Ingestable drug delivery devices

Abstract

We provide ingestible drug delivery devices. [Solution] A drug delivery device 100 for administration to a target may include a reservoir 110 containing an active pharmaceutical ingredient and a potential energy source. The drug delivery device may also include a trigger 112 operationally associated with the potential energy source. The trigger 112 may be configured to activate at a predetermined location within the target and deploy a spray of the active pharmaceutical ingredient into the tissue of an adjacent portion of the gastrointestinal tract. In some cases, the spray may be deployed into the tissue of the stomach and / or small intestine of the target. Furthermore, in some embodiments, the operating parameters of the spray may be selected so that the spray penetrates the tissue of the gastrointestinal tract and forms a depot of the active pharmaceutical ingredient that is disposed within the tissue.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application asserts the interests under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 063,818, filed on 10 August 2020, which is incorporated herein by reference in its entirety.

[0002] The disclosed embodiments relate to an ingestible drug delivery device and related methods of use. [Background technology]

[0003] Some therapeutic drugs consist of large, complex molecules that readily denature when administered via the oral-gastrointestinal (GI) route. Therefore, patients requiring these drugs typically use more invasive forms of drug administration outside the GI route, such as subcutaneous injection. [Overview of the Initiative] [Means for solving the problem]

[0004] 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, and a trigger operationally associated with the potential energy source, the trigger being configured to act within the stomach of the subject, and an outlet in fluid communication with the reservoir. When the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the stomach tissue adjacent to the outlet. The peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 9 watts (W) to 130 watts (W).

[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, and a trigger operationally associated with the potential energy source, the trigger being configured to act within the stomach of the subject, and an outlet in fluid communication with the reservoir. When the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate the stomach tissue adjacent to the outlet. The outlet, reservoir, and potential energy source are configured to form a deposit of the active pharmaceutical ingredient within the stomach tissue without perforating the muscular layer of the stomach.

[0006] In some embodiments, a method for administering an active pharmaceutical ingredient to a subject includes triggering the deployment of a jet of the active pharmaceutical ingredient within the subject's stomach and using the jet to penetrate the stomach tissue of the subject, wherein the peak power applied to form the jet of the active pharmaceutical ingredient is 9 watts (W) to 130 watts (W).

[0007] In some embodiments, a method for administering an active pharmaceutical ingredient to a subject includes triggering the deployment of a jet of the active pharmaceutical ingredient within the subject's stomach, using the jet to penetrate the stomach tissue of the subject, and forming a deposit of the active pharmaceutical ingredient within the stomach tissue without perforating the stomach muscular layer.

[0008] 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 operationally associated with the potential energy source, the trigger configured to act within the small intestine of the subject, and an outlet in fluid communication with the reservoir. When the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the tissue of the small intestine adjacent to the outlet. The peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 3 watts (W) to 6.5 watts (W).

[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 potential energy source, a trigger operationally associated with the potential energy source, the trigger configured to act within the small intestine of the subject, and an outlet in fluid communication with the reservoir. When the trigger is activated, the potential energy source compresses the reservoir, ejecting the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate the small intestinal tissue adjacent to the outlet. The outlet, reservoir, and potential energy source are configured to form a depot of the active pharmaceutical ingredient within the small intestinal tissue without perforating the muscular layer of the small intestine.

[0010] In some embodiments, a method for administering an active pharmaceutical ingredient to a subject includes triggering the deployment of a jet of the active pharmaceutical ingredient within the subject's small intestine and using the jet to penetrate the tissue of the subject's small intestine, wherein the peak power applied to form the jet of the active pharmaceutical ingredient is 3 watts (W) to 6.5 watts (W).

[0011] In some embodiments, a method for administering an active pharmaceutical ingredient to a subject includes triggering the deployment of a jet of the active pharmaceutical ingredient within the subject's small intestine, using the jet to penetrate the tissue of the subject's small intestine, and forming a deposit of the active pharmaceutical ingredient within the tissue of the small intestine without perforating the muscular layer of the small intestine.

[0012] 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 operationally associated with the potential energy source, the trigger being configured to act in response to one or more predetermined conditions, and an outlet in fluid communication with the reservoir. In some embodiments, when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 20 m / s to 250 m / s. In some embodiments, the peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 9 watts (W) to 130 W. In some embodiments, the trigger may be configured to act within the stomach of the subject. In some embodiments, when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the stomach tissue adjacent to the outlet.

[0013] 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 operationally associated with the potential energy source, the trigger configured to act in response to one or more predetermined conditions, and an outlet in fluid communication with the reservoir. In some embodiments, when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 20 m / s to 250 m / s. In some embodiments, the outlet, reservoir, and potential energy source are configured to form a deposit of the active pharmaceutical ingredient within the gastric tissue without perforating the muscular layer of the stomach. In some embodiments, the trigger may be configured to act within the stomach of the subject. In some embodiments, when the trigger is activated, the potential energy source may compress the reservoir and eject the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the gastric tissue adjacent to the outlet.

[0014] 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 operationally associated with the potential energy source, the trigger being configured to act in response to one or more predetermined conditions, and an outlet in fluid communication with the reservoir. In some embodiments, when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 40 m / s to 80 m / s. In some embodiments, the peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 3 W to 6.5 W. In some embodiments, the trigger may be configured to act within the small intestine of the subject. In some embodiments, when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the tissue of the small intestine adjacent to the outlet.

[0015] 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 operatively associated with the potential energy source, the trigger being configured to operate 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 potential energy source compresses the reservoir and injects the active pharmaceutical ingredient from the reservoir through the outlet at a velocity of 40 m / s to 80 m / s adjacent to the outlet. In some embodiments, the outlet, reservoir, and potential energy source are configured to form a depot of the active pharmaceutical ingredient within the tissue of the small intestine without perforating the muscular layer of the small intestine. In some embodiments, the trigger may be configured to operate within the small intestine of the subject. In some embodiments, when the trigger is actuated, the potential energy source compresses the reservoir and injects the active pharmaceutical ingredient from the reservoir through the outlet at a velocity sufficient to penetrate the tissue of the small intestine adjacent to the outlet.

