Intake drug delivery device

Abstract

The ingestible device has a liquid within a housing. The piston is longitudinally movable within the housing. A driving force generator including compressed gas or a spring exerts a driving force on the release member. The release member may have an annular surface held against a retaining ring at an end of the housing. The release member resists the driving force before the ingestible device is ingested, and the release member releases the driving force to act on the piston after the ingestible device is ingested. The rapid release of the driving force causes one or more jets of liquid to enter the gastrointestinal tract of the patient.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 580,213, entitled “TRIGGER ASSEMBLY FOR INGESTIBLE DRUG DELIVERY DEVICE,” filed September 1, 2023; U.S. Provisional Application No. 63 / 584,466, entitled “INGESTIBLE DRUG DELIVERY DEVICE,” filed September 21, 2023; and U.S. Provisional Application No. 63 / 654,834, entitled “INGESTIBLE DRUG DELIVERY DEVICE,” filed May 31, 2024, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] The field of this invention is an ingestible device for delivering drugs into the gastrointestinal tract. Background Technology

[0004] Ingestible devices for delivering drugs into the gastrointestinal tract have been developed, such as those described in U.S. Patent Application Publication US20230017603A1 and International Patent Application PCT / US2023 / 064716 (both incorporated by reference only to the U.S. national phase). In these types of devices, a release element or trigger dissolves in the stomach or intestine after the device is swallowed, causing actuation of the device. In some devices, actuation is generated via a puncturist releasing a puncture compressed gas container through a dissolved trigger. The released compressed gas drives a piston to generate one or more liquid jets, thereby providing local, epithelial, or transepithelial drug delivery. Nevertheless, engineering challenges remain in achieving improved performance. Summary of the Invention

[0005] The ingestible device contains liquid within a housing. A piston is capable of longitudinal movement within the housing. A force generator, including compressed gas or a spring, applies a driving force to a release member. The release member may have an annular surface held by a retaining ring abutting an end of the housing. The release member resists the driving force before the ingestible device is ingested, and releases the driving force to act on the piston after the ingestible device is ingested. The rapid release of the driving force results in one or more jets of liquid entering the patient's gastrointestinal tract. Attached Figure Description

[0006] Figure 1 This is a perspective cross-sectional view of the ingestible device.

[0007] Figure 2This is an elevation cross-sectional view of another embodiment of the ingestible device.

[0008] Figure 3 yes Figure 2 An exploded perspective view of the device.

[0009] Figure 4 yes Figure 3 Another exploded perspective view of the device shown.

[0010] Figure 5 yes Figure 1 The diagram shows a perspective cross-sectional view of the trigger or release component assembly.

[0011] Figure 6 It has an increased size. Figure 5 A line diagram of a cross-section.

[0012] Figure 7 yes Figure 1 and Figure 5 The top perspective view of the release component support shown.

[0013] Figure 8 yes Figure 7 The plan view of the release component support shown.

[0014] Figure 9 yes Figure 7 and Figure 8 The side view of the release component support shown.

[0015] Figures 10A-10E This is a side view of the alternative release component support with different heights.

[0016] Figure 11A This is a cross-sectional view of a release component support with a compression washer.

[0017] Figure 11B yes Figure 11A The top perspective cross-section of the compression washer shown.

[0018] Figure 12A It is a side view of an ingestible device with a flexural crown.

[0019] Figure 12B yes Figure 12A A cross-sectional view of the ingestible device.

[0020] Figure 12C yes Figure 12A and Figure 12B A cross-sectional view of the ingestible device, which is now in the actuated position.

[0021] Figure 12D This is a cross-sectional view of an ingestible device without a flexible crown, shown for comparison.

[0022] Figure 12E It is shown Figure 12A Top perspective view of the release component and the flexural crown.

[0023] Figure 12F Is it like this? Figure 12E The top view of the ingestible device shown.

[0024] Figure 12G Is it like this? Figure 12E The top perspective view of the ingestible device shown, with the release component removed for illustrative purposes.

[0025] Figure 12H Is it like this? Figure 12G The top view of the ingestible device shown.

[0026] Figure 13A This is a side view of an alternative embodiment of an ingestible device with a raised release component housing collar.

[0027] Figure 13B yes Figure 13A A cross-sectional view of the ingestible device.

[0028] Figure 13C yes Figure 13A Top perspective view of the ingestible device.

[0029] Figure 13D yes Figure 13A The top plan view of the ingestible device shows the release component housing collar as circumferentially spaced arc segments.

[0030] Figure 13E yes Figure 13A The top perspective view of the ingestible device, with the release component removed for illustrative purposes.

[0031] Figure 13F Is it like this? Figure 13E The top view of the ingestible device shown.

[0032] Figure 14A This is a graph showing the jet force versus time for seven samples using nozzle caps coated with parylene.

[0033] Figure 14B This is a graph of another test sample.

[0034] Figure 14C It has such Figure 10C The graph shown shows the jet force of the test sample of the release component support at the first height as a function of time.

[0035] Figure 14D It has such Figure 10D The graph shows the jet force of the test sample of the release component support at the second height as a function of time.

[0036] Figure 15 This is a graph showing the bioavailability of semaglutide in Yucatan pig test samples over time.

[0037] Figure 16 It is a graph showing the jet force of a test sample with design parameters that lead to less than optimal results as a function of time.

[0038] Figure 17 It is a graph showing the jet force versus time for three samples using the flexural crown.

[0039] Figure 18A and Figure 18B It shows Figure 1 The nozzle cap, in which dimensions are provided in millimeters.

[0040] Figures 19A-19D A method for assembling gas containers and valve assemblies is shown.

[0041] Figure 19A It is a perspective view showing the holder and gas container separately.

[0042] Figure 19B A retainer installed on a gas container is shown.

[0043] Figure 19C The installation of the valve assembly into the gas container is shown.

[0044] Figure 19D It is a cross-sectional view of the assembled device, in which the retainer holds the valve assembly in the gas container.

[0045] Figure 20A-20D The diagram illustrates the assembly of an end cap with a release mechanism to... Figure 19D The method on the container and valve assembly shown.

[0046] Figure 20A It is placed in Figure 19D Side view of the valve assembly O-ring and end cap on the valve assembly shown.

[0047] Figure 20B This is a cross-sectional view of the valve assembly O-ring now moving upward against the valve flange and the end cap snapping onto the flange of the container.

[0048] Figure 20C Is it like this? Figure 20B A perspective view of the device shown.

[0049] Figure 20DThis is a side view showing the removal of the retainer.

[0050] Figure 21A It is used for assembly Figure 20D A side view of the container and end cap valve assembly or drive module with a method for filling and assembling a drug module.

[0051] Figure 21B This is a side view showing the completed device ready for use.

[0052] Figure 21C This is the completed side view, showing the drive and drug modules attached together by laser welding.

[0053] Figure 21D yes Figure 21C Magnified details of the laser-welded joint.

[0054] Figure 21E A side view of the complete device is shown, in which the drive module and the drug module are attached together by threads.

[0055] Figure 21F It is shown Figure 21B A cross-sectional view of the operation of the completed device shown.

[0056] Figure 22A-22G It shows Figure 21B The actuation sequence of the device.

[0057] Figure 22A yes Figure 21B A cross-sectional view of the device before actuation.

[0058] Figure 22B The first actuation stage is shown.

[0059] Figure 22C The second actuation stage is shown.

[0060] Figure 22D The third actuation stage is shown.

[0061] Figure 22E yes Figure 22D A schematic diagram of the jet cover O-ring before actuation.

[0062] Figure 22F yes Figure 22D A schematic diagram of the jet cover O-ring after actuation.

[0063] Figure 22G It is in the subsequent actuation phase during drug delivery. Figure 21B A cross-sectional view of the device.

[0064] Figure 22H yes Figures 22A to 22H A magnified detail of the driver module.

[0065] Figure 22I Showing more details Figure 22A The jet cover.

[0066] Figure 22J An alternative jet cover with double O-rings is shown.

[0067] Figures 23A-23F An apparatus with a gas container lid is shown.

[0068] Figures 24A to 24I An apparatus with a puncture device connected to a gas container is shown.

[0069] Figures 25A-25E A device with a detachable cover is shown.

[0070] Figure 26A and 26B An apparatus using a two-piece gas container is shown.

[0071] Figure 26C and 26D A device with a release component is shown that maintains a sealed engagement between the bottle cap and the gas container.

[0072] Figures 27A-27D An apparatus having a release component and a valve including an O-ring is shown.

[0073] Figure 28A and Figure 28B An example of a release component with a representative size is shown.

[0074] Figure 29A and Figure 29B An apparatus for testing dry-release and wet-release components is shown.

[0075] Figure 30A and 30B An embodiment of the jet cap is shown, wherein one or more O-rings are not placed on one or more nozzles, thereby leaving the nozzles unsealed but sealing the drug payload in the reservoir.

[0076] Figure 31A , 31B Figures 31C and 31D illustrate an embodiment in which one or more nozzles are placed in the jet cap instead of the drug module housing, thereby increasing the volume of the reservoir using one or two O-rings, as shown.

[0077] Figure 32A , Figure 32B , Figure 32C and Figure 32D Alternative end cap valve assemblies are shown, in which circular or cylindrical elements (such as ball bearings) are incorporated into the valve design.

[0078] Figure 33 Another end cap valve assembly is shown, which contains gas that may permeate through the piston or main O-ring 252 of the sealed gas container.

[0079] Figure 34 This is a box plot showing the Instron test of a dry, uncoated release component. Detailed Implementation

[0080] For example in Figure 21A-22J The drug delivery device of the present invention, illustrated herein, is intended to be swallowed to deliver a payload to the gastrointestinal (GI) tissue via one or more liquid jets. The payload is typically a drug deposited into one or more layers of the gastrointestinal tissue, such as the submucosa. Following deposition, the drug is absorbed into the systemic circulation, for example, as measured by the bioavailability of the drug. When administered orally without the device, the drug can be a large molecule with a bioavailability of less than 1%. The drug can be a large molecule greater than about 2,000 or 3,000 Daltons (Da). In some embodiments, the drug bioavailability is greater than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% when administered using the device described herein, relative to intravenous administration.

