Drug delivery device

Abstract

This relates to drug delivery devices and related methods of use. [Solution] The drug delivery device 100 includes a reservoir 110 containing an active pharmaceutical ingredient and a potential energy source. The drug delivery device 100 also includes a trigger 116 operably associated with the potential energy source and configured to act at a predetermined location within the target. The drug delivery device 100 also includes a ruptureable membrane 114 disposed along a flow path extending between the reservoir 110 and the outlet 118 and configured to rupture when the trigger 116 is activated. When the trigger 116 is activated, potential energy is released from the potential energy source, allowing the active pharmaceutical ingredient to be jetted out through the outlet 118.

Description

[Technical Field]

[0001] The disclosed embodiments relate to drug delivery devices and related methods of use. [Background technology]

[0002] Certain therapeutic substances consist of large, complex molecules that readily denature when administered via the oral-gastrointestinal (GI) route. Therefore, patients requiring these therapeutic substances typically use more invasive forms of drug administration outside the GI route, such as subcutaneous injection. [Overview of the project]

[0003] A drug delivery device that is ingestible, insertable, or implantable, configured to be administered to a target, according to one aspect of the present invention, is described in claim 1.

[0004] In the context of the present invention, the term "insertable" is intended to encompass endoscopic, transrectal, transvaginal, transnasal, or transurethral administration of a drug delivery device.

[0005] Other advantageous features of the present invention are described in the dependent claims.

[0006] In some embodiments, a drug delivery device configured to administer to a target includes a reservoir configured to contain an active pharmaceutical ingredient, a potential energy source, a trigger operably associated with the potential energy source and configured to act in response to one or more predetermined conditions, a port in fluid communication with the reservoir, and a burstable membrane disposed along a flow path extending between the reservoir and the port, sealing the reservoir from the port. When the trigger is activated, the potential energy source compresses the reservoir, causing the burstable membrane to burst, and the active pharmaceutical ingredient flows from the reservoir through the port. The flow path has a first maximum lateral dimension downstream of the burstable membrane that is greater than a second maximum lateral dimension upstream of the burstable membrane, such that the burstable membrane bursts in the central portion of the burstable membrane.

[0007] In some embodiments, a drug delivery device configured to administer to a target includes: a reservoir configured to contain an active pharmaceutical ingredient; a potential energy source; a trigger operably associated with the potential energy source and configured to act in response to one or more predetermined conditions; a first channel in fluid communication with the reservoir; a second channel downstream of the first channel, wherein the first channel has a first maximum lateral dimension and the second channel has a second maximum lateral dimension greater than the first maximum lateral dimension; and a ruptureable membrane disposed between the first channel and the second channel.

[0008] The nomenclature, such as "first channel" and "second channel," is not restrictive, and these terms may be interchangeable. For example, it will be understood that the second channel may be referred to as the first channel, and the first channel as the second channel.

[0009] Similarly, the nomenclature of the first and second maximum lateral dimensions is not limiting, and these terms may be interchangeable. For example, the second maximum lateral dimension may be referred to as the first maximum lateral dimension, and the first maximum lateral dimension may be referred to as the second maximum lateral dimension.

[0010] In some embodiments, a drug delivery device configured to administer to a target includes a reservoir configured to contain an active pharmaceutical ingredient, a potential energy source, an outlet in fluid communication with the reservoir, a ruptureable membrane disposed along a flow path extending between the reservoir and the outlet, and a solubility trigger operably associated with the potential energy source and disposed within the outlet. The solubility trigger is configured to dissolve at a predetermined location within the target while in vivo, and the solubility trigger is disposed in contact with and supporting the downstream surface of the ruptureable membrane.

[0011] This disclosure is not limited in this respect, and it should be understood that the concepts described above and any additional concepts described below may be arranged in any preferred combination. Furthermore, other advantages and novel features of this disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0012] The attached drawings are not intended to be drawn to actual size. In the drawings, identical or nearly identical components illustrated in various figures may be represented by the same numbers. For clarity, not all components may be labeled in all drawings. In the drawings, [Figure 1A] This diagram shows a schematic representation of one embodiment of a drug delivery device in a first state. [Figure 1B] This represents the drug delivery device in the second state, as shown in Figure 1A. [Figure 2A] This represents one embodiment of a ruptureable membrane and trigger for a drug delivery device in a first state. [Figure 2B]Represents the frangible membrane and trigger of FIG. 2A in the second state. [Figure 2C] Represents the frangible membrane and trigger of FIG. 2A in the third state. [Figure 2D] Represents the frangible membrane and trigger of FIG. 2A in the fourth state. [Figure 3] Scanning electron microscope photographic image of one embodiment after rupture of the frangible membrane. [Figure 4A] Represents a schematic diagram of another embodiment of the drug delivery device in the first state. [Figure 4B] Represents the drug delivery device of FIG. 4A in the second state. [Figure 5A] Represents a schematic diagram of another embodiment of the drug delivery device in the first state. [Figure 5B] Represents the drug delivery device of FIG. 5A in the second state. [Figure 6A] Represents a perspective view of another embodiment of the drug delivery device. [Figure 6B] Represents a cross-sectional view of the drug delivery device of FIG. 6A cut along line 6B-6B. [Figure 6C] Represents an enlarged cross-sectional exploded view of the bottom portion of the drug delivery device of FIG. 6B. [Figure 6D] Represents an enlarged non-exploded cross-sectional view of the bottom portion of the drug delivery device of FIG. 6B. [Figure 7A] Represents a schematic diagram of another embodiment of the frangible membrane and trigger of the drug delivery device in the first state. [Figure 7B] Represents the frangible membrane and trigger of FIG. 7A in the second state. [Figure 7C] Represents the frangible membrane and trigger of FIG. 7A in the third state. [Figure 7D] Represents the frangible membrane and trigger of FIG. 7A in the fourth state. [Figure 8] Represents a schematic diagram of another embodiment of the frangible membrane and trigger of the drug delivery device in the first state. [Figure 9] Represents a schematic diagram of another embodiment of the frangible membrane and trigger of the drug delivery device in the first state. [Modes for carrying out the invention]

[0013] Large, complex molecules that readily denature when administered via the oral-gastrointestinal (GI) route are regularly administered as part of therapeutic procedures. Patients requiring these therapeutic substances often have to use more invasive forms of drug administration, such as subcutaneous injection. The use of these more invasive forms of delivery can lead to a lack of routine adherence and / or a reduced quality of life.

[0014] Considering the above, the inventors recognized the benefit of an ingestible delivery device that utilizes a needleless microjet to deliver a desired dose of an active pharmaceutical ingredient (API) at a desired location along the gastrointestinal (GI) tract without impairing the purity, efficacy, and / or dosage of the drug. Specifically, the inventors recognized that the benefit of ingestible delivery is the devising of using a trigger that automatically releases the dose at a desired location within the GI tract. As used herein, the GI tract includes the esophagus, stomach, duodenum, jejunum, small intestine, and large intestine. The delivery device is suitable for the delivery of large and complex molecules such as proteins and other organisms that may otherwise be unsuitable for delivery through the GI tract, but any suitable API can be used. According to the exemplary embodiments described herein, an ingestible delivery device using a microjet for delivering an active pharmaceutical ingredient (API) has many potential benefits. First, the ingestible delivery device according to the exemplary embodiments described herein may not include a sharp tip. Secondly, the microjet eliminates the need for mechanisms associated with acting on and / or retracting the needle, thereby reducing the complexity and cost of the system compared to needle-based systems. Finally, the implementations of the needle-free delivery systems of the exemplary embodiments described herein may result in less pain and / or trauma at the injection site compared to needle-based delivery and extended pharmacokinetic (PK) systems.

[0015] In some cases, an effective implementation of a needle-free drug delivery device may be at least partially based on contact with the target tissue and trigger mechanism. In subcutaneous systems, contact is ensured by the manual positioning of the jet nozzle against the skin, whereas in ingestible devices, neither manual positioning nor triggering is possible. The jet performance of the drug delivery device can also affect the effectiveness of API delivery to the patient.

[0016] Considering the above, the inventors also recognized the benefit of a robust trigger system for a drug delivery device deployed within a patient's GI tubule. Specifically, the inventors recognized the benefit of a ruptureable (i.e., fragile) membrane sealing a reservoir containing the API. The ruptureable membrane may be physically supported by a trigger, such as a sugar plug, enteric coating, or other soluble trigger, configured to dissolve in the GI tubule after a predetermined period and / or at a predetermined location within the GI tubule while located in vivo. When the trigger is activated, the membrane ruptures, allowing a controlled microjet of the API to be released into the inner lining of the GI mucosa. The inventors also recognized the particular benefit of abrupt transitions between upstream and downstream fluid pathways for the ruptureable membrane. More specifically, in some embodiments, the inventors recognized the benefit of a pathway having a first maximum lateral dimension (e.g., first maximum diameter) downstream of the ruptureable membrane that is greater than a second maximum lateral dimension (e.g., second maximum diameter) of the upstream pathway of the ruptureable membrane. Such an arrangement may promote membrane rupture in the central portion of the membrane rather than at the edge locations adjacent to stress concentrations. While we do not wish to be constrained by theory, providing such functionality may help ensure a consistent, regenerative jet with appropriate penetration characteristics for delivering the API to the GI mucosa lining.