[0016] It should be understood that, since the present disclosure is not limited in this regard, the foregoing concepts and additional concepts discussed below may be arranged in any suitable combination. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying figures. The present invention provides, for example, the following items. (Item 1) A drug delivery device configured for administration to a subject, the device comprising a reservoir configured to contain an active pharmaceutical ingredient, a potential energy source, a trigger operatively associated with the potential energy source, the trigger being configured to operate within the stomach of the subject, The outlet is in fluid communication with the reservoir, and when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the stomach tissue adjacent to the outlet, and the peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 9 watts (W) to 130 watts, and A device equipped with the following features. (Item 2) A drug delivery device configured for administration to a target, wherein the device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to act in response to one or more predetermined conditions, The outlet is in fluid communication with the reservoir, and when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 20 m / s to 250 m / s, and the peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 9 watts (W) to 130 watts, and the outlet and A device equipped with the following features. (Item 3) The drug delivery device according to item 2, wherein the trigger is configured to operate within the stomach of the target. (Item 4) A drug delivery device according to item 2 or 3, wherein when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the stomach tissue adjacent to the outlet. (Item 5) The drug delivery device according to any one of the above items, wherein the peak power is 9W to 70W. (Item 6) The drug delivery device according to any one of the above items, wherein the peak power is 9W to 12W. (Item 7) The drug delivery device according to any one of the above items, wherein the outlet, the reservoir, and the potential energy source are configured to form a depot of the active pharmaceutical ingredient within the gastric tissue without perforating the muscular layer of the stomach. (Item 8) A drug delivery device configured for administration to a target, wherein the device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to operate within the stomach of the target, An outlet that is in fluid communication with the reservoir, and when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the stomach tissue adjacent to the outlet, and the outlet, the reservoir, and the potential energy source are configured to form a deposit of the active pharmaceutical ingredient in the stomach tissue without perforating the stomach muscular layer, and A device equipped with the following features. (Item 9) A drug delivery device configured for administration to a target, wherein the device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to act in response to one or more predetermined conditions, An outlet that is in fluid communication with the reservoir, and when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 20 m / s to 250 m / s, and the outlet, the reservoir, and the potential energy source are configured to form a deposit of the active pharmaceutical ingredient in the stomach tissue without perforating the muscular layer of the stomach, and A device equipped with the following features. (Item 10) The drug delivery device according to item 9, wherein the trigger is configured to operate within the stomach of the subject. (Item 11) A drug delivery device according to item 9 or 10, wherein when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the stomach tissue adjacent to the outlet. (Item 12) A drug delivery device according to any one of items 8-11, wherein the peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 9W to 130W. (Item 13) The drug delivery device according to any one of the above items, wherein the outlet, the reservoir, and the potential energy source are configured to form the depot in the submucosal tissue with a depot efficiency of at least 50%. (Item 14) The drug delivery device according to any one of the above items, wherein the injection speed is 80 m / sec to 130 m / sec. (Item 15) The drug delivery device according to any one of the above items, wherein the maximum transverse dimension of the outlet is 50 μm to 450 μm. (Item 16) The drug delivery device according to any one of the above items, wherein the potential energy source comprises at least one of compressed gas, a spring, an explosive, and a reaction chamber. (Item 17) The drug delivery device according to any one of the above items, wherein the total volume of the drug delivery device is less than 3,000 mm³. (Item 18) Any of the above items further comprising the active pharmaceutical ingredient disposed within the reservoir A drug delivery device as described in item 1. (Item 19) The subject is a human subject, and is a drug delivery device as described in any one of the above items. (Item 20) A method for administering an active pharmaceutical ingredient to a target, wherein the method is To trigger the deployment of the spray of the active pharmaceutical component within the stomach of the target, The method involves penetrating the stomach tissue of the target using a jet, and the peak power applied to form the jet of the active pharmaceutical ingredient is 9W to 130W. Methods that include... (Item 21) The aforementioned peak power is 9W to 70W, as described in item 20. (Item 22) The method according to any one of the above items, wherein the peak power is 9W to 12W. (Item 23) The method according to any one of the above items, further comprising forming a depot of the active pharmaceutical ingredient in the tissue of the stomach without perforating the muscular layer of the stomach. (Item 24) A method for administering an active pharmaceutical ingredient to a target, wherein the method is To trigger the deployment of the spray of the active pharmaceutical component within the stomach of the target, The injection is used to penetrate the stomach tissue of the target, To form a depot of the active pharmaceutical ingredient within the stomach tissue without perforating the muscular layer of the stomach. Methods that include... (Item 25) The method according to item 24, wherein the peak power applied to form the spray of the active pharmaceutical ingredient is 9W to 130W. (Item 26) The method according to any one of items 20-25, wherein the depot efficiency of the depot formed by the active pharmaceutical ingredient is at least 50%. (Item 27) The method according to any one of the above items, wherein the velocity of the injection is 80 m / sec to 130 m / sec. (Item 28) The injection is the method described in any one of the above items, having a maximum transverse dimension of 50 μm to 450 μm. (Item 29) The method according to any one of the above items, further comprising positioning a drug delivery device containing the active pharmaceutical ingredient within the stomach of the subject. (Item 30) The method according to item 29, wherein the total volume of the drug delivery device is less than 3,000 mm³. (Item 31) The method described in any one of the above items, wherein the subject is a human subject. (Item 32) A drug delivery device configured for administration to a target, wherein the device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to operate within the small intestine of the subject, An outlet that is in fluid communication with the reservoir, and when the trigger is activated, the potentiometer The potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the tissue of the small intestine adjacent to the outlet, and the peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 3W to 6.5W, the outlet and A device equipped with the following features. (Item 33) A drug delivery device configured for administration to a target, wherein the device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to act in response to one or more predetermined conditions, The outlet is in fluid communication with the reservoir, and when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 40 m / s to 80 m / s, with the peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient being 3W to 6.5W. A device equipped with the following features. (Item 34) The drug delivery device according to item 33, wherein the trigger is configured to operate within the small intestine of the target. (Item 35) A drug delivery device according to item 33 or 34, wherein when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the tissue of the small intestine adjacent to the outlet. (Item 36) A drug delivery device according to any one of items 32-35, wherein the outlet, the reservoir, and the potential energy source are configured to form a depot of the active pharmaceutical ingredient within the tissue of the small intestine without perforating the muscular layer of the small intestine. (Item 37) A drug delivery device configured for administration to a target, wherein the device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to operate within the small intestine of the subject, An outlet that is in fluid communication with the reservoir, and when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the tissue of the small intestine adjacent to the outlet, and the outlet, the reservoir, and the potential energy source are configured to form a deposit of the active pharmaceutical ingredient in the tissue of the small intestine without perforating the muscular layer of the small intestine, and A device equipped with the following features. (Item 38) A drug delivery device configured for administration to a target, wherein the device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to act in response to one or more predetermined conditions, An outlet that is in fluid communication with the reservoir, and when the trigger is activated, the potential energy source compresses the reservoir and injects the active pharmaceutical ingredient from the reservoir through the outlet at a speed of 40 m / s to 80 m / s adjacent to the outlet, and the outlet, the reservoir, and the potential energy source are configured to form a deposit of the active pharmaceutical ingredient within the tissue of the small intestine without perforating the muscular layer of the small intestine, and A device equipped with the following features. (Item 39) The drug delivery device according to item 38, wherein the trigger is configured to operate within the small intestine of the target. (Item 40) A drug delivery device according to item 38 or 39, wherein when the trigger is activated, the potential energy source compresses the reservoir and ejects the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the tissue of the small intestine adjacent to the outlet. (Item 41) A drug delivery device according to any one of items 37-40, wherein the peak power provided by the potential energy source to form the ejection of the active pharmaceutical ingredient is 3W to 6.5W. (Item 42) A drug delivery device according to any one of items 32-41, wherein the outlet, the reservoir, and the potential energy source are configured to form the depot in the submucosal tissue with a depot efficiency of at least 50%. (Item 43) A drug delivery device according to any one of items 32 to 42, wherein the velocity of the ejection is 40 m / s to 80 m / s. (Item 44) A drug delivery device according to any one of items 32-43, wherein the maximum transverse dimension of the aforementioned outlet is 50 μm to 450 μm. (Item 45) The drug delivery device according to any one of items 32-44, wherein the potential energy source comprises at least one of compressed gas, a spring, an explosive, and a reaction chamber. (Item 46) The drug delivery device according to any one of items 32-45, wherein the total volume of the drug delivery device is less than 3,000 mm³. (Item 47) A drug delivery device according to any one of items 32-46, further comprising the active pharmaceutical ingredient disposed within the reservoir. (Item 48) The subject is a drug delivery device as described in any one of items 32-47, which is intended for human subjects. (Item 49) A method for administering an active pharmaceutical ingredient to a target, wherein the method is To trigger the deployment of the active pharmaceutical component in the small intestine of the target, The method involves using the aforementioned jet to penetrate the tissue of the small intestine of the target, and the peak power applied to form the jet of the active pharmaceutical ingredient is 3W to 6.5W. Methods that include... (Item 50) The method according to item 49, further comprising forming a depot of the active pharmaceutical ingredient within the tissue of the small intestine without perforating the muscular layer of the small intestine. (Item 51) A method for administering an active pharmaceutical ingredient to a target, wherein the method is To trigger the deployment of the active pharmaceutical component in the small intestine of the target, The injection is used to penetrate the tissue of the small intestine of the target, To form a depot of the active pharmaceutical ingredient within the tissue of the small intestine without perforating the muscular layer of the small intestine. Methods that include... (Item 52) The method according to item 51, wherein the peak power applied to form the spray of the active pharmaceutical ingredient is 3W to 6.5W. (Item 53) The method according to any one of items 49-52, wherein the depot efficiency of the depot formed by the active pharmaceutical ingredient is at least 50%. (Item 54) The method according to any one of items 49-53, wherein the velocity of the injection is 80 m / s to 130 m / s. (Item 55) The injection is as described in any one of items 49-54, having a maximum transverse dimension of 50 μm to 450 μm. (Item 56) The method according to any one of items 49-55, further comprising positioning a drug delivery device containing the active pharmaceutical ingredient within the small intestine of the subject. (Item 57) The method according to item 56, wherein the total volume of the drug delivery device is less than 3,000 mm³. (Item 58) The subject is a human subject, and the method is described in any one of items 49-57. [Brief explanation of the drawing]

[0017] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component shown in various drawings may be represented by similar numbers. For clarity, not all components may be labeled in all drawings.

[0018] [Figure 1A] Figure 1A shows a schematic diagram of one embodiment of a drug delivery device.

[0019] [Figure 1B] Figure 1B depicts a cross-sectional view of the drug delivery device shown in Figure 1A in the first state.

[0020] [Figure 1C] Figure 1C depicts a cross-sectional view of the drug delivery device in Figure 1A in the second state.

[0021] [Figure 2A] Figure 2A depicts one embodiment of a drug delivery device in a first state.

[0022] [Figure 2B] Figure 2B depicts a cross-sectional view of the drug delivery device shown in Figure 2A in the second state.

[0023] [Figure 3] Figure 3 illustrates one embodiment of a drug delivery device that travels through the target gastrointestinal tract.

[0024] [Figure 4] Figure 4 shows a schematic graph of injection power versus time.

[0025] [Figure 5A] Figure 5A depicts the calculated jet force versus time graphs for different nozzle sizes.

[0026] [Figure 5B]Figure 5B depicts the calculated injection power versus time graphs for different nozzle sizes.

[0027] [Figure 5C] Figure 5C depicts experimental jet force versus time graphs for different nozzle sizes.

[0028] [Figure 5D] Figure 5D illustrates the experimental graph of injection power versus injection diameter.

[0029] [Figure 5E] Figure 5E illustrates the graph of experimental delivery efficiency versus nozzle size.

[0030] [Figure 5F] Figure 5F shows a graph illustrating the experimental injection power versus nozzle size.

[0031] [Figure 6A] Figure 6A depicts the measured and predicted jet performance parameters in different anatomical structures along the gastrointestinal tract.

[0032] [Figure 6B] Figure 6B illustrates the measured injection efficiency versus injection force graphs for various gastrointestinal tissues.

[0033] [Figure 7] Figure 7 is a schematic diagram of a tethered drug delivery device for administering an API into the stomach.

[0034] [Figure 8A] Figure 8A shows a preliminary experimental overview of parameter inputs, including jet force, and the resulting delivery efficiency within gastric tissue.

[0035] [Figure 8B] Figure 8B shows a preliminary experimental overview of parameter inputs, including injection pressure, and the resulting delivery efficiency within gastric tissue.

[0036] [Figure 9A] Figure 9A shows a preliminary experimental overview of parameter inputs, including ejection force, and the resulting delivery efficiency within the intestinal tissue.

[0037] [Figure 9B] Figure 9B shows a preliminary experimental overview of parameter inputs, including injection pressure, and the resulting delivery efficiency within the intestinal tissue. [Modes for carrying out the invention]

[0038] Detailed explanation Large, complex molecules that readily denature when administered via the oral-gastrointestinal (GI) route are regularly administered as part of therapeutic treatment. Patients requiring these medications often have to use more invasive forms of drug administration, such as subcutaneous injection. The use of these more invasive forms of delivery sometimes leads to loss of adherence to routine procedures and / or a reduced quality of life.

