Method for making a tissue-interfacing component

Abstract

Disclosed herein are methods for manufacturing tissue-interfacing assemblies, such as solid needles, that include one or more therapeutic agents. In some embodiments, a method for manufacturing a tissue-interfacing assembly includes compressing a granular therapeutic agent within a mold cavity of a mold to form a solid tissue-interfacing assembly. The mold cavity can define an elongated shape extending along a longitudinal axis from an opening of the mold cavity to a distal end of the mold cavity, and the granular therapeutic agent can be compressed by moving a mold punch along the longitudinal axis toward the distal end. After compressing the granular therapeutic agent to form the solid tissue-interfacing assembly, the tissue-interfacing assembly can be removed from the mold and subsequently inserted into tissue to deliver the therapeutic agent to a subject.

Description

Technical Field

[0001] The present disclosure generally relates to methods for making tissue-interfacing assemblies, such as needles, that include one or more therapeutic agents. Background Art

[0002] The gastrointestinal tract (GI) provides incredible opportunities for diagnosing and treating patients. Smart dosage systems and products developed to achieve this goal have achieved significant growth in the past decade. One of the most important challenges in maximizing delivery and interaction with the mucosa is to ensure the juxtaposition between the product and / or drug delivery system and the GI mucosa. Previous attempts to do so included introducing mucoadhesives and texturing one side of the system on both sides. Orally ingested drugs generally diffuse through the GI tract tissue wall to enter the bloodstream. Typical pills or products taken in randomly release their cargo into the GI tract and allow it to move to the tissue wall via convection and diffusion. However, many biopharmaceuticals (such as insulin) cannot move through the liquid in the GI tract because they will, for example, be degraded by enzymes even if they are contained in solid formulations.

[0003] Additionally, many pharmaceutical formulations on the market require administration via injection, including many vaccines, RNA, and peptides. Traditionally, injections involve the use of liquid formulations that are passed through a hollow needle and introduced into the body intravenously or intramuscularly. However, these liquid formulations can cause the active pharmaceutical ingredient (API) to become unstable and may require refrigeration and / or significantly increase the volume of the dose due to the need for dilution. Summary of the Invention

[0004] In one embodiment, a method of forming a tissue-interfacing assembly includes depositing a first granular therapeutic agent into a mold cavity of a mold. The mold cavity defines an elongated shape extending along a longitudinal axis from an opening of the mold cavity to a distal tip at a distal end of the mold cavity within the mold, and the distal tip is sized and shaped to facilitate insertion into tissue. The method further includes compressing the first granular therapeutic agent within the mold in a direction toward the distal end, forming the tissue-interfacing assembly from the first granular therapeutic agent at least in part due to the compression of the first granular therapeutic agent within the mold, and removing the tissue-interfacing assembly from the mold cavity.

[0005] In another embodiment, a method of forming a tissue-interfacing component includes depositing a first granular therapeutic agent into a mold and applying a pressure greater than or equal to 20 MPa to at least a portion of the first granular therapeutic agent to compress the first granular therapeutic agent and form the tissue-interfacing component. The therapeutic agent comprises greater than or equal to 80 wt % of the total tissue-interfacing component weight, and the tissue-interfacing component is configured to penetrate at least 1 mm into human gastrointestinal mucosal tissue with a force less than or equal to 5 N.

[0006] It should be understood that the aforementioned concepts and the additional concepts discussed below may be arranged in any suitable combination, as the present disclosure is not limited in this respect. In addition, 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 drawings.

[0007] In the event that this specification and a document incorporated by reference contain conflicting and / or inconsistent disclosure, the present specification controls. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying drawings, which are schematic and not intended to be drawn to scale. In the drawings, each identical or nearly identical component illustrated is generally represented by a single numeral. For clarity, not every component is labeled in every figure, nor is every component of every embodiment of the invention shown, where illustration is not necessary for one of ordinary skill in the art to understand the present invention. In the drawings:

[0009] Figure 1 is a schematic diagram of a mold for forming a tissue-interfacing component according to some embodiments;

[0010] Figure 2 yes Figure 1 a schematic diagram of a mold, which additionally illustrates a particulate therapeutic agent deposited within the mold;

[0011] Figure 3 yes Figure 1 a schematic diagram of a die, which additionally illustrates the die punch and a particulate therapeutic agent contained within the die;

[0012] Figure 4 yes Figure 1 a schematic diagram of a mold of , which further illustrates separation of the mold portions to remove the tissue interfacing component;

[0013] Figure 5 yes Figure 1 A schematic diagram of a mold, wherein two granular materials are contained in the mold;

[0014] Figure 6A is a perspective view of a mold for forming a tissue-interfacing component according to some embodiments;

[0015] Figure 6B yes Figure 6A Exploded view of the mold;

[0016] Figure 7 is a schematic diagram of an article for administering a tissue-interfacing component according to some embodiments;

[0017] Figure 8is a schematic cross-sectional view of an article for use in applying a tissue interfacing component according to some embodiments; and

[0018] Figure 9 is a schematic illustration of an article of manufacture for administering a tissue interfacing component according to some embodiments. DETAILED DESCRIPTION

[0019] The inventors have recognized and appreciated the many benefits associated with tissue-interfacing components, which include active pharmaceutical ingredients (APIs) or other therapeutic agents that can be injected or otherwise physically inserted into tissues. For example, some biotherapeutic products (e.g., peptides or larger molecules) may not be well absorbed from the gastric cavity (e.g., after oral ingestion). In order to increase the absorption of such products, therapeutic agents can be physically deposited into mucosal tissue (e.g., around the stomach) or other suitable tissues. Therefore, the inventors have recognized and appreciated the many benefits associated with methods for manufacturing tissue-interfacing components containing APIs, which are constructed and arranged to be inserted into tissues (e.g., mucosal tissues) and subsequently release the API into the tissues for absorption. As used herein, the term "therapeutic agent" (also referred to as "drug," "active pharmaceutical ingredient" or similar terms) refers to an agent that is administered to a subject to treat a disease, illness, or other clinically recognized condition, or is used for preventive purposes, and has a clinically significant effect on the subject's body to treat and / or prevent a disease, illness, or condition. Additionally, these terms may be used interchangeably in various embodiments, as the present disclosure is not limited to any particular type of therapeutic agent.

[0020] In some embodiments, the tissue-interfacing component can be configured as an elongated structure (e.g., an elongated cylindrical or prismatic structure), and the tissue-interfacing component can have a pointed distal tip, which can facilitate penetration of the tissue-interfacing component into tissue, such as mucosal tissue or other suitable tissue. Thus, in some embodiments, the tissue-interfacing component can be described herein as a needle or similar elongated structure that can be injected into tissue, and upon injection, the needle can at least partially dissolve and release one or more APIs and / or other therapeutic agents into the tissue.

