Ingestible device for delivering therapeutic agents to the gastrointestinal tract

Abstract

Ingestible devices can deliver therapeutic agents directly to desired tissues of a subject's GI tract, such as the submucosa, mucosa, and / or mucus layer of the GI tract, and methods of using the same. 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.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority under 35 U.S.C. §119 to USSN 62 / 948,082, filed December 13, 2019, and entitled “Ingestible Device for Delivery of Therapeutic Agent to the Gastrointestinal Tract”; USSN 63 / 027,427, filed May 20, 2020, and entitled “Ingestible Device for Delivery of Therapeutic Agent to the Gastrointestinal Tract”; and USSN 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

[0003] The present disclosure generally relates to ingestible devices capable of delivering dispensable substances, such as therapeutic agents, and related components, systems, and methods. Background Art

[0004] The gastrointestinal (GI) tract generally provides therapeutic media to an individual's body. Sometimes, it is desirable to distribute a therapeutic agent to the GI tract to treat a medical condition. Summary of the Invention

[0005] The present disclosure provides an ingestible device that can deliver a therapeutic agent directly to a desired tissue of the GI tract of a subject (e.g., the submucosa, mucosa, and / or mucus layer of the GI tract), and methods of using the same. The ingestible device can deliver the therapeutic agent in a safe, effective, and reliable manner. The present disclosure also provides a pharmaceutical composition for use in a method of treating a disease or condition in a subject in need thereof.

[0006] The ingestible devices of the present disclosure are configured to provide at least three different modes of delivering therapeutic agents directly to the GI tract of a subject, referred to herein as transepithelial delivery, epithelial delivery, and topical delivery. As used herein, direct delivery refers to a force-driven delivery mechanism.

[0007] Therefore, on the one hand, the present disclosure relates to delivering therapeutic agents across the epithelium to the GI tract of the subject. Accordingly, the present disclosure provides a kind of ingestible device, which can deliver therapeutic agents directly across the epithelial cell layer of the mucosa of the subject's GI tract, to produce therapeutic agents to the whole body (systemic, systemic) exposure of the subject. In such an embodiment, the ingestible device is configured to deliver therapeutic agents directly across the epithelial cell layer of the mucosa of the GI tract and to the submucosa and / or to the mucosal region below the epithelial layer (for example, to the lamina propria), where it can be used for systemic absorption. When the oral bioavailability of the therapeutic agent is otherwise low, this can be particularly relevant. In some embodiments, the systemic exposure of the therapeutic agent is achieved by delivering the therapeutic agent across the epithelium to the submucosa of the small intestine (for example, in the duodenum, jejunum and / or ileum) and / or to the mucosal region below the epithelial layer (for example, to the lamina propria). In further embodiments, transepithelial delivery delivers the therapeutic agent directly into the submucosal layer of the GI tract and / or into the mucosal region below the epithelial layer (e.g., into the lamina propria) such that the percent systemic absorption from transepithelial delivery relative to intravenous or subcutaneous administration is at least about 10% (e.g., at least about 15%, at least about 20%, at least about 25%, or more).

[0008] Without wishing to be bound by theory, it is believed that transepithelial delivery to the submucosal layer of the GI tract and / or to the mucosal region below the epithelial layer (e.g., into the lamina propria) is achieved by using appropriate values ​​of one or more performance parameters associated with an ingestible device configured for such use. Such performance parameters include, for example, the internal pressure of the ingestible device, the peak fluid pressure of the ingestible device, the nozzle pressure of the ingestible device, the peak jet power of a dispensable substance (e.g., a pharmaceutical formulation containing a therapeutic agent) delivered from the ingestible device, the peak jet velocity of a dispensable substance (e.g., a pharmaceutical formulation containing a therapeutic agent) delivered from the ingestible device, the peak jet pressure of a dispensable substance (e.g., a pharmaceutical formulation containing a therapeutic agent) delivered from the ingestible device, the peak jet force of a dispensable substance (e.g., a pharmaceutical formulation containing a therapeutic agent) delivered from the ingestible device, the peak jet plateau length of a dispensable substance (e.g., a pharmaceutical formulation containing a therapeutic agent) delivered from the ingestible device, nozzle shape, nozzle length, and nozzle diameter.

[0009] In another aspect, the present disclosure relates to epithelial delivery of therapeutic agents to the GI tract of a subject. Accordingly, the present disclosure provides an ingestible device configured to deliver a therapeutic agent directly into the mucus of the small or large intestine and / or onto the epithelial layer, but not across the epithelial layer of the mucosa, from which it can act locally and, in some cases, away from the site of direct delivery. In some embodiments, the device is configured such that the therapeutic agent is delivered from the device with sufficient force to provide epithelial delivery, which force is lower than the force required for transepithelial delivery.

[0010] In yet another aspect, the present disclosure relates to local delivery of therapeutic agents to the GI tract of a subject. Accordingly, the present disclosure provides an ingestible device configured to deliver a therapeutic agent into the lumen of the small or large intestine and / or to mucus or other surfaces of the GI tract facing the lumen, from which it can act locally, and in some cases remote from the site of delivery. In some embodiments, the device is configured such that the therapeutic agent is delivered from the device with sufficient force to deliver the therapeutic agent locally, the force being less than that required for epithelial or transepithelial delivery.

[0011] Ingestible devices, whether configured for transepithelial, epithelial, or topical delivery, can have a streamlined and / or relatively simple mechanical design, be relatively small, and / or be inexpensive to manufacture. Generally speaking, the device protects a dispensable substance (e.g., a therapeutic agent or a pharmaceutical formulation comprising a therapeutic agent) until the device reaches a desired location in the subject. As an example, the device can be designed to deliver a dispensable substance to a desired location in the GI tract of a subject, and the device can be designed so that the dispensable substance does not experience components of the GI tract (e.g., acids, enzymes) before reaching the desired location in the GI tract. As another example, the device can be designed to deliver a dispensable substance so that the therapeutic properties of the dispensable substance do not change during delivery (e.g., the dispensable substance is a therapeutic agent that binds to its therapeutic target after delivery).

[0012] The present disclosure provides an ingestible device that can deliver a therapeutic agent directly to a desired tissue of the GI tract of a subject (e.g., the submucosa, mucosa, and / or mucus layer of the GI tract), e.g., to treat a particular class of diseases or a specific disease. Relatedly, methods of using the device to deliver a therapeutic agent to a desired tissue of the GI tract, e.g., to treat a particular class of diseases or a specific disease, are disclosed. These disclosures also inherently provide disclosures of corresponding medical uses—i.e., disclosures of the listed therapeutic agents for use in methods of treating the listed classes of diseases or specific diseases by using the device to deliver the listed therapeutic agents to a desired tissue of the GI tract of a subject.

[0013] In one aspect, the present disclosure provides an ingestible device comprising: a housing comprising an interior and an opening; a cylinder in the interior of the housing, the 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 retains the retainer in a first position; the retainer retains the perforator in a first position in which the perforator does not break the breakable seal of the 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 through the opening in the housing.

[0014] In some embodiments, in the 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.

[0015] In some embodiments, in the second state of the ingestible device: the spring applies a force to the perforator to move the perforator such that the perforator breaks a breakable seal of the cylinder; releases gas from the cylinder; the gas applies a force to the piston such that the piston applies a force to the dispensable substance; and the dispensable substance is delivered from the ingestible device through an opening in the housing.

[0016] The ingestible device may further include a seal between the piston and the housing, and / or a seal between the piercer and the housing.

[0017] In one aspect, the present disclosure provides an ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent within an interior of the housing; a cylinder within the interior of the housing; a spring within the interior of the housing; a piston within the interior of the housing; a seal between the piston and the housing; a perforator within the interior of the housing; a retainer; and a trigger exposed to an environment external to the housing.

[0018] In one aspect, the present disclosure provides an ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent within an interior of the housing; a cylinder within the interior of the housing; a spring within the interior of the housing; a piston within the interior of the housing; a perforator within 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.

[0019] In one aspect, the present disclosure provides an ingestible device comprising: a housing configured to contain a dispensable substance comprising a therapeutic agent within an interior of the housing; a cylinder within the interior of the housing; a spring within the interior of the housing; a piston within the interior of the housing; a first seal between the piston and the housing; a perforator within 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.

[0020] The ingestible device may be a 00 size device.

[0021] The trigger may comprise an enteric material.

[0022] The housing may comprise first and second housing portions, wherein the piston and dispensable substance are interior to the first housing portion and the spring and retainer are interior to the second housing portion.

[0023] The opening of the ingestible device may be a nozzle, for example a nozzle having a diameter of about 325 μm to 375 μm.

[0024] In some embodiments, at least one of the following is true: the ingestible device is configured for transepithelial 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 topical delivery of the dispensable object to the GI tract of the subject.

[0025] The ingestible device may further comprise a dispensable substance. In some embodiments, the dispensable substance is a solution or a suspension.

[0026] In some embodiments, at least one of the following is true: the ingestible device is configured to deliver the dispensable substance to the tissue of the GI tract of the subject as a jet having a peak jet power of about 1 watt to about 3 watts; the ingestible device is configured to deliver the dispensable substance at a peak jet velocity of about 25 meters per second to about 45 meters per 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 with 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 having a jet stabilization length of at least about 0.5 mm; 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.

[0027] In some embodiments, at least one component of the ingestible device comprises a cyclic olefin polymer.

[0028] In some embodiments, the frangible seal is scored.

[0029] In some embodiments, the frangible seal has a varying thickness.

[0030] In some embodiments, the cylinder has a burst pressure of about 2,800 psig to about 4,500 psig.

[0031] In some embodiments, the gas cylinder contains at least one gas selected from the group consisting of air, nitrogen, oxygen, carbon dioxide, hydrofluorocarbon gases, and noble gases.

[0032] In some embodiments, the ingestible device further comprises an element having a first state and a second state, wherein in the first state the element at least partially covers the opening in the housing, and in the second state the element does not cover the opening in the housing, wherein the ingestible device is configured such that, when the piston moves, the element moves from its first state to its second state. The element may move synchronously with the piston. When the piston moves a distance, the element may move the same distance. The ingestible device may further comprise a seal mechanically coupled to the piston and the element. The seal may be configured to cause movement of the piston to result in movement of the element. The element may conform to an inner radius of the housing.

[0033] In some embodiments, the ingestible device further comprises a cover over the opening in the housing. The cover may be removable from the ingestible device. The cover may be configured to be removed from the housing due to pressure exerted by the dispensable substance. The cover may comprise an enteric material. The cover may be a film, foil, tape, plug, or patch. The cover may have a burst pressure of up to 420 psig.

[0034] In some embodiments, the ingestible device further includes a second piston configured such that, when the first piston applies a force to the dispensable substance, the dispensable substance applies a force to the second piston to cause the second piston to slide to expose the opening and the dispensable substance to be forced to exit the ingestible device through the opening.

[0035] In some embodiments, the ingestible device further includes a removable cap secured to the ingestible device and configured such that, when the piston moves to apply force to the dispensable substance, the dispensable substance applies force to the cap to slide the cap to expose the opening in the housing.

[0036] In some embodiments, the ingestible device further includes an inflated membrane volume covering the opening and configured such that, when the piston moves to apply force to the dispensable substance, the dispensable substance applies force to the inflated membrane volume and the inflated membrane volume is compressed to expose the opening in the housing.

[0037] In one aspect, the present disclosure provides methods comprising delivering a dispensable substance to the GI tract of a subject using an ingestible device according to the present disclosure.

[0038] The details of one or more embodiments of the apparatus and method are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1A are schematic cross-sections of different regions of healthy intestinal tissue.

[0040] Figure 1B corresponds to Figure 1A Schematic cross-section of intact but diseased intestinal tissue.

[0041] Figure 2 is a cross section of an ingestible device.

[0042] Figure 3 is a cross section of an ingestible device.

[0043] Figure 4 An exemplary process flow diagram is shown for use with an ingestible device in which no pressure is applied to the dispensable substance prior to swallowing the ingestible device by a subject.

[0044] Figures 5A-5C Shown with Figure 4 Ingestible devices of similar aspects to those shown in .

[0045] Figures 6A-6C Shown with Figure 4 and ingestible devices of similar aspects to those shown in 5.

[0046] Figure 7-13 An ingestible device having multiple chambers for one or more dispensable substances is shown.

[0047] Figure 14-17 An ingestible device is shown.

[0048] Figure 18 Shown Figure 19 ingestible device.

[0049] Figure 19 and 20Shows the status of the ingestible device.

[0050] Figure 21 and 22 Shows the status of the ingestible device.

[0051] Figure 23 and 24 Shows the status of the ingestible device.

[0052] Figure 25-27 An ingestible device is shown.

[0053] Figures 28-30 Shows the status of the ingestible device.

[0054] Figures 31-34 Shows the status of the ingestible device.

[0055] Figures 35-40 An ingestible device is shown.

[0056] Figures 41A-41C Aspects of an ingestible device are shown.

[0057] Figures 42A-47C Aspects of an ingestible device are shown.

[0058] Figure 48 and 49 Shows the status of the ingestible device.

[0059] Figure 50A and 50B An exploded view of the ingestible device is shown.

[0060] Figure 51A and 51B An exploded view of the ingestible device is shown.

[0061] Figures 52A-52D A view of an ingestible device is shown.

[0062] Figure 53A and 53B A view of a portion of an ingestible device is shown.

[0063] Figure 54A and 54B A view of a portion of an ingestible device is shown.

[0064] Figure 55 A view of a portion of an ingestible device is shown. DETAILED DESCRIPTION

[0065] Incorporated by reference

[0066] This application incorporates by reference in their entirety the following patent applications: USSN 62 / 769,496, filed on November 19, 2018, and entitled “Ingestible Device With High Pressure Substance Delivery to the Gastrointestinal Tract”; USSN 62 / 818,731, filed on March 14, 2019, and entitled “Ingestible Device With High Pressure Substance Delivery to the Gastrointestinal Tract”; USSN 62 / 819,513, filed on March 15, 2019, and entitled “Ingestible Device With High Pressure Substance Delivery to the Gastrointestinal Tract”; and USSN 62 / 932,459, filed on November 7, 2019, and entitled “Ingestible Device and Method of Use to Deliver Therapeutic Agent to the Gastrointestinal Tract”.

[0067] definition

[0068] "Ingestible," as used herein with reference to a device, means that the device can be swallowed whole.

[0069] As used herein with respect to any substance, "dispensable" refers to any substance that can be released from an ingestible device as disclosed herein or from a component (e.g., a reservoir) of the device. For example, a dispensable substance can be a therapeutic agent as disclosed herein, and / or a formulation comprising a therapeutic agent as disclosed herein. The dispensable substance can be a fluid, such as a liquid, a suspension, or a semisolid. For example, the dispensable substance can be a liquid in the form of a solution, such as an aqueous solution. In some embodiments, when placed in an ingestible device, the substance is a non-fluid, such as a solid. In such an embodiment, the substance can be converted into a fluid before being delivered from the ingestible device. In some embodiments, the therapeutic agent is a small molecule. In other embodiments, the therapeutic agent is a macromolecule, such as a biopharmaceutical. Non-limiting examples of biopharmaceuticals 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, the dispensable substance is a pharmaceutical formulation comprising a therapeutic agent and a liquid carrier. In some embodiments, the pharmaceutical formulation comprising a therapeutic agent and a liquid carrier is a solution formulation. In other embodiments, the pharmaceutical formulation comprising a therapeutic agent and a liquid carrier is a suspension formulation or an emulsion formulation. In some embodiments, the distributable material delivered as described herein is particularly suitable for treating diseases and disorders of the endodermal layer, for example, compared with subcutaneous or intravenous administration, it can be more effective in the gut-associated lymphoid tissue (GALT) or liver system. In general, the viscosity of the distributable material can be appropriately selected. In some embodiments, the dispensable 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 to at most about 9 cP, at most about 8 cP, at most about 7 cP). In certain embodiments, the dispensable 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, the dispensable 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).

[0070] As used herein, the term "enteric" refers to a material that allows the drug to be transferred to a desired location in the GI tract (e.g., through the stomach to the intestine) before dissolving / degrading / eroding due to exposure to certain conditions of the GI tract (e.g., pH, temperature, enzymes). Enteric materials can prevent the drug from being degraded by gastric juices and enzymes. In some embodiments, the enteric composition (e.g., when forming a coating (coating) on ​​the housing of an ingestible device) is selected from: a mixture of fat and fatty acids; shellac and shellac derivatives; and cellulose acetate phthalate. The enteric material may be an enteric polymer. In some embodiments, the enteric polymer may 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: Colorcon's Opadry Enteric 91 series polyvinyl acetate phthalate, Opadry Enteric 94 series methacrylic acid, Opadry Enteric 95 series methacrylic acid, Sureteric PVAP (polyvinyl acetate phthalate), Nutrateric ethylcellulose Evonik Acryl-EZE (Colorcon & Evonik collaboration-Eudragit L 100-55 mixture methacrylic acid copolymer); Evonik's Eudragit L100-55 methacrylic acid copolymer, Eudragit L 30D-55 methacrylic acid copolymer (30%), Eudragit L100 methacrylic acid copolymer, Eudragit L 12,5 methacrylic acid copolymer (12.5%), Eudragit S100 methacrylic acid copolymer, Eudragit S12,5 methacrylic acid copolymer (12.5%), Eudragit FS 30D methacrylic copolymer (30%); Kerry's SheffCoat ENT cellulose acetate phthalate, acrylates copolymer, HPMC-P; Eastman's CAP NF cellulose acetate phthalate; Sensient's PROTECT TMENTERIC shellac & sodium alginate. In certain embodiments, enteric materials dissolve in the small intestine and are suitable for small intestine 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 RL100 (e.g., HP-55), malic acid-propane 1,2-diol, polyvinyl acetate phthalate, anionic polymers of methacrylic acid and methyl methacrylate, hydroxypropyl cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylate-methacrylic acid copolymer, styrene, maleic acid copolymer, shellac, etc. Other suitable enteric materials are aqueous emulsions of ethyl acrylate methacrylic acid copolymer or hydroxypropyl methylcellulose acetate succinate (HPMAS). (See, for example, U.S. Patent No. 5,591,433). In some embodiments, enteric materials dissolve in the large intestine and are suitable for colon release. Enteric materials suitable for release in the large intestine (e.g., colon) are known to those skilled in the art. In some embodiments, the degradation of the coating is microbially triggered, for example, bacterial enzymes in the colon trigger the degradation of the coating (see, for example, 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 the pH increases. In some embodiments, the coating is a polymethacrylate having a pH-dependent dissolution threshold of about pH 6.0 to about 7.0. Examples of suitable enteric materials include, but are not limited to, chitosan, alginates (e.g., as calcium salts), L (e.g. 100), S (e.g. S100), L (e.g. L-30D), FS (e.g. FS 30D), hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55 and cellulose acetate trimellitate. In some embodiments, the enteric material is a material described in: US10,226,430; 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 herein by reference in its entirety. In some embodiments, colon-specific degradation of the enteric material may be based on the presence of microorganisms that reside only in the colon, more particularly, biodegradable enzymes produced by these microorganisms. In general, such microorganisms are anaerobic bacteria, such as Bacteroides, Bifidobacteria, Enterobacteria, Eubacteria, Clostridia, Enterococci and Ruminococcus etc. These microflora satisfy their energy needs by fermenting various types of substrates (such as polysaccharides, disaccharides and trisaccharides etc.) that are not digested in the small intestine. These polymers are stable in the environment of the stomach and small intestine. When arriving at the colon, the polymer experience is degraded by enzyme, or the decomposition of the polymer backbone causes the subsequent reduction of its molecular weight, thereby losing mechanical strength.

[0071] As used herein, the term "jet" refers to a collimated stream of fluid (e.g., liquid or suspension) that is stable and does not disintegrate into a spray. A jet can be formed by forcing a fluid (e.g., liquid or suspension) through an opening in an ingestible device. Typically, the jet remains in a stable form and is able to achieve its intended purpose by maintaining (e.g., for penetrating a surface) appropriate properties such as its diameter and / or velocity.

[0072] As used herein, "jet diameter" is the cross-sectional diameter of a jet at a given location.

[0073] As used herein, "average jet diameter" refers to the average cross-sectional diameter of the jet between the location where the jet is formed (e.g., the nozzle opening through which the dispensable substance is delivered from the ingestible device) and the location where the jet impacts the GI tissue of the subject.

[0074] As used herein, "jet stability length" refers to the distance from an opening of an ingestible device (eg, a nozzle opening) at which a dispensable substance delivered through the opening remains in the form of a jet.

[0075] As used herein, "jet velocity" is the average fluid velocity across a cross-section of a jet at a given point in time.

[0076] As used herein, "peak jet velocity" refers to the maximum jet velocity of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, the peak jet velocity is reached upon initial delivery of the dispensable substance from the ingestible device.

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

[0078] As used herein, "mean jet velocity" and "average jet velocity" refer to the average velocity of the jet at the interface of the lumen and the lumen-facing surface of the GI tract determined over the time that the ingestible device delivers the dispensable substance.

[0079] As used herein, "peak jet power" refers to the maximum power of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, peak jet power is reached upon initial delivery of the dispensable substance from the ingestible device.

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

[0081] As used herein, "mean jet power" and "average jet power" refer to the average power of the jet at the interface of the lumen and the lumen-facing surface of the GI tract determined over the time that the ingestible device delivers the dispensable substance.

[0082] As used herein, "jet power during delivery" refers to the jet power at the interface of the lumen of a subject and the mucosa of the GI tract.

[0083] As used herein, "jet pressure" refers to the pressure of the jet stream at the interface of the lumen and the lumen-facing surface of the GI tract. As an example, the jet pressure can be the pressure of the jet stream measured at the intestinal wall. In some embodiments, the jet pressure is referred to herein as the "impact pressure."

[0084] As used herein, "peak jet pressure" refers to the maximum pressure of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, peak jet pressure is reached upon initial delivery of the dispensable substance from the ingestible device.

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

[0086] As used herein, "mean jet pressure" and "average jet pressure" refer to the average pressure of the jet at the interface of the lumen and the lumen-facing surface of the GI tract determined over the time that the ingestible device delivers the dispensable substance.

[0087] As used herein, "jet force" refers to the force of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. In some embodiments, the jet force is referred to herein as the "impact force."

[0088] As used herein, "peak jet force" refers to the maximum force of the jet at the interface of the lumen and the lumen-facing surface of the GI tract. Generally speaking, the peak jet force is reached upon initial delivery of the dispensable substance from the ingestible device. In some embodiments, the peak jet force is referred to herein as the "impact force."

[0089] As used herein, "minimum jet force" refers to the minimum force of the jet at the interface of the lumen of a subject and the mucosa of the GI tract. Generally speaking, the minimum jet force is reached at the end of delivery of the dispensable substance from the ingestible device.

[0090] As used herein, "mean jet force" and "average jet force" refer to the average pressure of the jet at the interface of the lumen and the lumen-facing surface of the GI tract determined over the time that the ingestible device delivers the dispensable substance.

[0091] As used herein, "fluid volume" refers to the volume of a dispensable substance contained in an ingestible device.

[0092] As used herein, "initial fluid volume" refers to the volume of the dispensable substance contained in the ingestible device just before the dispensable substance is delivered from the ingestible device.

[0093] As used herein, "final fluid volume" refers to the volume of the dispensable substance contained in the ingestible device just after delivery of the dispensable substance from the ingestible device is complete.

[0094] As used herein, "delivered fluid volume" refers to the volume of a dispensable substance delivered from an ingestible device. In some embodiments, the delivered fluid volume is less than the fluid volume.

[0095] As used herein, "end circle" is the radius on the curve at the end of the housing of the ingestible device.

[0096] As used herein, "fluid pressure" refers to the pressure within a volume of fluid.

[0097] As used herein, "peak fluid pressure" refers to the maximum pressure generated in a volume of fluid. Typically, peak fluid pressure is reached upon initial delivery of a dispensable substance from an ingestible device. In some embodiments, peak fluid pressure is referred to herein as "the internal pressure on the drug formulation in the device prior to release from the device."

[0098] As used herein, "minimum fluid pressure" refers to the minimum pressure generated in a volume of fluid. Typically, the minimum fluid pressure is reached at the end of delivery of the dispensable substance from the ingestible device.

[0099] As used herein, "fluid pressure during delivery" refers to the pressure in the volume of a fluid as the volume of the fluid decreases during the delivery process.