[0039] In consideration of the foregoing, the inventors recognize the benefits of ingestible delivery devices that utilize needleless micro-injections to deliver a desired dose of an active pharmaceutical ingredient (API) to a desired location along the gastrointestinal (GI) tract without impairing drug purity, efficacy, and / or dosage. In particular, the inventors recognize the benefits of ingestible delivery devices that employ a trigger to automatically release the dose to a desired location within the GI tract. As used herein, the GI tract includes the esophagus, stomach, duodenum, jejunum, small intestine, and large intestine. The delivery device may be suitable for the delivery of large, complex molecules such as proteins and other biopharmaceuticals, which may otherwise be unsuitable for delivery through the GI tract, but any suitable API may be used. According to the exemplary embodiments described herein, ingestible delivery devices employing micro-injections for the delivery of active pharmaceutical ingredients (APIs) have many potential benefits. Firstly, the ingestible delivery devices according to the exemplary embodiments described herein do not have to include a sharp tip. Secondly, microinjection avoids the mechanisms associated with needle action and / or retraction, thereby reducing system complexity and cost compared to needle-based systems. The use of spray-deployed APIs can also result in a significant increase in the bioavailability of the API, comparable to subcutaneous injection, compared to other ingested APIs that possess common chemical penetration enhancers (approximately 2% bioavailability). Finally, the implementation of needleless delivery systems of the exemplary embodiments described herein can result in less pain and / or trauma at the injection site and enhanced pharmacokinetics (PK) compared to needle-based delivery.

[0040] In consideration of the above, the inventors recognize the benefits associated with the injection of an active pharmaceutical ingredient into the target gastrointestinal tissue using a spray base. However, due to the needleless nature of the spray-based deployment of the active pharmaceutical ingredient (API), controlling the various operating parameters associated with the spray can determine the anatomical structure into which the API spray is deployed. For example, a drug delivery device may be configured to provide a spray of API, appropriately tuned for intraluminal delivery of the API into the luminal space of the gastrointestinal tract (i.e., a wet shot), intramucosal delivery of the API into the mucosal tissue of the gastrointestinal tract, submucosal delivery of the API into the submucosal tissue of the gastrointestinal tract, intraperitoneal delivery of the API into the peritoneal space of the target, combinations thereof, and / or any other suitable form of delivery. Depending on the target tissue and specific parameters of the spray, in some embodiments, a depot of the API may be formed within the target tissue, and the depot may be a certain volume of API located within the target tissue and / or between different tissue layers of the gastrointestinal tract. In some embodiments, a drug delivery device may be configured to deliver a spray of the API into the tissues within the stomach and / or small intestine of the target. Specific operating parameters that can be selected to optimize the injection for delivery into these different tissue locations may include, for example, injection power, diameter, dosage, isolation distance, fluid viscosity, fluid density, and other appropriate parameters as further detailed below.

[0041] In some embodiments, the active pharmaceutical ingredient may be administered to a subject by triggering the deployment of a spray of the active pharmaceutical ingredient from the drug delivery device when the drug delivery device is located at a desired location within the subject's gastrointestinal tract. According to the exemplary embodiments described herein, the spray may be triggered by predetermined conditions. In some embodiments, the predetermined conditions include a predetermined time after ingestion of the drug delivery device, a predetermined location within the GI tube, physical contact with the GI tube, physical manipulation within the GI tube (e.g., compression via peristalsis), one or more properties of the GI tube (e.g., pH, pressure, acidity, temperature, etc.), or one or more of a combination thereof. In some embodiments, the spray may be deployed when the drug delivery device is located within the subject's stomach and / or small intestine. In any case, the operating parameters of the spray are such that the spray is released from the drug delivery device at a sufficient velocity and therefore penetrates the tissue of the subject's gastrointestinal tract adjacent to the drug delivery device, and, depending on the activation, forms a deposit of the active pharmaceutical ingredient in the tissue of the gastrointestinal tract adjacent to the drug delivery device. Appropriate selection may be made. In some embodiments, the spray may form a depot of the active pharmaceutical ingredient within the gastrointestinal tissue without perforating the muscular layer of the gastrointestinal tract beneath the injection site where the spray strikes the tissue of the gastrointestinal tract. As used herein, the terms “proximity to” and “adjacent to” are used synonymously and are defined herein as meaning that specified elements are in direct contact or sufficiently close in space to achieve a specified function, such as being separated for an isolation distance as used herein.

[0042] While not wishing to be constrained by theory, the inventors recognize that one of the control parameters for delivering an active pharmaceutical ingredient (API) to a desired target location within the target gastrointestinal tract tissue is the peak power of the spray during delivery of the API into the target tissue. For example, the peak power of the spray used to deploy the API into the target tissue may be selected so that the spray forms a depot of the API placed within the target tissue without perforating the layers beneath the gastrointestinal tract. Advantageously, this parameter may allow for the design and comparison of delivery devices with different APIs and / or deployment systems for desired applications, taking into account various other operating parameters such as deployment force, density, viscosity, spray area, and spray velocity. In addition, the inventors recognize that the appropriate peak power for forming a depot within the target tissue varies depending on the location of the delivery device within the target gastrointestinal tract. For example, the optimal peak power for operation within the target stomach may differ from the optimal peak power for operation within the target small intestine and / or other parts of the gastrointestinal tract.

[0043] As described above, in some embodiments, it is desirable to deliver the active pharmaceutical ingredient to the target stomach tissue. Therefore, an appropriate peak power may be selected to allow the spray to penetrate the stomach tissue adjacent to the drug delivery device placed in the target stomach. In some cases, the peak power may be selected to avoid perforating the stomach muscular layer. In such embodiments, the peak power of the spray oriented toward the surface of the target stomach may be above or equal to 9W, 10W, 12W, 15W, 20W, 25W, 50W, 100W, and / or any other appropriate power. Correspondingly, the peak power of the spray may be below or equal to 130W, 100W, 50W, 25W, 21W, 15W, 12W, and / or any other appropriate power. 9W~130W, 9W~100W, 9W~50W, 9W~25W, 9W~21W, 9W~15W, 9W~12W, 10W~130W, 10W~100W, 10W~50W, 1 0W~25W, 10W~21W, 10W~15W, 12W~130W, 12W~100W, 12W~50W, 12W~25W, 12W~21W, 12W~15W, 15W~1 Combinations of the aforementioned ranges are envisioned, including peak powers of 30W, 15W-100W, 15W-50W, 15W-25W, 15W-21W, 20W-130W, 20W-100W, 20W-50W, 20W-21W, 25W-130W, 25W-100W, 25W-50W, 50W-130W, 50W-100W, or 100W-130W. As described herein, the phrase "one value to another value" includes all values ​​between the endpoints. In some cases, the above powers may be appropriate for forming a depot in the submucosa and / or muscular layer of the target stomach. Alternatively, embodiments are also envisioned in which the drug delivery device is configured to provide a spray for intraluminal delivery, in which the majority of the active pharmaceutical ingredient is injected into the luminal space of the stomach. In such embodiments, the peak power of the injection may be less than 9W. In addition, embodiments in which the drug delivery device is configured for intraperitoneal delivery, in which the majority of the active pharmaceutical ingredient is injected into the peritoneal space by perforating the muscular layer of the stomach, are also envisioned.In some embodiments, intraperitoneal injection into the stomach may correspond to a jet with a peak power exceeding approximately 40W.

[0044] Furthermore, as described above, in some embodiments, it is desirable to deliver the active pharmaceutical ingredient to the target small intestinal tissue. Therefore, an appropriate peak power is selected to allow the spray to penetrate the small intestinal tissue adjacent to the drug delivery device positioned within the target small intestine. This is also acceptable. In some cases, the peak power may be selected to avoid perforating the muscular layer of the small intestine. In such embodiments, the peak power of the jet directed toward the surface of the small intestine in question may be above or equal to 3.0W, 3.1W, 3.2W, 3.3W, 3.4W, 3.5W, 4.0W, 4.5W, 5W, 5.5W, 6.0W, and / or any other suitable power. Correspondingly, the peak power of the jet may be below or equal to 6.5W, 6.4W, 6.3W, 6.2W, 6.1W, 6.0W, 5.5W, 5.0W, 4.5W, and / or any other suitable power.3.0W~6.5W, 3.0W~6.4W, 3.0W~6.3W, 3.0W~6.2W, 3.0W~6.1W, 3.0W~6.0W , 3.0W~5.5W, 3.0W~5.0W, 3.0W~4.5W, 3.1W~6.5W, 3.1W~6.4W, 3.1W~6.3 W, 3.1W~6.2W, 3.1W~6.1W, 3.1W~6.0W, 3.1W~5.5W, 3.1W~5.0W, 3.1W~4. 5W, 3.2W~6.5W, 3.2W~6.4W, 3.2W~6.3W, 3.2W~6.2W, 3.2W~6.1W, 3.2W~6 .0W, 3.2W~5.5W, 3.2W~5.0W, 3.2W~4.5W, 3.3W~6.5W, 3.3W~6.4W, 3.3W~ 6.3W, 3.3W~6.2W, 3.3W~6.1W, 3.3W~6.0W, 3.3W~5.5W, 3.3W~5.0W, 3.3W ~4.5W, 3.4W~6.5W, 3.4W~6.4W, 3.4W~6.3W, 3.4W~6.2W, 3.4W~6.1W, 3.4 W~6.0W, 3.4W~5.5W, 3.4W~5.0W, 3.4W~4.5W, 3.5W~6.5W, 3.5W~6.4W, 3. 5W~6.3W, 3.5W~6.2W, 3.5W~6.1W, 3.5W~6.0W, 3.5W~5.5W, 3.5W~5.0W, 3 .5W~4.5W, 4.0W~6.5W, 4.0W~6.4W, 4.0W~6.3W, 4.0W~6.2W, 4.0W~6.1W, 4.0W~6.0W, 4.0W~5.5W, 4.0W~5.0W, 4.0W~4.5W, 4.5W~6.5W, 4.5W~6.4W , 4.5W~6.3W, 4.5W~6.2W, 4.5W~6.1W, 4.5W~6.0W, 4.5W~5.5W, 4.5W~5.0 A combination of the aforementioned ranges is assumed, including peak power values ​​of W, 5.0W~6.5W, 5.0W~6.4W, 5.0W~6.3W, 5.0W~6.2W, 5.0W~6.1W, 5.0W~6.0W, 5.0W~5.5W, 5.5W~6.5W, 5.5W~6.4W, 5.5W~6.3W, 5.5W~6.2W, 5.5W~6.1W, 5.5W~6.0W, 6.0W~6.5W, 6.0W~6.4W, 6.0W~6.3W, 6.0W~6.2W, 6.0W~6.1W, and / or any other suitable peak power ranges.In some cases, injection powers of 3.5W to 6.5W or 4.0W to 6.5W may be preferred because these injection powers may have higher injection efficiency than other injection powers. In some cases, the above powers may be appropriate for forming a depot in the submucosa and / or muscular layer of the target small intestine. Alternatively, embodiments are also conceivable in which the drug delivery device is configured to provide an injection for intraluminal delivery, in which the majority of the active pharmaceutical ingredient is injected into the luminal space of the small intestine. In such embodiments, the peak power of the injection may be less than 3.0W. In addition, embodiments are also conceivable in which the drug delivery device is configured for intraperitoneal delivery, in which the majority of the active pharmaceutical ingredient is injected into the peritoneal space by perforating the muscular layer of the small intestine. In some embodiments, intraperitoneal injection into the small intestine may correspond to an injection with a peak power exceeding about 6.5W, 7.0W, and / or any other suitable power range.

