality, e.g., providing a barrier between a dispensable substance (e.g., a liquid containing a drug) held within a drug housing and the environment outside of the ingestible device.

[0276] In some embodiments, as depicted in FIGS. 42A-42B, a nozzle opening 4202 can be covered by a covering (including member 4248, e.g., a patch, film, foil, band, etc.) that forms a barrier between a fluid volume 4210 including a dispensable substance (e.g., a liquid containing a drug) held within a housing and the environment outside of the ingestible device. Figure 17 and 42B In some embodiments, as depicted in FIGS. 42A-42B, a nozzle opening 4202 can be covered by a covering (including member 4248, e.g., a patch, film, foil, band, etc.) that forms a barrier between a fluid volume 4210 including a dispensable substance (e.g., a liquid containing a drug) held within a housing and the environment outside of the ingestible device. Figure 42A 、 18 , 19A-N discussed and optionally applicable to Figure 43A and 42B .

[0277] 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 or partially peel away / detach the covering member from the outer surface of the ingestible device to allow a jet stream 4262 containing the dispensable substance to form. The covering member 4248 can be composed of various materials, e.g., PE, PP, PVC, cellulose acetate, hot blocking film, etc. In some embodiments, the covering member can be composed of a material that is intended to be insoluble in gastric media, but can be broken down in the small intestine based on pH (e.g., an enteric material) or one or more enzymes, e.g., one or more pancreatic enzymes (e.g., a lipid-based material). The covering member 4248 can be composed of a material that can hydrate and / or soften 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 film (e.g., which can aid in degassing during filling of the ingestible device). The covering member can be applied, e.g., from a spool, in a post-molding operation, for example.

[0278] In some embodiments, the covering member 4248 can be a thin shrink-fit film or adhesive label member 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, for example, a barrier having a thickness of 20 μιη to 40 μιη (e.g., 25 μιη to 35 μιη, 30 μιη).

[0279] In some embodiments, the covering member 4248 can be an external band applied to cover the nozzle opening 4202. In certain embodiments, the band can be, for example, 100 μιη to 200 μιη (e.g., 125 μιη to 175 μιη, for example, 150 μιη) thick. Optionally, the band can be composed of a material that is soluble in gastric media, for example, gelatin, HPMC, or other material, or can be composed of an enteric material.

[0280] In some embodiments, the covering member 4248 can be a partial film or covering, for example, an external cap, applied to the exterior of the ingestible device to cover the nozzle opening 4202. The cap can be, for example, 100 μιη to 200 μιη (e.g., 125 μιη to 175 μιη, for example, 150 μιη) thick and / or cover less than the entire exterior of the ingestible device.

[0281] In some embodiments, as Figure 44A and 43BAs depicted, a cover member 4348, e.g., patch, film, foil, tape, coating, etc., forming a barrier between the fluid volume 4310 of dispensable substance (e.g., liquid containing a drug) held within the housing 4304 and the environment external to the ingestible device can be applied and / or affixed to the inner surface 4364 of the ingestible device. In some embodiments, the cover member 4348 is a thin film 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 pressurization of the dispensable substance) can cause the dispensable substance to pierce the cover member or partially peel off / away from the outer surface of the ingestible device to allow the formation of a jet stream 4362 containing the dispensable substance. The cover member 4348 can be composed of various materials, e.g., a COC-based film, e.g., a COC+LLDPE laminate, etc. In some embodiments, the cover member 4348 can be composed of a material that is intended to be insoluble in gastric media, but can be broken down in the small intestine based on pH (e.g., an enteric material) and / or one or more enzymes, e.g., one or more pancreatic enzymes (e.g., a lipid-based material). The cover member 4348 can be composed of a material that can hydrate and / or soften without significant dissolution when exposed to gastric media. The cover member 4348 in this and other embodiments described herein can be composed of a gas permeable film (e.g., which can aid in degassing during the filling process of the ingestible device). The cover member 4348 can be applied to the inner surface 4364 of the ingestible device, e.g., using a molding process (e.g., based on in-mold labeling or blow molding). The cover member can be, e.g., 20-40 μιη (e.g., 25-35 μιη, 30 μιη) thick. In some embodiments, the cover member can be applied / affixed without adhesive, e.g., a molded bond.

[0282] In some embodiments, as Figure 45A and 44BAs depicted, the cover member can be a feature, e.g., a molded feature 4466, formed on (or adjacent to) the inner end of the nozzle opening 4402 and forming a barrier between a fluid volume 4410 comprising a dispensable substance (e.g., a liquid containing a drug) held within the housing 4404 and the ingestible device's external environment. Internal pressure from the pressurized dispensable substance (e.g., during release of the pressurized dispensable substance) can cause the dispensable substance to pierce the cover member 4466, causing the cover member to fully or partially peel off / disengage from the ingestible device's outer surface to allow formation of a jet stream 4464 containing the dispensable substance. The cover member can be composed of various materials, e.g., a COC-based film, e.g., a COC+LLDPE laminate, etc. In some embodiments, the cover member 4466 can be composed of a material that is intended to be insoluble in gastric media, but can be broken down in the small intestine based on pH (e.g., an enteric material) and / or one or more enzymes, e.g., one or more pancreatic enzymes (e.g., a lipid-based material). The cover member 4466 can be composed of a material that can hydrate and / or soften without significant dissolution when exposed to gastric media.

[0283] In some embodiments, as depicted in FIGS. 45A-45B, the cover member 4548 can be a cover member tethered 4568 to the ingestible device, e.g., tethered to an outer portion of the housing 4504. The cover member 4548 can be formed of a flexible material, e.g., 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 ingestible device's nozzle opening 4502 to allow formation of a jet stream 4562 containing the dispensable substance. Figure 46A and 45B In some embodiments, as depicted in FIGS. 45A-45B, the cover member 4548 can be a cover member tethered 4568 to the ingestible device, e.g., tethered to an outer portion of the housing 4504. The cover member 4548 can be formed of a flexible material, e.g., 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 ingestible device's nozzle opening 4502 to allow formation of a jet stream 4562 containing the dispensable substance.

[0284] In some embodiments, as depicted in FIGS. 45A-45B, the cover member 4548 can be a cover member tethered 4568 to the ingestible device, e.g., tethered to an outer portion of the housing 4504. The cover member 4548 can be formed of a flexible material, e.g., 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 ingestible device's nozzle opening 4502 to allow formation of a jet stream 4562 containing the dispensable substance. Figures 47A-47C and 46B In some embodiments, as depicted in FIGS. 45A-45B, the cover member 4548 can be a cover member tethered 4568 to the ingestible device, e.g., tethered to an outer portion of the housing 4504. The cover member 4548 can be formed of a flexible material, e.g., 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 ingestible device's nozzle opening 4502 to allow formation of a jet stream 4562 containing the dispensable substance.

[0285] In some embodiments, as depicted in FIGS. 45A-45B, the cover member 4548 can be a cover member tethered 4568 to the ingestible device, e.g., tethered to an outer portion of the housing 4504. The cover member 4548 can be formed of a flexible material, e.g., 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 ingestible device's nozzle opening 4502 to allow formation of a jet stream 4562 containing the dispensable substance. Figure 48As depicted, the nozzle opening 4702 can be blocked by a plug 4750 formed of a liquid-filled gel applied from an external device 4770 of the ingestible device (e.g., via a nozzle or rotating mandrel). The liquid-filled gel can be hardened to provide the plug 4750 prior to the dispensable substance filling process. The gel can be composed of a material that is substantially insoluble in gastric media / dispensible substance, but can be broken down in small intestine-based pH (e.g., enteric material) and / or one or more enzymes, such as one or more pancreatic enzymes (e.g., lipid-based material). Internal pressure from the pressurized dispensable substance (e.g., during pressurized dispensable substance release) 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 stream 4762 containing the dispensable substance.

[0286] Figure 48 and 49 An embodiment of an ingestible device 4800 utilizing an internal piston is depicted. The ingestible device 4800 contains a dispensable substance that is not under pressure when ingested by a subject. In Figure 49 the nozzle 4802 is depicted as being covered, and in Figure 50A the nozzle 4802 is uncovered. The ingestible device 4800 has a housing portion 4804 and 4806 connected by a union 4808 and has a fluid volume 4810 containing a dispensable substance, a spring 4814, a gas cartridge 4816, a first piston 4818a and a second piston 4818b, a perforator 4820, and an O-ring 4832. The perforator 4820 is held in place with an enteric trigger 4826 that dissolves and acts as a trigger mechanism. When the device 4800 is ingested 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 perforator 4820 in place. When the device 4800 reaches the appropriate location in the GI tract, the enteric trigger 4826 degrades and / or dissolves (e.g., due to pH, change in pH, presence of certain enzymes, and / or concentration of certain enzymes), causing the spring 4814 to force the perforator 4820 into the gas cartridge 4816, thereby puncturing the gas cartridge 4816 and causing gas under elevated pressure to exit the gas cartridge 4816. This causes the gas cartridge 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, such that the dispensable substance is delivered out of the nozzle 4802 in the form of a jet stream. This can result in trans-epithelial and / or epithelial delivery of a therapeutic agent contained in the dispensable substance.

[0287] In some embodiments, a plug / cover can be secured over a nozzle opening, wherein the plug / cover is further connected to a piercer component of an ingestible device via a connector and a loop component. Figure 51A and 50B An embodiment of an ingestible device 5000 comprising a plug / cover assembly is depicted. The ingestible device 5000 comprises: a nozzle opening 5002, a drug reservoir 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 cartridge 5016, a union 5008, and a piston 5018. The ingestible device 5000 optionally comprises a nozzle cover 5048.

[0288] The plug / cover assembly can be a single shaped piece, for example composed 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 / cover assembly can further comprise a connector 5052 that connects the plug / cover assembly to a loop 5054 component that can be attached to the top of the piercer 5020 and the outside of the trigger element 5026, such that when the piercer is released, for example after the trigger element 5026 dissolves / degrades, the loop component 5054 is pulled down by the piercer 5020, and by the movement of the loop 5054, the plug / cover 5050 is pulled away from the nozzle opening 5002. In some embodiments, the plug / cover 5050 is pulled away from the nozzle opening 5002 by the movement of the loop 5054 in a direction parallel to the length of the ingestible device 5000, for example along the outside surface of the ingestible device. In some embodiments, the plug / cover 5050 is pulled away from the nozzle opening 5002 by the movement of the loop 5054 in a direction outward (for example normal or at an angle) from the outside surface of the ingestible device 5000.

[0289] In some embodiments, a band can be secured over one or more nozzle openings, wherein the band is further connected to a piercer component of an ingestible device via a connector and a loop component. Figures 52A-52D and 51B An embodiment of an ingestible device 5100 comprising a band assembly is depicted. The ingestible device 5100 comprises: a nozzle opening 5102, a drug reservoir 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 cartridge 5116, a union 5108, and a piston 5118. The ingestible device 5100 optionally comprises a nozzle cover 5148.

[0290] The band assembly can be a single formed piece, for example composed of plastic material, including the band 5156, the connector 5152, and the loop component 5154. The band assembly can instead be a multi-piece assembly composed of the band 5156, which is placed around the ingestible device 5100 during the filling process, and a connector / loop assembly, which is secured to the band 5156 and the perforator component 5120. The band assembly can be connected to the perforator 5120 by the loop component 5154, which can be attached to the top of the perforator component and the outside of the trigger element 5126, such that when the perforator is released, for example after the trigger element 5126 dissolves / degrades, the loop component 5154 is pulled down by the perforator 5120, and the band 5156 is pulled away from the nozzle opening 5102 (for example along the length of the ingestible device 5100) to expose the nozzle opening 5102 by the movement of the loop 5154, after which or simultaneously the dispensable substance is delivered via the nozzle opening 5102.

[0291] In some embodiments, as depicted in Figure 53A The ingestible device 5200 can include a sliding cover 5248. The sliding cover 5248 can be a single formed piece, for example a sleeve composed of 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 perforator component 5220 and the outside of the trigger element 5226, such that when the perforator is released, for example after the trigger element 5226 dissolves / degrades, the sliding cover 5248 is pulled down by the perforator 5220, and by the movement of the perforator 5220, the sliding cover 5248 is 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, for example along the outer surface of the ingestible device, the sliding cover 5248 can be pulled away from the nozzle opening 5202, after which or simultaneously the dispensable substance within the fluid volume 5210 is delivered via the nozzle opening 5202.

[0292] In some embodiments, as depicted in Figure 54A and 53BAs depicted in the partial rendering of ingestible device 5300 in FIG. 53, ingestible device 5300 includes a cap 5334 that is secured over one end of ingestible device 5300 and partially encloses volume 5310. A seal 5358, such as a plasticized elastomer-based seal, can be used to seal the dispensable substance within volume 5310 while cap 5334 is secured over the end of ingestible device 5300 and to prevent dispensing of the dispensable substance. Seal 5358 can additionally prevent cap 5334 from moving prior to delivery of the dispensable substance. When device 5300 is swallowed by a subject, the enteric trigger prevents the dispensable substance in the fluid volume from being under pressure by holding the spring and perforator in place. When the device reaches the appropriate location in the GI tract, the enteric trigger degrades and / or dissolves (e.g., due to pH, changes in pH, presence of certain enzymes, and / or concentrations of certain enzymes), causing the spring to force the perforator into the gas cylinder, thereby puncturing the gas cylinder and causing the gas under elevated pressure to exit the gas cylinder. This causes the gas cylinder 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, causing the dispensable substance to be delivered from the nozzle in a jet stream. This can result in trans-epithelial and / or epithelial delivery of a therapeutic agent contained in the dispensable substance.

[0293] In some embodiments, as depicted in the partial rendering of ingestible device in FIG. 54, Figure 55 and 54B As depicted in the partial rendering of ingestible device 5400 in FIG. 54, ingestible device 5400 includes an inflatable membrane volume 5460, such as a gas bladder or the like, positioned within volume 5410 that includes a dispensable substance and arranged to seal nozzle opening 5402 when inflatable volume 5460 is inflated. In some embodiments, inflatable membrane volume 5460 can be conformal with one or more contours of ingestible device housing 5404, such as internal curvatures. Inflatable membrane volume 5460 can be composed of a bladder and / or a soft material, such as a low durometer elastomer. When device 5400 is swallowed by a subject, the enteric trigger prevents the dispensable substance in the fluid volume from being under pressure by holding the spring and perforator in place. When the device reaches the appropriate location in the GI tract, the enteric trigger degrades and / or dissolves (e.g., due to pH, changes in pH, presence of certain enzymes, and / or concentrations of certain enzymes), causing the spring to force the perforator into the gas cylinder, thereby puncturing the gas cylinder and causing the gas under elevated pressure to exit the gas cylinder. This causes the gas cylinder to press against the piston and apply pressure to the fluid volume. The pressurized fluid volume applies pressure to inflatable membrane volume 5460 and causes inflatable membrane volume to deflate or otherwise reposition to expose nozzle opening 5402, causing the dispensable substance to be delivered from the nozzle in a jet stream. This can result in trans-epithelial and / or epithelial delivery of a therapeutic agent contained in the dispensable substance.

