Ingestible drug delivery device

Abstract

A drug delivery device for administration to a subject can include a reservoir containing an active pharmaceutical ingredient and a source of potential energy. The drug delivery device can also include a trigger operatively associated with the source of potential energy. The trigger can be configured to be actuated at a predetermined location in the subject to deploy a jet of the active pharmaceutical ingredient into tissue of an adjacent portion of the gastrointestinal tract. In some cases, the jet can be deployed into tissue of the stomach and / or small intestine of the subject. Furthermore, in some embodiments, the operating parameters of the jet can be selected such that the jet penetrates tissue of the gastrointestinal tract to form a depot of the active pharmaceutical ingredient disposed in the tissue.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 063,818, filed August 10, 2020, pursuant to 35 U.SC §119(e), which is incorporated herein in its entirety. Technical Field

[0003] The disclosed implementation schemes involve ingestible drug delivery devices and related methods of use. Background Technology

[0004] Some therapeutic agents consist of large and complex molecules that are prone to denaturation when administered via the oral-gastrointestinal (GI) route. Therefore, patients requiring these agents often receive more invasive forms of drug administration outside the GI route, including, for example, subcutaneous injection. Summary of the Invention

[0005] In some embodiments, a drug delivery device configured for administration to a subject includes: a reservoir configured to contain an active pharmaceutical ingredient; a potential energy source; a trigger effectively associated with the potential energy source, wherein the trigger is configured to actuate in the subject's stomach; and an outlet in fluid communication with the reservoir. When the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate gastric tissue near the outlet. The peak power provided by the potential energy source to form the jet of the active pharmaceutical ingredient is between 9 watts (W) and 130 W.

[0006] In some embodiments, a drug delivery device configured for administration to a subject includes: a reservoir configured to contain an active pharmaceutical ingredient; a potential energy source; a trigger effectively associated with the potential energy source, wherein the trigger is configured to actuate in the subject's stomach; and an outlet in fluid communication with the reservoir. When the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate gastric tissue near the outlet. The outlet, reservoir, and potential energy source are configured to form a depot of the active pharmaceutical ingredient in the gastric tissue without penetrating the muscularis layer.

[0007] In some embodiments, the method of administering an active pharmaceutical ingredient to a subject includes triggering the deployment of a jet of the active pharmaceutical ingredient in the subject's stomach and penetrating the subject's stomach tissue with the jet, wherein the peak power applied to form the jet of the active pharmaceutical ingredient is from 9 watts (W) to 130 W.

[0008] In some embodiments, a method of administering an active pharmaceutical ingredient to a subject includes triggering deployment of a jet of the active pharmaceutical ingredient in the stomach of the subject, penetrating stomach tissue of the subject with the jet, and forming a depot of the active pharmaceutical ingredient in the stomach tissue without penetrating the muscularis layer of the stomach.

[0009] In some embodiments, a drug delivery device configured for administration to a subject includes a reservoir configured to contain an active pharmaceutical ingredient, a source of potential energy, a trigger operatively associated with the source of potential energy, wherein the trigger is configured to be actuated in the small intestine of the subject, and an outlet in fluid communication with the reservoir. When the trigger is actuated, the source of potential energy compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate small intestine tissue in the vicinity of the outlet. The peak power provided by the source of potential energy to form the jet of the active pharmaceutical ingredient is 3 Watts (W) to 6.5 W.

[0010] In some embodiments, a drug delivery device configured for administration to a subject includes a reservoir configured to contain an active pharmaceutical ingredient, a source of potential energy, a trigger operatively associated with the source of potential energy, wherein the trigger is configured to be actuated in the small intestine of the subject, and an outlet in fluid communication with the reservoir. When the trigger is actuated, the source of potential energy compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate small intestine tissue in the vicinity of the outlet. The outlet, reservoir, and source of potential energy are configured to form a depot of the active pharmaceutical ingredient in the small intestine tissue without penetrating the muscularis layer of the small intestine.

[0011] In some embodiments, a method of administering an active pharmaceutical ingredient to a subject includes triggering deployment of a jet of the active pharmaceutical ingredient in the small intestine of the subject, and penetrating small intestine tissue of the subject with the jet, wherein the peak power applied to form the jet of the active pharmaceutical ingredient is 3 Watts (W) to 6.5 W.

[0012] In some embodiments, a method of administering an active pharmaceutical ingredient to a subject includes triggering deployment of a jet of the active pharmaceutical ingredient in the small intestine of the subject, penetrating small intestine tissue of the subject with the jet, and forming a depot of the active pharmaceutical ingredient in the small intestine tissue without penetrating the muscularis layer of the small intestine.

[0013] In some embodiments, a drug delivery device configured for administration to a subject comprises a reservoir configured to contain an active pharmaceutical ingredient; a source of potential energy; a trigger operatively associated with the source of potential energy, wherein the trigger is configured to actuate in response to one or more predetermined conditions; and an outlet in fluid communication with the reservoir. In some embodiments, when the trigger is actuated, the source of potential energy compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity of 20 m / s to 250 m / s. In some embodiments, the peak power provided by the source of potential energy to form a jet of the active pharmaceutical ingredient is 9 Watts (W) to 130 W. In some embodiments, when the trigger is actuated, the source of potential energy can compress the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate stomach tissue proximate the outlet.

[0014] In some embodiments, a drug delivery device configured for administration to a subject comprises a reservoir configured to contain an active pharmaceutical ingredient; a source of potential energy; a trigger operatively associated with the source of potential energy, wherein the trigger is configured to actuate in response to one or more predetermined conditions; and an outlet in fluid communication with the reservoir. In some embodiments, when the trigger is actuated, the source of potential energy compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity of 20 m / s to 250 m / s. In some embodiments, the outlet, reservoir, and source of potential energy are configured to form a depot of the active pharmaceutical ingredient in stomach tissue without penetrating the muscularis layer of the stomach. In some embodiments, the trigger can be configured to actuate in the stomach of the subject. In some embodiments, when the trigger is actuated, the source of potential energy can compress the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate stomach tissue proximate the outlet.

[0015] In some embodiments, a drug delivery device configured for administration to a subject comprises a reservoir configured to contain an active pharmaceutical ingredient; a source of potential energy; a trigger operatively associated with the source of potential energy, wherein the trigger is configured to actuate in response to one or more predetermined conditions; and an outlet in fluid communication with the reservoir. In some embodiments, when the trigger is actuated, the source of potential energy compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity of 40 m / s to 80 m / s. In some embodiments, the peak power provided by the source of potential energy to form a jet of the active pharmaceutical ingredient is 3 W to 6.5 W. In some embodiments, the trigger can be configured to actuate in the small intestine of the subject. In some embodiments, when the trigger is actuated, the source of potential energy compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate small intestine tissue proximate the outlet.

[0016] In some embodiments, a drug delivery device configured for administration to a subject comprises a reservoir configured to contain an active pharmaceutical ingredient; a source of potential energy; a trigger operatively associated with the source of potential energy, wherein the trigger is configured to be actuated in response to one or more predetermined conditions; and an outlet in fluid communication with the reservoir. In some embodiments, when the trigger is actuated, the source of potential energy compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity of 40 m / sec to 80 m / sec proximate the outlet. In some embodiments, the outlet, reservoir, and source of potential energy are configured to form a depot of the active pharmaceutical ingredient in the small intestinal tissue without penetrating the small intestinal muscularis. In some embodiments, the trigger can be configured to be actuated in the small intestine of the subject. In some embodiments, when the trigger is actuated, the source of potential energy compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate the small intestinal tissue proximate the outlet.

[0017] It is to be understood that the above concepts and further concepts discussed below can be arranged in any suitable combination, as the disclosure is not limited in this respect. Moreover, other advantages and novel features of the present disclosure will become apparent to those skilled in the art from the following detailed description, when considered in conjunction with the non-limiting embodiments illustrated in the figures. BRIEF DESCRIPTION OF DRAWINGS

[0018] The drawings are not intended to be to scale. In the drawings, each identical, or nearly identical, component that is illustrated in various figures is represented with a like numeral. For purposes of clarity, not every component is called out in every drawing. In the drawings:

[0019] Figure 1A depicts a schematic view of one embodiment of a drug delivery device;

[0020] Figure 1B depicts a cross-sectional view of the drug delivery device of Figure 1A in a first state;

[0021] Figure 1C depicts a cross-sectional view of the drug delivery device of Figure 1A in a second state;

[0022] FIG. 2A depicts one embodiment of a drug delivery device in a first state;

[0023] FIG. 2B depicts a cross-sectional view of the drug delivery device of FIG. 2A in a second state;

[0024] Figure 3 depicts one embodiment of a drug delivery device traversing a gastrointestinal system of a subject;

[0025] Figure 4A schematic plot depicting jet power versus time;

[0026] Figure 5A A plot depicting calculated jet force versus time for different nozzle sizes;

[0027] Figure 5B A plot depicting calculated jet power versus time for different nozzle sizes;

[0028] Figure 5C A plot depicting experimental jet force versus time for different nozzle sizes;

[0029] Figure 5D A plot depicting experimental jet power versus jet diameter;

[0030] Figure 5E A plot depicting experimental delivery efficiency versus nozzle size;

[0031] Figure 5F A plot depicting experimental jet power versus nozzle size;

[0032] Figure 6A A plot depicting measured and predicted jet performance parameters along different anatomical structures of the gastrointestinal tract;

[0033] Figure 6B A plot depicting measured jet injection efficiency versus jet force for a variety of gastrointestinal tissues;

[0034] Figure 7 A schematic of a tethered drug delivery device for administering an API in the stomach;

[0035] Figure 8A A parameter input: preliminary experimental summary including jet force and the delivery efficiency it produces in stomach tissue;

[0036] Figure 8B A parameter input: preliminary experimental summary including jet pressure and the delivery efficiency it produces in stomach tissue;

[0037] Figure 9A A parameter input: preliminary experimental summary including jet force and the delivery efficiency it produces in intestinal tissue; and

[0038] Figure 9B A parameter input: preliminary experimental summary including jet pressure and the delivery efficiency it produces in intestinal tissue. DETAILED DESCRIPTION

[0039] Large and complex molecules that are susceptible to denaturation are often administered as part of a therapeutic treatment when administered via the oral-gastrointestinal (GI) route. Patients in need of these therapeutics often must use more invasive forms of drug administration, such as subcutaneous injection. The use of these more invasive delivery forms can sometimes result in decreased daily compliance and / or decreased quality of life.