[0045] The efficiency of depot formation in target tissue may depend on the specific target tissue and the operating parameters applied when directing the spray of the active pharmaceutical ingredient toward the tissue. As used herein, the dosage of the API refers to the amount of API initially contained within the drug delivery device. Depot efficiency refers to the percentage of the amount of API initially contained within the drug delivery device and subsequently delivered into a depot located within the target tissue. For example, the depot may be formed in the submucosa and / or muscular tissue of the stomach and / or small intestine of the target. Depot efficiencies exceeding 40% may be achieved by appropriately selecting the spray operating parameters, as detailed below. For example, in some embodiments, the depot of the drug delivery device The depot efficiency may be above or equal to 40%, 50%, 60%, 70%, and / or any other appropriate percentage. Correspondingly, the depot efficiency of the drug delivery device may be below or equal to 95%, 90%, 80%, 70%, 60%, and / or any other appropriate percentage. The aforementioned combinations, including depot efficiencies in the following cases, are assumed: 40%~95%, 50%~95%, 60%~95%, 70%~95%, 40%~90%, 50%~90%, 60%~90%, 70%~90%, 40%~80%, 50%~80%, 60%~80%, 70%~80%, 40%~70%, 50%~70%, 60%~70%, 40%~60%, 50%~60%, and / or other appropriate combinations. Furthermore, since this disclosure is not so limited, it should be understood that both higher and lower depot efficiencies than those described above are possible.

[0046] Depending on the specific API to be administered to the target, the drug delivery device of the exemplary embodiments described herein may be configured to deliver various different dose volumes of API to the target. According to the exemplary embodiments described herein, the drug delivery device may include an API reservoir volume in which the API is placed, which is less than or equal to 500 μL, 300 μL, 200 μL, 150 μL, 100 μL, 75 μL, 50 μL, 25 μL, 10 μL, and / or any other suitable volume. Correspondingly, the drug delivery device may include an API reservoir volume greater than or equal to 1 μL, 5 μL, 10 μL, 25 μL, 50 μL, 75 μL, 100 μL, 200 μL, 300 μL, and / or any other suitable volume. While not limited to these, the available sizes are 1μL~500μL, 1μL~300μL, 1μL~200μL, 1μL~150μL, 1μL~100μL, 1μL~75μL, 1μL~50μL, 1μL~25μL, 1μL~10μL, 10μL~500μL, 10μL~300μL, 10μL~200μL, and 10μL~ 150μL, 10μL~100μL, 10μL~75μL, 10μL~50μL, 10μL~25μL, 25μL~500μL, 25μL~300 μL, 25μL~200μL, 25μL~150μL, 25μL~100μL, 25μL~75μL, 25μL~50μL, 50μL~500μL, 50μL~300μL, 50μL~200μL, 50μL~150μL, 50μL~100μL, 50μL~75μL, 75μL~500μL, 7 5μL~300μL, 75μL~200μL, 75μL~150μL, 75μL~100μL, 100μL~500μL, 100μL~300μL, Combinations of the volumes described above are envisioned, including reservoir volumes of 100 μL to 200 μL, 100 μL to 150 μL, 150 μL to 500 μL, 150 μL to 300 μL, 150 μL to 200 μL, 200 μL to 500 μL, 200 μL to 300 μL, or 300 μL to 500 μL. Naturally, the disclosure is not so limited, and any suitable reservoir volume may be employed in the drug delivery device. In addition, the API depot placed in the target tissue may have a volume related to the volumes described above by the corresponding depot efficiency described above.

[0047] To efficiently form a deposit within the target tissue, it may be desirable to maintain the injection power within a predetermined range of the injection's peak power over a predetermined period of time. As defined herein and shown in Figure 4, the injection's peak power (P peak ) refers to the maximum power of the jet. Threshold power refers to the minimum jet power required to penetrate the target tissue at the location in the gastrointestinal tract of interest. In some embodiments, peak power is greater than or equal to threshold power. "Optimal peak power" refers to the minimum peak jet power appropriate for forming a desired depot with at least 50% depot efficiency in the target tissue at the location in the gastrointestinal tract of interest. For example, the jet power may be maintained within 5%, 10%, or other appropriate percentage of the peak power over a predetermined period of time. For example, as shown in Figure 4, the jet power is initially set to the threshold power P at time t1. Th It can increase until it exceeds [a certain value], and thereafter the power reaches peak power P peak The power can continue to increase up to a certain point. The injection power can then decrease until it equals the threshold power at time t2, with a given period corresponding to the difference between time t1 and t2. As shown in the figure, this may continue to decrease after this time. Depending on the specific application, the given period may be greater than or equal to 1 millisecond, 10 milliseconds, 50 milliseconds, 100 milliseconds, and / or any other suitable period. Correspondingly, the given period may be less than or equal to 300 milliseconds, 200 milliseconds, 100 milliseconds, 50 milliseconds, and / or any other suitable period. For example, the aforementioned combinations are envisioned, including predetermined periods of 1 m / s to 300 m / s, 1 m / s to 200 m / s, 1 m / s to 100 m / s, 1 m / s to 50 m / s, 10 m / s to 300 m / s, 10 m / s to 200 m / s, 10 m / s to 100 m / s, 10 m / s to 50 m / s, 50 m / s to 300 m / s, 50 m / s to 200 m / s, 50 m / s to 100 m / s, 100 m / s to 300 m / s, or 100 m / s to 200 m / s. Of course, since this disclosure is not so limited, it should be understood that other predetermined periods and appropriate ranges of injection power for peak power are also envisioned.

[0048] According to exemplary embodiments described herein, a trigger for a drug delivery device may be configured to activate the drug delivery device within a target GI tube at a predetermined time and / or location within the GI tube. In some embodiments, the trigger may be a passive component configured to interact with the environment of the GI tube and activate the drug delivery device. For example, in some embodiments, the trigger may be a sugar plug or other soluble material configured to dissolve within the GI tube. The soluble plug may have a certain thickness and / or shape that at least partially determines the rate at which the soluble plug dissolves and ultimately activates the drug delivery device. In another embodiment, the trigger may be at least partially formed by an enteric coating. For example, in some embodiments, the trigger may include both a soluble plug and an enteric coating disposed on the outer surface of the soluble plug, as this disclosure is not so limited. Other suitable materials for soluble triggers may 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 materials that can dissolve in the target GI tube. In some embodiments, the trigger may include a triggerable membrane containing ethylenediaminetetraacetic acid, glutathione, or another suitable chemical. In some embodiments, the sugar alcohol trigger may be employed in combination with an enteric coating configured to protect the sugar alcohol trigger until the drug delivery device is received in the target GI tube. In other embodiments, the trigger may include a pH-responsive coating to help delay the trigger until after ingestion. In some embodiments, the trigger may be a sensor and / or electrode configured to either detect or interact with one or more properties of the GI in order to activate the device. For example, a sensor that detects contact with the inner wall of the GI mucosa may be used to activate the device.In embodiments employing a sensor, the trigger may also include an active component that moves or acts otherwise in response to a predetermined condition being detected by the sensor. For example, a gate may move when contact with a GI mucosal tubule is detected. In other embodiments, the trigger may employ power to trigger a ruptureable membrane and / or a chemical reaction (e.g., by applying a voltage across the conductive ruptureable membrane). Naturally, the disclosure is not so limited, and any suitable active or passive trigger may be employed for drug delivery devices.

[0049] According to the exemplary embodiments described herein, the drug delivery device includes a potential energy source used to store the energy within the drug delivery device used to generate the injection of the API when the drug delivery device is activated. In some embodiments, the potential energy source may be a compressed gas. The compressed gas may be stored directly within the drug delivery device, or the compressed gas may undergo a chemical reaction or phase change. Potential energy may be generated via a reaction chamber. For example, in some embodiments, dry ice may be stored in the chamber of the drug delivery device such that compressed gas is generated when the dry ice sublimes. Alternatively, compressed gas may be supplied to the desired chamber prior to sealing the drug delivery device. In some embodiments, the potential energy source may be a spring (e.g., a compressed spring). In some embodiments, the potential energy source may be a reaction chamber. For example, a reaction chamber may be a combination of acid and base that allows for the generation of a gas, which may lead to the discharge of the API from the drug delivery device when the device is activated. Alternatively, in another embodiment, the trigger may detonate an explosive material located in the chamber to generate pressurized gas for discharging the API from the drug delivery device. Naturally, the disclosure is not so limited, and any suitable reaction or other potential energy source may be employed to pressurize and drive the API in the injection when the drug delivery device is activated.