[0294] In some implementation schemes, such as in DELIVERY OF THERAPEUTIC AGENTS As depicted in the partial representation of the ingestible device, the ingestible device 5500 does not include a covering member. For example, the nozzle opening 5502 may be exposed, such that when the ingestible device 5500 is swallowed / inserted, the air gap and / or surface tension effect in the nozzle opening 5502 may prevent or avoid damage to the internal components or dispensable substances (e.g., liquids containing medication) within the ingestible device by gastric movement. In other words, a differential force may be generated between external intestinal forces / pressures and the internal forces of the dispensable substances within the volume of the ingestible device by movement of the ingestible device within the gastric region. For example, the surface tension of the dispensable substances within the volume 5510 of the ingestible device may be higher than that of the surrounding environment within the gastric region of the body, such as external intestinal forces / pressures, such that a significant percentage of the dispensable substances are retained within the volume of the ingestible device until the point of delivery of the dispensable substances, e.g., until the piston 5518 applies pressure to the volume 5510 to force the dispensable substances retained within the volume 5510 out of the nozzle opening 5502. In one instance, at least 75% (e.g., at least 85%, at least 95%) of the dispensable substance is retained within the volume of the ingestible device until the point of delivery of the dispensable substance to the stomach region of the body.

[0295] Device for epithelial delivery

[0296] Typically, epithelial delivery can be achieved at any desired location within the subject's GI tract. In some embodiments, epithelial delivery is achieved in the subject's small intestine, such as in the duodenum, jejunum, and / or ileum. In some embodiments, epithelial delivery is achieved in the subject's large intestine (e.g., cecum or colon).

[0297] In some implementations, epithelial delivery can be achieved using any of the ingestible devices described above regarding epithelial delivery. In such implementations, the relevant parameters are typically modified accordingly. Typically, this modification involves changing the values ​​of the relevant parameters. Examples are provided in the following paragraphs.

[0298] Generally, an ingestible device for epithelial delivery is configured to deliver a jet stream of dispensable material having a peak jet power of at least about 1 mW (e.g., at least about 1.5 mW, at least about 2 mW, at least about 2.5 mW) and / or up to about 4 mW (e.g., up to about 3.5 mW, up to about 3 mW). In some embodiments, the ingestible device for epithelial delivery is configured to deliver a jet stream of dispensable material having a peak jet power of about 1 mW to about 4 mW (e.g., about 1 mW to about 3.5 mW, about 2 mW to about 3 mW).

[0299] Generally, the ingestible device for epithelial delivery is configured to deliver a jet stream of dispensable substance having a peak jet pressure of at least about 2 psig (e.g., at least about 2.5 psig, at least about 3 psig, at least about 3.5 psig, at least 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 epithelial delivery is configured to deliver a jet stream of dispensable substance 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).

[0300] Generally, the ingestible device for epithelial delivery is configured to deliver a jet stream of dispensable substance having a peak jet force of at least about 0.5 mN (e.g., at least about 0.6 mN, at least about 0.7 mN, at least about 0.8 mN, at least about 0.9 mN) and / or at most about 2 mN (e.g., at most about 1.8 mN, at most about 1.6 mN, at most about 1.4 mN, at most about 1.2 mN). In some embodiments, the ingestible device for epithelial delivery is configured to deliver a jet stream of dispensable substance having a peak jet force of about 0.5 mN to about 2 mN (e.g., about 0.6 mN to about 1.8 mN, about 0.7 mN to about 1.6 mN, about 0.8 mN to about 1.4 mN, about 0.9 mN to about 1.2 mN).

[0301] Generally, the ingestible device for epithelial delivery is configured to deliver a jet stream of dispensable substance having 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). In some embodiments, the ingestible device for epithelial delivery is configured to deliver a jet stream of dispensable substance having a peak jet velocity of about 2 m / s to about 20 m / s (e.g., about 3 m / s to about 15 m / s, about 4 m / s to about 10 m / s, about 5 m / s to about 8 m / s).

[0302] Generally, the ingestible device for epithelial delivery is configured to provide an internal 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).

[0303] Generally, the ingestible device for epithelial delivery is 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).

[0304] Generally, the ingestible device for epithelial delivery is configured to contain a dispensable substance at a peak fluid pressure of 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).

[0305] Generally, the ingestible device for epithelial delivery contains a dispensable substance at an initial fluid volume of at least about 50 microliters (pL) (e.g., at least about 100 pL, at least about 150 pL, at least about 200 pL, at least about 250 pL) and / or at most about 800 pL (e.g., at most about 700 pL, at most about 600 pL, at most about 500 pL, at most about 400 pL). In some embodiments, the ingestible device for epithelial delivery contains a dispensable substance at an initial fluid volume of about 50 pL to about 800 pL (e.g., about 100 pL to about 600 pL, about 200 pL to about 400 pL).

[0306] Generally, the ingestible device for epithelial delivery is configured to provide a delivery fluid volume of a dispensable substance of at least about 50 microliters (pL) (e.g., at least about 100 pL, at least about 150 pL, at least about 200 pL, at least about 250 pL) and / or at most about 800 pL (e.g., at most about 700 pL, at most about 600 pL, at most about 500 pL, at most about 400 pL). In some embodiments, the ingestible device for epithelial delivery has a fluid volume of a dispensable substance of about 50 pL to about 800 pL (e.g., about 100 pL to about 600 pL, about 200 pL to about 400 pL).

[0307] Generally, ingestible devices for epithelial delivery accommodate dispensable substances in a final fluid volume of at most about 100 microliters (mL) (e.g., at least about 90 mL, at least about 80 mL, at least about 70 mL, at least about 60 mL) and / or at most at least 5 mL (e.g., at most about 10 mL, at most about 20 mL, at most about 30 mL, at most about 40 mL). In some embodiments, ingestible devices for epithelial delivery accommodate dispensable substances in a fluid volume of about 30 mL to about 70 mL (e.g., about 40 mL to about 60 mL, about 45 mL to about 55 mL).

[0308] Generally, ingestible devices for epithelial delivery are 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.

[0309] Generally, ingestible devices for epithelial delivery are configured to provide a delivery fluid volume of at least about 20 microliters (mL) (e.g., at least about 25 mL, at least about mL, at least about 50 mL, at least about 75 mL, at least about 100 mL) and / or at most about 800 mL (e.g., at most about 700 mL, at most about 600 mL, at most about 500 mL, at most about 400 mL, at most about 300 mL) per opening (e.g., per nozzle) for delivering the dispensable substance. In some embodiments, ingestible devices for epithelial delivery are configured to provide a delivery fluid volume of about 25 mL to about 400 mL (e.g., about 25 mL to about 300 mL, about 100 mL to about 300 mL) per opening (e.g., per nozzle) for delivering the dispensable substance.

[0310] In certain embodiments, ingestible devices for epithelial delivery are configured as disclosed above with respect to trans-epithelial delivery, but with a relatively large number of nozzles and a relatively large nozzle diameter, such that the performance properties (discussed above) for epithelial delivery can be achieved. As an example, in some embodiments, ingestible devices for epithelial delivery have at least 25 nozzles (e.g., at least 30 nozzles, at least 40 nozzles, 50 nozzles). In some embodiments, such ingestible devices for epithelial delivery have 30 nozzles, 31 nozzles, 32 nozzles, 33 nozzles, 34 nozzles, 35 nozzles, 36 nozzles, 37 nozzles, 38 nozzles, or 40 nozzles. Each nozzle can have, for example, a diameter of at least about 1 mm (e.g., at least about 1.5 mm, at least about 2 mm) and / or at most about 3 mm (e.g., at most about 2.5 mm). For example, in such ingestible devices, each nozzle can have a diameter of about 1 mm to about 3 mm (e.g., about 1 mm to about 2.5 mm, about 2 to about 2.5 mm).

[0311] Devices for local delivery

[0312] Generally, local delivery can be achieved at any desired location within the GI tract of a subject. In some embodiments, local delivery is achieved in the small intestine of a subject, e.g., in the duodenum, jejunum, and / or ileum. In certain embodiments, local delivery is achieved in the large intestine of a subject, e.g., the cecum or colon.

[0313] Generally, the ingestible device for local delivery is configured to provide an internal pressure of at least about 5 psig (e.g., at least about 8 psig, at least about 10 psig) and / or at most about 50 psig (e.g., at most about 40 psig, at most about 30 psig, at most about 20 psig, at most about 15 psig). In certain embodiments, the ingestible device for local delivery is configured to provide an internal pressure of about 5 psig to about 50 psig (e.g., about 5 psig to about 30 psig, about 5 psig to about 20 psig, about 8 psig to about 20 psig, about 10 psig to about 15 psig).

[0314] Generally, the ingestible device for local delivery is configured to contain a dispensable substance at a peak fluid pressure of at least about 5 psig (e.g., at least about 8 psig, at least about 10 psig) and / or at most about 50 psig (e.g., at most about 40 psig, at most about 30 psig, at most about 20 psig, at most about 15 psig). In certain embodiments, the ingestible device for local delivery is configured to deliver a jet of dispensable substance having a peak fluid pressure of about 5 psig to about 50 psig (e.g., about 5 psig to about 30 psig, about 5 psig to about 20 psig, about 8 psig to about 20 psig, about 10 psig to about 15 psig).

[0315] Generally, the ingestible device for local 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.

[0316] Generally, ingestible devices for local delivery hold dispensable substance in an initial fluid volume of at least about 50 microliters (mL) (e.g., at least about 100 mL, at least about 150 mL, at least about 200 mL, at least about 250 mL) and / or at most about 800 mL (e.g., at most about 700 mL, at most about 600 mL, at most about 500 mL, at most about 400 mL). In some embodiments, ingestible devices for local delivery hold dispensable substance in an initial fluid volume of about 50 mL to about 800 mL (e.g., about 100 mL to about 600 mL, about 200 mL to about 400 mL).

[0317] Generally, ingestible devices for local delivery hold dispensable substance in a final fluid volume of at most about 100 microliters (mL) (e.g., at least about 90 mL, at least about 80 mL, at least about 70 mL, at least about 60 mL) and / or at most at least 5 mL (e.g., at most about 10 mL, at most about 20 mL, at most about 30 mL, at most about 40 mL). In some embodiments, ingestible devices for local delivery hold dispensable substance in a fluid volume of about 30 mL to about 70 mL (e.g., about 40 mL to about 60 mL, about 45 mL to about 55 mL).

[0318] In certain embodiments, ingestible devices for local delivery are configured as disclosed above in relation to the discussion of trans-epithelial delivery, but with a relatively larger number of nozzles and a relatively larger nozzle diameter, such that the performance properties (discussed above) for local delivery can be achieved. As an example, in some embodiments, ingestible devices for local delivery have at least 25 nozzles (e.g., at least 30 nozzles, at least 40 nozzles, 50 nozzles). In some embodiments, such ingestible devices for local delivery have 30 nozzles, 31 nozzles, 32 nozzles, 33 nozzles, 34 nozzles, 35 nozzles, 36 nozzles, 37 nozzles, 38 nozzles, or 40 nozzles. Each nozzle can have, for example, a diameter of at least about 1 mm (e.g., at least about 1.5 mm, at least about 2 mm) and / or at most about 3 mm (e.g., at most about 2.5 mm). For example, in such ingestible devices, each nozzle can have a diameter of about 1 mm to about 3 mm (e.g., about 1 mm to about 2.5 mm, about 2 to 2.5 mm).

[0319] THERAPEUTIC AGENTS FOR DELIVERY

[0320] Provided herein are ingestible devices and methods of delivering a therapeutic agent into the lumen of the intestine, mucus, mucosa, and / or submucosa of the GI tract of a subject by local, epithelial, or trans-epithelial administration to the GI tract. Current methods of administration for most poorly orally bioavailable macromolecular or small molecule therapeutic agents are subcutaneous (SC), intramuscular (IM), or bolus intravenous (IV) injection targeting systemic circulation. The devices and methods described herein provide an alternative route of administration to current injectable medications that can result in greater convenience and compliance as they minimize or avoid the logistical challenges, patient compliance and dependency challenges, pain and discomfort associated with traditional routes of administration.

[0321] In some embodiments of the devices or methods described herein, 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 a proximal portion of the small intestine, e.g., the duodenum or jejunum. In some embodiments of any of the devices or methods described herein, the location is in a 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 a proximal portion of the large intestine, e.g., the cecum, ascending colon, or transverse colon. In some embodiments of any of the devices or methods described herein, the location is in a distal portion of the large intestine, e.g., the transverse colon or descending colon.

[0322] Further, by providing a higher concentration of therapeutic agent in the GI tissue, the devices and methods described herein are particularly well-suited for treating diseases and conditions of the endoderm, including the liver.

[0323] In some embodiments of any of the devices or methods described herein, the 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, e.g., about 7.0.

[0324] In some embodiments of any of the devices or methods described herein, release of the therapeutic agent is triggered by degradation of a release component located in the device. In some embodiments of any of the devices or methods described herein, release of the therapeutic agent is dependent on enzyme activity at or near the site. In some embodiments of any of the devices or methods described herein, the composition includes a plurality of electrodes including a coating, and release of the therapeutic agent is triggered by an electrical signal of the electrodes resulting from interaction of the coating with the intended release site of the therapeutic agent. In some embodiments of any of the devices or methods described herein, release of the therapeutic agent is triggered by a remote electromagnetic signal. In some embodiments of any of the devices or methods described herein, release of the therapeutic agent is triggered by generation of a gas in the composition in an amount sufficient to expel the therapeutic agent. In some embodiments of any of the devices or methods described herein, release of the therapeutic agent is triggered by an electromagnetic signal generated within the device according to a predetermined drug release profile.

[0325] INHIBITORY NUCLEIC ACIDS OF TNFα

[0326] Therapeutic agents suitable for use in the devices and methods described herein include 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 (e.g., inhibitory nucleic acids, antisense nucleic acids, siRNA, ribozymes, etc.). In some embodiments, the therapeutic agent is a macromolecule having a molecular weight of at least about 60 kilodaltons (kDa), or from about 60 kDa to about 200 kDa, from about 60 kDa to about 175 kDa, or from about 60 kDa to about 150 kDa.

[0327] 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 from about 20 kDa to about 200 kDa, from about 20 kDa to about 175 kDa, or from about 20 kDa to about 150 kDa.

[0328] In some embodiments, the therapeutic agent is a molecule such as a protein or peptide having a molecular weight of 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 from 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 having a molecular weight of from about 5 kDa to about 10 kDa, e.g., 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.