[0021] According to some aspects, a method for manufacturing a tissue interfacing component may include compressing a granular material within a mold. For example, a granular therapeutic agent and / or other granular material (e.g., a powdered API or drug or other suitable powdered or granular material) may be deposited or otherwise loaded into a mold cavity of a mold. The mold cavity may define a longitudinal axis extending from an opening of the mold cavity to a distal tip located at the distal end of the mold cavity, and the distal tip of the mold cavity may be closed within the mold. Thus, the mold cavity may be referred to herein as a blind receptacle or blind cavity. After loading the granular therapeutic agent, the granular therapeutic agent may be compressed within the mold cavity in a direction oriented substantially along the longitudinal axis and toward the distal tip and the tissue interfacing component. At least in part due to the compression of the granular therapeutic agent, a solid or substantially solid tissue interfacing component may be formed within the mold cavity. In some embodiments, such compression of the granular therapeutic agent may be achieved using a mold punch. For example, a die punch can be inserted into the opening of the die cavity, and the die punch can be moved toward the distal end of the die cavity to compress and compact the particulate therapeutic agent within the die cavity and form a solid tissue-interfacing component. In this manner, the compressive force applied by the die punch to form the tissue-interfacing component from the particulate therapeutic agent can be directed substantially along the longitudinal axis of the tissue-interfacing component. For example, as described above, in some embodiments, the tissue-interfacing component can be formed as a needle, and thus, the compressive force applied by the die punch can be applied along the longitudinal axis of the needle toward the needle tip.

[0022] After the therapeutic agent is compressed in the mold, thereby forming the tissue interfacing assembly in some cases, the tissue interfacing assembly can be removed from the mold. In some embodiments, the mold can be constructed and arranged to facilitate such removal of the tissue interfacing assembly. For example, in some embodiments, the mold can be formed from corresponding first and second mold portions that can be coupled to each other to form a mold cavity. For example, each mold portion can include a wall portion that defines the mold cavity when the mold portions are coupled. In some embodiments, the mold portions can be separable along a plane that is substantially parallel to the longitudinal axis of the tissue interfacing assembly. For example, the wall portion of each mold portion can be configured to define approximately half of the tissue interfacing assembly when the mold portions are coupled to each other by a parting line that is appropriately aligned with the geometry of the ultimately formed tissue interfacing assembly to allow the mold portions to be separated and allow removal of the tissue interfacing assembly.

[0023] As used herein, granular material generally refers to a material, such as a powdered material, comprising a plurality of discrete solid particles or granules that can be compressed and compacted to form a substantially solid mass. For example, a granular therapeutic agent can include a powdered drug or other powdered API that can be compacted in a mold to form a solid drug-containing component.

[0024] As described above, in some embodiments, the tissue interfacing component can be formed as a needle or other elongated structure having a pointed distal tip. In some embodiments, the mold cavity can be configured to form such features when the granular therapeutic agent is compressed within the mold cavity. For example, the distal end of the mold cavity opposite the opening of the mold cavity can have a shape corresponding to a desired geometry. When the granular therapeutic agent is compressed with the mold punch, the granular therapeutic agent can conform to the geometry of the mold cavity to form a solid tissue interfacing component having a desired distal tip geometry that is configured to facilitate insertion into tissue (e.g., a pointed tip or other suitable geometry).

[0025] In some embodiments, a variety of granular materials can be deposited into a mold cavity to form a tissue interfacing component. For example, a first granular material (e.g., a granular therapeutic agent) can be first deposited into a mold cavity to form the distal portion of a tissue interfacing component, and then a second granular material (e.g., a second granular therapeutic agent or other granular material) can be deposited into the mold cavity to form the proximal portion of the tissue interfacing component. The first and second granular materials can be compressed together with a mold punch to compact and solidify the first and second granular materials, thereby forming a tissue interfacing component. However, embodiments in which the first and second granular materials are compressed in separate compression steps are also contemplated, as the present disclosure is not so limited. In some embodiments, such an arrangement can allow the desired therapeutic agent to be positioned at the distal portion of the tissue interfacing component for dissolution after being injected or otherwise inserted into the tissue, and the second granular material can provide structural support to the tissue interfacing component for easy insertion into the tissue.

[0026] In some embodiments, the tissue intermediary component may include a relatively high load of active pharmaceutical ingredients (e.g., drugs or other therapeutic agents). In certain embodiments, the tissue intermediary component may be formed entirely of a therapeutic agent (e.g., an API) such that the therapeutic agent comprises approximately 100% of the weight of the tissue intermediary component. In other embodiments, the granular therapeutic agent forming the tissue intermediary component includes a solid therapeutic agent (e.g., a solid API) and, optionally, a supporting material (e.g., an adhesive, such as a polymer) such that the solid therapeutic agent is present in the component in a relatively high amount (e.g., greater than or equal to 80 wt %) relative to the total weight of the tissue intermediary component. This type of tissue intermediary component with a high load of therapeutic agent can be used to deliver an API dose (e.g., to a subject). Advantageously, in some embodiments, the reduced volume required to deliver the desired API dose compared to a liquid formulation allows for the creation of a solid needle delivery system for a variety of drugs in various locations / tissues (e.g., tongue, GI mucosal tissue, skin). The disclosed structure can also reduce and / or eliminate the application of external force to inject a drug solution through a small opening in the needle. In some cases, a physiologically relevant dose may be present in a single tissue-interfacing component (eg, with a relatively high API loading).

[0027] Depending on the particular embodiment, the die punch and associated actuation system or other suitable system can be constructed and arranged to apply any suitable amount of pressure to compress and compact the particulate therapeutic agent to form a solid tissue-interfacing component. For example, in some embodiments, the tissue-interfacing component is formed using a pressure of at least 1 MPa, a pressure of at least 2 MPa, a pressure of at least 3 MPa, a pressure of at least 5 MPa, a pressure of at least 7 MPa, a pressure of at least 10 MPa, a pressure of at least 12 MPa, a pressure of at least 15 MPa, a pressure of at least 20 MPa, a pressure of at least 25 MPa, a pressure of at least 30 MPa, a pressure of at least 40 MPa, a pressure of at least 50 MPa, a pressure of at least 75 MPa, a pressure of at least 150 MPa, a pressure of at least 300 MPa, a pressure of at least 600 MPa, a pressure of at least 900 MPa, a pressure of at least 1 GPa, or a pressure of at least 1.2 GPa. In some embodiments, the tissue interfacing component is formed using: a pressure of less than or equal to 1.4 GPa, a pressure of less than or equal to 1.2 GPa, a pressure of less than or equal to 1 GPa, a pressure of less than or equal to 900 MPa, a pressure of less than or equal to 600 MPa, a pressure of less than or equal to 300 MPa, a pressure of less than or equal to 150 MPa, a pressure of less than or equal to 100 MPa, a pressure of less than or equal to 75 MPa, a pressure of less than or equal to 50 MPa, a pressure of less than or equal to 40 MPa, a pressure of less than or equal to 30 MPa, a pressure of less than or equal to 25 MPa, a pressure of less than or equal to 20 MPa, a pressure of less than or equal to 15 MPa, a pressure of less than or equal to 12 MPa, a pressure of less than or equal to 10 MPa, a pressure of less than or equal to 7 MPa, a pressure of less than or equal to 5 MPa, a pressure of less than or equal to 3 MPa, or a pressure of less than or equal to 2 MPa. Combinations of the above-referenced ranges are also possible (e.g., a pressure of at least 1 MPa and less than or equal to 100 MPa, a pressure of at least 20 MPa and less than or equal to 100 MPa, a pressure of at least 100 MPa and less than or equal to 1.4 GPa). In some embodiments, the applied pressure may be between about 25 MPa and about 1000 MPa. Other ranges are also possible.

