Ingestible drug delivery device

Abstract

An ingestible device has a liquid within a housing. A piston is longitudinally movable within the housing. A drive force generator comprising compressed gas or a spring, exerts a drive force on a release component. The release component may have an annular surface held against a holding ring at an end of the housing. The release component resists the drive force before the ingestible device is ingested, and the release component releases the drive force to act on the piston after the ingestible device is ingested. The fast release of the drive force results in one or more jets of the liquid into the gastrointestinal tract of a patient.

Description

INGESTIBLE DRUG DELIVERY DEVICECROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims priority to and benefit of U.S. Provisional Application No. 63 / 580,213, filed September 1 , 2023, titled TRIGGER ASSEMBLY FOR INGESTIBLE DRUG DELIVERY DEVICE, U.S. Provisional Application No. 63 / 584,466, filed September 21 , 2023, titled INGESTIBLE DRUG DELIVERY DEVICE, and U.S. Provisional Application No. 63 / 654,834, filed May 31 , 2024, titled INGESTIBLE DRUG DELIVERY DEVICE, the disclosures of which are incorporated herein by reference in their entireties.TECHNICAL FIELD

[0002] The field of the invention is ingestible devices for delivery of a drug to the gastrointestinal tract.BACKGROUND OF THE INVENTION

[0003] Ingestible devices have been developed for delivery of a drug to the gastrointestinal tract, such as described in U.S. Patent Application Publication US20230017603A1 and International Patent Application PCT / US2023 / 064716, (both incorporated by reference for the U.S. National Phase only). In these types of devices, a release component or trigger dissolves in the stomach or intestines after the device is swallowed, causing the device to actuate. In some devices actuation results via the dissolved trigger releasing a piercer which pierces a compressed gas container. The released compressed gas drives a piston to create one or more liquid jets providing topical, epithelial, or trans-epithelial drug delivery. Still, engineering challenges remain in achieving improved performance.BRIEF STATEMENT OF THE INVENTION

[0004] An ingestible device has a liquid within a housing. A piston is longitudinally movable within the housing. A drive force generator comprising compressed gas or aspring, exerts a drive force on a release component. The release component may have an annular surface held against a holding ring at an end of the housing. The release component resists the drive force before the ingestible device is ingested, and the release component releases the drive force to act on the piston after the ingestible device is ingested. The fast release of the drive force results in one or more jets of the liquid into the gastrointestinal tract of a patient.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Fig. 1 is a perspective section view of an ingestible device.

[0006] Fig. 2 is an elevation section view of another embodiment of an ingestible device.

[0007] Fig. 3 is an exploded perspective view of the device of Fig. 2.

[0008] Fig. 4 is another exploded perspective view of the device shown in Fig. 3.

[0009] Fig. 5 is a perspective section view of the trigger or release component assembly shown in Fig. 1.

[0010] Fig. 6 is a line drawing of the section view of Fig. 5 with added dimensions.

[0011] Fig. 7 is a top end perspective view of the release component support shown in Figs. 1 and 5.

[0012] Fig. 8 is a plan view of the release component support shown in Fig. 7.

[0013] Fig. 9 is a side view of the release component support shown in Figs. 7 and8.

[0014] Figs. 10A-10E are side views of alternative release component supports having different heights.

[0015] Fig. 11 A is a section view of a release component support with a compression washer.

[0016] Fig. 1 1 B is a top perspective section view of the compression washer shown in Fig. 1 1 A.

[0017] Fig. 12A is a side view of an ingestible device having a flex crown.

[0018] Fig. 12B is section view of the ingestible device of Fig. 12A.

[0019] Fig. 12C is section view of the ingestible device of Figs. 12A and 12B, now in the actuated position.

[0020] Fig. 12D is a section view of an ingestible device having no flex crown, shown for comparison.

[0021] Fig. 12E is a top perspective view showing the release component and flex crown of Fig. 12A.

[0022] Fig. 12F is a top plan view of the ingestible device as shown in Fig. 12E.

[0023] Fig. 12G is a top perspective view of the ingestible device as shown in Fig.12E with the release component removed for purpose of illustration.

[0024] Fig. 12H is a top plan view of the ingestible device as shown in Fig. 12G.

[0025] Fig. 13A is side view of alternative embodiment of an ingestible device having a raised release component housing collar.

[0026] Fig. 13B is a section view of the ingestible device of Fig. 13A.

[0027] Fig. 13C is a top perspective view of the ingestible device of Fig. 13A.

[0028] Fig. 13D is a top view of the ingestible device of Fig. 13A showing the raised release component housing collar as circumferentially spaced apart arc segments.

[0029] Fig. 13E is a top perspective view of the ingestible device of Fig. 13A with the release component removed for purpose of illustration.

[0030] Fig. 13F is a top view of the ingestible device as shown in Fig. 13E.

[0031] Fig. 14A are graphs of jet force over time for seven samples using a parylene coated nozzle cover.

[0032] Fig. 14B are graphs of additional test samples.

[0033] Fig. 14G are graphs of jet force over time for test samples having a release component support of a first height as shown in Fig. 10C.

[0034] Fig. 14D are graphs of jet force over time for test samples having a release component support of a second height as shown in Fig. 10D.

[0035] Fig. 15 are graphs of bioavailability of semaglutide over time in Yucatan pig test samples.

[0036] Fig. 16 are graphs of jet force over time for test samples having design parameters resulting in less preferred results.

[0037] Fig. 17 are graphs of jet force over time for three samples using a flex crown.

[0038] Figs. 18A and 18B show the nozzle cover of Fig. 1 with dimensions provided in millimeters.

[0039] Figs. 19A-19D show a method for assembling a gas container and a valve assembly.

[0040] Fig. 19A is a perspective view separately showing a keeper and the gas container.

[0041] Fig. 19B shows the keeper installed on the gas container.

[0042] Fig. 19C shows mounting of a valve assembly to the gas container.

[0043] Fig. 19D is a section view of the assembled device, with the keeper holding the valve assembly into the gas container.

[0044] Fig. 20A-20D show a method for assembling an end cap with a release component onto the container and valve assembly shown in Fig. 19D.

[0045] Fig. 20A is a side view of a valve assembly O-ring and the end cap placed on the valve assembly shown in Fig. 19D.

[0046] Fig. 20B is a section view of the valve assembly O-ring now moved up against the valve flange, and the end cap snapped onto the flange of the container.

[0047] Fig. 20C is a perspective view of the device as shown in Fig. 20B.

[0048] Fig. 20D is a side view showing removal of the keeper.

[0049] Fig. 21 A is a side view of a method for assembling the container and end cap valve assembly or drive module of Fig. 20D with a filled and assembled drug module.

[0050] Fig. 21 B is a side view showing the completed device, ready for use.

[0051] Fig. 21 C is a side view of the completed with the drive and drug modules attached together by laser welding.

[0052] Fig. 21 D is an enlarged detail of the laser welding joint of Fig. 21 C.

[0053] Fig. 21 E shows a side view of a completed device with the drive and drug modules attached together by screw threads.

[0054] Fig. 21 F is a section view showing operation of the completed device shown in Fig. 21 B.

[0055] Figs. 22A-22G show an actuation sequence of the device of Fig. 21 B.

[0056] Fig. 22A is a section view of the device of Fig. 21 B before actuation.

[0057] Fig. 22B shows a first actuation stage.

[0058] Fig. 22C shows a second actuation stage.

[0059] Fig. 22D shows a third actuation stage.

[0060] Fig. 22E is a schematic diagram of the jet cap O-ring of Fig. 22D before actuation.

[0061] Fig. 22F is a schematic diagram of the jet cap O-ring of Fig. 22D, after actuation.

[0062] Fig. 22G is a section view of the device of Fig. 21 B in a subsequent actuation stage, during drug delivery.

[0063] Fig. 22H is an enlarged detail view of the drive module of Figs. 22A to 22H.

[0064] Fig. 22I shows the jet cap of Fig. 22A in more detail.

[0065] Fig. 22J shows an alternative jet cap with a double O-ring.

[0066] FIGS. 23A-23F show devices having a gas container cap.

[0067] FIGS. 24A-24I show devices with a piercer coupled to a gas container.

[0068] FIGS. 25A-25E show devices with a breakaway cap.

[0069] FIGS. 26A and 26B show devices using a two-piece gas container.

[0070] FIGS. 260 and 26D show a device having a release component holding a cylinder cap in sealed engagement with a gas container.

[0071] FIGS. 27A-27D show devices having a release component and valves including O-rings.

[0072] Figs. 28A and 28B show an example of a release component with representative dimensions.

[0073] Figs. 29A and 29B show apparatus for testing dry and wet release components.

[0074] Figs. 30A and 30B show an embodiment of the jet cap wherein the one or more O-rings are not placed on the one or more nozzles, thereby leaving the nozzles unsealed but sealing the drug payload in the storage reservoir.

[0075] Figs. 31 A, 31 B, 31 C and 31 D show an embodiment wherein the one or more nozzles are placed in the jet cap rather than the drug module housing thereby adding volume to the storage reservoir, using either one or two O-rings, as shown.

[0076] Figs. 32A, 32B, 320 and 32D show an alternative end cap valve assembly wherein round or cylindrical shaped elements, for example ball bearings, are incorporated into the valve design.

[0077] Fig. 33 shows another end cap valve assembly that accommodates gas that may permeate through the piston or primary O-ring 252 which seals the gas container.

[0078] Fig. 34 is a box plot showing Instron testing of dry uncoated release components.DETAILED DESCRIPTION

[0079] The present drug delivery devices, shown for example in Figs. 21 A-22J, are intended to be swallowed to deliver a payload into gastrointestinal (Gl) tissue via one or more liquid jets. The payload is typically a drug that is deposited into one or more layers of the gastrointestinal tissue, for example, the submucosa. After deposition, the drug isabsorbed into systemic circulation, for example, as measured by the drug’s bioavailability. The drug may be a large molecule with a bioavailability less than 1% when administered orally without a device. The drug may be a large molecule greater than about 2,000 or 3,000 Daltons (Da). In some embodiments, the drug bioavailability when administered using the device described herein is greater than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to intravenous administration.

[0080] In some embodiments, the size of the device is approximately the size of a 00-sized capsule or smaller, with an overall length of about 23 mm, or less, and an external diameter of about 8.5 mm, or less. In some embodiments, the device has an overall density when ready to use of greater than 1000 kg / m3.