[0100] As used herein, "nozzle" refers to the passageway between the fluid reservoir space and the external environment. Typically, in embodiments where a nozzle is used, the pressure in the fluid volume creates a high velocity flow of the fluid through the nozzle to produce a fluid jet at the opening of the nozzle through which the dispensable substance exits the ingestible device and enters the environment external to the ingestible device.

[0101] As used herein, "nozzle diameter" refers to the diameter of the opening of the nozzle at the opening of the nozzle through which a dispensable substance exits the ingestible device and enters the environment external to the ingestible device.

[0102] As used herein, "nozzle length" refers to the length of the opening of the nozzle.

[0103] As used herein, "nozzle stand-off distance" refers to the distance between: 1) the opening of the nozzle through which the dispensable substance exits the ingestible device and enters the external environment of the ingestible device; and 2) the interface between the lumen and the lumen-facing surface of the GI tract.

[0104] As used herein, the "internal pressure" of an ingestible device refers to the pressure applied to the dispensable material (e.g., a therapeutic agent or a formulation containing a therapeutic agent) contained in the ingestible device before the dispensable material is delivered from the ingestible device. In some embodiments, the internal pressure is provided by a driving force generator of the ingestible device. In certain embodiments, the internal pressure is greater than the fluid pressure. For example, this may be due to friction acting on the drive coupling of the ingestible device, such as O-ring friction. This friction is referred to herein as "piston friction."

[0105] As used herein, "nozzle pressure" refers to the pressure of the dispensable substance at the nozzle opening as measured at the surface facing the interior of the nozzle when the dispensable substance is being delivered from the ingestible device. Generally speaking, for a given ingestible device at a given point in time, the nozzle pressure is approximately the same as the fluid pressure.

[0106] 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) wherein the dispensable substance is delivered to a localized area of ​​the body or to the surface of a body part, regardless of the location of the effect; more particularly, local administration of the dispensable substance includes releasing the dispensable substance into the lumen of the GI tract of a subject, the lumen-facing surface of the GI tract, the mucosa and / or lining of the gastrointestinal tract, including but not limited to surfaces, mucosa, or lining containing one or more disease sites (e.g., gastrointestinal mucosal lesions). The effect of local delivery or local administration of a dispensable substance can be local to the site of local administration, or remote from the site of local administration (e.g., distal thereto).

[0107] As used herein, "epithelial delivery" or "epithelial administration" refers to a route of administration of a dispensable substance (e.g., a therapeutic agent or a pharmaceutical formulation containing a therapeutic agent) in which the dispensable substance is delivered directly into the mucus or onto the epithelium of the GI tract (e.g., the small intestine or large intestine) of a subject, but does not extend beyond the epithelial layer, from which the dispensable substance can act locally or peripherally. In some embodiments of epithelial delivery or epithelial administration, the therapeutic agent can move deeper into the GI tissue (i.e., through the epithelial layer) away from the direct delivery site, for example, by diffusion or active transport.

[0108] As used herein, "transepithelial delivery" or "transepithelial administration" refers to a route of administration of a dispensable substance (e.g., a therapeutic agent or a pharmaceutical formulation containing a therapeutic agent) wherein the dispensable substance is delivered directly to the submucosa of the GI tract of a subject through the epithelial layer of the mucosa of the GI tract; optionally, at least a portion of the dispensable substance is delivered directly across the epithelial layer to the mucosal area below the epithelial layer. In embodiments of transepithelial delivery in which a portion of the dispensable substance is delivered directly to the mucosal area below the epithelial layer, at least some (e.g., all) of the portion of the dispensable substance is delivered directly to the lamina propria. Once the therapeutic agent or pharmaceutical formulation containing the therapeutic agent is delivered directly across the epithelial layer of the GI tract, the therapeutic agent is exposed systemically to the subject.

[0109] General Introduction

[0110] Figure 1ASchematically depicting the different regions of healthy intestinal tissue presented in cross-section. These regions include the lumen of the GI tract, the mucus of the GI tissue, the mucosa of the GI tissue, and the submucosa of the GI tissue. The mucosa of the GI tissue includes an epithelial layer and a lamina propria. The muscularis mucosae separates the mucosa from the submucosa. The muscularis extrema is located below the submucosa. Figure 1B The corresponding area of ​​diseased intestinal tissue presented in cross section is schematically depicted.

[0111] The ingestible devices described herein can deliver therapeutic agents via topical delivery (not directly to the mucus, mucosa, or submucosa), epithelial delivery (directly to the mucus or epithelium without direct delivery across the epithelial layer to the mucosa or submucosa), or transepithelial delivery (directly to the submucosa and / or to mucosal areas below the epithelial layer (e.g., the lamina propria).

[0112] In general, the delivery form 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 transepithelial delivery. During transepithelial delivery, a bolus of the therapeutic agent initially contained in the dispensable substance can be formed within the submucosal layer and / or into the mucosal region (e.g., lamina propria) below the epithelial layer.

[0113] In some embodiments, the following is established. The ingestible device is designed to deliver dispensable substances, such as therapeutic agents or pharmaceutical formulations containing therapeutic agents, through the epithelial layer of the mucosa of the GI tract. In some embodiments, the dispensable substance is a solution formulation; optionally, a suspension. In some embodiments, the dispensable substance enters the submucosal layer of the small intestine and / or to the mucosal area (e.g., lamina propria) below the epithelial layer, where it can be absorbed systemically. After the patient swallows the device, it passes through the GI tract and eventually reaches the small intestine. The device includes a restraining mechanism, optionally a triggering mechanism (e.g., a degradable and / or erodible coating, such as an enteric coating, which partially or completely degrades and / or erodes when the device reaches the desired position in the GI tract). The desired position can be the small intestine or the large intestine. When the device is configured for delivery across the epithelial GI tract to the submucosal layer and / or to the mucosal area (e.g., lamina propria) below the epithelial layer, the preferred position can be the small intestine. As the restraining element is removed, relative movement between certain components (e.g., sliding of components) occurs such that one or more openings in the ingestible device (e.g., in a compartment containing the dispensable substance (e.g., a reservoir, sometimes referred to herein as a "drug reservoir," "storage reservoir," or "substance reservoir")) align with one or more additional openings (e.g., one or more nozzles) in the ingestible device (e.g., in 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 piston)) forces the dispensable substance to exit the device from the drug reservoir via the one or more openings (e.g., one or more nozzles). The dispensable substance is delivered as a jet of fluid (e.g., liquid) in the form of a single or multiple boluses through the epithelial layer of the mucosa of the GI tract and directly into the submucosa and / or into the mucosal region below the epithelial layer (e.g., the lamina propria). After the device is swallowed, the device travels through the GI tract (mouth, esophagus, stomach, duodenum, jejunum, ileum, cecum, and colon), ultimately exiting the GI tract via the anus.

[0114] Therefore, in general, the ingestible device disclosed herein provides the delivery of a therapeutic agent to the GI tract of a subject. On the one hand, the present disclosure relates to the trans-epithelial delivery of a dispensable substance (such as a therapeutic agent or a formulation comprising a therapeutic agent) to the GI tract of a subject. Accordingly, the present disclosure provides a kind of ingestible device, which can deliver a dispensable substance (such as a therapeutic agent or a formulation comprising a therapeutic agent) directly to the submucosal layer of the GI tract of the subject and / or to the mucosal region (such as the lamina propria) below the epithelial layer, which can result in systemic exposure of the therapeutic agent to the subject. In such an embodiment, the ingestible device is configured to deliver the dispensable substance directly across the epithelial cell layer of the mucosa of the GI tract and to the submucosal layer and / or to the mucosal region (such as the lamina propria) below the epithelial layer, where the therapeutic agent so delivered can be used for systemic absorption. In some embodiments, systemic exposure of the therapeutic agent is achieved by delivering the dispensable substance transepithelially into the submucosal layer of the small intestine (e.g., in the duodenum, jejunum, and / or ileum) and / or into the mucosal region below the epithelial layer (e.g., lamina propria). In some further embodiments, transepithelial delivery delivers the dispensable substance directly into the submucosal layer of the GI tract and / or into the mucosal region below the epithelial layer (e.g., lamina propria) such that the percentage systemic absorption of the therapeutic agent via transepithelial delivery relative to intravenous or subcutaneous administration is at least about 10% (e.g., at least about 15%, at least about 20%, at least about 25%, or more).

[0115] In some embodiments, delivery of a therapeutic agent directly to the submucosa and / or to the mucosal region beneath the epithelial layer (e.g., the lamina propria) via transepithelial delivery can also or alternatively provide a therapeutic effect locally at the direct delivery site and / or distal to the direct delivery site (e.g., distal thereto).

[0116] In some embodiments, transepithelial 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 another portion 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 transepithelial delivery can provide a therapeutic effect locally at the direct delivery site and / or distal to the direct delivery site (e.g., distal thereto).

[0117] On the other hand, present disclosure relates to dispensable material (such as therapeutic agent or the preparation comprising therapeutic agent) to the epithelium of experimenter's GI tract. Accordingly, present disclosure provides a kind of ingestible device, it is configured to dispensable material (such as therapeutic agent or the preparation comprising therapeutic agent) directly delivered to the mucus of small intestine or large intestine, but not across the epithelial layer of mucosa, it can provide therapeutic effect from there in direct delivery site locally and / or away from direct delivery site (such as its distal end). In some further embodiments, ingestible device directly delivers dispensable material so that it contacts the surface of the mucosal epithelial cell layer facing the lumen, but as previously mentioned, epithelial delivery does not directly deliver dispensable material across the epithelial layer of mucosa. In some embodiments, the device is configured to make dispensable material delivered from the device with enough force to provide epithelial delivery, and this force is lower than the force required for transepithelial delivery to GI tract. In some further embodiments, epithelial delivery delivers the dispensable substance directly into the mucus of the GI tract such that the percentage systemic absorption relative to the intravenously or subcutaneously administered transepithelially delivered therapeutic agent is greater than the percentage of local delivery but less than the percentage of transepithelial delivery. In other embodiments, epithelial delivery delivers the dispensable substance directly into the mucus of the GI tract such that the percentage systemic absorption relative to the intravenously or subcutaneously administered transepithelially delivered therapeutic agent is from 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%, or greater).

[0118] In some embodiments of epithelial delivery, therapeutic agents delivered directly to the mucus of the GI tract via epithelial delivery 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 away from 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 induces other pharmacodynamic effects locally at the site of delivery or away from the site of delivery via immune cells or tissues (e.g., dendritic cells, lymphocytes, mucosa-associated lymphoid tissue) in the GI tract.

[0119] In yet another aspect, the present disclosure relates to 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 or large intestine and / or to mucus or other surfaces of the GI tract facing the lumen (e.g., a diseased surface), from which it can provide a therapeutic effect locally at the delivery site and / or away from the delivery site (e.g., its distal end). In some embodiments, the device is configured so that the dispensable substance is delivered from the device with sufficient force to locally deliver the dispensable substance, the force being lower than the force required for epithelial or transepithelial delivery to the GI tract. In some embodiments, local delivery to the GI tract results in reduced systemic absorption of the therapeutic agent compared to transepithelial delivery to the GI tract, intravenous, or subcutaneous delivery.

[0120] In some further embodiments, local delivery delivers the dispensable substance into the lumen and / or to the mucus or other surface of the GI tract facing the lumen such that the percentage systemic absorption of the therapeutic agent via local delivery relative to intravenous or subcutaneous administration is less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%. In some embodiments, local delivery to the GI tract results in negligible or no systemic absorption of the therapeutic agent compared to transepithelial delivery to the GI tract, intravenous or subcutaneous delivery.

[0121] In some embodiments, the topically delivered dispensable substance may spread over the mucus or other lumen-facing surface of the GI tract, thereby coating the surface of the GI tract at and / or distal to the site of delivery (e.g., distal end thereof). In some embodiments, upon or after the topical delivery of the dispensable substance, the therapeutic agent may undergo transport (e.g., diffusion) from the mucus surface into the mucus, and optionally, active or passive transport or diffusion across the epithelial layer of the mucosa.

[0122] In some embodiments, the epithelial layer of mucus and / or mucosa can be destroyed or even missing, such as in patients with diseases or conditions of the GI tract. In such embodiments, local delivery of dispensable substances to the GI tract of the patient can provide for direct delivery of dispensable substances to the surface of the GI tract facing the lumen, such as mucosal tissue exposed by the destruction and / or missing (for example, due to a disease or condition, both the mucus layer and / or the epithelial layer are completely or partially missing or damaged in the part of the GI tract). For example, in some embodiments, local delivery of dispensable substances 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 condition is inflammatory bowel disease. In some further embodiments, inflammatory bowel disease is ulcerative colitis. In some other embodiments, inflammatory bowel disease is Crohn's disease.

[0123] Accordingly, provided herein are novel systemic delivery devices and methods for delivering therapeutic agents to the small intestinal mucosa and / or submucosa by jet injection. Current methods of administration for most macromolecular therapeutics are subcutaneous (SC), intramuscular (IM), or bolus intravenous (IV) injections targeting the systemic circulation. The devices and methods described herein provide alternative routes of administration for current injectable drugs, which can lead to greater convenience and compliance because they minimize or avoid the logistical challenges, patient compliance and attachment challenges, pain, and discomfort associated with traditional routes of administration.

[0124] Furthermore, by providing higher concentrations of therapeutic agents in GI tissues, the devices and methods described herein are particularly well-suited for treating diseases and disorders of the endoderm, including the liver.

[0125] Device Description

[0126] overall

[0127] In general, an ingestible device is adapted to be swallowed by a patient and to pass safely and effectively through the patient's GI tract. Typically, the device may be in the shape of a capsule, pill, or any other swallowable form that can be consumed orally by a subject. In some embodiments, the ingestible device may be swallowed voluntarily under medical supervision or in a home use environment with instructions provided prior to subsequent ingestion. Typically, the ingestible device is intended for single subject, single use. The ingestible device may have a sufficiently high density to allow the ingestible device to sink into human gastric fluid, for example, an unfilled ingestible device may have a density greater than 1.01 g / cm 3density. The ingestible device may have a maximum size that allows the ingestible device to pass through the GI tract of an average person. In some embodiments, the ingestible device is configured to prevent rolling in the small intestine of a person. For example, the ingestible device has sufficient length so that it does not roll in the small intestine of a person before, during, or after the release of the dispensable substance. Typically, the ingestible device is configured to deliver a sufficient amount of the therapeutic agent contained in the dispensable substance to be effective for its intended purpose. In general, the patient contact portion (e.g., outer surface) and the dispensable substance contact portion of the ingestible device are biocompatible. Preferably, the device can withstand indirect bite forces without damaging the housing or causing leakage. As an example, when accommodating the dispensable substance, the ingestible device can withstand a bite force of at least about 60 Newtons (N). Typically, unless otherwise intended (see discussion below), the components of the ingestible device can withstand exposure to the pH range expected in the human GI tract without significant functional loss, significant structural damage, or significant leakage. As an example, in some embodiments, the ingestible device can withstand immersion in a fluid environment at a pH of 1.5±0.5 for at least about 24 hours without significant loss of function, significant structural damage, or significant leakage. Generally speaking, the ingestible device can maintain an external fluid barrier between the interior of the ingestible device and the GI tract of the subject during transit therethrough. Typically, the ingestible device can withstand the external fluid pressure to which it is exposed during use without significant loss of function, significant structural damage, or significant leakage. As an example, in some embodiments, the ingestible device does not experience significant loss of function, significant structural damage, or significant leakage when exposed to a continuous 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.

[0128] In general, the ingestible devices disclosed herein include the following features.

[0129] shell

[0130] 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 actuating member on the housing and a second actuating member within the housing. In some embodiments, a storage reservoir is located within the housing, wherein the storage reservoir is configured to store dispensable substances. 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 produce one or more openings in the ingestible device, wherein substances can be dispensed through the openings, as described in PCT application number PCT / US2019 / 021814, which is published as WO2019178071 and is incorporated herein by reference. For example, the housing may include an external electrolytic circuit (an electrolytically erodible surface is on the outside of the device), whereby the surrounding gastric fluid is the electrolyte that completes the electrolytic circuit between the anode and cathode. By applying a sufficient bias voltage (e.g., 1.5-15 volts, e.g., 3-5 volts), the anode will electrolytically erode or dissolve, thereby creating an opening in the housing within the desired time interval. In some embodiments, the one or more openings created by the electrolytic mechanism are connected to one or more nozzles, thereby allowing transepithelial, 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 only covers certain areas 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 may further include: a liquid silicone rubber material (e.g., manufactured by NuSil) having a hardness level of 10 to 90 as measured using a durometer; TM Manufactured by MED-4942 TM ), soft biocompatible polymeric materials such as, but not limited to, polyvinyl chloride (PVC), polyethersulfone (PE), polyethylene (PE), polyurethane (PU), or polytetrafluoroethylene (PTFE), and rigid polymeric materials coated with soft or flexible biocompatible materials (e.g., poly(methyl methacrylate) (PMMA) materials coated with silicone polymers). Using different materials for different components can enable functionalization of certain surfaces to interact with proteins, antibodies, and other biomarkers. For example, in an ingestible device, As a material for movable parts to reduce friction between these parts. Other example materials may include other materials commonly used in microfabrication, such as polydimethylsiloxane (PDMS), borosilicate glass and / or silicon. Although specific materials may be referred to herein as being used to construct the device for illustrative purposes, the materials listed are not intended to be restrictive, and those skilled in the art can easily transform the device into using any number of different materials without affecting the overall operation or function of the device. In some embodiments, the housing of the ingestible device may be made of a type of plastic (such as a photosensitive acrylic polymer material or an inert polycarbonate material). The housing may also be formed using materials that can be sterilized by chemicals. In some embodiments, the wall of the housing may have a thickness of, for example, about 0.5 mm to about 1 mm. In some embodiments, in addition to biocompatibility, the material used to make the housing is also non-ferrous and non-magnetic. Such materials include various plastics (such as PVC or polycarbonate). Optionally, the housing may include metal-based materials, such as alloys, stainless steel, or substantially pure metal. Such materials can be sterilized without affecting the mechanical working of the ingestible device or the outer surface of the ingestible device. In some embodiments, the material based on metal is compatible with the dispensable substance over the long-term storage duration. Various stainless steel alloys meet these standards, including SAE grades 303, 304, 304L, 316, 316L, 440. Taking into account nickel content, purity and / or traceability, in some embodiments, stainless steel grades are approved for use as surgical implant materials, such as ASTM grades F138, F1314, F1586, F2229 or F2581. The wall of the shell of the ingestible device is generally thick enough to withstand the internal and external pressures to which they are exposed without significant functional loss, significant structural damage or significant leakage. In general, the wall of the shell is ideally as thin as possible to enhance the volume that can be used to accommodate the dispensable substance. As an example, in some embodiments, the wall is about 0.05mm to about 0.5mm thick (for example, if made of metal-based material such as stainless steel) or about 0.1 to about 1mm thick (for example, if made of plastic such as polycarbonate). In general, the housing is made of a material having a coefficient of thermal expansion that is low enough so that the device does not deform significantly at temperatures encountered during transport and storage or within the GI tract. In some embodiments, the walls of the housing are made of 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 the nozzle for exposing the liquid volume to its surroundings. The exposed metal anode material of the valve may include a metal alloy or substantially pure metal that is acceptable for human ingestion in terms of the amount electrolyzed during the opening of the valve, taking into account its biocompatibility.It may be desirable to keep the metal thickness in the valve region small (e.g., to reduce the time and amount of current required to open the valve). For example, the metal portion of the drug container may be 0.025 mm thick at a diameter that matches or slightly exceeds the diameter of the attached nozzle (e.g., 0.60 mm). Generally speaking, the thickness of the metal in the valve region may be in the range of 0.002 mm to 0.200 mm.

[0131] In some embodiments, the housing of an ingestible device is assembled by a plurality of modules. For example, in some embodiments, the housing is assembled by two modules. In such an embodiment, one of the modules can accommodate dispensable substances ("drug module"), and another module can accommodate a driving force generator and a drive coupling ("drive module"). Typically, the drug module includes a housing portion with the appropriate size, shape, and material as discussed herein. Typically, the housing portion is sterilized, and the dispensable substances are subsequently arranged in the housing under aseptic conditions. Optionally, a sterile seal (such as a sterile foil seal) is incorporated into the drug module. The components of the drug module (such as housing portion, driving force generator, drive coupling) are assembled in a clean environment. Subsequently, the drug module and the drive module are combined to form an ingestible device. Representative examples of modules for forming an ingestible device, their individual components, and their combinations are provided elsewhere herein.

[0132] Typically, the size and shape of the ingestible device is designed for relatively safe and efficient movement within the GI tract of a subject and for its intended use. In certain embodiments, the ingestible device is a capsule having industry-standard dimensions. For example, in some embodiments, the ingestible device is configured as a 00 capsule or a 000 capsule.

[0133] 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).

[0134] 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).

[0135] 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).

[0136] In certain embodiments, the housing of the ingestible device has a wall thickness of at least about 0.05 mm (e.g., at least about 0.5 mm, at least about 0.6 mm, at least about 0.7 mm) and / or at most about 1 mm (e.g., at most about 0.9 mm, at most about 0.8 mm). In certain embodiments, the ingestible device has a wall thickness of about 0.05 mm to about 0.5 mm. In some embodiments, the ingestible device has a wall thickness of about 0.1 mm to about 1 mm. In certain embodiments, the wall thickness of one area of ​​the housing of the ingestible device may be different from the wall thickness of a different area of ​​the housing of the ingestible device.

[0137] In some embodiments, the housing of the ingestible device has a splined or spherical end circle. In certain embodiments, the ingestible device has an end circle of about 1 mm to about 2 mm (e.g., about 1.5 mm). In some embodiments, the ingestible device has an end circle of about 4 mm to about 4.5 mm (e.g., about 4.25 mm). In certain embodiments, the ingestible device has an end circle of about 4.9 to about 5 mm (e.g., about 4.95 mm). In some embodiments, the ingestible device has an end circle of about 5.4 mm to about 5.6 mm (e.g., about 5.5 mm).

[0138] In some 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).

[0139] In one exemplary embodiment, the housing of the ingestible device has a diameter of about 11 mm, a length of about 26 mm, a wall thickness of about 0.8 mm, an end circle of about 1.5 mm, and an internal volume of about 1685 μL.

[0140] In another exemplary embodiment, the housing of the ingestible device has a diameter of about 11 mm, a length of about 26 mm, a wall thickness of about 0.8 mm, an end rounding (spherical) of about 5.5 mm, and an internal volume of about 1475 μL.

[0141] In a further exemplary embodiment, the housing of the ingestible device has a diameter of about 9.9 mm, a length of about 26 mm, a wall thickness of about 0.8 mm, an end circle of about 1.5 mm, and an internal volume of about 1315 μL.

[0142] 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 circle (spherical) of about 4.95 mm, and an internal volume of about 1177 μL.

[0143] In a further exemplary embodiment, the housing of the ingestible device has a diameter of about 8.5 mm, a length of about 23.3 mm, a wall thickness of about 0.7 mm, an end circle of about 1.5 mm, and an internal volume of about 861 μL.

[0144] In yet a further exemplary embodiment, the housing of the ingestible device has a diameter of about 8.5 mm, a length of about 23.3 mm, a wall thickness of about 0.7 mm, an end circle (spherical) of about 4.25 mm, and an internal volume of about 773 μL.

[0145] In yet a further exemplary embodiment, the housing of the ingestible device has a diameter of about 8.5 mm, a length of about 23.3 mm, a wall thickness of about 0.7 mm, splined end circles, and an internal volume of about 820 μL.

[0146] Fluid volume

[0147] The ingestible device includes a fluid volume for accommodating a dispensable substance (e.g., a liquid, a suspension). In some embodiments, the fluid volume is entirely disposed 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 prepared separately from the housing. In such a storage reservoir, the dispensable substance can be disposed in the storage reservoir before the storage reservoir is associated with the ingestible device.

[0148] Dispensable substances

[0149] The device may include one or more dispensable substances, each dispensable substance including one or more therapeutic agents and / or one or more pharmaceutical formulations including one or more therapeutic agents.