[0040] In view of the above, the present inventors have recognized the benefit of an ingestible delivery device that takes full advantage of needleless microjetting to deliver a dose of a desired active pharmaceutical ingredient (API) along the gastrointestinal tract (GI) to a desired location without compromising drug purity, potency, and / or dose. In particular, the present inventors have recognized the benefit of an ingestible delivery device that employs a trigger for automatic release of the dose at the desired location in the GI tract. The GI tract as used herein includes the esophagus, stomach, duodenum, jejunum, small intestine, and large intestine. The delivery device can be adapted to deliver large and complex molecules, such as proteins and other biologies, which can otherwise not be suitable for delivery through the GI tract, but can use any suitable API. According to some example embodiments described herein, the use of microjetting for delivery of an active pharmaceutical ingredient (API) with an ingestible delivery device has a number of potential benefits. First, the ingestible delivery device according to some example embodiments described herein can not include a sharp point. Second, microjetting avoids the mechanisms associated with actuating and / or retracting a needle, thereby reducing the complexity and cost of the system relative to needle-based systems. The use of jetting deployed APIs can also result in a significant increase in bioavailability of the API (about 2% bioavailability) comparable to subcutaneous injection as compared to other ingested APIs provided with ordinary chemical permeation enhancers. Finally, the implementation of a needleless delivery system of some example embodiments described herein can result in less pain and / or trauma at the injection site relative to needle-based delivery, as well as enhanced pharmacokinetics (PK).

[0041] In view of the foregoing, the inventors have recognized benefits associated with jetting an active pharmaceutical ingredient into a subject's gastrointestinal tissue. However, because jet-based deployment of an active pharmaceutical ingredient (API) is needleless, control of a number of operating parameters associated with the jet can determine into which anatomical structure the jet of the API is deployed. For example, a drug delivery device can be configured to provide a jet of an API that is appropriately adjusted for: intraluminal delivery of the API into an intraluminal space of the gastrointestinal tract (i.e., wet jetting); intramucosal delivery of the API into mucosal tissue of the gastrointestinal tract; submucosal delivery of the API into submucosal tissue of the gastrointestinal tract; intraperitoneal delivery of the API into a peritoneal space of the subject; a combination of the foregoing; and / or any other suitable delivery modality. In some embodiments, depending on the target tissue of the jet and specific parameters, a depot of the API can form in the target tissue, where the depot can be a volume of the API disposed in the target tissue and / or between different tissue layers of the gastrointestinal tract. In some embodiments, a drug delivery device can be configured for delivering a jet of an API into tissue in the stomach and / or small intestine of a subject. Specific operating parameters that can be selected to optimize the jet for delivery into these different tissue locations can include, for example, jet power, diameter, dose, standoff distance, fluid viscosity, fluid density, and other suitable parameters as further detailed below.

[0042] In some embodiments, the active pharmaceutical ingredient can be administered to the subject by triggering the deployment of a jet of active pharmaceutical ingredient from the drug delivery device when the drug delivery device is located at a desired location within the gastrointestinal tract of the subject. According to some example embodiments described herein, the jet can be triggered by a predetermined condition. In some embodiments, the predetermined condition comprises one or more of: a predetermined time after ingestion of the drug delivery device, a predetermined location in the GI tract, physical contact with the GI tract, physical manipulation in the GI tract (e.g., compression by peristalsis), one or more characteristics of the GI tract (e.g., pH, pressure, acidity, temperature, etc.), or combinations thereof. In some embodiments, the jet can be deployed when the drug delivery device is located in the stomach and / or small intestine of the subject. In either case, the operating parameters of the jet can be appropriately selected so that the jet is emitted from the drug delivery device at a sufficient velocity to penetrate the gastrointestinal tissue of the subject in the vicinity of the drug delivery device to form a depot of active pharmaceutical ingredient in the gastrointestinal tissue proximate to the drug delivery device upon actuation. In some embodiments, the jet can form a depot of active pharmaceutical ingredient in the gastrointestinal tissue without traversing the muscularis layer of the gastrointestinal tract under the injection site where the jet impacts the gastrointestinal tissue. The terms "proximate to" and "in the vicinity of" are used interchangeably herein and are defined herein to mean that a particular element is in direct contact or spatially close enough to achieve a particular function, e.g., separated by a distance as used herein.

[0043] Without wishing to be bound by theory, the present inventors have recognized that one of the control parameters for delivering an active pharmaceutical ingredient (API) to a desired target location in the gastrointestinal tissue of a subject is the peak power of the jet during delivery of the API into the target tissue. For example, the peak power of the jet used to deploy the API into the target tissue can be selected so that the jet forms a depot of the API disposed in the target tissue without traversing the underlying layers of the gastrointestinal tract. Advantageously, this parameter can take into account a variety of other operating parameters, such as deployment force, density, viscosity, area of the jet, and velocity of the jet, so that delivery devices with different APIs and / or deployment systems can be designed and compared for a desired application. Additionally, the present inventors have recognized that the peak power suitable for forming a depot in the target tissue varies based on the location of the delivery device in the gastrointestinal tract of the subject. For example, the optimal peak power for operating in the stomach of a subject is different from the optimal peak power for operating in the small intestine and / or other portions of the gastrointestinal tract of a subject.

[0044] As noted above, in some embodiments, it can be desirable to deliver the active pharmaceutical ingredient to the stomach tissue of the subject. Accordingly, a suitable peak power can be selected to allow the jet to penetrate the stomach tissue proximate to the drug delivery device disposed in the stomach of the subject. In some cases, the peak power can be selected to avoid penetration through the muscularis layer of the stomach. In one such embodiment, the peak power of the jet directed toward the surface of the stomach of the subject can be greater than or equal to 9 W, 10 W, 12 W, 15 W, 20 W, 25 W, 50 W, 100 W, and / or any other suitable power. Correspondingly, the peak power of the jet can be less than or equal to 130 W, 100 W, 50 W, 25 W, 21 W, 15 W, 12 W, and / or any other suitable power. Combinations of the foregoing ranges are contemplated, including peak powers of 9 W to 130 W, 9 W to 100 W, 9 W to 50 W, 9 W to 25 W, 9 W to 21 W, 9 W to 15 W, 9 W to 12 W, 10 W to 130 W, 10 W to 100 W, 10 W to 50 W, 10 W to 25 W, 10 W to 21 W, 10 W to 15 W, 12 W to 130 W, 12 W to 100 W, 12 W to 50 W, 12 W to 25 W, 12 W to 21 W, 12 W to 15 W, 15 W to 130 W, 15 W to 100 W, 15 W to 50 W, 15 W to 25 W, 15 W to 21 W, 20 W to 130 W, 20 W to 100 W, 20 W to 50 W, 20 W to 21 W, 25 W to 130 W, 25 W to 100 W, 25 W to 50 W, 50 W to 130 W, 50 W to 100 W, or 100 W to 130 W. As described herein, the phrase“one value to another value” includes the endpoints and all values in between. In some cases, the above powers can be suitable to form a depot in the submucosal tissue and / or muscularis layer of the stomach of the subject. Alternatively, some embodiments are also contemplated in which the drug delivery device is configured to provide a jet for intraluminal delivery (in which a majority of the active pharmaceutical ingredient is injected into the intraluminal space of the stomach). In one such embodiment, the peak power of the jet can be less than 9 W. Additionally, some embodiments are also contemplated in which the drug delivery device is configured for intraperitoneal delivery (in which a majority of the active pharmaceutical ingredient is injected into the peritoneal space by penetration through the muscularis layer of the stomach). In some embodiments, intraperitoneal injection in the stomach can correspond to a jet having a peak power greater than about 40 W.