[0017] In some embodiments, a drug delivery device configured to administer a drug to a target includes a reservoir configured to contain an API, a potential energy source, and a trigger configured to act at a predetermined location within the target. The reservoir may be a liquid reservoir and may contain a solution containing a predetermined dose of the API. The potential energy source may store energy released when the trigger is activated within the drug delivery device. The drug delivery device may also include a port in fluid communication with the reservoir and a ruptureable membrane positioned along a flow path extending between the reservoir and the port. The ruptureable membrane may seal the reservoir from the port so that the API is contained within the reservoir until the membrane ruptures. The potential energy source may pressurize or otherwise compress the reservoir to apply pressure to the ruptureable membrane. When the trigger is activated, the ruptureable membrane ruptures, allowing the API to flow through the flow path and out the port. The flow path of the drug delivery device may have a first maximum lateral dimension (e.g., first maximum diameter) downstream of the burstable membrane that is larger than a second maximum lateral dimension (e.g., second maximum diameter) of the flow path upstream of the burstable membrane, thereby applying pressure to the membrane to the central portion of the membrane which is removed from the outer edge of the membrane. In some embodiments, the burstable membrane may define a transition between the first diameter and the second diameter such that the flow path has discontinuous walls and the flow path is stepped from the first diameter to the second diameter in the burstable membrane. Drug delivery devices according to exemplary embodiments described herein may generate an incompressible liquid jet, and in other embodiments, the jet generated by the drug delivery device may be formed of gas, viscous fluid, aerosolized powder, and / or other suitable material, but this disclosure is not limited thereto.

[0018] In the context of this invention, "jet" means a parallel flow of gas, viscous fluid, aerosolized powder, and / or other suitable material.

[0019] According to exemplary embodiments described herein, the rupture membrane of a drug delivery device may be formed of a brittle material configured to rupture or otherwise break when an unsupported threshold pressure is applied to the membrane. In some embodiments, the rupture membrane is composed of one or more materials selected from metals, polymer materials, elastomer materials, plastic materials, ceramic materials, composite materials, and / or any other suitable brittle or brittle materials for target delivery of an active API. In some embodiments, the rupture membrane is composed of a metal foil, elastomer film, rigid plastic film, flexible plastic film, and / or any other suitable material that can rupture when a given threshold pressure is applied to the membrane. In some embodiments, the metal is aluminum. In some embodiments, the metal is a biodegradable metal such as iron. In some embodiments, the plastic material is a reinforced plastic material. In some embodiments, the composite material includes carbon fiber. In some embodiments, the material of the rupture membrane may be selected to promote brittle fracture of the membrane during operation. The rupture membrane may be configured to rupture in such a manner that a jet of fluid is formed by the drug delivery device. In some embodiments, the burstable membrane may be configured to function as a nozzle defining the jet exiting the drug delivery device. Naturally, the burstable membrane may be formed of any suitable material configured to burst when the trigger of the drug delivery device is activated, but this disclosure is not limited thereto. According to the exemplary embodiments described herein, the burstable membrane may have thicknesses of 150 μm or less, 100 μm or less, 75 μm or less, 50 μm or less, 25 μm or less, 15 μm or less, and / or any other suitable thickness. Accordingly, the burstable membrane may have thicknesses of 10 μm or more, 15 μm or more, 25 μm or more, 50 μm or more, 75 μm or more, and / or any other suitable thickness.Combinations of the above ranges can be conceivable, including thicknesses of 10μm~25μm, 10μm~50μm, 10μm~75μm, 10μm~100μm, 10μm~150μm, 15μm~25μm, 15μm~50μm, 15μm~75μm, 15μm~100μm, 15μm~150μm, 25μm~50μm, 25μm~100μm, 25μm~150μm, 25μm~75μm, 50μm~75μm, 50μm~100μm, 50μm~150μm, 75μm~100μm, 75μm~150μm, or 100μm~150μm. As described herein, the expression “one value to another value” includes all values ​​at both ends and in between.

[0020] According to exemplary embodiments described herein, a trigger for a drug delivery device may be configured to activate the drug delivery device within a target GI tube under predetermined conditions. In some embodiments, predetermined conditions include one or more of the following: a predetermined time after ingestion of the drug delivery device, a predetermined location within the GI tube, physical contact with the GI tube, physical manipulation within the GI tube (e.g., compression via peristalsis), one or more properties of the GI tube (e.g., pH, pressure, acidity, temperature, etc.), or a combination thereof. In some embodiments, the trigger may be a passive component configured to interact with the environment of the GI tube to activate the drug delivery device. For example, in some embodiments, the trigger may be a sugar plug or other soluble material configured to dissolve within the GI tube. The soluble plug may have a specific thickness and / or shape that at least partially determines the rate at which the sugar plug dissolves and ultimately activates the drug delivery device. In some embodiments, the trigger may have an oval, oval, spherical, elliptical, cylindrical, conical, or spherical-cylindrical shape. In another embodiment, the trigger may be formed by at least partially enteric coating. For example, in some embodiments, the trigger may include both a sugar plug and an enteric coating, but this disclosure is not limited thereto. Other suitable materials for soluble triggers include, but are not limited to, sugar alcohols such as disaccharides (e.g., isomalt), water-soluble polymers such as polyvinyl alcohol, enteric coatings, time-dependent coatings, enteric time-dependent coatings, temperature-dependent coatings, light-dependent coatings, and / or any other suitable material that can dissolve in the target GI tube. In some embodiments, the trigger may include a triggerable membrane containing EDTA, glutathione, or another suitable chemical. In some embodiments, a sugar alcohol trigger may be used in combination with an enteric coating configured to protect the sugar alcohol trigger until the drug delivery device is received in the target GI tube. In some embodiments, the trigger may include a pH-responsive coating to help delay the trigger until after ingestion. In some embodiments, the trigger may be a sensor that detects one or more properties of the GI tube. For example, a sensor that detects contact with the inner lining of the GI mucosa may be used to activate the device. In embodiments where sensors are used, the trigger may also include an active component that moves in response to the detection of predetermined conditions by the sensor. For example, a gate may move when contact with a GI mucosal pathway is detected. In other embodiments, the trigger may use power to melt or weaken a burstable membrane (e.g., by applying a voltage across the entire conductive burstable membrane) and / or trigger a chemical reaction. Naturally, any suitable active or passive trigger may be used in a drug delivery device, but this disclosure is not limited thereto.

[0021] According to exemplary embodiments described herein, a drug delivery device includes a potential energy source used to store energy in the drug delivery device that is used to generate a jet of API when the drug delivery device is activated. In some embodiments, the potential energy source may be a compressed gas. The compressed gas may be stored directly in the drug delivery device, or it may be generated via a chemical reaction or phase change. For example, in some embodiments, dry ice may be stored in a chamber of the drug delivery device, thereby generating a compressed gas when the dry ice sublimes. Alternatively, the compressed gas may be supplied to the desired chamber before sealing the drug delivery device. In some embodiments, the potential energy source may be a spring (e.g., a compressed spring). In some embodiments, the potential energy source may be a reaction chamber. For example, a reaction chamber may allow a combination of acids and bases to generate a gas, which leads to the discharge of API from the drug delivery device when a trigger is activated. Alternatively, in another embodiment, the trigger may detonate an explosive material located in the chamber to generate a pressurized gas for discharging API from the drug delivery device. Naturally, any suitable reaction or other potential energy source may be used to pressurize the API and drive it in a jet when the drug delivery device is activated, but this disclosure is not limited to such reactions.

[0022] While we do not wish to be constrained by theory, the jet force can be tuned to deliver the API to target tissue in different GI tubules with different penetration characteristics. The jet force can be determined at least in part by the jet velocity, fluid density, and jet diameter. Thus, the drug delivery devices according to the exemplary embodiments described herein may be appropriately sized and contain an appropriate amount of potential energy to generate a jet with sufficient force to deliver the API to the inner lining of the GI mucosa at the desired location.