[0150] nozzle

[0151] In some embodiments, the ingestible device includes one or more nozzles that are fluidly connected to one or more openings in the ingestible device. The nozzle is configured so that when the dispensable material is delivered from the ingestible device, the dispensable material passes through the nozzle. Generally speaking, the nozzle can have any desired size and shape suitable for the delivery of the desired type of the dispensable material from the ingestible device. In certain embodiments, the nozzle has a shape and / or size suitable for transepithelial delivery, epithelial delivery or local delivery. In some embodiments, the ingestible device includes more than one nozzle. For example, the ingestible device may include, for example, up to 50 nozzles (for example, 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 2 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 even intervals (optionally in pairs if an even number of nozzles are used) around the circumference of the device.

[0152] Restraint mechanism

[0153] In some embodiments, the ingestible device includes a restraining mechanism. Typically, the restraining mechanism has: a first state, wherein it is configured to prevent the dispensable substance from leaving the ingestible device through the opening, and a second state, wherein it is configured such that it does not prevent the dispensable substance from leaving the ingestible device through the opening. The restraining mechanism may be configured to transition from its first state to its second state when it is exposed to a triggering condition. The restraining mechanism may be provided by one or more restraining elements. The restraining element may have: a first state, wherein it is configured to prevent the dispensable substance from leaving the ingestible device through the opening, and a second state, wherein it is configured to allow the dispensable substance to leave the ingestible device through the opening. The restraining element may be configured to transition from the first state to the second state when the restraining element is exposed to a triggering condition. In some embodiments, the restraining element includes a first type of restraining element and a second type of restraining element that is different from the first type of restraining element. The first type of restraining element may be configured to transition to its second state before the second type of restraining element transitions to its second state. In some embodiments, the constraining element comprises a cap, a pin, a band, a plug, a dowel, a buckle, a clip, a flange, a rivet, an annulus, a torus, a ring, a wafer, a cylinder, an asymmetric shape such as a partial annulus, a partial torus, a partial ring, a partial wafer, a partial cylinder, or any combination thereof (e.g., two partial torus). Optionally, the constraining element may have a filled interior (e.g., no holes). Optionally, the constraining element may have a varying thickness (e.g., a central region thinner than the edges). In some embodiments, the constraining element comprises a plasticizer such as triethyl citrate (TEC). In some embodiments, the constraining element comprises a degradable and / or erodible material, such as an enteric material. The enteric material may be degradable and / or erodible in the small intestine of the GI tract, or may be degradable and / or erodible in the large intestine (e.g., colon) of the GI tract. In some embodiments, the restraining mechanism can be a mechanism that prevents the dispensable substance from being delivered from the ingestible device even when an internal force is applied by the drive force generator (or optionally the drive 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 the dispensable substance can be delivered from the ingestible device. Such a restraining element can be formed, for example, from a degradable and / or eroding material as described above.

[0154] Generally speaking, the restraining mechanism comprises a material that will lose a sufficient degree of its mechanical strength at the desired location to cause the ingestible device to deliver the dispensable substance. The material may experience a loss of mechanical strength due to any suitable mechanism or combination of mechanisms, including, for example, moisture ingress, solubility, swelling, leaching, erosion, and / or the like.

[0155] In some embodiments, the restraining mechanism comprises a degradable and / or erodible material, such as a water-soluble material, optionally with one or more coatings of one or more enteric materials. The degradable and / or erodible material is designed to lose its mechanical strength in the presence of moisture (e.g., liquids present in the GI tract).

[0156] Typically, enteric materials erode after being swallowed, for example, in the small intestine or in the large intestine. In some embodiments, the degradable and / or erodible material is coated with an enteric material that limits the amount of moisture or fluid that reaches the degradable and / or erodible material, thereby enabling the degradable and / or erodible material to resist a triggering load, for example, at a pH of 1.1 for at least two hours. In certain embodiments, the enteric material decomposes to release the triggering 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.

[0157] The enteric material may be in the form of one or more coatings (e.g., one or more spray-on coatings and / or one or more dip-on coatings) of varying coating weights on a degradable and / or erodible material (e.g., a water-soluble material). For example, in some embodiments, the coating weight may be 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or more, compared to the weight of the degradable and / or erodible material. Generally, the coating weight is selected as desired, for example, based on the intended use of the ingestible device. For example, the coating weight may be selected to select a desired location and / or time for the degradable and / or erodible material to degrade and / or erode to a sufficient extent to trigger delivery of the dispensable substance from the ingestible device.

[0158] Desirably, the degradable and / or erodible material is strong enough to resist a trigger load when dry, but is also capable of weakening sufficiently to release a trigger load when the degradable and / or erodible material is exposed to an aqueous environment for a desired period of time (e.g., at least two minutes, e.g., 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).

[0159] In some embodiments, the trigger mechanism has a mass of about 1 g / cm 3 About 3 g / cm 3 (e.g. about 1.3 g / cm 3 to about 2g / cm 3 ) density.

[0160] In certain embodiments, the trigger mechanism is about 1 mm to about 5 mm thick (eg, about 1 mm to about 2 mm thick).

[0161] In some embodiments, the coating of enteric material has a viscosity of about 0.5 mg / cm 2 Up to 20 mg / cm 2 (e.g. about 2 mg / cm 2 to about 6 mg / cm 2 ) density.

[0162] The example of degradable and / or erodible material includes polyethylene glycol (PEG) and isomalt (Isolmalt).In some embodiments, degradable and / or erodible material includes one or more diluents / fillers, one or more binding agents and / or one or more disintegrants.The example of diluent / filler includes lactose, starch, mannitol, microcrystalline cellulose, carboxymethyl cellulose and dicalcium phosphate.The example of binding agent includes polyvidone, hypromellose, hydroxypropyl cellulose, copolyvidone and microcrystalline cellulose.The example of disintegrant includes cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose (SD-711), sodium starch glycolate and low-substituted hydroxypropyl cellulose.Optionally, degradable and / or erodible material can include lubricant such as magnesium stearate.

[0163] As an example, degradable and / or erodible materials include 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 include talc (e.g., PSD<75 μm grade from Acros), enteric methacrylate polymer (e.g., FL30D-55 grade from Evonik), and HPMC polymer subcoat (e.g., Opadry 03K19229 grade from Colorcon). As an example, the degradable and / or erodible material may include starch 1500 (e.g., 49.6% w / w), microcrystalline cellulose 102 starch (e.g., 49.6% w / w); and 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 may 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 may 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 may 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 may 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 may include dicalcium phosphate (e.g., 33.25% w / w), microcrystalline cellulose 102 starch (e.g., 33.25% w / w); mannitol (e.g., 33.25% w / w); and magnesium stearate (e.g., 0.25% w / w).

[0164] Examples of enteric materials coated on degradable and / or erodible materials include: sprayed Eudragit FL30D-55 (e.g., 12 mg / cm2 sprayed directly on a water-soluble material). 2 Eudragit FL 30D-55); dip-coated Eudragit L 100D-55 (e.g., 4 mg / cm2 dip-coated onto HPMC capsule caps); 2 Eudragit L 100D-55); and sprayed Eudragit FL 30D-55 (e.g., 9 mg / cm sprayed directly on water-soluble materials 2 Eudragit FL 30D-55; 6 mg / cm2 sprayed directly on water-soluble materials 2 Eudragit FL 30D-55).

[0165] Trigger mechanism

[0166] In some embodiments, the ingestible device includes a trigger mechanism. In some embodiments, the trigger mechanism is configured to cause the dispensable material in the fluid volume to be released under one or more trigger conditions. In some embodiments, the trigger mechanism starts the driving force generator. In some embodiments, the trigger mechanism combines mechanical features such as a constraint mechanism. As an example, one or more constraint elements degrade and / or erode in the presence of certain GI tract conditions (e.g., pH greater than 5), thereby triggering the driving force generator, such as a compression spring. As another example, the spring may have a piercing element that pierces a cylinder with compressed gas, whereby the released gas acts as a force applied to the dispensable material. In some embodiments, the trigger mechanism combines electrical features. 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 the conductor to intestinal fluid, which acts as a liquid conductor to trigger the driving force generator. In some embodiments, the trigger condition relates to the conditions of the GI tract. In some embodiments, the conditions of the GI tract include at least one condition selected from temperature, pH, the presence of one or more enzymes, and time. In some more specific embodiments, the conditions of the GI tract are a pH greater than 5. In certain embodiments, the trigger mechanism is configured such that the release mechanism is triggered autonomously (eg, due to degradation, dissolution, and / or erosion of the restraining mechanism caused by conditions in the GI tract).

[0167] In some embodiments, the constraining element may include one or more small molecule therapeutic agents, for example, one or more small molecule therapeutic agents disclosed herein. In certain embodiments, the small molecule therapeutic agent contained in the constraining mechanism may be the same as the therapeutic agent contained in the dispensable substance. In some embodiments, the small molecule therapeutic agent contained in the constraining mechanism may be different from the therapeutic agent contained in the dispensable substance. In certain embodiments, the constraining mechanism includes multiple small molecule therapeutic agents, and the dispensable substance includes the same therapeutic agent. In some embodiments, the constraining mechanism includes multiple small molecule therapeutic agents, and the dispensable substance includes one or more different therapeutic agents. In certain embodiments, the dispensable substance includes a therapeutic agent capable of treating a condition, and the small molecule therapeutic agent contained 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 condition, and the small molecule therapeutic agent contained 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 condition, and the small molecule therapeutic agent contained 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 contained in the constraining element is capable of treating a condition, and the dispensable substance includes a therapeutic agent capable of treating at least one different condition. Other combinations are possible.

[0168] Generally speaking, the initial gas pressure within the gas cylinder (the gas pressure before the gas cylinder is implemented as a force generator) is suitable for providing 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 cylinder is about 500 psig to about 1,200 psig (e.g., about 600 psig to about 1,100 psig, about 700 psig to about 1,000 psig, about 750 psig to about 950 psig, about 800 psig to about 950 psig, about 850 psig to about 950 psig).

[0169] The burst pressure of a gas cylinder (the minimum pressure at which the gas cylinder bursts) is generally based on the desired initial gas pressure within the gas cylinder. For the initial gas pressures mentioned in the previous paragraph, the burst pressure of the gas 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 the cylinder is from about 2,800 psig to about 4,500 psig (e.g., from about 2,900 psig to about 4,400 psig, from about 3,000 psig to about 4,300 psig, from about 3,100 psig to about 4,200 psig, from about 3,200 psig to about 4,100 psig, from about 3,100 psig to about 4,000 psig, from about 3,200 psig to about 3,900 psig, from about 3,300 psig to about 3,800 psig, from about 3,400 psig to about 3,800 psig, from about 3,500 psig to about 3,800 psig, from about 3,600 psig to about 3,800 psig, from about 3,700 psig to about 3,800 psig).

[0170] Typically, the gas in the gas cylinder can be a single gas or a mixture of two or more gases. Exemplary gases include air, nitrogen, oxygen, carbon dioxide, hydrofluorocarbons, and noble gases (e.g., helium, neon, argon, krypton, xenon). In some embodiments, the gas in the gas cylinder is a gas mixture that includes helium (e.g., a nitrogen / helium mixture, an argon / helium mixture). Optionally, such a gas mixture includes up to about 5% helium. The presence of helium in the gas mixture can allow the gas cylinder to be checked for leaks based on the presence of helium adjacent to the outside of the gas cylinder.

[0171] In general, the gas cylinder can be made of any suitable and / or desired material. Examples include metal, plastic, and / or composite materials. In some embodiments, the gas cylinder is made of stainless steel or galvanized steel. In certain embodiments, the gas cylinder can be made of a material that is itself prepared by processes including drawing, stamping, machining, casting, molding, and / or the like (e.g., deep drawing from sheet metal). In some embodiments, the gas cylinder can be made of ceramic, alloys, aluminum, and / or titanium.

[0172] In some embodiments, the gas cylinder includes a frangible seal (e.g., a membrane) that is ruptured by an element (e.g., a perforator) when the gas cylinder is used as a force generator, as described in more detail below. Typically, the frangible seal is part of the gas cylinder's end cap. The end cap and / or the frangible seal may be formed from one or more of the materials mentioned in the previous paragraph. Fragmenting the frangible seal may involve, for example, tearing a portion of the frangible seal and / or piercing a portion of the frangible seal. More typically, frangible seal alters the seal in such a way that the frangible seal is no longer able to confine the gas within the gas cylinder. Generally speaking, the frangible seal is made of a material having at least one region that is relatively thin and / or configured to rupture (e.g., with a score). Optionally, the entire barrier is relatively thin. As an example, the barrier may have a relatively thin outer periphery with a relatively thicker portion within the outer periphery (e.g., a central portion), such that when the element (e.g., a perforator) applies an appropriate force, the relatively thin portion of the frangible seal ruptures. As another example, the barrier may have an inner (e.g., center) portion surrounded by a scored portion so that when an element (e.g., a perforator) applies appropriate force, the scored portion of the breakable seal is broken. In some embodiments, the breakable seal has a substantially constant thickness and has a portion configured (e.g., scored) to break when an element (e.g., a perforator) applies appropriate force. Generally speaking, such scoring can be configured as desired. As an example, the scoring can be configured as a series of parallel lines. As another example, the scoring can be configured as a grid (grid-lined). As a further example, the scoring can be configured as a plurality of points (e.g., equidistant points).

[0173] In some embodiments, an element (e.g., a perforator) has a contact point on the frangible seal. Optionally, the contact points are concentrated in a relatively small local area. For example, the perforator can be a needle or a thin rod element cut at an angle to initially produce a single point of contact. The point of initial contact can be on the center or off-center relative to the frangible seal. Having the initial contact point off-center relative to the frangible seal can result in a reduction in the force applied by the element (e.g., a perforator). In embodiments where the modified (e.g., scored) area of ​​the frangible seal is off-center, placing the element (e.g., a perforator) off-center means that at the point of contact between the element (e.g., a perforator) and the frangible seal, the contact point is closer to the modified (e.g., thinner scored) area of ​​the frangible seal. In certain embodiments where the modified (e.g., scored) area of ​​the frangible seal is a circle, the element (e.g., a perforator) can be configured so that its point of contact with the frangible seal is close to a point on the circle. Generally speaking, the closer the contact point is to the modified region of the frangible seal, the lower the force required by the element (e.g., perforator) to break the frangible seal. To achieve a relatively rapid release, the modified (e.g., scored) portion of the frangible seal is desirably broken over a substantial portion of the 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 contact point is to the center of the scored circle, the more likely the seal will break over the entire circumference of the scored circle. In such embodiments, it is typically desirable to have the contact point of the element (e.g., perforator) close to the circle, but not on it. Optionally, the contact point can be moved inward to achieve rapid release properties. Optionally, in some embodiments, a wider footprint for initial contact of the element (e.g., perforator) can be implemented. For example, the contact point can be an arc-shaped sector positioned near the circular score of the frangible seal. This can encourage the frangible seal to break over a larger sector of the scored region, which can result in faster gas escape.

[0174] In some embodiments, before the gas cylinder is used as a force generator, the element (e.g., perforator) is not in contact with the frangible seal. In certain embodiments, before the gas cylinder is used as a force generator, the element (e.g., perforator) may contact the frangible seal so that the element (e.g., perforator) applies a relatively low pressure to the frangible seal. The pressure may be, for example, at least about 1 Newton (e.g., at least about 2 Newtons, at least about 3 Newtons, at least about 4 Newtons, at least about 5 Newtons) and / or at most about 15 Newtons (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 from about 1 Newton to about 15 Newtons.

[0175] Typically, to release the gas from the cylinder, a member (e.g., a perforator) applies a relatively high pressure to the frangible seal. The relatively high pressure may 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 may be from about 5 Newtons to about 35 Newtons.

[0176] Examples of gas cylinders (including those with end caps and / or frangible seals) are disclosed, for example, in US 2017 / 0258583, the entire disclosure of which is incorporated herein by reference.

[0177] In some embodiments, element (such as perforator) is coupled to the actuator in actuator assembly.In some embodiments, actuator assembly has a total length less than about 10mm (such as, less than about 9mm, less than about 8mm, less than about 7mm, less than about 6mm, less than about 5mm, less than about 4mm, less than about 3mm, less than about 2mm).In some embodiments, actuator is a spring (such as a wave spring).In some embodiments, spring has a compression length less than about 5mm, less than about 4mm, less than about 3.5mm, less than about 3mm, less than about 2.5mm).In some embodiments, spring has a stroke length less than about 0.8mm (such as, less than about 0.7mm, less than about 0.6mm, less than about 0.5mm, less than about 0.4mm, less than about 0.3mm).

[0178] In some embodiments, the element (e.g., perforator) is moved relatively quickly when a relatively high force is applied to the breakable seal. In certain embodiments, the element (e.g., perforator) is moved relatively slowly when a relatively high force is applied to the breakable seal. In some embodiments, using a lower speed of movement of the element (e.g., perforator) allows for the use of a lower force to break the breakable seal than would be required to break the breakable seal if the element (e.g., perforator) were moved at a higher speed.

[0179] In some embodiments, the element (e.g., perforator) moves relative to the cylinder. In certain embodiments, the cylinder moves relative to the element (e.g., perforator). For example, the cylinder can be coupled to an actuator that causes the cylinder to move.

[0180] 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 middle small intestine of about 7.0 to about 7.8, a pH in the ileum of about 7.0 to about 8.0, a pH in the right colon of about 5.7 to about 7.0, a pH in the middle colon of about 5.7 to about 7.4, or a pH in the left colon of about 6.3 to about 7.7, e.g., about 7.0.

[0181] driving force generator

[0182] The driving force generator is configured to provide the necessary force to the dispensable substance so that when the restraining mechanism is removed, the dispensable substance is delivered from the ingestible device as needed. The driving force generator can use different mechanisms to apply force, including, for example, compressed gas, gas generated by a chemical reaction, a spring, a liquid-gas mixture, an impact plunger, a sudden expansion caused by a controlled exothermic reaction, and the like. When the driving force generator is a spring, the spring may have one or more of the following properties: the outer diameter of the spring is smaller than the inner diameter of the ingestible device; the compressed length of the spring is minimized to leave more room 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 greater than the free length of the inner cavity of the ingestible device to ensure that an acceptable driving pressure is provided throughout the delivery time step; and the spring rate is large enough to provide an acceptable pressure of the dispensable substance from the beginning until the end of delivery. Examples of springs include parallel springs, wave springs, and conical springs. Examples of chemical reactants include air bag inflators, hydrogen batteries (e.g., Varta hydrogen batteries), sodium bicarbonate, and acids (e.g., seltzer and water, seltzer, and GI tract fluids on an ingestible device). Examples of compressed gases include gases loaded into ingestible devices, and containers of compressed gas (e.g., gas cylinders). In some embodiments, the compressed gas is a gas cylinder from Picocyl. Exemplary gas cylinders are disclosed, for example, in US2017-0258583, which is incorporated herein by reference. An example of a liquid-gas mixture is liquid nitrogen / HFA (hexafluoroacetone) / propane. An example of an impact plunger is a two-phase spring / plunger. Other examples of driving force generators include wax actuators, heat generated by electricity (a mechanism based on the Peltier effect), and mechanical puncture of the tissue delivered thereafter.

[0183] Drive connector

[0184] In general, the driving force coupling transmits force from the driving force generator to the dispensable material. Examples of driving couplings include pistons and membranes. Examples of membranes include air bags (balloons) and elastomeric materials. An example of a piston is an O-ring sealed piston. In some embodiments, the piston is provided by a gas cylinder (e.g., with additional O-rings or custom housings). In some embodiments, the driving coupling is a vein, such as a rotary vein. In certain embodiments, the driving coupling is a double piston configured to offset the impact of the cover. In certain embodiments, the driving coupling is a folding bag, such as a folding foil bag. In some embodiments, the driving coupling is a folding bellows (bellows).

[0185] Storage

[0186] In some embodiments, the ingestible device includes a storage reservoir configured to store a dispensable substance. In some embodiments, the storage reservoir stores the dispensable substance. In some embodiments, the storage reservoir is completely disposed within the housing.

[0187] Figure 2 2 is a schematic diagram of an ingestible device 200 that includes a housing 202, a fluid volume 204 containing a dispensable substance, a nozzle 206 having a nozzle opening 208, a restraining mechanism 210, a trigger mechanism 212, a driving force generator 214, and a drive coupling 216. During use, the ingestible device 200 is swallowed by a subject and passes through the GI tract. At the appropriate position, the trigger mechanism 212 is triggered, thereby allowing the driving force generator to apply pressure to the drive coupling 216, which then applies pressure to the fluid volume 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 trigger mechanism 212 is triggered. As an example, at the appropriate position, the trigger mechanism 212 is triggered, thereby allowing the drive coupling 216 to apply pressure to the fluid volume 204. In certain embodiments, internal pressure is not applied until the trigger mechanism 212 is triggered.

[0188] Devices for transepithelial delivery

[0189] In general, transepithelial delivery can be achieved at any desired location within the GI tract of a subject. In some embodiments, transepithelial delivery is achieved in the small intestine of a subject, for example, in the duodenum, jejunum, and / or ileum. In certain embodiments, transepithelial delivery is achieved in the large intestine (e.g., cecum or colon) of a subject.

[0190] Generally, ingestible devices for transepithelial delivery are 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 watts, at least about 1.2 watts, at least about 1.3 watts, at least about 1.4 watts, at least about 1.5 watts, at least about 1.6 watts, at least about 1.7 watts, at least about 1.8 watts) and / or at most about 3 watts (e.g., at most about 2.9 watts, at most about 2.8 watts, at most about 2.7 watts, at most about 2.6 watts, at most about 2.5 watts, at most about 2.4 watts, at most about 2.3 watts, at most about 2.2 watts, at most about 2.1 watts). In some embodiments, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable substance having a peak jet power of about 1 watt to about 3 watts (e.g., about 1.3 watts to about 2.8 watts, about 1.5 watts to about 2.5 watts).

[0191] Generally speaking, the ingestible device for transepithelial 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 transepithelial 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).

[0192] Generally speaking, the ingestible device for transepithelial delivery is configured to deliver a jet 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, the device for transepithelial delivery is configured to deliver a jet 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). Typically, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable material 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, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable material 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).

[0193] Generally speaking, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable substance having a minimum ejection 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, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable substance having a minimum ejection 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).

[0194] Generally speaking, the ingestible device for transepithelial delivery is configured to deliver a jet 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, the ingestible device for transepithelial delivery is configured to deliver a jet 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).

[0195] Generally speaking, the ingestible device for transepithelial delivery is configured to deliver a jet 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 transepithelial delivery is configured to deliver a jet 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.

[0196] Generally speaking, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable substance having a minimum ejection 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 to at most about 0.04 N). In some embodiments, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable substance having a minimum ejection 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).

[0197] Generally speaking, the ingestible device for transepithelial delivery is configured to deliver a jet 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 transepithelial delivery is configured to deliver a jet 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).

[0198] Typically, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable material 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 transepithelial 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).

[0199] In general, the ingestible device for transepithelial 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 transepithelial 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).

[0200] In general, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable material 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 transepithelial delivery is configured to deliver a jet of dispensable material 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 transepithelial 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).

[0201] In general, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable material 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, the ingestible device for transepithelial delivery is configured to deliver a jet of dispensable material 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).

[0202] In some embodiments, the ingestible device for transepithelial delivery is configured to deliver a jet 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 an ingestible device for transepithelial delivery is configured to deliver a jet 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).

[0203] Generally, ingestible devices for transepithelial 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, an ingestible device for transepithelial delivery is 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).

[0204] In general, ingestible devices for transepithelial delivery are 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 transepithelial 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).

[0205] Typically, an ingestible device for transepithelial delivery is configured to deliver the drug at a 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). In some embodiments, the ingestible device for transepithelial delivery is configured to accommodate the dispensable substance at a peak fluid pressure of 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 some embodiments, the ingestible device for transepithelial delivery is configured to accommodate the dispensable substance at a peak fluid pressure having any of the endpoints mentioned in the previous sentence (e.g., about 150 psig to about 400 psig).

[0206] Typically, the ingestible device for transepithelial delivery is configured to contain the 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 transepithelial delivery is configured to contain the 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).

[0207] Generally speaking, the ingestible device for transepithelial 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 to at most about 12 N). In certain embodiments, the ingestible device for transepithelial 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).

[0208] In general, the ingestible device for transepithelial delivery holds the dispensable substance in an initial fluid volume of at least about 50 microliters (μL) (e.g., at least about 100 μL, at least about 150 μL, at least about 200 μL, at least about 250 μL) and / or at most about 800 μL (e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL, at most about 400 μL). In some embodiments, the ingestible device for transepithelial delivery holds the dispensable substance in an initial fluid volume of about 50 μL to about 800 μL (e.g., about 100 μL to about 600 μL, about 200 μL to about 400 μL).