[0329] In some embodiments, the therapeutic agent is a small molecule. As used herein, a “small molecule” is a compound, typically an organic compound, having a molecular weight of about 50 Da to about 1500 Da, about 60 Da to about 1500 Da, about 500 Da to about 1000 Da, or no more than about 1500 Da, e.g., about 1000 Da, about 750 Da, or about 500 Da. In some embodiments, the therapeutic agent is a small molecule having a molecular weight of about 50 Da to about 1500 Da. In some embodiments, the therapeutic agent is a small molecule having a molecular weight of about 150 Da to about 1500 Da.

[0330] 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 agonist, cetrelimab, ligelizumab, PF-06801591, JNJ-64407564, polatuzumab vedotin, PF-06817024, NOV-12, BIIB-054, CTL-119, JNJ-61178104, spartalizumab, RNA CART123, LY-3300054, PD-1 mAb agonist, CART-EGFRvIII, NOV-10, TQJ-230, PF-06863135, PCA-062, JNJ-64041757, CNTO-2476, tiragolumab, PF-06946860, 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 1.

[0331] Table 1

[0332]

[0333]

[0334] a Capsule number assumes a drug reservoir of about 400 microliters

[0335] sq: subcutaneous

[0336] IFU: instructions for use

[0337] IU: international unit

[0338] 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, galunisertib, 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 formulations, TAK-418, and vonoprazan fumarate + aspirin combination.

[0339] 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 that 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 to angiopoietin 2 (Ang2). An exemplary mAb selective to Ang2 is LY3127804.

[0340] Therapeutic agents for growth disorders

[0341] In some embodiments, a therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent for treating a growth disorder. In some embodiments, the growth disorder is growth hormone deficiency or disorder (GHD). In some embodiments, the GHD is acquired, congenital, or idiopathic; or a combination thereof. In some embodiments, the GHD is a result of trauma, infection, radiation therapy, or tumor growth. In some embodiments, the GHD is adult-onset GHD.

[0342] Exemplary therapeutic agents for treating growth impairment include, but are not limited to, growth hormone, including, but not limited to, somatropin (growth hormone), lonapegsomatropin, YPEG-somatropin, efpeg somatropin, human growth hormone (HGH), recombinant HGH (rHGH), PEGylated rHGH, somapacitan, somatrogon, genotropin, humatrope, norditropin, nutropin, omnitrope, Serostim, TJ-101, ALT-P1, and JR-142; and biosimilars and follow-on biologies thereof. In some embodiments, the growth hormone is rHGH. Examples of suitable rHGH include, but are not limited to, recombinant somatropin, such as genotropin, humatrope, norditropin, nutropin, omnitrope, Serostim, and

[0343] In some embodiments, the therapeutic agent for treating growth impairment suitable for use with the devices and methods described herein is somatropin or a biosimilar or follow-on biologic thereof.

[0344] In some embodiments, the therapeutic agent for treating growth impairment suitable for use with the devices and methods described herein is somapacitan or a biosimilar or follow-on biologic thereof.

[0345] Therapeutic agents for fibrosis

[0346] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent for treating fibrosis. In some embodiments, the therapeutic agent is a biologic therapeutic agent. In some embodiments, the therapeutic agent is a small molecule. In some embodiments, the therapeutic agent is a non-oral therapeutic agent.

[0347] In some embodiments, the fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the fibrosis is cystic fibrosis.

[0348] Exemplary therapeutic agents for treating fibrosis for delivery using any of the devices or methods described herein include those listed in Table 2.

[0349] Table 2: Therapeutic agents for treating fibrosis suitable for delivery via an ingestible device

[0350]

[0351]

[0352] Therapeutic agents for asthma

[0353] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a drug for treating asthma. Asthma is a chronic inflammatory disorder of the pulmonary airways that causes difficulty breathing. In some embodiments, the drug for treating asthma is a small molecule. In some embodiments, the small molecule drug or combination of drugs for treating asthma is selected from RG-6151, mometasone + indacaterol, indacaterol + glycopyrronium bromide + mometasone furanoate, and fevipiprant. In some embodiments, the drug for treating asthma is an antibody or fragment thereof. In some embodiments, the antibody drug for treating asthma is selected from omalizumab, tezepelumab, benralizumab, afasevikumab, RG-6149, dectrekumab + VAK-694, NOV-14, CSJ-117, or a biosimilar thereof. In some embodiments, the drug for treating asthma is a combination of a small molecule and / or an antibody or fragment thereof.

[0354] Therapeutic agents for neurological and / or psychiatric disorders or conditions

[0355] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a drug for treating a neurological or psychiatric disorder condition. Examples of neurological or psychiatric diseases or conditions include, but are not limited to, Alzheimer’s disease, anxiety, Parkinson’s disease, multiple sclerosis, panic disorder, schizophrenia, chronic pain, neuropathic pain, migraine, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, cerebral aneurysm, muscular dystrophy, obsessive-compulsive disorder, eating disorder, bipolar disorder, depression, narcolepsy, and insomnia.

[0356] In some embodiments, the drug used to treat a neurological or psychiatric disorder and related symptoms is an antibody and biologic analogs thereof. In some embodiments, the drug used to treat a neurological or psychiatric disorder and related symptoms is an antibody-drug conjugate. In some embodiments, the drug used to treat a neurological or psychiatric disorder and related symptoms is a small molecule. In some embodiments, the drug used to treat a neurological or psychiatric disorder and related symptoms is an inhibitory nucleic acid such as an antisense nucleic acid. In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is an imaging agent used to diagnose a neurological or psychiatric disorder. In some embodiments, the imaging agent is a radiolabeled protein or peptide. In some embodiments, the imaging agent is a radiolabeled small molecule.

[0357] In some embodiments, the neurological disorder is Alzheimer’s disease. In some embodiments, the drug used to treat Alzheimer’s disease is selected from solanezumab, donanemab, LY-3303560, LY-3372993, liraglutide, MEDI-1814, MC-1, LY-3002815, LY-3154207, ACI-35, JNJ-63733657, BAN-2401, gosuranemab, IONIS-MAPTRx, BIIB-076, elenbecestat, RG-6100, crenezumab, amilomotide, and umibecestat.

[0358] In some embodiments, the neurological disorder is Parkinson’s disease. In some embodiments, the drug used to treat Parkinson’s disease is selected from PF-06412562, LY-3154207, and MEDI-1341.

[0359] In some embodiments, the neurological disorder is pain. In some embodiments, the pain is chronic pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is migraine. In some embodiments, the drug used to treat pain is selected from fentanyl, PACAP38 mAb, BIIB-095, vixotrigine, lasmiditan, and olodanrigan.

[0360] In some embodiments, the psychiatric disorder is schizophrenia. In some embodiments, the drug for treating schizophrenia is selected from paliperidone palmitate, TAK-831, BIIB-104, TAK-041, and erteberel.

[0361] In some embodiments, the psychiatric disorder is depression. In some embodiments, the drug for treating depression includes aticaprant, esketamine, PF-04995274, JNJ-39393406, TAK-653, seltorexant, NR2B negative allosteric modulator, and MIJ-821.

[0362] Other therapeutic and imaging agents for treating or diagnosing neurological or psychiatric disorders suitable for use with the devices and methods described herein include, but are not limited to, glibenclamide, IONIS-C9Rx, [18F]MNI-968, 11C-PF-06809247, opicinumab, 18F-JNJ-64511070, PF-3463275, ADX-71149, JNJ-18038683, GDC-0134, tau-protein PET tracer (18F-JNJ-067), diroximel fumarate, 18F-GTP1 (RO-6880276), tofersen sodium, flortaucipir (18F) (18F-MNI-798), JNJ-61393215, JNJ-54175446, siponimod, branaplam, LML-134, mavoglurant, JNJ-48816274, SAF-312, JNJ-55375515, 18F-MNI-792, TAK-935, and TAK-925.

[0363] Therapeutic agents for metabolic and / or endocrine diseases or disorders

[0364] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent for treating a metabolic or endocrine disease or disorder. Examples of metabolic or endocrine diseases or disorders include, but are not limited to, diabetes, insulin resistance, hyperglycemia, hyperlipidemia, obesity, hepatic steatosis, hyperinsulinemia, obstructive sleep apnea, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, liver cirrhosis, hypertension, cardiovascular disease (CVD), pulmonary hypertension, primary sclerosing cholangitis, high blood triglycerides, hypertriglyceridemia, dyslipidemia, lipid disorder, type I hyperlipoproteinemia, familial hypercholesterolemia, hypercholesterolemia, lipodystrophy, acromegaly, myocardial infarction, and thromboembolic occlusion; and combinations thereof. In some embodiments, the metabolic or endocrine disease or disorder is obesity.

[0365] Therapeutic agents suitable for treating a metabolic or endocrine disease or disorder include, but are not limited to, abatacept, aldesleukin, allogeneic human langerhans islets, alogliptin, alpha-1 antitrypsin, anagliptin, atorvastatin, benaglutide, berberine, bermekimab, bimagrumab, cibinetide, cotadutide, diabecell, diamyd, dutogliptin, ebenatide, efpeglenatide, evogliptin, fluvastatin, FSI-965, gemigliptin, glutazumab, gosogliptin, hinsbet, iscalimab, LAI-287, linagliptin, lovastatin, mecasermin, omarigliptin, osilodrostat, otelixizumab, pegapamodutide, PEG-loxenatide, pitavastatin, pramlintide acetate, prolastin, protrans, pravastatin, rexmyelocel-t, rosuvastatin, saxagliptin, simvastatin, sitagliptin, somatostatin, teneligliptin, teplizumab, tirzepatide, trelagliptin, vildagliptin, and combinations thereof. In some embodiments, the therapeutic agent suitable for treating a metabolic or endocrine disease or disorder is STT-5058 (also known as ARGX-116), an antibody-based apolipoprotein C III (apoC-III) inhibitor that modulates blood triglyceride levels.Antibody-based apolipoprotein C III (apoC-III) inhibitors are described in WO 2004 / 081046, WO 2014 / 131008, WO 2018 / 193427, WO 2019 / 087115, and WO 2020 / 070678, each of which is hereby incorporated by reference. In some embodiments, the therapeutic agent suitable for treating a metabolic or endocrine disease or disorder is selected from the group consisting of bortezomib, fulvestrant, bendamustine (treanda), itolizumab, golimumab, canakinumab, porcine whipworm ova, NNC-0385-0434, NGM-282, BMS-986036, DACRA-089, RG-7992, cetilistat, and remestemcel-L; and biosimilars thereof. In some embodiments, the therapeutic agent suitable for treating a metabolic or endocrine disease or disorder is a bile acid sequestrant. Bile acid sequestrants are a group of lipid-lowering agents that are used to bind certain components of bile in the GI tract, thereby disrupting the reabsorption of bile acids from the intestinal tract and leading to an overall reduction in LDL cholesterol (LDL-c) in the blood. In some embodiments, the bile acid sequestrant is colesevelam. In some embodiments, the bile acid sequestrant is cholestyramine. In some embodiments, the bile acid sequestrant is colestipol. In some embodiments, the therapeutic agent suitable for treating a metabolic or endocrine disease or disorder is a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor. In some embodiments, the PCSK9 inhibitor is alirocumab or evolocumab. Other exemplary PCSK9 inhibitors for treating metabolic or endocrine diseases or disorders include those listed in Table 9.

[0366] Therapeutic agents for diabetes

[0367] In some embodiments, the metabolic or endocrine disease or disorder is diabetes. In some embodiments, the diabetes is Type I or Type II diabetes. In some embodiments, the diabetes is insulin-dependent diabetes mellitus. In some embodiments, the diabetes is non-insulin dependent diabetes mellitus. In some embodiments, the diabetes is gestational diabetes.

[0368] In some embodiments, the metabolic or endocrine disease or disorder is diabetes in combination with other diseases or disorders including, but not limited to, diabetes with Alzheimer's disease, diabetes with dementia, diabetes with Alzheimer's disease and dementia, diabetes with obesity, diabetes with NAFLD, diabetes with NASH, diabetes with NAFLD and NASH, and diabetes with cardiovascular disease. In some embodiments, the diabetes is diabetes with obesity.

[0369] Therapeutic agents suitable for treating a metabolic or endocrine disease or disorder include, but are not limited to, insulin, glucagon receptor agonists or glucagon-like peptide- 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, biguanides, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas, alpha-glucosidase inhibitors, maglitinides, thiazolidinediones, dopamine-2-agonists, bile acid sequestrants, peptide YY ligands, and amylin analogs.

[0370] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a peptide YY ligand. The gut hormone peptide YY (PYY), also known as peptide tyrosine tyrosine, is a 36-amino acid peptide that is synthesized and released by specific enteroendocrine cells called L-cells, primarily found in the distal GI tract (see, e.g., Karra et al., J. Physiol. 587(Pt 1): 19-25 (2009)). In some embodiments, the peptide YY ligand is NN-9747, NN-9748, NN-9775, or any of the peptide YY ligands disclosed in WO2016 / 198682, incorporated by reference herein in its entirety. In some embodiments, the peptide YY ligand is NN-9747 (PYY 1562, NNC0165-1562, NN-9748), an analog of the appetite-regulating hormone PYY, which can be used in monotherapy or in combination with the GLP-1 analog semaglutide. In some embodiments, NN-9747 or NN-9748 is administered subcutaneously qd. In some embodiments, NN-9747 is indicated for obesity. In October 2015, a phase I trial began and was completed in February 2017; N=93 (clinical trial identifier: NCT02568306; source: Novo Nordisk 2018 Annual Report). In some embodiments, NN-9748 is indicated for diabetes. In some embodiments, the peptide YY ligand is NN-9775 (NNC0165-1875), a peptide tyrosine 1875 analog (PYY 1875 analog) for potential SC treatment of obesity and overweight. NN-9748 is an analog of the appetite-regulating hormone PYY, intended for monotherapy or in combination with the GLP-1 analog semaglutide. In October 2018, the first human dose of NNC0165-1875 as monotherapy and in combination with semaglutide began, a phase I study; N=88 (clinical trial identifier: NCT03707990; source: Novo Nordisk 2018 Annual Report). In some embodiments, NN-9747 is the same drug substance as NN-9748.

[0371] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is an amylin analog. In some embodiments, the amylin analog is AM-833. In some embodiments, the metabolic or endocrine disease or disorder is obesity or diabetes with obesity.

[0372] In some embodiments, the therapeutic agent is NNC0247-0829. In some embodiments, the metabolic or endocrine disease or disorder is obesity or diabetes with obesity.

[0373] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a glucagon receptor agonist or a glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is glucagon. In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is NN-9277 (see, e.g., Brandt et al., J. Endocrinol. 283(2):R109-R119 (2018)). In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is NN-9423, which is a tri-agonist of human glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP), and glucagon receptor (GCG). In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is semaglutide; or a biosimilar thereof, or a reformulation thereof, e.g., In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is dulaglutide; or a biosimilar thereof. In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is albiglutide; or a biosimilar thereof. In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is exenatide; or a biosimilar thereof. In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is liraglutide; or a biosimilar thereof. In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is lixisenatide; or a biosimilar thereof. In some embodiments, the glucagon receptor agonist or GLP-1 receptor agonist is NNC-0090-2746.