[0023] As described above, the jet force of the drug delivery device can affect the effectiveness of delivering the API to the GI mucosa. Therefore, the drug delivery device may use an appropriate jet force and velocity to penetrate the GI mucosa and deliver the API to the target. In some embodiments, the jet force of the drug delivery device according to the exemplary embodiments described herein is 250W or less, 200W or less, 150W or less, 100W or less, 75W or less, 50W or less, 20W or less, 10W or less, 5W or less, 1W or less, 100mW or less, and / or any other suitable force. Accordingly, the jet force of the drug delivery device may be 50mW or more, 100mW or more, 1W or more, 5W or more, 10W or more, 20W or more, 50W or more, 75W or more, 100W or more, 150W or more, 200W or more, and / or any other suitable force. 50mW~250W, 50mW~200W, 50mW~150W, 50mW~100W, 50mW~75W, 50mW~50W, 50mW~20W, 50mW~10W, 50mW~5W, 50mW~1W, 100mW~200W, 100mW~150W, 100mW~100W, 100mW~75W , 100mW~50W, 100mW~20W, 100mW~10W, 100mW~5W, 100mW~1W, 1W~200W, 1W~150W, 1W ~100W, 1W~75W, 1W~50W, 1W~20W, 1W~10W, 1W~5W, 5W~200W, 5W~150W, 5W~100W, 5W~ 75W, 5W~50W, 5W~20W, 5W~10W, 10W~200W, 10W~150W, 10W~100W, 10W~75W, 10W~50W , 10W~20W, 20W~200W, 20W~150W, 20W~100W, 20W~75W, 20W~50W, 50W~200W, 50W~15 Combinations of the above ranges can be conceivable, including jet forces of 0W, 50W-100W, 50W-75W, 75W-200W, 75W-150W, 75W-100W, 75W-200W, 75W-150W, 75W-100W, 100W-200W, 100W-150W, or 150W-200W. Naturally, any jet force suitable for delivering the API to the endomucosal layer of the GI can be used, but this disclosure is not limited to these.

[0024] To achieve the exemplary jet forces described herein, the jets generated by the drug delivery devices of the exemplary embodiments described herein may have corresponding velocities. Thus, in some embodiments, the drug delivery devices may be configured to generate jets having velocities of 250 m / s or less, 200 m / s or less, 150 m / s or less, 100 m / s or less, 75 m / s or less, 50 m / s or less, and / or other suitable velocities. Accordingly, the drug delivery device may be configured to generate a jet having a speed of 20 m / s or more, 30 m / s or more, 50 m / s or more, 100 m / s or more, 150 m / s or more, 200 m / s or more, and / or another suitable speed. 20m / s~250m / s, 20m / s~200m / s, 20m / s~100m / s, 20m / s~150m / s, 20m / s~100m / s, 20m / s~75m / s, 20m / s~50m / s, 5 0m / s~250m / s, 50m / s~200m / s, 50m / s~100m / s, 50m / s~150m / s, 50m / s~100m / s, 50m / s~75m / s, 75m / s~250m / s, 7 Jet velocities include, but are not limited to, those of 5 m / s to 200 m / s, 75 m / s to 100 m / s, 75 m / s to 150 m / s, 75 m / s to 100 m / s, 100 m / s to 250 m / s, 100 m / s to 200 m / s, 100 m / s to 150 m / s, 150 m / s to 250 m / s, 150 m / s to 200 m / s, or 200 m / s to 250 m / s. Combinations of the above ranges can be conceivable. Naturally, any jet velocity suitable for delivering the API to the inner lining of the GI mucosa, or other structures associated with the target GI tube, may be used, but are not limited to these.

[0025] In some embodiments, the maximum lateral dimension (e.g., diameter) of the outlet and / or jet may be 600 μm or less, 350 μm or less, 300 μm or less, 250 μm or less, 200 μm or less, 150 μm or less, 100 μm or less, 75 μm or less, 50 μm or less, 25 μm or less, 10 μm or less, and / or any other suitable dimension. Accordingly, the maximum lateral dimension of the outlet and / or jet may be 5 μm or more, 10 μm or more, 25 μm or more, 50 μm or more, 75 μm or more, 100 μm or more, 150 μm or more, 200 μm or more, 250 μm or more, 300 μm or more, 600 μm or more, and / or any other suitable dimension.5μm~600μm, 10μm~600μm, 25μm~600μm, 50μm~600μm, 75μm~600μm, 100μm~600μm, 150μm~600μm, 200μm~600μm, 250μm~60 0μm, 300μm~600μm, 350μm~600μm, 5μm~350μm, 10μm~350μm, 25μm~350μm, 50μm~350μm, 75μm~350μm, 100μm~350μm, 150μm m~350μm, 200μm~350μm, 250μm~350μm, 300μm~350μm, 5μm~300μm, 10μm~300μm, 25μm~300μm, 50μm~300μm, 75μm~300μm, 100μm~300μm, 150μm~300μm, 200μm~300μm, 250μm~300μm, 5μm~250μm, 10μm~250μm, 25μm~250μm, 50μm~250μm, 75μm~250 μm, 100μm~250μm, 150μm~250μm, 200μm~250μm, 5μm~200μm, 10μm~200μm, 25μm~200μm, 50μm~200μm, 75μm~200μm, 100μm ~200μm, 150μm~200μm, 5μm~150μm, 10μm~150μm, 25μm~150μm, 50μm~150μm, 75μm~150μm, 100μm~150μm, 5μm~100μm, 10μm Maximum lateral dimensions of jets and / or outlets include, but are not limited to, ~100 μm, 25 μm~100 μm, 50 μm~100 μm, 75 μm~100 μm, 5 μm~75 μm, 10 μm~75 μm, 25 μm~75 μm, 50 μm~75 μm, 5 μm~50 μm, 10 μm~50 μm, 25 μm~50 μm, 5 μm~25 μm, 10 μm~25 μm, or 5 μm~10 μm, and combinations of the above ranges can be conceivable. Naturally, any jet diameter suitable for delivering the API to the inner lining of the GI mucosa may be used, but is not limited to these.

[0026] According to exemplary embodiments described herein, the drug delivery device includes a potential energy source configured to pressurize the API so that the API can be released in a jet into the inner lining of the GI tube mucosa. The pressure applied to the reservoir may affect the jet force and / or jet velocity of the API jet released by the drug delivery device. In some embodiments, the potential energy source may apply pressures of 1000 bar or less, 800 bar or less, 600 bar or less, 500 bar or less, 250 bar or less, 100 bar or less, 60 bar or less, 40 bar or less, 10 bar or less, 1 bar or less, and / or any other suitable pressure to the API reservoir. Accordingly, the potential energy source may apply pressures of 0.1 bar or more, 1 bar or more, 10 bar or more, 40 bar or more, 60 bar or more, 100 bar or more, 250 bar or more, 500 bar or more, 600 bar or more, 800 bar or more, and / or any other suitable pressure to the API reservoir.0.1 bar to 1000 bar, 0.1 bar to 800 bar, 0.1 bar to 600 bar, 0.1 bar to 500 bar, 0.1 bar to 250 bar, 0.1 bar to 100 bar, 0.1 bar to 60 bar, 0.1 bar to 40 bar, 0.1 bar to 10 bar, 0.1 bar to 1 bar, 1 bar to 1000 bar, 1 bar to 800 bar, 1 bar to 600 bar, 1 bar to 500 bar, 1 bar ~250 bar, 1 bar ~ 100 bar, 1 bar ~ 60 bar, 1 bar ~ 40 bar, 1 bar ~ 10 bar, 10 bar ~ 1000 bar, 10 bar ~ 800 bar, 10 bar ~ 600 bar, 10 bar ~ 500 bar, 10 bar ~ 250 bar, 10 bar ~ 100 bar, 10 bar ~ 60 bar, 10 bar ~ 40 bar, 10 bar ~ 800 bar, 10 bar ~ 600 bar, 10 bar ~ 50 0 bar, 10 bar to 250 bar, 10 bar to 100 bar, 10 bar to 60 bar, 10 bar to 40 bar, 40 bar to 800 bar, 40 bar to 600 bar, 40 bar to 500 bar, 40 bar to 250 bar, 40 bar to 100 bar, 40 bar to 60 bar, 60 bar to 800 bar, 60 bar to 600 bar, 60 bar to 500 bar, 60 bar to 250 bar, 60 bar Pressures such as ~100 bar, 100 bar~800 bar, 100 bar~600 bar, 100 bar~500 bar, 100 bar~250 bar, 250 bar~800 bar, 250 bar~600 bar, 250 bar~500 bar, 500 bar~800 bar, 500 bar~600 bar, or 600 bar~800 bar are examples, but are not limited to, combinations of the above ranges. Naturally, any suitable pressure can be applied to the API reservoir, but this disclosure is not limited to them.