[0028] In some embodiments, the tissue interfacing component has a specific maximum dimension (e.g., length). In certain embodiments, the length of the tissue interfacing component may be between about 1 mm and about 10 mm (e.g., between about 1.5 mm and about 8 mm). In some embodiments, the length is greater than or equal to 1 mm, greater than or equal to 2 mm, greater than or equal to 3 mm, greater than or equal to 5 mm, greater than or equal to 7 mm, or greater than or equal to 10 mm. In some embodiments, the maximum dimension of the tissue interfacing component is less than or equal to 10 mm, less than or equal to 7 mm, less than or equal to 5 mm, less than or equal to 3 mm, less than or equal to 2 mm, or less than or equal to 1.5 mm. Combinations of the above reference ranges are also possible, although sizes greater than or less than the above sizes are also contemplated.

[0029] In certain embodiments, the average cross-sectional dimension of the tissue interfacing component, perpendicular to the maximum dimension of the component (e.g., diameter), is between about 0.5 mm and about 2 mm (e.g., between about 0.8 mm and 1.6 mm). In some embodiments, the diameter can be greater than or equal to 0.5 mm, greater than or equal to 0.6 mm, greater than or equal to 0.7 mm, greater than or equal to 0.8 mm, greater than or equal to 0.9 mm, greater than or equal to 1 mm, greater than or equal to 1.1 mm, greater than or equal to 1.2 mm, greater than or equal to 1.3 mm, greater than or equal to 1.4 mm, greater than or equal to 1.6 mm, or greater than or equal to 1.8 mm. In some embodiments, the average cross-sectional dimension of the tissue interfacing component is less than or equal to 2.0 mm, less than or equal to 1.9 mm, less than or equal to 1.7 mm, less than or equal to 1.5 mm, less than or equal to 1.4 mm, less than or equal to 1.3 mm, less than or equal to 1.2 mm, less than or equal to 1.1 mm, less than or equal to 1 mm, less than or equal to 0.9 mm, less than or equal to 0.8 mm, less than or equal to 0.7 mm, or less than or equal to 0.6, or less than or equal to 0.5 mm. Combinations of the above reference ranges are also possible (e.g., greater than or equal to 0.5 mm and less than or equal to 2.0 mm). Other ranges are also possible.

[0030] According to some aspects of the present disclosure, tissue-interfacing components manufactured using the methods described herein can be administered via a device that can be ingested by a patient. In some embodiments, the device can be a self-righting article that can be configured so that the article can orient itself relative to a surface (e.g., a surface of a subject's tissue). The self-righting articles described herein may include one or more tissue-interfacing surfaces configured to engage with a surface (e.g., a surface of a subject's tissue) (e.g., interface with a surface, inject into a surface, anchor a surface). For example, the self-righting article can be placed at any orientation near a surface and the self-righting article will (re)orient itself so that the tissue-interfacing surface contacts (e.g., directly contacts) the surface. In some embodiments, the self-righting article may have, for example, a specific shape and / or density (or mass) distribution that achieves the self-righting behavior of the article. In some such embodiments, a capsule containing the self-righting article can be administered to a subject (e.g., for delivering the self-righting article to a location inside the subject, such as the gastrointestinal tract). In some embodiments, self-righting may include a tissue-interfacing component and / or a pharmaceutical agent (e.g., for delivering an active agent to a location inside the subject). In some cases, the self-righting article can be configured to release one or more tissue-interfacing components when tissue contacts the tissue-engaging surface of the article. In some cases, the tissue-interfacing component is associated with a self-actuating component. For example, a self-righting article can include a self-actuating component that is configured to release the tissue-interfacing component from the self-righting article when exposed to a fluid. In some cases, the tissue-interfacing component can include and / or be associated with a pharmaceutical agent (e.g., for delivery to a location inside a subject).

[0031] In some cases, the tissue interfacing component can be configured to penetrate a specific depth into the gastrointestinal mucosal tissue of the human body with a specific force. For example, the tissue interfacing component can be configured to penetrate greater than or equal to 1 mm (e.g., greater than or equal to 2 mm, greater than or equal to 3 mm, greater than or equal to 4 mm, or greater than or equal to 5 mm) with a force less than or equal to 30 N (e.g., less than or equal to 30 N, less than or equal to 20 N, less than or equal to 10 N, or less than or equal to 5 N). In certain embodiments, the penetration force can be between about 6 N and about 30 N. Of course, penetration depths and forces greater than and less than the above values ​​are also contemplated, as the present disclosure is not so limited.

[0032] In some cases, the tissue interfacing component can be configured to deliver a specific amount of active agent per square centimeter of tissue of the subject. For example, in some embodiments, the tissue interfacing component is configured to deliver greater than or equal to 0.01 μg, greater than or equal to 0.05 μg, greater than or equal to 0.1 μg, greater than or equal to 0.2 μg, greater than or equal to 0.5 μg, greater than or equal to 0.7 μg, greater than or equal to 1 μg, greater than or equal to 2 μg, greater than or equal to 5 μg, or greater than or equal to 10 μg of agent per square centimeter of tissue of the subject near the penetration location of the tissue interfacing component. In certain embodiments, the tissue interfacing component is configured to deliver less than or equal to 20 μg, less than or equal to 5 μg, less than or equal to 2 μg, less than or equal to 1 μg, less than or equal to 0.7 μg, less than or equal to 0.5 μg, less than or equal to 0.2 μg, less than or equal to 0.1 μg, or less than or equal to 0.05 μg of agent per square centimeter of tissue. Combinations of the above reference ranges are also possible (e.g., greater than or equal to 1 μg and less than or equal to 20 μg). In some embodiments, the tissue interfacing component is configured to deliver greater than or equal to 1 μg of agent per square centimeter of subject tissue within any suitable time period (e.g., greater than or equal to 0.1 seconds, greater than or equal to 0.5 seconds, greater than or equal to 1 second, greater than or equal to 5 seconds, greater than or equal to 30 seconds, greater than or equal to 1 minute, greater than or equal to 5 minutes, 10 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 4 hours, greater than or equal to 24 hours, greater than or equal to 48 hours, greater than or equal to 72 hours, greater than or equal to 96 hours, greater than or equal to 120 hours, greater than or equal to 144 hours, greater than or equal to 168 hours). Of course, since the present disclosure is not limited to any particular dose and / or time period, it is also contemplated that doses greater than or less than the doses described above, as well as time periods different from those described above, may be delivered.