[0050] As described above, the injection power may be adjusted to deliver the API into different target tissues within the GI tube with different penetration characteristics. The injection power may be determined at least in part by the injection velocity, fluid density, and injection diameter. Thus, the drug delivery device according to the exemplary embodiments described herein may be appropriately sized and contain an appropriate amount of potential energy to generate an injection with sufficient power to deliver the API into the tissue of the GI tube at the desired location.

[0051] To achieve the exemplary injection power described herein, the injections generated by the drug delivery devices of the exemplary embodiments described herein may have corresponding velocities. Therefore, in some embodiments, the drug delivery device may be configured to generate injections having velocities below or equal to 250 m / s, 200 m / s, 150 m / s, 130 m / s, 100 m / s, 75 m / s, 50 m / s, and / or other suitable velocities. Correspondingly, the drug delivery device may be configured to generate injections having velocities above or equal to 20 m / s, 30 m / s, 50 m / s, 80 m / s, 100 m / s, 150 m / s, 200 m / s, and / or other suitable velocities. Not limited to, but 20m / sec-250m / sec, 20m / sec-200m / sec, 20m / sec-100m / sec, 20m / sec-150m / sec, 20m / sec-100m / sec, 20m / sec-75m / sec, 20m / sec-50m / sec, 50m / sec-250m / sec, 50m / sec-200m / sec, 50m / sec-100m / sec, 50m / sec-150m / sec, 50m / sec-100m / sec, 50m / sec-75m / sec, 75m / sec Combinations of the ranges described above are assumed, including injection velocities of ~250 m / s, 75 m / s~200 m / s, 75 m / s~100 m / s, 75 m / s~150 m / s, 75 m / s~100 m / s, 100 m / s~250 m / s, 100 m / s~200 m / s, 100 m / s~150 m / s, 150 m / s~250 m / s, 150 m / s~200 m / s, or 200 m / s~250 m / s. In one specific embodiment, the target tissue location may correspond to the stomach, and the injection velocity may preferably be 80 m / s~130 m / s or 40 m / s~60 m / s. In another embodiment, the target tissue location may correspond to the small intestine, and the injection velocity may preferably be 40 m / s~80 m / s. Naturally, since this disclosure is not so limited, any spray velocity suitable for delivering the API into the corresponding tissue of the gastrointestinal tract may be used.

[0052] In some embodiments, the maximum transverse dimension (e.g., diameter) of an outlet such as a nozzle from which the spray is emitted and / or the maximum transverse dimension (e.g., diameter) of the spray emitted from the outlet may be less than or equal to 550 μm, 450 μm, 400 μm, 350 μm, 300 μm, 250 μm, 200 μm, 150 μm, 100 μm, 75 μm, 50 μm, 25 μm, 10 μm, and / or any other suitable dimension. Alternatively, the maximum transverse dimension of the spray may exceed or be equal to 5 μm, 10 μm, 25 μm, 50 μm, 75 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, and / or any other suitable dimension. Not limited to these, but 5μm~550μm, 5μm~450μm, 10μm~450μm, 25μm~450μm, 50μm~450μm, 75μm~450μm, 100μm~450μm, 150μm~450μm, 200μm~450μm, 250μm~450μm, 300μm~450μm, 5μm~400μm, 10μm~400μm, 25μm~400μm, 50μm~400μm, 75μm~400μm, 100μm~400μm, 150μm~400μm, 200μm~400μm, 25 0μm~400μm, 300μm~400μm, 5μm~350μm, 10μm~350μm, 25μm~350μm, 50μm~350μm, 75μm~350μm, 100μm~350μm, 150μm~350μm, 200μm~350μm, 250μm~350μm, 300μm~350μm, 5μm~300μm, 10μm~300μm, 25μm~300μm, 50μm~300μm, 75μm~300μm, 100μm~300μm, 150μm~300μm, 200μm~300μm m, 250μm~300μm, 5μm~250μm, 10μm~250μm, 25μm~250μm, 50μm~250μm, 75μm~250μm, 100μm~250μm, 150μm~250μm, 200μm~250μm, 5μm~200μ m, 10μm~200μm, 25μm~200μm, 50μm~200μm, 75μm~200μm, 100μm~200μm, 150μm~200μm, 5μm~150μm,, 10μm~150μm, 25μm~150μm, 50μm~150μ Combinations of the ranges described above are assumed, including the maximum transverse dimensions of the spray and / or outlet of m, 75μm~150μm, 100μm~150μm, 5μm~100μm, 10μm~100μm, 25μm~100μm, 50μm~100μm, 75μm~100μm, 5μm~75μm, 10μm~75μm, 25μm~75μm, 50μm~75μm, 5μm~50μm, 10μm~50μm, 25μm~50μm, 5μm~25μm, 10μm~25μm, or 5μm~10μm.Naturally, since this disclosure is not so limited, any suitable dimensions of an outlet and / or spray suitable for delivery of the API into the tissue of a desired portion of the gastrointestinal tract may be employed.

[0053] According to the exemplary embodiments described herein, the drug delivery device includes a potential energy source configured to pressurize the API so that the API can be released in a jet into the mucosal wall of the GI tube. The pressure applied to the reservoir may affect the jet power and / or jet velocity of the API jet released by the drug delivery device. In some embodiments, the potential energy source may be configured to apply a pressure to the API reservoir that is below or equal to 1,000 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 potential energy source may apply a pressure to the API reservoir that is above 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. Not limited to, but 0.1 bar to 1,000 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 1,000 bar, 1 bar to 800 bar, 1 bar to 600 bar, 1 bar 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 1,000 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 Bars up 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 Combinations of the above-described ranges are assumed, including pressures of 15-250 bar, 60-100 bar, 100-800 bar, 100-600 bar, 100-500 bar, 100-250 bar, 250-800 bar, 250-600 bar, 250-500 bar, 500-800 bar, 500-600 bar, or 600-800 bar. In some embodiments, pressures applied to an API reservoir of 15-60 bar, more preferably 15-45 bar, when combined with a appropriately sized nozzle, may be particularly effective in forming a highly efficient depot within the submucosal tissue of the stomach. Similarly, pressures applied to an API reservoir of 10 to 20 bar, when combined with a properly sized nozzle, may be effective in forming a highly efficient depot within the submucosa of the target intestine. Of course, any suitable pressure may be applied to the API reservoir, as this disclosure is not so limited.

[0054] In some embodiments, the drug delivery device is sized and shaped to be ingested by a subject. Thus, the drug delivery device may be appropriately small such that the drug delivery device can be easily swallowed and subsequently pass through the GI tract including the esophagus and the pylorus in the stomach. In some embodiments, the drug delivery device may include an overall length such as a maximum dimension along the longitudinal axis of the device that is less than or equal to 40 mm, 30 mm, 20 mm, 10 mm, 5 mm, and / or another appropriate length. Correspondingly, the drug delivery device may have an overall length that is greater than or equal to 3 mm, 5 mm, 10 mm, 20 mm, 25 mm, and / or another appropriate length. Combinations of the ranges described above are envisioned, including but not limited to overall lengths 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 may have a maximum outer cross-sectional dimension such as a diameter or other dimension that may be perpendicular to the longitudinal axis and that is less than or equal to 11 mm, 10 mm, 7 mm, 5 mm, and / or another appropriate dimension. Correspondingly, the drug delivery device may have a maximum outer cross-sectional dimension that is greater than or equal to 3 mm, 5 mm, 7 mm, 9 mm, and / or another appropriate dimension. Combinations of the ranges described above are envisioned, including but not limited to maximum outer cross-sectional dimensions 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 is 3,500 mm 3 , 3,000 mm 3 , 2,500 mm 3 , 2,000 mm 3 , 1,500 mm 3 , 1,000 mm 3 , 750 mm 3 , 500 mm 3 , 250 mm 3 , 100 mm 3 , and / or may have an overall volume that is less than or equal to any other appropriate volume. Correspondingly, the drug delivery device is 50 mm 3 , 100 mm 3 , 250 mm 3 , 500 mm3 , 750mm 3 , 1,000mm 3 , 1,500mm 3 , 2,000mm 3 , 2,500mm 3 , and / or may have an overall volume exceeding or equal to any other suitable volume. Not limited to, but 1,000 mm 3 ~3,000mm 3 , 1,500mm 3 ~3,000mm 3 , 50mm 3 ~500mm 3 , 50mm 3 ~100mm 3 , and 2,000mm 3 ~3,000mm 3 A combination of the ranges described above, including the volume, is assumed. Of course, since this disclosure is not so limited, any preferred overall length, maximum cross-sectional dimension, and volume for the ingestible delivery device may be adopted.

[0055] According to the exemplary embodiments described herein, the drug delivery device is administered orally to the subject. In other embodiments, the drug delivery device may be administered orally to the subject. The drug may be administered transrectally, endoscopically, or transnasally. Therefore, it should be understood that the drug delivery device disclosed herein may be delivered to a desired portion of the target gastrointestinal tract in several different ways, and that this disclosure is not limited to specific methods of deploying the drug delivery device.

[0056] In some embodiments, to help ensure delivery of the API into the desired tissue, it may be desirable to position the nozzle of the spray close to the surface of the target GI tube and / or orient the nozzle toward the surface prior to activating the delivery device. Therefore, depending on the particular embodiment, various different strategies may be employed. For example, various mucosal adhesion materials, dissolvable hooks for attachment to tissue, mucosal contact sensors, self-orienting delivery devices (e.g., buoyancy and / or center-of-gravity-based orientation systems), and other methods may be used to maintain contact between the delivery device and the desired tissue within the GI tube, or to determine when the delivery device is close to and / or oriented toward it. For example, various self-restoring or self-orienting structures and / or methods described in WO 2018 / 213600 Al may be employed by the drug delivery device according to this disclosure. Al is incorporated herein by reference as a whole. In addition, in some embodiments, multiple outlets and corresponding multiple sprays located at different positions on the exterior of the delivery device may be used to increase the chance that one of the sprays is directed toward the tissue adjacent to the delivery device. Naturally, it should be understood that embodiments are also conceivable in which the delivery device does not include sensors and / or components to be attached thereto for sensing contact with the inner wall of the target mucosa.