[0209] Typically, the ingestible device for transepithelial delivery is configured to provide a delivery fluid volume of at least about 50 microliters (μL) (e.g., at least about 100 μL, at least about 150 μL, at least about 200 μL, at least about 250 μL) and / or at most about 800 μL (e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL, at most about 400 μL) of the dispensable substance. In some embodiments, the ingestible device for transepithelial delivery has a fluid volume of about 50 μL to about 800 μL (e.g., about 50 μL to about 500 μL, about 100 μL to about 450 μL, about 100 μL to about 600 μL, about 200 μL to about 400 μL, about 250 μL to about 400 μL, about 300 μL to about 400 μL) of the dispensable substance.

[0210] In general, the ingestible device for transepithelial delivery contains the dispensable substance in a final fluid volume of at most about 100 microliters (μL) (e.g., at least about 90 μL, at least about 80 μL, at least about 70 μL, at least about 60 μL) and / or at most at least 5 μL (e.g., at most about 10 μL, at most about 20 μL, at most about 30 μL, at most about 40 μL). In some embodiments, the ingestible device for transepithelial delivery contains the dispensable substance in a fluid volume of about 30 μL to about 70 μL (e.g., about 40 μL to about 60 μL, about 45 μL to about 55 μL). Generally, ingestible devices for transepithelial 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 submucosa and / or mucosa (e.g., into the lamina propria).

[0211] In general, the ingestible device for transepithelial delivery has at least one opening for delivery of a dispensable substance (e.g., at least two openings for delivery of a dispensable substance, at least three openings for delivery of a dispensable substance, at least four openings for delivery of a dispensable substance) and / or at most about eight openings for delivery of a dispensable substance (e.g., at most seven openings for delivery of a dispensable substance, at most six openings for delivery of a dispensable substance, at most five openings for delivery of a dispensable substance, at most four openings for delivery of a dispensable substance). In certain embodiments, the ingestible device for transepithelial delivery has 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, the ingestible device for transepithelial delivery has one or more nozzles, each nozzle having a nozzle opening for delivering a dispensable substance. In such embodiments, the ingestible device may 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 may have 1 to 8 nozzles (e.g., 1 to 5 nozzles, 2 to 4 nozzles, 2 nozzles). In embodiments where the ingestible device for transepithelial delivery comprises one or more nozzles, each nozzle may 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 may have a nozzle length of about 0.2 mm to about 5 mm. In embodiments where the ingestible device for transepithelial delivery comprises 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 about 0.1 mm to about 2 mm (e.g., about 0.1 mm to about 1 mm, about 0.15 mm to about 0.5 mm, about 0.2 mm to about 0.8 mm, about 0.25 mm to about 0.45 mm, about 0.3 mm to about 0.4 mm, about 0.3 mm to about 0.5 mm, about 0.34 mm to about 0.36 mm, about 0.35 mm).

[0212] In general, the ingestible device for transepithelial delivery is configured to provide a delivery fluid volume of at least about 20 microliters (μL) (e.g., at least about 25 μL, at least about μL, at least about 50 μL, at least about 75 μL, at least about 100 μL) and / or at most about 800 μL (e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL, at most about 400 μL, at most about 300 μL) per opening (e.g., each nozzle) for delivery of a dispensable substance. In some embodiments, the ingestible device for transepithelial delivery is configured to provide a delivery fluid volume of about 25 μL to about 400 μL (e.g., about 25 μL to about 300 μL, about 100 μL to about 300 μL) per opening (e.g., each nozzle) for delivery of a dispensable substance.

[0213] In one example, an ingestible device having a nozzle with a nozzle diameter of 0.35 mm and containing a dispensable substance at a peak fluid pressure of 150 psig can deliver a jet of dispensable substance at an average jet velocity of about 20 m / s and an average jet impact pressure of about 29 psig.

[0214] In another example, an ingestible device with a nozzle pressure of 300 psig can deliver a dispensable substance at an average jet velocity of about 27 m / s and an average jet impact pressure of about 58 psig. In some embodiments, such an arrangement results in puncture of the intestinal wall.

[0215] In another example, an ingestible device having a nozzle with a nozzle diameter of 0.35 mm and containing a dispensable substance at a peak fluid pressure of 320 psig can deliver a jet of dispensable substance having an average jet velocity of about 28 m / s and an average jet impact pressure of about 62.4 psig.

[0216] Figure 3 A cross-sectional view of a representative ingestible device 400 for transepithelial delivery is shown, schematically illustrating certain parameters and functional components of the device 400. These include a drive force generator 42 that applies a force (generating internal pressure) to a drive coupling 44. The drive coupling 44 transmits the force from the force generator 42 to a fluid volume 46 containing a dispensable substance (e.g., a liquid, a suspension). The force applied to the fluid volume 46 by the drive coupling 44 generates a pressure (fluid pressure) in the fluid volume 46. The pressure in the fluid volume 46 generates a high velocity flow through an open nozzle 48 to produce a jet 50 of fluid at a nozzle outlet 52 having a nozzle diameter 72 and the nozzle having a nozzle length 74.

[0217] During transepithelial delivery, the fluid jet 50 has a jet stabilization length 54 that is sufficient for the fluid jet 50 to travel across the nozzle separation distance 56 to reach the interface between the lumen of the GI tract and the lumen-facing surface of the GI tract. Ultimately, the fluid (e.g., liquid, suspension) impacts the mucosal layer of the GI tract (e.g., the epithelial layer and any mucus that may be present on the epithelial layer) as a stable fluid stream with little to no breakup into a spray and is deposited in the submucosa and / or mucosal tissue 58. That is, between the nozzle outlet 52 and the impact site at the mucosa, the jet 50 has a jet diameter 76 that can vary in the manner discussed above with respect to the average jet diameter.

[0218] Fluid volume 46 experiences peak fluid pressure 60, which generates fluid jet 50, which exits device 40 at peak jet velocity and impacts the lumen of the GI tract and the interface of the lumen-facing surface of the GI tract at peak jet power, peak jet pressure, and peak jet force. Those skilled in the art recognize that these three parameters are interrelated.

[0219] The pressure in the fluid volume 46 decreases during delivery, causing the fluid pressure to change during delivery 70, as does the jet power, jet force, and jet pressure. The fluid pressure during delivery 70 maintains the fluid jet stream 50 at a sufficient jet impact force during delivery to continue delivering the fluid (including the dispensable substance of one or more therapeutic agents) from the fluid volume 46 into the submucosa and / or mucosal tissue 58. The surrounding tissue can then absorb the delivered therapeutic agent for systemic delivery of the therapeutic agent.

[0220] 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 eroded pin or plug) until movement of the drive coupling is triggered by a triggering mechanism and / or the opening becomes open.

[0221] Figure 4Shown is an exemplary process flow chart 400 for using an ingestible device, wherein no pressure is applied to the dispensable material before the subject swallows the ingestible device. The process begins in step 402, when the patient swallows the ingestible device. In step 404, a trigger condition (e.g., pH, pH change, the presence of certain enzymes, the concentration of certain enzymes) is met in the GI tract, thereby triggering the driving force generator. In step 406, the driving force mechanism applies pressure to the dispensable material, resulting in a jet of the dispensable material being delivered from the ingestible device for each opening. In step 408, the jet has sufficient jet stability length for the jet to impact the subject's GI tissue. In step 410, the peak jet power of the jet is sufficient to achieve transepithelial delivery of the therapeutic agent contained in the dispensable material. In step 412, the fluid pressure of the dispensable material decreases during delivery, but is sufficient to cause the peak jet power to continue to be sufficient to achieve transepithelial delivery of the therapeutic agent contained in the dispensable material.

[0222] Figures 5A-5CA view of the assembled ingestible device 500, an exploded view of the ingestible device, and aspects of the assembly process of the ingestible device are shown respectively. 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 fixed on a portion of the ingestible device 500 and removed before swallowing. The ingestible device 500 can be used for transepithelial delivery. The ingestible device 500 is configured so that when the subject swallows the ingestible device 500, the dispensable substance 516 retained in the device is not under pressure. The ingestible device has two housing parts, a primary container 518 and a secondary container 520. The primary container 518, which includes a fluid volume for holding the 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 cylinder 504 with 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, for example, by gastric fluid, causing the cover 522 to dissolve / degrade and expose the nozzle 502. In some embodiments, the O-ring 526 can be lubricated. Similarly, any O-ring disclosed elsewhere herein can optionally be lubricated.

[0223] The ingestible device 500 also includes a collar-shaped trigger element 528 as a trigger mechanism. Figure 5B The trigger element 528 is depicted as being collar-shaped, but other shapes may be used. In general, the trigger element 528 may have any suitable shape. Examples of shapes for the trigger element include a complete ring, a ring divided into two pieces. In some embodiments, the trigger element comprises two or more sectors of a ring with gaps between the sectors. In some embodiments, such a design may increase surface exposure to the environment (e.g., an aqueous environment) to promote degradation. For example, Figure 5C A separate two-piece collar is shown, e.g., separate component modules 530 and 532, which are assembled to form the ingestible device 500.

[0224] Figures 6A-6CA view of the assembled ingestible device 600, an exploded view of the ingestible device 600, and a view of aspects of the assembly process of the ingestible device 600 are shown respectively. The ingestible device 600 can be used for transepithelial delivery or for other forms of delivery as discussed elsewhere herein, as appropriate. The ingestible device 600 includes a nozzle 602, a cylinder 604, a piston 606, a seal 608, a piercing pin 610, and a perforator 612. A removable cap 614 can be secured to a portion of the ingestible device 600 and removed prior to swallowing. The ingestible device is configured so that when the subject swallows the ingestible device, the dispensable substance 616 in the device is not under pressure. The ingestible device has two housing portions, a primary container 618 and a secondary container 620. The primary container 618, which includes a fluid volume for holding the dispensable substance, can be formed from a cyclic olefin copolymer (COC), such as molded COC, or any other suitable material as disclosed elsewhere herein. The primary container 618 includes a nozzle 602 having a nozzle opening. In some embodiments, the nozzle length is approximately equal to the primary container wall thickness. 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 cylinder 604 with 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 Figures 6A-6C The trigger element 628 is depicted as being collar-shaped, but other shapes may be used as disclosed elsewhere herein.

[0225] Figures 6A-6C The device shown in has an enhanced piston stabilization length 634 (eg, approximately 2 mm). Figures 6A-6C The device shown in has a metal spring slider 636, which enhances space efficiency. Figures 6A-6C The device shown in has a punch slide 638 (e.g., a metal punch slide) that bottoms out on the spring housing during assembly. This can enhance space efficiency. Figures 6A-6C In the device shown in , the two-part perforator reduces (eg, removes) tolerances from the perforator to cylinder spacing when manufacturing the trigger element. Figures 6A-6C In the device shown in FIG, the piercer seal 640 (eg, an O-ring) has a relatively small diameter, which may enhance stability and / or reduce drag buildup along its travel length. Figures 6A-6CIn the device shown in FIG, spring 624 has a tapered end coil 642, which increases the maximum force potential. In some embodiments, a wave spring may be used. Figures 6A-6C A hermetic seal 644 (eg, an ultrasonic weld) is shown. Figures 6A-6C Gas cylinder retention feature 646 is also shown.

[0226] In addition, the ingestible device includes a removable cap 614 that is removed (e.g., by the user) before the ingestible device is swallowed. When the subject swallows the device 600, 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 the appropriate position in the GI tract, the trigger element 628 at least partially erodes, degrades, and / or dissolves (e.g., due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), and the trigger element 628 is no longer sufficient to suppress the pressure from the spring 624. In some embodiments, the trigger element 628 at least partially erodes, degrades, and / or dissolves in the presence of water. In such embodiments, the trigger element may include a covering of a film of a material that preferentially degrades due to, for example, pH changes and / or the presence of enzymes. The spring 624 forces the piercing pin 610 of the perforator 612 into the frangible seal 608, thereby causing the frangible seal to break. This causes the gas under increased pressure to leave the gas cylinder 604, thereby causing the increased pressure to press against the piston 606 and apply pressure to the fluid volume 616. This causes the cover 622 of the nozzle opening (which is made of a relatively low mechanical strength material (e.g., foil or film)) to break, causing the dispensable substance to be delivered from the nozzle opening in the form of a jet. In certain embodiments, the cover 622 of the nozzle opening is made of a material that erodes, degrades, and / or dissolves in the presence of, for example, water or an increased pH (e.g., an enteric strip or a strip of water-soluble polymer material). The cover can be partially or completely displaced from the capsule upon actuation of the trigger element. This results in transepithelial delivery of the therapeutic agent contained in the dispensable substance.

[0227] Figure 6C Aspects of the assembly process of the ingestible device are shown, such as individual component modules 630 and 632, which are assembled to form the ingestible device 600. Figure 6CThe primary container, in combination with the cap and nozzle cover, is depicted as being filled with the dispensable substance followed by the addition of the piston. This can be performed in a sterile or other environment suitable for drug filling and independent of the environment in which the mechanical drive assembly is constructed. The other housing portion and its components are assembled in a clean environment, where the perforator is held in place by a trigger element. The cylinder 604 is held in place by components of the assembly, which include an assembly housing that includes features for positioning the cylinder in the correct position in the assembled ingestible device. Positioning and installation of the cylinder can be assisted by mounting features, such as flanges, formed integrally with the cylinder components.

[0228] Figure 7-13 Various views of an ingestible device 700 and / or aspects of an ingestible device 700 are shown. Notably, the delivery mechanism of the ingestible device 700 is shown as having a substantially similar design to that of the device shown in FIG. 5 , although more generally, Figure 7-13 The ingestible device 700 depicted in may have a delivery mechanism as described elsewhere herein.

[0229] Ingestible device 700 includes cylinder 716 , union 708 , O-ring 732 , enteric trigger 726 , piercer 720 , spring 724 , spring retaining cup 722 , retaining element 728 , drug housing 704 , drive housing 706 , and piercer retainer 724 .

[0230] The ingestible device 700 has two chambers 710a, 710b, each of which contains a dispensable substance. The chambers are separated by a partition 705 (e.g., a rib) (which prevents the dispensable substance in one chamber from entering the other chamber, for example, 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, may be the same or different from the dispensable substance in another chamber, such as chamber 710b. Although shown as having two chambers 710a, 710b, the present disclosure is not limited in this sense. More generally, the ingestible device 700 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). Generally, each chamber 710a, 710b will have a corresponding piston 718a, 718b, and there will be a partition 705 between adjacent chambers. In some embodiments, each chamber has the same internal volume. In certain embodiments, different chambers can have different volumes. Combinations of such embodiments are also possible.

[0231] In some embodiments, the present disclosure provides an ingestible device comprising an element 712 (e.g., a cover) 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 coupling (e.g., pistons 718a, 718b) moves, the element 712 moves from its first state to its second state. In certain embodiments, the element 712 is conformal to the inner radius of the housing 704, is flexible and / or includes a cylindrical portion. In some embodiments, the element 712 is removable from the ingestible device 700 (e.g., when the element 712 is in its second state, the element 712 is removed from the ingestible device). Such a removable element 712 can be, for example, a cap. Optionally, the movement of the element 712 can be synchronized with the movement of the driving force coupling, e.g., pistons 718a, 718b. In some embodiments, when the drive force coupler moves a distance, the element 712 moves the same distance. The ingestible device can include a seal 718 (e.g., an O-ring) that mechanically couples (e.g., seals) the drive force coupler and the element 712. Using this arrangement, the seal 718 can be configured to cause movement of the drive force coupler to result in movement of the element 712.

[0232] Figure 14-18 An ingestible device 1400 is shown containing a dispensable substance that is not under pressure when the subject swallows the ingestible device. Figure 14 In FIG. 1 , the injection opening 1402 is depicted as being covered, and in FIG. Figure 15 The middle ejection opening 1402 is not covered.

[0233] Figure 16 and 17Ingestible device 1400 is shown in greater detail. Ingestible device 1400 has housing portions 1404 and 1406 connected by a union 1408 and having a fluid volume 1410 containing a dispensable substance, an opening 1402, and a jet cover 1412, such as a cylindrical sleeve (made of a flexible material that conforms to the inner radius of housing 1406 and slides to open or seal opening 1402), a spring 1414, a gas cylinder 1416, a piston 1418, a piercer 1420, and an O-ring 1432. Gas cylinder 1416 is retained by a retaining element 1428. Seal 1430 forms a gas seal between piercer 1420 and housing 1404. Spring retaining cup 1422 retains spring-loaded piercer 1420. The perforator holder 1424 is held in place by the perforator 1420 together with the enteric trigger 1426, which holds the perforator holder in place and serves as a trigger mechanism until it dissolves. When the device 1400 is swallowed by the experimenter, the enteric trigger 1426 prevents the dispensable material in the fluid volume 1410 from being under pressure by holding the spring 1414 and the perforator 1420 in place. When the device 1400 arrives in the appropriate position in the GI tract, the enteric trigger 1426 degrades and / or dissolves (e.g., due to pH, pH changes, the presence of some enzymes, and / or the concentration of some enzymes), making it no longer enough to suppress the pressure from the spring 1414 by the piercing pin holder 1424. The spring 1414 forces the perforator 1420 to enter the gas cylinder 1416, thereby piercing the gas cylinder 1416 and causing the gas under the pressure of the increase to leave the gas cylinder 1416. This causes cylinder 1416 to press against piston 1418 and apply pressure to fluid volume 1410. The piston provides friction to slide jet cover 1412 open, exposing jet opening 1402, allowing the dispensable substance to be delivered in the form of a jet from jet opening 1402. This results in transepithelial delivery of the therapeutic agent contained in the dispensable substance. Figure 17 An embodiment of the ingestible device 1400 is shown in which the jet cover 1412 is slid open to expose the jet opening 1402.

[0234] Typically, the ingestible device 1400 is used for transepithelial 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.

[0235] In some embodiments, the housing of the ingestible device 1400 has a diameter of about 9.5 mm to about 10.5 mm (e.g., about 9.8 mm to about 10 mm), a length of about 23 mm to about 26.5 mm (e.g., about 23.3 mm to about 26.1 mm), a wall thickness of about 0.4 mm to about 0.6 mm (e.g., about 0.5 mm), a fluid volume of about 425 μL to about 600 μL (e.g., about 450 μL to about 585 μL), and / or a gas volume in the cylinder 1416 of about 150 μL to about 175 μL (e.g., about 160 μL). Figure 18 An ingestible device 1400 is shown with a jet cover 1412 conforming to a radius of the ingestible device 1400.

[0236] Figure 19 and 20 Ingestible device 1900 is shown in its closed and open states, respectively. Ingestible device 1900 contains a dispensable substance that is not under pressure when a subject swallows the ingestible device. Ingestible device 1900 has housing portions 1904 and 1906 connected by a union 1908 and having a fluid volume 1910 containing the dispensable substance, a spring 1914, a cylinder 1916, a piston 1918, a perforator 1920, and an O-ring 1932. The cylinder 1916 is retained by a retaining element 1928. A seal 1930 forms a gas seal between the perforator 1920 and the housing 1906. A spring retaining cup 1922 holds the spring-loaded perforator 1920 in place. The perforator holder 1924 holds the perforator 1920 in place together with the enteric trigger 1926, which holds the perforator holder in place and serves as a trigger mechanism until it dissolves. When the device 1900 is swallowed by the subject, the enteric trigger 1926 prevents the dispensable substance in the fluid volume 1910 from being under pressure by holding the spring 1914 and the perforator 1920 in place. When the device 1900 reaches the appropriate position in the GI tract, the enteric trigger 1926 degrades and / or dissolves (e.g., due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), making the perforator holder 1924 no longer sufficient to suppress the pressure from the spring 1914. The spring 1914 forces the perforator 1920 into the gas cylinder 1916, thereby piercing the gas cylinder 1916 and causing the gas under elevated pressure to leave the gas cylinder 1916. This causes cylinder 1916 to press against piston 1918 and apply pressure to fluid volume 1910. The piston provides friction to cause cap 1934 to open / expand, allowing the dispensable substance to be delivered from volume 1910. This results in the release of the therapeutic agent into the subject's GI tract.

[0237] In some embodiments, the housing of the 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 the cylinder 1916 of about 150 μL to about 175 μL (e.g., about 160 μL).

[0238] Generally speaking, ingestible device 1900 is used for topical delivery.

[0239] Figure 21 and 22 The ingestible device 2100 is shown in its closed and open states, respectively. The ingestible device 2100 contains a dispensable substance that is not under pressure when the subject swallows the ingestible device. The ingestible device 2100 has: housing portions 2104 and 2106 connected by a union 2108 and having a fluid volume 2110 containing the dispensable substance, a spring 2114, a cylinder 2116, a piston 2118, a perforator 2120, and an O-ring 2132. The cylinder 2116 is retained by a retaining element 2128. A seal 2130 forms a gas seal between the perforator 2120 and the housing 2106. A spring retaining cup 2122 retains the spring-loaded perforator 2120. Perforator holder 2124 is held in place by perforator 2120 together with enteric-coated trigger 2126, and enteric-coated trigger 2126 is held in place by perforator holder 2124 and is used as trigger mechanism until it dissolves.When device 2100 is swallowed by experimenter, enteric-coated trigger 2126 is by spring 2114 and perforator 2120 are held in place and stop the dispensable material in fluid volume 2110 from being under pressure.When device 2100 arrives in the appropriate position in GI tract, enteric-coated trigger 2126 degrades and / or dissolves (for example, due to pH, pH change, the presence of some enzymes and / or the concentration of some enzymes), makes perforator holder 2124 no longer enough to suppress the pressure from spring 2114.Spring 2114 forces perforator 2120 to enter in gas cylinder 2116, thereby piercing gas cylinder 2116 and causing the gas under the pressure of raising to leave gas cylinder 2116. This causes the cylinder 2116 to press against the piston 2118 and apply pressure to the fluid volume 2110. The piston provides friction to cause the cap 2134 to open / expand, causing the dispensable substance to be delivered from the volume 2110. This results in delivery (e.g., localized delivery) of the therapeutic agent contained in the dispensable substance.

[0240] In some embodiments, the housing of the ingestible device 2100 has a diameter of about 10 mm to about 12 mm (e.g., about 11.3 mm to about 11.5 mm), a length of about 23 mm to about 26.5 mm (e.g., about 23.3 mm to about 26.3 mm), a wall thickness of about 0.4 mm to about 0.6 mm (e.g., about 0.5 mm), a fluid volume of about 565 μL to about 630 μL (e.g., about 574 μL to about 623 μL), and / or a gas volume in the cylinder 2116 of about 150 μL to about 175 μL (e.g., about 160 μL).

[0241] Figure 23 and 24 Ingestible device 2300 is shown in its closed and open states, respectively. Ingestible device 2300 contains a dispensable substance that is not under pressure when a subject swallows the ingestible device. Ingestible device 2300 has housing portions 2304 and 2306 connected by a union 2308 and having a fluid volume 2310 containing the dispensable substance, a spring 2314, a cylinder 2316, a piston 2318, a perforator 2320, and an O-ring 2332. Cylinder 2316 is retained by a retaining element 2328. Seal 2330 forms a gas seal between perforator 2320 and housing 2306. Spring retaining cup 2322 retains spring-loaded perforator 2320. Perforator holder 2324 is held in place by perforator 2320 together with enteric-coated trigger 2326, and enteric-coated trigger 2326 is held in place by perforator holder 2324 and is used as trigger mechanism until it dissolves.When device 2300 is swallowed by experimenter, enteric-coated trigger 2326 is by spring 2314 and perforator 2320 are held in place and stop the dispensable material in fluid volume 2310 from being under pressure.When device 2300 arrives in the appropriate position in GI tract, enteric-coated trigger 2326 degrades and / or dissolves (for example, due to pH, pH change, the presence of some enzymes, and / or the concentration of some enzymes), so that perforator holder 2324 is no longer enough to suppress the pressure from spring 2314.Spring 2314 forces perforator 2320 to enter into gas cylinder 2316, thereby piercing gas cylinder 2316 and causing the gas under the pressure of raising to leave gas cylinder 2316. This causes the cylinder 2316 to press against the piston 2318 and apply pressure to the fluid volume 2310. The piston provides friction to cause the cap 2334 to open / expand, causing the dispensable substance to be delivered from the volume 2310. This results in the delivery (e.g., localized delivery) of the therapeutic agent contained in the dispensable substance.