[0045] As also noted above, in some embodiments, it is desirable to deliver the active pharmaceutical ingredient to the small intestinal tissue of the subject. Thus, a suitable peak power can be selected to allow the jet to penetrate the small intestinal tissue proximate to the drug delivery device disposed in the small intestine of the subject. In some cases, the peak power can be selected to avoid penetration through the small intestinal muscularis. In one such embodiment, the peak power of the jet directed toward the surface of the small intestine of the subject can be greater than or equal to 3.0 W, 3.1 W, 3.2 W, 3.3 W, 3.4 W, 3.5 W, 4.0 W, 4.5 W, 5 W, 5.5 W, 6.0 W, and / or any other suitable power. Correspondingly, the peak power of the jet can be less than or equal to 6.5 W, 6.4 W, 6.3 W, 6.2 W, 6.1 W, 6.0 W, 5.5 W, 5.0 W, 4.5 W, and / or any other suitable power.Combinations of the foregoing ranges are contemplated, including peak power of 3.0 W to 6.5 W, 3.0 W to 6.4 W, 3.0 W to 6.3 W, 3.0 W to 6.2 W, 3.0 W to 6.1 W, 3.0 W to 6.0 W, 3.0 W to 5.5 W, 3.0 W to 5.0 W, 3.0 W to 4.5 W, 3.1 W to 6.5 W, 3.1 W to 6.4 W, 3.1 W to 6.3 W, 3.1 W to 6.2 W, 3.1 W to 6.1 W, 3.1 W to 6.0 W, 3.1 W to 5.5 W, 3.1 W to 5.0 W, 3.1 W to 4.5 W, 3.2 W to 6.5 W, 3.2 W to 6.4 W, 3.2 W to 6.3 W, 3.2 W to 6.2 W, 3.2 W to 6.1 W, 3.2 W to 6.0 W, 3.2 W to 5.5 W, 3.2 W to 5.0 W, 3.2 W to 4.5 W, 3.3 W to 6.5 W, 3.3 W to 6.4 W, 3.3 W to 6.3 W, 3.3 W to 6.2 W, 3.3 W to 6.1 W, 3.3 W to 6.0 W, 3.3 W to 5.5 W, 3.3 W to 5.0 W, 3.3 W to 4.5 W, 3.4 W to 6.5 W, 3.4 W to 6.4 W, 3.4 W to 6.3 W, 3.4 W to 6.2 W, 3.4 W to 6.1 W, 3.4 W to 6.0 W, 3.4 W to 5.5 W, 3.4 W to 5.0 W, 3.4 W to 4.5 W, 3.5 W to 6.5 W, 3.5 W to 6.4 W, 3.5 W to 6.3 W, 3.5 W to 6.2 W, 3.5 W to 6.1 W, 3.5 W to 6.0 W, 3.5 W to 5.5 W, 3.5 W to 5.0 W, 3.5 W to 4.5 W, 4.0 W to 6.5 W, 4.0 W to 6.4 W, 4.0 W to 6.3 W, 4.0 W to 6.2 W, 4.0 W to 6.1 W, 4.0 W to 6.0 W, 4.0 W to 5.5 W, 4.0 W to 5.0 W, 4.0 W to 4.5 W, 4.5 W to 6.5 W, 4.5 W to 6.4 W, 4.5 W to 6.3 W, 4.5 W to 6.2 W, 4.5 W to 6.1 W, 4.5 W to 6.0 W, 4.5 W to 5.5 W, 4.5 W to 5.0 W, 5.0 W to 6.5 W, 5.0 W to 6.4 W, 5.0 W to 6.3 W, 5.0 W to 6.2 W, 5.0 W to 6.1 W, 5.0 W to 6.0 W, 5.0 W to 5.5 W, 5.5 W to 6.5 W, 5.5 W to 6.4 W, 5.5 W to 6.3 W, 5.5 W to 6.2 W, 5.5 W to 6.1 W, 5.5 W to 6.0 W, 6.0 W to 6.5 W, 6.0 W to 6.4 W, 6.0 W to 6.3 W, 6.0 W to 6.2 W, 6.0 W to 6.1 W, and / or any other appropriate peak power range. In some cases, it can be preferred that the jetting power be 3.5 W to 6.5 W, or 4.0 W to 6.5 W, as those jetting powers can have higher injection efficiency than other jetting powers.In some cases, the above power can be suitable for forming a depot in the submucosal tissue and / or muscularis layer of the small intestine of the subject. Alternatively, some embodiments are also contemplated in which the drug delivery device is configured to provide a jet for intraluminal delivery in which a majority of the active pharmaceutical ingredient is injected into the intraluminal space of the small intestine. In one such embodiment, the peak power of the jet can be less than 3.0 W. Additionally, some embodiments are also contemplated in which the drug delivery device is configured for intraperitoneal delivery in which a majority of the active pharmaceutical ingredient is injected into the peritoneal space by penetrating the muscularis layer of the small intestine. In some embodiments, intraperitoneal injection in the small intestine can correspond to a jet having a peak power greater than about 6.5 W, 7.0 W, and / or any other suitable power range.

[0046] The efficiency of depot formation in a target tissue can depend on the particular target tissue and the operating parameters applied when directing a jet of active pharmaceutical ingredient to the tissue. The dose of API used herein refers to the amount of API initially contained in the drug delivery device. Depot efficiency refers to the percentage of the amount of API initially contained in the drug delivery device that is subsequently delivered to a depot disposed in the target tissue. For example, a depot can be formed in the submucosal tissue and / or muscularis tissue of the stomach and / or small intestine of the subject. As detailed below, by appropriate selection of the operating parameters of the jet, a depot efficiency greater than 40% can be achieved. For example, in some embodiments, the depot efficiency of the drug delivery device can be greater than or equal to 40%, 50%, 60%, 70%, and / or any other suitable percentage. Accordingly, the depot efficiency of the drug delivery device can be less than or equal to 95%, 90%, 80%, 70%, 60%, and / or any other suitable percentage. Combinations of the foregoing are contemplated, including a depot efficiency of 40% to 95%, 50% to 95%, 60% to 95%, 70% to 95%, 40% to 90%, 50% to 90%, 60% to 90%, 70% to 90%, 40% to 80%, 50% to 80%, 60% to 80%, 70% to 80%, 40% to 70%, 50% to 70%, 60% to 70%, 40% to 60%, 50% to 60%, and / or other suitable combinations. Additionally, it should be understood that both cases of a depot efficiency greater than and less than the above depot efficiencies are possible as the present disclosure is not limited in this manner.

[0047] According to the particular API administered to a subject, the drug delivery device of some example embodiments described herein can be configured to deliver a range of different dose volumes of the API to the subject. According to some example embodiments described herein, the drug delivery device can include an API reservoir volume in which the API is disposed that is less than or equal to 500 μΙ_, 300 μΙ_, 200 μΙ_, 150 μΙ_, 100 μΙ_, 75 μΙ_, 50 μΙ_, 25 μΙ_, 10 μΙ_, and / or any other suitable volume. Accordingly, the drug delivery device can include an API reservoir volume that is greater than or equal to 1 μΙ_, 5 μΙ_, 10 μΙ_, 25 μΙ_, 50 μΙ_, 75 μΙ_, 100 μΙ_, 200 μΙ_, 300 μΙ_, and / or any other suitable volume. Combinations of the above-mentioned volumes are contemplated, including but not limited to reservoir volumes of 1 μΙ_ to 500 μΙ_, 1 μΙ_ to 300 μΙ_, 1 μΙ_ to 200 μΙ_, 1 μΙ_ to 150 μΙ_, 1 μΙ_ to 100 μΙ_, 1 μΙ_ to 75 μΙ_, 1 μΙ_ to 50 μΙ_, 1 μΙ_ to 25 μΙ_, 1 μΙ_ to 10 μΙ_, 10 μΙ_ to 500 μΙ_, 10 μΙ_ to 300 μΙ_, 10 μΙ_ to 200 μΙ_, 10 μΙ_ to 150 μΙ_, 10 μΙ_ to 100 μΙ_, 10 μΙ_ to 75 μΙ_, 10 μΙ_ to 50 μΙ_, 10 μΙ_ to 25 μΙ_, 25 μΙ_ to 500 μΙ_, 25 μΙ_ to 300 μΙ_, 25 μΙ_ to 200 μΙ_, 25 μΙ_ to 150 μΙ_, 25 μΙ_ to 100 μΙ_, 25 μΙ_ to 75 μΙ_, 25 μΙ_ to 50 μΙ_, 50 μΙ_ to 500 μΙ_, 50 μΙ_ to 300 μΙ_, 50 μΙ_ to 200 μΙ_, 50 μΙ_ to 150 μΙ_, 50 μΙ_ to 100 μΙ_, 50 μΙ_ to 75 μΙ_, 75 μΙ_ to 500 μΙ_, 75 μΙ_ to 300 μΙ_, 75 μΙ_ to 200 μΙ_, 75 μΙ_ to 150 μΙ_, 75 μΙ_ to 100 μΙ_, 100 μΙ_ to 500 μΙ_, 100 μΙ_ to 300 μΙ_, 100 μΙ_ to 200 μΙ_, 100 μΙ_ to 150 μΙ_, 150 μΙ_ to 500 μΙ_, 150 μΙ_ to 300 μΙ_, 150 μΙ_ to 200 μΙ_, 200 μΙ_ to 500 μΙ_, 200 μΙ_ to 300 μΙ_, or 300 μΙ_ to 500 μΙ_. Of course, any suitable reservoir volume can be employed in the drug delivery device, as the present disclosure is not so limited. Additionally, the depot of API disposed in the target tissue can have a volume that is related to the above-mentioned volumes by the above-mentioned respective depot efficiencies.

[0048] To form an effective depot in the target tissue, it can be desirable to maintain the power of the jet within a predetermined range of the peak power of the jet for a predetermined period of time. As defined herein and as shown in FIG. 6, the peak power (P Figure 4 of the jet can be determined by the product of the current (I) and the voltage (V) of the jet. As defined herein, the peak power (P 峰The peak power refers to the maximum power of the jet. The threshold power is the minimum jet power required to penetrate the target tissue at a specific location within the gastrointestinal tract of the subject. In some embodiments, the peak power is greater than or equal to the threshold power. "Optimal peak power" refers to the minimum peak power of the jet suitable for forming a desired reservoir in the target tissue at a specific location within the gastrointestinal tract of the subject with a reservoir efficiency of at least 50%. For example, the jet power can be maintained within 5%, 10%, or other suitable percentages of the peak power for a predetermined period of time. For example, as... Figure 4 As shown, the jet power can initially be increased until it exceeds the threshold power P at time t1. Th The power can then be further increased to the peak power P. 峰 Then, the jet power can be reduced until it equals the threshold power at time t2, where the predetermined time period corresponds to the difference between times t1 and t2. As shown in the figure, the power can continue to decrease after this time. Depending on the specific application, the predetermined time period can be greater than or equal to 1 millisecond, 10 milliseconds, 50 milliseconds, 100 milliseconds, and / or any other suitable time period. Accordingly, the predetermined time period can be less than or equal to 300 milliseconds, 200 milliseconds, 100 milliseconds, 50 milliseconds, and / or any other suitable time period. Combinations of the foregoing are contemplated, including, for example, predetermined time periods of 1 millisecond to 300 milliseconds, 1 millisecond to 200 milliseconds, 1 millisecond to 100 milliseconds, 1 millisecond to 50 milliseconds, 10 milliseconds to 300 milliseconds, 10 milliseconds to 200 milliseconds, 10 milliseconds to 100 milliseconds, 10 milliseconds to 50 milliseconds, 50 milliseconds to 300 milliseconds, 50 milliseconds to 200 milliseconds, 50 milliseconds to 100 milliseconds, 100 milliseconds to 300 milliseconds, or 100 milliseconds to 200 milliseconds. Of course, it should be understood that, in addition to those described above, appropriate ranges and predetermined time periods of jet power relative to peak power are also anticipated, as this disclosure is not limited thereto.