[0027] The drug delivery devices of the exemplary embodiments described herein may be configured to deliver a predetermined dose of API to a target. According to the exemplary embodiments described herein, the drug delivery device may include an API reservoir volume of 500 μL or less, 300 μL or less, 200 μL or less, 150 μL or less, 100 μL or less, 75 μL or less, 50 μL or less, 25 μL or less, 10 μL or less, and / or any other suitable volume. Accordingly, the drug delivery device may include an API reservoir volume of 1 μL or more, 5 μL or more, 10 μL or more, 25 μL or more, 50 μL or more, 75 μL or more, 100 μL or more, 200 μL or more, 300 μL or more, and / or any other suitable volume. 1μL~500μL, 1μL~300μL, 1μL~200μL, 1μL~150μL, 1μL~100μL, 1μL~75μL, 1μL~50μL L, 1μL~25μL, 1μL~10μL, 10μL~500μL, 10μL~300μL, 10μL~200μL, 10μL~150μL, 10μL L~100μL, 10μL~75μL, 10μL~50μL, 10μL~25μL, 25μL~500μL, 25μL~300μL, 25μL~2 00μL, 25μL~150μL, 25μL~100μL, 25μL~75μL, 25μL~50μL, 50μL~500μL, 50μL~300μL Possible reservoir volumes include L, 50μL~200μL, 50μL~150μL, 50μL~100μL, 50μL~75μL, 75μL~500μL, 75μL~300μL, 75μL~200μL, 75μL~150μL, 75μL~100μL, 100μL~500μL, 100μL~300μL, 100μL~200μL, 100μL~150μL, 150μL~500μL, 150μL~300μL, 150μL~200μL, 200μL~500μL, 200μL~300μL, or 300μL~500μL, but are not limited to these and other combinations of the above volumes can be conceivable. Naturally, any suitable reservoir volume may be used in the drug delivery device, but this disclosure is not limited to them.

[0028] In some embodiments, the drug delivery device is sized and shaped to be ingested by a subject. Thus, the drug delivery device can be appropriately small such that the drug delivery device can be easily swallowed and subsequently pass through the GI tract including the esophagus and the pylorus in the stomach. In some embodiments, the drug delivery device can include an overall length such as a maximum dimension along the longitudinal axis of the device that is 40 mm or less, 30 mm or less, 20 mm or less, 10 mm or less, 5 mm or less, and / or another suitable length. Accordingly, the drug delivery device can have an overall length of 3 mm or more, 5 mm or more, 10 mm or more, 20 mm or more, 25 mm or more, and / or another suitable length. Combinations of the ranges described above are contemplated, such as, but not limited to, 5 mm to 30 mm, 10 mm to 30 mm, 20 mm to 30 mm, 25 mm to 30 mm, 5 mm to 25 mm, 10 mm to 25 mm, 20 mm to 25 mm, 5 mm to 20 mm, 10 mm to. In some embodiments, the drug delivery device can have a maximum outer lateral dimension such as a diameter or other dimension that can be perpendicular to the longitudinal axis that is 11 mm or less, 10 mm or less, 7 mm or less, 5 mm or less, and / or another suitable dimension. Accordingly, the drug delivery device can have a maximum outer lateral dimension of 3 mm or more, 5 mm or more, 7 mm or more, 9 mm or more, and / or another suitable dimension. Combinations of the ranges described above are contemplated, such as, but not limited to, 3 mm to 11 mm, 3 mm to 10 mm, 3 mm to 7 mm, 3 mm to 5 mm, 5 mm to 11 mm for the maximum outer lateral dimension. In some embodiments, the drug delivery device is 3500 mm 3 or less, 3000 mm 3 or less, 2500 mm 3 or less, 2000 mm 3 or less, 1500 mm 3 or less, 1000 mm 3 or less, 750 mm 3 or less, 500 mm 3 or less, 250 mm 3 or less, 100 mm 3 or less, and / or can have an overall volume of any other suitable volume. Accordingly, the drug delivery device is 50 mm 3 or more, 100 mm 3 or more, 250 mm 3Above 500mm 3 More than 750mm 3 Above 1000mm 3 Above 1500mm 3 Above, 2000mm 3 More than 2500mm 3 The total volume may be the above and / or any other suitable volume. 1000 mm 3 ~3000mm 3 , 1500mm 3 ~3000mm 3 , 50mm 3 ~500mm 3 , 50mm 3 ~100mm 3 , and 2000mm 3 ~3000mm 3 While the volumes mentioned above are possible, other combinations within the aforementioned ranges are conceivable. Naturally, any suitable overall length, maximum outer lateral dimension, and volume of the ingestible delivery device may be used, but the disclosure is not limited thereto.

[0029] According to the exemplary embodiments described herein, the drug delivery device is administered orally to the subject. In other embodiments, the drug delivery device may be administered endoscopically, transrectally, transvaginally, transnasally, or transurethrally, but this disclosure is not limited thereto. Additionally, depending on the circumstances, the drug delivery device according to the exemplary embodiments described herein may be implanted in the organ of the subject. For example, the drug delivery device may be implanted in the subject's arm, brain, peritoneum, etc.

[0030] In some embodiments, it may be desirable to orient the jet outlets toward the surface of the target GI tube before the delivery device is activated in order to help ensure that the API is delivered to the desired tissue. Thus, a variety of different measures may be used depending on the particular embodiment. For example, various mucosal-adherent soluble hooks for attachment to tissue, mucosal contact sensors, and other methods may be used to maintain contact between the delivery device and the desired tissue in the GI tube, and / or to determine when the delivery device is close to the desired tissue in the GI tube. For example, various self-restoring or self-orienting structures and / or methods described in WO2018 / 213600(A1) may be used by the drug delivery device according to this disclosure. WO2018 / 213600(A1) is incorporated herein by reference in its entirety. Additionally, in some embodiments, a number of outlets and corresponding number of jets located at different positions on the outside of the delivery device may be used to increase the likelihood that one of the jets will be oriented toward the tissue close to the delivery device. Naturally, it should be understood that embodiments may also be conceivable in which the delivery device does not include sensors for detecting contact with the inner mucosal layer of the target and / or components for attachment to the inner mucosal layer of the target.

[0031] As used herein, the term “active pharmaceutical ingredient” (also referred to as “drug” or “therapeutic agent”) means an agent administered to a subject to treat or prevent a disease, disorder, or other clinically recognized condition, and which produces a clinically significant effect on the subject’s body to treat, prevent, and / or diagnose the disease, disorder, or condition. An active pharmaceutical ingredient may be delivered to a subject in amounts greater than trace amounts to influence the subject’s therapeutic response. In some embodiments, an active pharmaceutical ingredient (API) may include, but is not limited to, any synthetic or naturally occurring bioactive compound or composition that, when administered to a subject (e.g., a human or a non-human animal), induces a desired pharmacological, immunogenic, and / or physiological effect by local and / or systemic action. For example, compounds or chemicals conventionally considered as drugs, vaccines, and biopharmaceuticals are useful or potentially useful within the context of a particular embodiment. Certain such APIs may include molecules such as proteins, peptides, hormones, nucleic acids, and gene constructs for use in therapeutic, diagnostic, and / or enhancement fields. In certain embodiments, the APIs are small molecules and / or large molecules. Therefore, it should be understood that the APIs described herein are not limited to any particular type of API.

[0032] Certain non-limiting embodiments will be described in further detail with reference to the drawings. Since this disclosure is not limited to the specific embodiments described herein, it should be understood that the various systems, components, features, and methods described in connection with these embodiments may be used individually and / or in any desired combination.

[0033] Figure 1A is a schematic diagram of one embodiment of the drug delivery device 100 in a first state, representing the state before the drug delivery device 100 is activated. As shown in Figure 1A, the drug delivery device 100 includes a housing 102 which includes a potential energy source configured as a compressed gas compartment 104 and an active pharmaceutical ingredient (API) reservoir 110. The compressed gas compartment 104 and the reservoir 110 are separated by a piston 106 which is slidably received inside the housing 102. The piston 106 includes a piston seal 108 configured to restrict fluid transfer between the compressed gas compartment 104 and the reservoir 110. The piston 106 transmits pressure from the compressed gas compartment 104 to the reservoir 110. That is, the compressed gas inside the gas compartment 104 pressurizes the API inside the reservoir 110. As shown in Figure 1A, the reservoir 110 is fluidly connected to a nozzle 112 that reduces the maximum lateral dimension of the fluid passage, and the fluid passage may include a downstream opening of the nozzle, ranging from the lateral dimension of the reservoir to a maximum lateral dimension corresponding to a desired maximum lateral dimension of the jet (e.g., diameter). The nozzle 112 is configured to generate a jet of API when the pressurized API flows out of the nozzle 112. The drug delivery device also includes a fluid outlet 118 that is in fluid communication with the nozzle 112. In the embodiment shown, the maximum lateral dimension of the outlet is greater than the maximum lateral dimension of the downstream opening formed in the nozzle. A rupturable membrane 114 is positioned between the nozzle 112 and the outlet 118. According to the particular embodiment of Figure 1A, the rupturable membrane may be formed of metal foil, but other rupturable membranes may also be used. The rupturable membrane is configured to rupture under the pressure of the pressurized API in the reservoir 110. However, the apparatus includes a trigger 116 in the form of a dissolving plug that is physically held within the apparatus outlet 118, and this plug is positioned in contact with the surface of the membrane on the side of the membrane opposite the nozzle. The dissolving plug may be configured to physically support the ruptureable membrane before it dissolves. Thus, while the trigger 116 is positioned in the outlet 118, the ruptureable membrane is supported and does not rupture under the pressure of the API.