[0081] In some embodiments, the device is approximately the size of a size 00 capsule or smaller, with a total length of approximately 23 mm or smaller and an outer diameter of approximately 8.5 mm or smaller. In some embodiments, the device has a strength greater than 1000 kg / m² when ready for use. 3 Total density.

[0082] The device has at least one nozzle, and typically has two or more nozzles, which can be equidistantly spaced, for example, two nozzles spaced 180 degrees apart. Figure 22D As shown. In some embodiments, the nozzle diameter is about 0.3 to 0.4 mm, and the nozzle length is about 0.5 to 0.9 mm or 0.6 to 0.8 mm.

[0083] In some embodiments, as measured at a temperature of 23°C ± 5°C from a nozzle spacing of 5 mm, the liquid jet delivered via the jet nozzle has a time to reach peak force of less than 1 ms. The device can produce a liquid jet with a peak force of about 300 to 500 mN or about 350 to 450 mN, optionally with a variation of less than about 15%. In some embodiments, the device produces a liquid jet with an average force of about 200 to 300 mN and a variation of less than 15% between 2 and 5 ms, as measured at a temperature of 23°C ± 5°C from a nozzle spacing of 5 mm. In some embodiments, as measured at a temperature of 23°C ± 5°C from a nozzle spacing of 5 mm, the device produces a liquid jet with a force measured between 5 and 20 ms, which is at least about 90% of the average force measured between 2 and 5 ms, and not less than about 80% at the end of jet ejection, after which the jet force rapidly decreases by about 50% or more in the last about 10 ms of deposition. Figure 14A -D illustrates an exemplary jet force distribution.

[0084] The device is configured not to activate in the subject's stomach for at least approximately 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours, and can be activated in the small intestine for at least approximately 15 minutes, 30 minutes, 45 minutes, 60 minutes, or longer.

[0085] like Figure 1 and Figure 2 As shown, the housing 12 of the ingestible device 10 may include a connector 38 between the drive module 44 and the drug module 30. A reservoir or space 39 within the drug module 30 contains liquid medication. A nozzle cap 33 may optionally be disposed within the drug module 30 (e.g., Figure 1 (as shown), or placed above the drug module (such as...) Figure 3 (As shown), where the nozzle cap prevents liquid from leaving the drug module through the nozzle before the device is started. The housing may have a length LL of approximately 20 mm to approximately 27 mm, as measured from the front end of the drug module to the rear end 62 of the drive module 44, as shown. Figure 1 and Figure 6 As shown. The housing 12 may have a diameter AA of approximately 8 to 11 mm. (Temporary reference) Figure 18A and Figure 18B The nozzle cap 33 may have a recessed radius CR of about 3.8 mm to 4.4 mm and an outer cylindrical edge OC of about 0.4 mm to 0.6 mm in length.

[0086] The nozzle cap 33 may include a protective coating, such as a parylene coating. The protective coating may be used to waterproof, increase dry lubrication, or strengthen the barrier between the nozzle cap and the drug module 30, thereby reducing evaporation or leakage of liquid drug from the drug module. Methods for applying parylene are well known and include chemical vapor deposition in an atmosphere of monomeric parylene. Figure 14A The image shows the jet force distribution of five devices with nozzle caps coated with parylene.

[0087] Parylene is a trade name for a poly(p-xylene) polymer produced by chemical vapor deposition (CVD), which can be used as a moisture and dielectric barrier. Other alternatives to parylene (XY) coating include fluoropolymer (FC) coating (e.g., FluroTec films manufactured by West Pharmaceuticals in Exton, Pennsylvania, USA), atomic layer deposition (ALD), and molecular vapor deposition (MVD). In some embodiments, parylene coating is performed with parylene C at a coating thickness of about 0.5 to 2 μm. Parylene C is produced from the same raw material (dimer) as parylene N, modified only by shifting one of the aromatic hydrogen atoms with a chlorine atom. Parylene C exhibits low permeability to moisture and corrosive gases.

[0088] like Figures 2 to 6 As shown, the ingestible device 10 may include one or more nozzles 31, a gas container or bottle 40, and a piston 32 with a piston seal 34 that slides and seals against the inner surface of the drug module 30 when the device 10 is actuated. A spring 48 applies force to a puncture device 50, which is positioned to puncture the seal on the gas container 40. A puncture device seal or O-ring 52 provides a sliding seal between the puncture device 50 and the release member housing. A trigger or release member 60 prevents the puncture device 50 from moving until the device is actuated. Accordingly, the ingestible device is configured such that after a user swallows the ingestible device, the medication (e.g., formulated as a liquid) in the drug module 30 is not under pressure until the device is actuated. Figure 3 As shown, the retaining element 42 can be used to position the gas container 40. (As indicated...) Figure 5 As shown, the cylindrical surface or portion 76 of the release component support 70 can contact and remain abut against the circumferential ring 58 on the puncture device 50. Alternatively, as Figure 6 As shown, the cylindrical portion 76 can be spaced apart from the circumferential ring 58 on the puncture device.

[0089] The release component 60 may include a release component support 70 and a release component 66. In the illustrated design, the release component support 70 has an internal thread that engages with the threaded rear end of the puncture device 50. This prevents the puncture device 50 from moving forward (towards) via the spring 48. Figure 2-4 (on the left side of the device), until the release component 66 is no longer intact, that is, until the release component is at least partially dissolved, corroded, softened, weakened or disintegrated (e.g., due to liquid absorption, pH, pH changes, the presence and / or concentration of certain enzymes) when the device reaches the appropriate location in the gastrointestinal tract. When the release component 66 is no longer intact, it can no longer resist the force of the spring 48, and the device is actuated.

[0090] Performance is improved if the release component 60 is released in a single catastrophic step. This allows the spring 48 to rapidly and smoothly accelerate the puncture device 50 into the seal (or diaphragm) of the gas container 40 in a single step. The compressed gas is then released substantially instantaneously, driving the piston 32 toward the front end of the device to displace the nozzle cap 33 and generate one or more liquid jets.

[0091] like Figure 6 and Figure 9 The shape of the release component support 70 shown facilitates single-step movement. Figure 6 In this configuration, 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 approximately 3.5 mm to 5.5 mm or 4.3 to 4.7 mm. (Reference) Figure 9 The first conical surface 72 has a minimum diameter of approximately 3.3 mm to 3.9 mm or 3.5 mm to 3.7 mm. The second conical surface 74 is joined to or integral with the first conical surface 72. The lower cylindrical surface 76 has a diameter HH of approximately 2.3 mm to 2.9 mm or approximately 2.5 mm to 2.7 mm.

[0092] The included angle EE of the first conical surface 72 is approximately 89° to 99° or approximately 92° to 95°. The height of the aforementioned surface, as... Figure 9 The dimensions JJ, KK, and LL are shown below: for JJ: approximately 1.6 mm to 2.4 mm or approximately 1.8 mm to 2.2 mm; for KK: approximately 1.0 mm to 1.6 mm or approximately 1.2 mm to 1.4 mm; and for LL: 0.6 to 11 mm or approximately 0.7 mm to 0.9 or 1 mm. (Reference) Figure 7 and Figure 8 The release component support 70 may have a curved top surface with intersecting tool slots 82. For example... Figure 9 As shown, the second conical portion 74 has an included angle that is 6° to 20° smaller than the angle EE.

[0093] refer to Figures 10A-10EThe total height JJ of the release component support 70 can be varied, for example, by increasing the height (or length) NN of the cylindrical portion 76, while other dimensions are optionally maintained as described above. In these examples, Figures 10A-10E The dimensions JJ in the figures are 1.76, 1.86, 1.96, 2.06 and 2.16 mm, respectively.

[0094] The release member support 70 interacts with the release member 66 to actuate the device via a single-step movement. In addition to the shape of the release member support 70 as described above, the dimensions of the release member support 70 relative to the release member 66 also contribute to the single-step movement. For example, in a housing 12 with a diameter AA of 9.5 mm… Figure 6 In this embodiment, the release member 66 may have an outer diameter BB of 6.6 mm and an inner diameter DD of 3.2 mm, wherein the flange 84 of the release member support 70 has a diameter CC of 5.1 mm. In this example, the CC / AA ratio is designated as 0.54 or about 0.5 to 0.6, and correspondingly the CC / BB ratio is designated as 0.77 or about 0.6 to 0.8 or 0.9. Similarly, the CC / DD ratio is designated as 1.6 or about 1.4 to 1.8.

[0095] The effect of the ratio of release component support to release component in Figure 11A As shown, the smaller ratio allows more biofluid to enter the release component. The smaller ratio also generates a radial vector force that helps to displace the release component away from the flat surface of the shell as it degrades in the gastrointestinal tract.

[0096] like Figure 11A-13E As shown, shear or stress elements can be added below the release component to improve the actuation of the device through single-step movement. Figure 11A In this configuration, a compression washer 90 is introduced below the release member, allowing biofluid to pass between the housing and the washer. The release member 66 can rest on top of the compression washer 90, with its bottom surface spaced apart from the end of the housing 62. The compression washer 90 can have an angled surface 92 complementary to an angled annular surface 94 on the end of the housing 62. The compression washer 90 can also have an inner flange 96 with a centrally located protrusion surrounding a collar 98 on the puncture device 50. Holes can be added to the compression washer to allow more or more uniform fluid to enter the release member, further hydrating it. On the circumference outside the hole, as... Figure 11B As shown, the raised sharp point 97 can be used to induce circumferential stress on the release component to better destroy the release component. As the torque on the release component support increases (1), it contacts the compression washer, and the compression washer rises upward, thereby providing additional stress on the release component through the raised feature on the washer.

[0097] Figure 12A -G illustrates another embodiment in which a raised feature or flexural crown 102 is added beneath the release member. The flexural crown 102 allows for increased or more uniform hydration of the release member. The crown may include one or more ribs or other features for applying concentrated pressure on the release member, which facilitates actuation of the device in a single step. The ribs 104 of the flexural crown may be angled or inclined, which also helps to break down the release member and guide debris from the degraded release member away from the housing and release member support. Furthermore, the crown may be made of a material that allows for moderate flexure or compression, thereby increasing the stability of the release member prior to oral administration. Figure 12A-12G In the example, four equally spaced radial ribs 104 are used. The ribs 104 (if used) provide discrete contact lines with the release component. Figure 12D In this design, the flat end of the release component housing is designed to capture and release the component.