[0033] In certain embodiments, the tissue interfacing component includes an adhesive. Non-limiting examples of suitable adhesives include sugars such as sorbitol and sucrose, gelatin, polymers such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), polycaprolactone (PCL), and polyvinyl pyrrolidone (PVP), and polymers including ethanol or other Class 3 organic solvents (e.g., acetic acid, heptane, acetone, formic acid, isobutyl acetate, etc.).

[0034] In an exemplary embodiment, relative to the total product weight, the tissue intermediary component includes a solid active agent greater than or equal to 80wt%. In certain embodiments, the tissue intermediary component includes an active agent greater than or equal to 1mg. According to some embodiments, the agent is selected from the group consisting of: bacteriophage, DNA, mRNA, insulin, human growth hormone, monoclonal antibody, adalimumab, epinephrine and ondansetron. In certain exemplary embodiments, the active agent is cast into a mold to form the tissue intermediary component. In certain embodiments, the mold is centrifuged. According to certain embodiments, the tissue intermediary component additionally includes an adhesive. In certain embodiments, the adhesive includes sugars such as sorbitol or sucrose, gelatin, polymers such as PVA, PEG, PCL, PVA or PVP and / or ethanol. According to certain embodiments, the Young's modulus of elasticity of the tissue intermediary component is greater than or equal to 100MPa. In some embodiments, the tissue intermediary component is configured to penetrate at least 1mm into the gastrointestinal mucosal tissue of the human body with a force less than or equal to 20mN. According to certain embodiments, the tissue-interfacing component is configured to deliver at least 1 mg of agent per square centimeter of subject tissue, and / or the tissue-interfacing component includes greater than or equal to 1 mg of active agent per square centimeter.

[0035] In one specific non-limiting embodiment, a method of forming a tissue interfacing component comprises introducing a composition (comprising greater than 80 wt % of a solid pharmaceutical agent, relative to the total weight of the composition) into a mold, applying a pressure greater than or equal to 1 MPa to the composition, and heating the composition to a temperature of at least 70° C. for at least 1 minute.

[0036] According to some embodiments, the methods described herein are compatible with one or more therapeutic agents, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the therapeutic agent is pharmaceutical, biological, nutritional, preventive, diagnostic, contrast agent (i.e., for imaging), or any other suitable agent that can be injected into a subject. Although most of the description describes the use of active pharmaceutical ingredients, it should be understood that any desired therapeutic agent for any appropriate application can be used, as the present disclosure is not so limited.

[0037] Therapeutic agents may include, but are not limited to, any synthetic or naturally occurring biologically active compound or composition of matter that, when administered to a subject (e.g., a human or non-human animal), induces a desired pharmacological, immunogenic, and / or local and / or systemic physiological effect. For example, compounds or chemicals that are traditionally considered drugs, vaccines, and biopharmaceuticals are useful or may be useful in the context of certain embodiments, and certain such agents may include molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, and the like that are used in the field of therapy, diagnosis, and / or enhancement, including but not limited to, medical or veterinary treatment, prevention, diagnosis, and / or alleviation of disease or illness (e.g., HMG-CoA reductase inhibitors (statins) such as rosuvastatin; nonsteroidal anti-inflammatory drugs such as meloxicam; selective serotonin reuptake inhibitors such as escitalopram). talopram; blood thinners such as clopidogrel; steroids such as prednisone; antipsychotics such as aripiprazole and risperidone; analgesics such as buprenorphine; antagonists such as naloxone, montelukast, and memantine; cardiac glycosides such as digoxin; alpha blockers such as tamsulosin; cholesterol absorption inhibitors such as ezetimibe; metabolites such as colchicine; antihistamines such as loratadine and cetirizine; opioids such as loperamide; proton pump inhibitors such as omeprazole; antiretroviral agents such as entecavir, dolutegravir, rilpivirine, and cabotegravir; and levothyroxine); substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal contraception); performance enhancement (e.g., stimulants such as caffeine); and nutrition and supplements (e.g., protein, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, and other vitamin or mineral supplements).

[0038] In certain embodiments, as used herein, the term "therapeutic agent," or also referred to as "drug" or "active pharmaceutical ingredient," refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and has a clinically significant effect on the subject's body to treat and / or prevent the disease, disorder, or condition. Lists of examples of known therapeutic agents can be found, for example, in the United States Pharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Katzung, B. (ed.), Basic and Clinical Pharmacology, McGraw-Hill / Appleton & Lange; 8th ed. (September 21, 2000); Physician's Desk Reference (Thomson Publishing) and / or The Merck Manual of Diagnosis and Therapy, 17th ed., (1999) or its subsequent 18th ed. (2006), Mark H. Beers and Robert Berkow (ed.), Merck Publishing Group, or, with respect to animals, The Merck Veterinary Manual, 9th ed., Kahn, CA (ed.), Merck Publishing Group, 2005; and Approved Drug Products with Therapeutic Equivalence and Evaluations, published by the United States Food and Drug Administration (FDA) ("The Orange Book"). Examples of drugs approved for human use are listed by the FDA under 21 CFR §§330.5, 331 to 361, and 440 to 460, which are incorporated herein by reference; veterinary drugs are listed by the FDA under 21 CFR §§500 to 589, which are incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule.The exemplary categories of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antipsychotics, neuroprotectants, antiproliferative drugs, such as anticancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, antianxiety drugs, antibacterials, immunosuppressants, sedatives, sleeping pills, antipsychotics, bronchodilators, antiasthmatics, cardiovascular drugs, anesthetics, anticoagulants, an inhibitor of an enzyme, steroidal agents, steroidal or nonsteroidal anti-inflammatory agents, corticosteroids, dopaminergic drugs, electrolytes, gastrointestinal drugs, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, appetite suppressants and anti-narcolepsy drugs. Nutritious foods can also be incorporated into the drug delivery device. These can be vitamins, supplements such as calcium or biotin, or natural ingredients such as plant extracts or plant hormones.

[0039] In certain embodiments, therapeutic agent is one or more antimalarial drugs. Exemplary antimalarial drugs include quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfonamides such as sulfadoxine and sulfamethoxypyridazine, mefloquine, atovaquone, primaquine, halofantrine, doxycycline, clindamycin, artemisinin and artemisinin derivatives. In certain embodiments, antimalarial drugs are artemisinin or its derivatives. Exemplary artemisinin derivatives include artemether, dihydroartemisinin, arteether and artesunate. In certain embodiments, artemisinin derivatives are artesunate.