[0034] In the embodiment shown in Figure 1A, the drug delivery device 100 includes a diffusion barrier 120 positioned between the gas compartment 104 and the piston 106. The gas diffusion barrier 120 may be configured to prevent the gas contained in the gas compartment 104 from diffusing over time into the API reservoir 110. Additionally, the diffusion barrier 120 may be configured to prevent the gas contained in the gas compartment 104 from diffusing over time from the housing 102. The diffusion barrier 120 can suppress gas diffusion more effectively than the piston seal 108 alone, making the device 100 suitable for a longer shelf life. The diffusion barrier 120 may be a burstable barrier configured to rupture when a burstable membrane 114 ruptures. In some embodiments, the diffusion barrier may be formed of metal foil, but other materials may also be used. Like the burstable membrane 114, the diffusion barrier 120 may be configured to rupture under the pressure of the gas inside the gas compartment 104. However, the piston 106 and the fluid in the lower API reservoir 110 are configured to support the diffusion barrier. That is, the diffusion barrier 120 is supported by the piston 106 until the device 100 is activated and the ruptureable membrane 114 ruptures. When the piston 106 moves toward the nozzle 112 and discharges the API from the API reservoir 110, the support from the diffusion barrier 120 is removed, causing the diffusion barrier 120 to rupture, allowing the gas in the gas compartment to continue applying pressure to the piston 106 (see Figure 1B).

[0035] As shown in Figure 1B, when the trigger 116 dissolves inside the target GI tube, the physical support of the ruptureable membrane 114 is removed. Thus, the pressure from the API through the nozzle 112 applies an unsupported force to the ruptureable membrane 114 sufficient to rupture it. Upon rupture, the API flows out of the nozzle 112 in a jet through the reservoir 110 and into the target GI tube mucosal tissue 200. As shown in Figure 1B, the jet may have an appropriate combination of force, velocity, and diameter to penetrate the tissue 200 to the desired depth. Again, as the piston 106 advances toward the nozzle 112, the diffusion barrier 120 ruptures under the gas pressure of the gas compartment 104, and the ruptured diffusion barrier is shown in Figure 1B.

[0036] According to embodiments shown in Figures 1A and 1B, the nozzle 112 and outlet 118 are configured to ensure consistent jet performance by allowing the ruptureable membrane 114 to easily rupture in the central portion of the membrane. Specifically, as shown in Figures 1A and 1B, the nozzle 112 has an outlet port flow path adjacent to the membrane having a first diameter (e.g., a first maximum lateral dimension). The outlet 118 has a second diameter (e.g., a second maximum lateral dimension) that is larger than the first diameter. Thus, the flow path upstream of the membrane 114 has a smaller diameter than the flow path downstream of the membrane 114, and the membrane 114 defines a transition (i.e., a step) between the first and second diameters. As a result, the pressure applied to the membrane 114 is concentrated in the central portion of the membrane 114, while the physical support is distributed over a larger area. Therefore, even if the trigger 116 melts unevenly, the stress on the membrane 114 is concentrated in the central portion of the membrane 114 aligned with the nozzle 112. Thus, when the membrane 114 ruptures, the API has a free flow path from the API reservoir 110 to the outlet 118, and the jet is directed through the outlet 118 without contacting the walls of the outlet 118 before impacting the underlying tissue 200. The rupture process is clearly illustrated in Figures 2A to 2D.

[0037] Figures 2A to 2D illustrate the process by which the trigger 116 is activated, causing the ruptureable membrane 114 of the drug delivery device 100 to burst. Figure 2A shows the drug delivery device 100 in a state prior to ingestion by the subject. In the represented state, the trigger 116 is configured as a soluble plug before dissolution in the GI tube. The soluble plug seals the outlet 118 of the drug delivery device 100, is held within it, and supports the ruptureable membrane 114. An API reservoir 110 containing a pressurized API applies pressure to the membrane 114 on the membrane side opposite the trigger 116. Specifically, the API applies pressure to the ruptureable membrane 114 through the opening of the nozzle 112 of the drug delivery device 100, the opening may have a downstream opening close to the membrane 114 and a trigger having a maximum lateral dimension (i.e., diameter) smaller than the corresponding maximum lateral dimension of the fluidically connected reservoir 110.

[0038] Figures 2B and 2C represent the stages in which the trigger 116 is activated. As shown in Figure 2B, the trigger 116 is beginning to dissolve in the GI tube. According to embodiments 2A to 2D, the soluble plug 116 is configured so that the central portion of the soluble plug (i.e., further from the wall of the outlet 118) dissolves more rapidly. Nevertheless, the soluble plug 116 may dissolve unevenly with respect to its longitudinal centerline due to environmental factors in the GI tube and the irregularities of the soluble plug. As shown in Figure 2C, the trigger 116 has dissolved further than the state shown in Figure 2B. The trigger 116 has dissolved to the extent that the central portion of the membrane 114 is no longer physically supported by the trigger 116. Thus, the membrane 114 bulges under the pressure of the API in the API reservoir 110. As shown in Figure 2D, the continued dissolution of the trigger 116 eventually leads to the rupture of the bulge, and the API is jetted out of the API reservoir 110 through the nozzle 112.

[0039] As shown in Figures 2C to 2D, even if the soluble plug trigger 116 dissolves unevenly, the membrane 114 can rupture in the central portion aligned with the nozzle. As discussed above, this can be made possible by providing a nozzle 112 having a first diameter smaller than the second diameter of the outlet 118. Thus, since the trigger 116 dissolves most rapidly in the central portion of the soluble plug away from the wall of the outlet 118, a bulge is formed in the portion of the membrane 114 aligned with the nozzle 112. The edges of the membrane 114 remain supported and therefore do not cause peeling that could result in an inefficient or insufficient jet of API. The stress concentration in the central portion of the ruptureable membrane 114 also helps ensure a clean rupture that does not interfere with the formation of a jet of API from the nozzle 112 directed outwards from the outlet 118 without affecting the wall of the outlet 118.

[0040] According to embodiments shown in Figures 2A to 2D, the dissolvable plug trigger 116 is configured such that the center of the trigger 116 dissolves more rapidly. To achieve this, the dissolvable trigger 116 may be potted and polished so that its outer surface, exposed to the ambient environment, is concave and moistened relative to the outlet of the delivery device. The dissolvable trigger 116 may also be inspected for bubbles, cracks, and incomplete melting, such features which may affect the dissolution pattern of the dissolvable trigger. Naturally, any preferred configuration of the dissolvable trigger 116 may be used, but this disclosure is not limited thereto. Additional configurations of the dissolvable trigger are shown and described with reference to Figures 7A to 9.

[0041] Embodiments in Figures 1A-1B and 2A-2D represent a drug delivery device 100 having a single nozzle 112 and outlet 118, but it should be noted that in other embodiments, the drug delivery device 100 may have multiple nozzles 112 and / or outlets 118. In some embodiments, a ruptureable membrane may be positioned in the flow path upstream of the multiple nozzles 112 and / or outlets 118. In some cases, including multiple outlets 118 in the drug delivery device 100 may improve the success rate of penetration into GI tubule tissue, as multiple outlets 118 may compensate for variability in the orientation of the drug delivery device 100. However, additional outlets may come at the expense of payload efficiency, as a single payload is divided among each of the outlets, and only a selected subset of outlets actually delivers the dose to the GI tubule tissue. Therefore, in some embodiments, the drug delivery device may include two outlets to improve reliability in terms of orientation variation without significantly reducing payload efficiency. Naturally, the drug delivery device may include any suitable number of outlets, but this disclosure is not limited thereto.