[0098] Figure 13A -F illustrates another embodiment in which a raised release member housing element or lug 110 is incorporated into the release member housing. The lug 110 applies concentrated pressure on the release member, thereby causing the device to actuate in a single step. For all the above embodiments, the component added to improve the actuation of the device may be a separate component added to the release member housing, or a component added to the release member housing to form a single component.

[0099] Example 1

[0100] Jet force apparatus (JFR) tests were conducted on different constructions of the ingestible device for jet delivery. The test device was made of plastic components (e.g., polycarbonate) bonded with UV adhesive. The release component was uncoated to facilitate faster release during testing. Unless otherwise specified, the nominal gas container fill volume was 17.2 mg, generating a driving pressure (pressure acting on the piston) of approximately 350 PSI. In the cases indicated in the examples and figures, the device included a nozzle cap that sealed the nozzle during storage and passage through the stomach, and subsequently displaced after release to allow jet delivery. In some cases, the nozzle cap was coated with parylene. The nozzle cap may alternatively be referred to as a second piston.

[0101] Jet Equipment Method

[0102] The following is an overview of the hardware and setup for jet force measurement equipment:

[0103] 1. Equipment Setup for Jet Force System

[0104] a. Power on the Kistler and open the PicoScope software (version 6) on your laptop. Ensure the laptop is connected to both the Kistler and the jet force apparatus fixture.

[0105] b. Load one (1) device into the jet force equipment fixture and visually align the nozzle of the device with the sensor of the fixture. Ensure that the nozzle is positioned near the jet force equipment sensor (Kistler), within 5 mm of the device nozzle. An exemplary jet force sensor is a piezoelectric low-force sensor from Kistler.

[0106] 2. Start recording with the hyperspectral video (HSV) camera.

[0107] 3. Fill the prototype support connected to the device with tap water to initiate the device release or triggering process. Once the device is exposed to water, start the timer. Observe the device release. Once the device releases and camera recording stops, stop the timer. Record the following data according to the jet force equipment operating procedure:

[0108] a. Jet impact force distribution

[0109] b. Peak force (derived from force distribution)

[0110] c. Time to reach peak force (from force distribution)

[0111] d. Jet delivery time (from force distribution and timer) - also known as deployment time.

[0112] 4. Once the device is activated, turn off the HSV camera and save the captured video.

[0113] JFR Results (“JFR”) - “More Preferred” JFR Data vs. “Less Preferred” JFR Data

[0114] refer to Figure 14B "Preferred" JFR data is generated by the following configuration:

[0115] · 350 PSI internal pressure

[0116] • 0.35 mm nozzle diameter

[0117] • 2 radial nozzles

[0118] • P-xylene-coated nozzle cap version F

[0119] • 4.5 mm diameter of release component support

[0120] • 1.9 mm release component support height

[0121] • N=4 test devices

[0122] like Figure 14B As shown, the JFR distributions of all four devices reached peak force within 5 milliseconds (ms) or less, and then gradually decreased before a sharp decline after approximately 30 ms (i.e., deployment time). These JFR distributions can provide improved in vivo performance, as measured by bioavailability. Figure 14A A similar JFR distribution is shown.

[0123] Example 2

[0124] Jet Equipment Results - JFR Data for Nozzle Caps Coated with P-xylene

[0125] The ingestible device with a nozzle cap coated with parylene was tested using the above-described jet force equipment. The ingestible device is further constructed as follows:

[0126] • 350 PSI internal pressure or drive pressure

[0127] • 0.35 mm nozzle diameter

[0128] • 2 radial nozzles

[0129] • P-xylene-coated nozzle cap version F

[0130] • 4.5 mm diameter of release component support

[0131] • 1.9 mm release component support height

[0132] • N=7 test setups

[0133] like Figure 14A As shown, the JFR distribution reaches peak force in less than 5 ms and has a deployment time of greater than 30 ms. This device configuration can provide improved bioavailability.

[0134] Example 3

[0135] JFR data for trigger supports with different neck lengths:

[0136] The above-mentioned jet force equipment was used for testing, as follows: Figure 10C and Figure 10D The ingestible device shown has a trigger support with varying height. The ingestible device is further constructed as follows:

[0137] • 350 PSI internal pressure or drive pressure

[0138] • 0.35 mm nozzle diameter

[0139] • 2 radial nozzles

[0140] • P-xylene-coated nozzle cap version F

[0141] • 4.5 mm diameter of release component support

[0142] • 2.0 mm release component support height (~ Figure 10C ) and 2.1 mm trigger support height (~ Figure 10D )

[0143] • N=6 devices for testing the height of the 2.0 mm trigger support, and N=7 devices for testing the height of the 2.1 mm release component support.

[0144] like Figure 14C As shown, a 2.0 mm release component support height produces a more preferred JFR distribution. In contrast, a 2.1 mm release component support height results in two of the seven devices having a less preferred JFR distribution, such as... Figure 14D As shown in the figure, devices 1 and 4 rapidly decreased from the start within 5 or 10 milliseconds, while the jet force of the other devices remained near the initial maximum jet force for approximately 30 to 35 milliseconds. The inventors believe that a longer or taller release component support (e.g., 2.1 mm high) may not allow for a proper puncture travel length, resulting in partial, incomplete, or slow release of compressed gas from the gas container.

[0145] Example 4

[0146] Performance evaluation of an ingestible multi-nozzle jet delivery device in Yucatan pigs

[0147] The study used a molded ingestible device designed and constructed for jet delivery into the gastrointestinal tract. The ingestible device operates by releasing a liquid jet with sufficient energy to deposit a drug payload into the gastrointestinal tissue, triggered by the disintegration of the release component at the desired site. Following deposition, the drug can be absorbed into the 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, in particular, by measuring the pharmacokinetics of submucosal injection compared to subcutaneous or intravenous administration of the same test article.

[0148] To evaluate the injection efficiency of the ingestible jet delivery device, an autonomous device with a non-enteric-coated release component was positioned via endoscopic placement (ID) into the proximal small intestine of female Yucatan pigs and released. The device configuration is as follows:

[0149] • 350 PSI internal pressure or drive pressure

[0150] • 0.35 mm nozzle diameter

[0151] • 2 radial nozzles

[0152] • Nozzle cap version D

[0153] • 4.5 mm diameter of release component support

[0154] • 1.9 mm release component support height

[0155] • Test drug: Semagranitide

[0156] • N = 7 test animals + 1 control animal administered the test drug subcutaneously (SQ)

[0157] result:

[0158] Seven of the seven devices were successfully advanced via endoscopic placement through the pyloric sphincter and triggered in the proximal small intestine. All seven animals showed detectable drug levels up to 72 hours post-administration. Figure 15 Furthermore, the mean oral bioavailability was 19% compared to the IV control (from the earlier study PSS2) and 25% compared to the SQ control (from this study and the earlier study PSS4). No significant adverse clinical signs were observed in animals before or up to 10 days after administration.

[0159] Figure 15 The results are shown.

[0160] Example 5

[0161] Result data of jet equipment using flexible crown trigger support.

[0162] like Figure 12A and 12B The ingestible device with a flexible crown shown was tested using the aforementioned jet force testing equipment. These ingestible devices are further configured as follows:

[0163] • 400 PSI internal pressure or drive pressure

[0164] • 0.35 mm nozzle diameter

[0165] • 2 radial nozzles

[0166] • Nozzle cap version F

[0167] • Flexural crown release component support

[0168] • N=3 test devices

[0169] like Figure 17 As shown, these three devices illustrate a more preferred JFR distribution.

[0170] Example 6

[0171] refer to Figure 16 The "less preferred" JFR data is generated by the following configuration:

[0172] • 400 PSI internal pressure or drive pressure

[0173] • 0.40 mm nozzle diameter

[0174] • 2 radial nozzles

[0175] • Nozzle cap version D

[0176] • 5.7 mm diameter of release component support

[0177] • 1.4 mm release component support height

[0178] • N=4 test devices

[0179] like Figure 16 As shown, the JFR distribution did not reach peak force within 5 milliseconds (ms). Instead, the force increased sloping over time and did not reach peak force within 5 ms or less. Furthermore, the deployment time or delivery duration was less than approximately 30 ms. Figure 16 The JFR distribution shown can indicate slow piston-like or multi-stage release events (i.e., not a single step). This can lead to inconsistent or low bioavailability in vivo.

[0180] Figure 19A -D illustrates an assembly method in which gas container 208 is filled with compressed gas. This method allows the gas container (e.g., with a volume of 50-140 μL, 80-110 μL, or 90-100 μL) to be filled with high-pressure gas (e.g., 1,000 psi to 2,500 psi). A retainer 202 is coupled to an unfilled gas container, such as... Figure 19A and 19B As shown. In Figure 19C In the process, the gas container 208 is filled in the pressurized filling chamber. Figure 19D The diagram shows the valve plug 215 of valve assembly 214 being pressed into the opening of the neck 224 of the gas container and secured in place against gas pressure by retainer 202. Retainer 202 can be secured to gas container 208 using hook 209 that engages with valve retainer 218 of valve assembly 214. Once gas container 208 is filled and sealed with valve assembly 214, it can be transported or stored for future use, for example, as part of an ingestible device.

[0181] Figure 20A-D illustrates an assembly method in which an end cap 212 having a trigger or release component 210 and an end cap seal or O-ring 230 are press-fitted to... Figure 19D The end cap 212 is attached to the pressurized gas container 208 shown. It can be attached in various ways, for example, such as... Figure 20B As shown, the end cap 212 can snap onto the flange 222 on the gas container 208. After the end cap 212 is press-fitted, for example, onto the pressurized gas container 208 and / or the valve assembly 214, the retainer 202 is removed, and the resulting end cap valve assembly 206 can be coupled to the drug module, such as... Figure 21A As shown in -B and 22A. It has Figure 19C , 19D Embodiments of the end cap valve assembly 206 with more or fewer elements as shown in 21A, 21B and 22A are also referred to herein as drive module 44.