[0374] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a dual GIP and GLP-1 receptor agonist. In some embodiments, the dual GIP and GLP-1 receptor agonist is LY3298176, which is a fatty acid-modified peptide with dual GIP and GLP-1 receptor agonist activity that can be used to treat type 2 diabetes. See, e.g., Coskun et al., Mol. Metab., 18:3-14 (2018).

[0375] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent for treating diabetes.

[0376] In some embodiments, the therapeutic agent for treating diabetes suitable for use with the devices and methods described herein is insulin. In some embodiments, the insulin is selected from the group consisting of human insulin, insulin aspart, insulin aspart 25, insulin degludec, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, and tregopil insulin.

[0377] In some embodiments, the therapeutic agent for treating diabetes suitable for use with the devices and methods described herein is a dipeptidyl peptidase-4 inhibitor (DPP-4). DPP-4 inhibitors are oral hypoglycemic agents that can be used to treat type 2 diabetes. Examples of DPP-4 inhibitors include, but are not limited to, sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gemigliptin, dutogliptin, and berberine.

[0378] In some embodiments, the therapeutic agent for treating diabetes suitable for use with the devices and methods described herein is an SGLT-2 inhibitor. SGLT-2 inhibitors are oral hypoglycemic agents that inhibit the reabsorption of glucose in the kidney and can be used to treat type 2 diabetes. Examples of SGLT-2 inhibitors include, but are not limited to, canagliflorzin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, sotagliflozin, and tofogliflozin.

[0379] In some embodiments, the therapeutic agent for treating diabetes suitable for use with the devices and methods described herein is an alpha-glucosidase inhibitor. Alpha-glucosidase inhibitors (AGIs) are oral hypoglycemic agents that can inhibit the digestion of carbohydrates by alpha-glucosidase enzymes in the gut into monosaccharides, thereby reducing blood glucose levels. Examples of alpha-glucosidase inhibitors include, but are not limited to, acarbose, miglitol, and voglibose.

[0380] Exemplary therapeutic agents for the treatment of diabetes for delivery using any of the devices or methods described herein include those listed in Table 3, and any combination thereof.

[0381] Table 3: Therapeutic agents for the treatment of diabetes suitable for delivery via an ingestible device

[0382]

[0383]

[0384]

[0385]

[0386]

[0387] Therapeutic agents for NASH / NAFLD

[0388] In some embodiments, the disease or disorder is NASH and / or NAFLD. In some embodiments, the therapeutic agents suitable for use with the devices and methods described herein are therapeutic agents for the treatment of nonalcoholic steatohepatitis (NASH) and / or nonalcoholic fatty liver disease (NAFLD). NASH (nonalcoholic steatohepatitis) is a fatty liver disease that affects up to 12% of American adults.

[0389] There are a number of potential drugs to treat this disease, which are selected from the group consisting of selonsertib, cenicriviroc, elafibranor, ocaliva, tropifexor, firocostat, cilofexor, aramchol, obeticholic acid, ARX618, BI 1467335, DS102, EDP-305, emricasan, gemcabene, belapectin (GR-MD-02), GRI-0621, firsocostat (GS-0976), GS-9674, IMM-124E, IONIS-DGAT2Rx, lanifibranor (IVA-337), lipaglyn, tropifexor (LJN452), nidufexor (LMB-763), licogliflozin bis (proline salt), resmetirom (MGL-3196), tipelukast (MN-001), MSDC-0602K, NC101, aldafermin (NGM282), NGM313, NS-0200, ozempic, PF-05221304, PF-06835919, PF-07055341, regrametraal, volixibat (SHP626), TVB-2640, VK2809, butyric acid, CER209, elafibranor, DUR928, MK-4074, OPRX-106, PF-06865571, PF-06882961, PXS-5382A, RG-125 (AZD4076), RYI-018, seladelpar, SGM-1019, and TVB-2640. In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is selected from the group consisting of selonsertib, cenicriviroc, elafibranor, ocaliva, tropifexor, firocostat, and cilofexor. These represent several biological mechanisms. Combinations of multiple drugs can be needed. In some embodiments, the drug is selected from the group consisting of selonsertib, cenicriviroc, elafibranor, ocaliva, tropifexor, firocostat, and cilofexor.

[0390] Exemplary therapeutic agents for the treatment of NASH and / or NAFLD for delivery using any of the devices or methods described herein include those listed in Table 4.

[0391] Table 4: Therapeutic agents for the treatment of NASH / NAFLD suitable for delivery via an ingestible device

[0392]

[0393] Therapeutic agents for rheumatoid arthritis

[0394] In some embodiments, the therapeutic agents suitable for use with the devices and methods described herein are therapeutic agents for the treatment of rheumatoid arthritis. Exemplary therapeutic agents for the treatment of rheumatoid arthritis for delivery using any of the devices or methods described herein include those listed in Table 5.

[0395] Table 5: Therapeutic agents for the treatment of rheumatoid arthritis suitable for delivery via an ingestible device

[0396]

[0397]

[0398]

[0399] Therapeutic agents for IBD

[0400] In some embodiments, the therapeutic agents suitable for use with the devices and methods described herein are therapeutic agents for the treatment of inflammatory bowel disease (IBD). Exemplary therapeutic agents for the treatment of IBD for delivery using any of the devices or methods described herein include those listed in Table 6.

[0401] Table 6: Therapeutic agents for the treatment of IBD suitable for delivery via an ingestible device

[0402]

[0403]

[0404] Therapeutic agents for short bowel syndrome

[0405] Short bowel syndrome (SBS) is a malabsorption disorder caused by a lack of functional small intestine. The main symptom is diarrhea, which can lead to dehydration, malnutrition, and weight loss. An exemplary therapeutic agent for the treatment of SBS for delivery using any of the devices or methods described herein includes teduglutide, which is a GLP-2 receptor agonist. Teduglutide is described in U.S. Patent Nos. 5,789,379 and 7,056,886, both of which are hereby incorporated by reference.

[0406] Therapeutic agents for blood disorders

[0407] In some embodiments, a therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent for the treatment of a blood disorder. In some embodiments, the blood disorder is anemia. In some embodiments, the therapeutic agent for the treatment of anemia is recombinant human erythropoietin. In some embodiments, the therapeutic agent for the treatment of anemia is a human erythropoietin analog. In some embodiments, the therapeutic agent for the treatment of anemia is selected from darbepoetin alfa / alpha and epoetin alfa; and biological analogs thereof.

[0408] Ziltivekimab (COR-001), a human IgGlk anti-inflammatory IL-6 monoclonal antibody, is being developed for potential treatment of anemia, chronic kidney disease, and / or cardiovascular disease. Ziltivekimab is an exemplary therapeutic agent for the treatment of any one or more of these conditions via delivery using any of the devices or methods described herein. Ziltivekimab is described in PCT Publication No. WO-2019136312, which is hereby incorporated by reference.

[0409] In some embodiments, the blood disorder is sickle cell disease. In some embodiments, the blood disorder is thalassemia. In some embodiments, the therapeutic agent for the treatment of sickle cell disease or thalassemia is selected from PF-04447943, crizanlizumab, EPI-01, and rivipansel sodium.

[0410] In some embodiments, the blood disorder is hemophilia. In some embodiments, the hemophilia is hemophilia A, hemophilia B, or Von Willebrand disease.

[0411] In some embodiments, the therapeutic agent for treating hemophilia is a replacement coagulation-promoting agent (ACP). In some embodiments, the ACP is an anti-tissue factor pathway inhibitor (anti-TFPI). Exemplary anti-TFPIs include, but are not limited to, concizumab, MG-1113A (GC Pharma, Gyeonggi-do, South Korea), marstacimab (PF-6741086), or BAY-1093884; or a biosimilar thereof. In some embodiments, the anti-TFPI is concizumab or a biosimilar thereof.

[0412] In some embodiments, the therapeutic agent for treating hemophilia is a Factor VIII mimetic. In some embodiments, the Factor VIII mimetic is emicizumab or a biosimilar thereof. In some embodiments, the Factor VIII mimetic is a bispecific antibody such as NNC0365-3769 A (Mim8) described in WO 2019 / 096874, which is incorporated by reference herein in its entirety.

[0413] In some embodiments, the therapeutic agent for treating hemophilia is selected from albutrepenonacog alfa, AMT-061, becotocog alfa, betafact, BIVV-001, BS027125, byclot, catridecacog, clotnine, dalcinonacog alfa, damoctocog alfa pegol, DTX-201, eftrenonacog alfa, eptacog alfa, Factor VIII, Factor IX, Factor X, fidanacogene elaparvovec, fitusiran, FLT-180a, hemoleven, lonoctocog alfa, LR-769, marzeptacog alfa, monofix, moroctocog alfa, NIBX-2101, nonacog alfa, nonacog beta pegol, octocog alfa, OPK-88005, recolyl, recombinate, rurioctocog alfa pegol, simoctocog alfa, SHP-654, SB-525, SPK-8011, SPK-8016, SCT-800, AAV2 / 8-HLP-FVIII-v3, susoctocog alfa, trenonacog alfa, and valoctocogene roxaparvovec; and biosimilars thereof.

[0414] In some embodiments, the therapeutic agent for treating hemophilia is recombinant Factor VIIa. Exemplary recombinant Factor VIIa include OPK-88005 (OPKO Health, Miami, FL) and LR-769 (see, e.g., Chevreux et al., Haemophilia 23(4):e324-e334 (2017)). Additional exemplary therapeutic agents for treating hemophilia for delivery using any of the devices or methods described herein include those listed in Table 7.

[0415] Table 7: Therapeutic agents for treating hemophilia suitable for delivery via an ingestible device

[0416]

[0417]

[0418]

[0419]

[0420] Therapeutic agents for hepatocellular carcinoma

[0421] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a hepatocellular carcinoma drug. Hepatocellular carcinoma is the most common type of primary liver cancer and is the most common cause of death in people with cirrhosis. Drugs that treat hepatocellular carcinoma include, but are not limited to, nivolumab, lenvatinib, sorafenib, regorafenib, PF-04518600, emibetuzumab, and carbozantinib.

[0422] Target-based therapeutic agents

[0423] GLP-1 receptor agonists

[0424] 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 type 2 diabetes mellitus (T2DM). In some embodiments, the GLP-1 receptor agonist is a peptide. In some embodiments, the GLP-1 receptor agonist is a small molecule. In some embodiments, the GLP-1 receptor agonist is formulated with a carrier or delivery agent. In some embodiments, the carrier or delivery agent is a salt of a medium-chain fatty acid derivative. In some embodiments, the carrier or delivery agent is the sodium salt of N-[8-(2-hydroxybenzoyl)amino]octanoic acid (SNAC). In some embodiments, the carrier or delivery agent is biotin.

[0425] In some embodiments, the GLP-1 receptor agonist is exanatide (synthetic exendin-4), a 39-residue peptide with 53% sequence identity to GLP-1, which has the following sequence: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS - NH2 (SEQ ID NO: 1).

[0426] In some embodiments, the GLP-1 receptor agonist is a compound having a structure selected from the group consisting of:

[0427]

[0428] or any pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide (Compound 3) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is semaglutide (Compound 4) or a pharmaceutically acceptable salt thereof.

[0429] In some embodiments, the GLP-1 receptor agonist is a compound having the structure:

[0430]

[0431] or a pharmaceutically acceptable salt thereof.

[0432] In some embodiments, the GLP-1 receptor agonist is an 11-mer GLP-1 receptor agonist. Exemplary 11-mer GLP-1 receptor agonists are represented by the structures and table below.

[0433]

[0434] In some embodiments, the GLP-1 receptor agonist is a compound having the structure:

[0435]

[0436] or a pharmaceutically acceptable salt thereof.

[0437] In some embodiments, the GLP-1 receptor agonist is a compound having a structure selected from:

[0438]

[0439] or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is Boc5 (Compound 12) or a pharmaceutically acceptable salt thereof.

[0440] In some embodiments, the GLP-1 receptor agonist is a compound having a structure selected from:

[0441]

[0442]

[0443] or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is TTP-054 or a pharmaceutically acceptable salt thereof, e.g., described in Edmonds et al., Annu. Rep. Med. Chem. (2013) 48: 119-130, which is incorporated by reference in its entirety.

[0444] In some embodiments, the GLP-1 receptor agonist is TTP273 or a pharmaceutically acceptable salt thereof, e.g., as described in Freeman et al., Diabetol. Conf. 53rd Annu. Meet. Eur. Assoc. study diabetes, EASD 2017. Port. Vol. 60. No. 1 Supplement 1. 2017, which is incorporated by reference in its entirety.

[0445] In some embodiments, the GLP-1 receptor agonist is OWL883, e.g., as described in Kawai et al., Diabetes (2018) 67 (Supplement 1): 1118-P, which is incorporated by reference in its entirety.

[0446] In some embodiments, the GLP-1 receptor agonist is a compound described in Edmonds and Price, “Chapter Nine: Oral GLP-1 Modulators for the Treatment of Diabetes,” Ann. Rep. Med. Chem. (2013) 48: 119-130, which is incorporated by reference in its entirety.

[0447] Other exemplary GLP-1 receptor agonists for delivery using any of the devices or methods described herein include those listed in Table 8.

[0448] Table 8: GLP-1 receptor agonists suitable for delivery via an ingestible device for the treatment of listed diseases and conditions

[0449]

[0450] PCSK9 inhibitors

[0451] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor. In some embodiments, the PCSK9 inhibitor treats one or more of an endocrine and / or metabolic disease or condition, a cardiovascular disease, and an infection. In some embodiments, the endocrine and / or metabolic disease or condition is familial hypercholesterolemia, hypercholesterolemia, or hyperlipidemia.

[0452] In some embodiments, the PCSK9 inhibitor is alirocumab. In some embodiments, the PCSK9 inhibitor is evolocumab. Other exemplary PCSK9 inhibitors for delivery using any of the devices or methods described herein include those listed in Table 9.

[0453] Table 9: PCSK9 inhibitors for the treatment of the listed diseases and conditions suitable for delivery via an ingestible device

[0454]

[0455]

[0456]

[0457] TNFα inhibitors

[0458] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a TNFα inhibitor. The term "TNFα inhibitor" or "TNF-α inhibitor" refers to an agent that directly or indirectly inhibits, impairs, reduces, down-regulates, or blocks TNFα activity and / or expression. In some embodiments, the TNFα inhibitor is an inhibitory nucleic acid, an antibody or antigen-binding fragment thereof, a fusion protein, a soluble TNFα receptor (soluble TNFR1 or soluble TNFR2), or a small molecule TNFα antagonist. In some embodiments, the inhibitory nucleic acid is a ribozyme, a small hairpin RNA, a small interfering RNA, an antisense nucleic acid, or an aptamer.