[0057] In embodiments where a system and / or method is used to actuate API delivery, when the outlet is oriented toward gastrointestinal tissue adjacent to the drug delivery device, it may be desirable to maintain the orientation of the outlet and the corresponding spray within a predetermined range of angles relative to the underlying tissue. This may help to provide a desired combination of spray force and / or power in a direction oriented perpendicular to the surface of the adjacent tissue. For example, the angle of the spray emitted from the outlet with respect to the direction normal to the underlying tissue surface may be any other suitable range of angles, including angles below or equal to 20°, 15°, 10°, 5°, and / or angles above and below those described above. The angular relationship described above between the spray direction emitted from the device outlet and the direction normal to the underlying tissue surface may be provided using any of the methods and structures described above for actinguate the delivery device while it is in the desired orientation toward the underlying tissue.

[0058] In some embodiments, the spray may be emitted from an outlet at a distance from the tissue beneath the delivery device upon which the spray impacts. We recognize that the minimum difference in tissue penetration and API delivery has been pointed out with respect to isolation distances between the outlet and the underlying tissue that are below a threshold distance. As defined herein, isolation distance refers to the shortest distance between the outlet and the surface of the underlying tissue upon which the spray emitted from the outlet impacts. Thus, in some embodiments, the isolation distance may be below 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 a specific range of distances is given above, it should be understood that the acceptable isolation distance between the outlet and the underlying tissue may vary depending on the specific spray parameters and the tissue being deployed, and the specific application in which the drug delivery device is used. Thus, both isolation distances greater than and below those described above are assumed, as this disclosure is not so limited.

[0059] In some embodiments, it may be desirable to form one or more components of a drug delivery device from biocompatible and / or bioinert materials. For example, Various components may be exposed to fluids and / or solids present in the target gastrointestinal tract when ingested. Therefore, components that may be exposed to fluids and / or solids present in the gastrointestinal tract may be made from materials including, but are not limited to, metals relatively inert to the gastrointestinal environment such as titanium, non-toxic and / or inert polymers such as polydimethylsiloxane (PDMS) and polycaprolactone (PCL), salts, carbohydrates, and / or any other suitable materials for the desired application. In cases where a particular component used in a delivery device may be unsuitable with respect to exposure to the environment within the target gastrointestinal system, non-reactive polymer and / or metal coatings may be applied to the component to isolate the underlying material from the external environment. Alternatively, such components may be contained within a portion of the delivery device that is not exposed to the external environment during operation. In consideration of the foregoing, it should be understood that, since this disclosure is not limited to any specific structure and / or combination of materials for various components, the various components disclosed herein may be made using any suitable combination of materials.

[0060] As used herein, the term “active pharmaceutical ingredient” (also referred to as “drug” or “therapeutic agent”) means a substance that is administered to a subject for the treatment or preventive purposes of a disease, disorder, or other clinically recognized condition, and that exerts a clinically significant effect on the subject’s body to treat, prevent, and / or diagnose the disease, disorder, or condition. The active pharmaceutical ingredient may be delivered to the subject in amounts greater than trace amounts to influence the therapeutic response in the subject. In some embodiments, the active pharmaceutical ingredient (API) may include, but is not limited to, any synthetic or naturally occurring biologically active compound or composition that, when administered to a subject (e.g., human or non-human animal), induces a desired pharmacological, immunogenic, and / or physiological effect by topical and / or systemic action. For example, useful or potentially useful in the context of some embodiments are compounds or chemicals conventionally considered drugs, vaccines, and biologics. Some such APIs may include molecules such as proteins, peptides, hormones, nucleic acids, and gene constructs for use in the fields of therapy, diagnosis, and / or enhancement. In some embodiments, the API is a small molecule and / or a large molecule. Therefore, it should be understood that the APIs described herein are not limited to any particular type of API. In addition, while a drug delivery device can deliver an API in the form of an incompressible liquid spray according to the exemplary embodiments described herein, the disclosure is not so limited, and in other embodiments, the spray containing the API generated by the drug delivery device may be formed from a gas, a viscous fluid, an aerosolized powder, and / or other suitable material.

[0061] In some embodiments, as used herein, injection may refer to the parallel flow of gas, fluid, aerosolized powder, the aforementioned combinations, and / or other suitable materials.

[0062] Turning to the figures, specific non-limiting embodiments are described in further detail. Since this disclosure is not limited to the specific embodiments described herein, it should be understood that the various systems, components, features, and methods described for these embodiments may be used individually and / or in any desired combination.

[0063] Figures 1A-1C illustrate a schematic diagram of one embodiment of the drug delivery device 100. As shown in Figure 1B, the drug delivery device 100 includes a housing 102 containing a potential energy source configured as a compressed gas compartment 104 and an active pharmaceutical ingredient (API) reservoir 110. The compressed gas compartment 104 and the reservoir 110 are separated by a piston 106 which is slidably received inside the housing 102 between the gas compartment 104 and the reservoir 110. The piston 106 includes a piston seal 108 configured to prevent fluid transfer between the compressed gas compartment 104 and the reservoir 110. The piston 106 absorbs the pressure from the compressed gas compartment 104. The compressed gas is transferred to the reservoir 110. That is, the compressed gas inside the gas compartment 104 pressurizes the API located inside the reservoir 110. As shown in Figure 1A, the reservoir 110 includes an outlet 114 that fluidly communicates with the external environment of the device. In some embodiments, the outlet 114 may function as a nozzle for forming an injection 116. The maximum transverse dimension (e.g., diameter) of the outlet may be selected to provide a desired maximum transverse dimension of the corresponding injection 116 discharged from the outlet 114 as the pressurized API flows out of the reservoir 110.

[0064] The device may also include a trigger 112, which is operationally associated with a potential energy source, in this case a pressurized gas compartment 104. The trigger 112 is configured to activate the device 100 at a predetermined location within the target gastrointestinal tract such that the potential energy source, which is the compressed gas compartment 104, compresses the reservoir 110 and sprays an active pharmaceutical ingredient 116 out of the outlet 114 into the tissue 200 of the corresponding portion of the gastrointestinal tract located close to the device and toward which the outlet 114 is oriented. For example, in the embodiment described, the trigger 112 may correspond to a dissolvable plug that is physically retained within the outlet 114 of the device, such that when the trigger 112 dissolves, the device operates as detailed below, but any suitable trigger may be used, as the disclosure is not so limited.

[0065] As shown in Figure 1C, when the trigger 112 is dissolved or otherwise activated inside the GI tube of the subject, the barrier preventing the deployment of the API through the outlet 114 is removed. Thus, the pressure applied to the API reservoir 110 by the piston 106 associated with the compressed gas compartment 104 moves the piston 106 in a direction that compresses the reservoir 110. As the reservoir 110 is compressed, the API flows out of the outlet 114 in the form of a jet 116 at a speed sufficient to penetrate the gastrointestinal tract tissue 200 located in close proximity to the outlet 114. Again, the depicted gastrointestinal tract tissue 200 may correspond to the stomach, small intestine, and / or any other anatomical structure of the gastrointestinal tract of the subject described herein. Depending on the embodiment, the jet 116 may form a depot 118 of the API within the gastrointestinal tract tissue 200 without perforating the gastrointestinal tract. For example, the outlet 114, API reservoir 110, and associated potential energy source (e.g., compressed gas compartment 104) may be appropriately configured to provide an injection optimized to form a depot corresponding to the volume of API to be placed within the submucosa of the gastrointestinal tract without perforating the muscular layer 202 of the gastrointestinal tract. Furthermore, depending on the specific operating parameters, the depot 118 may be placed at least partially within the submucosa and / or muscular layer 202 of the gastrointestinal tract.

[0066] Figures 2A-2B depict schematic embodiments of the drug delivery device 100, including different types of potential energy sources and triggers. In the embodiments depicted, 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. As in the embodiment of Figure 1A-1C, the device also includes a piston 106 configured to transfer pressure between the reaction chamber 104a and the API reservoir 110 so that the piston 106 compresses the reservoir 110 in response to the device's operation. The API reservoir 110 may also be in fluid communication with an outlet 114. In some embodiments, a ruptureable membrane 120 or other seal is located on the outlet 114, located in or otherwise associated with it, to seal the API inside the API reservoir 110 until the device is activated and the membrane 120 ruptures. In the embodiment described, the reaction chamber 104a is not pressurized in the state shown in Figure 2A so that no pressure is applied to the ruptureable membrane 120 in a static state. Instead, the trigger is an electrical trigger (e.g., a sensor) and / or chemical trigger that is activated at a predetermined time and / or location within the gastrointestinal tract of the target (e.g., within the stomach and / or small intestine) using one of the methods described above. A trigger may also be used. The reaction chamber 104a may contain reactants configured to generate pressure when activated by the trigger. In some embodiments, an electrical sensor may trigger an acid-base reaction, an explosive reaction, and / or any other suitable reaction for generating pressurized gas. Naturally, the disclosure is not so limited, and any suitable reactant may be used to generate pressure. Naturally, a dissolving trigger is not used in the embodiments of Figures 2A-2B, but in other embodiments, a dissolving trigger may be employed with the reaction chamber 104a, so that the dissolvable trigger exposes the reaction chamber 104a to the external gastric environment in accordance with dissolution, so that the reactants can react to generate gas when exposed to the gastric environment.

[0067] As shown in Figure 2B, when the reaction is triggered inside the reaction chamber 104a to pressurize the reaction chamber 104a, the piston 106 is pushed downward, pressurizing the API in the API reservoir 110, which ruptures the rupturable membrane 120 or other seal. The API is then propelled out of the outlet 114 of the reservoir 110 in a jet 116 with sufficient power to penetrate the GI tube tissue 200 and deliver a therapeutic dose of the API to the patient, as described above.