[0081] The device has at least one jet nozzle and typically two or more jet nozzles that may be equidistance apart, for example, two nozzles are 180 degrees apart as shown in Fig. 22D. In some embodiments, the jet nozzle diameter is about 0.3 to 0.4 mm, and the jet nozzle length is about 0.5 to 0.9 mm or 0.6 to 0.8 mm.

[0082] In some embodiments, the liquid jet delivered via the jet nozzles has a Time To Peak Force of less than 1 ms, as measured from a nozzle standoff distance of 5mm at a temperature of 23°C ± 5°C. The device may produce a liquid jet with a Peak Force Value of about 300 to 500 mN or about 350 to 450 mN, optionally with variation less than about 15%. In some embodiments, the device produces a liquid jet with an Average Force Value of about 200 mN to 300 mN and variation less than 15% between 2-5 ms, as measured from a nozzle standoff distance of 5 mm at a temperature of 23°C ± 5°C. In some embodiments, the device produces a liquid jet with a force, measured between 5- 20 ms, that is at least about 90% of the average force measured between 2-5 ms and not less than about 80% at the end of the jet injection before the jet force rapidly drops about 50% or more in the final about 10 ms of the deposition, as measured from a nozzle standoff distance of 5 mm at a temperature of 23°C ± 5°C. Figs. 14A-D show exemplary Jet Force Profiles.

[0083] The devices are configured to not actuate in the stomach of a subject for at least about 1 -hour, 2-hours, 3-hours, 4-hours, or 5-hours, and may actuate in the smallintestine of a human in at least about 15-minutes, 30-minutes, 45-minutes, 60-minutes or more.

[0084] As shown in Figs. 1 and 2, the housing 1 of an ingestible device 10 may include a connector 38 in between a drive module 44 and a drug module 30. A storage reservoir or space 39 within the drug module 30 contains a liquid drug. A nozzle cover 33 may optionally be provided in the drug module 30 as shown in Fig. 1 , or over the drug module, as shown in Fig. 3, wherein the nozzle cover prevents the liquid from exiting the drug module via the nozzles prior to device actuation. The housing may have a length LL of about 20 mm to about 27 mm, as measured from the front end of the drug module to the back end 62 of the drive module 44, as shown in Figs. 1 and 6. The housing 12 may have a diameter AA of about 8 to 1 1 mm. Referring momentarily to Figs. 18A and 18B, the nozzle cover 33 may have a concave radius CR of about 3.8 to 4.4 mm, and an outer cylindrical edge OC with a length of about 0.4 to 0.6 mm.

[0085] The nozzle cover 33 may comprise a protective coating, such as parylene coating. The protective coating may serve to waterproof, add dry lubricity, or enhance the barrier between the nozzle cover and the drug module 30, thereby reducing evaporation or leakage of the liquid drug from the drug module. Methods for applying parylene are well known and include chemical vapor deposition in an atmosphere of the monomer para-xylylene. Jet force profiles for five devices with parylene coated nozzle covers are shown in Fig. 14A.

[0086] Parylene is the trade name for the chemical vapor-deposited poly(p-xylylene) polymers, which can be used as moisture and dielectric barriers. Other alternatives to Parylene (XY) coating include Fluoropolymer (FC) coating (e.g., FluroTec film from West Pharmaceuticals, Exton PA, USA), Atomic layer deposition (ALD), and Molecular vapor deposition (MVD). In some embodiments, the Parylene-coating is done with Parylene C at a coating thickness of about 0.5 to 2um. Parylene C is produced from the same raw material (dimer) as Parylene N, modified only by the substitution of a chlorine atom for one of the aromatic hydrogens. Parylene C has a low permeability to moisture and corrosive gases.

[0087] As shown in Figs. 2-6, the ingestible device 10 may include one or more nozzles 31 in the drug module 30, a gas container or cylinder 40, and a piston 32 having piston seal 34 which slides and seals against an inner surface of the drug module 30 when the device 10 is actuated. A spring 48 exerts force on a piercer 50 which is positioned to pierce a seal on the gas container 40. A piercer seal or O-ring 52 provides a sliding seal between the piercer 50 and the release component housing . A trigger or release assembly 60 prevents movement of the piercer 50 until the device is actuated. Correspondingly, the ingestible device is configured so that the drug (e.g., formulated as a liquid formulation) in the drug module 30 is not under pressure until the device is actuated, after the user swallows the ingestible device. As shown in Fig. 3, a retention element 42 may be used to position the gas container 40. As shown in Fig. 5, a cylindrical surface or section 76 of the release component support 70 may contact and be held against a circumferential ring 58 on the piercer 50. Alternatively, as shown in Fig. 6, the cylindrical section 76 may be spaced apart from a circumferential ring 58 on the piercer.

[0088] The release assembly 60 may include a release component support 70 and a release component 66. In the design shown, the release component support 70 has internal screw threads engaged with a threaded back end of the piercer 50. This prevents forward movement of the piercer 50 via the spring 48 (to the left in Figs. 2-4) until the release component 66 is no longer intact, that is, until the release component at least partially dissolves, erodes, softens, weakens or disintegrates, when the device reaches an appropriate location in the Gl tract (e.g., due to liquid absorption, pH, change in pH, presence of certain enzyme, and / or concentration of certain enzyme). When the release component 66 is no longer intact, it cannot hold back the force of the spring 48, and the device actuates.

[0089] Performance is improved if the release assembly 60 releases in a single, catastrophic step. This allows the spring 48 to quickly and smoothly accelerate the piercer 50 into the seal (or septum) of the gas container 40 in single step movement. The compressed gas is then released substantially instantaneously driving the piston 32 toward the front end of device to displace the nozzle cover 33 and generate one or more jets of liquid.

[0090] The shape of the release component support 70 as shown in Figs. 6 and 9 contributes to single step movement. In Fig. 6, when used with a housing 12 having a diameter of 8 to 11 mm or 9.5 to 10.5 mm, the flange 84 of the release component support 70 has a diameter CC of about 3.5 mm to 5.5 mm or 4.3 to 4.7 mm. Referring to Fig. 9, the minimum diameter of the first conical surface 72 has a diameter GG of about 3.3 mm to 3.9 mm or 3.5 to 3.7 mm. A second conical surface 74 is joined to or integral with the first conical surface 72. The diameter HH of the lower cylindrical surface 76 is about 2.3 mm to 2.9 mm or about 2.5 to 2.7 mm.

[0091] The included angle EE of the first conical surface 72 is about 89° to 99° or about 92° to 95°. The height of the surfaces described above, shown as dimensions J J, KK and LL in Fig. 9 are, for JJ: about 1 .6 mm to 2.4 mm or about 1 .8 mm to 2.2 mm; for KK about 1 .0 mm to 1 .6 mm or about 1 .2 mm to 1 .4 mm; and for LL: 0.6 to 11 mm or about 0.7 mm to 0.9 or 1 mm. Referring to Figs. 7 and 8, the release component support 70 may have a curved top surface with intersecting tool slots 82. As shown in Fig. 9, the second conical section 74 has an included angle which is 6 to 20° less than angle EE.

[0092] Referring to Figs. 10A-10E, the overall height JJ of the release component support 70 may vary for example by increasing the height (or length) NN of the cylindrical section 76, with the other dimensions optionally remaining as described above. In these examples, dimension JJ in Figs. 10A-10E is 1.76; 1.86; 1.96; 2.06 and 2.16 mm, respectively.

[0093] The release component support 70 interacts with the release component 66 to actuate the device with a single step movement. In addition to the shape of the release component support 70 as described above, the size of the release component support 70 relative to the release component 66 also contributes toward singe step movement. For example, in Fig. 6 with a housing 12 having a diameter AA of 9.5 mm, the release component 66 may have an outer diameter BB of 6.6 mm and an inner diameter DD of 3.2 mm, with the flange 84 of the release component support 70 having a diameter CC of 5.1 mm. In this example, the ratio of CC / AA is nominally 0.54 or about 0.5 to 0.6, correspondingly the ratio of CC / BB is nominally 0.77 or about 0.6 to 0.8 or 0.9. Similarly, the ratio of CC / DD is nominally 1 .6 or about 1 .4 to 1 .8.

[0094] The effects of the release component support to release component ratio are shown in Fig. 11 A, wherein the smaller ratio allows for greater biological fluid access to the release component. The smaller ratio also creates a radial vector force that helps displace the release component away from the flat surface of housing as the release component degrades in the Gl tract.

[0095] As shown in Figs. 11 A-13E, shear or stress elements may be added underneath the release component to improve actuation of the device with a single step movement. In Fig. 11 A, a compression washer 90 is introduced underneath the release component , which allows for the passage of biological fluid between the housing and the washer. The release component 66 may rest on top of the compression washer 90, with the bottom surface of the release component spaced apart from the end of the housing 62. The compression washer 90 may have an angled surface 92 complimentary to an angled annular surface 94 on the end of the housing 62. The compression washer 90 may also have a raised inner flange 96 centered around a collar 98 on the piercer 50. Holes may be added to the compression washer to allow for greater or more uniform fluid access to the release component, for further hydration of the release component. On a circumference outside of the holes, as shown in Fig. 1 1 B, raised sharp points 97 may be used to induce circumferential stress on the release component to better break up the release component. As the torque on the release component support increases (1 ), contact is made with the compression washer and the compression washer lifts upward providing additional stress on the release component via the raised features on the washer.

[0096] Figs. 12A-G show another embodiment wherein a raised feature, or flex crown 102, is added underneath the release component. The flex crown 102 allows for increased hydration or more uniform hydration of the release component. The crown may include one or more ribs or other features that serve to apply concentrated pressure on the release component, which helps contribute to actuation of the device with a single step movement. The ribs 104 of the flex crown may be angled or slanted, which also helps to break up the release component and direct debris from the degrading release component away from the housing and release component support. Also, the crown maybe made of material the allows for moderate flex or compression, thereby increasing stability of the release component prior to oral administration. In the example of Figs. 12A- 12G, four equally spaced apart radial ribs 104 are used. The ribs 104, if used, provide discrete lines of contact with the release component. In Fig. 12D, a flat end of the release component housing is designed to capture the release component

[0097] Figs. 13A-F show another embodiment wherein raised release component housing elements or lugs 110 are incorporated into the release component housing. The lugs 1 10 apply concentrated pressure on the release component, leading to actuation of the device with a single step movement. For all the above embodiments, components added to improve actuation of the device may be separate parts added to the release component housing, or parts that are added to the release component housing to make a single part.