[0459] In other examples, such indirect TNFα inhibitors can be small molecule inhibitors of signaling components downstream of the TNFα receptor (such as any signaling component downstream of the TNFα receptor described herein or known in the art), small molecule inhibitors of proteins encoded by TNFα-induced genes (such as any protein encoded by a TNFα-induced gene known in the art), and small molecule inhibitors of transcription factors selected from the group consisting of NF-κΒ, c-Jun, and ATF2.

[0460] TNFα INHIBITOR ANTIBODIES

[0461] Exemplary TNFα inhibitors, as inhibitory nucleic acids targeting TNFα, include, for example, antisense DNA (e.g., Myers et al., J Pharmacol Exp Ther. 304(1): 411-424, 2003; Wasmuth et al., Invest. Opthalmol. Vis. Sci, 2003; Dong et al., J. Orthop. Res. 26(8): 1114-1120, 2008; U.S. Patent Application Serial Nos. 2003 / 0083275, 2003 / 0022848, and 2004 / 0770970; ISIS 104838; U.S. Patent Nos. 6,180,403, 6,080,580, and 6,228,642; Kobzik et al., Inhibition of TNF Synthesis by Antisense Oligonucleotides, in Manual of Antisense Methodology, Kluwer Academic Publishers, Vol. 4, pp. 107-123, 1999; Taylor et al., Antisense Nucleic Acid Drug Develop. 8(3): 199-205, 1998; Mayne et al., Stroke 32: 240-248, 2001; Mochizuki et al., J. Controlled Release 151(2): 155-161, 2011; Dong et al., J. Orthopaedic Res. 26(8): 1114-1120, 2008; Dong et al., Pharm. Res. 28(6): 1349-1356, 2011; and Pampfer et al., Biol. Reproduction 52(6): 1316-1326, 1995), antisense RNA, short interfering RNA (siRNA) (e.g., Taishi et al., Brain Research 1156: 125-132, 2007; Presumey et al., Eur. J. Pharm. Biopharm. 82(3): 457-467, 2012; Laroui et al., J. Controlled Release 186: 41-53, 2014; D’Amore et al., Int. J. Immunopathology Pharmacol. 21: 1045-1047, 2008; Choi et al., J. Dermatol. Sci. 52: 87-97, 2008; Qin et al., Artificial Organs 35: 706-714, 2011; McCarthy et al., J.Controlled Release 168:28-34, 2013; Khoury et al., Current Opin. Mol. Therapeutics 9(5):483-489, 2007; Lu et al., RNA Interference Technology From Basic Science to Drug Development 303, 2005; Xie et al., PharmaGenomics 4(6):28-34, 2004; Aldawsari et al., Current Pharmaceutical Design 21(31):4594-4605, 2015; Zheng et al., Arch. Med. Sci. 11:1296-1302, 2015; Peng et al., Chinese J. Surgery 47(5):377-380, 2009; Aldayel et al., Molecular Therapy. Nucleic Acids 5(7):e340, 2016; Bai et al., Current Drug Targets 16:1531-1539, 2015; U.S. Patent Application Publication Nos. 2008 / 0097091, 2009 / 0306356, and 2005 / 0227935; and WO 14 / 168264), short hairpin RNA (shRNA) (e.g., Jakobsen et al., Mol. Ther. 17(10): 1743-1753, 2009; Ogawa et al., PLoS One 9(3):e92073, 2014; Ding et al., Bone Joint 94-6 (Suppl. 11):44, 2014; and Hernandez-Alejandro et al., J. Surgical Res. 176(2):614-620, 2012), and microRNAs (see, e.g., WO 15 / 26249). In some embodiments, the inhibitory nucleic acid blocks splicing of the pre-mRNA of TNFa (e.g., Chiu et al., Mol. Pharmacol. 71(6): 1640-1645, 2007).

[0462] In some embodiments, the inhibitory nucleic acid, such as an aptamer (e.g., Orava et al., ACS Chem Biol. 2013; 8(1): 170-178, 2013), can block binding of the TNFa protein to its receptors (TNFR1 and / or TNFR2).

[0463] In some embodiments, the inhibitory nucleic acid can down-regulate the expression of a TNFα-induced downstream mediator (e.g., TRADD, TRAF2, MEKK1 / 4, MEKK4 / 7, JNK, AP-1, ASK1, RIP, MEKK 3 / 6, MAPK, NIK, IKK, NF-κΒ, p38, JNK, ΙκΒ-α, or CCL2). Further teachings of downstream TNFα-induced mediators can be found in, e.g., Schwamborn et al., BMC Genomics 4:46, 2003; and Zhou et al., Oncogene 22:2034-2044, 2003, incorporated herein by reference. Additional aspects of inhibitory nucleic acids are described in Aagaard et al., Adv. Drug Delivery Rev. 59(2):75-86, 2007, and Burnett et al., Biotechnol. J. 6(9): 1130-1146, 2011.

[0464] TNFα INHIBITOR FUSION PROTEINS

[0465] In some embodiments, the TNFα inhibitor is an antibody or antigen-binding fragment thereof (e.g., Fab or scFv). In some embodiments, the antibody or antigen-binding fragment described herein specifically binds to any of TNFα, TNFR1, or TNFR2. In some embodiments, the antibody or antigen-binding fragment of an antibody described herein can specifically bind to TNFα. In some embodiments, the antibody or antigen-binding fragment of an antibody described herein can specifically bind to a TNFα receptor (TNFR1 or TNFR2).

[0466] Non-limiting examples of TNF inhibitors that are antibodies that specifically bind to TNFa are described in Elliott et al., Lancet 1994; 344: 1125-1127, 1994; Rankin et al., Br. J. Rheumatol. 2:334-342, 1995; Butler et al., Eur. Cytokine Network 6(4):225-230, 1994; Lorenz et al., J. Immunol. 156(4): 1646-1653, 1996; Hinshaw et al., Circulatory Shock 30(3):279-292, 1990; Wanner et al., Shock 11(6):391-395, 1999; Bongartz et al., JAMA 295(19):2275-2285, 2006; Knight et al., Molecular Immunol. 30(16): 1443-1453, 1993; Feldman, Nature Reviews Immunol. 2(5):364-371, 2002; Taylor et al., Nature Reviews Rheumatol. 5(10):578-582, 2009; Garces et al., Annals Rheumatic Dis. 72(12): 1947-1955, 2013; Palladino et al., Nature Rev. Drug Discovery 2(9):736-746, 2003; Sandborn et al., Inflammatory Bowel Diseases 5(2): 119-133, 1999; Atzeni et al., Autoimmunity Reviews 12(7):703-708, 2013; Maini et al., Immunol. Rev. 144(1): 195-223, 1995; Ordas et al., Clin. Pharmacol. Therapeutics 91(4):635-646, 2012; Cohen et al., Canadian J. Gastroenterol. Hepatol. 15(6):376-384, 2001; Feldmann et al., Ann. Rev. Immunol. 19(1): 163-196, 2001; Ben-Horin et al., Autoimmunity Rev. 13(1):24-30, 2014; and U.S. Patent Nos. 6,090,382; 6,258,562; and 6,509,015).

[0467] In certain embodiments, the TNFa inhibitor can include or be infliximab (Remicade TM ), CDP571, CDP 870, golimumab (Simponi TM ), adalimumab (Humira TM ), or certolizumab pegol (Cimzia TM ). In certain embodiments, the TNFa inhibitor can be a TNFa inhibitor biosimilar. Examples of approved and late-stage TNFa inhibitor biosimilars include, but are not limited to: infliximab biosimilars such as Remsima TM and (CT-P13) from Celltrion / Pfizer, GS071 from Aprogen, Flixabi TM (SB2) from Samsung Bioepis, PF-0643817 from Pfizer / Sandoz, NI-071 from Nichi-Iko Pharmaceutical Co., and ABP 710 from Amgen; adalimumab biosimilars such as Exemptia TM (ZRC3197) from Indian Zydus Cadila, and and Adalimumab biosimilars in development are Adalimumab biosimilars by Adello Biologies, Adalimumab biosimilars by AET Biotech / BioXpress Therapeutics, Adalimumab biosimilars by mAbxience, Adalimumab biosimilars by PlantForm, and Adalimumab biosimilars by Prestige Biopharma; and Etanercept biosimilars such as Erelzi™ from Sandoz / Novartis, Brenzys from Samsung Bioepis TM (SB4), GP2015 from Sandoz, PF-0528521 from Mycenax LBEC0101 from LG Life, PF-688 from Pfenex (a biosimilar of Certolizumab pegol), and CHS-0214 from Coherus.

[0468] In some embodiments, the TNFa inhibitor can be SAR252067 (e.g., a monoclonal antibody that specifically binds to TNFSF14, described in U.S. Patent Application Publication No. 2013 / 0315913) or MDGN-002 (described in U.S. Patent Application Publication No. 2015 / 0337046). In some embodiments, the TNFa inhibitor can be PF-06480605, which specifically binds to TNFSF15 (e.g., described in U.S. Patent Application Publication No. 2015 / 0132311). Additional examples of TNFa inhibitors include DLCX105 (described in Tsianakas et al., Exp. Dermatol. 25:428-433, 2016) and PF-06480605, which specifically binds to TNFSF15 (described in U.S. Patent Application Publication No. 2015 / 0132311). Other examples of TNFa inhibitors that are antibodies or antigen-binding antibody fragments are described, e.g., in WO 17 / 158097, EP 3219727, WO 16 / 156465, and WO 17 / 167997.

[0469] In some embodiments, the TNFa inhibitor is DLX-105, e.g., a gel formulation.

[0470] In some embodiments, the TNFa inhibitor is adalimumab. Adalimumab is a recombinant human IgGl monoclonal antibody that is specific for human tumor necrosis factor and is indicated for the treatment of various inflammatory diseases, such as rheumatoid arthritis, Crohn’s disease, and ulcerative colitis.

[0471] Adalimumab is currently delivered as a SC injection of 40 mg in 0.4-0.8 mL once every 1-2 weeks. It is marketed as a pre-filled pen for self-administration. The bioavailability of SC injection is about 64%, the half-life is about 2 weeks, and intracellular catabolism is the main mode of elimination. Adalimumab must be refrigerated, but can be stored temporarily at room temperature prior to use.

[0472] Adalimumab is a suitable therapeutic agent for delivery via an ingestible device as described herein. It is currently provided as a liquid, administered by self-injection, and adverse reactions at the site of injection are not uncommon, patients can readily adopt an alternative dosage form. Finally, the likelihood of acute reactions from overdosing is low, which, in theory, could allow for increased dosing to compensate for lower bioavailability than SC injection.

[0473] TNFα INHIBITOR SMALL MOLECULES

[0474] In some embodiments, the TNFa inhibiting agent is a fusion protein that specifically binds to TNFa (e.g., an extracellular domain of a TNFR fused to a partner peptide, e.g., an Fc region of an immunoglobulin (e.g., human IgG)) (see, e.g., Peppel et al., J. Exp. Med. 174(6): 1483-1489, 1991; Deeg et al., Leukemia 16(2): 162, 2002) or a soluble TNFR (e.g., TNFR1 or TNFR2). In some embodiments, the TNFa inhibitor includes or is etanercept (Enbrel®) TM (see, e.g., WO 91 / 03553 and WO 09 / 406,476, incorporated herein by reference). In some embodiments, the TNFa inhibitor includes or is r-TBP-I (e.g., Gradstein et al., J. Acquir. Immune Defic. Syndr. 26(2): 111-117, 2001). In some embodiments, the TNFa inhibitor includes or is a soluble TNFa receptor (e.g., Watt et al., J Leukoc Biol. 66(6): 1005-1013, 1999; Tsao et al., Eur Respir J. 14(3): 490-495, 1999; Kozak et al., Am. J. Physiol. Reg. Integrative Comparative Physiol. 269(1): R23-R29, 1995; Mohler et al., J. Immunol. 151(3): 1548-1561, 1993; Nophar et al., EMBO J. 9(10): 3269, 1990; Bjornberg et al., Lymphokine Cytokine Res. 13(3): 203-211, 1994; Piguet et al., Eur. Respiratory J. 7(3): 515-518, 1994; and Gray et al., Proc. Natl. Acad. Sci. U.S.A. 87(19): 7380-7384, 1990).

[0475] In some embodiments, the TNFa inhibitor is tildaceront.

[0476] INHIBITORY NUCLEIC ACIDS OF IL-1

[0477] In some embodiments, the TNFa inhibitor is a small molecule. In some embodiments, the TNFa inhibitor is C87 (Ma et al., J. Biol. Chem. 289(18): 12457-66, 2014). In some embodiments, the small molecule is LMP-420 (e.g., Haraguchi et al., AIDS Res. Ther. 3:8, 2006). In some embodiments, the small molecule is a tumor necrosis factor-converting enzyme (TACE) inhibitor (e.g., Moss et al., Nature Clinical Practice Rheumatology 4:300-309, 2008). In some embodiments, the TACE inhibitor is TMI-005 and BMS-561392. Additional examples of small molecule inhibitors are described, e.g., He et al., Science 310(5750): 1022-1025, 2005.

[0478] In some examples, the TNFa inhibitor is a small molecule that inhibits the activity of one of TRADD, TRAF2, MEKK1 / 4, MEKK4 / 7, JNK, AP-1, ASK1, RIP, MEKK 3 / 6, MAPK, NIK, IKK, and NF-κB in a mammalian cell.

[0479] In some examples, the TNFa inhibitor is a small molecule that inhibits the activity of one of CD14, MyD88 (see, e.g., Olson et al., Scientific Reports 5: 14246, 2015), IRAK (Chaudhary et al., J. Med. Chem. 58(1): 96-110, 2015), lipopolysaccharide binding protein (LBP) (see, e.g., U.S. Pat. No. 5,705,398), TRAF6 (e.g., 3-[(2,5-dimethylphenyl)amino]-l-phenyl-2-propen-l-one), ras (e.g., Baker et al., Nature 497:577-578, 2013), raf (e.g., vemurafenib (PLX4032, RG7204), sorafenib tosylate, PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372, sorafenib, GW5074, TAK-632, CEP-32496, encorafenib (LGX818), CCT196969, LY3009120, RO5126766 (CH5126766), PLX7904, and MLN2480), MEK1 / 2 (e.g., Facciorusso et al., Expert Review Gastroentrol. Hepatol. 9:993-1003, 2015), ERK1 / 2 (e.g., Mandal et al., Oncogene 35:2547-2561, 2016), NIK (e.g., Mortier et al., Bioorg. Med. Chem. Lett. 20:4515-4520, 2010), IKK (e.g., Reilly et al., Nature Med. 19:313-321, 2013), IKB (e.g., Suzuki et al., Expert. Opin. Invest. Drugs 20:395-405, 2011), NF-KB (e.g., Gupta et al., Biochim. Biophys. Acta 1799(10-12):775-787, 2010), rac (e.g., U.S. Pat. No.9,278,956), MEK4 / 7, JNK (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), c-jun (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), MEK3 / 6 (e.g., Akinleye et al., J. Hematol. Oncol. 6:27, 2013), p38 (e.g., AL 8697, AMG 548, BIRB 796, CMPD-1, DBM 1285 dihydrochloride, EO 1428, JX 401, ML 3403, Org 48762-0, PH 797804, RWJ 67657, SB 202190, SB203580, SB 239063, SB 706504, SCIO 469, SKF 86002, SX 011, TA 01, TA 02, TAK 715, VX702, and VX 745), PKR (e.g., 2-aminopurine or CAS 608512-97-6), TTP (e.g., CAS 329907-28-0), and MK2 (PF 3644022 and PHA767491).