[0042] Figure 3 is an SEM image of one embodiment after the rupture of the ruptureable membrane. As shown in Figure 3, the arrangement in which the ruptureable membrane ruptures in the central portion of the membrane provides a clean opening through which the API jet can pass cleanly. Thus, the API jet may have sufficient energy to penetrate the GI tube tissue and deliver the API to the target.

[0043] Figures 4A and 4B show schematic diagrams of another embodiment of the drug delivery device 300. According to the embodiments of Figures 4A and 4B, the trigger is based on a reaction rather than the dissolution of a soluble plug. As shown in Figure 4A, the device 300 includes a housing 302 having a reaction chamber 304 and an API reservoir 310. As in the embodiments of Figures 1A and 1B, the device 300 also includes a piston 306 with a seal 308 configured to transfer pressure between the reaction chamber 304 and the API reservoir 310. The API reservoir 310 is in fluid communication with a nozzle 312. A ruptureable membrane 314 is positioned between the outlet 316 and the nozzle 312, and the membrane 314 seals the API inside the API reservoir 310 until the membrane ruptures. The device 300 does not include a soluble trigger at the outlet 316. The reaction chamber 304 is not pressurized in the state shown in Figure 4A, and therefore no pressure is applied to the ruptureable membrane 314 in a static state. Instead, the trigger may be an electrical trigger (e.g., a sensor) and / or a chemical trigger. The reaction chamber 304 may contain reactants configured to generate pressure when activated by the trigger. In some embodiments, an electrical sensor may trigger an acid-base reaction, an explosive reaction, and / or any other suitable reaction to generate a pressurized gas. Naturally, any suitable reactant may be used to generate pressure, but this disclosure is not limited thereto. Naturally, a solubility trigger is not used in the embodiments of Figures 4A and 4B, but in other embodiments, a solubility trigger may be used with the reaction chamber, which, in response to dissolution, exposes the reaction chamber 304 to the external gastric environment, and thus the reactants may react and generate gas when exposed to the gastric environment.

[0044] As shown in Figure 4B, when the reaction inside the reaction chamber 304 is triggered and the reaction chamber 304 is pressurized, the piston 306 is pushed down, pressurizing the API in the API reservoir 310. Since there is no soluble plug in the outlet 316 of the device, the membrane 314 ruptures under pressure, and the API is pushed out in a jet with enough force to penetrate the GI tube tissue 200 and deliver a therapeutic dose of the API to the patient.

[0045] Figures 5A and 5B show schematic diagrams of yet another embodiment of the drug delivery device 400. The embodiment shown in Figures 5A and 5B is similar to that in Figures 1A and 1B in that the device 400 includes a soluble trigger 414 (i.e., a soluble plug) configured to activate the drug delivery device 400. However, in contrast to the conventional embodiment, the device 400 of Figures 5A and 5B does not include a piston; instead, the device 400 includes a flexible diffusion barrier 406 configured to allow pressure transfer between a potential energy source and the API. As shown in Figure 5A, the device 400 includes a housing 402 having a gas compartment 404 configured to contain a pressurized gas and an API reservoir 408 configured to contain a solution containing the API. The gas compartment 404 and the API reservoir 408 are separated by a flexible diffusion barrier 406, which is configured to maintain pressure between the gas compartment 404 and the API reservoir 408, while allowing pressure to be transferred from the gas compartment 404 to the API reservoir 408. To suppress gas diffusion between the gas compartment 404 and the API reservoir 408, a metallized seal 416 may be fabricated between the diffusion barrier 406 and the housing 402. As in previous embodiments, the API reservoir 408 is in fluid communication with a nozzle 410 configured to focus the API into a jet. A rupturable membrane 412 is configured to seal the API inside the API reservoir 408 until the membrane ruptures. A soluble trigger 414 provides physical support for the rupturable membrane 412 and prevents the membrane from rupturing until the trigger 414 dissolves. According to embodiments of Figures 5A to 5B, the apparatus 400 also includes a plurality of metallized seals 416 configured to ensure an airtight seal of the fluid within the apparatus 400. Specifically, the seals 416 can suppress the diffusion of gas between various compartments and from the inside of the housing 402 to the external environment.

[0046] As shown in Figure 5B, when the soluble trigger 414 (see Figure 5A) dissolves, the ruptureable membrane 412 may rupture, releasing the API contained in the API reservoir 408. The pressure applied by the compressed gas in the gas compartment 404 (see arrow) pushes the API out of the nozzle 410 in a jet. The jet may have a suitable velocity and diameter for puncturing the GI tube tissue 200 and delivering a dose of API to the tissue. As in previous embodiments, the diameter of the nozzle 410 upstream of the ruptureable membrane 412 is smaller than the diameter of the outlet channel 418 containing the soluble trigger 414. Therefore, the ruptureable membrane 412 ruptures in a central portion aligned with the nozzle 410 so that the rupture of the ruptureable membrane does not significantly obstruct the jet.

[0047] Figures 6A–6D illustrate various diagrams of another embodiment of the drug delivery device 500 for delivering an API to the mucosal lining tissue of a target GI tubule. As shown in Figure 6A, the device 500 is oval-shaped with flattened ends and may include an upper housing 502 and a lower housing. According to the embodiments of Figures 6A–6D, the upper housing 502 and the lower housing 504 may be screw-connected to each other, as described below with reference to Figure 6B. However, embodiments have also been conceived in which the housings are attached to each other using adhesive, welding, brazing, mechanical interference, and / or any other suitable mounting method.

[0048] Figure 6B shows a cross-sectional view of the drug delivery device 500 of Figure 6A, cut along line 6B-6B. As shown in Figure 6B, the upper housing 502 and the lower housing 504 are screw-connected by threads 506. The upper housing 502 includes a gas compartment 508 configured to receive and hold a compressed gas (e.g., a potential energy source). According to embodiments of Figures 6A-6D, the gas compartment 508 is configured to receive dry ice that can sublimate to provide a predetermined pressure within the gas compartment 508. In this way, the gas compartment 508 can be filled without an external filling port. Of course, in other embodiments, the gas compartment 508 may include a gas filling port and / or be filled under a pressurized environment, but the disclosure is not limited thereto. As shown in Figure 6B, the lower housing 504 includes an API reservoir 510 and a nozzle 512 that is in fluid communication with the API reservoir 510. In the embodiments shown, the nozzle 512 is formed within the lower housing 504. However, embodiments have also been conceived in which the nozzle 512 is a separately formed component assembled together with the housing. The lower housing 504 also includes a piston 513 configured to transfer pressure from the compressed gas compartment 508 to the API in the API reservoir 510. According to embodiments of Figures 6A–6D, the piston 513 includes an API filling port 514 that allows the API reservoir 510 to be filled when the upper housing 502 is removed from the lower housing 504, and a sealant 515. The sealant 515 can be applied after the API reservoir 510 is filled to prevent fluid from being transferred across the piston 513. As in other embodiments discussed herein, the drug delivery device 500 may also include a gas diffusion barrier 516 configured to prevent compressed gas from leaking out of the gas compartment 508 when stored over a long period of time. The gas diffusion barrier 516 may be a metal barrier and may be configured to rupture when the device 500 is activated, releasing the gas and applying pressure to the piston 513.

[0049] According to the embodiment of Figure 6B, the drug delivery device 500 includes a ruptureable membrane 518, which is positioned adjacent to and in contact with the nozzle 512 and configured to seal the API inside the API reservoir 510 until the membrane 518 ruptures. The ruptureable membrane 518 is supported by a solubility trigger 520 (e.g., a solubility plug) so that the membrane 518 does not rupture under the pressure applied by the API through the nozzle. The trigger 520 and the ruptureable membrane 518 are connected to the lower housing 504 together with a trigger plug 522 that screws into the lower housing 504. The trigger plug 522 will be discussed further below with reference to Figures 6C-6D. According to the embodiment of Figure 6B, the ruptureable membrane 518 may be formed of fluorinated ethylene propylene (FEP). Of course, in other embodiments, any suitable membrane material may be used, but this disclosure is not limited thereto.

[0050] According to embodiments of Figures 6A to 6B, the process of filling the drug delivery device 500 includes providing a separate upper housing 502 and lower housing 504. A piston 513 may be located inside the lower housing 504, and a trigger plug 522 may be screwed into the lower housing 504. Next, the API reservoir 510 may be filled through an API filling port 514 formed in the piston 513. For example, a pipette or syringe may be used to fill the API reservoir 510 through the API filling port 514. Once the API reservoir 510 is filled, a sealant 515 may be applied to close the API filling port 514. Next, dry ice may be placed inside the upper housing 502 together with a diffusion barrier 516, and the upper housing 502 may be screwed into the lower housing 504 to complete the filling process.