[0098] EXAMPLE 1

[0099] Jet force rig (JFR) testing was carried out on different configurations of ingestible devices for jet delivery. The tested devices were made of plastic parts (e.g., polycarbonate) connected with LIV adhesive. The release component was uncoated to facilitate faster releasing during testing. Except where indicated elsewhere, the nominal gas container fill was 17.2 mg , which produces a drive pressure (pressure acting on the piston) of approximately 350 PSI. Where indicated in the Examples and Figures, the devices include nozzle covers, which seal the nozzles during storage and during passage through the stomach and are subsequently displaced to allow jet delivery after releasing. In some instances, the nozzle covers are parylene-coated. A nozzle cover may alternatively be referred to as a second piston.

[0100] Jet Rig Methods

[0101] Below is a summary of the jet force rig hardware and setup used to measure jet performance:1 . Jet Force Rig System Equipment Setupa. Power up the Charge Meter (Kistler) and open PicoScope software (VER6) on the laptop. Ensure the laptop is connected the both the Charge Meter and the Jet Force Rig fixture. b. Load one (1 ) device into Jet Force Rig fixture and visually align the nozzle of the device to the sensor of the fixture. Ensure the nozzle is positioned in proximity to the Jet Force Rig sensor (Kistler) within 5 mm from the device nozzle. An exemplary jet force sensor is the Piezoelectric Low Force Sensor from Kistler.2. Start hyper-spectral video (HSV) camera recording.3. Fill the Prototype Mount connected to the device with tap water to initiate the process of device releasing or triggering. Start timer once the device is exposed to water. Observe the device releasing. Stop the timer once the device releases and stop camera recording. Record the following data as per Jet Force Rig operating procedure: a. Jet impact force profile b. Peak Force (from force profile) c. Time to Peak Force (from force profile) d. Jet Delivery Time (from force profile and timer) - also called Deployment Time.4. Once device actuation is complete, turn off HSV Camera and save captured video.

[0102] Jet Rig Results (“JFR”) - 'More Preferred' JFR Data vs. 'Less Preferred' JFR Data

[0103] Referring to Fig. 14B, 'More Preferred' JFR Data resulted with the following configuration:• 350 PSI internal pressure• 0.35 mm nozzle diameter• 2 radial nozzles• Parylene-coated nozzle cover version F• 4.5 mm release component support diameter• 1 .9 mm release component support height• N=4 devices tested

[0104] As shown in Fig. 14B, the JFR profiles for all four devices reach peak force in 5 milliseconds (ms) or less, then gradually decrease before a sharp drop off after about 30 ms (i.e., the deployment time). These JFR profiles may provide improved in vivo performance as measured by bioavailability. Fig. 14A shows similar JFR profiles.

[0105] EXAMPLE 2

[0106] Jet Rig Results - JFR Data Using Parylene-Coated Nozzle Covers

[0107] Ingestible devices with parylene-coated nozzle covers were tested using the jet force rig described above. The ingestible devices were further configured as follows:• 350 PSI internal pressure or drive pressure• 0.35 mm nozzle diameter• 2 radial nozzles• Parylene-coated nozzle cover version F• 4.5 mm release component support diameter• 1 .9 mm release component support height• N=7 devices tested

[0108] As shown in Fig. 14A, the JFR profiles reach peak force in less than 5 ms and have a deployment time greater than 30 ms. This device configuration can provide improved bioavailability.

[0109] EXAMPLE S

[0110] JFR Data Using Trigger Supports of Varying Neck Length:

[0111] Ingestible devices with trigger supports of varying heights as shown in Fig. 10C and. Fig. 10D were tested using the jet force rig described above. The ingestible devices were further configured as follows:• 350 PSI internal pressure or drive pressure• 0.35 mm nozzle diameter• 2 radial nozzles• Parylene-coated nozzle cover version F• 4.5 mm release component support diameter• 2.0 mm release component support height (~Fig. 10C) vs 2.1 mm trigger support height (~Fig. 10D)• N=6 devices tested for 2.0 mm trigger support height and N=7 devices 2.1 mm release component support height

[0112] As shown in Fig. 14C, the 2.0 mm release component support height yielded more preferred JFR profiles. In contrast, the 2.1 mm release component support height resulted in two of the seven devices with less preferred JFR profiles as shown in Fig. 14D. As shown, device Nos. 1 and 4rapidly decline from the outset over 5 or 10 ms, while the jet force of the other devices is maintained near the initial maximum jet force for about 30 to 35 ms. The inventors believe the longer or taller release component supports (e.g., 2.1 mm height) may not allow for proper piercer stroke length resulting in partial, incomplete or slow release of compressed gas from the gas container.

[0113] EXAMPLE 4

[0114] Evaluation of the Performance of an Ingestible Multi-Nozzle Jet Delivery Device in Yucatan Pigs

[0115] Studies were performed using molded ingestible devices designed and constructed for jet delivery to the Gl tract. The ingestible devices operate by the release of a liquid jet with sufficient energy to deposit the drug payload into gastrointestinal tissue initiated by the disintegration of a release component at a desired location. After deposition, the drug may be absorbed into systemic circulation. In this Example, the performance of the ingestible device placed endoscopically in the small intestine of Yucatan pigs is described. Performance was determined, inter alia, by measuring submucosal injection pharmacokinetics as compared to subcutaneous or intravenous administration of the same test article.

[0116] To evaluate the injection efficiency of the ingestible jet delivery device, autonomous devices with non-enteric coated release components were positioned by intraduodenal endoscopic placement (ID) and released into the proximal small intestines of female Yucatan pig. The devices were configured as follows:• 350 PSI internal pressure or drive pressure• 0.35 mm nozzle diameter• 2 radial nozzles• Nozzle cover version D• 4.5 mm release component support diameter• 1 .9 mm release component support height• Test drug: semaglutide• N=7 animals tested + 1 control animal administered test drug subcutaneously (SQ)

[0117] Results:

[0118] Seven out of 7 devices were successfully advanced through the pyloric sphincter via endoscopic placement and triggered in the proximal small intestine. All seven animals showed detectable drug levels up to 72 hours post-dosing (FIG. 15) and had an oral bioavailability average of 19% compared to the IV control (from earlier study PSS2), and an oral bioavailability average of 25% compared to the SQ control (from present study and earlier study PSS4). No adverse significant clinical signs were observed in the animals before or after dosing for up to 10 days.

[0119] Fig. 15 shows results.

[0120] EXAMPLE 5

[0121] Jet Rig Results Data Using a Flex Crown Trigger Support

[0122] An ingestible devices with a flex crown as shown in Figs. 12A and 12B was tested using the jet force testing rig described above. These ingestible devices were further configured as follows:• 400 PSI internal pressure or drive pressure• 0.35 mm nozzle diameter• 2 radial nozzles• Nozzle cover version F• Flex crown release component support• N=3 devices tested

[0123] As shown in Fig. 17, the three devices show a more preferred JFR profile.

[0124] EXAMPLE S

[0125] Referring to Fig. 16 'Less Preferred' JFR Data resulted with the following configuration:• 400 PSI internal pressure or drive pressure• 0.40 mm nozzle diameter• 2 radial nozzles• nozzle cover version D• 5.7 mm release component support diameter• 1 .4 mm release component support height• N=4 devices tested

[0126] As shown in Fig. 16 the JFR profiles do not reach peak force within 5 milliseconds (ms). Instead, the force ramps over time and does not reach peak force in 5 ms or less. Also, the deployment time or duration of delivery is less than about 30 ms. The JFR profiles shown in Fig. 16 may be indicative of a slow piston or multi-stage releasing event (i.e., not one-step). This may lead to inconsistent or low bioavailability in vivo.

[0127] FIGS. 19A-D show an assembly method wherein a gas container 208 is filled with compressed gas. The method allows for filling a gas container (for example, with a volume of 50-140 l or 80-1 10pJ, or 90-100pl) with highly pressurized gas (for example, 1 ,000 psi to 2,500 psi). A keeper 202 is coupled to the unfilled gas container as shown in FIGS. 19A and 19B. In Fig. 19C, the gas container 208 is filled in a pressurized filling chamber. Fig. 19D shown a valve plug 215 of a valve assembly 214 is pressed into an opening in the neck 224 of the gas container and is held in place against gas pressure by the keeper 202. The keeper 202 can be secured onto the gas container 208 using hooks 209 engaging with a valve retainer 218 of the valve assembly 214. Once the gas container 208 is filled and sealed with the valve assembly 214, it can be shipped or stored for future use, for example, as part of an ingestible device.

[0128] FIGS. 20A-D show an assembly method wherein the end cap 212 with the trigger or release component 210 and an end cap seal or O-ring 230 are press fit onto the pressurized gas container 208 shown in Fig. 19D. The end cap 212 can be attachedin various ways, for example, as shown in FIG. 20B, the end cap 212 may snap onto a flange 222 on the gas container 208. After the end cap 212 is e.g., press fit onto the pressurized gas container 208 and / or the valve assembly 214, the keeper 202 is removed, and the resulting end cap valve assembly 206 can be coupled to a drug module as shown in FIGS. 21A-B and 22A. Embodiments of the end cap valve assembly 206 having more or fewer of the elements shown in Figs. 19C, 19D, 21 A, 21 B and 22A, are also referred to here as a drive module 44.

[0129] FIGS. 21 A-B show an assembly method for coupling a drug module 30 to the drive module 44 of FIGS. 20A-D. The components can be coupled by any method strong enough to withstand the pressures and forces described in FIG. 21 F, such as adhesives, ultrasonic welding, laser welding as shown in FIGS. 21 C and 21 D, or screw threads 47, as shown in FIG. 21 E. The screw threads 47 allow for height adjustment of the valve assembly relative to the release component, to accommodate any potential variation of the release component. It also allows for reuse of the device or parts of the device. Laser welding allows for precise control of the welding area with tight mechanical contact. Unlike threaded coupling, laser welding is permanent, therefore, many of the components cannot be reused.

[0130] Laser welding eliminates the need for fasteners or adhesives. As shown in Fig. 21 D, the interface between the drive module 44 and drug module 30 may be tapered at 279, above the nozzle openings 274 to accommodate the laser welding process, or to increase frictional resistance. The interface may use an interference fit. In some embodiments, as shown in Fig. 21 D, a cavity or a projection 45 on the end cap of the drug module housing provides excess material to accommodate the laser weld. The drug module housing may be transparent or semi-transparent to accommodate laser welding.