[0480] IL-1 inhibitors

[0481] In some embodiments, a therapeutic agent suitable for use with the devices and methods described herein is an IL-1 inhibitor. The term "IL-1 inhibitor" refers to an agent that reduces the expression of an IL-1 cytokine or an IL-1 receptor and / or reduces the ability of an IL-1 cytokine to specifically bind to an IL-1 receptor. Non-limiting examples of IL-1 cytokines include IL-1a, IL-1b, IL-18, IL-36a, IL-36b, IL-36y, IL-38, and IL-33. In some examples, the IL-1 cytokine is IL-1a. In some examples, the IL-1 cytokine is IL-1b.

[0482] In some embodiments, the IL-1 inhibitory agent is an inhibitory nucleic acid, an antibody or fragment thereof, or a fusion protein. In some embodiments, the inhibitory nucleic acid is an antisense nucleic acid, a ribozyme, or a small interfering RNA.

[0483] IL-1 INHIBITOR ANTIBODIES

[0484] Inhibitory nucleic acids that can reduce the expression of IL-1a, IL-1b, IL-18, IL-36a, IL-36b, IL-36y, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Ra, IL-1RL2, or IL1RL1 mRNA in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequences are complementary to all or a portion of IL-1a, IL-1b, IL-18, IL-36a, IL-36b, IL-36y, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Ra, IL-1RL2, or IL1RL1 mRNA.

[0485] Examples of modified nucleotides that can be used to produce antisense nucleic acids include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5- oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-mercaptopurine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, expression vectors that have been subcloned in antisense orientation can be used to

[0486] Inhibitory nucleic acids preferentially bind (e.g., hybridize) to nucleic acids encoding IL-1a, IL-1b, IL-18, IL-36a, IL-36b, IL-36y, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Ra, IL-1RL2, or IL1RL1 proteins to treat allergic diseases (e.g., asthma (Corren et al., N. Engl. J. Med. 365: 1088-1098, 2011)), radiation-induced lung injury (Chung et al., Sci. Rep. 6:39714, 2016), ulcerative colitis (Hua et al., Br. J. Clin. Pharmacol. 80: 101-109, 2015), dermatitis (Guttman-Yassky et al., Exp. Opin. Biol. Ther. 13(4): 1517, 2013), and chronic obstructive pulmonary disease (COPD) (Walsh et al. (2010) Curr. Opin. Investig Drugs. 11(11): 1305-1312, 2010).

[0487] Exemplary IL-1 inhibitors as antisense nucleic acids are described in Yilmaz-Elis et al., Mol. Ther. Nucleic Acids 2(1): e66, 2013; Lu et al., J. Immunol. 190(12): 6570-6578, 2013), small interfering RNA (siRNA) (e.g., Ma et al., Ann. Hepatol. 15(2): 260-270, 2016), or combinations thereof. In certain embodiments, a therapeutically effective amount of an inhibitory nucleic acid targeting nucleic acids encoding IL-1a, IL-1b, IL-18, IL-36a, IL-36b, IL-36y, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Ra, IL-1RL2, or IL1RL1 proteins can be administered to a subject (e.g., a human subject) in need thereof.

[0488] IL-1 INHIBITOR FUSION PROTEINS OR SOLUBLE RECEPTORS

[0489] In some embodiments, the IL-1 inhibitor is an antibody or antigen-binding fragment thereof (e.g., Fab or scFv). In some embodiments, the IL-1 inhibitor is canakinumab (ACZ885, (Dhimolea, MAbs 2(1): 3-13, 2010; Yokota et al., Clin. Exp. Rheumatol. 2016; Torene et al., Ann. Rheum. Dis. 76(1): 303-309, 2017; Gram, Curr. Opin. Chem. Biol. 32: 1-9, 2016; Kontzias et al., Semin. Arthritis Rheum 42(2): 201-205, 2012). In some embodiments, the IL-1 inhibitor is anakinra (KINERET®; ; Beynon et al., J. Clin. Rheumatol. 23(3): 181-183, 2017; Stanam et al., Oncotarget 7(46): 76087-76100, 2016; Nayki et al., J. Obstet Gynaecol. Res. 42(11): 1525-1533, 2016; Greenhalgh et al., Dis. Model Mech. 5(6): 823-833, 2012), or a variant thereof. In some embodiments, the IL-1 inhibitor is gevokizumab (XOMA 052; Knicklebein et al., Am. J. Ophthalmol. 172: 104-110, 2016; Roubille et al., Atherosclerosis 236(2): 277-285, 2014; Issafras et al., J. Pharmacol. Exp. Ther. 348(1): 202-215, 2014; Handa et al., Obesity 21(2): 306-309, 2013; Geiler et al., Curr. Opin. Mol. Ther. 12(6): 755-769, 2010), LY2189102 (Bihorel et al., AAPS J. 16(5): 1009-1117, 2014; Sloan-Lancaster et al., Diabetes Care 36(8): 2239-2246, 2013), MABpl (Hickish et al., Lancet Oncol. 18(2): 192-201, 2017; Timper et al., J. Diabetes Complications 29(7): 955-960, 20150), CDP-484 (Braddock et al., Drug Discov. 3: 330-339, 2004), or a variant thereof (Dinarello et al., Nat. Rev. Drug Discov. 11(8): 633-652, 2012).

[0490] Further teachings of IL-1 inhibitors as antibodies or antigen-binding fragments thereof are described in U.S. Patent Nos. 5,075,222; 7,446,175; 7,531,166; 7,744,865; 7,829,093; and 8,273,350; US2016 / 0326243; US2016 / 0194392, and US2009 / 019167, each of which is incorporated by reference in its entirety.

[0491] IL-1 INHIBITOR ENDORGENOUS PEPTIDES

[0492] In some embodiments, the IL-1 inhibitor is a fusion protein or soluble receptor. For example, the fusion can include an extracellular domain of any of IL-1R1, IL1RAP, IL-18R alpha, IL-1RL2, and IL1RL1 fused to a partner amino acid sequence (e.g., a stabilizing domain, such as an IgG Fc region, e.g., a human IgG Fc region). In some embodiments, the IL-1 inhibitor is a soluble form of one or both of IL-1RL1 and IL1RAP. In some embodiments, the IL-1 inhibitor is a soluble form of IL-18R alpha. In some embodiments, the IL-1 inhibitor is a soluble form of one or both of IL-1RL2 and IL-1RAP.

[0493] In some embodiments, the IL-1 inhibitor is a fusion protein comprising rilonacept (IL-1 Trap, ) or consisting of rilonacept (IL-1 Trap, (see, e.g., Kapur & Bonk, P.T. 34(3): 138-141, 2009; Church et al., Biologics 2(4): 733-742, 2008; McDermott, Drugs Today (Barc) 45(6): 423-430, 2009). In some embodiments, the IL-1 inhibitor is a chimeric fusion protein (e.g., EBI-005 (Furfine et al., Invest. Ophthalmol. Vis. Sci. 53(14): 2340-2340, 2012; Goldstein et al., Eye Contact Lens 41(3): 145-155, 2015; Goldstein et al., Eye Contact Lens, 2016).

[0494] In some embodiments, the IL-1 inhibitor is a soluble receptor comprising or consisting of sIL-1RI and / or sIL-1RII (Svenson et al., Eur. J. Immunol. 25(10): 2842-2850, 1995).

[0495] INHIBITORY NUCLEIC ACIDS OF IL-6

[0496] In some embodiments, the IL-1 inhibitor can be an endogenous ligand or active fragment thereof, such as IL-1Ra or IL-36Ra. IL-1Ra is an endogenous soluble protein that reduces the ability of IL-1a and IL-1b to bind to its receptor (e.g., the complex of IIL-1R1 and IL1RAP proteins). IL-36Ra is an endogenous soluble protein that reduces the ability of IL-36a, IL-36b, and IL-36y to bind to its receptor (e.g., the complex of IL-1RL2 and IL-1RAP proteins). Exemplary sequences of IL-1Ra and IL-36Ra are shown below.

[0497] In some embodiments, the IL-1 inhibitor is a K(D)PT.

[0498] IL-6 receptor inhibitors

[0499] In some embodiments, a therapeutic agent suitable for use with the devices and methods described herein is an IL-6 receptor inhibitor. The term "IL-6 receptor inhibitor" refers to an agent that reduces the expression of IL-6 receptor and / or the ability of IL-6 to bind to IL-6 receptor. In some embodiments, the IL-6 receptor inhibitor targets the IL-6 receptor beta-subunit glycoprotein 130 (sIL6gpl30). In other embodiments, the IL-6 receptor inhibitor targets the IL-6 receptor subunit (IL6R). In other embodiments, the IL-6 receptor inhibitor targets the complex consisting of the IL-6 receptor subunit (IL6R) and the IL-6 receptor beta-subunit glycoprotein 130 (sIL6gpl30). In some embodiments, the IL-6 receptor inhibitor targets IL-6.

[0500] In some embodiments, the IL-6 receptor inhibitor is an inhibitory nucleic acid, an antibody or antigen-binding fragment thereof, a fusion protein, an IL-6 receptor antagonist, or a small molecule. In some embodiments, the inhibitory nucleic acid is a small interfering RNA, an antisense nucleic acid, an aptamer, or a microRNA. Exemplary IL-6 receptor inhibitors are described herein. Additional examples of IL-6 receptor inhibitors are known in the art.

[0501] IL-6 INHIBITOR ANTIBODIES

[0502] An antisense nucleic acid molecule can be complementary to all or part of the non-coding region of the coding strand of a nucleotide sequence encoding an IL6R, sIL6gpl30, or IL-6 protein. Non-coding regions (5' and 3' untranslated regions) are sequences flanking the coding region of a gene, 5' and 3', and are not translated into amino acids.

[0503] Exemplary antisense nucleic acids that are IL-6 receptor inhibitors are described in Keller et al., J. Immunol. 154(8): 4091-4098, 1995; and Jiang et al., Anticancer Res. 31(9): 2899-2906, 2011.

[0504] Non-limiting examples of short interfering RNA (siRNA) that are IL-6 receptor inhibitors are described in Yi et al., Int. J. Oncol. 41(1): 310-316, 2012; and Shinriki et al., Clin. Can. Res. 15(17): 5426-5434, 2009). Non-limiting examples of microRNAs that are IL-6 receptor inhibitors are described in miR34a (Li et al., Int. J. Clin. Exp. Pathol. 8(2): 1364-1373, 2015) and miR-451 (Liu et al., Cancer Epidemiol. 38(1): 85-92, 2014).

[0505] Non-limiting examples of aptamers that are IL-6 receptor inhibitors are described in Meyer et al., RNA Biol. 11(1): 57-65, 2014; Meyer et al., RNA Biol. 9(1): 67-80, 2012; and Mittelberger et al., RNA Biol. 12(9): 1043-1053, 2015. Additional examples of inhibitory nucleic acids that are IL-6 receptor inhibitors are described in, e.g., WO 96 / 040157.

[0506] IL-6 INHIBITOR FUSION PROTEINS

[0507] In some embodiments, the IL-6 receptor inhibitor is an antibody or antigen-binding fragment thereof (e.g., Fab or scFv). In some embodiments, the antibody or antigen-binding fragment described herein specifically binds to IL-6. In some embodiments, the antibody or antigen-binding fragment described herein specifically binds to IL-6 receptor (e.g., one or both of IL6R and sIL6gpl30).

[0508] In certain embodiments, the antibody comprises or consists of an antigen-binding fragment or portion of artlizumab, Sebba, Am. J. Health Syst. Pharm. 65(15): 1413-1418, 2008; Tanaka et al., FEBS Letters 585(23): 3699-3709, 2011; Nishimoto et al., Arthritis Rheum. 50: 1761-1769, 2004; Yokota et al., Lancet 371(9617): 998-1006, 2008; Emery et al., Ann. Rheum. Dis. 67(11): 1516-1523, 2008; Roll et al., Arthritis Rheum. 63(5): 1255-1264, 2011); clazakizumab (BMS945429; ALD518, a humanized monoclonal antibody that binds circulating IL-6 cytokine rather than IL-6 receptor, blocking classical signaling and trans-signaling (Weinblatt, Michael E. et al. "The Efficacy and Safety of Subcutaneous Clazakizumab in Patients With Moderate-to-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results From a Multinational, Phase IIb, Randomized, Double-Blind, Placebo / Active-Controlled, Dose-Ranging Study." Arthritis & Rheumatology 67.10 (2015): 2591-2600.)); sarilumab (REGN88 or SAR153191; Huizinga et al., Ann. Rheum. Dis. 73(9): 1626-1634, 2014; Sieper et al., Ann. Rheum. Dis. 74(6): 1051-1057, 2014; Cooper, Immunotherapy 8(3): 249-250, 2016); MR-16 (Hartman et al., PLoS One 11(12): e0167195, 2016; Fujita et al., Biochim. Biophys. Acta. 10: 3170-80, 2014; Okazaki et al., Immunol. Lett.84(3):231-40, 2002; Noguchi-Sasaki et al., BMC Cancer 16:270, 2016; Ueda et al., Sci. Rep. 3:1196, 2013); rhPM-1 (MRA; Nishimoto et al., Blood 95:56-61, 2000; Nishimoto et al., Blood 106:2627-2632, 2005; Nakahara et al., Arthritis Rheum. 48(6): 1521-1529, 2003); NI-1201 (Lacroix et al., J. Biol. Chem. 290(45):26943-26953, 2015); EBI-029 (Schmidt et al., Eleven Biotherapeutics Poster #B0200, 2014). In some embodiments, the antibody is a nanobody (e.g., ALX-0061 (Van Roy et al., Arthritis Res. Ther. 17:135, 2015; Kim et al., Arch. Pharm. Res. 38(5):575-584, 2015)). In some embodiments, the antibody is NRI or a variant thereof (Adachi et al., Mol. Ther. 11(1):S262-263, 2005; Hoshino et al., Can. Res. 67(3):871-875, 2007). In some embodiments, the antibody is PF-04236921 (Pfizer) (Wallace et al., Ann. Rheum. Dis. 76(3):534-542, 2017).