[0182] Figure 21A -B illustrates the method for connecting the drug module 30 to... Figure 20A Assembly method of the -D drive module 44. The component can be strong enough to withstand... Figure 21F Any method of joining using pressure and force as described in the text, such as adhesives, ultrasonic welding, etc. Figure 21C and 21D Laser welding as shown or as Figure 21E The thread 47 is shown. Thread 47 allows for height adjustment of the valve assembly relative to the release member to accommodate any potential changes in the release member. It also allows for the reuse of the device or a portion thereof. Laser welding allows for precise control of welded areas with tight mechanical contact. Unlike threaded connections, laser welding is permanent; therefore, many parts cannot be reused.

[0183] Laser welding eliminates the need for fasteners or adhesives. For example... Figure 21D As shown, the interface between the drive module 44 and the drug module 30 may taper at 279, above the nozzle opening 274, to accommodate the laser welding process or increase frictional resistance. The interface may use an interference fit. In some embodiments, such as... Figure 21D As shown, the cavity or protrusion 45 on the end cap of the drug module housing provides excess material to accommodate laser welding. The drug module housing can be transparent or translucent to accommodate laser welding.

[0184] Figure 21F The relationship between pressure, force, and volume is shown for various devices. Figure 21FThe area within the dashed line AAA indicates 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. The pressure in the container is determined by the desired drive pressure on the piston 250, the available volume of the gas container, and the volume to which the gas will initially expand upon opening. Assuming this pressure is fixed by other components of the device, the force applied to the release component can be adjusted by changing the area of ​​the valve plug 215, thus confirming the effect of friction on reducing this force.

[0185] In some embodiments, the gas in the gas container includes at least one gas selected from the group consisting of air, nitrogen, oxygen, carbon dioxide, hydrofluorocarbons, and rare gases or mixtures. The container may also contain a relatively small amount of helium for easier gas detection. In some embodiments, the gas container is filled with a liquefied gas, such as difluoromethane (R-32, CH2F2), carbon dioxide, or argon. Liquefied gases offer advantages over non-liquefied gases. For example, difluoromethane allows for a smaller bottle volume compared to non-liquefied gases, and liquefied gases provide a more consistent gas pressure throughout the piston stroke. Argon has the advantage of being less sensitive to temperature changes compared to difluoromethane.

[0186] exist Figure 21F The area within the dashed line BBB represents the initial system volume, which is a portion of the total expansion gas volume required to drive the end cap nozzle. This volume is defined as the space from the end cap seal or O-ring 230 to the piston seal or O-ring 252 minus the space occupied by the gas container 208 and valve assembly 214. Finally, Figure 21F The device portion of CCC shows the liquid drug container. The volume of the drug container is related to the amount of pressure drop the device can tolerate while still successfully delivering the drug. Larger drug payloads require larger allowable pressure drops, and vice versa. The payload can be at least 300 μL, with the total device size approximating the size of a size 00 capsule.

[0187] Figure 22A This illustrates the initial state of the actuation sequence of the assembled device 200, which can be ingested prior to administration in vivo. The valve holding force is the force on the trigger or release component 210 prior to device actuation (e.g., before administering the device to a human or animal subject). The valve holding force is a function of the valve area and the container filling pressure.

[0188] For example, in Figure 22A Medium: 2 mm outer diameter valve * 1,400psi ≈ 30N

[0189] Example of "low" force: 1mm valve * 1, 400psi ≈ 7.5N

[0190] Example of "high" force: 3mm valve * 2,000psi ≈ 100N

[0191] The range of 7.5N to 100N is an exemplary range of force acting on the release component before the ingestible device is actuated in the subject's gastrointestinal tract (i.e., in phase 0 of device actuation).

[0192] Figure 22B Phase 1 of the actuation sequence of device 200 is shown. The release component 210 is designed to degrade in the gastrointestinal tract of the subject (the treated patient) after the device 200 is administered. The release component 210 may include an enteric material that prevents degradation in the relatively low pH environment of the stomach and subsequently as it travels to the relatively high pH environment of the small intestine. In some embodiments, all or part of the ingestible device 200 is covered with an enteric material, exposing portions of the ingestible device, such as the release component, upon degradation. As the release component 210 begins to degrade (e.g., dissolves in the presence of a biofluid in the gastrointestinal tract), the valve assembly 214 may travel longitudinally, thereby initiating displacement from the container opening. With sufficient movement, the displaced valve assembly 214 allows gas to exit the gas container 208 and fill the initial system volume, such as... Figure 22B As shown. The initial system volume also helps to contain any potential gas leakage from gas container 208 before the device is actuated.

[0193] Figure 22C Phase 2 of the actuation sequence of device 200 is shown. In phase 0 (as in... Figure 22A Prior to actuation, pressure from the gas container acts on a relatively small cross-sectional area of ​​the valve (e.g., 2 mm valve plug 215). After the release member 210 begins to degrade and the valve assembly can partially travel into the space occupied by the release member 210, gas from the container 208 can act on a larger cross-sectional area of ​​the valve assembly (e.g., ...). Figure 22H The 5 mm valve base or plate 216 shown. This increases the force acting on the valve assembly 214 (e.g., 60+ N), which further helps the valve assembly 214 push in or displace the release component, allowing more gas to quickly leave the gas container 208 and fill the initial system volume 260. Once sufficient internal capsule pressure is achieved, this multi-stage actuation allows for the formation of a near-instantaneous single-step liquid jet.

[0194] Figure 22DPhase 3 of the actuation sequence of device 200 is shown. In phase 0, the jet cap O-ring 272 on the jet cap 270 blocks one or more nozzles 274 during device filling and maintains a sterile seal before device startup, thereby preventing the payload from leaving device 200. In phase 3, the release component is fully degraded or ejected, and valve assembly 214 is now fully open, allowing all gas pressure to act on piston 250. When this occurs, 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, e.g., away from the drive module. The device can be sterilized before filling with the drug, e.g., using radiation or gas sterilization methods.

[0195] Figure 22E and 22F The transition of the actuation sequence of device 200 from stage 3 to stage 4 is shown. When the jet cover O-ring 272 is driven by gas pressure (in... Figure 22E As it moves from center to left, it is pushed against the angled (e.g., approximately 10-30%) inner lip 276 and becomes increasingly compressed. This begins to open via longitudinal movement, thereby exposing one or more nozzles 274, as... Figure 22F As shown, this provides a path for the liquid drug dispensing device housing 204, for example, as a liquid jet. Figure 22E As shown, the jet cap O-ring 272 is initially under a certain pressure (e.g., resulting in 5-25% O-ring compression). As the pressure increases, the O-ring compression also increases (e.g., resulting in 40% or more O-ring compression), and the jet cap 270 can overcome the frictional forces generated by the housing 204 (see...). Figure 22E (The lip 276 in the middle). Once overcome, the movement of the jet cap 270 provides an opening for one or more nozzles. The pressure required to initiate the movement of the jet cap can be 5-30 psi or 10-20 psi. The jet cap can be a rigid material, which can be the same material as the device housing 204, such as polycarbonate, and / or a material compatible with the drug payload, such as Makrolon® polycarbonate.

[0196] In alternative embodiments, such as... Figure 22JAs shown, a second O-ring is incorporated into the jet cap. In one embodiment, the primary jet cap O-ring 281 covers one or more nozzles prior to actuation, while the secondary jet cap O-ring 283 is positioned above one or more nozzles. The device housing 204 may have an internal draft taper above one or more nozzles to increase frictional resistance as the jet cap shifts and travels longitudinally to expose one or more nozzles. In this embodiment, the jet cap may not include a jet cap lip or step 276. In another embodiment, any O-ring described in the device, such as the valve O-ring 226, end cap seal 230, piston O-ring 252, or jet cap O-ring, may include a second O-ring, such as... Figure 22J As shown. In relevant embodiments, as Figure 22J As shown, one or more O-rings may have a square profile. Additionally, in some embodiments, one or more O-rings are made of butyl rubber, a fluorinated elastomer (e.g., fluororubber), or nitrile rubber.

[0197] Figure 22J The design eliminated Figure 22I The lip or step 276 shown is provided, and a draft taper (e.g., a 2-degree wedge) is introduced above the nozzle to increase frictional resistance as the jet cover travels longitudinally.

[0198] Device seals can be made of thermoplastic elastomer materials and are overmolded onto valve, end cap, piston, or jet cap components to provide sealing integrity for device performance in place of O-rings. Overmolded elastomer seals can include single, double, or multiple seal configurations necessary to achieve permeability and performance requirements.

[0199] In one embodiment involving O-rings or overmolded thermoplastic elastomer seals, the lubricant is incorporated into the O-ring or elastomer. Alternatively, the lubricant can be applied directly to the O-ring or thermoplastic seal. The lubricant, if used, is intended to address the high static friction associated with long shelf life.

[0200] Figure 22G Phase 4 of the actuation sequence of device 200 is shown. In phase 4, the movement of the jet cover 270 and piston 250 increases the volume of the capsule, which improves pressure control and reduces the pressure drop when the payload is discharged from device 200 via nozzle 274. The ingestible device 200 may include an external nozzle cover 278 on the outside of housing 204 that blocks nozzle 274. The external nozzle cover is specifically designed to prevent fluid or GI material from entering one or more nozzles before device actuation. When the device is actuated, the movement of the jet cover 270 displaces the external nozzle cover 278, thereby opening the exterior of nozzle 274.

[0201] refer to Figure 22HThe release component may have an annular surface or shoulder abutting the retaining ring 238 of the end cap 212. The annular surface of the retaining ring 238 may be oriented at an acute angle to the central axis of the housing. The valve retainer 218 on the valve assembly 214 (if used) may extend through an opening in the flange 222 on the gas container 208. An O-ring 226 on the valve plug or pin 215 seals against the inner surface of the neck 224 of the gas container 208. An O-ring 230 on the end cap seals against the inner bore of the end cap 212.

[0202] like Figure 22H As shown, valve assembly 214 may include valve plug 215, valve plate 216, and retainer 218. End cap latch 236 attaches end cap 212 to gas container 208. Piston seal 252 may be included in a seat formed by flange 254 on the piston. Piston seal may include a second O-ring. Whether piston seal 252 includes one or two O-rings, the O-rings serve as a seal between the drug payload and drive module 44 during filling-completion and actuation of the device. The seal is designed to maintain a dynamic seal as piston 250 moves to withstand high-pressure expansion of gas from gas container.