[0049] According to some example embodiments described herein, a trigger of the drug delivery device can be configured to actuate the drug delivery device in the GI tract of the subject at a predetermined time and / or at a predetermined location in the GI tract. In some embodiments, the trigger can be a passive component configured to interact with the environment of the GI tract to actuate the drug delivery device. For example, in some embodiments, the trigger can be a sugar plug or other dissolvable substance configured to dissolve in the GI tract. The dissolvable plug can have a thickness and / or shape that at least partially determines the speed at which the dissolvable plug dissolves and ultimately actuates the drug delivery device. In another embodiment, the trigger can be at least partially formed of an enteric coating. For example, in some embodiments, the trigger can include both a dissolvable plug and an enteric coating disposed on the outer surface of the dissolvable plug, as the disclosure is not limited in this respect. Other suitable materials for a dissolvable trigger can 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 and time-dependent coatings, temperature-dependent coatings, light-dependent coatings, and / or any other suitable material capable of dissolving in the GI tract of the subject. In some embodiments, the trigger can include a triggerable membrane including ethylenediaminetetraacetic acid, glutathione, or another suitable chemical. In some embodiments, a sugar alcohol trigger can be used in combination with an enteric coating configured to protect the sugar alcohol trigger until the drug delivery device is received in the GI tract of the subject. In other embodiments, the trigger can include a pH-responsive coating to help delay triggering until after ingestion. In some embodiments, the trigger can be a sensor and / or electrode configured to detect one or more features of the GI tract or interact with one or more features of the gastrointestinal tract to actuate the device. For example, a sensor that detects contact with the GI mucosal lining can be used to actuate the device. In some embodiments employing a sensor, the trigger can also include an active component that moves or is otherwise actuated in response to a predetermined condition detected by the sensor. For example, a gate can be moved when contact with the GI tract mucosa is detected. In other embodiments, the trigger can employ electricity to melt or weaken a breakable membrane (e.g., by applying a voltage across a conductive breakable membrane) and / or trigger a chemical reaction. Of course, any suitable active or passive trigger can be applied to the drug delivery device, as the disclosure is not limited in this respect.

[0050] According to some example embodiments described herein, the drug delivery device includes a source of potential energy for storing energy in the drug delivery device for use in generating a jet of API when the drug delivery device is actuated. In some embodiments, the source of potential energy can be compressed gas. The compressed gas can be stored directly in the drug delivery device, or can be generated by a chemical reaction or phase change. For example, in some embodiments, dry ice can be stored in a chamber of the drug delivery device such that compressed gas is generated when the dry ice sublimates. Alternatively, compressed gas can be provided to the desired chamber prior to sealing the drug delivery device. In some embodiments, the source of potential energy can be a spring (e.g., a compressed compression spring). In some embodiments, the source of potential energy can be a reaction chamber. For example, the reaction chamber can allow an acid and a base to combine to generate a gas, resulting in the expulsion of API from the drug delivery device when the device is actuated. Alternatively, in another embodiment, a trigger can detonate an explosive material located in a chamber to generate pressurized gas for expelling API from the drug delivery device. Of course, any suitable reaction or other source of potential energy can be employed to pressurize and drive the API in the jet when the drug delivery device is actuated, as the present disclosure is not limited in this respect.

[0051] As described above, the jet power can be adjusted to deliver API into different target tissues in the GI tract having different penetration characteristics. The jet power can be determined at least in part by the jet velocity, fluid density, and jet diameter. Accordingly, the drug delivery devices according to some example embodiments described herein can be appropriately sized and include an appropriate amount of potential energy to generate a jet having sufficient power to deliver API into the tissue at the desired location in the GI tract.

[0052] To achieve the exemplary jetting powers described herein, the jets produced by the drug delivery devices of some exemplary embodiments described herein can have respective velocities. Thus, in some embodiments, the drug delivery devices can be configured to produce jets having a velocity of less than or equal to 250 m / second, 200 m / second, 150 m / second, 130 m / second, 100 m / second, 75 m / second, 50 m / second, and / or another suitable velocity. Accordingly, the drug delivery devices can be configured to produce jets having a velocity of greater than or equal to 20 m / second, 30 m / second, 50 m / second, 80 m / second, 100 m / second, 150 m / second, 200 m / second, and / or another suitable velocity. Combinations of the above-mentioned ranges are contemplated, including but not limited to jet velocities of 20 m / second to 250 m / second, 20 m / second to 200 m / second, 20 m / second to 100 m / second, 20 m / second to 150 m / second, 20 m / second to 100 m / second, 20 m / second to 75 m / second, 20 m / second to 50 m / second, 50 m / second to 250 m / second, 50 m / second to 200 m / second, 50 m / second to 100 m / second, 50 m / second to 150 m / second, 50 m / second to 100 m / second, 50 m / second to 75 m / second, 75 m / second to 250 m / second, 75 m / second to 200 m / second, 75 m / second to 100 m / second, 75 m / second to 150 m / second, 75 m / second to 100 m / second, 100 m / second to 250 m / second, 100 m / second to 200 m / second, 100 m / second to 150 m / second, 150 m / second to 250 m / second, 150 m / second to 200 m / second, or 200 m / second to 250 m / second. In one particular embodiment, the target tissue location can correspond to the stomach, and the jet velocity of the jet can preferably be 80 m / second to 130 m / second, or 40 m / second to 60 m / second. In another embodiment, the target tissue location can correspond to the small intestine of the subject, and the jet velocity of the jet can preferably be 40 m / second to 80 m / second. Of course, any jet velocity suitable for delivering the API to the respective tissue of the gastrointestinal tract of the subject can be used, as the present disclosure is not limited in this regard.

[0053] In some embodiments, a maximum lateral dimension (e.g., diameter) of an outlet (e.g., a nozzle from which a jet is emitted) and / or a maximum lateral dimension (e.g., diameter) of a jet emitted by the outlet can be less than or equal to 550 pm, 450 pm, 400 pm, 350 pm, 300 pm, 250 pm, 200 pm, 150 pm, 100 pm, 75 pm, 50 pm, 25 pm, 10 pm, and / or any other suitable dimension. Accordingly, a maximum lateral dimension of an outlet and / or a jet can be greater than or equal to 5 pm, 10 pm, 25 pm, 50 pm, 75 pm, 100 pm, 150 pm, 200 pm, 250 pm, 300 pm, and / or any other suitable dimension.Combinations of the above ranges are anticipated, including but not limited to the following: maximum lateral dimensions of the jet and / or outlet of 5 μm to 550 μm, 5 μm to 450 μm, 10 μm to 450 μm, 25 μm to 450 μm, 50 μm to 450 μm, 75 μm to 450 μm, 100 μm to 450 μm, 150 μm to 450 μm, 200 μm to 450 μm, 250 μm to 450 μm, 300 μm to 450 μm, 5 μm to 400 μm, 10 μm to 400 μm, 25 μm to 45 ... μm to 400μm, 50μm to 400μm, 75μm to 400μm, 100μm to 400μm, 150μm to 400μm, 200μm to 400μm, 250μm to 400μm, 300μm to 400μm, 5μm to 350μm, 10μm to 350μm, 25μm to 350μm, 50μm to 350μm, 75μm to 350μm, 100μm to 350μm, 150μm to 350μm, 200μm m to 350μm, 250μm to 350μm, 300μm to 350μm, 5μm to 300μm, 10μm to 300μm, 25μm to 300μm, 50μm to 300μm, 75μm to 300μm, 100μm to 300μm, 150μm to 300μm, 200μm to 300μm, 250μm to 300μm, 5μm to 250μm, 10μm to 250μm, 25μm to 250μm, 50μm to 250μm 0μm, 75μm to 250μm, 100μm to 250μm, 150μm to 250μm, 200μm to 250μm, 5μm to 200μm, 10μm to 200μm, 25μm to 200μm, 50μm to 200μm, 75μm to 200μm, 100μm to 200μm, 150μm to 200μm, 5μm to 150μm, 10μm to 150μm, 25μm to 150μm, 50μm to 150μm, 7 5μm to 150μm, 100μm to 150μm, 5μm to 100μm, 10μm to 100μm, 25μm to 100μm, 50μm to 100μm, 75μm to 100μm, 5μm to 75μm, 10μm to 75μm, 25μm to 75μm, 50μm to 75μm, 5μm to 50μm, 10μm to 50μm, 25μm to 50μm, 5μm to 25μm, 10μm to 25μm, or 5μm to 10μm. Of course, any suitable size outlet and / or jet suitable for delivering the API to the desired portion of the gastrointestinal tract of the object can be used, as this disclosure is not limited thereto.

[0054] According to some example embodiments described herein, the drug delivery device includes a source of potential energy configured to pressurize the API such that the API can be released into the GI tract lining in a jet. The pressure applied to the reservoir can affect the jet power and / or jet velocity of the API jet emitted by the drug delivery device. In some embodiments, the source of potential energy can be configured to apply a pressure to the API reservoir of less than or equal to 1000 bar, 800 bar, 600 bar, 500 bar, 250 bar, 100 bar, 60 bar, 45 bar, 40 bar, 10 bar, 1 bar, and / or any other suitable pressure. Correspondingly, the source of potential energy can apply a pressure to the API reservoir of greater than or equal to 0.1 bar, 1 bar, 10 bar, 15 bar, 20 bar, 40 bar, 45 bar, 60 bar, 100 bar, 250 bar, 500 bar, 600 bar, 800 bar, and / or any other suitable pressure. Combinations of the above-mentioned ranges are contemplated, including but not limited to pressures of 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 to 250 bar, 1 bar to 100 bar, 1 bar to 60 bar, 1 bar to 40 bar, 1 bar to 10 bar, 10 bar to 1000 bar, 10 bar to 800 bar, 10 bar to 600 bar, 10 bar to 500 bar, 10 bar to 250 bar, 10 bar to 100 bar, 10 bar to 60 bar, 10 bar to 40 bar, 10 bar to 800 bar, 10 bar to 600 bar, 10 bar to 500 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 to 100 bar, 100 bar to 800 bar, 100 bar to 600 bar, 100 bar to 500 bar, 100 bar to 250 bar, 250 bar to 800 bar, 250 bar to 600 bar, 250 bar to 500 bar, 500 bar to 800 bar, 500 bar to 600 bar, or 600 bar to 800 bar. In some embodiments, a pressure of 15 bar to 60 bar, and more preferably 15 bar to 45 bar, applied to the API reservoir when combined with a properly sized nozzle can be particularly effective in forming a high efficiency depot in the submucosal tissue of the stomach. Similarly, a pressure of 10 bar to 20 bar applied to the API reservoir when combined with a properly sized nozzle can be effective in forming a high efficiency depot in the submucosal tissue of the subject's intestine.Of course, any suitable pressure can be applied to the API reservoir as the present disclosure is not limited in this regard.