[0509] In some embodiments, the IL-6 receptor inhibitor is olokizumab (CDP-6038).

[0510] IL-6 INHIBITOR SMALL MOLECULES

[0511] In some embodiments, the IL-6 receptor inhibitor is a fusion protein, a soluble receptor, or a peptide (see, e.g., U.S. Patent No. 5,591,827). In some embodiments, the IL-6 receptor fusion protein comprises or consists of soluble gpl30 (Jostock et al., Eur. J. Biochem. 268(1):160-167, 2001; Richards et al., Arthritis Rheum. 54(5):1662-1672, 2006; Rose-John et al., Exp. Opin. Ther. Targets 11(5):613-624, 2007).

[0512] In some embodiments, the IL-6 receptor fusion protein comprises or consists of FE999301 (Jostock et al., Eur. J. Biochem. 268(1): 160-167, 2001) or sgp130Fc protein (Jones et al., J. Clin. Invest. 121(9): 3375-3383, 2011). In some embodiments, the IL-6 receptor inhibitor is a peptide (e.g., S7 (Su et al., Cancer Res. 65(11): 4827-4835, 2005). In some embodiments, the IL-6 receptor inhibitor is a triterpene saponin (e.g., chikusetsuaponin IVa butyl ester (CS-Iva-Be) (Yang et al., Mol. Cancer. Ther. 15(6): 1190-200, 2016).

[0513] NUCLEIC ACIDS AND VECTORS ENCODING IL-10 RECEPTOR AGONISTS

[0514] In some embodiments, the IL-6 receptor inhibitor is a small molecule (see, e.g., U.S. Patent No. 9,409,990). In some embodiments, the small molecule is: LMT-28 (Hong et al., J. Immunol. 195(1): 237-245, 2015); ERBA (Enomoto et al., Biochem. Biophys. Res. Commun. 323: 1096-1102, 2004; Boos et al., J. Nat. Prod. 75(4): 661-668, 2012), ERBF (TB-2-081) (Hayashi et al., J. Pharmacol. Exp. Ther. 303: 104-109, 2002; Vardanyan et al., Pain 151(2): 257-265, 2010; Kino et al., J. Allergy Clin. Immunol. 120(2): 437-444, 2007), or a variant thereof.

[0515] In some embodiments, the IL-6 receptor inhibitor is YSIL6.

[0516] IL-10 receptor agonists

[0517] In some embodiments, a therapeutic agent suitable for use with the devices and methods described herein is an IL-10 receptor agonist. The term “IL-10 receptor agonist” is any molecule that binds to and activates a receptor for IL-10 expressed on a mammalian cell or a nucleic acid encoding any such molecule. The receptor for IL-10 can include, for example, a complex of two IL-10 receptor-1 (IL-10R1) proteins and two IL-10 receptor 2 (IL-10R2) proteins. In some examples, the IL-10 receptor agonist is an antibody or antigen-binding antibody fragment that specifically binds to and activates a receptor for IL-10 (e.g., a human receptor for IL-10). In some examples, the IL-10 receptor agonist is a recombinant IL-10 (e.g., a recombinant human IL-10). In some examples, the IL-10 receptor agonist is a PEGylated recombinant IL-10 (e.g., a PEGylated recombinant human IL-10). In some examples, the IL-10 receptor agonist is a fusion protein. In some examples, the IL-10 receptor agonist is an IL-10 peptide mimetic.

[0518] IL-10 INHIBITOR ANTIBODIES AND ANTIGEN- BINDING FRAGMENTS

[0519] In some examples, the IL-10 receptor agonist can be a nucleic acid (e.g., a vector) comprising a sequence encoding an IL-10 receptor agonist (e.g., any of the IL-10 proteins described herein). A non-limiting example of a composition comprising a nucleic acid encoding an IL-10 receptor agonist is XT-150 (Xalud Therapeutics).

[0520] IL-10 INHIBITOR FUSION PROTEINS

[0521] In some embodiments, the IL-10 receptor agonist is an antibody or antigen-binding antibody fragment that binds to and activates an IL-10 receptor (e.g., a human IL-10 receptor). In some embodiments, the antibody or antigen-binding antibody fragment specifically binds to an epitope on an IL-10R-1 protein (e.g., a human IL-10R-1 protein). In some embodiments, the antibody or antigen-binding antibody fragment specifically binds to an epitope on an IL-10R-2 protein (e.g., a human IL-10R-2 protein). In some embodiments, the antibody or antigen-binding antibody fragment specifically binds to epitopes on IL-10R-1 and IL-10R-2 proteins (e.g., a human IL-10R-1 and a human IL-10R-2 protein).

[0522] In some embodiments, the IL-10 receptor agonist is an antibody, such as F8-IL10 (also known as DEKAVIL) or a variant thereof (see, e.g., Schwager et al., Arthritis Res. Ther. 11(5):R142, 2009; Franz et al., Int. J. Cardiol. 195:311-322, 2015; Galeazzi et al., Isr. Med. Assoc. J. 16(10):666, 2014).

[0523] IL-10 PEPTIDE MIMETIC

[0524] In some embodiments, the IL-10 receptor agonist is a fusion protein. In some embodiments, the fusion protein comprises an amino acid sequence of an IL-10 protein (or a functional fragment thereof) and a fusion partner, such as an Fc region (e.g., human IgG Fc) or human serum albumin. In some embodiments, the fusion partner can be an antibody or an antigen-binding antibody fragment (e.g., scFv) that targets the IL-10 receptor agonist to inflamed tissue. In some embodiments, the antibody or antigen-binding fragment as a fusion partner can specifically or preferentially bind to inflamed gastrointestinal cells, such as by CD69. In some embodiments, the IL-10 receptor agonist as a fusion protein can be, e.g., F8-IL-10, such as Dekavil (Philogen).

[0525] In some embodiments, the fusion protein is an L19-IL-10 fusion protein, a HyHEL10-IL-10 fusion protein, or a variant thereof. See, e.g., Trachsel et al., Arthritis Res. Ther. 9(1):R9, 2007, and Walmsley et al., Arthritis Rheum. 39:495-503, 1996.

[0526] In some embodiments, the IL-10 receptor agonist is RG-7880.

[0527] RECOMBINANT IL-10

[0528] In some embodiments, the IL-10 receptor agonist is an IL-10 peptide mimetic. A non-limiting example of an IL-10 peptide mimetic is IT 9302 or a variant thereof (Osman et al., Surgery 124(3):584-92, 1998; Lopez et al., Immunobiology 216(10): 1117-1126, 2011). Additional examples of IL-10 peptide mimetics are described in DeWitt, Nature Biotech. 17:214, 1999, and Reineke et al., Nature Biotech. 17:271-275, 1999.

[0529] CELLS PRODUCING RECOMBINANT IL-10

[0530] In some examples, the IL-10 receptor agonist is a recombinant IL-10 protein. In some examples, the recombinant human IL-10 protein can be enovil TM (Schering Corporation). In some examples, the recombinant IL-10 protein is a functional fragment of a human IL-10 protein.

[0531] In some embodiments, the IL-10 receptor agonist is rhuIL-10 (Tenovil) or a variant thereof. See, e.g., McHutchison et al., J. Interferon Cytokine Res. 1:1265-1270, 1999; Rosenblum et al., Regul. Toxicol. Pharmacol. 35:56-71, 2002; Schreiber et al., Gastroenterology 119(6):1461-1472, 2000; Maini et al., Arthritis Rheum. 40(Suppl):224, 1997.

[0532] Exemplary methods of manufacturing recombinant human IL-10 are described in Pajkrt et al., J. Immunol. 158:3971-3977, 1997). Additional exemplary methods of manufacturing recombinant IL-10 are described herein and are known in the art.

[0533] In some embodiments, the recombinant IL-10 is a poly-PEGylated recombinant IL-10 (e.g., PEGylated recombinant human IL-10) (e.g., IL-10 in a 5 kDa N-terminal PEGylated form; AM0010) (Infante et al., ASCO Meeting Abstracts 33(15_suppl):3017, 2015; Chan et al., PLoS One 11(6):e0156229, 2016; Mumm et al., Cancer Cell 20(6):781-796, 2011; Teng et al., Cancer Cell 20(6):691-693, 2011; U.S. Patent Nos. 8,691,205; 8,865,652; 9,259,478; and 9,364,517; and U.S. Patent Application Publication Nos. 2008 / 0081031; 2009 / 0214471; 2011 / 0250163; 2011 / 0091419; 2014 / 0227223; 2015 / 0079031; 2015 / 0086505; 2016 / 031402; 2016 / 0367689; 2016 / 0375101; and 2016 / 0166647).

[0534] In some embodiments, the recombinant IL-10 is a stable isoform of recombinant IL-10. In some embodiments, the stable isoform of recombinant IL-10 is a viral IL-10 protein (e.g., human cytomegalovirus IL10 (e.g., cmv-IL10, LA-cmv-IL-10 (e.g., Lin et al., Virus Res. 131(2):213-223, 2008; Jenkins et al., J. Virol. 78(3):1440-1447, 2004; Kotenko et al., Proc. Natl. Acad. Sci. U.S.A. 97(4): 1695-1700, 2000; Jones et al., Proc. Natl. Acad. Sci. U.S.A. 99(14):9404-9409, 2002) or a latency-associated virus IL-10 protein (e.g., Poole et al., J. Virol. 88(24): 13947-13955, 2014).

[0535] In some embodiments, the recombinant IL-10 is a mammalian IL-10 homolog (see, e.g., WO 00 / 073457). In some embodiments, the mammalian IL-10 homolog is BCRF1, an EBV homolog of human IL-10, also known as viral IL-10, or a variant thereof (Liu et al., J. Immunol. 158(2):604-613, 1997).

[0536] FURTHER EXAMPLES OF IL-10 INHIBITORS

[0537] In some embodiments, any of the devices or compositions described herein can include a recombinant cell (e.g., a recombinant mammalian cell) that secretes a recombinant IL-10 (e.g., any of the recombinant IL-10 proteins described herein). In some embodiments, any of the devices or compositions described herein can include a cell (e.g., a mammalian cell) that secretes IL-10 (e.g., human IL-10). In some embodiments, the mammalian cell can be a mammalian cell obtained from a subject, and the cell is incorporated into any of the compositions or devices described herein after introducing a nucleic acid encoding a recombinant IL-10 (e.g., any of the recombinant IL-10 proteins described herein) into the cell obtained from the subject.

[0538] Non-limiting examples of methods that can be used to introduce a vector or nucleic acid into a cell (e.g., a mammalian cell) include lipofection, transfection, electroporation, microinjection, calcium phosphate transfection, dendrimer-based transfection, cationic polymer transfection, cell extrusion, sonoporation, optical transfection, impalefection, hydrodynamic delivery, magnetofection, viral transduction (e.g., adenoviral and lentiviral transduction), and nanoparticle transfection. These and other methods of introducing a vector or nucleic acid into a cell are well known in the art.

[0539] In some examples, the recombinant mammalian cell can be a Chinese hamster ovary (CHO) cell, a B cell, a CD8 + T cell, a dendritic cell, a keratinocyte, or an epithelial cell. See, e.g., Mosser et al., Immunol. Rev. 226:205-218, 2009; Fillatreau et al., Nat. Rev. Immunol. 8:391-397, 2008; Ryan et al., Crit. Rev. Immunol. 27:15-32, 2007; Moore et al., Annu. Rev. Immunol. 19:683-765, 2001. In some embodiments, the recombinant mammalian cell can be a mesenchymal stem cell (e.g., Gupte et al., Biomed. J. 40(1):49-54, 2017).

[0540] IL-12 / IL-23 INHIBITOR ANTIBODIES

[0541] In some embodiments, the recombinant cell is a recombinant gram-positive bacterial cell (e.g., a genetically modified Lactococcus lactis (LL-Thy12) (see, e.g., Steidler et al., Science 289: 1352-1355, 2000; Braat et al., Clin. Gastroenterol. Hepat. 4: 754-759, 2006). In some embodiments, the recombinant cell is a recombinant gram-negative bacterial cell (e.g., a Shigella flexneri cell) that secretes an IL-10 receptor agonist (e.g., a recombinant IL-10 protein) (Chamekh et al., J. Immunol. 180(6): 4292-4298, 2008).

[0542] In some embodiments, the IL-10 receptor agonist is a cell (e.g., a Clostridium tyrobutyricum cell) that induces IL-10 production and secretion by a different cell (e.g., a macrophage) (e.g., Hayashi et al., Cell Host Microbe 13: 711-722, 2013). In some embodiments, the IL-10 receptor agonist is a recombinant bacterial cell (e.g., a Lactobacillus acidophilus cell) that lacks lipoteichoic acid and induces IL-10 production and secretion by a different cell (e.g., a dendritic cell) (e.g., Mohamadzadeh et al., Proc. Natl. Acad. Sci. U.S.A. 108(suppl 1): 4623-4630, 2011; Konstantinov et al., Proc. Natl. Acad. Sci. U.S.A. 105(49): 19474-9, 2008). In some embodiments, the IL-10 receptor agonist is a bacterial cell or a fragment of a bacterial cell that is maintained in a supernatant that induces IL-10 secretion by a different cell (e.g., an immune cell) (e.g., a Faecalibacterium prausnitzii cell or a Faecalibacterium prausnitzii supernatant) (see, e.g., Sokol et al., Proc. Natl. Acad. Sci. U.S.A. 105(43): 16731-16736, 2008).

[0543] Additional examples of other IL-10 receptor agonists are described in, e.g., U.S. Patent No. 6,936,586; WO 96 / 01318; WO 91 / 00349; and WO 13 / 130913; each of which is incorporated by reference herein in its entirety.

[0544] IL-12 / IL-23 Inhibitors

[0545] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is an IL-12 / IL-23 inhibitor. The term "IL-12 / IL-23 inhibitor" refers to an agent that reduces the ability of IL-12 or IL-23 expression and / or the ability of IL-12 binding to IL-12 receptor or the ability of IL-23 binding to IL-23 receptor. In some embodiments, the IL-12 / IL-23 inhibitory agent targets the IL-12B (p40) subunit. In some embodiments, the IL-12 / IL-23 inhibitory agent targets IL-12A (p35). In some embodiments, the IL-12 / IL-23 inhibitory agent targets IL-23 (pl9). In some embodiments, the IL-12 / IL-23 inhibitory agent targets a receptor of IL-12 (one or both of IL-12Rpi or IL-12Rb2). In some embodiments, the IL-12 / IL-23 inhibitory agent targets a receptor of IL-23 (one or both of IL-12Rpi and IL-23R).

[0546] In some embodiments, the IL-12 / IL-23 inhibitor can be an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid can be an antisense nucleic acid, a ribozyme, and a small interfering RNA (siRNA).