[0051] Figure 6C shows an enlarged sectional exploded view, and Figure 6D shows an enlarged sectional unexploded view of the lower portion of the drug delivery device 500 of Figure 6B. As shown in Figure 6C, the lower housing 504 includes a nozzle 512 that is in fluid communication with the API reservoir. The lower housing 504 also includes one or more threads 524 configured to receive a trigger plug 522 having one or more corresponding threads 526. The trigger plug 522 includes an outlet channel 521 and a soluble trigger 520 disposed and held within an internal channel 523 extending through the trigger plug 522. The trigger 520 is disposed in contact with and configured to support a ruptureable membrane 518 when screwed into the housing 504 until the soluble trigger 520 dissolves. As shown in Figures 6C and 6D, the lower housing 504 includes a cutout 528 configured to accommodate the membrane 518. As shown in Figure 6D, the cutout 528 includes one or more sealing protrusions 530 configured to engage with the ruptureable membrane 518 to form a reliable seal. In the shown embodiment, one or more sealing protrusions 530 are provided in the form of circular protrusions on which the sealing plug clamps the membrane 518. While not wishing to be bound by theory, surface finish and / or variations of the membrane 518 may affect the sealing properties when sealing the membrane 518 against a flat surface. Therefore, by providing the protrusions 530, it may be possible to ensure that the sealing force is concentrated at the contact location between the membrane 518 and the protrusions 530 to create a proper seal between the membrane 518 and the lower housing 504. By concentrating the sealing pressure away from the central portion of the ruptureable membrane 518, the cutout 528 may provide a small cavity on the membrane 518 that can pool pressurized API and eventually rupture the ruptureable membrane 518. In other words, the API can form bubbles within the central portion of the ruptureable membrane 518, thereby causing the membrane to rupture cleanly (i.e., without significant interference with the API jet). Naturally, in other embodiments, any preferred sealing configuration of the ruptureable membrane 518 may be used, but this disclosure is not limited thereto.

[0052] Figures 7A–7D show schematic diagrams of another embodiment of the soluble trigger 600 of a drug delivery device undergoing a dissolution process. Figure 7A shows the drug delivery device in a state prior to ingestion by the subject. In the shown state, the trigger 600 is configured as a soluble hollow plug before dissolution in the GI tube. The soluble plug 600 is held within the outlet 118 of the drug delivery device and supports a ruptureable membrane 114 along the outer circumference of the membrane. As shown in Figure 7A, the soluble trigger 600 includes a cylindrical cavity 602 extending over the length of the soluble trigger. This arrangement of the soluble trigger 600 can ensure that the membrane 114 ruptures in the central portion of the membrane, provided that the cavity 602 is preferably narrow enough not to cause premature membrane rupture. As shown in Figure 7A, an API reservoir 110 containing a pressurized API applies pressure to the membrane 114 on the opposite side of the membrane from the trigger 600. Specifically, the API applies pressure to the ruptureable membrane 114 through the opening of the nozzle 112 of the drug delivery device. As shown in Figures 7B to 7D, the soluble trigger 600 may dissolve outward from the cavity 602, resulting in a clean rupture of the membrane 114 as shown in Figure 7D.

[0053] Figure 8 shows another schematic diagram of the solubility trigger 700 of the drug delivery device. Similar to the embodiments in Figures 7A to 7D, the drug delivery device in Figure 8 includes a housing 102, an API reservoir 110, a nozzle 112, and an outlet 118. The solubility trigger 700 is configured to physically support the membrane 114 until the solubility trigger 700 dissolves in the GI tube. According to the embodiment in Figure 8, the solubility trigger 700 includes a conical cavity 702 configured to facilitate the dissolution of the solubility trigger 700 outward from the central portion of the solubility trigger 700.

[0054] Figure 9 shows another schematic diagram of the solubility trigger 800 of the drug delivery device. Similar to the embodiments in Figures 7A–7D and Figure 8, the drug delivery device of Figure 9 includes a housing 102, an API reservoir 110, a nozzle 112, and an outlet 118. The solubility trigger 800 is configured to physically support the membrane 114 until the solubility trigger 800 dissolves in the GI tube. According to the embodiment of Figure 8, the solubility trigger 800 includes a concave semi-elliptical cavity 802 configured to facilitate the dissolution of the solubility trigger 800 from the central portion outward.

[0055] Although this instruction has been described in conjunction with various embodiments and examples, it is not intended to limit this instruction to such embodiments or examples. On the contrary, this instruction encompasses various substitutes, variations, and equivalents, as will be understood by those skilled in the art. Therefore, the above description and drawings are merely examples.

[0056] Preferred embodiments of the present invention According to a first aspect of the present invention, a drug delivery device is provided which is configured to administer to a subject, the device comprising: a reservoir configured to contain an active pharmaceutical ingredient; a potential energy source; a trigger operably associated with the potential energy source and configured to act in response to one or more predetermined conditions; a port in fluid communication with the reservoir; and a rupture membrane disposed along a flow path extending between the reservoir and the port, which seals the reservoir from the port, wherein when the trigger is activated, the potential energy source compresses the reservoir, causing the rupture membrane to burst, and the active pharmaceutical ingredient flows from the reservoir through the port, the flow path having a first maximum lateral dimension downstream of the rupture membrane which is greater than a second maximum lateral dimension upstream of the rupture membrane which is greater than a second maximum lateral dimension upstream of the rupture membrane which is greater than a second maximum lateral dimension upstream of the rupture membrane which is greater than the second maximum lateral dimension upstream of the rupture membrane which is greater than the second maximum lateral dimension upstream of the rupture membrane which is greater than the second maximum lateral dimension upstream of the rupture membrane which is greater than the second maximum lateral dimension upstream of the rupture membrane which is greater than the second maximum lateral dimension upstream of the rupture membrane which is greater than the second maximum lateral dimension upstream of the rupture membrane which is greater than of

[0057] In a drug delivery device according to a first aspect of the present invention, the potential energy source may include at least one of compressed gas, a spring, and a reaction chamber.

[0058] In a drug delivery device according to a first aspect of the present invention, the trigger may be a soluble plug configured to dissolve in the target gastrointestinal tract.

[0059] In such a drug delivery device, the trigger may further be provided with an enteric coating.

[0060] In a drug delivery device according to a first aspect of the present invention, the ruptureable membrane may be a metal foil.

[0061] In a drug delivery device according to a first aspect of the present invention, a ruptureable membrane may be disposed in a transitional area between a first maximum lateral dimension and a second maximum lateral dimension.

[0062] In the drug delivery device according to the first aspect of the present invention, the total volume of the drug delivery device may be less than 3000 mm³.

[0063] A drug delivery device according to a first aspect of the present invention may further include a nozzle between a ruptureable membrane and a reservoir, the outlet portion of which defines a second maximum lateral dimension, the second maximum lateral dimension being 50 μm to 350 μm.

[0064] In a drug delivery device according to a first aspect of the present invention, the flow of the active pharmaceutical component may be a jet of the active pharmaceutical component having a speed sufficient to penetrate the tissue adjacent to the outlet.

[0065] A drug delivery device according to a first aspect of the present invention may further comprise a cavity located upstream of a ruptureable membrane, configured to apply pressure to the central portion of the ruptureable membrane.

[0066] A drug delivery device according to a first aspect of the present invention may further comprise a piston configured to apply pressure to a reservoir under the force of a potential energy source.

[0067] In such a drug delivery device, the potential energy source may be a compressed gas, and it further comprises a gas diffusion barrier that is physically supported by a piston and configured to rupture when a ruptureable membrane ruptures.

[0068] A second aspect of the present invention provides a drug delivery device configured to administer a drug to a target, the device comprising: a reservoir configured to contain an active pharmaceutical ingredient; a potential energy source; a trigger operably associated with the potential energy source and configured to act in response to one or more predetermined conditions; a first channel in fluid communication with the reservoir; a second channel downstream of the first channel, wherein the first channel has a first maximum lateral dimension and the second channel has a second maximum lateral dimension greater than the first maximum lateral dimension; and a ruptureable membrane disposed between the first channel and the second channel.

[0069] In a drug delivery device according to a second aspect of the present invention, the potential energy source may include at least one of compressed gas, a spring, and a reaction chamber.

[0070] In a drug delivery device according to a second aspect of the present invention, the trigger may be a soluble plug configured to dissolve in the target gastrointestinal tract.

[0071] In such a drug delivery device, the trigger may further be provided with an enteric coating.

[0072] In a drug delivery device according to a second aspect of the present invention, the ruptureable membrane may be a metal foil.

[0073] In a drug delivery device according to a second aspect of the present invention, a ruptureable membrane may be disposed in the transition between a first maximum lateral dimension and a second maximum lateral dimension.