[0040] In another embodiment, the therapeutic agent is an immunosuppressant. Exemplary immunosuppressants include glucocorticoids, cytostatics (such as alkylating agents, antimetabolites, and cytotoxic antibodies), antibodies (such as antibodies to T cell receptors or Il-2 receptors), drugs that act on immunophilins (such as cyclosporine, tacrolimus, and sirolimus), and other drugs (such as interferons, opioids, TNF binding proteins, mycophenolate, and other small molecules such as fingolimod).

[0041] In certain embodiments, the therapeutic agent is a hormone or a derivative thereof. Non-limiting examples of hormones include insulin, growth hormone (e.g., human growth hormone), vasopressin, melatonin, thyroxine, thyrotropin-releasing hormone, glycoprotein hormones (e.g., luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone), eicosanoids, estrogen, progesterone, testosterone, estradiol, cortisol, epinephrine, and other steroids.

[0042] In some embodiments, the therapeutic agent is a small molecule drug having a molecular weight of less than about 2500 Daltons, less than about 2000 Daltons, less than about 1500 Daltons, less than about 1000 Daltons, less than about 750 Daltons, less than about 500 Daltons, or less than about 400 Daltons. In some cases, the therapeutic agent is a small molecule drug having a molecular weight between 200 Daltons and 400 Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltons and 2500 Daltons.

[0043] In some embodiments, the therapeutic agent is selected from the group consisting of active pharmaceutical agents such as insulin, nucleic acids, peptides, phages, DNA, mRNA, human growth hormone, monoclonal antibodies, adalimumab, epinephrine, GLP-1 receptor agonists, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, small molecule drugs, precursor proteins, vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines and conjugate vaccines, toxoid vaccines, influenza vaccines, herpes zoster vaccines, prevnar pneumonia vaccines, mmr vaccines, tetanus vaccines, hepatitis vaccines, HIV vaccines Ad4-env clade C, HIV vaccines Ad4-mGag, DNA vaccines, RNA vaccines, etanercept, infliximab, filgastrim, glatiramer acetate,

[0014] The present invention also includes but is not limited to the following: acetate, rituximab, bevacizumab, any molecule encapsulated in nanoparticles, epinephrine, lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, certolizumab pegol, ustekinumab, ixekizumab, golimumab, brodalumab, guselu,ab, secikinumab, omalizumab, TNF-α inhibitors, interleukin inhibitors, vedolizumab, octreotide, teriperatide, CRIPR Cas9, insulin glargine, insulin detemir, insulin lispro, insulin aspart, human insulin, antisense oligonucleotides, and ondansetron.

[0044] In an exemplary embodiment, the therapeutic agent is insulin.

[0045] In certain embodiments, the therapeutic agent is present in the tissue-interfacing component at a concentration at which, upon release from the tissue-interfacing component, the therapeutic agent elicits a therapeutic response.

[0046] In some cases, the therapeutic agent may be present at a concentration that is less than the minimum concentration generally associated with an active therapeutic agent (e.g., at a microdose concentration). For example, in some embodiments, the tissue interfacing component includes a relatively low dose of a first therapeutic agent (e.g., a steroid) (e.g., without wishing to be bound by theory, a low dose of a therapeutic agent such as a steroid may mediate a foreign body response in the subject at a location within the subject (e.g., in response to contact with the tissue interfacing component)). In some embodiments, the concentration of the therapeutic agent is a microdose of less than or equal to 100 μg and / or 30 nMol. However, in other embodiments, the therapeutic agent is not provided in a microdose, but is present in one or more of the amounts listed above.

[0047] In certain embodiments, the tissue intermediary component (for example, oral) is applied to the subject. In certain embodiments, the product can be administered orally, rectally, vaginally, nasally or urethrally. In certain embodiments, the tissue intermediary component (for example, and / or the API contained therein) is applied by contacting the skin of the subject with the component. In an exemplary embodiment, the tissue intermediary component (for example, and / or the API contained therein) is applied by contacting the buccal tissue (for example, lip, palate area, cheek, sublingual, tongue) of the subject with the component. In another exemplary embodiment, the tissue intermediary component is orally applied, and when arriving at the position (for example, GI tract, such as colon, duodenum, ileum, jejunum, stomach, buccal space, esophagus, etc.) inside the subject, the tissue intermediary component is interfaced (for example, contacted) with the tissue of the subject at the position inside the subject and at least partially penetrates the tissue. In certain embodiments, at least a portion of the tissue intermediary component penetrates the tissue of the subject and at least a portion of the supporting material and / or the active agent is dissolved in the tissue of the subject.

[0048] Advantageously, administering a tissue-interfacing component with a relatively high API load to the GI tract can allow for more efficient delivery of the API compared to traditional methods. For example, without wishing to be bound by theory, drug delivery to the GI tract via injection has been shown to have higher bioavailability than other methods.

[0049] As used herein, "subject" refers to any animal, such as a mammal (e.g., a human). Non-limiting examples of subjects include humans, non-human primates, cattle, horses, pigs, sheep, goats, dogs, cats, or rodents, such as mice, rats, hamsters, birds, fish, or guinea pigs. In general, the present invention is intended for use with humans. In some embodiments, the subject may exhibit health benefits, for example, upon administration of the self-righting article.

[0050] Turning now to the drawings, specific non-limiting embodiments are described in additional detail. It should be understood that the various systems, components, features, and methods described with respect to these embodiments may be used alone and / or in any desired combination, as the present disclosure is not limited to the specific embodiments described herein.

[0051] Figure 1 is a schematic side view of a mold 10 that can be used to form a tissue interfacing assembly according to some embodiments. The mold includes a first mold portion 12 and a second mold portion 14 that can be coupled to each other to define a mold cavity 16 disposed between the two mold portions. The mold cavity extends along a longitudinal axis 22 from an opening 18 of the mold cavity to a distal end 20 of the mold cavity. The distal end of the mold cavity can have a distal tip geometry that is configured to mold a distal tip of the resulting tissue interfacing assembly that is shaped and sized for insertion into tissue. For example, as shown, the distal end 20 of the mold cavity can be positioned within the interior of the mold 10, and the distal end can define a distal tip of the mold cavity that can be configured as a pointed tip or other suitable geometry as described herein.