[0055] In some embodiments, the drug delivery device is sized and shaped to be ingested by a subject. Thus, the drug delivery device can be suitably small so that the drug delivery device can be easily swallowed and subsequently pass through the GI tract, including the esophageal and pyloric orifices in the stomach. In some embodiments, the drug delivery device can include a total length (e.g., a maximum dimension along a longitudinal axis of the device) of less than or equal to 40 mm, 30 mm, 20 mm, 10 mm, 5 mm, and / or another suitable length. Correspondingly, the drug delivery device can have a total length of greater than or equal to 3 mm, 5 mm, 10 mm, 20 mm, 25 mm, and / or another suitable length. Combinations of the above-mentioned ranges are contemplated, including but not limited to a total length of 5 mm to 30 mm, 10 mm to 30 mm, 5 mm to 20 mm, and 5 mm to 10 mm. In some embodiments, the drug delivery device can have a maximum external lateral dimension (e.g., a diameter or other dimension that can be perpendicular to the longitudinal axis) of less than or equal to 11 mm, 10 mm, 7 mm, 5 mm, and / or another suitable dimension. Correspondingly, the drug delivery device can have a maximum external lateral dimension of greater than or equal to 3 mm, 5 mm, 7 mm, 9 mm, and / or another suitable dimension. Combinations of the above-mentioned ranges are contemplated, including but not limited to a maximum external lateral dimension of 3 mm to 11 mm, 3 mm to 10 mm, 3 mm to 7 mm, 3 mm to 5 mm, and 5 mm to 11 mm. In some embodiments, the drug delivery device can have a total volume of less than or equal to 3500 mm 3 , 3000 mm 3 , 2500 mm 3 , 2000 mm 3 , 1500 mm 3 , 1000 mm 3 , 750 mm 3 , 500 mm 3 , 250 mm 3 , 100 mm 3 , and / or another suitable volume. Correspondingly, the drug delivery device can have a total volume of greater than or equal to 50 mm 3 , 100 mm 3 , 250 mm 3 , 500 mm 3 , 750 mm 3 , 1000 mm 3 , 1500 mm 3 , 2000 mm 3 , 2500 mm 3and / or any other suitable volume. Combinations of the above-mentioned ranges are contemplated, including but not limited to a volume of 1000 mm 3 to 3000 mm 3 , 1500 mm 3 to 3000 mm 3 , 50 mm 3 to 500 mm 3 , 50 mm 3 to 100 mm 3 , and 2000 mm 3 to 3000 mm 3 . Of course, the ingestible delivery device can take any suitable overall length, maximum external lateral dimension, and volume, as the present disclosure is not limited in this regard.

[0056] According to some example embodiments described herein, the drug delivery device is orally administered to the subject. In other embodiments, the drug delivery device can be administered rectally, endoscopically, or nasally, as the present disclosure is not limited in this regard. Thus, it should be appreciated that the presently disclosed drug delivery devices can be delivered to the desired portion of the subject’s gastrointestinal tract in a variety of different ways, and the present disclosure is not limited to a particular method of deploying the drug delivery device.

[0057] In some embodiments, it can be desirable to position the jet outlet proximate to and / or orient the outlet toward the surface of the subject’s GI tract prior to actuating the delivery device to help ensure that the API is delivered into the desired tissue. Thus, a variety of different strategies can be employed according to particular embodiments. For example, a variety of mucosal adhesives, dissolvable hooks for attachment to tissue, mucosal contact sensors, self-orienting delivery devices (e.g., orientation systems based on buoyancy and / or center of gravity), and other methods of keeping the delivery device in contact with the desired tissue within the GI tract and / or determining when the delivery device is proximate to and / or oriented toward the desired tissue within the GI tract can be used. For example, the drug delivery devices according to the present disclosure can use a variety of self-righting or self-orienting structures and / or methods described in WO 2018 / 213600 Al. WO 2018 / 213600 Al is incorporated by reference herein in its entirety. Additionally, in some embodiments, multiple outlets and corresponding multiple jets located at different locations on the exterior of the delivery device can be used to increase the chances that one of the jets is oriented toward the tissue proximate to the delivery device. Of course, it should be appreciated that some embodiments in which the delivery device does not include a sensor for sensing contact with the subject’s mucosal lining and / or components for attachment to the subject’s mucosal lining are also contemplated.

[0058] In some embodiments in which the system and / or method is used to actuate delivery of the API when the outlet is positioned towards gastrointestinal tissue proximal to the drug delivery device, it can be desirable to maintain the orientation of the outlet and the corresponding jet relative to the underlying tissue within a predetermined angular range. This can help to provide the desired combination of jet force and / or jet power in a direction that is oriented perpendicular to the surface of the adjacent tissue. For example, the angle of the jet emitted from the outlet relative to a direction perpendicular to the surface of the underlying tissue can be less than or equal to 20°, 15°, 10°, 5°, and / or any other suitable angular range, including angles both greater and less than the above-mentioned angles. The above-mentioned angular relationship of the direction of the jet emitted from the outlet of the device relative to a direction perpendicular to the surface of the underlying tissue can be provided using any of the above-mentioned methods and structures for actuating the delivery device when in the desired orientation relative to the underlying tissue.

[0059] In some embodiments, the jet can be emitted from an outlet that is distanced from the tissue underlying the delivery device that the jet impacts. The inventors have recognized that for a separation distance between the outlet and the underlying tissue that is less than a threshold distance, minimal differences in tissue penetration and API delivery have been noted. As defined herein, the separation distance refers to the shortest distance between the outlet and the surface of the underlying tissue on which the jet emitted from the outlet impacts. Thus, in some embodiments, the separation distance can be less than or equal to 10 mm, 7.5 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, and / or any other suitable distance. While specific distance ranges are given above, it should be understood that the acceptable separation distance between the outlet and the underlying tissue can vary depending on the specific jet parameters of the drug delivery device used and the tissue on which it is deployed as well as its specific application. Thus, separation distances both greater and less than the above-mentioned distances are contemplated as the present disclosure is not so limited.

[0060] In some embodiments, it can be desirable for one or more components of a drug delivery device to be formed from a biocompatible and / or biologically inert material. For example, a variety of components can be exposed to fluids and / or solids present within a subject's gastrointestinal tract upon ingestion. Accordingly, components that can be exposed to fluids and / or solids present within the gastrointestinal tract can be made from materials including, but not limited to: metals that are relatively inert to the gastrointestinal environment, such as titanium; non-toxic and / or inert polymers such as polydimethylsiloxane (PDMS), polycaprolactone (PCL); salts; carbohydrates; and / or any other suitable material for the desired application. In cases where a particular component for a delivery device can not be suitable for exposure to the environment within a subject's gastrointestinal system, a non-reactive polymer coating and / or metal coating can be applied to the component to separate the underlying material from the external environment. Alternatively, such components can be included in a portion of the delivery device that is not exposed to the external environment during operation. In light of the above, it should be appreciated that a variety of components disclosed herein can be made using any suitable combination of materials, as the present disclosure is not limited to any particular configuration and / or combination of materials for the components.

[0061] The term "active pharmaceutical ingredient" (also referred to as "drug" or "therapeutic agent") as used herein refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and has a clinically significant effect on the body of the subject to be treated, prevented, and / or diagnosed of the disease, disorder, or condition. An active pharmaceutical ingredient can be delivered to a subject in an amount greater than a trace amount to affect a therapeutic response in the subject. In some embodiments, an active pharmaceutical ingredient (API) can include, but is not limited to, any synthetic or naturally occurring biologically active compound or composition of matter that, when administered to a subject (e.g., a human or non-human animal), induces a desired pharmacological, immunogenic, and / or physiological effect by local and / or systemic action. For example, useful or potentially useful in the context of certain embodiments are compounds or chemicals traditionally considered to be drugs, vaccines, and biopharmaceuticals. Certain such APIs can include molecules such as proteins, peptides, hormones, nucleic acids, genetic constructs, and the like for use in the therapeutic, diagnostic, and / or enhancement arts. In certain embodiments, an API is a small molecule and / or a macromolecule. Thus, it should be appreciated that the APIs described herein are not limited to any particular type of API. Additionally, although a drug delivery device can deliver an API in the form of a non-compressible fluid jet in accordance with some example embodiments described herein, in other embodiments, a jet comprising an API produced by a drug delivery device can be formed from a gas, a viscous fluid, an atomized powder, and / or other suitable material, as the present disclosure is not limited thereto.

[0062] In some embodiments, the jet as used herein can refer to a collimated stream of a gas, a fluid, an atomized powder, a combination of the foregoing, and / or other suitable material.

[0063] Turning to the drawings, some specific non-limiting embodiments are described in further detail. It should be understood that various systems, components, features and methods described in relation to these embodiments can be used individually and / or in any desired combination, as the present disclosure is not limited in this regard to the specific embodiments described herein.

[0064] Figures 1A to 1C A schematic diagram of one embodiment of a drug delivery device 100 is depicted. As shown in Figure 1B The drug delivery device 100 includes a housing 102 containing a potential energy source configured as a compressed gas chamber 104 and an active pharmaceutical ingredient (API) reservoir 110. The compressed gas chamber 104 and the reservoir 110 are separated by a piston 106 slidably received within an interior of the housing 102 between the gas chamber 104 and the reservoir 110. The piston 106 includes a piston seal 108 configured to inhibit fluid transfer between the compressed gas chamber 104 and the reservoir 110. The piston 106 transfers pressure from the compressed gas chamber 104 to the reservoir 110. In other words, the compressed gas within the interior of the gas chamber 104 pressurizes the API disposed within the interior of the reservoir 110. As shown in Figure 1A The reservoir 110 includes an outlet 114 in fluid communication with an exterior environment of the device. In some embodiments, the outlet 114 can function as a nozzle forming a jet 116. The maximum lateral dimension (e.g., diameter) of the outlet can be selected to provide a desired maximum lateral dimension of the corresponding jet 116 emitted from the outlet 114 as the pressurized API flows out of the reservoir 110.