[0068] Figure 3 depicts one embodiment of a drug delivery device 100 that is ingested orally and travels through the gastrointestinal tract 300 of a subject. While not intended to limit the examples to an exemplary set of such embodiments, the system may be administered orally to a subject, which then travels through the gastrointestinal tract 300 of the subject until it is activated within the gastrointestinal tract 300 at a predetermined time and / or location. For example, as schematically shown in Figure 3, the drug delivery device 100 may be administered to a subject (e.g., orally) so that the device enters the gastrointestinal tract 300 of the subject via the esophagus 302 (device 100a). The device may then travel through the gastrointestinal system until it reaches the stomach 304 of the subject (device 100b). In some embodiments, the drug delivery device 100 is denser than the surrounding fluid in the stomach 304 or other part of the GI tubule, and the device may sink to the bottom of the stomach 304 so that the outer surface of the device contacts the inner surface of the stomach 304 (100c). Depending on the embodiment, the device may be attached to the surface of the stomach 304 using an appropriate mounting method as described above, and / or the system may simply operate without being attached to the tissue of the stomach 304. In either case, the device may self-actuate when in an appropriate location within the gastrointestinal tract 300 to deploy a spray of the active pharmaceutical ingredient into the tissue of the gastrointestinal tract 300 located in close proximity to the device (e.g., the surface of the stomach). Subsequently, the device may pass through the pylorus of the stomach 304 and through the rest of the gastrointestinal tract 300 in question (device 100d). Figure 3 illustrates the operation of a device for deploying an active pharmaceutical ingredient into the stomach 304 of a target. Those skilled in the art will understand, based on the teachings herein, that the drug delivery devices disclosed herein may deploy an active pharmaceutical ingredient at any desired location along the length of the gastrointestinal tract 300 of a target, including the small intestine of a target, and that the spray may form a deposit of the active pharmaceutical ingredient in any suitable tissue of the target portion of the gastrointestinal tract 300, including, but not limited to, the mucosa, submucosa, and / or muscular tissue layers. As described above, in some embodiments, the spray may form a deposit in one or more layers of the tissues of the gastrointestinal tract without perforating the muscular tissue of the gastrointestinal tract. [Examples]

[0069] Example: Comparison of gastrointestinal tissues

[0070] Table I below presents a comparison of the anatomical structural characteristics of different gastrointestinal tissues. Generally, GI tissue consists of four broad cell layers: the mucosa, which secretes mucus and acts as the primary barrier to the absorption of macromolecules and other substances; the submucosa, located beneath the mucosa and rich in blood vessels for transporting nutrients from it; and the submucosa, located beneath the submucosa and involved in motility. It consists of a muscular layer and a serous membrane located beneath the muscular layer, which functions as the outermost protective layer for each organ. [Table 1]

[0071] Considering the above comparison of organ parameters, the stomach is an attractive target location due to its relatively long bolus transit time and greater wall thickness. In addition, although the small intestinal wall can be relatively thin (1-2 mm), the relatively small diameter of the small intestine makes it attractive for API injection deployment, as all sides of the device will be relatively close to the intestinal wall. Therefore, both the stomach and small intestine are attractive targets for API deployment using the injection method disclosed herein.

[0072] Example: Spray power

[0073] Due to differences in the location of different tissues along the length of the target gastrointestinal tract, it is expected that each type of gastrointestinal tissue will have different power requirements for depot formation within the target tissue. Given these differences, it is not expected that a spray optimized for depot formation in the stomach will be appropriate for depot formation in the small intestine or other anatomical structures. When dealing with APIs, if these differences are not properly considered, it may result in either the dosage not being delivered to the target tissue or / or unintentionally perforating one or more anatomical structures. Therefore, in order to deliver the desired amount of API to the desired target tissue, it is desirable to characterize both the way the spray is deployed and the specific power requirements for depot formation in the desired portion of the target gastrointestinal tract.

[0074] A model for the power of the ejection from a drug delivery device was developed. The model assumed the use of a linear compression spring as a potential energy source used to drive a piston to propel the fluid through the corresponding outlet. The spring was modeled as a linear spring with a stored compressive force prior to deployment and a "dissipated" compressive force after expansion and ejection. The model did not consider friction. However, as discussed below, some energy may be lost due to friction imparted by the sliding of the piston and flow constriction from the nozzle during actual use. Bernoulli's equation was used to model the flow of the liquid ejection from the device, with a fluid density of 1,000 kg / m³. 3 It was assumed that the initial boundary conditions used to solve the model were that the initial piston position at time zero and the time required for piston acceleration were negligible (i.e., the velocity boundary condition was "none" 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.

[0075] The resulting models were used to determine the injection force and power versus time for different nozzle diameters. The results are shown in Figures 5A–5F. The models clearly illustrate how changing the nozzle diameter for a given power system can affect both the peak injection force and injection power, as well as the duration of the injection with respect to a set potential energy source, such as a linear spring assumed in the model.

[0076] To validate the above model, a handheld system and force transducers were used. The test stand was designed to measure the injection force while varying parameters including nozzle orifice size, initial and final spring forces, isolation distance, fluid viscosity, incidence angle, and discharge volume. The test stand consisted primarily of a handheld injection device mounted on an aluminum rail with sensors for measuring the resulting injection force. This device allowed for rapid measurement of several different combinations of injection parameters, enabling the operator to quickly switch nozzles and springs as desired. The experiment was conducted using a coil spring with an initial spring force of 66 N and a final spring force-to-initial spring force ratio of 0.45 after injection. A quick-release hose fitting was used as a trigger for the test device. A pressure-power transducer was used to measure the thrust from the injection. High-speed video was also used to observe the shape of the injection to verify that the injection was indeed cylindrical and not a spray. Five iterations were performed for each experimental data point. A 200 μL ampoule volume of 100% deionized water was used for all experiments except those in which the fluid viscosity varied.

[0077] In each case, nozzle efficiency was inferred by comparing it to the theoretical energy input to the injection (i.e., after subtracting piston friction). The resulting nozzle efficiencies used to fit experimentally measured data varied from approximately 75% to 85%, although the efficiency for the 200 μm nozzle was approximately 88%, as shown in Figures 5C-5F. Therefore, when designing a device to deliver a desired injection power, it may be desirable to determine the nozzle efficiency at the outlet from which the injection is released. In all cases, the experiments confirmed the ability to predict the injection power of the device using appropriate parameter modeling and experimental determination.

[0078] Examples: In vitro tests

[0079] While not wishing to be constrained by theory, in some embodiments, gastrointestinal-based injection devices can achieve two types of injection: submucosal injection, where the depot is formed directly beneath or within the submucosal tissue, and intramuscular injection, where the injection is deposited within the muscular layer. It was also assumed that the power requirements for depot formation within the gastrointestinal tract are lower than those of the skin, because mucosal cells are softer and, in most cases, much thinner than dermal cells. To support these assumptions, 200 μL of contrast agent and / or tissue dye was injected into 5 cm × 5 cm samples of porcine intestinal and gastric tissue. A pneumatic cylinder with a final-to-initial compression ratio of 0.90 was used for all tests to displace the piston to eject the injection through outlets of various diameters. The device was mounted vertically, and the tissue was placed directly beneath it on a sponge soaked in saline in a Petri dish. The tissue was then brought into direct contact with the outlet nozzle using a benchtop scissor jack. The tissue was collected from laboratory-fed pigs and tested within 6 hours of excision. Micro-CT was used to analyze the delivery depot efficiency for each sample. A suspension of 5 wt% barium sulfate was employed as a contrast agent for injection. Tissue samples were scanned within 10 minutes of injection to minimize diffusion prior to evaluation.

[0080] Through the application of the experiments and imaging methods mentioned above, different initial pressures The jet performance in the GI tube in anatomical structures was determined to correspond to wet shots, depot formation, and tissue perforation, respectively, where the majority of the fluid could not penetrate the tissue. Depot formation was determined when a visible depot was observed both visually and through micro-CT scanning. Perforation was defined as a clear wound being visible on the serosal side of the tissue, with little to no contrast agent present in the tissue. Figure 6A shows the initial pressure and corresponding orifice diameter used to form jets in different tissues, including the esophagus, colon, rectum, cheek, and stomach. Wet shots, depot formation, and tissue perforation are indicated by dashed lines, circles, and × symbols, respectively. In addition, predicted jet performance is indicated by dashed line symbols. Figure 6B shows additional measurement data regarding jet injection efficiency versus jet force for various tissues, including the cheek, esophagus, stomach, small intestine (SI), colon, rectum, and canine SI. The experimental data was used to calculate the minimum observed peak power for depot formation in each organ based on the measured data. The results are summarized in Table II. Note that lower minimum requirements may be possible assuming smaller nozzle sizes that were not measured. The calculated jet power was calculated assuming an 80% nozzle efficiency. As expected, the minimum peak power for depot formation in each tissue type varied considerably from organ to organ.

[0081] [Table 2] Regarding the stomach, the optimal power for forming a highly efficient depot was approximately 21.4 W. However, depot formation began at approximately 9 W, and perforation was observed with higher injection efficiency at approximately 30 W and a nozzle diameter of 450 μm. In addition, perforation began to be observed at approximately 40 W.

[0082] The tests were also conducted on small intestinal tissue. The peak power range for depot formation in the intestine ranged from approximately 3W to 6.5W before perforation was observed.

[0083] Example: Depot efficiency test

[0084] From the models and experimental data described above, although we do not wish to be constrained by theory, increasing the outlet diameter results in higher force, and therefore higher peak power. Thus, to achieve the highest efficiency of depot formation (volume of loaded drug versus volume of formed depot), it may be desirable to identify the largest nozzle orifice diameter and the smallest input force. To verify this concept, tests of depot formation efficiency were conducted.