[0203] In another embodiment, the valve allows pressure to be applied to a freely moving sealing element to generate a force in the direction of valve movement. Different valve designs achieve this in... Figures 32A-32D As shown in the diagram. The valve design incorporates circular or cylindrical components, such as ball bearing 300 or cylinder 302, but can also have other cross-sectional shapes, as long as sufficient sealing is maintained. For example... Figures 32A-32C As shown, an O-ring or other sealing element passes through a side port to deliver gas into the expansion space.

[0204] exist Figure 33 In another embodiment shown, the valve assembly is designed to accommodate the permeation of gas from the gas container through the main O-ring or valve O-ring 226 of the sealed gas container. This gas fills the initial system volume BBB (in Figure 21C As shown in the diagram, if overpressurized, the initial system volume BBB can generate sufficient force on piston 250 to prematurely displace the jet cover and eject the liquid drug from one or more device nozzles. Figure 33 The valve assembly shown includes an auxiliary O-ring or end cap seal 230, which is larger than the valve O-ring 226. Assuming the same cross-section, it has greater permeability due to its larger area. If a material with higher permeability than the valve O-ring is chosen, the area and permeability can be combined to allow gas to pass through the end-sealed O-ring under expansion space pressure, which will prevent drug extrusion.

[0205] For example, if the average diameter of the valve O-ring is 1.5 mm, the diameter of the end cap sealing O-ring is 5 mm, and the cross-sections are the same, the permeation area ratio is 3.3. According to data from Marco Rubber & Plastics in West Brook, New Hampshire, USA, Viton fluorocarbons have a nitrogen permeability of 0.05-0.7 x 10⁻⁸ sccm–cm / sec–cm²–atm, silicone is 200 x 10⁻⁸, and EPDM elastomer is 6-7 x 10⁻⁸. Therefore, in one embodiment, using a fluorocarbon as the valve (main) O-ring and EPDM or silicone as the end seal (auxiliary) O-ring can result in the same rate of gas permeation at pressures 1 / 28 to 1 / 13,000 times that of the fluorocarbon. Thus, the permeation flow can be supported by expansion space pressures far below the gas container pressure. In one embodiment, the valve O-ring 226 is made of a low-permeability material such as fluorocarbons or butyl rubber, and the end cap O-ring or seal 230 is made of a higher-permeability material such as EPDM or silicone.

[0206] like Figure 22I As shown, the jet cap may include a jet cap vent J 277, which allows filling, for example, with a 21-gauge needle. After filling, the jet cap vent 277 may be sealed, for example, with a low-profile heat-fused column, thereby maintaining the sterility of the drug payload. Figure 22I The vent cap 277 shown can be incorporated into other ingestible devices for delivering drug payloads, such as those described in PCT application WO2019246273.

[0207] exist Figures 23A-23C In this embodiment, the release component housing does not include a spring. Instead, the container cap 8100 locks into the gas container to prevent the release of 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... Figure 23C As shown. A second O-ring 8106 is mounted on the container cap, and both the release component and the gas container assembly are inserted into the release component housing. The cap is rotated again, for example, 90 degrees, to unlock it, and the gas pressure from the gas container now pushes the container cap against the release component. After administration, the release component is introduced into the biofluid, where it dissolves or degrades at a predetermined anatomical location based on physiological conditions such as pH. When the release component dissolves or degrades, the container cap displaces from the gas container, and gas is released from the pressurized container, thereby actuating the device. Therefore, in this design, no spring or puncture device is used.

[0208] refer to Figure 23E and 23FThe release component housing may include one or more ribs 8110 or other features for applying concentrated pressure to the release component, which contributes to catastrophic failure of the release component. In this case, gas from the gas container applies force to the release component, which also helps to remove the release component or debris from the release component housing. The release component housing or end cap may optionally include openings or windows that allow for increased or more uniform hydration of the release component.

[0209] The release component housing may include one or more ribs or other features for applying concentrated pressure to the release component, which can contribute to catastrophic failure of the release component. Additionally, the release component housing may provide space for debris from the release component to disperse, thereby preventing blockage of any moving parts on the device, such as bottle caps.

[0210] In another embodiment, similar to Figures 23A to 23F The device shown omits a spring in the release housing; instead, a puncture element is used to seal the gas container. These two components are connected via a pressure fit, as... Figures 24A to 24I As shown. The puncture device may include an O-ring 8200 to improve sealing. The puncture device disrupts a destructible seal or diaphragm of the gas container. After the puncture device is coupled to the gas container, the release component housing or drive module housing engages with the drug module housing. Similar to... Figures 23A to 23F The device shown has a release component that helps maintain a seal between the puncture device and the gas container. When the release component dissolves or degrades in the presence of the biofluid, the puncture device displaces from the gas container, and gas is released from the gas container, thereby actuating the device.

[0211] Similar to Figures 23A-23F The apparatus shown in 24A-24I, in Figures 25A-25E In this design, the release component housing does not include a spring; instead, a puncture device or puncture-shaped plug 8300 is used to seal the gas container. These two components are connected via a slide valve 8302. The shape and position of the release component put the corrosive surface under tension to accelerate structural failure or degradation of the release component, thereby actuating the device. In another embodiment, the device includes a second piston 8304 for blocking the opening, wherein the second piston includes an internal release cap 8306. Figure 25C and Figure 25D As shown, the separation section is accommodated in a housing recess after the driven piston is displaced. The drug payload can flow through a channel in the housing and out of the opening. Alternatively, the second piston 8304 is movable to expose the opening, and the separation cap can be used as a vent.

[0212] Figure 26A and Figure 26B The device shown is similar to Figures 23A-23F and Figures 24A-24IThe device shown, however, includes a second piston 8400 that blocks one or more openings until the device is actuated. Furthermore, the gas container 8402 has a first portion 8404 sealed with an end cap 8406. These two portions separate to allow gas to escape when the release mechanism weakens. The gas container can be reduced to a total volume of approximately 80-100 pL, and the drug volume can be increased to 500-600 pL. In this embodiment, neither a spring nor a puncture device is used.

[0213] Similar to Figure 26A and Figure 26B , Figure 26C and Figure 26D The device 8401 shown has a gas container 8402 sealed with a second portion, such as an end cap 8406. The end cap 8406 may or may not include an inner O-ring on a portion of the end cap extending into the opening of the gas container, and an outer O-ring that slidably seals the end cap against the inner wall of the release member housing. The end cap 8406 is held in a sealed position against the opening of the gas container by a release member 8408. The end cap 8406 prevents gas from escaping from the gas container (while the release member remains intact). When the release member is partially or completely eroded, degraded, cracked, and / or dissolved, the end cap is pushed away from the gas container, allowing gas to escape, which actuates the device. As shown, no puncture device or spring is used. In some embodiments, the device does not include... Figure 26D The second piston shown, and in other embodiments, includes, for example, a second piston. Figure 26A and 26B The second piston is shown. In some embodiments, the release component housing or end cap includes an opening or window that allows for increased or more uniform hydration of the release component and allows degradable material from the release component to displace away from the housing. In some embodiments, the window is covered with an enteric material to prevent fluid from entering until the enteric material degrades at the desired location in the gastrointestinal tract.

[0214] In some embodiments, O-rings are used to seal gas containers, such as Figures 27A-27B As shown, the release mechanism uses one or more O-rings 8500 and 8501 in the receiver or end cap 8502 for gas displacement. Figure 27B An ingestible device 8510 with a gas container is shown, the gas container having a first or spherical portion 8512, a sealing plate 8514 coupled to the neck or narrow end of the spherical portion 8512, and a diaphragm or seal 8516 on the sealing plate 8514, which can be punctured by a puncture device 8518. The puncture device 8518 may have a length measured from the top of the shield (its bottom abutting against the release component housing), which is approximately 2-3 mm or approximately 2.4 to 2.6 mm. In this design, the puncture device parameters are shown in the table below.

[0215]

[0216]

[0217] Therefore, the spring can apply a force of approximately 35 N to 45 N.

[0218] Figure 27C and Figure 27D An alternative device 8600 is shown, which has an O-ring 8602 surrounding the outside of the neck of the gas container, the O-ring 8602 protruding into a recess 8604 in the end cap 8606. Figure 27C The device 8600 before actuation is shown. Figure 27D The device 8600 after actuation is shown.

[0219] This device has a release component 210 that, upon degradation in the GI tract, allows actuation of the device and deposition of a drug payload into the gastrointestinal tissue for systemic uptake. In some embodiments, the release component can withstand (i.e., not degrade) forces greater than about 10 N, 15 N, 20 N, 25 N, 30 N, 35 N, 40 N, 45 N, 50 N, or greater in a gastric environment for more than 1, 2, 3, or 4 hours. As used herein, a gastric environment refers to a low pH environment 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 by less than about 0.10 mm, 0.15 mm, 0.20 mm, 0.25 mm, 0.30 mm, or 0.35 mm in the gastric environment. In another embodiment, the release component degrades in the small intestinal environment within 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, or 60 minutes, thereby actuating the device described herein. In some embodiments, the release component is displaced in the small intestinal environment by more than about 0.55 mm, 0.65 mm, 0.75 mm, 0.85 mm, 0.95 mm, or more. As used herein, the small intestinal environment refers to a pH environment 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 generated by a 1-3 mm valve pin or plug 215 that seals a gas container 208 having a gas pressure of about 800 psi to 2000 psi.

[0220] In another embodiment, the release component 210 comprises a rapidly disintegrating effervescent material that selectively degrades in the presence of a fluid (e.g., a biofluid) 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., superdisintegrants), or multiple fillers or swelling 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., superdisintegrants), or more fillers or swelling agents, one or more binders, and one or more lubricants.

[0221] 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., superdisintegrants), or more fillers or expanders, one or more adhesives, 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., superdisintegrants), or more fillers or expanders, one or more adhesives, and one or more lubricants. In another embodiment, the release component 210 comprises each of one or more of the following materials: one or more effervescent materials, one or more wicking agents (e.g., superdisintegrants), or multiple fillers or expanders, one or more adhesives, and one or more lubricants.