[0065] The device can also include a trigger 112 in operative association with the potential energy source, in this case the pressurized gas chamber 104. The trigger 112 is configured to actuate the device 100 at a predetermined location in the gastrointestinal tract of a subject such that the potential energy source, which in the present embodiment is the compressed gas chamber 104, compresses the reservoir 110 for deployment as follows: a jet 116 of active pharmaceutical ingredient comes out of the outlet 114 and into tissue 200 located proximate to the device and a corresponding portion of the gastrointestinal tract toward which the outlet 114 is oriented. For example, in the depicted embodiment, the trigger 112 can correspond to a dissolvable plug physically retained in the outlet 114 of the device such that when the trigger 112 dissolves, the device is actuated as detailed below, although any suitable trigger can be used as the present disclosure is not limited in this regard.

[0066] As shown in Figure 1CAs shown, when trigger 112 dissolves or otherwise actuates within the GI tract of the object, the barrier preventing the API from being deployed through outlet 114 is removed. Therefore, pressure applied to the API reservoir 110 by piston 106 associated with compressed gas chamber 104 causes piston 106 to move in the direction of compressing reservoir 110. When reservoir 110 is compressed, API flows out from outlet 114 in the form of jet 116 at a sufficient velocity to penetrate the tissue 200 of the gastrointestinal tract located near outlet 114. Similarly, the depicted tissue 200 of the gastrointestinal tract may correspond to the stomach, small intestine, and / or any other anatomical structure of the gastrointestinal tract of the object described herein. According to this embodiment, jet 116 may form a reservoir 118 of API in the tissue 200 of the gastrointestinal tract without penetrating the gastrointestinal tract. For example, outlet 114, API reservoir 110, and associated potential energy source (e.g., compressed gas chamber 104) may be suitably configured to provide a jet optimized to form a reservoir corresponding to the volume of API disposed in the submucosal tissue of the gastrointestinal tract without penetrating the muscular layer 202. Furthermore, depending on specific operating parameters, reservoir 118 may be at least partially disposed in the submucosal tissue and / or muscular layer 202 of the gastrointestinal tract.

[0067] Figures 2A and 2B depict schematic embodiments of a drug delivery device 100 including different types of potential energy sources and triggers. In the depicted embodiments, the trigger is based on a reaction rather than the dissolution of a soluble plug. For example, the drug delivery device 100 may include a housing 102 having a reaction chamber 104a and an API reservoir 110. Similar to... Figures 1A to 1CIn some embodiments, the device further includes a piston 106 configured to transfer pressure between the reaction chamber 104a and the API reservoir 110, such that the piston 106 compresses the reservoir 110 when actuated. The API reservoir 110 can also be in fluid communication with an outlet 114. In some embodiments, a rupturable membrane 120 or other seal is disposed on, in, or otherwise associated with the outlet 114 to seal the API inside the API reservoir 110 until the device is actuated and the membrane 120 is ruptured. In the depicted embodiment, the reaction chamber 104a is not pressurized in the state shown in FIG. 2A, such that no pressure is applied to the rupturable membrane 120, which is at rest. In contrast, the trigger can be an electrical trigger (e.g., a sensor) and / or a chemical trigger that is actuated at a predetermined time and / or location in the gastrointestinal tract (e.g., in the stomach and / or small intestine) of the subject using any of the foregoing methods. The reaction chamber 104a can include a reactant configured to generate pressure when actuated by the trigger. In some embodiments, the electrical sensor can trigger an acid-base reaction, an explosive reaction, and / or any other suitable reaction to generate pressurized gas. Of course, any suitable reactant can be used to generate pressure, as the present disclosure is not so limited. Of course, while a dissolution trigger is not used in the embodiments of FIGS. 2A-2B, in other embodiments a dissolution trigger can be used with the reaction chamber 104a, where the dissolvable trigger, when dissolved, exposes the reaction chamber 104a to the external gastric environment, such that the reactant can react to generate gas upon exposure to the gastric environment.

[0068] As shown in FIG. 2B, when the reaction is triggered inside the reaction chamber 104a to pressurize the reaction chamber 104a, the piston 106 is forced downward to pressurize the API in the API reservoir 110, causing the rupturable membrane 120 or other seal to rupture. The API is then forced out of the outlet 114 of the reservoir 110 in the form of a jet 116 having sufficient power to penetrate the tissue 200 of the GI tract to deliver a therapeutic dose of the API to the patient as previously described.

[0069] Figure 3 One embodiment of a drug delivery device 100 that is orally ingested and passes through the gastrointestinal tract 300 of a subject is depicted. By way of example, and without wishing to be limited by such example embodiments, the system can be orally administered to a subject, in which case the system passes through the gastrointestinal tract 300 of the subject until it is actuated at a predetermined time and / or at a predetermined location in the gastrointestinal tract 300. For example, as shown in FIG. 3, the device 100 is orally ingested by a subject and passes through the gastrointestinal tract 300 of the subject until it is actuated at a predetermined time and / or at a predetermined location in the gastrointestinal tract 300. For example, the device 100 can be actuated by a sensor that is triggered by a pH level in the stomach of the subject, by a temperature sensor that is triggered by a temperature in the stomach of the subject, by a pressure sensor that is triggered by a pressure in the stomach of the subject, by a chemical trigger that is triggered by a chemical in the stomach of the subject, and / or by any other suitable trigger. Figure 3As shown schematically, the drug delivery device 100 can be administered (e.g., orally) to a subject such that the device enters the subject's gastrointestinal tract 300 via the esophagus 302 (device 100a). The device can pass through the gastrointestinal system until reaching the subject's stomach 304 (device 100b). In some embodiments, the drug delivery device 100 can be more dense than the surrounding fluid in the stomach 304 or other portions of the GI tract, causing the device to sink to the bottom of the stomach 304 (device 100c) such that the outer surface of the device contacts the inner surface of the stomach 304. According to this embodiment, the device can be attached to the surface of the stomach 304 using a suitable attachment method as previously described, and / or the system can be simply actuated without attachment to the tissue of the stomach 304. In either case, while at a suitable location in the gastrointestinal tract 300, the device can self-actuate to deploy a jet of active pharmaceutical ingredient into the tissue of the gastrointestinal tract 300 (e.g., the surface of the stomach) located proximal to the device. Subsequently, the device can pass through the pyloric orifice of the stomach 304 and through the remainder of the subject's gastrointestinal tract 300 (device 100d). While the device is in the small intestine 306, it can self-actuate to deploy a jet of active pharmaceutical ingredient into the tissue of the small intestine 306 (e.g., the surface of the small intestine) located proximal to the device. Subsequently, the device can pass through the ileocecal valve and into the large intestine 308 (device 100e). While the device is in the large intestine 308, it can self-actuate to deploy a jet of active pharmaceutical ingredient into the tissue of the large intestine 308 (e.g., the surface of the large intestine) located proximal to the device. Subsequently, the device can pass through the rectum and exit the subject's body (device 100f). Figure 3 Operation of the device to deploy active pharmaceutical ingredient in the stomach 304 of a subject is shown, but based on the teachings of this specification, those of ordinary skill in the art will appreciate that the drug delivery devices disclosed herein can deploy active pharmaceutical ingredient at any desired location along the length of the gastrointestinal tract 300 of a subject (including the small intestine of a subject), and that the jet can form a depot of active pharmaceutical ingredient in any suitable tissue of the target portion of the gastrointestinal tract 300, including but not limited to mucosal, submucosal, and / or muscularis tissue layers. As previously described, in some embodiments, the jet can form a depot in one or more layers of gastrointestinal tissue without penetrating the muscularis tissue of the gastrointestinal tract.

[0070] Example: Comparison of Gastrointestinal Tissues

[0071] The following Table I gives a comparison of the characteristics of different gastrointestinal tissue anatomies. Generally, GI tissue is composed of four broad layers of cells: the mucosa, which secretes mucus and serves as a first barrier to absorption of substances such as macromolecules; the submucosa, which lies beneath the mucosa and is rich in vasculature for transport of nutrients to and from the mucosa; the muscularis, which lies beneath the submucosa and is responsible for motility; and the serosa, which lies beneath the muscularis and functions as the outermost protective layer of each organ.

[0072] Table I

[0073]

[0074] In view of the above comparison of organ parameters, the stomach is an attractive target site due to the relatively long bolus transit time and larger wall thickness. Additionally, while the small intestine wall can be relatively thin (1 to 2 mm), the relatively small diameter of the small intestine makes it attractive for jet deployment of APIs as all sides of the device are relatively close to the intestinal wall. Thus, both the stomach and small intestine of a subject are attractive targets for deployment of APIs using the jetting methods disclosed herein.

[0075] Example: Jet Power

[0076] Due to differences in different tissues positioned along the length of a subject's gastrointestinal tract, each type of gastrointestinal tissue is expected to have different power requirements for formation of a depot in the target tissue. In view of these differences, a jet optimized for depot formation in the stomach is not expected to be suitable for depot formation in the small intestine or other anatomical structures. In handling APIs, these differences can result in a dose not being delivered to the target tissue and / or unintentional penetration of one or more anatomical structures if not properly accounted for. Thus, it can be desirable to characterize both how a jet is deployed and the specific power requirements for forming a depot in a desired portion of a subject's gastrointestinal tract to provide a desired amount of API to a desired target tissue.

[0077] A model was developed for the power of a jet emitted from a drug delivery device. The model assumes the use of a linear compression spring as the source of potential energy for driving a piston to force fluid through a corresponding outlet. The spring was modeled as a linear spring with stored compression force prior to deployment and a "dead" compression force after deployment and jet ejection. Friction was not accounted for in the model. However, as discussed below, some energy can be lost during actual use due to friction from piston sliding and flow constriction from the nozzle. The flow of the fluid jet ejected from the device was modeled using Bernoulli's equation, with the fluid density assumed to be 1000 kg / m3. The initial boundary conditions used to solve the model were the initial piston position at time zero and the time required for piston acceleration to be negligible (i.e., "no" velocity boundary condition at t = 0). To improve the accuracy of the model, two types of friction losses were used, including friction from the piston and nozzle efficiency losses.