[0052] refer to Figure 1-4 The granular material 30 (e.g., granular therapeutic agent) may be Figure 2 As shown, the granular material 30 is deposited into the mold cavity 16. For example, the longitudinal axis 22 can be aligned with the vertical direction, and the granular material 30 can be deposited into the mold in that direction (e.g., via gravity feeding or by otherwise pouring or distributing the granular material into the mold cavity 16 in a vertical direction). Once positioned in the cavity, the granular material can then be compressed within the mold cavity, such as with Figure 4 The die punch 40 is shown. For example, the die punch 40 can have a portion configured to be received in the opening 18 of the die cavity 16, and the die punch can be moved in a direction 42, which can correspond to movement of the die punch 40 along the longitudinal axis 22 toward the distal end 20 of the die cavity 16. In this manner, the die punch can apply a compressive force to the granular material 30 to compress and compact the granular material, thereby forming the solid tissue interfacing component 50 having a shape corresponding to the distal portion of the die cavity 16.

[0053] Subsequently, the tissue interfacing assembly 50 may be removed from the mold cavity 16. For example, Figure 4As shown, in some embodiments, the first mold portion 12 and the second mold portion 14 may be separable and movable apart from each other in directions 44 and 46, respectively, to facilitate removal of the tissue interfacing assembly. In some such embodiments, each of the first mold portion 12 and the first and second mold portions 14 may include wall portions 24 and 26 that are configured to form a mold cavity 16 when the mold portions are coupled to each other. As shown, the wall portions 24 and 26 may extend from the opening 18 of the mold cavity 16 to the distal end 20 of the mold cavity. Additionally, in some embodiments, the mold portions may be manually separated and / or they may be automatically separated during molding using an automatic mold opening mechanism (e.g., opening and return pins); hydraulic, pneumatic, and / or electric actuators; and / or any other suitable mold opening mechanism. In some cases, the mold may also include ejector pins to assist in removing the molded tissue interfacing assembly.

[0054] The mold comprising two mold parts is depicted in Figure 1-4 In the present invention, it should be understood that other arrangements, such as molds formed from three or more mold sections that can be coupled to each other to form a mold cavity, may be suitable. Therefore, it should be understood that the present disclosure is not limited to molds comprising any particular number of mold sections.

[0055] As described above, in some embodiments, the tissue interfacing component may be formed from a single granular material (e.g., a granular therapeutic agent) or a plurality of granular materials. Figure 5 An embodiment of a mold 10 is depicted in which two different granular materials are deposited into the mold cavity 16. In particular, a first granular material 32 (e.g., a first granular therapeutic agent) can be first deposited into the mold cavity to form a distal portion of the tissue interfacing component, and a second granular material 34 (e.g., a second granular therapeutic agent or other suitable granular material) can be subsequently deposited into the mold to form a proximal portion of the tissue interfacing component. Figure 5 Two granular materials are depicted in , but it will be understood that any suitable number of granular materials may be deposited in any suitable proportion to form a tissue interfacing component having a plurality of sequenced portions having a corresponding number of different compositions.

[0056] Now refer to Figures 6A-6B, another embodiment of a mold 500 for forming a tissue interfacing component is described in more detail. Similar to the above-described embodiments, the mold 500 includes a first mold portion 502 and a second mold portion 504 that can be coupled to each other to define a mold cavity 508, and a mold punch 506 can be inserted into the mold cavity to compress the granular therapeutic agent and form the tissue interfacing component 520. In this embodiment, each mold portion includes an alignment feature to assist in aligning the mold portions. In particular, each mold portion includes a protrusion 510 and a recess 512. When the mold portions are coupled together, the protrusion 510 on one mold portion is received in the corresponding recess 512 on the other mold portion. Although the alignment features in this embodiment are depicted as cylindrical protrusions and corresponding circular recesses, it should be understood that the present disclosure is not limited to any particular geometry or arrangement for the alignment features.

[0057] Now refer to Figure 7-9 , describes in more detail exemplary embodiments of articles for administering tissue-interfacing components such as solid needles formed from particulate therapeutic agents. However, it should be understood that the presently disclosed tissue-interfacing components can be deployed using any suitable deployment device and are not limited to being deployed with only Figure 7-9 In some embodiments, such articles may include self-righting articles that may include a tissue-interfacing component and a self-actuating component associated with the tissue-interfacing component (e.g., including a spring and / or support material). Figure 7 As shown, in some embodiments, system 100 (e.g., a self-righting article) includes a tissue engaging surface 150. Although the embodiments described herein refer to a single tissue interfacing surface, in some embodiments, there may be two or more tissue interfacing surfaces. In certain embodiments, the self-righting article may be designed and configured so that the tissue engaging surface contacts a surface (e.g., the surface of a tissue at a location inside a subject, such as the surface of a subject's stomach). In some embodiments, system 100 will self-right (e.g., will be oriented without the need or use of an external force applied to the self-righting article) so that the tissue engaging surface 150 contacts the surface. In certain embodiments, the self-righting article is configured so that an axis substantially perpendicular to the tissue engaging surface is preferentially aligned parallel to the direction of gravity. The self-righting article may be configured so that an axis substantially perpendicular to the tissue engaging surface can maintain an orientation of 20 degrees or less from the vertical under an externally applied torque. In some embodiments, the self-righting article is configured so that the longest longitudinal axis of the tissue interfacing component is oriented within 15 degrees of vertical when self-righting.

[0058] Without wishing to be bound by theory, a self-righting article may be designed to self-right due to a density (and / or mass) distribution within the self-righting article. For example, in some embodiments, system 100 (e.g., a self-righting article) includes a first portion 110 and a second portion 115, the first portion and the second portion having different densities and / or different masses. In certain embodiments, the self-righting article may have a specific shape that enables self-righting behavior. For example, Figure 7 As shown, system 100 includes a monostable shape (e.g., a mono-monostable shape, a gomboc-type shape) as indicated by the outer surface 170 of system 100. As used herein, the term "monostable" is given its ordinary meaning in the art and generally refers to a three-dimensional shape with a single stable static orientation (e.g., equilibrium point). As used herein, the term "monostable" is given its ordinary meaning in the art and generally refers to a three-dimensional shape with a single stable static orientation and a single unstable static orientation. For example, and without wishing to be bound by theory, a sphere with a mass center offset from a geometric center is generally considered to be a mono-monostable shape. As used herein, the term "gomboc" is given its ordinary meaning in the art and generally refers to a convex three-dimensional shape that, when placed on a flat surface, has a single stable equilibrium point (or orientation) and a single unstable equilibrium point (or orientation). For example, and without wishing to be bound by theory, when placed on a surface in any orientation different from the single stable orientation of the shape, a gomboc-type shape will tend to reorient to its single stable orientation.