[0131] FIG. 21 F shows the relationship among the various device pressures, forces and volumes. The device section indicated as the area within dashed lines AAA in Fig. 21 F is the interface between the release component 210 and the valve assembly 214. Here the force on the release component 210 is a function of the diameter of the valve plug 215 extending into the gas container and the gas pressure in the gas container 208. Pressure in the container is determined by the desired drive pressure on the piston 250,available volume for the gas container, and the volume which the gas will expand into initially upon opening. Assuming that this pressure is fixed by other elements of the device, then the force applied to the release component can be adjusted by varying the area of the valve plug 215, acknowledging the effect of friction on reducing this force.

[0132] In some embodiments, the gas in the gas container comprises at least one gas selected from the group consisting of air, nitrogen, oxygen, carbon dioxide, hydrofluorocarbon gases and noble gases, or a mixture. The container may also have a relatively small amount of helium to make it easier to detect the gas. In some embodiments, the gas container is filled with a liquified gas such as difluoromethane (R- 32, CH2F2), carbon dioxide, or argon. Liquified gas provides advantages over nonliquified gas. For example, difluoromethane allows for smaller cylinder volume compared to non-liquified gas, and liquified gas provides a more consistent gas pressure through the piston stroke. Argon has the advantage of being less sensitive to temperature changes than difluoromethane.

[0133] The device section indicated as the area within the dashed lines BBB in Fig. 21 F shows the Initial System Volume, which is a portion of the entire expansion gas volume needed for driving the end cap nozzle(s). This volume is defined as the space from the end cap seal or O-ring 230 to the piston seal or O-ring 252, less the space occupied by the gas container 208 and the valve assembly 214. Finally, Device section CCC in Fig. 21 F shows the liquid drug container. The volume of the drug container correlates to the amount of pressure drop the device can tolerate while still successfully delivering the drug. A larger drug payload requires a larger allowable pressure drop, and vice versa. The payload may be at least 300pl with the total device size approximately the size of an 00 capsule.

[0134] FIG. 22A shows the starting state of the actuation sequence of the ingestible assembled device 200 before in vivo administration. A valve holding force is the force on the trigger or release component 210 before device actuation, for example, before administration of the device to a human or animal subject. The valve holding force is a function of the valve area and the container fill pressure:

[0135] For example, in FIG. 22A: 2 mm outside diameter valve * 1 ,400 psi » 30N

[0136] “Low” force example: 1 mm valve * 1 ,400 psi « 7.5N

[0137] “High” force example: 3mm valve * 2,000 psi ~ 100N

[0138] The 7.5N to 100N range is an exemplary range of forces acting on the release component before the ingestible device actuates in the Gl tract of a subject (i.e., at Stage 0 of device actuation).

[0139] FIG. 22B shows Stage 1 of the actuation sequence of the device 200. The release component 210 is designed to degrade in the Gl tract of the subject, after the device 200 is administered to the subject (a patient being treated). The release component 210 may include an enteric material that prevents the release component 210 from degrading in the relatively low pH environment of the stomach, and later degrade when it travels to the relatively higher pH environment of the small intestine. In some embodiments all or part of the ingestible device 200 is covered with an enteric material that, when it degrades, reveals parts of the ingestible device, for example, the release component. When the release component 210 begins to degrade (e.g., dissolve in the presence of biological fluids in the Gl tract), the valve assembly 214 can travel longitudinally and thereby begins to be displaced from the container opening. With enough movement, the displaced valve assembly 214 allows gas to leave the gas container 208 and fill the Initial System Volume as show as shown in FIG. 22B. The Initial System Volume also helps accommodate any potential gas seepage from the gas container 208 before device actuation.

[0140] FIG. 22C shows Stage 2 of the Actuation Sequence of the device 200. In Stage 0 (before actuation as shown in Figs. 22A), the pressure from the gas container acts on a relatively smaller cross section area of the valve (e.g., a 2 mm valve plug 215). After the release component 210 begins to degrade and the valve assembly can partially travel into the space occupied by the release component 210, gas from the container 208 is able to act on the larger cross section area of the valve assembly (e.g., a 5 mm valve base or plate 216 shown in Fig. 22H). This increases the force acting on the valve assembly 214 (e.g., 60+N), which further helps the valve assembly 214 push into or displace the release component thereby allowing more gas to rapidly leave the gas container 208 and fill the Initial System Volume 260. This multi-stage actuation allows fornearly instantaneous, single-step liquid jet formation once a sufficient internal capsule pressure capsule is achieved.

[0141] FIG. 22D shows Stage 3 of the actuation sequence of the device 200. In Stage 0, the jet cap O-ring 272 on the jet cap 270 blocks the one or more nozzles 274 during fill-finish of the device and maintains a sterile seal prior to actuation of the device thereby preventing the payload from exiting the device 200. In Stage 3, the release component is entirely degraded or ejected and the valve assembly 214 is now fully open, will full gas pressure acting on the piston 250. As this happens, the jet cap 270 compresses the jet cap seal or O-ring 272, which allows the jet cap 270 to begin longitudinal movement. In one embodiment, the jet cap is limited to longitudinal movement in one direction, for example, away from the drive module. The device may be sterilized prior to filling with drug, for example, using radiation or gas sterilization methods.

[0142] FIGS. 22E and 22F show transition from Stage 3 to Stage 4 of the actuation sequence of the device 200. As the jet cap O-ring 272 is driven (to the left in Fig. 22E) by gas pressure, it is pushed against an angled (e.g., about 10-30% angle) interior lip 276 and becomes increasingly compressed. This begins to open via longitudinal movement thereby exposing the one or more nozzles 274, as shown in Fig. 22F, providing a path for the liquid drug to exit the device housing 204, for example, as a liquid jet. As shown in FIG. 22E, the jet cap O-ring 272 is initially under some pressure (for example, resulting in 5-25% O-ring compression). As the pressure increases, the O-ring compression also increases (for example, resulting in 40% or more O-ring compression) and the jet cap 270 can overcome the friction force created by the housing 204 (see the lip 276 in FIG. 22E). Once overcome, the motion of the jet cap 270 provides an opening for the one or more nozzles. The pressure required to initiate jet cap movement may be 5-30 psi, or 10-20 psi. The jet cap may be a rigid material, which may be the same material as the device housing 204, for example, a polycarbonate, and / or a material that is compatible with the drug payload, for example Makrolon® polycarbonate.

[0143] In an alternative embodiment, for example as shown in FIG. 22J, a second O-ring is incorporated into the jet cap. In one embodiment, a primary jet cap O-ring 281 covers the one or more nozzles prior to actuation, while the secondary jet cap O-ring 283is located above the one or more nozzles. The device housing 204 can have an internal draft taper above the one or more nozzles to increase frictional resistance as the jet cap is displaced and travels longitudinally to reveal the one or more nozzles. In this embodiment, the jet cap may not include a jet cap lip or step 276. In another embodiment, any of the O-rings described in the devices, e.g., valve O-ring 226, end cap seal 230, piston O-ring 252, or jet cap O-ring, can include a second O-ring as shown in FIG 22J. In a related embodiment, as shown in FIG. 22J, the one or more O-rings may have a square profile. Also, in some embodiments, the one or more O-rings are made of butyl rubber, fluoroelastomer (e.g., Viton), or nitril rubber.

[0144] The design of Fig. 22J eliminates the lip or step 276 shown in Fig. 22I and introduces a draft taper (e.g., 2 degree wedge) above the nozzle to increase frictional resistance as the jet cap travels longitudinally.

[0145] The device seals may be a thermoplastic elastomer material and over molded onto the valve, end cap, piston, or jet cap components to provide seal integrity for device performance in place of O-rings. Over-molded elastomer seals may include single, double or multiple seal configurations necessary to achieve permeability and performance requirements.

[0146] In one embodiment relating to O-rings or over-molded thermoplastic elastomer seals, a lubricant is compounded within the O-ring or elastomer. Or a lubricant can be applied to the O-rings or thermoplastic seals. The lubricant, if used, is intended to address high static friction associated with long shelf life.

[0147] FIG. 22G shows Stage 4 of the actuation sequence of the device 200. In Stage 4, the movement of the jet cap 270 and the piston 250 increases the volume of the capsule which improves pressure control and reduces the pressure drop as the payload is expelled from the device 200 via the nozzles 274. The ingestible device 200 may include an external nozzle cover 278 on the outside of the housing 204 blocking the nozzles 274. The external nozzle cover is intended, inter alia, to prevent ingress of fluids or Gl material into the one or more nozzles prior to device actuation. When the device actuates, the movement of the jet cap 270 displaces the external nozzle cover 278, opening the outside of the nozzles 274.

[0148] Referring to FIG. 22H, the release component may have an annular surface or shoulder with abuts against a holding ring 238 of the end cap 212. The holding ring 238 annular surface may be oriented at an acute angle to a central axis of the housing. A valve retainer 218 on the valve assembly 214, if used, may extend through openings in the flange 222 on the gas container 208. The O-ring 226 on the valve plug or pin 215 seals against the inner surface of a neck 224 of the gas container 208. The end cap Ciring 230 seals against an interior bore of the end cap 212.

[0149] The valve assembly 214, as shown in Fig. 22H may include the valve plug 215, valve plate 216 and the retainer 218. End cap latches 236 can attach the end cap 212 to the gas container 208. The piston seal 252 may be contained in seat formed by a flange 254 on the piston. The piston seal may include a second O-ring. Whether the piston seal 252 comprises one or two O-rings, the O-ring serves as a seal between the drug payload and the drive module 44 during fill-finish and actuation of the device. The seal is designed to keep a dynamic seal as the piston 250 moves to withstand high pressure expansion of gas from the gas container.

[0150] In another embodiment, a valve allows for pressure on a sealing element, which is free to move, to generate a force in the direction of the valve movement. Different valve designs that accomplish this are shown in Figs. 32A-32D. This valve design incorporates round or cylindrical shaped components, for example ball bearings 300 or cylinders 302, but could also have other cross section shapes, to the extent that an adequate seal can be maintained. As shown in Figs. 32A-32C, an O-ring or other sealing element passes by a side port to communicate the gas to an expansion space.

[0151] In another embodiment shown in Fig. 33, the valve assembly is designed to accommodate permeation of gas from the gas container through the primary, or valve O- ring 226, which seals the gas container. This gas fills the Initial System Volume BBB (shown in Fig. 21 C) which, if over pressurized, can create enough force on the piston 250 to prematurely displace the jet cap and push liquid drug out of the one or more device nozzles. The valve assembly shown in Fig. 33 includes a secondary O-ring, or end cap seal 230, that is larger than the valve O-ring 226. Assuming the same cross section, it has a greater permeation because of the larger area. If a material is chosen that has ahigher permeability than the valve O-ring, the area and permeability can combine to allow gas to pass through the end seal O-ring at an expansion space pressure which will not allow drug to be forced out.