[0078] The resulting model was used to determine the jet force and jet power versus time for different nozzle diameters. The results are shown in FIGS. 1-3. Figures 5A to 5F The model clearly shows how changing the nozzle diameter can affect both the peak jet force and jet power for a given power system, as well as the jet duration for a given source of potential energy (e.g., the linear spring assumed in the model).

[0079] To validate the model, a handheld system and force sensors were used. The test bench was designed to measure jet force while varying parameters, including nozzle orifice size, initial and final spring forces, spacing, fluid viscosity, incident angle, and discharge volume. The test bench primarily consisted of a handheld jetting device mounted on an aluminum rail with sensors for measuring the resulting jet force. Because this device allowed the operator to quickly switch nozzles and springs (if desired), various combinations of jet parameters could be rapidly measured. Experiments were conducted using a helical spring with an initial spring force of 66 N and a final spring force to initial spring force ratio of 0.45 after jetting. A quick-disconnect hose connector was used as a trigger for the testing rig. Piezoelectric force sensors were used to measure the thrust from the jet. High-speed video was also used to observe the jet shape to verify that the jet was indeed columnar, rather than a spray. Five replicates were performed for each experimental data point. Except for those experiments involving changes in fluid viscosity, all experiments used 200 μL ampoules of 100% deionized water.

[0080] In each case, the nozzle efficiency is derived by comparing it with the theoretical energy input to the jet (i.e., minus piston friction). For example... Figures 5C to 5F As shown, the final nozzle efficiency used to fit the experimental measurements varies between approximately 75% and 85%, although the efficiency is approximately 88% for a 200 μm nozzle. Therefore, when designing a device for delivering desired jet power, it is desirable to determine the nozzle efficiency at the exit point from which the jet is emitted. In either case, experiments have confirmed the ability to predict the jet power of a device through modeling and experimental determination of appropriate parameters.

[0081] Example: Ex vivo Testing

[0082] Without wishing to be bound by theory, in some embodiments, a gastrointestinal-based jetting device can achieve two types of injection: submucosal injection, where the depot is formed directly under or in the submucosal tissue, and intramuscular injection, where the jet is deposited into the muscularis layer. It is also assumed that the power required for depot formation in the gastrointestinal tract is lower than that required for depot formation in the skin, as mucosal cells are softer than dermal cells and in most cases much thinner. To support these assumptions, 200 μί of contrast agent and / or tissue die was injected into 5 cm x 5 cm swine intestinal and stomach tissue samples. All tests used pneumatic cylinders with a final compression to initial compression ratio of 0.90 to replace the pistons to expel the jet through different diameter outlets. The device was mounted vertically and the tissue was placed directly underneath the device on top of a petri dish with a sponge soaked in saline. A bench-top scissor jack was then used to bring the tissue into direct contact with the outlet nozzle. The tissue was harvested from laboratory-raised pigs and tested within 6 hours of excision. Micro-CT (Micro-CT) was used to analyze the depot efficiency delivered for each sample. A 5% wt. barium sulfate suspension was used as the contrast agent for injection. The tissue samples were scanned within 10 minutes of injection to minimize diffusion prior to evaluation.

[0083] By applying the above experimental and imaging methods, the jetting performance of different initial pressures in different anatomical structures in the GI tract was determined, which corresponded to wet shots, depot formation, and tissue penetration, respectively, in which most of the fluid failed to penetrate the tissue. A depot was determined to have formed when a visible depot was observed both visually and through Micro-CT scans. "Penetration" was defined to mean that a clear wound was visible on the serosal side of the tissue, and that little or no contrast agent was contained in the tissue. Figure 6A Initial pressures and corresponding orifice diameters for forming jets in different tissues, including esophagus, colon, rectum, cheek, and stomach, are shown. Wet shots, depot formation, and penetration of the tissue are represented by dashed lines, circles, and x's, respectively. In addition, predicted jet performance is represented by the dashed symbol. Figure 6B Additional measured data for jet injection efficiency versus jetting force for a variety of tissues, including cheek, esophagus, stomach, small intestine (SI), colon, rectum, and dog SI, are shown.

[0084] Experimental data were used to calculate the minimum observed peak power for depot formation in each organ based on the measured data. The results are listed in Table II. Note that given the smaller nozzle size (not measured), a lower minimum requirement can be possible. The calculated jet power was calculated assuming 80% nozzle efficiency. As expected, the minimum peak power for depot formation in each tissue type varied widely from organ to organ.

[0085] Table II

[0086]

[0087]

[0088] With respect to the stomach, the optimal power for high efficiency reservoir formation was about 21.4 W. However, reservoirs began to form at about 9 W, and a breakthrough with higher ejection efficiency was observed at about 30 W and 450 pm nozzle diameter. Additionally, breakthroughs were observed starting at about 40 W.

[0089] Small intestine tissue was also tested. The range of peak power for reservoir formation in the intestine before breakthroughs were observed was about 3 W to 6.5 W.

[0090] Example: Depot Efficiency Testing

[0091] From the above model and experimental data, and without wishing to be bound by theory, an increase in the diameter of the outlet results in a higher force, and thus a higher peak power. Therefore, it would be desirable to determine the maximum nozzle hole orifice diameter and minimum input force that achieves the highest efficiency reservoir formation (volume of drug loaded vs. volume of reservoir formed). To validate this concept, the efficiency of reservoir formation was tested.

[0092] Figures 8A to 8B A summary of the experimental results of the parameter inputs (ejection force or pressure, nozzle diameter, and ejection power) and their resulting delivery efficiency in stomach tissue is depicted. Figure 8A Using force (N) applied to the API reservoir is plotted, and Figure 8B Using pressure (bar) applied to the API reservoir is plotted. The line defines the curve of constant power assuming a piston diameter of 6 mm, a density of 1200 kg / m 3 and a constant system efficiency of 80%. The shaded area labeled breakthrough is the data points where tissue breakthrough was observed. In the graph, the actual point to which the data can be applied for each box is the positive center of the box. As shown in FIG. 8, a wide range of ejection forces and pressures combined with varying diameters can result in injection efficiencies greater than 50% to the stomach. For stomach tissue, in different tests, for jet diameters from 150 pm to 550 pm, using ejection powers from 9 W to 40 W, and at Figure 8A Figure 8B ​In the stomach, high efficiency was achieved without penetration using a jet power of 5W to 45W. Greater depot formation was also observed at a combination of jet force of 75N to 200N and jet pressure of 15bar to 60bar. In particular, high efficiency of greater than 70% can be achieved for a jet power of 20W to 40W and jet diameter of 250pm to 550pm, and a jet force of 75N to 175N or equal to 75N and 175N and / or a jet pressure of 15bar to 45bar or equal to 15bar and 45bar. It is expected that further experimental testing will be used to determine more precise combinations of the above ranges. Thus, while certain ranges show higher efficiency than others in this particular experiment, it is expected that there are additional effective ranges for gastric delivery and the present disclosure is not limited thereto.

[0093] As shown in Figure 8B In the stomach, a wide range of jet pressures and diameters can result in injection efficiency of greater than 50% into the stomach. For stomach tissue, a jet power of 5W to 45W can be used for a jet diameter of 150pm to 550pm and a jet pressure of 15 to 60bar to achieve high efficiency without penetration. In particular, a jet diameter of 50pm to 550pm and a jet force of 15 to 45bar can be used for a jet power of 20W to 40W to achieve high efficiency of greater than 70%. It is expected that further experimental testing will be used to determine more precise combinations of the above ranges. Thus, while certain ranges show higher efficiency than others in this particular experiment, it is expected that there are additional effective ranges for gastric delivery and the present disclosure is not limited thereto.

[0094] Figure 9A A preliminary experimental summary of parameter inputs (jet force or pressure, nozzle diameter, and jet power) and their resulting delivery efficiency in intestinal tissue is depicted. Figure 9A Plotted using force (N) applied to the API reservoir, and Figure 9B Plotted using pressure (bar) applied to the API reservoir. The line defines the assumed piston diameter of 6mm, density of 1200kg / m 3The curve shows a constant power output with a constant system efficiency of 80%. The shaded areas marked as penetration are data points where tissue penetration was observed. In the graph, the actual point to which data applies to each box is the exact center of the box. As shown in Figure 9, a wide range of jet forces and diameters can result in injection efficiencies greater than 50% for intestinal tissue. For intestinal tissue, jet powers of 3W to 6.5W can be used with jet diameters of 150μm to 550μm and jet forces of 20 to 90N to achieve high efficiency without penetration. Specifically, jet powers of 3W to 6W can achieve efficiencies greater than 70% with jet diameters of 150μm to 350μm and jet forces of 30 to 80N. Further experimental testing is expected to determine more precise combinations of the above ranges. Therefore, although some ranges showed higher efficiency than others in this particular experiment, other effective ranges for intestinal tissue delivery are expected, and the invention is not limited thereto.

[0095] like Figure 9B As shown, a wide range of jet pressures and diameters can result in injection efficiencies exceeding 50% for intestinal tissue. For intestinal tissue, jet powers of 3W to 6.5W can be used with jet diameters of 150μm to 550μm and jet pressures of 5 to 20 bar to achieve high efficiency without penetration. Specifically, jet powers of 3W to 6W can achieve efficiencies greater than 70% with jet diameters of 150μm to 350μm and jet pressures of 10 to 20 bar. Further experimental testing is expected to determine more precise combinations of the aforementioned ranges. Therefore, although certain ranges have shown higher efficiency than others in this particular experiment, additional effective ranges for intestinal tissue delivery are expected, and this disclosure is not limited thereto.

[0096] Example: In vivo Testing

[0097] The studies were conducted by trained veterinary technicians at MIT's animal testing facilities. Yorkshire pigs weighing 70 to 90 kg were used. All studies were final (meaning the animals were euthanized immediately afterward). Figure 7 The use of a tethered device 100 for delivering an insulin jet to form a reservoir 118 in the stomach wall of an animal is shown. The test protocol will be described further below.