[0547] Non-limiting examples of siRNAs targeting IL-12A (p35), IL-12B (p40), IL-23 (pl9), IL-12Rpi, IL-12Rb2, or IL-23R are described in Tan et al., J. Alzheimers Dis. 38(3):633-646, 2014; Niimi et al., J. Neuroimmunol. 254(l-2):39-45, 2013. Non-limiting examples of short hairpin RNAs (shRNAs) targeting IL-12A (p35), IL-12B (p40), IL-23 (pl9), IL-12Rpi, IL-12Rb2, or IL-23R are described in Bak et al., BMC Dermatol. 11 :5, 2011.

[0548] Non-limiting examples of inhibitory nucleic acids are microRNAs (e.g., microRNA-29 (Brain et al., Immunity 39(3):521-536, 2013), miR-10a (Xue et al., J. Immunol. 187(11):5879-5886, 2011), microRNA-155 (Podsiad et al., Am. J. Physiol. Lung Cell Mol. Physiol. 310(5):L465-75, 2016).

[0549] IL-12 / IL-23 INHIBITOR FUSION PROTEINS

[0550] In some embodiments, the IL-12 / IL-23 inhibitor is an antibody or antigen binding fragment thereof (e.g., Fab or scFv). In some embodiments, the antibody or antigen binding fragment described herein specifically binds to any of IL-12A (p35), IL-12B (p40), IL-23 (pl9), IL-12Rβl, IL-12Rβ2, or IL-23R, or a combination thereof.

[0551] In some embodiments, the antibody is ustekinumab (CNTO 1275, ) or a variant thereof (Krueger et al., N. Engl. J. Med. 356(6):580-592, 2007; Kauffman et al., J. Invest. Dermatol. 123(6): 1037-1044, 2004; Gottlieb et al., Curr. Med. Res. Opin. 23(5): 1081-1092, 2007; Leonardi et al., Lancet 371(9625): 1665-1674, 2008; Papp et al., Lancet 371(9625): 1675-1684, 2008). In some embodiments, the antibody is briakinumab (ABT-874, J-695) or a variant thereof (Gordon et al., J. Invest. Dermatol. 132(2):304-314, 2012; Kimball et al., Arch Dermatol. 144(2):200-207, 2008).

[0552] In some embodiments, the antibody is: Guselkumab (CNTO-1959) (Callis-Duffin et al., J. Am. Acad. Dermatol. 70(5 Suppl 1), 2014); AB162 (Sofen et al., J. Allergy Clin. Immunol. 133:1032-40, 2014); Tildrakizumab (MK-3222, SCH900222) (Papp et al. (2015) Br. J. Dermatol. 2015); Langley et al., Oral Presentation at: American Academy of Dermatology, March 21-25, Denver CO, 2014); AMG 139 (MEDI2070, Brodalumab) (Gomollon, Gastroenterol. Hepatol. 38(Suppl. 1):13-19, 2015; Kock et al., Br. J. Pharmacol. 172(1): 159-172, 2015); FM-202 (Tang et al., Immunology 135(2): 112-124, 2012); FM-303 (Tang et al., Immunology 135(2): 112-124, 2012); ADC-1012 (Tang et al., Immunology 135(2): 112-124, 2012); LY-2525623 (Gaffen et al., Nat. Rev. Immunol. 14:585-600, 2014; Sands, Gastroenterol. Hepatol. 12(12):784-786, 2016), LY-3074828 (Coskun et al., Trends Pharmacol. Sci. 38(2): 127-142, 2017), BI-655066 (Risankizumab) (Singh et al., MAbs 7(4):778-791, 2015; Krueger et al., J. Allergy Clin. Immunol. 136(1): 116-124, 2015), or variants thereof.

[0553] Further teachings of IL-12 / IL-23 antibodies and antigen-binding fragments thereof are described in U.S. Patent Nos. 6,902,734; 7,247,711; 7,252,971; and 7,491,391; US2012 / 0288494; and US2013 / 0302343, each of which is incorporated by reference in its entirety.

[0554] In some embodiments, the IL-12 / IL-23 inhibitor is PTG-200, an IL-23R inhibitor currently under preclinical development by Protagonist Therapeutics.

[0555] In some embodiments, the IL-12 / IL-23 inhibitor is mirikizumab (LY 3074828), an IL-23R inhibitor currently under clinical development (Phase II) by Eli Lilly.

[0556] In some embodiments, the IL-12 / IL-23 inhibitor is AK-101.

[0557] In some embodiments, the IL-12 / IL-23 inhibitor is a bispecific antibody, such as IL-23 / CGRP currently under clinical development (Phase II) by Eli Lilly.

[0558] IL-12 / IL-23 INHIBITOR SMALL MOLECULES

[0559] In some embodiments, the IL-12 / IL-23 inhibitor is a fusion protein, a soluble antagonist, or an antimicrobial peptide. In some embodiments, the fusion protein comprises a soluble fragment of a receptor for IL-12 or a soluble fragment of a receptor for IL-23. In some embodiments, the fusion protein comprises an extracellular domain of a receptor for IL-12 or an extracellular domain of a receptor for IL-23.

[0560] In some embodiments, the fusion protein is an adnectin or a variant thereof (Tang et al., Immunology 135(2): 112-124, 2012). In some embodiments, the soluble antagonist is a human IL-23Ra-chain mRNA transcript (Raymond et al., J. Immunol. 185(12): 7302-7308, 2010). In some embodiments, the IL-12 / IL-23 is an antimicrobial peptide (e.g., MP-196 (Wenzel et al., PNAS 111(14): E1409-E1418, 2014)).

[0561] IL-13 INHIBITOR ANTIBODIES

[0562] In some embodiments, the IL-12 / IL-23 inhibitor is a small molecule. In some embodiments, the small molecule is STA-5326 (apilimod) or a variant thereof (Keino et al., Arthritis Res. Ther. 10:R122, 2008; Wada et al., Blood 109(3): 1156-1164, 2007; Sands et al., Inflamm. Bowel Dis. 16(7): 1209-1218, 2010).

[0563] IL-13 inhibitors

[0564] In some embodiments, a therapeutic suitable for use with the devices and methods described herein is an IL-13 inhibitor. The term "IL-13 inhibitor" refers to an agent that reduces IL-13 expression and / or reduces the ability of IL-13 to bind to an IL-13 receptor. In some embodiments, the IL-13 inhibitor reduces the ability of IL-13 to bind to an IL-13 receptor (e.g., a complex including IL-4Ra and IL-13Ral, or a complex including IL-13Ral and IL-13Ra2).

[0565] In some embodiments, the IL-13 inhibitor is an inhibitory nucleic acid, an antibody or antigen-binding fragment thereof, or a fusion protein. In some embodiments, the inhibitory nucleic acid can be an antisense nucleic acid, a ribozyme, a small interfering RNA, a small hairpin RNA, or a microRNA. Examples of aspects of these different inhibitory nucleic acids are described below. Any example of an inhibitory nucleic acid that can reduce the expression of IL-13, IL-13Ral, IL-13Ra2, or IL-4Ra mRNA in a mammalian cell can be synthesized in vitro.

[0566] Non-limiting examples of short interfering RNAs (siRNAs) as IL-13 inhibitors are described in Lively et al., J. Allergy Clin. Immunol. 121(1): 88-94, 2008). Non-limiting examples of short hairpin RNAs (shRNAs) as IL-13 inhibitors are described in Lee et al., Hum Gene Ther. 22(5):577-586, 2011, and Shilovskiy et al., Eur. Resp. J. 42:P523, 2013).

[0567] In some embodiments, the inhibitory nucleic acid can be a microRNA. A non-limiting example of a microRNA as an IL-13 inhibitor is let-7 (Kumar et al., J. Allergy Clin. Immunol. 128(5): 1077-1085, 2011).

[0568] IL-13 INHIBITOR FUSION PROTEINS

[0569] In some embodiments, the IL-13 inhibitor is an antibody or antigen-binding fragment thereof (e.g., Fab or scFv). In some embodiments, the antibody or antigen-binding fragment described herein specifically binds to any of: IL-13, IL-13Ra1, IL-13Ra2, or IL-4Ra, or a combination thereof. In some embodiments, the antibody or antigen-binding fragme...

Claims

1. An ingestible device comprising: a housing comprising an interior and an opening; a gas cartridge in the interior of the housing, the gas cartridge having a frangible seal; a spring in the interior of the housing; a piston in the interior of the housing; a perforator in the interior of the housing; a retainer; and a trigger exposed to an environment external to the housing, wherein, in a first state of the ingestible device: the trigger holds the retainer in a first position; the retainer holds the perforator in a first position in which the perforator does not fracture the frangible seal of the gas cartridge; 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. in a second state of the ingestible device:

2. The ingestible device of claim 1, wherein, the trigger is at least partially dissolved, degraded, and / or eroded such that the trigger is unable to hold the retainer in its first position; and the retainer is unable to hold the perforator in its first position. in the second state of the ingestible device:

3. The ingestible device of claim 2, wherein, the spring exerts a force on the perforator to move the perforator such that the perforator fractures the frangible seal of the gas cartridge; a gas is released from the gas cartridge; the gas exerts a force on the piston such that the piston exerts a force on the dispensable substance; and the dispensable substance is delivered from the ingestible device via the opening in the housing.

4. The ingestible device of any one of the preceding claims, further comprising a seal between the piston and the housing.

5. The ingestible device of any one of the preceding claims, further comprising a seal between the perforator and the housing.

6. An ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent in an interior of the housing; a gas cartridge in the interior of the housing; a spring in the interior of the housing; a piston in the interior of the housing; a seal between the piston and the housing; a perforator in the interior of the housing; a retainer; and a trigger exposed to an environment external to the housing.

7. An ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent in an interior of the housing; a gas cartridge in the interior of the housing; a spring in the interior of the housing; a piston in the interior of the housing; a perforator in the interior of the housing; a retainer; a seal between the retainer and the housing; and a trigger exposed to an environment external to the housing.

8. An ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent in an interior of the housing; a gas cartridge in the interior of the housing; a spring in the interior of the housing; a piston in the interior of the housing; a first seal between the piston and the housing; a perforator in the interior of the housing; a retainer; a second seal between the retainer and the housing; and a trigger exposed to an environment external to the housing.

9. The ingestible device of any one of the preceding claims, wherein the ingestible device is a 00 size device.

10. The ingestible device of any one of the preceding claims, wherein the trigger comprises an enteric material.

11. The ingestible device of any one of the preceding claims, wherein: the housing comprises first and second housing portions; the piston and the dispensable substance are within the first housing portion; and the spring and the retainer are within the second housing portion. ​ ​ ​ ​ 12. The ingestible device of any of the preceding claims, wherein the opening is a nozzle having a diameter of about 325 μm to 375 μm.

13. The ingestible device of any of the preceding claims, wherein at least one of the following is true: the ingestible device is configured for trans-epithelial delivery of the dispensable object to the GI tract of the subject; the ingestible device is configured for epithelial delivery of the dispensable object to the GI tract of the subject; and the ingestible device is configured for local delivery of the dispensable object to the GI tract of the subject.

14. The ingestible device of any of the preceding claims, further comprising a dispensable substance.

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

16. The ingestible device of any of the preceding claims, wherein at least one of the following is true: the ingestible device is configured to deliver the dispensable substance as a jet stream having a peak jet power of about 1 Watt to about 3 Watts to the tissue of the GI tract of the subject; the ingestible device is configured to deliver the dispensable substance at a peak jet velocity of about 25 meters / second to about 45 meters / second; the ingestible device is configured to deliver the dispensable substance to the tissue of the GI tract of the subject at a peak jet pressure of about 100 psig to about 250 psig; the ingestible device is configured to deliver the dispensable substance to the tissue of the GI tract of the subject at a peak jet force of about 0.09 N to about 0.15 N; the ingestible device is configured to deliver the dispensable substance as a jet stream having a jet stabilization length of at least about 0.5 millimeters; the ingestible device is configured to provide an internal pressure of about 225 psig to about 425 psig; and the ingestible device is configured to contain the dispensable substance at a peak fluid pressure of about 200 psig to about 400 psig.

17. The ingestible device of any of the preceding claims, wherein at least one component of the ingestible device comprises a cyclic olefin polymer.

18. The ingestible device of any of the preceding claims, wherein the frangible seal is scored.

19. The ingestible device of any of the preceding claims, wherein the frangible seal has a varying thickness.

20. The ingestible device of any of the preceding claims, wherein the gas cylinder has a burst pressure of about 2,800 psig to about 4,500 psig.

21. The ingestible device of any of the preceding claims, the gas cylinder comprising at least one gas selected from the group consisting of: air, nitrogen, oxygen, carbon dioxide, hydrofluorocarbon gas, and noble gas.

22. The ingestible device of any of the preceding claims, further comprising an element having a first state and a second state, in the first state the element at least partially covers the opening in the housing, 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.

23. The ingestible device of claim 22, wherein the element moves synchronously with the piston.

24. The ingestible device of claim 22 or claim 23, wherein, the element moves the same distance as the piston moves when the piston moves a distance.

25. The ingestible device of any of claims 22-24, further comprising a seal mechanically coupled to the piston and the element.

26. The ingestible device of claim 25, wherein the seal is configured such that movement of the piston causes movement of the element.

27. The ingestible device of any of claims 22-26, wherein the element is conformal to an inner radius of the housing.

28. The ingestible device of any of the preceding claims, further comprising a covering over the opening in the housing.

29. The ingestible device of claim 28, wherein the covering is removable from the ingestible device.

30. The ingestible device of claim 28 or 29, wherein the covering is configured to be removed from the housing due to pressure exerted by the dispensable substance.

31. The ingestible device of any of claims 28-30, wherein the covering comprises an enteric material.

32. The ingestible device of any of claims 28-31, wherein the covering comprises a member selected from the group consisting of a film, a foil, a band, a plug, and a patch.

33. The ingestible device of any of claims 28-32, wherein the covering has a burst pressure of at most 420 psig.

34. The ingestible device of any of the preceding claims, further comprising a second piston, the second piston configured such that, when the first piston exerts a force on the dispensable substance, the dispensable substance exerts a force on the second piston to slide the second piston to expose the opening and the dispensable substance is forced out of the ingestible device via the opening.

35. The ingestible device of any of the preceding claims, further comprising a removable cap, the removable cap secured to the ingestible device and configured such that, when the piston moves to exert a force on the dispensable substance, the dispensable substance exerts a force on the cap to slide the cap to expose the opening in the housing.

36. The ingestible device of any of the preceding claims, further comprising an inflatable membrane volume, the inflatable membrane volume covering the opening and configured such that, when the piston moves to exert a force on the dispensable substance, the dispensable substance exerts a force on the inflatable membrane volume and the inflatable membrane volume is compressed to expose the opening in the housing.

37. A method comprising: delivering a dispensable substance to a GI tract of a subject using an ingestible device according to any of the preceding claims.

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