[0152] For example, if the valve O-ring is 1 .5 mm mean diameter and the end cap seal O-ring is 5 mm diameter and the cross section is the same, the ratio of permeation area is 3.3. According to data from Marco Rubber & Plastics, Seabrook NH, USA, the permeability of Viton fluorocarbon to nitrogen is 0.05-0.7 x10-8 seem - cm / sec - cm2 - atm, silicone 200 x 10-8 and EPDM elastomer is 6-7 x 10-8. Thus, in one embodiment, use of fluorocarbon for the valve (primary) O-ring and EPDM or silicone for the end seal (secondary) O-ring can result in a net permeation of the same rate of gas at a pressure of 1 / 28 to 1 / 13,000 times that of fluorocarbon, therefore, the permeation flow can be supported with an expansion space pressure much lower than the gas container pressure. In one embodiment, the valve O-ring 226 is made of low permeability material such as fluorocarbon or butyl rubber, and the end cap O-ring or seal 230 is made of a higher permeability material such as EPDM or silicone.

[0153] The jet cap, as shown in Fig. 22I, may include a jet cap vent J 277 that allows for filling, for example with a 21 -gauge needle. After filling, the jet cap vent 277 can be sealed, for example with a low-profile heat stake, thereby maintaining sterility of the drug payload. The vent cap 277 shown in Fig. 22I can be incorporated into other ingestible devices used to deliver drug payload, for example, including the devices described in PCT application WO2019246273.

[0154] In the embodiment of Figs. 23A-23C, the release component housing does not include a spring. Instead, a container cap 8100 is lock fit to the gas container thereby preventing release of the pressurized gas. A threaded pin 8102 and a pin O-ring 8104 are assembled to the container cap 8100. After the gas container is pressurized, the container cap is attached to the gas container and rotated, for example 90 degrees, to lock it in place, as shown in Fig. 23C. A second O-ring 8106 is installed onto the container cap, and both a release component and the gas container assembly are inserted into the release component housing. The cap is again turned, for example 90 degrees, to unlock it, and now the gas pressure from the gas container pushes the container cap against therelease component. After the device is administered, the release component is introduced to biological fluid, where it dissolves or degrades at a predetermined anatomical location based on a physiological condition such as pH. As the release component dissolves or degrades, the container cap is displaced from the gas container, and gas is released from the pressurized container thereby actuating the device. Hence, in this design, no spring and no piercer is used.

[0155] Referring to Fig. 23E and 23F, the release component housing may include one or more ribs 81 10 or other features that serve to apply concentrated pressure on the release component, which helps contribute to catastrophic failure of the release component. In this case, gas from the gas container applies force to the release component, which also helps clear the release component, or pieces of the release component, from the release component housing. The release component housing or end cap optionally includes openings or windows that allow for increased or more uniform hydration of the release component.

[0156] The release component housing may include one or more ribs or other features that serve to apply concentrated pressure on the release component, which helps contribute to catastrophic failure of the release component. Further, the release component housing may provide space for debris from the release component to disperse, thereby preventing obstruction of any moving parts on the device such as the cylinder cap.

[0157] In another embodiment, similar to the device shown in Figs. 23A-23F, the release component housing does not include a spring, and instead uses the piercer to seal the gas container. The two components are coupled via a pressure fit as shown in Figs. 24A-24L The piercer may include an O-ring 8200 to improve the seal. The piercer breaks the breakable seal, or septum, of the gas container. The release component housing, or drive module housing, is joined to the drug module housing after the piercer is coupled to the gas container. Similar to the device shown in Figs. 23A-F, the release component helps maintain the seal between the piercer and gas container. When the release component dissolves or degrades in the presence of a biological fluid, the pierceris displaced from the gas container, and gas is released from the gas container, thereby actuating the device.

[0158] Similar to the devices shown in FIGS. 23A-23F and 24A-24I, in the design of FIGS. 25A-25E, the release component housing does not include a spring, and instead uses a piercer or piercer-like plug 8300 to seal the gas container. The two components are coupled via a spool valve 8302. The shape and position of the release component places the eroding surface in tension to accelerate structural failure or degradation of the release component thereby actuating the device. In another embodiment, the device comprises a second piston 8304 for blocking the openings, wherein the second piston includes an internal breakaway cap 8306. As shown in Figs. 25C and 25D, the breakaway section lodges into housing recess after it is displaced by the drive piston. The drug payload can flow through channels in the housing and out of the openings. Alternatively, the second piston 8304 can move to uncover openings, and the breakaway cap can serve as a vent.

[0159] The device shown in FIG. 26A and 26B is similar to the devices shown in 23A-23F and 24A-24I, however, this device includes a second piston 8400 that blocks the one or more openings until the device is actuated. In addition, the gas container 8402 has a first part 8404 sealed with an end cap 8406. These two parts separate allowing for gas escape when the release component weakens. The gas container can be reduced to about 80-100 pL total volume, and the drug volume can increase to 500-600 pL. In this embodiment as well, no spring and no piercer is used.

[0160] Similar to FIG. 26A and Fig. 26B, a device 8401 shown in FIG. 26C and 26D has a gas container 8402 sealed with a second part such as an end cap 8406. The end cap 8406 may or may not include an inner O-ring on a portion of the end cap extending into the opening of the gas container, and an outer O-ring which slidably seals the end cap against the inner walls of the release component housing. The end cap 8406 is retained in a sealed position held against the opening of the gas container by the release component 8408. The end cap 8406 prevents gas from escaping from the gas container (while the release component is intact). When the release component partially or fully erodes, degrades, fractures and / or dissolves, the end cap is pushed away from the gascontainer, allowing gas to escape, which actuates the device. As shown, no piercer and no spring is used. In some embodiments, the device does not include a second piston as shown in FIG 26D, and in other embodiments there is a second piston as shown in FIG. 26A and 26B. In some embodiments, the release component housing or end cap includes openings or windows that allow for increased or more uniform hydration of the release component and for degraded material from the release component to get displaced away from the housing. In some embodiments, the windows are covered with an enteric material to prevent fluid ingress until the enteric material degrades at the desired location in the Gl tract.

[0161] In some embodiments, O-rings are used to seal the gas container as shown in Figs 27A - 27 B, and the release mechanism uses one or more O-rings 8500 and 8501 in a receiver or end cap 8502 being displaced from the gas. Fig. 27B shows an ingestible device 8510 having a gas container having a first or bulb part 8512, a seal plate 8514 joined to the neck or narrow end of the bulb part 8512, and a septum or seal 8516 on the seal plate 8514 which is pierceable by a piercer 8518. The piercer 8518 may have a length measuring from the top of the shroud (which bottoms out against the release component housing) of about 2-3 mm or about 2.4 to 2.6 mm. In this design, piercer parameters are as shown in the Table below.Relaxation after Recommend ess. at SOU ten hm s %4.07 1.82.5

[0162] Thus, the spring may exert a force of about 35 to 45 N.

[0163] Figs. 27C and 27D show an alternative device 8600 having an O-ring 8602 around the outside of the neck of a gas container projecting into a recess 8604 in an endcap 8606. Fig. 27C shows the device 8600 before actuation. Fig. 27D shows the device 8600 after actuation.

[0164] The present device has a release component 210 that, when degraded in the Gl tract, allows actuation of the device and deposition of drug payload into gastrointestinal tissue for systemic uptake. In some embodiments, the release component can withstand ( / .e., not degrade) a force of greater than about 10N, 15N, 20N, 25N, 30N, 35N, 40N, 45N, 50N or more in a gastric environment for more than 1 , 2, 3, or 4 hours. As used herein, gastric environment refers to a low pH environment of less than or equal to about pH 3.6, 3.0, 2.6, 2.0, or 1 .6. In another embodiment, the release component is displaced less than about 0.10 mm, 0.15 mm, 0.20 mm, 0.25 mm, 0.30 mm. or 0.35 mm in a gastric environment. In another embodiment, the release component degrades, thereby actuating the device described herein, in a small intestinal environment within 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, or 60 minutes. In some embodiments, the release component is displaced more than about 0.55 mm, 0.65 mm, 0.75 mm, 0.85 mm, 0.95 mm or more in a small intestinal environment. As used herein, small intestinal environment refers to a pH environment of greater than or equal to about pH 3.0, 3.5, 4.0, 4.5, or 5.0, 5.5, 6.0, 6.5, 7.0, 7.5 or higher. In some embodiments, the force acting on the release component 210 is produced by a 1 -3 mm valve pin or plug 215 that seals a gas container 208 with a gas pressure of about 800 psi to 2000 psi.

[0165] In another embodiment, the release component 210 comprises fast disintegrating effervescent materials that selectively degrade when in the presence of a fluid (e.g., a biological fluid) with a pH greater than 3.0, 3.5, 4.0, 4.5, or 5.0, 5.5, 6.0, 6.5, 7.0, 7.5 or higher. In some embodiments, the release component 210 comprises one or more of the following materials: one or more effervescent materials, one or more wicking agents (e.g., super disintegrants), or more fillers or bulking agents, one or more binders, and one or more lubricants. In another embodiment, the release component 210 comprises two or more of the following materials: one or more effervescent materials, one or more wicking agents (e.g., super disintegrants), or more fillers or bulking agents, one or more binders, and one or more lubricants.

[0166] In another embodiment, the release component 210 comprises three or more of the following materials: one or more effervescent materials, one or more wicking agents (e.g., super disintegrants), or more fillers or bulking agents, one or more binders, and one or more lubricants. In another embodiment, the release component 210 comprises four or more of the following materials: one or more effervescent materials, one or more wicking agents (e.g., super disintegrants), or more fillers or bulking agents, one or more binders, and one or more lubricants. In another embodiment, the release component 210 comprises each of the one or more following materials: one or more effervescent materials, one or more wicking agents (e.g., super disintegrants), or more fillers or bulking agents, one or more binders, and one or more lubricants.

[0167] Release component effervescent materials release gas, typically carbon dioxide, when they dissolve in the presence of a fluid (e.g., liquid in the Gl tract). Examples of release component effervescent materials include, but are not limited to, sodium bicarbonate or magnesiu bicarbonate and an acid such as citric acid or tartaric acid. Effervescent materials may be present in the release component at about 17% to 37% of the total weight of the release component. Release component wicking agents serve to carry water to surfaces inside the release component, thereby accelerating disintegration of the release component. Examples of release component wicking agents include, but are not limited to, low molecular weight poly vinyl pyrrolidone (PVP), kaolin, alumina, bentonite, colloidal silicon dioxide, sodium carboxymethyl cellulose (NaCMC), sodium lauryl sulphate (SLS), and titanium dioxide. Wicking agents may be present in the release component at about 0.5% to 5.0% of the total weight of the release component.