[0242] In some embodiments, the housing of the 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 the cylinder 2316 of about 150 μL to about 175 μL (e.g., about 160 μL).

[0243] Figure 25 An embodiment of an ingestible device 2500 is shown that contains a dispensable substance that is not under pressure when a subject swallows the ingestible device. The ingestible device 2500 has: housing portions 2504 and 2506 connected by a union 2508 and having a fluid volume 2510 containing the dispensable substance, a spring 2514, a piston 2518, a spring retaining pin 2536, and an O-ring 2532. After the housing portion 2504 is filled with the dispensable substance (e.g., a liquid containing a drug), a cap 2538 containing the dispensable substance seals into the dispensable substance (e.g., a liquid containing a drug). A seal 2530 forms an airtight seal between the spring retaining pin 2536 and the housing portion 2506. A spring retaining cup 2522 retains the spring retaining pin 2536. Pin holder 2540 holds spring retaining pin 2536 in place together with enteric trigger 2526, which holds the pin holder in place until it dissolves and serves 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 holding spring 2514 and spring retaining pin 2536 in place. When device 2500 reaches the appropriate position in the GI tract, enteric trigger 2526 degrades and / or dissolves (e.g., due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), causing pin holder 2540 to no longer be sufficient to inhibit spring retaining pin 2536, thereby releasing spring 2514. Spring 2514 pushes piston 2518, causing piston 2518 to apply pressure to fluid volume 2510. The piston provides friction to cause cap 2534 to open / expand, causing dispensable substance to be delivered from volume 2510. This results in delivery (eg, localized delivery) of the therapeutic agent out of the dispensable mass.

[0244] In some embodiments, the housing of the 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), and a fluid volume of about 395 μL to about 570 μL (e.g., about 403 μL to about 559 μL).

[0245] Figure 26 and 27 Ingestible device 2600 is shown in its closed and open states, respectively. Ingestible device 2600 is configured similarly to ingestible device 2500 and has housing components 2604 and 2606 that have a smaller profile than the housing components of ingestible device 2500. Fluid volume 2610 of ingestible device 2600 may have a smaller capacity than fluid volume 2510 of ingestible device 2500.

[0246] In some embodiments, the housing of the 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), and a fluid volume of about 395 μL to about 570 μL (e.g., about 403 μL to about 559 μL).

[0247] Figure 28An embodiment of an ingestible device 2800 is shown that contains a dispensable substance that is not under pressure when a subject swallows the ingestible device. The ingestible device 2800 has: housing portions 2804 and 2806 connected by a union 2808 and having a fluid volume 2810 containing the dispensable substance, a spring 2814, a piston 2818, a spring retaining pin 2836, and an O-ring 2832. After the housing portion 2804 is filled with the dispensable substance (e.g., a liquid containing a drug), a cap 2838 containing the dispensable substance seals into the dispensable substance (e.g., a liquid containing a drug). A seal 2830 forms an airtight seal between the spring retaining pin 2836 and the housing 2806. A spring retaining cup 2822 retains the spring retaining pin 2836. Pin retainer 2840 holds spring retaining pin 2836 in place together with enteric trigger 2826, which holds the pin retainer in place until it dissolves and serves 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 holding spring 2814 and spring retaining pin 2836 in place. When device 2800 reaches the appropriate position in the GI tract, enteric trigger 2826 degrades and / or dissolves (e.g., due to pH, pH changes, the presence of certain enzymes, and / or the concentration of certain enzymes), causing pin retainer 2840 to no longer be sufficient to inhibit spring retaining pin 2836, thereby releasing spring 2814. Spring 2814 pushes piston 2818, causing piston 2818 to apply pressure to fluid volume 2810. The piston provides friction to cause cap 2834 to open / expand, allowing dispensable substance to be delivered from volume 2810. This results in delivery (eg, localized delivery) of the therapeutic agent contained in the dispensable substance.

[0248] In some embodiments, the housing of the 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), and a fluid volume of about 790 μL to about 870 μL (e.g., about 802 μL to about 855 μL).

[0249] Figure 29A An external view of an embodiment of an ingestible device 2800 is shown, and Figure 29B An exterior view of housing component 2804 holding a fluid volume 2810 is shown.

[0250] Figure 30 An embodiment of the ingestible device 2800 is shown with the cap 2834 opened / deployed.

[0251] Figure 31 An embodiment of an ingestible device 3100 is shown that contains a dispensable substance that is not under pressure when a subject swallows the ingestible device. The ingestible device 3100 has: housing portions 3104 and 3106 and a fluid volume 3110 containing the dispensable substance, a piston 3118, a wave spring 3142, and an O-ring 3132. After the housing portion 3104 is filled with the dispensable substance (e.g., a liquid containing a drug), a cap 3138 containing the dispensable substance seals into the dispensable substance (e.g., a liquid containing a drug). The seal 3130 forms an airtight seal between the switch 3146 and the housing 3106. The spring retaining cup 3122 holds the wave spring 3142. The pin retainer 3140 holds the switch 3146 in place together with the enteric-coated trigger 3126, which holds the pin retainer in place until it dissolves and serves as a trigger mechanism. When the device 3100 is swallowed by a subject, the enteric trigger 3126 prevents the dispensable substance in the fluid volume 3110 from being under pressure by holding the wave spring 3142 and the switch 3146 in place. When the device 3100 reaches the appropriate position in the GI tract, the enteric trigger 3126 degrades and / or dissolves (e.g., due to pH, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), so that the pin retainer 3140 is no longer sufficient to restrain the wave spring 3142 and releases the switch 3146. The switch 3146 completes the circuit together with the gas cell 3144, which begins to produce gas. As pressure builds, the piston 3118 slides along the track and closes the circuit via the conductive O-ring 3132. When the track ends at a defined travel distance, the circuit is disconnected to terminate gas production by the gas cell 3144. The piston 3118 applies pressure to the fluid volume 3110 and provides friction to cause the cap 3134 to open / expand, allowing the dispensable substance to be delivered from the volume 3110. This results in the delivery (e.g., localized delivery) of the therapeutic agent contained in the dispensable substance.

[0252] In some embodiments, the housing of the 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), and a fluid volume of about 880 μL to about 940 μL (e.g., about 890 μL to about 930 μL).

[0253] Figure 32A An external view of an embodiment of an ingestible device 3100 is shown, and Figure 32BAn exterior view of the housing component 3104 holding the fluid volume 3110 is shown.

[0254] Figure 33 Another view of an embodiment of the ingestible device 3100 is shown.

[0255] Figure 34 An embodiment of the ingestible device 3100 is shown with the cap 3134 opened / deployed.

[0256] 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 000. The reduced length of the ingestible device can result in a reduced volume available for the dispensable substance. Adjusting one or more dimensions of the cylinder within the ingestible device and / or changing the position of the piston can be used to increase the volume available for the dispensable substance while maintaining a threshold dispensable substance volume and / or pressure provided by the cylinder for the ingestible device. Figures 35-40 Example implementations are described.

[0257] Figure 35An embodiment of an ingestible device 3500 for epithelial delivery is shown, wherein the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and contains a dispensable substance that is not under pressure when the subject swallows the ingestible device. The ingestible device 3500 has: housing portions 3504 and 3506 connected by a union 3508 and having a fluid volume 3510 containing the dispensable substance, a spring 3514, a cylinder 3516, a piston 3518, a punch 3520, and an O-ring 3532. The cylinder 3516 is retained by a retaining element 3528. A seal 3530 forms a gas seal between the punch 3520 and the housing 3506. A spring retaining cup 3522 retains the spring-loaded punch 3520. Perforator retainer 3524 is held in place by perforator 3520 together with enteric-coated trigger 3526, and enteric-coated trigger 3526 is held in place by perforator retainer 3524 and is used as trigger mechanism until it dissolves.When device 3500 is swallowed by experimenter, enteric-coated trigger 3526 is by spring 3514 and perforator 3520 are held in place and stop the dispensable material in fluid volume 3510 from being under pressure.When device 3500 arrives in the appropriate position in GI tract, enteric-coated trigger 3526 degrades and / or dissolves (for example, due to pH, pH change, the presence of some enzymes, and / or the concentration of some enzymes), so that perforator retainer 3524 is no longer enough to suppress the pressure from spring 3514.Spring 3514 forces perforator 3520 to enter into gas cylinder 3516, thereby piercing gas cylinder 3516 and causing gas 3534 under elevated pressure to leave gas cylinder 3516. This causes the 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 / expand, allowing the dispensable substance to be delivered from the volume 3510. This results in epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0258] 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 cylinder fill volume of about 140 μL to about 150 μL (e.g., about 160 μL).

[0259] In some embodiments, one or more adjustments to the piston length and / or cylinder dimensions may be varied for an ingestible device, such as ingestible device 3500. Figures 36-40 Depicted reference Figure 35 Various variations of the piston length and / or cylinder dimensions of the ingestible device structures are described.

[0260] Figure 36An embodiment of an ingestible device 3600 is shown wherein the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and a reduced piston length. Figure 36 , the ingestible device 3600 includes a piston 3618, a cylinder 3616, and a fluid volume 3610. In some embodiments, the ingestible device 3600 can hold a dispensable substance volume of 300 μL to about 350 μL (e.g., about 322 μL), can have an expansion volume of about 350 μL to about 380 μL (e.g., about 372 μL), and can have a cylinder fill volume of about 35 μL to about 45 μL (e.g., about 40 μL). In some embodiments, a 280 PSIG fill pressure of the cylinder corresponds to an actuation pressure volume of about 70-80 μL (e.g., about 75 μL). In some embodiments, a 240 PSIG fill pressure of the cylinder corresponds to an actuation pressure volume of about 90-100 μL (e.g., about 95 μL).

[0261] Figure 37 An embodiment of an ingestible device 3700 is shown wherein the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and a reduced piston length. Figure 37 , the ingestible device 3700 includes a piston 3718, a cylinder 3716, and a fluid volume 3710. In some embodiments, the ingestible device 3700 can hold a dispensable substance volume of 300 μL to about 350 μL (e.g., about 332 μL), can have an expansion volume of about 320 μL to about 380 μL (e.g., about 336 μL), and can have a cylinder fill volume of about 65 μL to about 85 μL (e.g., about 75 μL). In some embodiments, a 280 PSIG fill pressure of the cylinder corresponds to an actuation pressure volume of about 140-150 μL (e.g., about 145 μL). In some embodiments, a 240 PSIG fill pressure of the cylinder corresponds to an actuation pressure volume of about 170-190 μL (e.g., about 180 μL).

[0262] Figure 38 An embodiment of an ingestible device 3800 is shown wherein the length of the ingestible device is reduced to achieve a modified size 00 submucosal device and a reduced piston length. Figure 38As depicted in FIG, ingestible device 3800 includes piston 3818, cylinder 3816, and fluid volume 3810. In some embodiments, ingestible device 3800 can hold a dispensable substance volume of 300 μL to about 350 μL (e.g., about 335 μL), can have an expansion volume of about 300 μL to about 320 μL (e.g., about 306 μL), and can have a cylinder fill volume of about 35 μL to about 45 μL (e.g., about 40 μL). The piston shape of piston 3818 can result in a residual dispensable substance volume of about 80 μL within the dispensable substance housing (out of a total of 335 μL delivered) after delivery.

[0263] Figure 39 An embodiment of an ingestible device 3900 is shown wherein the length of the ingestible device is reduced to achieve a changed size 00 submucosal device and a changed cylinder diameter. Figure 39 As depicted in FIG, the ingestible device 3900 includes a piston 3918, a cylinder 3916, and a fluid volume 3910. In some embodiments, the ingestible device 3900 can hold a dispensable substance volume of 300 μL to about 350 μL (e.g., about 335 μL), can have an expansion volume of about 250 μL to about 290 μL (e.g., about 271 μL), and can have a cylinder fill volume of about 70 μL to about 80 μL (e.g., about 75 μL). The piston shape of the piston 19166 can result in a residual dispensable substance volume of about 70-90 μL (e.g., about 80 μL) out of the total amount of dispensable substance volume delivered within the housing after delivery.

[0264] Figure 40 An embodiment of an ingestible device 4000 is shown wherein the length of the ingestible device is reduced to achieve a changed size 00 submucosal device and a changed cylinder diameter. Figure 40 , the ingestible device 4000 includes a piston 4018, a cylinder 4016, and a fluid volume 4010. In some embodiments, the ingestible device 4000 can hold a dispensable substance volume of 300 μL to about 350 μL (e.g., about 332 μL), can have an expansion volume of about 220 μL to about 270 μL (e.g., about 240 μL), and can have a cylinder fill volume of about 125 μL to about 145 μL (e.g., about 138 μL). In some embodiments, a 240 PSIG actuation pressure of the 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 cylinder corresponds to an actuation pressure of about 910-930 PSIG (e.g., about 925 PSIG). In some embodiments, a 320 PSIG drive pressure for the cylinder corresponds to a fill pressure of approximately 1040-1060 PSIG (eg, 1057 PSIG).

[0265] In some embodiments, the puncture force required to puncture the gas cylinder can be reduced, such that a shorter / lower force spring can be utilized and / or a shorter / stiffer spring can be utilized.

[0266] In some embodiments, as Figures 41A-41C As depicted in , the nozzle opening 4102 may be covered by a covering (including a member such as a patch 4104) that forms a barrier between the dispensable substance 4112 held within the housing 4110 and the environment outside the ingestible device. The patch 4104 may be formed of a material that is a degradable material, an erodible material, and a soluble material. The patch may be a barrier film made 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 barrier properties. The multilayer construction 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 construction of the patch may include a metal layer.

[0267] The patch 4104 can have various shapes, such as circular, rectangular, polygonal, or asymmetrical profiles. In some embodiments, as depicted in FIG41 , the patch can be affixed off-center 4106 above a nozzle opening 4102 on the outer surface of the ingestible device, such that the force of a jet of fluid discharged through the nozzle opening 4102 (e.g., by pressurized release of a dispensable substance) can preferentially move the patch away from the direction of the resulting jet.

[0268] The patch 4104 can be loosely fixed over the nozzle opening (e.g., using an adhesive or another pressure-sensitive method, or using static suction). The adhesive for fixing the patch can be used on the surface around the nozzle, but not directly on the nozzle.

[0269] In some embodiments, a film, coating, foil, tape, etc. may be provided on a patch fixed above the nozzle opening and may be composed of a soluble material, such as an enteric material, so that during operation (handling), storage, and intake of the ingestible device, the film, coating, foil, or tape holds the patch in place above the nozzle opening. In one example, tape 4108 is composed of a material that dissolves when entering the body. The film or tape may be composed of a water-soluble material, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or gelatin. The film or tape 4108 may be composed of a material comprising pH-dependent solubility, such as being composed of or comprising polymethacrylate, so that the material is more stable under acidic conditions, such as pH 1-4, and wherein the dissolution rate increases when the material is exposed to a higher pH, such as pH 5-7.

[0270] In some embodiments, the band covering the nozzle opening can be made of a heat-shrinkable material that heat-shrinks to the shell so that it provides a nozzle cover. An example of a heat-shrinkable material is polyethylene terephthalate (PET). Other examples of heat-shrinkable materials include polyolefins, polyethylene, LDPE, PTFE, FEP, and COC. Generally speaking, such heat-shrinkable materials do not work by being dissolved. On the contrary, they are broken (e.g., pierced) by the pressure applied to the heat-shrinkable material by dispensable materials. Such heat-shrinkable tapes can have, for example, a thickness of about 5 μm to about 100 μm (e.g., about 5 μm to about 50 μm, about 10 μm, about 12 μm, about 15 μm, about 50 μm). Specific examples include heat-shrinkable PET (e.g., medical film) with a thickness of about 12 μm, heat-shrinkable polyolefins (e.g., transport packaging film) with a thickness of about 15 μm, and heat-shrinkable polyethylene (e.g., transport packaging film) with a thickness of about 50 μm.

[0271] In general, the covering of the nozzle opening (e.g., a film, coating, foil, tape) may be scored, for example, to make it easier to break the seal when needed. Typically, such scoring can be configured as desired. As an example, the scoring can be configured as a series of parallel lines. As another example, the scoring can be configured as a grid (grid-lined). As a further example, the scoring can be configured as a plurality of points (e.g., equidistant points). In some embodiments of a scored seal, the seal is composed of LDPE, for example, LDPE having a thickness of 20 μm to 75 μm (e.g., 25 μm, 50 μm). For example, a seal composed of LDPE can be scored with stripes or a grid or a plurality of points, and the LDPE has a thickness of 25 μm or 50 μm.

[0272] 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, 1 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.

[0273] In some embodiments, a coating or film may be applied over the nozzle opening 4102 that dissolves / degrades or otherwise becomes unstable after ingestion by the ingestible device. In some embodiments, the coating or film is hydrophobic. The coating or film may be structurally weakened by drilling / scoring, such as using a laser, and / or may be composed of a material that weakens based on the material's surrounding environment, such as a material that is enteric soluble in the body. In one example, the coating or film may be thinned using laser microtomy techniques, such as a grinding / polishing process, to reduce the coating or film thickness. In some embodiments, a coating or film of enteric soluble material may be applied over the nozzle opening 4102 and over a portion of the outer surface of the ingestible device. Machining / polishing processes, such as centerless grinding or grinding, may be used to control the final thickness of the applied coating or film. The coating or film may be further processed using a laser to drill, score, and / or perforate a portion of the coating or film to mechanically weaken it.

[0274] Figures 42A-47CEmbodiments of patches, coatings, films, foils, and / or tapes that can be secured to or in contact with a nozzle opening are depicted. Although such embodiments are depicted in these figures, the present disclosure is not limited in this sense. In some embodiments, a combination of more than one (e.g., more than two, more than three) of such methods of covering a nozzle opening may be used in a given ingestible device. Further, variations of the methods disclosed herein are available so long as they generally meet 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 external to the ingestible device.

[0275] In some embodiments, as Figure 42A and 42B As depicted in FIG, the nozzle opening 4202 may be covered by a covering (comprising a member 4248, such as a patch, film, foil, tape, etc.) that forms a barrier between a fluid volume 4210 comprising a dispensable substance (e.g., a liquid containing a drug) held within the housing and the environment external to the ingestible device. Certain embodiments comprising a nozzle covering member 4202 formed of a film, foil, patch, tape, etc., are described, for example, in USSN 62 / 932,459. Figure 17 、 18 , 19A-N discuss and optionally apply to Figure 42A and 42B .

[0276] The internal pressure from the pressurized dispensable substance (e.g., during the release of the pressurized dispensable substance) can cause the dispensable substance to pierce the covering member or partially peel / detach the covering member from the outer surface of the ingestible device to allow the formation of a jet 4262 containing the dispensable substance. The covering member 4248 can be composed of various materials such as PE, PP, PVC, cellulose acetate, hot blocking film, etc. In some embodiments, the covering member can be composed of a material that is intended to be insoluble in the gastric medium but can be decomposed in the small intestine based on pH (e.g., enteric materials) or one or more enzymes such as one or more pancreatic enzymes (e.g., lipid-based materials). The covering member 4248 can be composed of a material that can hydrate and / or soften without significantly dissolving when exposed to the gastric medium. The covering member 4248 in this embodiment and other embodiments described herein can be composed of a gas permeable membrane (e.g., which can help degas during the filling process of the ingestible device). The covering member can be applied, for example, from a reel, in a post-molding operation.

[0277] In some embodiments, the covering member 4248 can be a thin shrink-fit film or adhesive label component applied to the outer surface of the ingestible device to cover the nozzle opening. In certain embodiments, the film or adhesive label can be a thin barrier, such as a barrier having a thickness of 20 μm to 40 μm (e.g., 25 μm to 35 μm, 30 μm).

[0278] In some embodiments, the covering member 4248 can be an outer band that is applied to cover the nozzle opening 4202. In certain embodiments, the band can be, for example, 100 μm to 200 μm thick (e.g., 125 μm to 175 μm, for example, 150 μm). Optionally, the band can be composed of a material that is soluble in the gastric medium, such as gelatin, HPMC, or other materials, or can be composed of an enteric material.

[0279] In some embodiments, the covering member 4248 can be a partial film or covering, such as an external cap, that is applied to the exterior of the ingestible device to cover the nozzle opening 4202. The cap can be, for example, 100 μm to 200 μm (e.g., 125 μm to 175 μm, such as 150 μm) thick and / or cover less than the entire exterior of the ingestible device.

[0280] In some embodiments, as Figure 43A and 43BAs depicted in FIG, a covering member 4348, such as a patch, film, foil, tape, coating, etc., that forms a barrier between a fluid volume 4310 comprising a dispensable substance (e.g., a liquid containing a drug) held within a housing 4304 and the environment external to the ingestible device can be applied and / or secured to an inner surface 4364 of the ingestible device. In some embodiments, the covering member 4348 is a thin film that is applied to the inner surface of the primary container 4304 of the ingestible device (e.g., during a molding process) to cover the nozzle opening 4302. Internal pressure from the pressurized dispensable substance (e.g., during the pressurization of the dispensable substance) can cause the dispensable substance to pierce the covering member or partially peel / detach the covering member from the outer surface of the ingestible device to allow formation of a jet 4362 containing the dispensable substance. The covering member 4348 can be composed of various materials, such as a COC-based film, such as a COC+LLDPE laminate, etc. In some embodiments, the covering member 4348 may be composed of a material that is intended to be insoluble in the gastric medium but can be broken down in the small intestine based on pH (e.g., an enteric material) and / or one or more enzymes, such as one or more pancreatic enzymes (e.g., a lipid-based material). The covering member 4348 may be composed of a material that can hydrate and / or soften without significantly dissolving when exposed to the gastric medium. The covering member 4348 in this embodiment and other embodiments described herein may be composed of a gas permeable membrane (e.g., which can aid in degassing during the filling process of the ingestible device). The covering member 4348 can be applied to the inner surface 4364 of the ingestible device, for example, using a molding process (e.g., based on in-mold labeling or blow molding). The covering member can be, for example, 20 μm to 40 μm thick (e.g., 25 μm to 35 μm, 30 μm). In some embodiments, the covering member can be applied / fixed without an adhesive, such as a molded adhesive.

[0281] In some embodiments, as Figure 44A and 44BAs depicted in FIG, the covering member can be a feature, such as a molded feature 4466, formed on (or adjacent to) the inner end of the nozzle opening 4402 and forming a barrier between the fluid volume 4410, including the dispensable substance (e.g., a liquid containing a medicament) held within the housing 4404, and the environment external to the ingestible device. Internal pressure from the pressurized dispensable substance (e.g., during release of the pressurized dispensable substance) can cause the dispensable substance to pierce the covering member 4466, causing the covering member to fully or partially peel / detach from the outer surface of the ingestible device to allow the formation of a jet 4464 containing the dispensable substance. The covering member can be composed of various materials, such as a COC-based film, such as a COC+LLDPE laminate, etc. In some embodiments, the covering member 4466 can be composed of a material that is intended to be insoluble in the gastric medium but can be broken down in the small intestine based on pH (e.g., an enteric material) and / or one or more enzymes, such as one or more pancreatic enzymes (e.g., a lipid-based material). The covering member 4466 can be composed of a material that can hydrate and / or soften without significantly dissolving when exposed to gastric media.

[0282] In some embodiments, as Figure 45A and 45B 45. As depicted in FIG, the cover member 4548 can be a cover member that is tethered 4568 to the ingestible device, for example, to an exterior portion of the housing 4504. The cover member 4548 can be formed from a flexible material, such as an elastomeric material. Internal pressure from the pressurized dispensable substance (e.g., during release of the pressurized dispensable substance) can cause the dispensable substance to disengage / displace a portion or all of the cover member from the nozzle opening 4502 of the ingestible device to allow a jet 4562 containing the dispensable substance to form.

[0283] In some embodiments, as Figure 46A and 46B As depicted in FIG, the covering member can be a plug 4650, such as an elastomeric plug, that can block the nozzle opening 4602 from the outer surface of the ingestible device. The plug can be tethered to the housing component 4604 of the ingestible device to prevent the released plug from being dispersed into the body. The plug 4650 can be formed of a biodegradable material so that the plug is processed by the body. Internal pressure from the pressurized dispensable substance (e.g., during release of the pressurized dispensable substance) can cause the dispensable substance to disengage / displace the plug 4650 from the nozzle opening of the ingestible device to allow a jet 4662 containing the dispensable substance to be formed.