[0222] Effervescent materials in release components release gas, typically carbon dioxide, when dissolved in a fluid (e.g., a fluid in the gastrointestinal tract). Examples of effervescent materials in release components include, but are not limited to, sodium bicarbonate or magnesium bicarbonate and acids such as citric acid or tartaric acid. Effervescent materials may be present in the release component at approximately 17% to 37% of its total weight. A wicking agent in the release component is used to carry water to the internal surfaces of the release component, thereby accelerating its disintegration. Examples of wicking agents in release components include, but are not limited to, low molecular weight polyvinylpyrrolidone (PVP), kaolin, alumina, bentonite, colloidal silica, sodium carboxymethyl cellulose (NaCMC), sodium dodecyl sulfate (SLS), and titanium dioxide. The wicking agent may be present in the release component at approximately 0.5% to 5.0% of its total weight.

[0223] Release component fillers are typically inert substances added to increase the volume or capacity of the release component. Examples of release component fillers include, but are not limited to, lactose, cellulose, microcrystalline cellulose (MCC), calcium carbonate, and starch. Fillers may be present in the release component at approximately 22% to 62% of its total weight. Release component binders are used to enhance the adhesion between different materials in the release component. Examples of release component binders include, but are not limited to, gum arabic, starch, including pregelatinized starches such as StarTab®, LYCATAB®, or Starch 1500®, gelatin, methylcellulose, and hydroxypropyl cellulose (HPC). Binders may be present in the release component at approximately 17% to 47% of its total weight. Release component lubricants are used to improve powder flow during the manufacture of the release component. Examples of release component lubricants include, but are not limited to, calcium stearate, magnesium stearate, sodium dodecyl sulfate (SLS), poloxamer 188, and poloxamer 407. Lubricants may be present in the release component at approximately 0.4% to 2.2% of its total weight.

[0224] In some embodiments, the release component has degradation properties consistent with plastic deformation. In one embodiment, the release component comprises approximately 37% to 73% of a combination of fillers and binders, resulting in the release component having degradation properties consistent with plastic deformation.

[0225] The release component can be shaped in any form to facilitate actuation of the device during degradation in the gastrointestinal tract. For example, such as... Figures 1 to 6 As shown, the release component releases a spring-loaded puncture device that punctures a diaphragm in a gas container, thereby actuating the device. And... Figure 22A In -D, the release component is used to hold the valve pin 215 in the opening of the neck 224 of the gas container 208 until the release component 210 begins to degrade and the valve can partially enter the space occupied by the release component 210, after which compressed gas from the container 208 rapidly exits the container and the device starts. In this embodiment, Figure 28A and 28B The release member shown carries a pre-actuated load as a compressive force on the shoulder 246, wherein the shoulder 246 contacts the retaining ring 238 on the end cap, as... Figure 22A -C is shown.

[0226] During the initial degradation of the release component, the load is transferred to the valve plunger 232. Gas pressure forces the plunger 232 to rest centrally against the front surface of the release component, thereby generating shear stress in the release component. In some embodiments, the force required to break the release component is lower than the force required to break it when it is a tensile or shear force, compared to a compressive force. In some embodiments, the plunger 232 is shaped to increase the force applied to a smaller area of ​​the release component. For example, the plunger 232 is wedge-shaped. In related embodiments, the release component may be scored or otherwise structurally weakened at or near the point where the plunger 232 contacts the release component when the device is initially actuated. Other examples of modifications to the release component include inlet holes, recesses, lines, or concave surfaces.

[0227] Figure 28A -B illustrates an example of a release component. The front and rear surfaces may be concave, as shown, where the front surface 241 has a radius of curvature 1.5 to 2.5 times that of the rear surface 244. From front to back, the release component can be described as having a concave front surface 241, an annular or cylindrical portion 242, a tapered or angled portion 243 adjacent to the cylindrical portion 243 via a radius 245, and a concave rear surface 244. The concave surface of the release component offers several advantages over a flat surface, namely, allowing for a more uniform coating shape of the release component, distributing force to or near the edges of the release component while maintaining integrity, or conforming to the contour of the end cap. The rear portion of the cylindrical portion 242 forms a shoulder 246 at a radius 245. In use, the shoulder 246 is pressed against the retaining ring 238 of the end cap, where the entire rear surface 244 is exposed to the external environment of the gastrointestinal tract. The figures provide representative dimensions when the release component is coated 20% (by weight). In some embodiments, the size may be 5-20% larger or smaller depending on the coating weight, the material of the release component, or the overall dimensions of the device. In some embodiments, the ratio of the valve support diameter to the width of the tapered portion is about 1.2, 1.3, 1.4, 1.5, or 1.6. In some embodiments, the release component expands by about 2-15% of its volume upon fluid introduction, thereby forming a seal with the end cap (including the retaining ring 238) and reducing fluid ingress into the end cap assembly before the release component is completely degraded.

[0228] In another embodiment, the release member is used to retain the valve pin 215 in the opening of the neck 224 of the gas container 208 until the release member 210 begins to degrade and the valve, after which the valve is displaced from the container opening. In this embodiment, the valve may be spring-loaded or threaded into the opening before actuation, such as... Figure 23D As shown in -E, the release component may be a latch or a pin, which allows the valve to be displaced from opening 224 (e.g., unscrewed) upon degradation.

[0229] 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 coating. In some embodiments, the base layer comprises a bottom coating or sealing layer and a top coating. The bottom and top coatings may be applied at different weights, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9% or more of the total weight of the release component. Examples of bottom (sealing) and top coatings include, but are not limited to, methylcellulose (MC), polyvinyl alcohol (PVA), hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), shellac, pure ethanol, and zein; similarly, enteric coatings may be applied at different weights, such as 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more of the total weight of the release component. Examples of enteric coatings include enteric polymers.

[0230] In some embodiments, the enteric polymer may remain insoluble in the stomach but dissolve at a higher pH in the intestine (e.g., the small or large intestine) and be used to deliver a drug into the intestine. Examples of such enteric materials that dissolve in the small intestine and are suitable for small intestinal release include, but are not limited to, cellulose derivatives such as cellulose acetate, hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and RL100 (e.g., HP-55), malate-propane 1,2-diol, polyvinyl acetate phthalate, anionic polymers of methacrylic acid and methyl methacrylate, hydroxypropyl cellulose acetate, polyvinyl acetate phthalate, methacrylate-methacrylic acid copolymers, styrene, maleic acid copolymers, shellac, etc. Other examples of enteric-coated materials include Colorcon's Opadry Enteric-coated 91 series polyvinyl acetate phthalates, Opadry Enteric-coated 94 series methacrylic acid, Opadry Enteric-coated 95 series methacrylic acid, Sureteric PVAP (polyvinyl acetate phthalates), Nutritric ethyl cellulose, and Evonik's Acrylic-EZE (Colorcon & Evonik collaboration - Eudragit L 100-55 blend methacrylic acid copolymer); Evonik's Eudragit L 100-55 methacrylic acid copolymer, Eudragit L 30 D-55 methacrylic acid copolymer (30%), Eudragit L 100 methacrylic acid copolymer, Eudragit L 12.5 methacrylic acid copolymer (12.5%), Eudragit S 100 methacrylic acid copolymer, Eudragit S 12.5 methacrylic acid copolymer (12.5%), and Eudragit FS 30. D-methacrylic acid copolymer (30%); Kerry's SheffCoat ENT cellulose acetate phthalate copolymer, HPMC-P; Eastman's CAP NF cellulose acetate phthalate; Sensient's PROTECT™ ENTERIC shellac and sodium alginate. Another suitable enteric coating material is an aqueous emulsion of ethyl acrylate methacrylic acid copolymer or hydroxypropyl methyl cellulose acetate succinate (HPMAS).

[0231] In some embodiments, the device described herein is designed to deliver a 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 release into the large intestine (e.g., the colon) are known to those skilled in the art. In some embodiments, the degradation of the coating is microbially triggered, for example, enzymatically triggered by bacteria in the colon (see, for example, 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 contains an acid, such as methacrylic acid. Examples include acrylic resins (EUDRAGIT)® L100-55, EUDRAGIT® L100, EUDRAGIT® S100, and EUDRAGIT® FS100. In some embodiments, the enteric coating is a polymethacrylate having 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.

[0232] In some embodiments, the enteric coating is a polymethacrylate having a pH-dependent dissolution threshold of about pH 6.0-7.0. Examples of suitable enteric coating materials include, but are not limited to, Evonik's Eudragit® L100 and Eudragit® L12.5. In some embodiments, the coating is a polymethacrylate having a pH-dependent dissolution threshold higher than about 7.0. Examples of suitable enteric coating materials include, but are not limited to, Evonik's Eudragit® S100, Eudragit® FS30D, and Eudragit® FS100. Other examples of suitable enteric coating materials include, but are not limited to, chitosan, alginate (e.g., as a calcium salt), hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, and cellulose trimellitate acetate. In some embodiments, the enteric material is the enteric material described in U.S. Patent 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 is incorporated herein by reference in its entirety (for the U.S. National Phase only).

[0233] In some embodiments, the colon-specific degradation of enteric-coated materials can be based on the presence of microorganisms present only in the colon, and more specifically, on biodegradable enzymes produced by these microorganisms. Typically, these microorganisms are anaerobic bacteria, such as Bacteroides, Bifidobacteria, Enterobacteriaceae, eubacteria, Clostridium, Enterococci, and Ruminococci. These microbiota meet their energy needs by fermenting various types of substrates (e.g., polysaccharides, disaccharides, and trisaccharides) that are undigested in the small intestine. These polymers are stable in the gastric and small intestinal environments. Upon reaching the colon, the polymers undergo enzymatic degradation or breakdown of the polymer backbone, resulting in a subsequent decrease in their molecular weight and loss of mechanical strength. In some embodiments, the device described herein is used for colonic delivery, which does not deliver the drug payload via liquid jet delivery. Instead, the device delivers the drug payload into the gastrointestinal lumen. This can be achieved by reducing the internal pressure (e.g., less than about 100 psi, 75 psi, 50 psi, or 25 psi) or increasing the nozzle diameter to one or more of about 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, or 1.5 mm or greater, or a combination of reducing the internal pressure and increasing the nozzle diameter as described above. The non-jet delivery device described herein can also be used to deliver drug payloads to other parts of the gastrointestinal tract, including the stomach, small intestine, or large colon.