[0168] Release component fillers are generally inert substances added to increase the bulk or volume of the release component. Examples of release component fillers include, but are not limited, lactose, cellulose, microcrystalline cellulose (MCC), calcium carbonate, and starch. Fillers may be present in the release component at about 22% to 62% of the total weight of the release component. Release component binders serve to enhance binding of the different materials in the release component. Examples of release component binders include, but are not limited to acacia gum, starch, including pregelatinized starch such as StarTab®, LYCATAB®, or Starch 1500®, gelatin,methylcellulose, and hydroxypropyl cellulose (HPC). Binders may be present in the release component at about 17% to 47% of the total weight of the release component. Release component lubricants serve to improve powder flow during manufacturing of the release components, Examples of release component lubricants include, but are not limited to, calcium stearate, magnesium stearate, sodium lauryl sulfate (SLS), Poloxamer 188, and Poloxamer 407. Lubricants may be present in the release component at about 0.4% to 2.2% of the total weight of the release component.

[0169] In some embodiments, the release component has degradation properties consistent with plastic deformation. In one embodiment, the release component comprises about 37% to 73% combined fillers and binders, which result in a release component with degradation properties consistent with plastic deformation.

[0170] The release component may be shaped in any form to facilitate actuation of the device upon degradation in the Gl tract. For example, as shown in Figs. 1 -6, the release component may release a spring-loaded piercer that pierces a septum in the gas container, thereby actuating the device. Whereas in Figs. 22A-D, the release component serves to keep the valve pin 215 in the opening in the neck 224 of the gas container 208 until the release component 210 begins to degrade and the valve can partially travel into the space occupied by the release component 210, thereafter the compressed gas from the container 208 rapidly leaves the container and the device actuates. In this embodiment, the release component shown in Fig. 28A and 28B, carries the pre-actuation load as a compression force on shoulder 246 where it is in contact with the holding ring 238 on the end cap as shown in Fig. 22A-C.

[0171] Upon initial degradation of the release component, the load shifts to the valve plunger 232 . Gas pressure forces the plunger 232 centrally against the front surface of the release component, creating shear stresses in the release component. In some embodiments, force required to break the release component is lower when it is a tension or shear force as compared to a compression force. In some embodiments, the plunger 232 is shaped to increase the applied force to a smaller area of the release component. For example, the plunger 232 be wedge shaped. In a related embodiment, the release component may be scored or otherwise structurally weakened at or near the site wherethe plunger 232 comes into contact with the release component as the device begins to actuate. Other examples of release component modifications include the introduction of holes, dimples, lines, or concaves.

[0172] Figs. 28A-B show one example of a release component. The front and back faces or surfaces may be concave, as shown, with the front surface 241 having a radius of curvature 1 .5 to 2.5 times greater than the back surface 244. From front to back, the release component may be described as having a concave front surface 241 , an annular or cylindrical section 242, a tapered or angled section 243 adjoining the cylindrical section 243 via a radius 245, and a concave back surface 244. The concave surfaces of the release component offer several advantages compared to flat surfaces, namely, a shape that allows for more uniform coating of the release component, distributes force to the edges or near the edges of the release component while intact, or fits the contour of the end cap. The back of the cylindrical section 242 forms a shoulder 246, at the radius 245. In use, the shoulder 246 is pressed against the holding ring 238 of the end cap, with the entire back surface 244 exposed to the external environment of the Gl tract. The figures provide representative dimensions when the release components are coated 20% (by weight). In some embodiments the dimensions are 5-20% larger or smaller depending on the coating weight, release component materials, or overall size of the device. In some embodiments the ratio of the valve support diameter to the taper width is about 1 .2, 1 .3, 1.4, 1.5, or 1.6. In some embodiments, the release component swells by about 2-15% volume when introduced to a fluid thereby forming a seal with the end cap, including the holding ring 238, and decreasing ingress of fluid into the end cap assembly before complete degradation of the release component.

[0173] In another embodiment, the release component serves to keep the valve pin 215 in the opening in the neck 224 of the gas container 208 until the release component 210 begins to degrade and the valve, thereafter the valve is displaced from the container opening. In this embodiment, the valve may be spring loaded or thread-fitted into the opening prior to actuation as shown in Fig, 23D-E, the release component may be a latch or pin that, upon degradation, allows the valve to be displaced (e.g., unscrew) from the opening 224.

[0174] In some embodiments, the release component comprises one or more layers or coatings. In one embodiment, the layers comprise a base layer and an enteric layer. In some embodiments, the base layer comprises a sub coat or seal layer and a top coat. The sub coats and top coats can be applied at different weights, for example, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9% or more of total release component weight. Examples of base coats (seal layer) and top coats, include but are not limited to, methylcellulose (MC), Polyvinyl alcohol (PVA) , hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), shellac, pure ethanol, and zein: Likewise, the enteric coating can be applied at different weights, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more of total release component weight. Examples of enteric coatings include enteric polymers.

[0175] In some embodiments, an enteric polymer can remain insoluble in the stomach, but dissolve at the higher pH of the intestine (e.g., small intestine or large intestine), and are used to deliver drugs to the intestine. Examples of such enteric materials that dissolve in the small intestine and are suitable for small intestine release include, but are not limited to, cellulose derivatives, e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose 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, hydroxypropylcellulose acetate phthalate, polyvinyl acetate phthalate, methacrylatemethacrylic acid copolymers, styrol, maleic acid copolymers, shellac, and others. Other examples of enteric materials 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 copolymers); Evonik's Eudragit L 100-55 Methacrylic copolymers, Eudragit L 30 D-55 Methacrylic copolymers (30%), Eudragit L 100 Methacrylic copolymers, Eudragit L 12.5 Methacrylic copolymers (12.5%), Eudragit S 100 Methacrylic copolymers, Eudragit S 12.5 Methacrylic copolymers (12.5%), Eudragit FS 30 D Methacrylic copolymers (30%); Kerry's SheffCoat ENT Cellulose Acetate Phthalate, Acrylate copolymer, HPMC-P; Eastman's C-A-P NF Cellulose Acetate Phthalate; Sensient's PROTECT™ ENTERICShellac & Sodium Alginate. Another suitable enteric material is a water emulsion of ethylacrylate methylacrylic acid copolymer, or hydroxypropyl methyl cellulose acetate succinate (HPMAS).

[0176] In some embodiments, the devices described herein are intended to deliver drug payload to the large intestine. In such cases, the enteric material dissolves in the large intestine and is suitable for colonic release. Enteric materials suitable for large intestine (e.g., colonic) release are known to one of skill in the art. In some embodiments, degradation of the coating is microbially triggered, e.g., the bacteria in the colon enzymatically trigger degradation of the coating (see, e.g., Archana et al., Int. J. Pharm. Sci. Res. (2016) 1 (5):40-47; and Sethi et aL, Int. J. Pharm. Sci. Res. (2012) 3(9):2989- 3000). In some embodiments, the coating is a pH-dependent polymer that is insoluble at low pH but becomes increasingly soluble as pH increases. In some embodiments, the enteric coating is an aqueous dispersion. In some embodiments, the enteric coating comprises an acid such as methacrylic acid. Examples include EUDRAGIT® L100-55, EUDRAGIT® L100, EUDRAGIT® S100, and EUDRAGIT® FS100. In some embodiments, the enteric coating is a polymeth acrylate with a pH-dependent dissolution threshold above about pH 5.5. Examples of suitable enteric materials include, but are not limited to Evonik’s Eudragit® L30D55, Eudragit® L100-55, or Eudragit® FL30D55.

[0177] In some embodiments, the enteric coating is a polymethacrylate with a pH- dependent dissolution threshold of about pH 6.0-7.0. Examples of suitable enteric materials include, but are not limited to Evonik’s Eudragit® L100 and Eudragit® L12.5. In some embodiments, the coating is a polymethacrylate with a pH-dependent dissolution threshold above about 7.0. Examples of suitable enteric materials include, but are not limited to Evonik’s Eudragit® S100, Eudragit® FS30D, and Eudragit® FS100. Other examples of suitable enteric materials include, but are not limited to, chitosan, alginates (e.g., as calcium salts), hydroxypropylmethylcellulose phthalate 50, hydroxypropylmethylcellulose phthalate 55, and cellulose acetate trimellate. In some embodiments, an enteric material is a material described in U.S. Pat. No. 10,226,430; Sethi et al., Int. J. Pharm. Sci. Res. (2012) 3(9):2989-3000; or Archana et al., Int. J.Pharm. Sci. Res. (2016) 1 (5):40-47, each of which are herein incorporated by reference in their entireties (for the U.S. national phase only).

[0178] In some embodiments, the colon-specific degradation of an enteric material can 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, e.g., Bacteroides, Bifidobacteria, Enterobacteria, Eubacteria, Clostridia, Enterococci, and Ruminococcus, etc. These micro floras fulfill their energy needs by fermenting various types of substrates that have been left undigested in the small intestine, e.g., polysaccharides, di- and tri-saccharides, etc. These polymers are stable in the environments of the stomach and small intestine. On reaching the colon, the polymers undergo degradation by the enzyme or break down of the polymer backbone leads to a subsequent reduction in their molecular weight and thereby loss of the mechanical strength. In some embodiments, wherein the devices described herein are used for colonic delivery, the devices do not deliver the drug payload via liquid jet delivery. Instead, the devices deliver the drug payload to the gastrointestinal lumen. This can be achieved by one or more of decreasing the internal pressure (e.g., less than about 100 psi, 75 psi, 50 psi, or 25 psi) or increasing the nozzle diameter to about 0.9 mm, 1 .0 mm, 1 .1 mm, 1 .2 mm, 1 .3 mm, 1 .4 mm, or 1 .5 mm or more, or a combination of decreasing the internal pressure and increasing the nozzle diameter as described above. The nonjet delivery device described here can also be used to deliver drug payload to other parts of the gastrointestinal tract, including the stomach, small intestine or large colon.