[0059] Figure 8A cross-sectional illustration of an exemplary system 102 is shown. In some embodiments, system 102 includes a self-actuating assembly 120. Self-actuating assembly 120 can be configured to release a tissue-interfacing assembly 130 associated with self-actuating assembly 120 from system 102, for example, upon exposure to a particular fluid. For example, in some cases, self-actuating assembly 120 includes a spring 125 such that upon actuation of the self-actuating assembly, spring 125 expands to push tissue-interfacing assembly 130 out of system 102 through aperture 140 (associated with tissue-engaging surface 150). In some cases, spring 125 includes a support material 160 that maintains spring 125 under compression (e.g., at least 5% compressive strain). In some cases, when buttress material 160 and / or spring 125 are exposed to a fluid, the spring can be configured to release at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, inclusive) of the spring's stored compression energy (e.g., causing tissue-interfacing component 130 to be released and deployed from an opening in the system). In some embodiments, the spring is associated with the buttress material (e.g., at least partially encapsulated by, in direct contact with, the buttress material).

[0060] In some embodiments, the aperture (e.g., Figure 8 The hole 140) may include a fluid gate (e.g., a plug, a coating, a membrane or other appropriate barrier). In some cases, the fluid gate prevents fluid (e.g., fluid external to the system) from entering the system at the hole until a desired time. In certain embodiments, the fluid gate comprises a barrier material. Non-limiting examples of suitable barrier materials include foils of polycaprolactone, thermoplastic elastomers, cellulose, and silicone. The barrier material may include one or more hydrophobic materials. In certain embodiments, the barrier material may include one or more hydrophilic materials (e.g., sugar, PEG). Possible methods of manufacturing these coatings include spraying, dipping, wrapping, deposition or other manufacturing methods. Alternatively, the fluid gate may be a separately formed membrane or a membrane assembled with other components of the system. One of ordinary skill in the art will be able to select suitable hydrophobic and hydrophilic materials as barrier materials based on the teachings of this specification.

[0061] In certain embodiments, the tissue-interfacing component 130 includes an active agent. In some embodiments, the active agent can be present in the tissue-interfacing component in a relatively high amount (e.g., greater than or equal to 10 wt %, greater than or equal to 80 wt %, or greater than or equal to 90 wt % API relative to the total weight of the tissue-interfacing component). In some cases, the self-righting articles described herein can be administered to a subject, e.g., such that the agent is delivered to the subject. For example, in some cases, the article can be administered to a subject and the agent released from the article at a location within the subject.

[0062] In some embodiments, the system is applied to a subject (e.g., orally). In certain embodiments, the system can be administered orally, rectally, vaginally, nasally, or urethrally. In certain embodiments, after reaching a position inside the subject (e.g., gastrointestinal tract), at least a portion of the support material degrades, causing the spring to extend and / or the tissue interfacing assembly to interface (e.g., contact, penetrate) with the tissue positioned inside the subject. In certain embodiments, the position inside the subject is the colon, duodenum, ileum, jejunum, stomach, or esophagus. In certain embodiments, the active pharmaceutical ingredient can be released during and / or after penetrating the tissue positioned inside the subject.

[0063] For example, and without wishing to be limited by such a set of exemplary embodiments, the system can be orally administered to a subject, where, in some cases, it travels to the subject's stomach, sinks to the fundus of the subject's stomach, and the system self-rights such that the tissue-engaging surface of the system contacts the stomach tissue (e.g., the system is at least partially supported by the stomach tissue). Figure 9 Schematically shown, the exemplary system 100 can be administered to a subject (e.g., orally) such that the system 100 enters the subject's gastrointestinal system 198. The system 100 can travel through the gastrointestinal system 198 until it reaches the subject's stomach 199 (system 100a). In some embodiments, the system 100 can be lowered to the bottom of the stomach 199 (system 100b) so that it contacts the surface of the stomach 199. In certain embodiments, the system 100 self-rights (system 100c) such that the tissue engaging surface 150 of the system 100 contacts the surface of the stomach 199, and the system 100 self-actuates such that the tissue interfacing component 130 interfaces with tissue at a location internal to the subject (the surface of the stomach 199). Although Figure 9 The tissue interfacing assembly is shown interfacing with the surface of the stomach 199, but one of ordinary skill in the art will understand, based on the teachings of this specification, that the tissue interfacing assembly may contact one or more layers beneath the surface of the stomach (or elsewhere within the subject) including, for example, mucosal, submucosal, and / or muscle tissue layers.

[0064] In some cases, as described herein, the self-righting of system 100 can be driven by gravity (e.g., acting on the center of mass of system 100). After a desired time period, in some embodiments, system 100 disengages (e.g., the tissue interfacing component 130 dissolves and / or is released) and exits stomach 199 (system 100d). The above description is not meant to be limiting and one of ordinary skill in the art will understand that other interactions between the system and the subject's gastrointestinal system are also possible, as described herein. Additional aspects of self-righting articles that can be used to administer tissue interfacing components are described in International Patent Application Publication No. WO 2018 / 213600, entitled "Self-righting systems and related components and methods," the contents of which are incorporated herein by reference.

[0065] Although several embodiments of the present disclosure have been described and illustrated herein, those skilled in the art will readily recognize various other means and / or structures for performing the functions described herein and / or obtaining the results and / or one or more of the advantages, and each of such variations and / or modifications is considered to be within the scope of the present disclosure. More generally, those skilled in the art will readily recognize that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that actual parameters, dimensions, materials, and / or configurations will depend on the specific application or applications for which the teachings of the present invention are used. Those skilled in the art will recognize or be able to ascertain, using only routine experimentation, many equivalents to the specific embodiments of the present invention described herein. Therefore, it should be understood that the foregoing embodiments are presented by way of example only, and that, within the scope of the appended claims and their equivalents, the present disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure relates to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present disclosure.

[0066] Unless clearly indicated to the contrary, the indefinite articles "a" and "an" as used herein in the specification and claims should be understood to mean "at least one."

[0067] As used herein in the specification, the phrase "and / or" should be understood to refer to "either or both" of the elements so associated, i.e., the elements are present together in some cases and separately in other cases. In addition to the elements specifically identified with the "and / or" phrase, other elements may optionally be present, whether related or unrelated to those specifically identified elements, unless expressly indicated to the contrary. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising," a reference to "A and / or B" may refer to A without B (optionally including elements in addition to B) in one embodiment; to B without A (optionally including elements in addition to A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; and so on.

[0068] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when the items in the list are separated, "or" or "and / or" should be interpreted as inclusive, that is, including at least one element in a plurality of elements or a list of elements, but also including more than one element, and optionally additionally unlisted items. Only when the opposite terms are clearly indicated, such as "only one of ... " or "just one of ... " or when used in the claims, "consisting of ... " will refer to including just one element in a plurality of elements or a list of elements. Generally speaking, when there is an exclusive term before, such as "any one", "one of ... ", "only one of ... " or "just one of ... ", the term "or" as used herein should only be interpreted to indicate an exclusive alternative (i.e., "one or the other but not both"). When used in the claims, "consisting essentially of ... " should have the common meaning as used in the field of patent law.