[0284] In some embodiments, as Figures 47A-47CAs depicted in FIG, the nozzle opening 4702 can be blocked by a plug 4750 formed by applying a liquid-filled gel from an external device 4770 of the ingestible device (e.g., via a nozzle or rotating mandrel). The liquid-filled gel can harden prior to the dispensable substance filling process to provide the plug 4750. The gel can be composed of a material that is substantially insoluble in the gastric medium / dispensable substance, but can be broken down based on the pH of the small intestine (e.g., an enteric material) and / or one or more enzymes such as one or more pancreatic enzymes (e.g., a lipid-based material). Internal pressure from the pressurized dispensable substance (e.g., during release of the pressurized dispensable substance) can cause the dispensable substance to displace the gel from the nozzle opening 4702 of the ingestible device, allowing the formation of a jet 4762 containing the dispensable substance.

[0285] Figure 48 and 49 One 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 the subject swallows the ingestible device. Figure 48 In the embodiment, nozzle 4802 is depicted as being covered and in Figure 49 The middle nozzle 4802 is uncovered. The ingestible device 4800 comprises housing portions 4804 and 4806 connected by a union 4808 and having a fluid volume 4810 containing a dispensable substance, a spring 4814, a cylinder 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 by an enteric trigger 4826 that dissolves and acts as a trigger mechanism. When the device 4800 is swallowed by a subject, the enteric trigger 4826 prevents the dispensable substance in the fluid volume 4810 from being under pressure by holding the spring 4814 and 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, changes in pH, the presence of certain enzymes, and / or the concentration of certain enzymes), causing the spring 4814 to force the perforator 4820 into the cylinder 4816, thereby puncturing the cylinder 4816 and causing gas under elevated pressure to exit the cylinder 4816. This causes the cylinder 4816 to press against the first piston 4818a and apply pressure to the fluid volume 4810. The pressurized fluid volume 4810 applies pressure to the second piston 4818b, causing the second piston 4818b to slide and expose the nozzle 4802, causing the dispensable substance to be delivered from the nozzle 4802 in the form of a jet. This can result in transepithelial and / or epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0286] In some embodiments, a plug / cap may be secured over the nozzle opening, wherein the plug / cap is further connected to a piercer component of the ingestible device via a connector and a collar component. Figure 50A and 50B One embodiment of an ingestible device 5000 including a stopper / cap assembly is depicted. The ingestible device 5000 includes a nozzle opening 5002, a drug container 5004, a drive housing 5006, an O-ring 5032, a retaining element 5028, a piercer 5020, a gas seal 5030, a trigger element 5026, a trigger support 5024, a spring 5014, a gas cylinder 5016, a union 5008, and a piston 5018. The ingestible device 5000 optionally includes a nozzle cap 5048.

[0287] The plug / cap assembly can be a single formed piece, for example, comprised of a plastic material, and externally mounted to the ingestible device such that the plug 5050 covers the nozzle opening 5002 on the ingestible device 5000. The plug / cap assembly can further include a connector 5052 that connects the plug / cap assembly to a collar 5054 component that can be attached to the top of the piercer 5020 and the exterior of the trigger element 5026 such that when the piercer is released, for example, after the trigger element 5026 dissolves / degrades, the collar component 5054 is pulled downward by the piercer 5020 and, through movement of the collar 5054, the plug / cap 5050 is pulled away from the nozzle opening 5002. In some embodiments, the plug / cap 5050 is pulled away from the nozzle opening 5002 by movement of the collar 5054 in a direction parallel to the length of the ingestible device 5000, for example, along an exterior surface of the ingestible device. In some embodiments, the plug / cap 5050 is pulled away from the nozzle opening 5002 by movement of the ring 5054 in a direction outward (e.g., normal or oblique) from the outer surface of the ingestible device 5000.

[0288] In some embodiments, a band may be secured over one or more nozzle openings, wherein the band is further connected to a piercer component of the ingestible device via a connector and loop component. Figure 51A and 51B One embodiment of an ingestible device 5100 including a belt assembly is depicted. The ingestible device 5100 includes a nozzle opening 5102, a drug reservoir 5104, a drive housing 5106, an o-ring 5132, a retaining element 5128, a perforator 5120, a gas seal 5130, a trigger element 5126, a trigger support 5124, a spring 5114, a gas cylinder 5116, a union 5108, and a piston 5118. The ingestible device 5100 optionally includes a nozzle cover 5148.

[0289] The strap assembly can be a single formed piece, e.g., composed of a plastic material, including the strap 5156, the connector 5152, and the loop member 5154. The strap assembly can alternatively be a multi-piece assembly composed of: the strap 5156, which is placed around the ingestible device 5100 during the filling process; and a connector / loop assembly, which is secured to the strap 5156 and the punch member 5120. The strap assembly can be connected to the punch member 5120 via the loop member 5154, which can be attached to the top of the punch member and the exterior of the trigger element 5126, such that when the punch is released, e.g., after the trigger element 5126 dissolves / degrades, the loop member 5154 is pulled downward by the punch member 5120 and the strap 5156 is pulled away from the nozzle opening 5102 (e.g., along the length of the ingestible device 5100) to expose the nozzle opening 5102 by movement of the loop 5154, followed by or simultaneously with the delivery of the dispensable substance through the nozzle opening 5102.

[0290] In some embodiments, as Figures 52A-52D As depicted in FIG, the ingestible device 5200 includes a sliding cover 5248. The sliding cover 5248 can be a single formed piece, such as a sleeve comprised of a plastic material, and is externally mounted to the ingestible device 5200 such that a portion of the sliding cover covers the nozzle opening 5202 on the ingestible device 5200. The sliding cover 5248 can be attached to the top of the piercer member 5220 and the exterior of the trigger element 5226 such that when the piercer is released, such as after the trigger element 5226 dissolves / degrades, the sliding cover 5248 is pulled downward by the piercer 5220 and, by movement of the piercer 5220, is pulled away from the nozzle opening 5202. By moving the sliding cover in a direction parallel to the length of the ingestible device 5200, such as along an outer surface of the ingestible device, the sliding cover 5248 can be pulled away from the nozzle opening 5202, followed by or simultaneously with the delivery of the dispensable substance within the fluid volume 5210 through the nozzle opening 5202.

[0291] In some embodiments, such as Figure 53A and 53BAs depicted in the partial rendering of ingestible device 5300 in FIG, ingestible device 5300 includes a cap 5334 that is secured to one end of ingestible device 5300 and partially encloses volume 5310. A seal 5358, such as an overmolded elastomeric seal, can be used to seal the dispensable substance within volume 5310 and prevent dispensing of the dispensable substance while cap 5334 is secured to the end of ingestible device 5300. Seal 5358 can further prevent cap 5334 from moving prior to delivery of the dispensable substance. When device 5300 is swallowed by a subject, an 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, the presence of certain enzymes, and / or the concentration of certain enzymes), allowing the spring to force the perforator into the cylinder, thereby puncturing the cylinder and causing gas under elevated pressure to exit the cylinder. This causes the 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 the form of a jet. This can result in transepithelial and / or epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0292] In some embodiments, such as Figure 54A and 54B As depicted in the partial representation of an ingestible device in FIG, ingestible device 5400 includes an inflatable membrane volume 5460, such as a gas bladder or the like, positioned within a volume 5410 comprising a dispensable substance and arranged to seal a nozzle opening 5402 when the inflatable volume 5460 is inflated. In some embodiments, the inflatable membrane volume 5460 may conform to one or more contours, such as an inner curvature, of the ingestible device housing 5404. The inflatable membrane volume 5460 may be comprised of a bladder and / or a soft material, such as a low durometer elastomer. When the device 5400 is swallowed by a subject, an 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, the presence of certain enzymes, and / or the concentration of certain enzymes), allowing the spring to force the perforator into the cylinder, thereby puncturing the cylinder and causing gas under elevated pressure to exit the cylinder. This causes the cylinder to press against the piston and apply pressure to the fluid volume. The pressurized fluid volume applies pressure to the inflatable membrane volume 5460 and causes the inflatable membrane volume to deflate or otherwise reposition to expose the nozzle opening 5402, allowing the dispensable substance to be delivered from the nozzle in the form of a jet. This can result in transepithelial and / or epithelial delivery of the therapeutic agent contained in the dispensable substance.

[0293] In some embodiments, such as Figure 55 As depicted in the partial rendering of the ingestible device in FIG, the ingestible device 5500 does not include a covering member. For example, the nozzle opening 5502 can be exposed such that when the ingestible device 5500 is swallowed / inserted, air gaps and / or surface tension effects in the nozzle opening 5502 can inhibit or prevent gastric media from damaging internal components or a dispensable substance (e.g., a liquid containing a medication) within the ingestible device. In other words, through movement of the ingestible device within the gastric region, a differential force can be generated between external intestinal forces / pressures and internal forces of the dispensable substance within the volume of the ingestible device. For example, the surface tension of the dispensable substance within the volume 5510 of the ingestible device can be higher than the surrounding environment, e.g., external intestinal forces / pressures, within the gastric region of the body, such that a significant percentage of the dispensable substance is retained within the volume of the ingestible device until the point of delivery of the dispensable substance, e.g., until the piston 5518 applies pressure to the volume 5510 to force the dispensable substance retained within the volume 5510 out of the nozzle opening 5502. In one example, at least 75% of the dispensable substance (e.g., at least 85%, at least 95% of the dispensable substance) is retained within the volume of the ingestible device until the dispensable substance is delivered to a point in the body within the gastric region.

[0294] Devices for epithelial delivery

[0295] Typically, epithelial delivery can be achieved at any desired location within the GI tract of a subject. In some embodiments, epithelial delivery is achieved in the small intestine of a subject, such as in the duodenum, jejunum, and / or ileum. In certain embodiments, epithelial delivery is achieved in the large intestine (e.g., cecum or colon) of a subject.

[0296] In some embodiments, epithelial delivery can be achieved using any of the ingestible devices described above for epithelial delivery. In such embodiments, the relevant parameters are generally modified accordingly. Typically, the modification involves modifying the values ​​of the relevant parameters. Examples are provided in the following paragraphs.

[0297] Generally speaking, the ingestible device for epithelial delivery is configured to deliver a jet of dispensable substance 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 at most about 4 mW (e.g., at most about 3.5 mW, at most about 3 mW). In some embodiments, the ingestible device for epithelial delivery is configured to deliver a jet of dispensable substance 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).

[0298] Typically, the ingestible device for epithelial delivery is configured to deliver a jet of dispensable material having a peak jet pressure of about 2 psig (e.g., about 2.5 psig, about 3 psig, about 3.5 psig, about 4 psig) and / or at most about 10 psig (e.g., at most about 8 psig, at most about 6 psig, at most about 5 psig). In some embodiments, the ingestible device for epithelial delivery is configured to deliver a jet of dispensable material having a peak jet pressure of about 2 psig to about 10 psig (e.g., about 2.5 psig to about 8 psig, about 3 psig to about 6 psig, about 3.5 psig to about 5 psig, about 4 psig to about 5 psig).

[0299] In general, the ingestible device for epithelial delivery is configured to deliver a jet of dispensable material 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 of dispensable material 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).

[0300] In general, the ingestible device for epithelial delivery is configured to deliver a jet of dispensable material 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 of dispensable material 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).

[0301] Generally, ingestible devices for epithelial delivery are 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).

[0302] Generally, ingestible devices for epithelial delivery are configured to provide a nozzle pressure of about 3.62 psig to about 21.76 psig (e.g., about 3.62 psig to about 18.13 psig, about 3.62 psig to about 14.50 psig, about 3.62 psig to about 10.88 psig, about 3.62 psig to about 7.25 psig, about 4.35 psig to about 7.25 psig, about 4.35 psig).

[0303] Typically, ingestible devices for epithelial delivery are 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).

[0304] In general, the ingestible device for epithelial delivery holds the dispensable substance in an initial fluid volume of at least about 50 microliters (μL) (e.g., at least about 100 μL, at least about 150 μL, at least about 200 μL, at least about 250 μL) and / or at most about 800 μL (e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL, at most about 400 μL). In some embodiments, the ingestible device for epithelial delivery holds the dispensable substance in an initial fluid volume of about 50 μL to about 800 μL (e.g., about 100 μL to about 600 μL, about 200 μL to about 400 μL).

[0305] Typically, the ingestible device for epithelial delivery is configured to provide a delivery fluid volume of at least about 50 microliters (μL) (e.g., at least about 100 μL, at least about 150 μL, at least about 200 μL, at least about 250 μL) and / or at most about 800 μL (e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL, at most about 400 μL) of the dispensable substance. In some embodiments, the ingestible device for epithelial delivery has a fluid volume of about 50 μL to about 800 μL (e.g., about 100 μL to about 600 μL, about 200 μL to about 400 μL) of the dispensable substance.

[0306] In general, the ingestible device for epithelial delivery holds the dispensable substance in a final fluid volume of at most about 100 microliters (μL) (e.g., at least about 90 μL, at least about 80 μL, at least about 70 μL, at least about 60 μL) and / or at most at least 5 μL (e.g., at most about 10 μL, at most about 20 μL, at most about 30 μL, at most about 40 μL). In some embodiments, the ingestible device for epithelial delivery holds the dispensable substance in a fluid volume of about 30 μL to about 70 μL (e.g., about 40 μL to about 60 μL, about 45 μL to about 55 μL).

[0307] 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.

[0308] In general, the ingestible device for epithelial delivery is configured to provide a delivery fluid volume of at least about 20 microliters (μL) (e.g., at least about 25 μL, at least about μL, at least about 50 μL, at least about 75 μL, at least about 100 μL) and / or at most about 800 μL (e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL, at most about 400 μL, at most about 300 μL) per opening (e.g., each nozzle) for delivery of a dispensable substance. In some embodiments, the ingestible device for epithelial delivery is configured to provide a delivery fluid volume of about 25 μL to about 400 μL (e.g., about 25 μL to about 300 μL, about 100 μL to about 300 μL) per opening (e.g., each nozzle) for delivery of a dispensable substance.

[0309] In certain embodiments, the ingestible device for epithelial delivery is configured as disclosed above in the discussion about transepithelial delivery, but with a relatively large number of nozzles and a relatively large nozzle diameter, so that the performance properties for epithelial delivery (discussed above) can be achieved. As an example, in some embodiments, the ingestible device for epithelial delivery has at least 25 nozzles (e.g., at least 30 nozzles, at least 40 nozzles, 50 nozzles). In some embodiments, such an ingestible device for epithelial delivery has 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 an ingestible device, 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).

[0310] Devices for local delivery

[0311] Typically, 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, such as in the duodenum, jejunum, and / or ileum. In certain embodiments, local delivery is achieved in the large intestine (e.g., cecum or colon) of a subject.

[0312] Generally speaking, 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).

[0313] Typically, the ingestible device for topical delivery is configured to contain the 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 topical 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).

[0314] Generally speaking, ingestible devices for local 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 from the ingestible device into the lumen of the GI tract.

[0315] In general, the ingestible device for topical delivery holds the dispensable substance in an initial fluid volume of at least about 50 microliters (μL) (e.g., at least about 100 μL, at least about 150 μL, at least about 200 μL, at least about 250 μL) and / or at most about 800 μL (e.g., at most about 700 μL, at most about 600 μL, at most about 500 μL, at most about 400 μL). In some embodiments, the ingestible device for topical delivery holds the dispensable substance in an initial fluid volume of about 50 μL to about 800 μL (e.g., about 100 μL to about 600 μL, about 200 μL to about 400 μL).

[0316] In general, the ingestible device for topical delivery holds the dispensable substance in a final fluid volume of at most about 100 microliters (μL) (e.g., at least about 90 μL, at least about 80 μL, at least about 70 μL, at least about 60 μL) and / or at most at least 5 μL (e.g., at most about 10 μL, at most about 20 μL, at most about 30 μL, at most about 40 μL). In some embodiments, the ingestible device for topical delivery holds the dispensable substance in a fluid volume of about 30 μL to about 70 μL (e.g., about 40 μL to about 60 μL, about 45 μL to about 55 μL).

[0317] In certain embodiments, the ingestible device for local delivery is configured as disclosed above in the discussion about transepithelial delivery, but has a relatively large number of nozzles and a relatively large nozzle diameter so that the performance properties for local delivery (discussed above) can be achieved. As an example, in some embodiments, the ingestible device for local delivery has at least 25 nozzles (e.g., at least 30 nozzles, at least 40 nozzles, 50 nozzles). In some embodiments, such an ingestible device for local delivery has 30 nozzles, 31 nozzles, 32 nozzles, 33 nozzles, 34 nozzles, 35 nozzles, 36 nozzles, 37 nozzles, 38 nozzles, or 40 nozzles. Each nozzle may have a diameter of, for example, 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 an ingestible device, each nozzle may 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).

[0318] Delivery of therapeutic agents

[0319] Provided herein are ingestible devices and methods for delivering therapeutic agents to the intestinal lumen, mucus, mucosa, and / or submucosa by topical, epithelial, or transepithelial administration to the GI tract of a subject. Current methods of administration for most macromolecular therapeutics or small molecule therapeutics with poor oral bioavailability are subcutaneous (SC), intramuscular (IM), or push intravenous (IV) injections targeting the systemic circulation. Devices and methods as described herein provide alternative routes of administration for current injectable drugs, which can result in greater convenience and compliance because they minimize or avoid the logistical challenges, patient compliance, and attachment challenges, pain, and discomfort associated with traditional routes of administration.

[0320] In some embodiments of the devices or methods described herein, the therapeutic agent is released at a position in the small intestine of the experimenter. In some embodiments of any device or method described herein, the position is in the proximal portion of the small intestine (e.g., duodenum or jejunum). In some embodiments of any device or method described herein, the position is in the distal portion of the small intestine (e.g., jejunum or ileum). In some embodiments of the devices or methods described herein, the therapeutic agent is released at a position in the large intestine of the experimenter. In some embodiments of any device or method described herein, the position is in the proximal portion of the large intestine (e.g., cecum, ascending colon, or transverse colon). In some embodiments of any device or method described herein, the position is in the distal portion of the large intestine (e.g., transverse colon or descending colon).

[0321] Furthermore, by providing higher concentrations of therapeutic agents in GI tissues, the devices and methods described herein are particularly well-suited for treating diseases and disorders of the endoderm, including the liver.

[0322] 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 middle small intestine of about 7.0 to about 7.8, a pH in the ileum of about 7.0 to about 8.0, a pH in the right colon of about 5.7 to about 7.0, a pH in the middle colon of about 5.7 to about 7.4, or a pH in the left colon of about 6.3 to about 7.7, e.g., about 7.0.

[0323] In some embodiments of any device or method as described herein, the release of therapeutic agent is triggered by the degradation of the release member in the device. In some embodiments of any device or method as described herein, the release of therapeutic agent depends on the enzymatic activity at or near the position. In some embodiments of any device or method as described herein, compositions include multiple electrodes including coatings (coatings), and the release of therapeutic agent is triggered by the electrical signal of the electrode, which is produced by the interaction of the coating with the expected release site of the therapeutic agent. In some embodiments of any device or method as described herein, the release of therapeutic agent is triggered by a remote electromagnetic signal. In some embodiments of any device or method as described herein, the release of therapeutic agent is triggered by a gas that produces an amount sufficient to discharge the therapeutic agent in the composition. In some embodiments of any device or method as described herein, the release of therapeutic agent is triggered by the electromagnetic signal generated according to a predetermined drug release curve in the device.

[0324] Therapeutic agents for delivery

[0325] Therapeutic agents suitable for 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 (such as inhibitory nucleic acids, antisense nucleic acids, siRNA, ribozymes, etc.). In some embodiments, the therapeutic agent is a macromolecule with a molecular weight of at least about 60 kilodaltons (kDa), or about 60kDa to about 200kDa, about 60kDa to about 175kDa, or about 60kDa to about 150kDa.

[0326] In some other embodiments, the therapeutic agent has a molecular weight of at least about 20 kDa, at least about 30 kDa, at least about 40 kDa, or at least about 50 kDa, or about 20 kDa to about 200 kDa, about 20 kDa to about 175 kDa, or about 20 kDa to about 150 kDa.

[0327] In some embodiments, the therapeutic agent is a molecule, such as a protein or peptide, having a molecular weight greater than about 1.5 kDa and less than about 20 kDa, less than about 30 kDa, less than about 40 kDa, less than about 50 kDa, or less than about 60 kDa. In some other embodiments, the therapeutic agent has a molecular weight of about 5 kDa to about 10 kDa, 20 kDa, 30 kDa, 40 kDa, or 50 kDa. In some embodiments, the therapeutic agent is a molecule with a molecular weight of about 5 kDa to about 10 kDa, such as about 6 kDa. In some embodiments, the therapeutic agent is a protein or peptide. In some embodiments, the therapeutic agent is a protein-drug conjugate. In some embodiments, the therapeutic agent is insulin.

[0328] 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 not more than about 1500 Da, such as about 1000 Da, about 750 Da, or about 500 Da. In some embodiments, the therapeutic agent is a small molecule with a molecular weight of about 50 Da to about 1500 Da. In some embodiments, the therapeutic agent is a small molecule with a molecular weight of about 150 Da to about 1500 Da.

[0329] 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, vedotin, Vedolizumab, natalizumab, interferon beta-1a, denosumab, alirocumab, evolocumab, adalimumab, etanercept, golimumab, trastuzumab, pembrolizumab, pertuzumab, ARO-HBV, glatiramer acetate LY-3321367, cetuximab Ipilimumab daratumumab Albumin-bound paclitaxel Tanezumab, LY-2510924, LCAR-B38M, PF-004518600, TAK-079, PF-06730512, LY-3076226, NOV-13, FAZ-053, LY-3375880, PF-06823859, CNGB3 gene therapy, mosunetuzumab, RG-6147, scAAV / JeT-GAN-based gene therapy, ranibizumab, cofetuzumab pelidotin, SHR-A1201, TAK-671, A-004 (AAV2 / 5-hRKp.RPGR) gene therapy, NG-HER2 antibody-drug conjugate, TAK-164, RG-7861, JNJ-61186372, PF-05206388, NJH-395, PF-05230907, BIIB-059, PF-06688992, ianalumab, TAK-573, PF-06755347, CD200R mAb agonists, cetrelimab, ligelizumab, PF-06801591, JNJ-64407564, polatuzumab vedotin, PF-06817024, NOV-12, BIIB-054, CTL-119, JNJ-61178104, spartalizumab, 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, LA G-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.

[0330] Table 1

[0331]

[0332]

[0333] a Capsule quantity assumes a drug reservoir of approximately 400 μL

[0334] sq: subcutaneous

[0335] IFU: Instructions for Use

[0336] IU: International Unit

[0337] In some embodiments, the therapeutic agent is a small molecule. Exemplary small molecule therapeutics 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, grunilofenol, lysozyme ... alunisertib), TBA-7371, LY-3381916, LY-2874455, erdafitinib, pimodivir, aprocitentan, JNJ-56136379, BMS-986177, lazertinib, JNJ-64619178, JNJ-55308942, AL-034, JNJ-67670187, JNJ-64264681, JNJ-64417184, JNJ-3534, JNJ-64991524 , JNJ-64140284, pimodivir + oseltamivir combination, JNJ-61803534, ipatasertib dihydrochloride, fenebrutinib, RG-6171, belvarafenib, RG-6174, alpelisib, asciminib, leniolisib, clofazimine, siremadlin, capmatinib, PBF -509, LNP-023, UNR-844, ganaplacide, cipargamin, adriforant, LYS-006, QCC-374, MAK-683, LCL-161, BLZ-945, LOU-064, VPM-087, WNT-974, totrombopag, hydroxychloroquine + trametinib combination, LTT-462, NOV-11, LSZ-102, allosteric inhibitor of SHP2 phosphatase, mocravimod dihydrochloride, BCL-201,Mivavotinib, DSM-265, sapanisertib, TAK-931, TAK-906, alisertib, TAK-580, pediatric azilsartan formulation, TAK-418, and vonoprazan fumarate + aspirin combination.

[0338] In some embodiments, the therapeutic agent is a monoclonal antibody (mAb). In some embodiments, the mAb is an anti-interleukin-17A (anti-IL-17A) mAb. In some embodiments, the mAb is an anti-interleukin-17A (anti-IL-17A) mAb, which can be used to treat inflammatory conditions and / or autoimmune diseases, including but not limited to rheumatoid arthritis, plaque psoriasis, active psoriatic arthritis, and ankylosing spondylitis. An exemplary anti-IL-17A mAb is ixekizumab. See, e.g., Genovese et al., Arthritis & Rheumatology, 66.7:1693-1704 (2014). In some embodiments, the mAb is selective for angiopoietin 2 (Ang2). An exemplary mAb selective for Ang2 is LY3127804.