[0179] In another embodiment, an enteric material covers all the exterior of the device, or the end cap of the device, or the jet cap of the device. For example, the enteric material covers the jet cap to serve as a chemical external nozzle cover similar to the external nozzle cover 278 shown in Figure 22G. In another example, the enteric material covers the end cap to prevent fluid ingress to the release component until said enteric material dissolves or degrades. In some embodiments, the enteric material on all or part of the exterior of the device is Evonik’s EUDRACAP® customized to fit the shape of the devices described herein, for example, a size 00 capsule. In some embodiments, an enteric material covers the end cap (e.g., attached to the holding rings 238), and, whenthe enteric material degrades, fluid enters into the end cap where an uncoated or partially coated (e.g., sealed with a base coat) release component degrades and the device actuates. In this embodiment, the enteric coating is a film or other substrate (e.g., gelatin) that is less than about 0.05 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm thick.

[0180] In some embodiments, the release component is manufactured using a rotary tablet press, for example, with a rotary press turret speed of about 100 - 400 mm / sec. In another embodiment, a hand press is used to manufacture the release component. In some embodiments, the compression pressure used to make the release component is about 60 MPa to 250 MPa; 75 MPa to 225 MPa; 100 MPa to 200 MPa; or 125 MPa to 175 MPa. The release component may be coated using fluid bed coating, pan coating, or dip coating.EXAMPLE 1 - Release Component Production, Coating & Testing

[0181] Release components, for example release components 5B, 5C, and 5D shown below, can be produced using known tablet presses such as rotary tablet presses. For example, a Natoli RD30 Rotary Tablet Press was used to make release components 5B with the following parameters:• Turret Speed: 15RPM which translates to 157mm / sec turret tangential velocity• Compaction Pressure: 188MPa - 204MPa• Dosing - Fill cam = 8 mm Weight cam = 4.3 mm• Force feeder speed = 7RPM

[0182] The resulting release components were coated with a colored base coat, followed by a colored enteric coat, and finally a top coat, all of which can be applied, for example, using a known coating methods, such as a fluid bed process. Both coated and uncoated release components were tested to evaluate their performance characteristics (e.g., ability to withstand load in a gastric environment and thereafter degrade in a small intestine environment under the same or a high load).

[0183] Exemplary release component formulations:

[0184] Experiment 1 : Coated Release Components 5B - Unstressed Acid Test at37C

[0185] Coated release components 5B were placed in 37C simulated stomach acid (2.05 pH) and observed for changes in coating at 5 min intervals. A load was not applied to the release components, therefore, it was considered an ‘unstressed’ test. The following observations were made:• Formula 5B, Production Release Component, Base Coat Only• Release component completely dissolved < 5 min• Formula 5B, Production Release component, Base Coat, 10% Enteric Coating• Spots of base coat showing through at 65 min, Release component dissolved at 90 min• Formula 5B, Production Release component, Base Coat, 15% Enteric Coating• Spots of base coat showing through at 75 min,• 120 Min test stopped, base coat showing through, release component still intact• Formula 5B, Production Release component, Base Coat, 20% Enteric Coating• 120 Min - test stopped coating still intact

[0186] The above Unstressed Acid Test showed that as the coating thickness increases the release component degrades slower in an acid. The 15% and 20% coated (by weight) release components met the 2-hour+ gastric threshold.

[0187] Experiment 2: Instron Testing - Dry Uncoated Release Components

[0188] Uncoated release components 5B at two different heights (2.0 mm vs. 2.5 mm) were tested using an Instron machine, which measures force and displacement, using the test fixture shown in Fig. 29A, that introduces a controlled force onto the release component using a shape (trapezoid foot 400) designed to mimic the valve plunger 232.

[0189] The 2.0 mm thick uncoated release components had a break force of approximately 10-12 N, while the 2.5 mm thick uncoated release components had a break force of approximately 20 N. This showed that as the uncoated release component height increases, particularly the ring height shown in Fig. 28B, the release component strength increases.

[0190] Experiment 3: Instron Testing - Dry Uncoated & Coated Release Components

[0191] Uncoated and coated release components 5B were tested using an Instron machine and a dry test fixture shown in Fig. 29A, that introduces a controlled force onto the release component using a shape (trapezoid foot 400) designed to mimic the valve plunger 232.

[0192] As shown in the box plot of Fig. 34, the dry release component break force increases as coating thickness increases, wherein BC = base coat; and EC = enteric coat. However, without any coating, the release component does not withstand a 30N force. When the enteric coating (EC) is added at 10% and 20% weight, the break force increases to over 70 N.

[0193] Experiment 4: Instron Testing - Wet Coated & Uncoated Release Components

[0194] Coated and uncoated release components 5B were tested under wet conditions using an Instron machine and a test fixture that allows for the introduction of a fluid as shown in Fig. 29B, to mimic the gastric and small intestine environments. Testing was used to determine failure conditions, for example, 0.6 mm of release component displacement under 30N of load from the Instron test machine, which measures force and displacement.

[0195] Uncoated Observation:

[0196] The thicker the coating, the longer it takes the release component to breakdown in the gastric environment, while both the 10% and 20% coated release components broke down in approximately the same amount of time in the small intestine environment.

[0197] Coated Observations:• 10% top coated release components• Gastric - Lasted for 13.3 mins up to 69 mins in 1 .6 pH acid @ 23°C• Small Intestine - Lasted for 7.5 mins up to 26.4 mins in 6.8 pH neutral @ 23°C• 20% top coated release components• Gastric - Lasted for at least 60 mins in 1 .6 pH acid @ 23°C• Small Intestine - Lasted roughly 21 mins in 6.8 pH neutral @ 23°C

[0198] This showed that 10% coated release components do not meet minimal time thresholds in the gastric environment. However, 20% coated release components last for at least 1 hour in gastric environment and show quick breakdown in the neutral small intestine environment. Finally, breakdown time can be increased by increasing coating thickness or by increasing the surface contact area of the trapezoid foot designed to mimic the valve plunger. As used here, the term ‘about’ means within + / - 10% of the stated value.

[0199] Figs. 30A and 30B show an embodiment of the jet cap wherein the one or more O-rings are not placed on the one or more nozzles, thereby leaving the nozzles unsealed but sealing the drug payload in the storage reservoir.

[0200] Figs. 31 A, 31 B, 31 C and 31 D show an embodiment wherein the one or more nozzles are placed in the jet cap rather than the drug module housing thereby adding volume to the storage reservoir, using either one or two O-rings, as shown.

[0201] The following are additional examples and / or statements of the inventions: Group 1 .1. An ingestible device includes: a storage reservoir in a housing; one or more nozzles leading from the storage reservoir; a piston slidable longitudinally within the housing; a compressed gas container in the housing; and a release component assembly configured to release compressed gas from the compressed gas container upon actuation of the device, the release component assembly having a release component support and a release component, with a ratio of the diameter of a flange on the release component support to the diameter of the housing equal to about 0.5 to 0.6.2. The flange of the release component support may have a diameter of about 3.5 mm to 5.5 mm or 4.3 to 4.7 mm.3. The ratio of the diameter of the flange of the release component support to an outer diameter of the release component may be about 0.6 to 0.8 or 0.9.4. The release component support may overlay about 30% to 70% of an outer diameter of the release component5. The release component support may have a first conical section and an adjoining second conical section, the first conical section having an included angle of about 89° to 99° or about 92° to 95°. One or more of Examples 2-5 may be used in the ingestible device of Example 1 .Group 2:6. An ingestible device includes a storage reservoir in a housing; one or more nozzles through the housing; a piston slidable longitudinally within the housing; a gas container in the housing; a piercer configured for piercing the gas container to release compressed gas from the gas container; a spring applying a spring force on the piercer in a first direction towards the gas container; a release component assembly holding the piercer in place against the spring force, the release component assembly having a release component support attached to the piecer and held against a release component by the spring force.7. The release component support may have a flange with a diameter of 3.5 to 5.5 mm or 4.3mm to 4.7 mm.8. The ratio of the diameter of the flange to the diameter of the release component may be about 0.6 to 0.8 or 0.9.9. The release component support may have a conical surface joined to the flange wherein only the flange contacts the release component.10. The release component can be held between the release component support and a flat back end of the housing by the spring force.1 1 . A compression washer may be spaced apart from the housing.12. A flex crown may be positioned between the housing and the release component. If used, the flex crown may have a plurality of radial ribs which make line contact with the release component.13. Raised lugs may be provided on the housing, with the release component resting on top of the raised lugs. If used, the raised lugs may be circumferentially spaced apart curved segments.14. When actuated, the ingestible device provides a jet of liquid with a jet force of 150 to 250 mN for at least 30 mSec. One or more of Examples 6-14 may be used in the ingestible device of Example 1 .Group 3:15. A method for delivering a drug includes the steps of administering an ingestible jet delivery device to a patient; and operating the delivery device to provide a jet force over time profile, wherein the jet force rise time from zero to 150 mN is less than 5 ms.16. The jet force rise time from zero to 150 mN may be less than 4, 3, 2 or 1 ms.17. The jet force rise time from zero to 200 mN may be less than 5, 4, 3, 2 or 1 ms.18. The jet force rise time from zero to 250 mN, may be less than 5, 4, 3, 2 or 1 ms.19. The jet force may remain above 150 mN for at least 20, 25, 30 or 35 ms.20. The jet force may remain above 200 mN for at least 20, 25, 30 or 35 ms.21 . The jet force at 25, 30, 35 or 40 ms may be less than 40% of the initial jet force. The method of Example 15 may be characterized by any of claims 16-18 and / or Examples 19-21.Group 4:22. An ingestible device includes: a storage reservoir in a housing containing a liquid; one or more nozzles leading from the storage reservoir; a piston slidable longitudinally within the housing; a compressed gas container in the housing; and a release component assembly configured to release compressed gas from the compressed gas container upon actuation of the device, the release component assembly having a release component support and a release component; wherein actuation of the device provides a jet of the liquid having a jet force rise time from zero to 150 mN is less than 5 ms.23. The jet force may remain above 150 mN for at least 20 ms.24. A ratio of the diameter of a flange on the release component support to the diameter of the housing may be about 0.5 to 0.6.25. Upon actuation, the compressed gas exerts 300 to 400 psi on the piston, and the release component support has a diameter of 4 to 5 mm and a height of 1 .7 to 2.1 mm.26. A Parylene-coated nozzle cover may be provided over the nozzle.27. A piercer, if used, is configured for piercing the gas container to release compressed gas from the gas container; and a spring applies spring force on the piercer in a first direction towards the gas container. The release component support may have a cylindrical section contacting a circumferential ring on the piercer.28. The release component support may have a conical surface joined to a flange, wherein only the flange contacts the release component.29. The release component can be held between the release component support and a flat back end of the housing by spring force. One or more of Examples 23- 29 may be used in the ingestible device of Example 22.Group 5:30. An ingestible device, including: a reservoir in the housing containing a liquid pharmaceutical; one or more nozzle openings adjacent to a second end of the housing; a piston in the housing between the reservoir and the first end of the housing; a valve assembly having a valve plug extending from a valve base into a gas container containing a compressed gas; a release component which changes from an intact state to a non-intact state, to allow movement of the valve assembly to actuate the ingestible device, after ingestion of the ingestible device, to release the compressed gas which exerts force on the piston, to drive a jet of liquid from the reservoir out of the device.31 . The release component and the valve assembly may be components of an end cap attached at a first end of the housing. The end cap, if used, may be attached to a flange of the gas container. The gas container may also be part of the end cap.32. The valve plug may extend longitudinally into a neck of the gas container and is sealed against an inner surface of the neck via a sliding seal.Optionally, with the valve plug on a second side of the valve base, the valve assembly further includes a plunger on a first side of the valve base. If used, a first side of the plunger contacts the release component. Upon actuation the plunger projects into or at least partially displaces the release component.33. A sliding end cap seal may be provided between the plunger and an inner surface of the end cap.34. The release component may have an angled annular surface abutting an end cap holding ring.35. A valve retainer may extend towards the second end of the housing. The valve retainer may extend through one or more openings in a flange on the neck of the gas container.36. Before actuation the compressed gas exerts gas pressure on the valve plug having a first area, and during actuation the compressed gas exerts gas pressure on the valve plug and on the valve base, the valve base having a second area greater than the first area.37. The piston may have a cylindrical body around the gas container and a sliding piston seal between the piston and an inner surface of the housing.38. Upon actuation, the released compressed gas exerts a first force on the first area, and a second force on the second area, with the second force 1 .5 to 3 times greater than the first force.39. Before actuation, gas pressure in the gas container exerts a first force on the valve assembly, which exerts the first force on the release component.40. Before actuation, when the release component is intact, the release component resists the first force and prevents movement of the valve assembly, maintaining the compressed gas sealed within the gas container, and when after ingestion the release component becomes non-intact, the valve assembly moves into the release component or at least partially displaces the release component, releasing compressed gas from the gas container, the released compressed gas acting ona larger surface area of the valve assembly in the second position relative to the first position.41 . A system volume space is a space within the housing between an end cap seal between the end cap and the valve assembly, and a piston seal between the piston and the housing.42. Before actuation, compressed gas in the gas container exerts a first force only a first surface area of the valve assembly including the surface area of the valve plug and a valve plug seal on the valve plug, and in a second position compressed gas is released from the gas container and exerts a second force a second surface area of the valve assembly, the second surface area greater than the first surface area. One or more of Examples 31 -43 may be used in the ingestible device of Example 30.