[0069] As used herein in the specification and claims, the phrase "at least one" with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one element of each element specifically listed in the list of elements and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently, "at least one of A and / or B") can, in one embodiment, mean at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment, mean at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment, mean at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0070] In the claims and the foregoing description, all transitional phrases such as "comprises," "comprising," "carrying," "having," "containing," "involving," "accommodating," and the like are to be construed as open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are to be closed or semi-closed transitional phrases, respectively, as provided in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0071] Unless otherwise defined and indicated, any terms used herein relating to, for example, the shape, orientation, alignment and / or geometric relationships of or between one or more articles, structures, forces, fields, flows, directions / trajectories and / or subcomponents thereof and / or combinations thereof and / or any other tangible or intangible elements not listed above that are suitable for characterization by such terms should be understood not to require absolute conformity with the mathematical definitions of such terms, but rather should be understood to indicate conformity with the mathematical definitions of such terms to the extent possible for the subject matter, as understood by those skilled in the art most closely related to such subject matter. Examples of such terms relating to shape, orientation and / or geometric relationships include, but are not limited to, terms describing: shape - such as circular, square, Gombutz, circular / circle, rectangular / rectangular, triangular / triangle, cylindrical / cylindrical, elliptical / elliptical, (n)polygonal / (n)polygonal, etc.; angular orientation - such as perpendicular, orthogonal, parallel, vertical, horizontal, colinear, etc.; profile and / or trajectory - such as plane / planar, coplanar, hemispherical, hemispherical, line / linear, hyperbola, parabola, flat, curved, straight line, arcuate, sinusoidal, tangent / tangent, etc.; direction - such as north, south, east, west, etc.; surface and / or bulk material properties and / or spatial / temporal resolution and / or distribution - such as smooth, reflective, transparent, clear, opaque, rigid, impermeable, uniform, inert, non-wettable, insoluble, stable, unchanging, constant, homogeneous, etc.; and many other terms that will be apparent to those skilled in the relevant art. As an example, an article of manufacture described herein as "square" does not require that such article have perfectly planar or linear faces or sides that intersect at exactly 90-degree angles (indeed, such articles exist only as mathematical abstractions), but rather, the shape of such article should be interpreted as approximating a "square" as defined mathematically to the extent that is generally achievable and achievable with the enumerated manufacturing techniques, as would be understood or specifically described by one skilled in the art. As another example, two or more articles of manufacture described herein as "aligned" do not require that such articles have perfectly aligned faces or sides (indeed, such articles exist only as mathematical abstractions), but rather, the arrangement of such articles should be interpreted as approximating "alignment" as defined mathematically to the extent that is generally achievable and achievable with the enumerated manufacturing techniques, as would be understood or specifically described by one skilled in the art.

Claims

1. A method of forming a tissue-interfacing component, the method comprising: depositing a first granular therapeutic agent into a mold cavity of a mold, the mold cavity defining an elongated shape extending along a longitudinal axis from an opening of the mold cavity to a distal tip at a distal end of the mold cavity within the mold, wherein the distal tip being sized and shaped to facilitate insertion into tissue, and wherein the mold comprises a first mold portion and a second mold portion selectively coupleable to one another to form the mold cavity; compressing the first granular therapeutic agent within the mold in a direction toward the distal end; forming a tissue interfacing component from the first granular therapeutic agent due at least in part to compression of the first granular therapeutic agent within the mold; and Removing the tissue interfacing assembly from the mold cavity includes separating the first and second mold portions along a separation plane parallel to the longitudinal axis of the mold cavity.

2. The method of claim 1 , wherein compressing the first granular therapeutic agent comprises: inserting a die punch into the opening of the die cavity; and The die punch is moved along the longitudinal axis toward the distal end of the die cavity. 3 . The method of claim 1 , wherein the mold comprises at least three mold sections that are coupleable to one another to form the mold cavity. 4 . The method of claim 1 , wherein the distal tip of the mold cavity is positioned on the separation plane when the first and second mold portions are coupled to one another.

5. The method of claim 1, wherein the first and second mold sections include corresponding wall portions that define the mold cavity when the first and second mold sections are coupled to one another. 6 . The method of claim 5 , wherein each of the wall portions extends from the opening of the mold cavity to the distal tip of the mold cavity when the first and second mold portions are coupled to one another. The method of claim 5 , wherein the mold cavity is a blind cavity.

8. The method of claim 1, wherein the distal tip of the mold cavity defines a point or sharp edge at the distal end of the mold cavity.

9. The method of claim 1, wherein the longitudinal axis is aligned with a vertical direction, and wherein depositing the first granular therapeutic agent into the mold cavity comprises depositing the first granular therapeutic agent along the vertical direction.

10. The method of claim 1, further comprising depositing a second granular material into the mold cavity after depositing the first granular therapeutic agent into the mold cavity.

11. The method of claim 10, wherein compressing the first granular therapeutic agent within the mold comprises compressing the first granular therapeutic agent and the second granular material together within the mold.

12. The method of claim 10, wherein the tissue-interfacing component comprises a distal portion formed from the first granular therapeutic agent and a proximal portion formed from the second granular material.

13. The method of claim 1, wherein removing the tissue interfacing component from the mold comprises ejecting the tissue interfacing component from the mold.

14. A method of forming a tissue-interfacing component, comprising: depositing a first particulate therapeutic agent into the mold, applying a pressure greater than or equal to 20 MPa to at least a portion of the first granular therapeutic agent to compress the first granular therapeutic agent and form the tissue interfacing component, and separating the first and second portions of the mold along a plane parallel to a longitudinal axis of the mold cavity of the mold; wherein the therapeutic agent comprises greater than or equal to 80 wt % of the total tissue interfacing component weight, and The tissue interfacing component is configured to penetrate at least 1 mm into human gastrointestinal mucosal tissue with a force less than or equal to 5N.

15. The method of claim 14, wherein applying the pressure to the first particulate therapeutic agent comprises: inserting a die punch into the opening of the die cavity of the die; and The die punch is moved along the longitudinal axis of the die cavity toward a distal end of the die cavity.

16. The method of claim 14, wherein the tissue-interfacing assembly includes a distal tip sized and shaped to facilitate insertion into tissue.

17. The method of claim 14, wherein the average cross-sectional dimension of the tissue interfacing component is greater than or equal to 0.5 mm.

18. The method of claim 14, wherein the tissue interfacing component is a needle.

19. The method of claim 14, further comprising depositing a second granular material into the mold after depositing the first granular therapeutic agent into the mold.

20. The method of claim 19, wherein applying the pressure to the first granular therapeutic agent within the mold comprises applying the pressure to the first granular therapeutic agent and the second granular material together within the mold.

21. The method of claim 14, wherein the first particulate therapeutic agent is mixed with a binder, the binder comprising less than or equal to 20 wt% of the total tissue interfacing component weight.

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