[0074] In a drug delivery device according to a second aspect of the present invention, the total volume of the drug delivery device may be less than 3000 mm³.

[0075] A drug delivery device according to a second aspect of the present invention may further include a nozzle between the first channel and the reservoir, wherein the first maximum lateral dimension is 50 μm to 350 μm.

[0076] In a drug delivery device according to a second aspect of the present invention, when a trigger is activated, a potential energy source compresses the reservoir, causing a ruptureable membrane to burst, thereby allowing the active pharmaceutical component to flow from the reservoir through a second channel, the flow of the active pharmaceutical component being a jet of the active pharmaceutical component having sufficient velocity to penetrate tissue adjacent to the second channel.

[0077] A drug delivery device according to a second aspect of the present invention may further comprise a cavity located upstream of a ruptureable membrane, configured to concentrate pressure in the central portion of the membrane.

[0078] A drug delivery device according to a second aspect of the present invention may further comprise a piston configured to apply pressure to a reservoir under the force of a potential energy source.

[0079] In such a drug delivery device, the potential energy source may be a compressed gas, and it further comprises a gas diffusion barrier that is physically supported by a piston and configured to rupture when a ruptureable membrane ruptures.

[0080] A third aspect of the present invention provides a drug delivery device configured to administer to a target, the device comprising: a reservoir configured to contain an active pharmaceutical ingredient; a potential energy source; an outlet in fluid communication with the reservoir; a ruptureable membrane disposed along a flow path extending between the reservoir and the outlet; and a solubility trigger operably associated with the potential energy source and disposed within the outlet, configured to dissolve at a predetermined location within the target while in vivo, and disposed in contact with and supporting the downstream surface of the ruptureable membrane.

[0081] In a drug delivery device according to a third aspect of the present invention, the potential energy source may include at least one of compressed gas, a spring, and a reaction chamber.

[0082] In a third aspect of the present invention, the drug delivery device may be a soluble plug configured to dissolve in the target gastrointestinal tract.

[0083] In a drug delivery device according to a third aspect of the present invention, the central portion of the soluble plug can dissolve at a faster rate than the outer portion of the soluble plug.

[0084] In such a drug delivery device, the trigger may further be provided with an enteric coating.

[0085] In a drug delivery device according to a third aspect of the present invention, the ruptureable membrane may be a metal foil.

[0086] In a third embodiment of the present invention, the total volume of the drug delivery device is 3000 mm². 3 It may be less than.

[0087] A third aspect of the present invention provides a drug delivery device that may further include a nozzle between the outlet and the reservoir, wherein the maximum lateral dimension of the nozzle outlet is 50 μm to 350 μm.

[0088] A third embodiment of the present invention may further comprise a cavity located upstream of a ruptureable membrane, configured to concentrate pressure in the central portion of the membrane.

[0089] A third embodiment of the present invention may further comprise a piston configured to apply pressure to a reservoir under the force of a potential energy source.

[0090] In such a drug delivery device, the potential energy source may be a compressed gas, and it further comprises a gas diffusion barrier that is physically supported by a piston and configured to rupture when a ruptureable membrane ruptures.

Claims

1. An ingestible, insertable, or implantable drug delivery device configured to administer a drug to a target, wherein the device is A reservoir configured to contain an active pharmaceutical ingredient, a potential energy source, A trigger operably associated with the potential energy source, configured to operate in response to one or more predetermined conditions, The aforementioned reservoir has an outlet that is in fluid communication with it, An ingestible, insertable, or implantable drug delivery device comprising: a ruptureable membrane disposed along a channel extending between the reservoir and the outlet, the ruptureable membrane sealing the reservoir from the outlet, wherein when the trigger is activated, the potential energy source ruptures the ruptureable membrane, thereby causing the active pharmaceutical ingredient to flow through the channel from the reservoir through the outlet, the channel having a second maximum lateral dimension downstream of the ruptureable membrane which is greater than a first maximum lateral dimension of the channel upstream of the ruptureable membrane.

2. The ingestible, insertable, or implantable drug delivery device according to claim 1, wherein when the trigger is activated, the potential energy source compresses the reservoir, causing the ruptureable membrane to burst, thereby allowing the active pharmaceutical ingredient to flow from the reservoir through the outlet.

3. The ingestible, insertable, or implantable drug delivery device according to claim 1 or 2, wherein the ruptureable membrane is disposed in the transition between the first maximum lateral dimension and the second maximum lateral dimension.

4. The ingestible, insertable, or implantable drug delivery device according to any one of the prior claims, wherein the second maximum lateral dimension downstream of the ruptureable membrane is greater than the first maximum lateral dimension of the channel upstream of the ruptureable membrane, so that the ruptureable membrane ruptures in the central portion of the ruptureable membrane.

5. The ingestible, insertable, or implantable drug delivery device according to claim 4, further comprising a cavity positioned upstream of the ruptureable membrane and configured to apply pressure to the central portion of the ruptureable membrane.

6. An ingestive, insertable, or implantable drug delivery device according to any one of the prior claims, further comprising a nozzle located upstream of the rupturable membrane and between the rupturable membrane and the reservoir, wherein when the trigger is activated, the outlet portion of the nozzle defines the first maximum lateral dimension such that the flow of the active pharmaceutical ingredient becomes a jet having sufficient velocity to penetrate tissue adjacent to the outlet.

7. The ingestionable, insertable, or implantable drug delivery device according to claim 6, wherein the outlet portion of the nozzle comprises a first channel having a first maximum lateral dimension, and the outlet comprises a second channel having a second maximum lateral dimension greater than the first maximum lateral dimension.

8. An ingestionable, insertable, or implantable drug delivery device according to any one of claims 1 to 5, wherein the flow path comprises a first channel having a first maximum lateral dimension, and the outlet comprises a second channel having a second maximum lateral dimension greater than the first maximum lateral dimension.

9. An ingestible, insertable, or implantable drug delivery device according to any one of the prior claims, wherein the potential energy source comprises at least one of compressed gas, a spring, and a reaction chamber.

10. An ingestible, insertable, or implantable drug delivery device according to any one of the prior claims, wherein the first maximum lateral dimension is 50 μm to 600 μm.

11. The ingestible, insertable, or implantable drug delivery device according to claim 10, wherein the first maximum lateral dimension is 50 μm to 350 μm.

12. An ingestible, insertable, or implantable drug delivery device according to any one of the prior claims, wherein the trigger is soluble and configured to dissolve at a predetermined location within the target while in vivo, and the soluble trigger is disposed in contact with and supporting the downstream surface of the ruptureable membrane.

13. An ingestible, insertable, or implantable drug delivery device according to any one of the prior claims, wherein the trigger is a soluble plug configured to dissolve in the gastrointestinal tract of the target.

14. The ingestible, insertable, or implantable drug delivery device according to claim 13, wherein the central portion of the soluble plug dissolves at a faster rate than the outer portion of the soluble plug.

15. The ingestible, insertable, or implantable drug delivery device according to claim 13 or 14, wherein the trigger further comprises an enteric coating.

16. The ingestible, insertable, or implantable drug delivery device according to any one of the prior claims, wherein the rupturable membrane is a metal foil.

17. The total volume of the drug delivery device is 3000 mm². ３ An ingestible, insertable, or implantable drug delivery device according to any one of the prior claims, which is less than [value missing].

18. An ingestive, insertable, or implantable drug delivery device according to any one of the prior claims, further comprising a piston configured to apply pressure to the reservoir under the force of the potential energy source.

19. The ingestible, insertable, or implantable drug delivery device according to claim 18, wherein the potential energy source is a compressed gas, and the device further comprises a gas diffusion barrier physically supported by the piston and configured to rupture when the rupturable membrane ruptures.

20. An ingestible, insertable, or implantable drug delivery device configured for administration to a target, the device comprising: a reservoir configured to contain an active pharmaceutical ingredient; a potential energy source; a trigger operably associated with the potential energy source and configured to act in response to one or more predetermined conditions; a first channel in fluid communication with the reservoir; a second channel downstream of the first channel, wherein the first channel has a first maximum lateral dimension and the second channel has a second maximum lateral dimension greater than the first maximum lateral dimension; and a ruptureable membrane disposed between the first channel and the second channel.

21. An ingestible, insertable, or implantable drug delivery device configured to administer to a target, the device comprising: a reservoir configured to contain an active pharmaceutical ingredient; a potential energy source; an outlet in fluid communication with the reservoir; a ruptureable membrane disposed along a flow path extending between the reservoir and the outlet; and a solubility trigger operably associated with the potential energy source and disposed within the outlet, configured to dissolve at a predetermined location within the target while in vivo, and disposed in contact with and supporting the downstream surface of the ruptureable membrane.

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