[0098] During the test period, the weight of the pig was determined and the amount of insulin to achieve a dose of 0.5 units per kg (1 unit = 0.0347 mg) was selected. The powdered insulin was then added to a 0.1 M NaOH solution and PF68 and HEPES were used as stabilizers. From there, 0.1 M HC1 was added to aid in dissolving the insulin and deionized water was added if further dilution was desired. Finally, a small amount of NaOH was added until the pH of the solution reached a value greater than 8.0 (at which point the insulin is most stable). This formulation process was performed in the morning or evening prior to each in vivo study and the resulting solution was stored at 4°C until the time of administration.

[0099] The device was loaded with API and C02 in an operating room where the animal was sedated and intubated. The device could be deployed either directly into the stomach through a laparotomy or through an over-tube with an endoscope and snare. Of the five deployments using the device, the first three were performed through a laparotomy and the last two through an endoscope. Triggering typically occurred within 15 minutes and could be determined by a small amount of foam and backwash near the base of the device.

[0100] Blood samples were collected through an ear or femoral catheter. Samples were taken at one hour prior to scheduled deployment at approximately 15 minute intervals to ensure stability of blood glucose levels. After deployment, blood samples were collected at 5 minute intervals for the first 30 minutes and then at 15 minute intervals until two hours after deployment. Samples were stored on ice in 3 mL EDTA tubes until the study was complete. Blood glucose levels were monitored at each draw using a commercial glucose monitoring strip. If levels dropped below 20 mg / dL, a 12 mL 50% dextrose solution was administered intravenously to avoid hypoglycemia. Samples were subsequently analyzed for blood glucose levels with a custom Ezyme-linked immunosorbent assay (ELISA).

[0101] Three of the five device tests resulted in a decrease in blood glucose levels and a corresponding increase in plasma insulin concentration. The fact that certain devices delivered insulin while others did not can be due to manufacturing differences in the device orifice size. For the prototype device, a wide variation in orifice size was observed, which was addressed in later versions through automated machining. In either case, these tests demonstrated the feasibility of orally delivering a biologic.

[0102] Similar tests were also performed in the small intestine of a pig model using tethered devices. For the jet of insulin deployed in the small intestine, similar results were observed that showed the bioavailability of the jet delivering insulin.

[0103] While the present teachings have been described in conjunction with various embodiments and implementations, it is not intended that the present teachings be limited to such embodiments or implementations. On the contrary, the present teachings encompass numerous alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art. Accordingly, the preceding description and drawings are by way of example only.

Claims

1. A drug delivery device configured for administration to a subject, the device comprising: A storage container configured to hold an active pharmaceutical ingredient; Source of potential energy; A trigger, which is effectively associated with the potential energy source, wherein the trigger is configured to actuate in the stomach of the object; and An outlet, which is in fluid communication with the reservoir, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate gastric tissue near the outlet, and wherein the peak power provided by the potential energy source to form the jet of the active pharmaceutical ingredient is from 9 watts (W) to 130 W, and wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir in the submucosal tissue, wherein the reservoir efficiency is at least 50%.

2. A drug delivery device configured for administration to a subject, the device comprising: A storage container configured to hold an active pharmaceutical ingredient; Source of potential energy; A trigger, effectively associated with the potential energy source, wherein the trigger is configured to actuate in response to one or more predetermined conditions; and An outlet, which is in fluid communication with the reservoir, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 20 m / s to 250 m / s, and wherein the peak power provided by the potential energy source to form the jet of the active pharmaceutical ingredient is 9 watts (W) to 130 W, and wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir in the submucosal tissue, wherein the reservoir efficiency is at least 50%.

3. The drug delivery device of claim 2, wherein the trigger is configured to actuate in the stomach of the subject.

4. The drug delivery device of claim 2 or claim 3, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active drug ingredient from the reservoir through the outlet at a speed sufficient to penetrate gastric tissue near the outlet.

5. The drug delivery device of claim 1 or claim 2, wherein the peak power is 9W to 70W.

6. The drug delivery device of claim 1 or claim 2, wherein the peak power is 9W to 12W.

7. The drug delivery device of claim 1 or claim 2, wherein the outlet, the reservoir and the potential energy source are configured to form a reservoir of the active pharmaceutical ingredient in the gastric tissue without penetrating the gastric muscle layer.

8. A drug delivery device configured for administration to a subject, the device comprising: A storage container configured to hold an active pharmaceutical ingredient; Source of potential energy; A trigger, which is effectively associated with the potential energy source, wherein the trigger is configured to actuate in the stomach of the object; and An outlet, which is in fluid communication with the reservoir, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate gastric tissue near the outlet, and wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir of the active pharmaceutical ingredient in the gastric tissue without penetrating the gastric muscle layer, wherein the peak power provided by the potential energy source to form the jet of the active pharmaceutical ingredient is 9W to 130W.

9. A drug delivery device configured for administration to a subject, the device comprising: A storage container configured to hold an active pharmaceutical ingredient; Source of potential energy; A trigger, effectively associated with the potential energy source, wherein the trigger is configured to actuate in response to one of a plurality of predetermined conditions; and An outlet, which is in fluid communication with the reservoir, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 20 m / s to 250 m / s, and wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir of the active pharmaceutical ingredient in the gastric tissue without penetrating the gastric muscle layer, and wherein the peak power provided by the potential energy source to form the jet of the active pharmaceutical ingredient is 9 W to 130 W.

10. The drug delivery device of claim 9, wherein the trigger is configured to actuate in the stomach of the subject.

11. The drug delivery device of claim 9 or claim 10, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate gastric tissue near the outlet.

12. The drug delivery device of any one of claims 8 to 10, wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir in submucosal tissue, wherein the reservoir efficiency is at least 50%.

13. The drug delivery device according to any one of claims 8 to 10, wherein the velocity of the jet is from 80 m / s to 130 m / s.

14. The drug delivery device according to any one of claims 8 to 10, wherein the maximum lateral dimension of the outlet is 50 μm to 450 μm.

15. The drug delivery device of any one of claims 8 to 10, wherein the potential energy source comprises at least one of compressed gas, a spring, an explosive, and a reaction chamber.

16. The drug delivery device according to any one of claims 8 to 10, wherein the total volume of the drug delivery device is less than 3000 mm². 3 .

17. The drug delivery device according to any one of claims 8 to 10, further comprising the active pharmaceutical ingredient disposed in the reservoir.

18. The drug delivery device according to any one of claims 8 to 10, wherein the object is a human object.

19. A drug delivery device configured for administration to a subject, the device comprising: A storage container configured to hold an active pharmaceutical ingredient; Source of potential energy; A trigger, effectively associated with the potential energy source, wherein the trigger is configured to actuate in the small intestine of the object; and An outlet, which is in fluid communication with the reservoir, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the small intestinal tissue near the outlet, and wherein the peak power provided by the potential energy source to form the jet of the active pharmaceutical ingredient is 3W to 6.5W, wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir in the submucosal tissue, wherein the reservoir efficiency is at least 50%.

20. A drug delivery device configured for administration to a subject, the device comprising: A storage container configured to hold an active pharmaceutical ingredient; Source of potential energy; A trigger, effectively associated with the potential energy source, wherein the trigger is configured to actuate in response to one or more predetermined conditions; and An outlet, which is in fluid communication with the reservoir, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 40 m / s to 80 m / s, and wherein the peak power provided by the potential energy source to form the jet of the active pharmaceutical ingredient is 3 W to 6.5 W, wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir in the submucosal tissue, wherein the reservoir efficiency is at least 50%.

21. The drug delivery device of claim 20, wherein the trigger is configured to actuate in the small intestine of the subject.

22. The drug delivery device of claim 20 or claim 21, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate small intestinal tissue near the outlet.

23. The drug delivery device of any one of claims 19 to 21, wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir of the active pharmaceutical ingredient in the small intestinal tissue without penetrating the intestinal muscular layer.

24. A drug delivery device configured for administration to a subject, the device comprising: A storage container configured to hold an active pharmaceutical ingredient; Source of potential energy; A trigger, effectively associated with the potential energy source, wherein the trigger is configured to actuate in the small intestine of the object; and An outlet, which is in fluid communication with the reservoir, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the small intestinal tissue near the outlet, and wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir of the active pharmaceutical ingredient in the small intestinal tissue without penetrating the muscular layer of the small intestine, wherein the reservoir efficiency is at least 50%, and wherein the peak power of the jet provided by the potential energy source to form the active pharmaceutical ingredient is 3W to 6.5W.

25. A drug delivery device configured for administration to a subject, the device comprising: A storage container configured to hold an active pharmaceutical ingredient; Source of potential energy; A trigger, effectively associated with the potential energy source, wherein the trigger is configured to actuate in response to one or more predetermined conditions; and An outlet, which is in fluid communication with the reservoir, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 40 m / s to 80 m / s near the outlet, and wherein the outlet, the reservoir, and the potential energy source are configured to form a reservoir of the active pharmaceutical ingredient in the small intestinal tissue without penetrating the intestinal muscle layer, wherein the reservoir efficiency is at least 50%, and wherein the peak power of the jet provided by the potential energy source to form the active pharmaceutical ingredient is 3 W to 6.5 W.

26. The drug delivery device of claim 25, wherein the trigger is configured to actuate in the small intestine of the subject.

27. The drug delivery device of claim 25 or claim 26, wherein when the trigger is actuated, the potential energy source compresses the reservoir to eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate small intestinal tissue near the outlet.

28. The drug delivery device according to any one of claims 19 to 21 or 24 to 26, wherein the velocity of the jet is from 40 m / s to 80 m / s.

29. The drug delivery device of any one of claims 19 to 21 or 24 to 26, wherein the maximum lateral dimension of the outlet is 50 μm to 450 μm.

30. The drug delivery device of any one of claims 19 to 21 or 24 to 26, wherein the potential energy source comprises at least one of compressed gas, a spring, an explosive, and a reaction chamber.

31. The drug delivery device according to any one of claims 19 to 21 or 24 to 26, wherein the overall volume of the drug delivery device is less than 3000 mm². 3 .

32. The drug delivery device according to any one of claims 19 to 21 or 24 to 26, further comprising the active pharmaceutical ingredient disposed in the reservoir.

33. The drug delivery device of any one of claims 19 to 21 or 24 to 26, wherein the object is a human object.

Images