[0234] In another embodiment, the enteric material covers all the exterior of the device, or the end caps of the device, or the jet caps of the device. For example, the enteric material covers the jet caps to function as similar to... Figure 22G The external nozzle cap 278 shown is a chemical external nozzle cap. In another example, an enteric material covers the end cap to prevent fluid from entering the release component until the enteric material dissolves or degrades. In some embodiments, the enteric material covering all or part of the device is Evonik's EUDRACAP® customized to fit the shape of the device described herein, such as a size 00 capsule. In some embodiments, the enteric material covers the end cap (e.g., attached to retaining ring 238), and when the enteric material degrades, fluid enters the end cap, where the uncoated or partially coated (e.g., sealed with a bottom coating) release component degrades and the device is actuated. In this embodiment, the enteric coating is a film or other substrate (e.g., gelatin) with a thickness of less than about 0.05 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, or 0.7 mm.

[0235] In some embodiments, the release component is manufactured using a rotary tablet press, for example, with a rotary tablet press turntable speed of about 100-400 mm / s. In another embodiment, a hand press is used to manufacture the release component. In some embodiments, the compression pressure used to prepare 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 can be coated using fluidized bed coating, pan coating, or dip coating.

[0236] Example 1 – Releasing Parts Production, Coating, and Testing

[0237] Release components, such as release components 5B, 5C, and 5D shown below, can be manufactured using known tablet presses such as rotary tablet presses. For example, release component 5B is prepared using a Natoli RD30 rotary tablet press and has the following parameters:

[0238] Turntable speed: 15 RPM, which translates to a turntable tangential speed of 157 mm / s.

[0239] Compaction pressure: 188MPa-204MPa

[0240] Quantitative feeding - filling cam = 8 mm, weight cam = 4.3 mm

[0241] Forced feeder speed = 7 RPM

[0242] The resulting release component is coated with a colored base coating, then with a colored enteric coating, and finally with a top coating, all of which can be applied, for example, using known coating methods (e.g., fluidized bed methods). The coated and uncoated release components are tested to evaluate their performance characteristics (e.g., their ability to withstand loads in the gastric environment and then degrade in the small intestinal environment under the same or high loads).

[0243] Exemplary release component formulation:

[0244]

[0245]

[0246]

[0247] Experiment 1 : Coated release component 5B - Stress-free acid test at 37°C

[0248] The coated release element 5B was placed in simulated gastric acid (2.05 pH) at 37°C, and changes in the coating were observed at 5-minute intervals. No load was applied to the release element; therefore, it was considered a "stress-free" test. The following observations were made:

[0249] Formula 5B, for producing release components, base coating only.

[0250] • Release components completely dissolve in <5 minutes

[0251] Formulation 5B, for producing release components, base coating, 10% enteric coating.

[0252] • The base coating spots became visible after 65 minutes, and the release components dissolved after 90 minutes.

[0253] Formulation 5B, for producing release components, base coating, 15% enteric coating.

[0254] • The spots on the bottom coating became visible after 75 minutes.

[0255] • The 120-minute test ended, revealing the bottom sheath; the release components remained intact.

[0256] Formulation 5B, for producing release components, base coating, 20% enteric coating.

[0257] • 120 minutes - Test stopped, coating still intact

[0258] The stress-free acid test results showed that the release component degraded more slowly in acid as the coating thickness increased. Release components with 15% and 20% coating (by weight) met the 2-hour+ gastric threshold.

[0259] Experiment 2: Instron Test – Dry Uncoated Release Component

[0260] Two uncoated release parts 5B with different heights (2.0 mm vs. 2.5 mm) were tested using an Instron machine. Figure 29A The test fixture shown measures force and displacement. The test fixture uses a shape designed to simulate a valve plunger 232 (trapezoidal foot 400) to introduce controlled force onto the release component.

[0261] A 2.0 mm thick uncoated release element exhibits a breaking force of approximately 10⁻¹² N, while a 2.5 mm thick uncoated release element exhibits a breaking force of approximately 20 N. This indicates that as the height of the uncoated release element increases, especially... Figure 28B As the ring height increases, the strength of the release component increases.

[0262] Experiment 3: Instron Test – Release of Dry Uncoated and Coated Components

[0263] Using Instron machines and Figure 29AThe drying test fixture shown tests uncoated and coated release components 5B, which uses a shape designed to simulate a valve plunger 232 (trapezoidal foot 400) to introduce controlled force onto the release component.

[0264] like Figure 34 As shown in the box plot, the breaking force of the dry release component increases with increasing coating thickness, where BC = base coating and EC = enteric coating. However, without any coating, the release component cannot withstand a force of 30 N. When enteric coating (EC) is added at 10 wt% and 20 wt%, the breaking force increases to over 70 N.

[0265] Experiment 4: Instron Test – Release Components with Wet Coating and Uncoated Coating

[0266] Using Instron machines and such Figure 29B The test fixture shown allows the introduction of fluid to test coated and uncoated release components 5B under humid conditions to simulate the environment of the stomach and small intestine. The test is used to determine failure conditions, such as a 0.6 mm displacement of the release component under a 30 N load from an Instron testing machine that measures both force and displacement.

[0267] Observations on uncoated products:

[0268] The thicker the coating, the longer it takes for the release components to break down in the gastric environment, while the release components with 10% and 20% coatings break down in the small intestinal environment in approximately the same amount of time.

[0269] Coated observe :

[0270] • 10% top coating release component

[0271] • Stomach - in 1.6 pH acid at 23°C for 13.3 to 69 minutes.

[0272] • Small intestine - sustained at 6.8 pH neutral @ 23°C for 7.5 to 26.4 minutes.

[0273] • 20% top coating release component

[0274] • Stomach - in acidic environment at pH 1.6 @ 23°C for at least 60 minutes.

[0275] • Small intestine - lasts approximately 21 minutes at pH 6.8 neutral @ 23°C.

[0276] This indicates that the 10% coated release component does not meet the minimum time threshold in the gastric environment. However, the 20% coated release component persists in the gastric environment for at least 1 hour and exhibits rapid decomposition in a neutral small intestine environment. Finally, the decomposition time can be increased by increasing the coating thickness or by increasing the surface contact area of ​​the trapezoidal foot designed to mimic a valve plunger. As used herein, the term "about" means within + / - 10% of the stated value.

[0277] Figure 30A and 30B An embodiment of the jet cap is shown, wherein one or more O-rings are not placed on one or more nozzles, thereby leaving the nozzles unsealed but sealing the drug payload in the reservoir.

[0278] Figure 31A , 31B Figures 31C and 31D illustrate an embodiment in which one or more nozzles are placed in the jet cap instead of the drug module housing, thereby increasing the volume of the reservoir using one or two O-rings, as shown.

[0279] The following are additional examples and / or statements of the present invention:

[0280] Group 1 :

[0281] 1. An ingestible device comprising: a reservoir in a housing; one or more nozzles extending from the reservoir; a piston capable of longitudinal sliding 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 the diameter of a flange on the release component support is in a ratio of about 0.5 to 0.6 to the diameter of the housing.

[0282] 2. The flange of the release component support may have a diameter of approximately 3.5 mm to 5.5 mm or 4.3 to 4.7 mm.

[0283] 3. The ratio of the diameter of the flange of the release component support to the outer diameter of the release component can be approximately 0.6 to 0.8 or 0.9.

[0284] 4. The release component support can cover approximately 30% to 70% of the outer diameter of the release component.

[0285] 5. The release component support may have a first conical portion and an adjacent second conical portion, the first conical portion 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.

[0286] Group 2 :

[0287] 6. An ingestible device comprising: a reservoir in a housing; one or more nozzles through the housing; a piston capable of longitudinal sliding within the housing; a gas container in the housing; a puncture device configured to puncture the gas container to release compressed gas from the gas container; a spring that applies a spring force on the puncture device in a first direction toward the gas container; and a release component assembly that holds the puncture device in place against the spring force, the release component assembly having a release component support attached to the puncture device and held against the release component by the spring force.

[0288] 7. The release component support may have a flange with a diameter of 3.5 mm to 5.5 mm or 4.3 mm to 4.7 mm.

[0289] 8. The ratio of the flange diameter to the release component diameter may be approximately 0.6 to 0.8 or 0.9.

[0290] 9. The release component support may have a tapered surface that engages with the flange, wherein only the flange contacts the release component.

[0291] 10. The release component can be held between the flat rear end of the release component support and the housing by spring force.

[0292] 11. Compression gaskets can be spaced apart from the housing.

[0293] 12. The flexural crown can be positioned between the housing and the release component. If used, the flexural crown may have multiple radial ribs that make line contact with the release component.

[0294] 13. A raised lug may be provided on the housing, wherein the release component rests on the top of the raised lug. If used, the raised lug may be circumferentially spaced curved segments.

[0295] 14. When actuated, the ingestible device provides a liquid jet with a jet force of 150 to 250 mN for at least 30 milliseconds. One or more of Examples 6-14 can be used in the ingestible device of Example 1.

[0296] Group 3 :

[0297] 15. A method for delivering a drug, comprising the steps of: administering an ingestible jet delivery device to a patient; and operating the delivery device to provide a jet force curve over time, wherein the jet force rise time from zero to 150 mN is less than 5 ms.

[0298] 16. The rise time of the jet force from zero to 150 mN can be less than 4, 3, 2 or 1 ms.

[0299] 17. The rise time of the jet force from zero to 200 mN can be less than 5, 4, 3, 2 or 1 ms.

[0300] 18. The rise time of the jet force from zero to 250 mN can be less than 5, 4, 3, 2 or 1 ms.

[0301] 19. The jet force can be maintained at or above 150 mN for at least 20, 25, 30 or 35 ms.

[0302] 20. The jet force can be maintained above 200 mN for at least 20, 25, 30 or 35 ms.

[0303] 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 one of claims 16-18 and / or Examples 19-21.

[0304] Group 4 :

[0305] 22. An ingestible device comprising: a reservoir containing a liquid within a housing; one or more nozzles extending from the reservoir; a piston capable of longitudinal sliding within the housing; a compressed gas container within 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 liquid jet with a jet force rise time of less than 5 ms from zero to 150 mN.

[0306] 23. The jet force can be maintained above 150 mN for at least 20 ms.

[0307] 24. The ratio of the diameter of the flange on the release component support to the diameter of the housing can be approximately 0.5 to 0.6.