[0339] Therapeutic agents for growth disorders

[0340] In some embodiments, therapeutic agents suitable for use with the devices and methods described herein are therapeutic agents for treating growth disorders. In some embodiments, the growth disorder is growth hormone deficiency or disorder (GHD). In some embodiments, GHD is acquired, congenital, or idiopathic; or a combination thereof. In some embodiments, GHD is the result of trauma, infection, radiation therapy, or tumor growth. In some embodiments, GHD is adult-onset GHD.

[0341] Exemplary therapeutic agents for treating growth disorders include, but are not limited to, growth hormones, including, but not limited to, somatropin (somatropin), long-acting somatropin (lonapegsomatropin), YPEG-somatropin, efpegsomatropin, 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 subsequent biologics thereof. In some embodiments, the growth hormone is rHGH. Examples of suitable rHGH include, but are not limited to, recombinant somatotropins, such as genotropin, humatrope, norditropin, nutropin, omnitrope, Serostim, TJ-101, ALT-P1, and JR-142. and

[0342] In some embodiments, a therapeutic agent for treating a growth disorder suitable for use with the devices and methods described herein is somatotropin or a biosimilar or subsequent biologic thereof.

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

[0344] Therapeutic agents for fibrosis

[0345] 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 biological therapeutic agent. In some embodiments, the therapeutic agent is a small molecule. In some embodiments, the therapeutic agent is a non-oral therapeutic agent.

[0346] In some embodiments, the fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the fibrosis is cystic fibrosis.

[0347] Exemplary therapeutic agents for treating fibrosis for delivery using any of the devices or methods described herein include those listed in Table 2.

[0348] Table 2: Therapeutic agents suitable for delivery via ingestible devices for the treatment of fibrosis

[0349]

[0350]

[0351] Therapeutic agents for asthma

[0352] 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 condition of the lungs and 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 drug combination for treating asthma is selected from RG-6151, mometasone + indacaterol, indacaterol + glycopyrronium bromide + mometasone furoate, and fevipiprant. In some embodiments, the drug for treating asthma is an antibody or a fragment thereof. In some embodiments, the antibody drug used to treat asthma is selected from omalizumab, tezepelumab, benralizumab, afasevikumab, RG-6149, dectrekumab + VAK-694, NOV-14, CSJ-117, or biosimilars thereof. In some embodiments, the drug used to treat asthma is a combination of small molecules and / or antibodies or fragments thereof.

[0353] Therapeutic agents for neurological and / or mental disorders or conditions

[0354] 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. Examples of neurological or psychiatric diseases or conditions include, but are not limited to, Alzheimer's disease, anxiety disorders, Parkinson's disease, multiple sclerosis, panic disorder, schizophrenia, chronic pain, neuropathic pain, migraine, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, brain aneurysms, muscular dystrophy, obsessive-compulsive disorder, eating disorders, bipolar disorder, depression, narcolepsy, and insomnia.

[0355] In some embodiments, the drugs used to treat neurological or psychiatric disorders and related symptoms are antibodies and their biosimilars. In some embodiments, the drugs used to treat neurological or psychiatric disorders and related symptoms are antibody-drug conjugates. In some embodiments, the drugs used to treat neurological or psychiatric disorders and related symptoms are small molecules. In some embodiments, the drugs used to treat neurological or psychiatric disorders and related symptoms are inhibitory nucleic acids such as antisense nucleic acids. In some embodiments, therapeutic agents suitable for use with the devices and methods described herein are imaging agents for diagnosing neurological or psychiatric disorders. In some embodiments, the imaging agent is a radiolabeled protein or peptide. In some embodiments, the imaging agent is a radiolabeled small molecule.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] In some embodiments, the psychiatric disorder is schizophrenia. In some embodiments, the drug used to treat schizophrenia is selected from paliperidone palmitate, TAK-831, BIIB-104, TAK-041, and erteberel.

[0360] In some embodiments, the psychiatric disorder is depression. In some embodiments, drugs used to treat depression include aticaprant, esketamine, PF-04995274, JNJ-39393406, TAK-653, seltorexant, NR2B negative allosteric modulators, and MIJ-821.

[0361] Other therapeutic agents and imaging agents suitable for use with the devices and methods described herein for treating or diagnosing neurological or psychiatric disorders 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, and 18F-JNJ-64511070. fumarate), 18F-GTP1 (RO-6880276), tofersen sodium, florbetapir (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.

[0362] Therapeutic agents for metabolic and / or endocrine diseases or disorders

[0363] 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 condition. Examples of metabolic or endocrine diseases or conditions include, but are not limited to, diabetes, insulin resistance, hyperglycemia, hyperlipidemia, obesity, hepatic steatosis, hyperinsulinemia, obstructive sleep apnea, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, hypertension, cardiovascular disease (CVD), pulmonary hypertension, primary sclerosing cholangitis, high blood triglycerides, hypertriglyceridemia, dyslipidemia, lipid disorders, type I hyperlipoproteinemia, familial hypercholesterolemia, hypercholesterolemia, lipodystrophy, acromegaly, myocardial infarction, and thromboembolism; and combinations thereof. In some embodiments, metabolic or endocrine diseases or conditions are obesity.

[0364] Therapeutic agents suitable for treating metabolic or endocrine diseases or disorders include, but are not limited to, abatacept, aldesleukin, allogeneic human islets of Langerhans, alogliptin, alpha-1 antitrypsin, anagliptin, atorvastatin, benaglutide, berberine, bermekimab, bimagrumab, cibinetide, cotadutide, diabecell, diamyd, dutogliptin, ebenatide, efpeglenati de), evogliptin, fluvastatin, FSI-965, gemigliptin, glutazumab, gosogliptin, hinsbet, iscalimab, LAI-287, linagliptin, lovastatin, mecasermin, omarigliptin, osilodrostat, otelixizumab, pegapamodutide, PEG-loxenatide, pitavastatin, pramlintide acetate

[00135] 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 regulates 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 condition is selected from bortezomib, fulvestrant, bendamustine, itolizumab, golimumab, canakinumab, Trichuris suis eggs, 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 condition 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 intestine 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 metabolic or endocrine diseases or disorders is a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor. In some embodiments, the PCSK9 inhibitor is alizumab or evolocumab. Other exemplary PCSK9 inhibitors for treating metabolic or endocrine diseases or disorders include those listed in Table 9.

[0365] Therapeutic agents for diabetes

[0366] In some embodiments, the metabolic or endocrine disease or condition is diabetes. In some embodiments, the diabetes is type I or type II diabetes. In some embodiments, the diabetes is insulin-dependent diabetes. In some embodiments, the diabetes is non-insulin-dependent diabetes. In some embodiments, the diabetes is gestational diabetes.

[0367] In some embodiments, the metabolic or endocrine disease or condition is a combination of diabetes and other diseases or conditions, 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, diabetes is diabetes with obesity.

[0368] Therapeutic agents suitable for treating metabolic or endocrine diseases or disorders 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 cotransporter-2 (SGLT-2) inhibitors, sulfonylureas, α-glucosidase inhibitors, maglitinides, thiazolidinediones, dopamine-2-agonists, bile acid sequestrants, peptide YY ligands, and amylin (amylin) analogs.

[0369] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a peptide YY ligand. The intestinal 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 herein by reference 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 for monotherapy or in combination therapy 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), a potential SC treatment for obesity and overweight. NN-9748 is an analog of the appetite-regulating hormone PYY and is intended for monotherapy or combination therapy with the GLP-1 analog semaglutide. In October 2018, the first human dose of NNC0165-1875 as a monotherapy and in combination with semaglutide, a Phase I study was initiated; N=88 (clinical trial identifier: NCT03707990; source: NovoNordisk 2018 annual report). In some embodiments, NN-9747 is the same drug substance as NN-9748.

[0370] 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.

[0371] 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.

[0372] In some embodiments, a 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 triple 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.

[0373] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a dual-effect (dual) GIP and GLP-1 receptor agonist. In some embodiments, the dual-effect GIP and GLP-1 receptor agonist is LY3298176, which is a fatty acid-modified peptide with dual-effect GIP and GLP-1 receptor agonist activity that can be used to treat type 2 diabetes. See, for example, Coskun et al., Mol. Metab., 18: 3-14 (2018).

[0374] In some embodiments, a therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent used to treat diabetes.

[0375] 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 human insulin, insulin aspart, super-fast-acting insulin aspart, insulin degludec, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, and insulin tregopil.

[0376] 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, gemagliptin, alagliptin, tenagliptin, alogliptin, trelagliptin, alogliptin, ipagliptin, guogliptin, dulagliptin, and berberine.

[0377] In some embodiments, the therapeutic agent for treating diabetes suitable for use with device and method as described herein is SGLT-2 inhibitor.SGLT-2 inhibitor is an oral hypoglycemic drug that suppresses the reabsorption of glucose in the kidney and can be used to treat type 2 diabetes.The example of SGLT-2 inhibitor includes but is not limited to canagliflorzin (canagliflorzin), dapagliflozin (dapagliflozin), empagliflozin (empagliflozin), ertugliflozin (ertugliflozin), ipragliflozin (ipragliflozin), luseogliflozin (luseogliflozin), remogliflozine tabonate (remogliflozine tabonate), sergliflozin etabonate (sergliflozin etabonate), sotagliflozin (sotagliflozin) and tofogliflozin (tofogliflozin).

[0378] In some embodiments, a therapeutic agent suitable for use with the devices and methods described herein for treating diabetes is an α-glucosidase inhibitor. α-glucosidase inhibitors (AGIs) are oral hypoglycemic agents that inhibit the digestion of carbohydrates into monosaccharides by α-glucosidase in the intestine, thereby lowering blood glucose levels. Examples of α-glucosidase inhibitors include, but are not limited to, acarbose, miglitol, and voglibose.

[0379] Exemplary therapeutic agents for treating diabetes for delivery using any of the devices or methods described herein include those listed in Table 3, and any combination thereof.

[0380] Table 3: Therapeutic agents suitable for delivery via an ingestible device for treating diabetes

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387] Therapeutic agents for NASH / NAFLD

[0388] In some embodiments, the disease or condition is NASH and / or NAFLD. In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent for treating non-alcoholic steatohepatitis (NASH) and / or non-alcoholic fatty liver disease (NAFLD). NASH (non-alcoholic steatohepatitis) is a fatty liver disease that affects up to 12% of adults in the United States.

[0389] There are many potential drugs for the treatment of this disease, which are listed below: 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, lanibibranor (IVA-337), lipaglyn, tripifaxol (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, repagliflozin etabonate, volixibat (SHP626), TVB-2640, VK2809, butyric acid, CER209, ipagliptin, 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 device and method as herein described is selected from therapeutic agent, and the therapeutic agent is selected from siromidine, Cinevir, elafibinor, ocaliva, tripifaxol, firocostat and sylofaxol. These represent several biological mechanisms. The combination of multiple drugs may be needed. In some embodiments, medicine is selected from siromidine, Cinevir, elafibinor, ocaliva, tripifaxol, firocostat and sylofaxol.

[0390] Exemplary therapeutic agents for 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 suitable for delivery via ingestible devices for the treatment of NASH / NAFLD

[0392]

[0393] Therapeutic agents for rheumatoid arthritis

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

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

[0396]

[0397]

[0398]

[0399]

[0400] Therapeutic agents for IBD

[0401] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent for treating inflammatory bowel disease (IBD). Exemplary therapeutic agents for treating IBD for delivery using any device or method described herein include those listed in Table 6.

[0402] Table 6: Therapeutic agents suitable for delivery via ingestible devices for the treatment of IBD

[0403]

[0404]

[0405]

[0406] Therapeutic agents for short bowel syndrome

[0407] Short bowel syndrome (SBS) is a malabsorption disorder caused by a lack of a functional small intestine. The primary symptom is diarrhea, which can lead to dehydration, malnutrition, and weight loss. Exemplary therapeutic agents for treating SBS that can be delivered using any of the devices or methods described herein include teduglutide, 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.

[0408] Therapeutic agents for blood disorders

[0409] In some embodiments, the therapeutic agent suitable for use with the devices and methods described herein is a therapeutic agent for treating a blood disorder. In some embodiments, the blood disorder is anemia. In some embodiments, the therapeutic agent for treating anemia is recombinant human erythropoietin. In some embodiments, the therapeutic agent for treating anemia is a human erythropoietin analog. In some embodiments, the therapeutic agent for treating anemia is selected from darbepoetin α / α and epoetin α; and biosimilars thereof.

[0410] Ziltivekimab (COR-001), a human IgG1k anti-inflammatory IL-6 monoclonal antibody, is being developed for the potential treatment of anemia, chronic kidney disease, and / or cardiovascular disease. Ziltivekimab is an exemplary therapeutic agent for treating 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.

[0411] In some embodiments, the blood disorder is sickle cell disease. In some embodiments, the blood disorder is thalassemia. In some embodiments, the therapeutic agent used to treat sickle cell disease or thalassemia is selected from PF-04447943, crizanlizumab, EPI-01, and rivipansel sodium.

[0412] In some embodiments, the blood disorder is hemophilia. In some embodiments, the hemophilia is hemophilia A, hemophilia B, or von Willebrand disease.

[0413] In some embodiments, the therapeutic agent used to treat hemophilia is an alternative coagulation promoter (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 biosimilars thereof. In some embodiments, the anti-TFPI is concizumab or a biosimilar thereof.

[0414] 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 herein by reference in its entirety).

[0415] In some embodiments, the therapeutic agent used to treat hemophilia is selected from albutrepenonacog alpha, AMT-061, beroctocog alpha, βfact, BIVV-001, BS027125, byclot, catridecacog, clotnine, dalcinonacog alpha, damoctocog alpha pegol, DTX-201, eftrenonacog alpha, eptacog alpha, factor VIII, factor IX, factor X, fidanacogene, and biosimilars thereof.

[0416] 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 that can be delivered using any of the devices or methods described herein include those listed in Table 7.

[0417] Table 7: Therapeutic Agents Suitable for Delivery via Ingestible Devices for Treating Hemophilia

[0418]

[0419]

[0420]

[0421]

[0422] Therapeutic agents for hepatocellular carcinoma

[0423] 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 the most common cause of death in people with cirrhosis. Drugs used to treat hepatocellular carcinoma include, but are not limited to, nivolumab, lenvatinib, sorafenib, regorafenib, PF-04518600, emibetuzumab, and carbozantinib.

[0424] Target-based therapeutics

[0425] GLP-1 receptor agonists

[0426] In some embodiments, a 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]caprylic acid (SNAC). In some embodiments, the carrier or delivery agent is biotin.

[0427] In some embodiments, the GLP-1 receptor agonist is exanatide (synthetic exendin-4), a 39-residue peptide with 53% sequence identity to GLP-1, having the following sequence: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO: 1).

[0428] In some embodiments, the GLP-1 receptor agonist is a compound having a structure selected from the group consisting of:

[0429]

[0430] 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.

[0431] In some embodiments, the GLP-1 receptor agonist is a compound having the following structure:

[0432]

[0433] or a pharmaceutically acceptable salt thereof.

[0434] 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 following structures and tables.

[0435]

[0436] In some embodiments, the GLP-1 receptor agonist is a compound having the following structure:

[0437]

[0438] or a pharmaceutically acceptable salt thereof.

[0439] In some embodiments, the GLP-1 receptor agonist is a compound having a structure selected from the group consisting of:

[0440]

[0441] In some embodiments, the GLP-1 receptor agonist is Boc5 (Compound 12) or a pharmaceutically acceptable salt thereof.

[0442] In some embodiments, the GLP-1 receptor agonist is a compound having a structure selected from the group consisting of:

[0443]

[0444]

[0445] In some embodiments, the GLP-1 receptor agonist is TTP-054 or a pharmaceutically acceptable salt thereof, such as described in Edmonds et al., Annu. Rep. Med. Chem. (2013) 48: 119-130, which is incorporated herein by reference in its entirety.

[0446] In some embodiments, the GLP-1 receptor agonist is TTP273 or a pharmaceutically acceptable salt thereof, such 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 herein by reference in its entirety.

[0447] In some embodiments, the GLP-1 receptor agonist is OWL883, such as described in Kawai et al., Diabetes (2018) 67(Supplement 1): 1118-P, which is incorporated herein by reference in its entirety.

[0448] 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 herein by reference in its entirety.

[0449] Other exemplary GLP-1 receptor agonists for delivery using any of the devices or methods described herein include those listed in Table 8.

[0450] Table 8: GLP-1 receptor agonists suitable for delivery via ingestible devices for the treatment of listed diseases and conditions

[0451]

[0452]

[0453] PCSK9 inhibitors

[0454] In some embodiments, therapeutic agents suitable for use with the devices and methods described herein are proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors. In some embodiments, PCSK9 inhibitors treat one or more of an endocrine and / or metabolic disease or condition, cardiovascular disease, and infection. In some embodiments, the endocrine and / or metabolic disease or condition is familial hypercholesterolemia, hypercholesterolemia, or hyperlipidemia.

[0455] 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.

[0456] Table 9: PCSK9 inhibitors suitable for delivery via ingestible devices for the treatment of the listed diseases and conditions

[0457]

[0458]

[0459]

[0460] TNFα inhibitors

[0461] 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, downregulates, or blocks TNFα activity and / or expression. In some embodiments, the TNFα inhibitor is an inhibitory nucleic acid, an antibody or its antigen-binding fragment, 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.

[0462] In other examples, such indirect TNFα inhibitors can be small molecule inhibitors of signaling components downstream of the TNFα receptor (e.g., any signaling components downstream of the TNFα receptor described herein or known in the art), small molecule inhibitors of proteins encoded by TNFα-inducible genes (e.g., any proteins encoded by TNFα-inducible genes known in the art), and small molecule inhibitors of transcription factors selected from NF-κB, c-Jun, and ATF2.

[0463] TNFα inhibitory nucleic acid

[0464] Exemplary TNFα inhibitors that are 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 Cancer Institute, 1996). AcademicPublishers, Vol.4, pp.107-123, 1999; Taylor et al., Antisense Nucleic Acid DrugDevelop.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.Orthopedic 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., RNAInterference Technology From Basic Science to Drug Development 303, 2005; Xie et al., PharmaGenomics 4(6): 28-34, 2004; Aldawsari et al., Current Pharmaceutical Design21(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 pre-mRNA splicing of TNFα (e.g., Chiu et al., Mol. Pharmacol. 71(6): 1640-1645, 2007).

[0465] In some embodiments, inhibitory nucleic acids such as aptamers (eg, Orava et al., ACS Chem Biol. 2013; 8(1): 170-178, 2013) can block the binding of TNFα protein to its receptors (TNFR1 and / or TNFR2).

[0466] In some embodiments, the inhibitory nucleic acid can downregulate the expression of TNFα-induced downstream mediators (e.g., TRADD, TRAF2, MEKK1 / 4, MEKK4 / 7, JNK, AP-1, ASK1, RIP, MEKK 3 / 6, MAPK, NIK, IKK, NF-κB, p38, JNK, IκB-α, or CCL2). Further teachings of downstream TNFα-induced mediators can be found in, for example, Schwamborn et al., BMC Genomics 4:46, 2003; and Zhou et al., Oncogene 22:2034-2044, 2003, which are incorporated herein by reference. Other 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.

[0467] TNFα inhibitor antibodies

[0468] In some embodiments, the TNFα inhibitor is an antibody or an antigen-binding fragment thereof (e.g., Fab or scFv). In some embodiments, the antibodies or antigen-binding fragments described herein specifically bind to any one of TNFα, TNFR1, or TNFR2. In some embodiments, the antibodies or antigen-binding fragments of antibodies described herein can specifically bind to TNFα. In some embodiments, the antibodies or antigen-binding fragments of antibodies described herein can specifically bind to TNFα receptors (TNFR1 or TNFR2).

[0469] Non-limiting examples of TNF inhibitors that are antibodies that specifically bind to TNFα 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 Biology 295(2): 234-236, 2006. 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. DrugDiscovery 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).

[0470] In certain embodiments, the TNFα inhibitor may include or be infliximab (Remicade TM ), CDP571, CDP 870, golimumab TM ), adalimumab (Humira TM ), or certolizumab (Cimzia TM In certain embodiments, the TNFα inhibitor may be a TNFα inhibitor biosimilar. Examples of approved and late-stage TNFα inhibitor biosimilars include, but are not limited to, infliximab biosimilars such as Remsima from Celltrion / Pfizer TM and (CT-P13), GS071 from Aprogen, Flixabi from Samsung Bioepis TM (SB2), PF-0643817 from Pfizer / Sandoz, NI-071 from Nichi-Iko Pharmaceutical Co., and ABP 710 from Amgen; adalimumab biosimilars such as Exemptia from Zydus Cadila in India TM (ZRC3197), from Amgen and (ABP 501), Imraldi (SB5) from Samsung Bioepis, GP-2017 from Sandoz, Switzerland, ONS-3010 from Oncobiologics / Viropro, USA, M923 from Momenta Pharmaceuticals / Baxalta (Baxter spinoff USA), PF-06410293 from Pfizer, BMO-2 or MYL-1401-A from Biocon / Mylan, CHS-1420 from Coherus, FKB327 from Fujifilm / Kyowa Hakko Kirin (Fujifilm Kyowa Kirin Biologics), Cyltezo (BI 695501) from Boehringer Ingelheim, CT-P17 from Celltrion, BAX 923 from Baxalta (now part of Shire), and from Fresenius MSB11022 from Kabi (acquired from Merck GaA (Merck Group) in 2017), LBAL from LG Life Sciences / Mochida Pharmaceutical of South Korea / Japan, PBP1502 from Prestige Biopharma, Adfrar from Torrent Pharmaceuticals of India, biosimilars of adalimumab being developed by Adello Biologics, biosimilars of adalimumab being developed by AET Biotech / BioXpress Therapeutics of Germany / Switzerland, biosimilars of adalimumab from mAbxience of Spain, biosimilars of adalimumab being developed by PlantForm of Canada; and etanercept biosimilars such as Erelzi from Sandoz / Novartis TM , Brenzys from Samsung Bioepis TM (SB4), GP2015 from Sandoz, and Mycenax LBEC0101 from LG Life, PF-688 (certolizumab pegol biosimilar) from Pfenex, and CHS-0214 from Coherus.

[0471] In some embodiments, the TNFα inhibitor may 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 TNFα inhibitor may be PF-06480605, which specifically binds to TNFSF15 (e.g., described in U.S. Patent Application Publication No. 2015 / 0132311). Additional examples of TNFα 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 TNFα inhibitors that are antibodies or antigen-binding antibody fragments are described in, for example, WO 17 / 158097, EP 3219727, WO 16 / 156465 and WO 17 / 167997.

[0472] In some embodiments, the TNFα inhibitor is DLX-105, eg, in a gel formulation.

[0473] In some embodiments, the TNFα inhibitor is adalimumab. Adalimumab is a recombinant human IgG1 monoclonal antibody that is specific for human tumor necrosis factor and is used to treat various inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, and ulcerative colitis.

[0474] Adalimumab is currently delivered as a 40 mg subcutaneous injection in 0.4-0.8 mL every 1-2 weeks. It is marketed in a prefilled pen syringe for self-administration. Subcutaneous injection has a bioavailability of approximately 64%, a half-life of approximately 2 weeks, and intracellular catabolism is the primary mode of elimination. Adalimumab must be refrigerated but can be temporarily stored at room temperature until use.

[0475] Adalimumab is a suitable therapeutic agent for delivery via an ingestible device as described herein. It is currently available as a liquid for self-administration, and since adverse reactions at the injection site are not uncommon, patients can easily adopt alternative dosage forms. Finally, the likelihood of acute reactions to overdose is low, which theoretically could allow for increased doses to compensate for lower bioavailability compared to SC injection.

[0476] TNFα inhibitor fusion protein

[0477] In some embodiments, the TNFα inhibitory agent is a fusion protein that specifically binds to TNFα (e.g., the extracellular domain of a TNFR fused to a partner peptide, such as the 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 TNFα 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 TNFα inhibitor comprises or is r-TBP-I (e.g., Gradstein et al., J. Acquir. Immune Defic. Syndr. 26(2): 111-117, 2001). In some embodiments, the TNFα inhibitor comprises or is a soluble TNFα 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. USA 87(19):7380-7384, 1990).