[0202] Thus, a novel ingestible drug delivery device has been shown and described. Various changes and substitutions may of course be made without departing from the spirit and scope of the invention. The invention, therefore, should not be limited, except to the following claims, and their equivalents. Elements of the various embodiments described above may be interchanged among those embodiments, as will be apparent to those skilled in the art.

Claims

CLAIMS1 . An ingestible device, comprising: a housing having a first end and a second end; a gas container end cap assembly at the first end of the housing; one or more nozzle openings towards a second end of the housing; a piston in the housing between the gas container end cap assembly and the nozzle openings, the piston movable within the housing and the piston sealed against the housing; the gas container end cap assembly including: an end cap attached to the housing; a release component in the end cap; a gas container containing a compressed gas; and a valve assembly between the gas container and the release component; the valve assembly movable from a first position wherein the valve assembly seals the gas container, to a second position upon actuation of the ingestible device via the release component, the valve assembly in the second position unsealing the gas container, wherein compressed gas from the unsealed gas container moves the piston to drive a liquid in the housing out through the nozzle openings in a jet.

2. The ingestible device of claim 1 wherein the compressed gas exerts a first force on the valve assembly in the first position, and the compressed gas exerts a second force on the valve assembly in the second position, the second force greater than the first force.

3. The ingestible device of claim 2 wherein the second force is 1 .5 to 3 times greater than the first force.

4. The ingestible device of claim 2 wherein in the first position the valve assembly exerts the first force on the release component, and in the second position the valve assembly exerts the second force on the release component.

5. The ingestible device of claim 1 or 2 wherein, when intact, the release component resists the first force and prevents movement of the valve assembly, maintaining the compressed gas sealed within the gas container, and when after ingestion the release component becomes non-intact, the valve assembly moves into the release component or at least partially displaces the release component, releasing compressed gas from the gas container, the released compressed gas acting on a larger surface area of the valve assembly in the second position relative to the first position.

6. An ingestible device, comprising: a liquid within a housing; a piston longitudinally movable within the housing; a drive force generator in the housing, the drive force generator configured to exert force on the piston, when actuated, with the piston exerting pressure on the liquid, and the liquid moving out of the housing as a jet through one or more nozzle openings; a release component changeable from an intact state before ingestion, to a nonintact state after ingestion, the release component in the intact state preventing actuation of the drive force generator, the release component in the non-intact state allowing actuation of the drive force generator; and the release component comprising one or more effervescent materials, one or more wicking agents, one or more fillers or bulking agents, and one or more binders.

7. The ingestible device of claim 6 wherein the one or more effervescent materials comprise about 17% to 37% of the total weight of the release component.

8. The ingestible device of claim 7 wherein the one or more wicking agents comprise about 0.5% to 5.0% of the total weight of the release component.

9. The ingestible device of claim 6 wherein the one or more fillers comprise about 22% to 62% of the total weight of the release component.

10. The ingestible device of claim 6 or 7 wherein the one or more binders comprise about 17% to 47% of the total weight of the release component.1 1. The ingestible device of claim 6 or 7 further including one or more lubricants comprising about 0.4% to 2.2% of the total weight of the release component.

12. The ingestible device of any of claims 7-11 wherein the release component comprises a base layer and an enteric layer.

13. An ingestible device, comprising: a liquid within a housing; a piston longitudinally movable within the housing; a drive force generator comprising compressed gas or a spring, the drive force generator exerting a drive force on a release component; the release component resisting the drive force before the ingestible device is ingested, and the release component releasing the drive force to act on the piston after the ingestible device is ingested; the release component having an annular surface held against a holding ring at an end of the housing.

14. The ingestible device of claim 13 wherein the annular surface is oriented at an acute angle to a central axis of the housing.

15. The ingestible device of claim 13 or 14 wherein the release component has a concave front surface and a concave back surface.

16. The ingestible device of claim 15 wherein the drive force generator comprises compressed gas in a compressed gas container, further including a valve assemblyhaving a valve plug inserted into an opening in the compressed gas container and a plunger against the front surface of the release component.

17. The ingestible device of claim 16 wherein the valve plug extends longitudinally into the opening in a neck of the gas container and is sealed against an inner surface of the neck via a sliding seal.

18. The ingestible device of claim 16 or 17 wherein upon actuation the plunger projects into or at least partially displaces the release component.

19. The ingestible device of claim 16 or 18 wherein before actuation the compressed gas exerts gas pressure on the valve plug having a first area, and during actuation the compressed gas exerts gas pressure on the valve plug and on a valve base of the valve assembly, the valve base having a second area greater than the first area.

20. The ingestible device of claim 13 or 15 wherein the release component has a first circumferential surface having a first width joined by a radius to a second circumferential surface having a second width less than the first width.21 . An ingestible device, comprising: a liquid in a liquid reservoir in a housing; a piston in the housing slidable at least partially through the liquid reservoir; at least one nozzle leading out from the reservoir, adjacent to a first end of the housing; an end cap valve assembly at a second end of the housing, the end cap valve assembly comprising: an end cap attached to the housing, the end cap having a retaining ring retaining a release component;a valve assembly at least partially in the end cap, a valve plug on a first side of the valve assembly, the valve plug inserted into a compressed gas container, and a plunger on a second side of the valve assembly; the release component configured to hold the valve assembly in place against a gas pressure force of 10 to 40 Newtons exerted on the valve assembly by compressed gas in the compressed gas container, until after the ingestible device is ingested.

22. The ingestible device of claim 21 wherein the release component extends through a central opening in the end cap.

23. The ingestible device of claim 22 wherein the plunger exerts a release force in a first direction on a first side of the release component, and the retaining ring exerts a holding force in a second direction, opposite to the first direction, only on an annular shoulder of the release component.

24. An ingestible device, comprising: a drug module containing a liquid pharmaceutical, one or more nozzle openings, and a piston slidable within the drug module; a drive module attached to the drug module, the drive module including a compressed gas container containing a compressed gas, and a valve assembly movable from a closed position to an open position, the valve assembly held in the closed position by a release component preventing release of compressed gas from the compressed gas container, and the valve assembly movable to the open position after ingestion of the device by at least partially displacing or projecting into the release component when the release component is no longer intact, the valve assembly in the open position releasing compressed gas from the compressed gas container, the released compressed gas moving the piston to provide a jet of the liquid pharmaceutical out through the one or more nozzles.

25. The device of claim 24 wherein the liquid pharmaceutical is in a reservoir formed partially around sides of the piston.

26. The device of claim 24 or 25 wherein, in the closed position, a first side of the valve assembly is engaged with the compressed gas container and a second side of the valve assembly is engaged with release component.

27. The device of claim 26 wherein, in the closed position, gas pressure continuously exerts force on the valve assembly, holding the valve assembly against the release component.

28. An ingestible device, comprising: a drug module containing a liquid pharmaceutical, one or more nozzle openings, and a piston movable within the drug module; a drive module attached to the drug module, the drive module including a drive force generator engaged with a release component comprising an effervescent material; the release component releasing the drive force generator to act on the piston after the device is ingested, the drive force generator then moving the piston to provide a jet of the liquid pharmaceutical out through the one or more nozzle openings.

29. An ingestible device, comprising: a drug module containing a liquid pharmaceutical, one or more nozzle openings, and a piston movable within the drug module; a drive module attached to the drug module, the drive module including a drive force generator engaged with a release component having a shoulder between a front surface and a tapered section, the shoulder pressed against a holding ring of the drive module by the drive force generator; the release component releasing the drive force generator to act on the piston after the device is ingested, the drive force generator then moving the piston to provide a jet of the liquid pharmaceutical out through the one or more nozzle openings.

30. The ingestible device of claim 29 wherein the front surface is concave, the release component further including a concave back surface adjoining the tapered section, and a cylindrical section between the tapered section and the concave front surface, with the shoulder formed by a radius leading from the tapered section to the cylindrical section.

Images