[0085] Figures 8A-8B show the parameter inputs (injection force or pressure, nozzle diameter, and injection power). Figure 8A outlines the experimental results of the delivery efficiency within gastric tissue and the resulting pressure (bars) applied to the API reservoir. Figure 8A plots using force (N), and Figure 8B plots using pressure (bars) applied to the API reservoir. The lines represent a piston diameter of 6 mm and a pressure of 1,200 kg / m². 3A curve is defined for the density and a constant power assuming a constant system efficiency of 80%. Shaded areas marked as perforated are data points where tissue perforation was observed. In the chart, the actual point where data is applicable within each box is the exact center of the box. As shown in Figure 8, a wide range of jet forces and pressures combined with various diameters can result in injection efficiencies exceeding 50% for the stomach. For gastric tissue, high efficiency without perforation was achieved in different tests with jet powers of 9W–40W in Figure 8A and 5W–45W in Figure 8B, for jet diameters of 150μm–550μm. Further depot formation was also observed using combinations of jet forces of 75N–200N and jet pressures of 15 bar–60 bar. In particular, high efficiencies exceeding 70% can be achieved with injection diameters of 250 μm to 550 μm, injection forces of 75 N to 175 N or equivalent, and / or injection powers of 20 W to 40 W with injection pressures of 15 Bar to 45 Bar or equivalent. More refined combinations of the ranges described above are expected to be identified through further experimental testing. Therefore, while some ranges have been shown to have higher efficiencies than others in this particular experiment, additional effective ranges for gastric delivery are expected, and this disclosure is not limited thereto.

[0086] As shown in Figure 8B, a wide range of injection pressures and diameters can result in injection efficiencies exceeding 50% with respect to the stomach. With respect to gastric tissue, high efficiency without perforation can be achieved with injection powers of 5W to 45W, with injection diameters of 150μm to 550μm and injection pressures of 15 to 60 bar. In particular, high efficiencies exceeding 70% can be achieved with injection powers of 20W to 40W, with injection diameters of 250μm to 550μm and injection forces of 15 to 45 bar. More refined combinations of the ranges described above are expected to be identified through further experimental testing. Therefore, while some ranges demonstrated higher efficiency than others in this particular experiment, additional effective ranges for gastric delivery are expected, and this disclosure is not limited thereto.

[0087] Figure 9A depicts a preliminary experimental overview of parameter inputs (injection force or pressure, nozzle diameter, and injection power) and the resulting delivery efficiency within the intestinal tissue. Figure 9A is plotted using force (N), and Figure 9B is plotted using pressure (bars) applied to the API reservoir. The line represents a piston diameter of 6 mm and a pressure of 1,200 kg / m². 3 A curve is defined for density and constant power assuming a constant system efficiency of 80%. Shaded areas marked as perforated are data points where tissue perforation was observed. In the chart, the actual point where data is applicable within 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 exceeding 50% with respect to intestinal tissue. With respect to intestinal tissue, high efficiency without perforation can be achieved with jet powers of 3W to 6.5W, with jet diameters of 150μm to 550μm and jet forces of 20 to 90N. In particular, high efficiency exceeding 70% can be achieved with jet powers of 3W to 6W, with jet diameters of 150μm to 350μm and jet forces of 30 to 80N. More refined combinations of the ranges described above are expected to be identified using further experimental testing. Therefore, while one range demonstrated higher efficiency than others in this particular experiment, additional effective ranges for intestinal tissue delivery are anticipated, and this disclosure is not limited thereto.

[0088] As shown in Figure 9B, a wide range of injection pressures and diameters can result in injection efficiencies exceeding 50% with respect to intestinal tissue. High efficiency without perforation can be achieved with injection powers of 3W to 6.5W for injection diameters of 150μm to 550μm and injection pressures of 5 to 20 bar, with respect to intestinal tissue. In particular, high efficiencies exceeding 70% can be achieved with injection diameters of 150μm to 350μm. This can be achieved with respect to diameter and injection power of 3W to 6W with injection pressure of 10 to 20 bar. More refined combinations of the ranges described above are expected to be identified through further experimental testing. Therefore, while some ranges have been shown to have higher efficiency than others in this particular experiment, additional effective ranges with respect to intestinal tissue delivery are expected, and this disclosure is not limited thereto.

[0089] Examples: In vivo testing

[0090] The studies were conducted by trained veterinary technicians at the MIT Animal Testing Facility. Yorkshire pigs weighing 70–90 kg were used. All studies were terminal studies (meaning the animals were euthanized immediately afterward). Figure 7 illustrates the use of a tethered device 100, which was used to deliver insulin injection to form a depot 118 within the stomach wall of the animals. The study protocol is described further below.

[0091] During the study, the weight of the pigs was determined, and the amount of insulin was selected to achieve a dose of 0.5 units / kilogram (1 unit = 0.0347 mg). Powdered insulin was then added to a 0.1 M NaOH solution, with PF68 and HEPES used as stabilizers. From there, 0.1 M HCl was added to aid in the dissolution of 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 above 8.0 (where insulin is most stable). This formulation procedure was performed in the morning or evening before each in vivo study, and the resulting solution was stored at 4°C until the time of administration.

[0092] The device was loaded with API and CO2 in an operating room where the animal was sedated and intubated. The device was deployed either by direct placement into the stomach via laparotomy or via an overtube with an endoscope and ligator. Of the five deployments performed using this device, the first three were performed via laparotomy, and the latter two were performed via endoscopy. Triggers generally occurred within 15 minutes and could be identified through a recoil and micro-bubbling near the base of the device.

[0093] Blood samples were collected via ear or femoral catheter. To ensure stability of blood glucose levels, samples were taken at approximately 15-minute intervals starting one hour before the scheduled deployment. After deployment, blood samples were collected at 5-minute intervals for the first 30 minutes, and then at 15-minute intervals for up to two hours after deployment. Samples were stored on ice in 3 mL EDTA tubes until completion of the study. Blood glucose levels were monitored at each blood draw using commercial glucose monitoring strips. If levels dropped below 20 mg / dL, an intravenous infusion of 12 mL of 50% glucose solution was administered to avoid hyperglycemia. Samples were then subsequently analyzed using a custom enzyme-linked immunosorbent assay (ELISA) for blood glucose levels.

[0094] Three out of five device trials resulted in a decrease in blood glucose levels and a corresponding increase in plasma insulin concentration. The fact that some devices delivered insulin while others did not was likely due to manufacturing variations in device orifice size. With respect to prototype devices, wide variations in orifice size were observed, but this issue was addressed in later versions through automated machining. In all cases, these trials confirmed the feasibility of oral delivery of the biologic.

[0095] Similar studies were also conducted in the small intestine of a porcine model using a tethered device. Similar results demonstrating the bioavailability of spray-delivered insulin were also observed for spray-deployed insulin in the small intestine.

[0096] Although this instruction has been described in conjunction with various embodiments and examples, it is not intended to be limited to such embodiments or examples. Rather, this instruction includes various alternatives, modifications, and equivalents, as will be understood by those skilled in the art. Therefore, the foregoing description and drawings are merely examples.

Claims

1. A drug delivery device configured for administration to a target, wherein the drug delivery device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to operate within the stomach of the subject, An outlet that is in fluid communication with the reservoir, the maximum transverse dimension of the outlet being 50 μm to 450 μm, and when the trigger is activated, the potential energy source compresses the reservoir, thereby ejecting the active pharmaceutical component from the reservoir through the outlet at a speed of 20 m / s to 250 m / s, and the peak power provided by the potential energy source to form the ejection of the active pharmaceutical component is 9 watts (W) to 130 W, the outlet and A drug delivery device equipped with the following features.

2. The drug delivery device according to claim 1, wherein when the trigger is activated, the potential energy source compresses the reservoir, thereby ejecting the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the stomach tissue of the target adjacent to the outlet.

3. The drug delivery device according to claim 1, wherein the peak power is 9W to 70W.

4. The drug delivery device according to claim 1, wherein the peak power is 9W to 12W.

5. The drug delivery device according to claim 1, wherein the outlet, the reservoir, and the potential energy source are configured to form a depot of the active pharmaceutical ingredient in the target stomach tissue without perforating the muscular layer of the stomach.

6. The drug delivery device according to claim 1, wherein the injection speed is 80 m / sec to 130 m / sec.

7. The drug delivery device according to any one of claims 1 to 6, wherein the potential energy source comprises at least one of compressed gas, a spring, an explosive, and a reaction chamber.

8. A drug delivery device configured for administration to a target, wherein the drug delivery device is A reservoir configured to contain an active pharmaceutical ingredient, Potential energy source, A trigger operationally associated with the potential energy source, wherein the trigger is configured to operate within the intestine of the subject, An outlet that is in fluid communication with the reservoir, the maximum transverse dimension of the outlet being 50 μm to 450 μm, and when the trigger is activated, the potential energy source compresses the reservoir, thereby ejecting the active pharmaceutical component from the reservoir through the outlet at a speed of 40 m / s to 80 m / s, and the peak power provided by the potential energy source to form the ejection of the active pharmaceutical component is 3.5 watts (W) to 6.5 watts, and A drug delivery device equipped with the following features.

9. The drug delivery device according to claim 8, wherein when the trigger is activated, the potential energy source compresses the reservoir, thereby ejecting the active pharmaceutical ingredient from the reservoir through the outlet at a speed sufficient to penetrate the intestinal tissue of the target adjacent to the outlet.

10. The drug delivery device according to claim 8, wherein the outlet, the reservoir, and the potential energy source are configured to form a depot of the active pharmaceutical ingredient within the target intestinal tissue without perforating the muscular layer of the intestine.

11. The drug delivery device according to claim 8, wherein the peak power is 3.5W to 5W.

12. The drug delivery device according to any one of claims 1 to 11, wherein the total volume of the drug delivery device is less than 3,000 mm³.

13. The drug delivery device according to any one of claims 1 to 12, further comprising the active pharmaceutical ingredient disposed within the reservoir.

14. The drug delivery device according to any one of claims 1 to 13, wherein the target is a human target.

Images