[0478] In some embodiments, the TNFα inhibitor is tulinasecept.

[0479] TNFα inhibitor small molecule

[0480] In some embodiments, the TNFα inhibitor is a small molecule. In some embodiments, the TNFα 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, for example, in He et al., Science 310 (5750): 1022-1025, 2005.

[0481] In some examples, the TNFα 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 mammalian cells.

[0482] In some examples, the TNFα inhibitor is a small molecule that inhibits the activity of one of the following: 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. Patent No. 5,705,398), TRAF6 (e.g., 3-[(2,5-dimethylphenyl)amino]-1-phenyl-2-propen-1-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), IκB (e.g., Suzuki et al., Expert. Opin. Invest. Drugs 20: 395-405, 2011), NF-κB (e.g., Gupta et al., Biochim. Biophys. Acta 1799(10-12): 775-787, 2010), rac (e.g., U.S. Patent 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).

[0483] IL-1 inhibitors

[0484] In some embodiments, the 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-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, IL-38, and IL-33. In some instances, the IL-1 cytokine is IL-1α. In some instances, the IL-1 cytokine is IL-1β.

[0485] 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.

[0486] IL-1 inhibitory nucleic acid

[0487] Inhibitory nucleic acids that can reduce the expression of IL-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Rα, IL-1RL2 or IL1RL1 mRNA in mammalian cells include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of IL-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Rα, IL-1RL2 or IL1RL1 mRNA.

[0488] Examples of modified nucleotides that can be used to generate antisense nucleic acids include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluracil, dihydrouracil, β-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-methylaminomethyl Uracil, 5-methoxyaminomethyl-2-thiouracil, β-D-mannosylquenoside, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyl adenine, uracil-5-oxyacetate (v), wybutoxosine, pseudouracil, quenoside, 2-mercaptocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetate methyl ester, uracil-5-oxyacetate (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, antisense nucleic acids can be produced biologically using expression vectors into which nucleic acids have been subcloned in the antisense orientation (ie, RNA transcribed from the inserted nucleic acid will have an antisense orientation to the target nucleic acid of interest).

[0489] Inhibitory nucleic acids preferentially bind (e.g., hybridize) to nucleic acids encoding IL-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Rα, IL-1RL2, or IL1RL1 proteins to treat allergic diseases (e.g., asthma (Corren et al., N. Engl. J. Med. 365: 1088-1098, 2011)), radiation lung injury (C Hung 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).

[0490] Exemplary IL-1 inhibitors that are 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 a combination thereof. In certain embodiments, a therapeutically effective amount of an inhibitory nucleic acid targeting a nucleic acid encoding an IL-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, IL-38, IL-33, IL-1R1, IL1RAP, IL-18Rα, IL-1RL2, or IL1RL1 protein can be administered to a subject in need thereof (e.g., a human subject).

[0491] IL-1 inhibitor antibodies

[0492] In some embodiments, the IL-1 inhibitor is an antibody or an 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 ( 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 variants 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), MABp1 (Hickish et al., Lancey 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 variants thereof (Dinarello et al., Nat. Rev. Drug Discov. 11(8):633-652, 2012).

[0493] Further teachings of IL-1 inhibitors that are 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.

[0494] IL-1 inhibitor fusion protein or soluble receptor

[0495] In some embodiments, the IL-1 inhibitor is a fusion protein or a soluble receptor. For example, the fusion may include an extracellular domain of any one of IL-1R1, IL1RAP, IL-18Rα, IL-1RL2, and IL1RL1 fused to a partner amino acid sequence (e.g., a stabilizing domain, such as an IgG Fc region, such as 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-18Rα. In some embodiments, the IL-1 inhibitor is a soluble form of one or both of IL-1RL2 and IL-1RAP.

[0496] In some embodiments, the IL-1 inhibitor is a fusion protein comprising Rilonacept (IL-1Trap, ) or by Rilonacept (IL-1Trap, ) (see, e.g., Kapur & Bonk, PT 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)).

[0497] 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).

[0498] IL-1 inhibitor endogenous peptide

[0499] In some embodiments, the IL-1 inhibitor may be an endogenous ligand or an active fragment thereof, such as IL-1Ra or IL-36Ra. IL-1Ra is an endogenous soluble protein that reduces the ability of IL-1α and IL-1β to bind to their receptors (e.g., a complex of IL-1R1 and IL1RAP proteins). IL-36Ra is an endogenous soluble protein that reduces the ability of IL-36α, IL-36β, and IL-36γ to bind to their receptors (e.g., a complex of IL-1RL2 and IL-1RAP proteins). Exemplary sequences of IL-1Ra and IL-36Ra are shown below.

[0500] In some embodiments, the IL-1 inhibitor is K(D)PT.

[0501] IL-6 receptor inhibitors

[0502] In some embodiments, the 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 IL-6 receptor expression and / or the ability of IL-6 to bind to the IL-6 receptor. In some embodiments, the IL-6 receptor inhibitor targets IL-6 receptor β-subunit glycoprotein 130 (sIL6gp130). In other embodiments, the IL-6 receptor inhibitor targets the IL-6 receptor subunit (IL6R). In other embodiments, the IL-6 receptor inhibitor targets a complex composed of an IL-6 receptor subunit (IL6R) and an IL-6 receptor β-subunit glycoprotein 130 (sIL6gp130). In some embodiments, the IL-6 receptor inhibitor targets IL-6.

[0503] In some embodiments, the IL-6 receptor inhibitor is an inhibitory nucleic acid, an antibody or its antigen-binding fragment, 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.

[0504] IL-6 inhibitory nucleic acid

[0505] The antisense nucleic acid molecule can be complementary to all or part of the noncoding region of the coding strand of the nucleotide sequence encoding IL6R, sIL6gp130 or IL-6 protein. The noncoding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region of a gene and are not translated into amino acids.

[0506] 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.

[0507] Non-limiting examples of short interfering RNA (siRNA) that are inhibitors of IL-6 receptor 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 microRNA that are inhibitors of IL-6 receptor 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).

[0508] 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, for example, in WO 96 / 040157.

[0509] IL-6 inhibitor antibodies

[0510] In some embodiments, the IL-6 receptor inhibitor is an antibody or an 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 an IL-6 receptor (e.g., one or both of IL6R and sIL6gp130).

[0511] In certain embodiments, the antibody comprises or consists of an antigen-binding fragment or portion of: tocilizumab ( 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 to circulating IL-6 cytokine but not the IL-6 receptor, blocking both canonical 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.)); salirumab (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).

[0512] In some embodiments, the IL-6 receptor inhibitor is olotzumab (CDP-6038).

[0513] IL-6 inhibitor fusion protein

[0514] 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 gp130 (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).

[0515] 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 triterpenoid saponin (e.g., chikusetsuaponin IVa butyl ester (CS-Iva-Be) (Yang et al., Mol. Cancer. Ther. 15(6):1190-200, 2016).

[0516] IL-6 inhibitor small molecule

[0517] In some embodiments, the IL-6 receptor inhibitor is a small molecule (see, eg, US 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.

[0518] In some embodiments, the IL-6 receptor inhibitor is YSIL6.

[0519] IL-10 receptor agonists

[0520] In some embodiments, the 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 mammalian cells, or a nucleic acid encoding any such molecule. The receptor for IL-10 may 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 instances, 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 instances, the IL-10 receptor agonist is recombinant IL-10 (e.g., human recombinant IL-10). In some instances, the IL-10 receptor agonist is PEGylated recombinant IL-10 (e.g., PEGylated recombinant human IL-10). In some instances, the IL-10 receptor agonist is a fusion protein. In some instances, the IL-10 receptor agonist is an IL-10 peptide mimetic.

[0521] Nucleic acids and vectors encoding IL-10 receptor agonists

[0522] 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 IL-10 protein described herein). A non-limiting example of a composition comprising a nucleic acid encoding an IL-10 receptor agonist is XT-150 (Xalud Therapeutics). IL-10 inhibitor antibodies and antigen-binding fragments

[0523] In some embodiments, the IL-10 receptor agonist is an antibody or antigen-binding antibody fragment that binds to and activates the IL-10 receptor (e.g., 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., 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., human IL-10R-2 protein). In some embodiments, the antibody or antigen-binding antibody fragment specifically binds to an epitope on both IL-10R-1 and IL-10R-2 proteins (e.g., human IL-10R-1 and human IL-10R-2 proteins).

[0524] 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).

[0525] IL-10 inhibitor fusion protein

[0526] In some embodiments, the IL-10 receptor agonist is a fusion protein. In some embodiments, the fusion protein comprises the 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 may be an antibody or 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 serving as the fusion partner can specifically or preferentially bind to inflamed gastrointestinal cells, such as through CD69. In some embodiments, the IL-10 receptor agonist as a fusion protein may be, for example, F8-IL-10, such as Dekavil (Philogen).

[0527] In some embodiments, the fusion protein is L19-IL-10 fusion protein, HyHEL10-IL-10 fusion protein, or variants thereof. See, for example, Trachsel et al., Arthritis Res. Ther. 9(1): R9, 2007, and Walmsley et al., Arthritis Rheum. 39: 495-503, 1996.

[0528] In some embodiments, the IL-10 receptor agonist is RG-7880.

[0529] IL-10 peptide mimetics

[0530] 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.

[0531] recombinant IL-10

[0532] In some embodiments, the IL-10 receptor agonist is a recombinant IL-10 protein. In some embodiments, the recombinant human IL-10 protein can be enovil TM (Schering Corporation). In some embodiments, the recombinant IL-10 protein is a functional fragment of a human IL-10 protein.

[0533] In some embodiments, the IL-10 receptor agonist is rhuIL-10 (Tenovil) or a variant thereof. See, for example, 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.

[0534] Exemplary methods for producing recombinant human IL-10 are described in Pajkrt et al., J. Immunol. 158:3971-3977, 1997). Additional exemplary methods for producing recombinant IL-10 are described herein and are known in the art.

[0535] In some embodiments, the recombinant IL-10 is a polyPEGylated recombinant IL-10 (e.g., PEGylated recombinant human IL-10) (e.g., a 5 kDa N-terminally PEGylated form of IL-10; 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).

[0536] 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. USA 97(4):1695-1700, 2000; Jones et al., Proc. Natl. Acad. Sci. USA 99(14):9404-9409, 2002) or a latency-associated viral IL-10 protein (e.g., Poole et al., J. Virol. 88(24):13947-13955, 2014).

[0537] 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, the 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).

[0538] Recombinant IL-10-producing cells

[0539] In some embodiments, any device or composition described herein may include a recombinant cell (e.g., a recombinant mammalian cell) that secretes recombinant IL-10 (e.g., any recombinant IL-10 protein described herein). In some embodiments, any device or composition described herein may include a cell (e.g., a mammalian cell) that secretes IL-10 (e.g., human IL-10). In some embodiments, the mammalian cell may be a mammalian cell obtained from a subject, and after a nucleic acid encoding recombinant IL-10 (e.g., any recombinant IL-10 protein described herein) is introduced into the cell obtained from the subject, the cell is incorporated into any composition or device described herein.

[0540] Non-limiting examples of methods that can be used to introduce vectors or nucleic acids into cells (e.g., mammalian cells) include lipofection, transfection, electroporation, microinjection, calcium phosphate transfection, dendrimer-based transfection, cationic polymer transfection, cell squeezing, sonoporation, optical transfection, puncture, hydrodynamic delivery, magnetofection, viral transduction (e.g., adenoviral and lentiviral transduction), and nanoparticle transfection. These and other methods for introducing vectors or nucleic acids into cells are well known in the art.

[0541] In some examples, the recombinant mammalian cell can be a Chinese hamster ovary (CHO) cell, a B cell, a CD8 + T cells, dendritic cells, keratinocytes, or epithelial cells. See, for example, 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 may be a mesenchymal stem cell (e.g., Gupte et al., Biomed. J. 40(1):49-54, 2017).

[0542] Additional Examples of IL-10 Inhibitors

[0543] 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. Heptal. 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).

[0544] In some embodiments, the IL-10 receptor agonist is a cell (e.g., Clostridium butyricum cell) that induces different cells (e.g., macrophages) to produce and secrete IL-10 (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., Lactobacillus acidophilus cell) that lacks lipoteichoic acid and induces different cells (e.g., dendritic cells) to produce and secrete IL-10 (e.g., Mohamadzadeh et al., Proc. Natl. Acad. Sci. USA 108(suppl 1):4623-4630, 2011; Konstantinov et al., Proc. Natl. Acad. Sci. USA 105(49):19474-9, 2008). In some embodiments, the IL-10 receptor agonist is a bacterial cell or a fragment of a bacterial cell maintained in a supernatant that induces IL-10 secretion in a different cell (e.g., an immune cell) (e.g., Faecalibacterium prausnitzii cells or Faecalibacterium prausnitzii supernatant) (see, e.g., Sokol et al., Proc. Natl. Acad. Sci. USA 105(43):16731-16736, 2008).

[0545] Additional examples of other IL-10 receptor agonists are described in, for example: US Patent No. 6,936,586; WO 96 / 01318; WO 91 / 00349; and WO 13 / 130913; each of which is herein incorporated by reference in its entirety.

[0546] IL-12 / IL-23 inhibitors

[0547] 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 IL-12 or IL-23 expression and / or the ability of IL-12 to bind to the IL-12 receptor or the ability of IL-23 to bind to the 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 (p19). In some embodiments, the IL-12 / IL-23 inhibitory agent targets the receptor for IL-12 (one or both of IL-12Rβ1 or IL-12Rβ2). In some embodiments, the IL-12 / IL-23 inhibitory agent targets the receptor for IL-23 (either or both IL-12Rβ1 and IL-23R).

[0548] 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).

[0549] Non-limiting examples of siRNAs targeting IL-12A (p35), IL-12B (p40), IL-23 (p19), IL-12Rβ1, IL-12Rβ2, or IL-23R are described in Tan et al., J. Alzheimers Dis. 38(3):633-646, 2014; Niimi et al., J. Neuroimmunol. 254(1-2):39-45, 2013. Non-limiting examples of short hairpin RNAs (shRNAs) targeting IL-12A (p35), IL-12B (p40), IL-23 (p19), IL-12Rβ1, IL-12Rβ2, or IL-23R are described in Bak et al., BMC Drug. 11:5, 2011.

[0550] 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).

[0551] IL-12 / IL-23 inhibitor antibodies

[0552] In some embodiments, the IL-12 / IL-23 inhibitor is an antibody or an 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 the following: IL-12A (p35), IL-12B (p40), IL-23 (p19), IL-12Rβ1, IL-12Rβ2, or IL-23R, or a combination thereof.

[0553] In some embodiments, the antibody is Ustekinumab (CNTO 1275, ) or variants 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).

[0554] 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, in: American Academy of Dermatology, March 21-25, Denver CO, 2014); AMG 139 (MEDI2070, brevituzumab) (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.

[0555] 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.

[0556] In some embodiments, the IL-12 / IL-23 inhibitor is PTG-200, an IL-23R inhibitor currently in preclinical development by Protagonist Therapeutics.

[0557] In some embodiments, the IL-12 / IL-23 inhibitor is migizone (LY 3074828), an IL-23R inhibitor currently in clinical development (Phase II) by Eli Lilly.

[0558] In some embodiments, the IL-12 / IL-23 inhibitor is AK-101.

[0559] In some embodiments, the IL-12 / IL-23 inhibitor is a bispecific antibody, such as IL-23 / CGRP, which is currently in clinical development (Phase I1) by Eli Lilly.

[0560] IL-12 / IL-23 inhibitor fusion protein

[0561] 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 the extracellular domain of a receptor for IL-12 or the extracellular domain of a receptor for IL-23.

[0562] 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 human IL-23Rα-chain mRNA transcript (Raymond et al., J. Immunol. 185(12):7302-7308, 2010). In some embodiments, IL-12 / IL-23 is an antimicrobial peptide (e.g., MP-196 (Wenzel et al., PNAS 111(14):E1409-E1418, 2014)).

[0563] IL-12 / IL-23 inhibitor small molecule

[0564] 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).

[0565] IL-13 inhibitors

[0566] In some embodiments, a therapeutic agent 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 IL-13 binding to the IL-13 receptor. In some embodiments, the IL-13 inhibitor reduces the ability of IL-13 to bind to the IL-13 receptor (e.g., a complex comprising IL-4Rα and IL-13Rα1, or a complex comprising IL-13Rα1 and IL-13Rα2).

[0567] 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 various aspects of these inhibitory nucleic acids are described below. Any example of an inhibitory nucleic acid that can reduce the expression of IL-13, IL-13Rα1, IL-13Rα2, or IL-4Rα mRNA in mammalian cells can be synthesized in vitro.

[0568] Non-limiting examples of short interfering RNAs (siRNAs) that are 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) that are 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).

[0569] In some embodiments, the inhibitory nucleic acid may be a microRNA. A non-limiting example of a microRNA that is an IL-13 inhibitor is let-7 (Kumar et al., J. Allergy Clin. Immunol. 128(5): 1077-1085, 2011).

[0570] IL-13 inhibitor antibodies

[0571] In some embodiments, the IL-13 inhibitor is an antibody or an antigen-binding fragment thereof (e.g., Fab or scFv). In some embodiments, the antibody or antigen-binding fragment described herein specifically binds to any one of the following: IL-13, IL-13Rα1, IL-13Rα2, or IL-4Rα, or a combination thereof. In some embodiments, the antibody or antigen-binding fragment of the antibody described herein can specifically bind to IL-13. In some embodiments, the antibody or antigen-binding fragment of the antibody described herein can specifically bind to an IL-13 receptor (e.g., a complex comprising IL-4Rα and IL-13Rα1, or a complex comprising IL-13Rα1 and IL-13Rα2).

[0572] In some embodiments, the IL-13 inhibitor is a monoclonal antibody (Bagnasco et al., Int. Arch. Allergy Immunol. 170: 122-131, 2016). In some embodiments, the IL-13 inhibitor is QAX576 (Novartis) or an antigen-binding fragment thereof (see, e.g., Kariyawasam et al., B92 New Treatment Approaches for Asthma and Allergy San Diego, 2009; Rothenberg et al., J. Allergy Clin. Immunol. 135: 500-507, 2015). In some embodiments, the IL-13 inhibitor is ABT-308 (Abbott) or an antigen-binding fragment thereof (see, e.g., Ying et al., American Thoracic Society 2010 International Conference, May 14-19, 2010, New Orleans; Abstract A6644). In some embodiments, the IL-13 inhibitor is CNTO-5825 (Centrocore) or an antigen-binding fragment thereof (see, e.g., van Hartingsveldt et al., British J. Clin. Pharmacol. 75: 1289-1298, 2013). In some embodiments, the IL-13 inhibitor is dupilumab (REGN668 / SAR231893) or an antigen-binding fragment thereof (see, e.g., Simpson et al., N. Eng. J. Med. 375: 2335-2348, 2016; Thaci et al., Lancet 387: 40-52, 2016). In some embodiments, the IL-13 inhibitor is AMG317 (Amgen) or an antigen-binding fragment thereof (Polosa et al., Drug Discovery Today 17:591-599, 2012; Holgate, British J. Clinical Pharmacol. 76:277-291, 2013). In some embodiments, the IL-13 inhibitor is an antibody that specifically binds to IL-13Rα1 (see, e.g., U.S. Patent No. 7,807,158; WO 96 / 29417; WO 97 / 15663; and WO 03 / 080675).

[0573] In some embodiments, the IL-13 inhibitor is a humanized monoclonal antibody (e.g., lebrikizumab (TNX-650) (Thomson et al., Biologics 6:329-335, 2012; and Hanania et al., Thorax 70(8):748-756, 2015). In some embodiments, the IL-13 inhibitor is an anti-IL-13 antibody, e.g., GSK679586 or a variant thereof (Hodsman et al., Br. J. Clin. Pharmacol. 75(1):118-128, 2013; and De Boever et al., J. Allergy Clin. Immunol. 133(4):989-996, 2014). In some embodiments, the IL-13 i...

Claims

1. An ingestible device comprising: shell; a storage reservoir within the housing, the storage reservoir configured to store a dispensable liquid; at least one nozzle in fluid communication with an opening in the housing, the opening in fluid communication with the storage reservoir; a driving force generator in the housing for applying a driving force to the dispensable liquid; a trigger mechanism configured to cause the dispensable liquid to be released under a trigger condition; and a piston in the housing for transmitting a driving force from the driving force generator to the dispensable liquid such that when the driving force generator is actuated, the driving force is applied to the piston; wherein the driving force generator comprises compressed gas which, when released, acts on the piston to provide a jet of dispensable liquid exiting the nozzle; and Wherein the compressed gas has an initial gas pressure of at least 500 psig.

2. The ingestible device of claim 1, wherein the compressed gas has an initial gas pressure of at least 600 psig.

3. The ingestible device of claim 2, wherein the compressed gas has an initial gas pressure of at least 700 psig.

4. The ingestible device of claim 3, wherein the compressed gas has an initial gas pressure of at least 750 psig.

5. The ingestible device of claim 4, wherein the compressed gas has an initial gas pressure of at least 800 psig.

6. The ingestible device of claim 5, wherein the compressed gas has an initial gas pressure of at least 850 psig.

7. The ingestible device of claim 6, wherein the compressed gas has an initial gas pressure of at least 900 psig.

8. The ingestible device of claim 1, wherein the compressed gas has an initial gas pressure of at most 1200 psig.

9. The ingestible device of claim 1, wherein the compressed gas is a gas container and the gas container has a gas volume of 150 μL to 175 μL.

10. The ingestible device of claim 1, wherein the nozzle has a length of 0.2 to 2 mm.

11. The ingestible device of claim 1 , wherein the driving force produces an average ejection power of 0.5 watts to 2 watts.

12. The ingestible device of claim 1, further comprising a restraint mechanism having: a first state in which the restraint mechanism prevents the liquid from being delivered out of the ingestible device, and a second state in which the restraint mechanism does not prevent the liquid from being delivered out of the ingestible device.

13. The ingestible device of claim 12, wherein the restraint mechanism comprises a dissolvable material.

14. The ingestible device of claim 12, wherein the restraining mechanism comprises an enteric material.

15. The ingestible device of claim 12, wherein the restraint mechanism comprises a degradable material.

16. The ingestible device of claim 12, wherein the restraint mechanism comprises an erodible material.

17. The ingestible device of claim 12, wherein the restraint mechanism comprises a seal.

18. The ingestible device of claim 12, wherein the restraint mechanism comprises a pin.

19. The ingestible device of claim 12, wherein the restraint mechanism comprises a strap.

20. The ingestible device of claim 12, wherein the restraint mechanism comprises a pin.

21. The ingestible device of claim 12, wherein the restraint mechanism comprises a buckle.

22. The ingestible device of claim 12, wherein the restraint mechanism comprises a clamp.

23. The ingestible device of claim 12, wherein the restraint mechanism comprises a flange.

24. The ingestible device of claim 12, wherein the restraining mechanism comprises a rivet.

25. The ingestible device of claim 12, wherein the driving force generator further comprises a spring configured to act on a piercing element, and when the driving force generator is actuated, the piercing element is constrained by the constraint mechanism until the ingestible device is actuated, whereupon the piercing element pierces the gas container, allowing the compressed gas to flow out of the gas container and act on the piston.

26. The ingestible device of claim 1, wherein the at least one nozzle is configured to direct the dispensable substance perpendicular to a longitudinal axis of the ingestible device.

27. The ingestible device of claim 1, further comprising a seal between the piston and the housing.

28. The ingestible device of claim 1, further comprising an element having a first state and a second state, wherein in the first state the element at least partially covers the opening in the housing, and in the second state the element does not cover the opening in the housing, wherein the ingestible device is configured such that when the piston moves, the element moves from its first state to its second state.

29. The ingestible device of claim 1, wherein the dispensable liquid has a viscosity of 1 centipoise to 50 centipoise.

30. The ingestible device of claim 1, wherein the nozzle has an opening diameter of 0.1 to 0.5 mm.

31. The ingestible device of claim 1, wherein when the driving force generator is actuated, the driving force is applied to the piston to produce a peak fluid pressure of the dispensable liquid of 150 psig to 400 psig.

32. The ingestible device of claim 1, wherein when the driving force generator is actuated, the driving force is applied to the piston causing the dispensable liquid to be delivered through the at least one nozzle, the dispensable liquid having a minimum ejection velocity of 15 m / s to 22 m / s.

Images