[0308] 25. During actuation, compressed gas is applied to the piston at 300 to 400 psi, and the release component support has a diameter of 4 to 5 mm and a height of 1.7 to 2.1 mm.

[0309] 26. A nozzle cap coated with parylene can be provided on the nozzle.

[0310] 27. A puncture device (if used) is configured to puncture the gas container to release compressed gas from the gas container; and a spring applies a spring force to the puncture device in a first direction toward the gas container. The release component support may have a cylindrical portion that contacts a circumferential ring on the puncture device.

[0311] 28. The release component support may have a tapered surface connected to the flange, wherein only the flange contacts the release component.

[0312] 29. The release component can be held between the release component support and the flat rear end of the housing by spring force. One or more of Examples 23-29 can be used in the ingestible device of Example 22.

[0313] Group 5 :

[0314] 30. An ingestible device comprising: a reservoir containing a liquid medication within a housing; one or more nozzle openings adjacent to a second end of the housing; a piston located within the housing between the reservoir and a first end of the housing; a valve assembly having a valve plug extending from a valve seat into a gas container containing compressed gas; and a release member that changes from an incomplete state to a non-incomplete state to allow movement of the valve assembly to actuate the ingestible device, thereby releasing the compressed gas exerting a force on the piston after ingestion of the ingestible device to eject liquid from the reservoir from the device.

[0315] 31. The release component and the valve assembly may be components of an end cap attached to 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.

[0316] 32. The valve plug may extend longitudinally into the neck of the gas container and be sealed against the inner surface of the neck by a sliding seal.

[0317] Optionally, with the valve plug located on the second side of the valve seat, the valve assembly also includes a plunger located on the first side of the valve seat. If used, the first side of the plunger contacts the release member. Upon actuation, the plunger protrudes into the release member or at least partially displaces the release member.

[0318] 33. The sliding end cap seal can be disposed between the inner surfaces of the plunger and the end cap.

[0319] 34. The release component may have an angled annular surface adjacent to the end cap retaining ring.

[0320] 35. The valve retainer may extend toward a second end of the housing. The valve retainer may extend through one or more openings in the flange on the neck of the gas container.

[0321] 36. Before actuation, compressed gas applies gas pressure to a valve plug having a first area, and during actuation, compressed gas applies gas pressure to the valve plug and a valve seat having a second area greater than the first area.

[0322] 37. The piston may have a cylindrical body surrounding the gas container and a sliding piston seal between the piston and the inner surface of the housing.

[0323] 38. During actuation, the released compressed gas applies a first force in a first region and a second force in a second region, wherein the second force is 1.5 to 3 times greater than the first force.

[0324] 39. Prior to actuation, the gas pressure in the gas container applies a first force to the valve assembly, which in turn applies a first force to the release component.

[0325] 40. Prior to actuation, when the release component is intact, the release component resists the first force and prevents movement of the valve assembly, keeping the compressed gas sealed within the gas container, and when the release component becomes incomplete after intake, the valve assembly moves into or at least partially displaces the release component, releasing the 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.

[0326] 41. A system volume space is the space within the housing between an end cap seal and a piston seal, the end cap seal being between the end cap and the valve assembly, and the piston seal being between the piston and the housing.

[0327] 42. Prior to actuation, the compressed gas in the gas container applies a first force only to a first surface region of the valve assembly, the first surface region including the surface region of the valve plug and the valve plug seal on the valve plug, and in a second position, the compressed gas is released from the gas container and applies a second force to a second surface region of the valve assembly, the second surface region being larger than the first surface region. One or more of Examples 31-43 may be used in the ingestible device of Example 30.

[0328] Therefore, a novel ingestible drug delivery device has been shown and described. Various changes and substitutions can, of course, be made without departing from the spirit and scope of the invention. Therefore, the invention should not be limited except for the following claims and their equivalents. Elements of the various embodiments described above can be interchanged between those embodiments, as will be apparent to those skilled in the art.

Claims

1. An ingestible device, comprising: A housing having a first end and a second end; A gas container end cap assembly, wherein the gas container end cap assembly is located at a first end of the housing; One or more nozzle openings facing the second end of the housing; A piston is located within the housing between the gas container end cap assembly and the nozzle opening, the piston is movable within the housing and the piston abuts against the housing for sealing; The gas container end cap assembly includes: End cap, the end cap being attached to the housing; The release component in the end cap; A gas container containing compressed gas; and A valve assembly located between the gas container and the release component; When the ingestible device is actuated via the release component, the valve assembly can move from a first position to a second position. In the first position, the valve assembly seals the gas container, and in the second position, the valve assembly releases the seal on the gas container, wherein compressed gas from the released gas container moves the piston to drive liquid in the housing out through the nozzle opening in a jet.

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

3. The ingestible device according to 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 applies the first force to the release member, and in the second position, the valve assembly applies the second force to the release member.

5. The ingestible device according to claim 1 or 2, wherein when intact, the release member resists a first force and prevents the valve assembly from moving, thereby keeping the compressed gas sealed within the gas container, and when the release member becomes incomplete after ingestion, the valve assembly moves into or at least partially displaces the release member, thereby releasing the compressed gas from the gas container, the released compressed gas acting on a larger surface area of ​​the valve assembly at a second position relative to the first position.

6. An ingestible device, comprising: The liquid inside the shell; Piston, which is capable of longitudinal movement within the housing; The driving force generator in the housing is configured to apply force to the piston when actuated, wherein the piston applies pressure to the liquid, and the liquid is ejected from the housing as a jet through one or more nozzle openings; A release component, which can change from an intact state before ingestion to a non-intact state after ingestion; the release component in the intact state prevents actuation of the drive force generator, while the release component in the non-intact state allows actuation of the drive force generator; and The release component comprises one or more effervescent materials, one or more wicking agents, one or more fillers or expanders, and one or more adhesives.

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 constitute 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 according to claim 6 or 7, wherein the one or more adhesives constitute about 17% to 47% of the total weight of the release component.

11. The ingestible device according to claim 6 or 7, further comprising one or more lubricants, said lubricants comprising about 0.4% to 2.2% of the total weight of said release component.

12. The ingestible device according to any one of claims 7-11, wherein the release component comprises a bottom layer and an enteric coating layer.

13. An ingestible device comprising: The liquid inside the shell; Piston, which is capable of longitudinal movement within the housing; A driving force generator, comprising compressed gas or a spring, applies a driving force to a release component; The release component resists the driving force before the ingestible device is ingested, and the release component releases the driving force to act on the piston after the ingestible device is ingested; The release component has an annular surface held by a retaining ring at the end of the housing.

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

15. The ingestible device according to claim 13 or 14, wherein the release member has a concave front surface and a concave rear surface.

16. The ingestible device of claim 15, wherein the driving force generator comprises compressed gas in a compressed gas container and a valve assembly having a valve plug inserted into an opening in the compressed gas container and a plunger abutting against a front surface of the release member.

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

18. The ingestible device according to claim 16 or 17, wherein, upon actuation, the plunger protrudes into the release member or at least partially displaces the release member.

19. The ingestible device according to claim 16 or 18, wherein prior to actuation, the compressed gas applies gas pressure to a valve plug having a first area, and during actuation, the compressed gas applies gas pressure to the valve plug and a valve seat of the valve assembly, the valve seat having a second area greater than the first area.

20. The ingestible device according to claim 13 or 15, wherein the release member has a first circumferential surface having a first width, the first circumferential surface being connected to a second circumferential surface by a radius, the second circumferential surface having a second width less than the first width.

21. An ingestible device comprising: Liquid in the liquid reservoir inside the casing; A piston that is at least partially slidable through the liquid reservoir within the housing; At least one nozzle, said at least one nozzle being extended from the reservoir, adjacent to a first end of the housing; End cap valve assembly, located at the second end of the housing, the end cap valve assembly comprising: An end cap, attached to the housing, having a retaining ring for retaining the release component; A valve assembly located at least partially in the end cap, a valve plug located on a first side of the valve assembly, the valve plug being inserted into a compressed gas container, and a plunger located on a second side of the valve assembly; The release component is configured to hold the valve assembly in place against a gas pressure of 10 to 40 Newtons exerted on the valve assembly by the compressed gas in the compressed gas container until the ingestible device is ingested.

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

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

24. An ingestible device comprising: A drug module comprising a liquid drug, one or more nozzle openings, and a piston slidable within the drug module; A drive module attached to the drug module includes a compressed gas container containing compressed gas and a valve assembly movable from a closed position to an open position. The valve assembly is held in the closed position by a release member to prevent the compressed gas from being released from the compressed gas container, and when the release member is no longer intact, the valve assembly is movable to the open position after being taken into the device by at least partially shifting or protruding into the release member. In the open position, the valve assembly releases compressed gas from the compressed gas container, and the released compressed gas moves a piston to provide a jet of liquid drug through one or more nozzles.

25. The apparatus of claim 24, wherein the liquid drug is in a reservoir formed partially around the side of the piston.

26. The apparatus of claim 24 or 25, wherein in the closed position, a first side of the valve assembly engages with the compressed gas container, and a second side of the valve assembly engages with a release member.

27. The apparatus of claim 26, wherein in the closed position, gas pressure continuously applies force to the valve assembly, thereby holding the valve assembly against the release member.

28. An ingestible device comprising: A drug module comprising a liquid drug, 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, the drive force generator being engaged with a release component including effervescent material; After the device is ingested, the release component releases the driving force generator to act on the piston, and then the driving force generator moves the piston to provide a jet of the liquid drug outward through the one or more nozzle openings.

29. An ingestible device comprising: A drug module comprising a liquid drug, one or more nozzle openings, and a piston movable within the drug module; A drive module attached to the drug module includes a drive force generator that engages with a release member having a shoulder between a front surface and a tapered portion, the shoulder being pressed against a retaining ring of the drive module by the drive force generator; After the device is ingested, the release component releases the driving force generator to act on the piston, and then the driving force generator moves the piston to provide a jet of the liquid drug outward through the one or more nozzle openings.

30. The ingestible device of claim 29, wherein the front surface is concave, the release member further includes a concave rear surface adjacent to the conical portion, and a cylindrical portion between the conical portion and the concave front surface, and the shoulder is formed by a radius extending from the conical portion to the cylindrical portion.

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