Methods for manufacturing tissue interface components

Abstract

Methods for manufacturing a tissue interface component, such as a solid needle, containing one or more therapeutic agents are disclosed. In some embodiments, the method for manufacturing the tissue interface component includes compressing a particulate therapeutic agent within a mold cavity of a mold to form the solid tissue interface component. 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 particulate therapeutic agent can be compressed by moving a mold punch along the longitudinal axis toward the distal end. After compressing the particulate therapeutic agent to form the solid tissue interface component, the tissue interface component can be removed from the mold and subsequently inserted into tissue to deliver the therapeutic agent to a subject.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates generally to methods for manufacturing tissue interface components, such as needles, that contain one or more therapeutic agents. [Background technology]

[0002] The gastrointestinal (GI) tract offers tremendous opportunities for diagnosing and treating patients. The development of smart administration systems and articles that enable this has shown significant growth over the past decade. One of the most important challenges in maximizing delivery and interaction with the mucosa is ensuring juxtaposition of the article and / or administration system with the digestive mucosa. Previous attempts to do this have included the introduction of mucoadhesives and texturing one side of double-sided systems. Orally ingested drugs generally diffuse through the GI tissue wall to enter the bloodstream. Typical ingested tablets or articles release their cargo randomly into the GI tract, allowing the cargo to migrate to the tissue wall by convection and diffusion. However, many biological drugs, such as insulin, even when packaged in solid formulations, are unable to travel through the fluids in the GI tract due to, for example, enzymatic degradation.

[0003] In addition, many pharmaceutical drug formulations on the market require administration by injection, including many vaccines, RNA, and peptides. Injection traditionally involves the use of liquid formulations that are passed through a hollow needle and enter the body intravenously or intramuscularly. However, these liquid formulations can destabilize the active pharmaceutical ingredient (API), thus requiring refrigeration for necessary dilution and / or significantly increasing the dosage. Summary of the Invention

[0004] In one embodiment, a method of forming a tissue interface component includes depositing a first particulate 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, the distal tip being sized and shaped to facilitate insertion into tissue. The method further includes compressing the first particulate therapeutic agent within the mold along a direction oriented toward the distal tip, forming a tissue interface component from the first particulate therapeutic agent at least partially by compressing the first particulate therapeutic agent within the mold, and removing the tissue interface component from the mold cavity.

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

[0006] It should be understood that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, and that the disclosure is not limited in this respect. Furthermore, 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. In the event that the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. [Brief explanation of the drawings]

[0007] Non-limiting embodiments of the present invention are 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 typically represented by a single numeral. For clarity, not every component is labeled in every drawing, nor is every component of each embodiment of the present invention shown unless an illustrative drawing is necessary to enable those skilled in the art to understand the invention. In the drawings, [Figure 1] 1 is a schematic diagram of a mold for forming a tissue interface component, according to some embodiments. [Figure 2] 2 is a schematic diagram of the mold of FIG. 1 further illustrating a particulate therapeutic agent deposited within the mold. [Figure 3] 2 is a schematic diagram of the die of FIG. 1 further illustrating the die punch and particulate therapeutic agent received in the die. [Figure 4] FIG. 2 is a schematic diagram of the mold of FIG. 1 further illustrating separation of the mold portions to remove the tissue interface component. [Figure 5] 2 is a schematic diagram of the mold of FIG. 1 with two granular materials received in the mold; [Figure 6A] FIG. 1 is a perspective view of a mold for forming a tissue interface component, according to some embodiments. [Figure 6B] FIG. 6B is an exploded view of the mold of FIG. 6A. [Figure 7] 1 is a schematic illustration of an article for administering a tissue interface component, according to some embodiments. [Figure 8] 1 is a schematic cross-sectional view of an article for administering a tissue interface component, according to some embodiments. [Figure 9] 1A-1C are schematic illustrations of an embodiment of an article for administering a tissue interface component. DETAILED DESCRIPTION OF THE INVENTION

[0008] The inventors have recognized and appreciated many advantages associated with tissue interface components containing an active pharmaceutical ingredient (API) or other therapeutic agent that can be injected or otherwise physically inserted into tissue. For example, some biological therapeutic products (e.g., peptides or larger molecules) may not be adequately absorbed from the gastric cavity (e.g., after oral ingestion). To increase absorption of such products, the therapeutic agent may be physically deposited in mucosal tissue (e.g., surrounding the stomach) or other suitable tissue. Accordingly, the inventors have recognized and appreciated many advantages associated with methods for manufacturing tissue interface components containing an API that are constructed and arranged to be inserted into tissue (e.g., mucosal tissue) and subsequently release the API into the tissue 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 or for preventative purposes a disease, disorder, or other clinically recognized abnormality, and that has a clinically significant effect on the subject's body to treat and / or prevent the disease, disorder, or abnormality. Furthermore, these terms may be used interchangeably in various embodiments, and the present disclosure is not limited to a particular type of therapeutic agent.

[0009] In some embodiments, the tissue interface component may be configured as an elongated structure (e.g., an elongated cylindrical or prismatic structure), and the tissue interface component may have a pointed distal tip, which may facilitate penetration of the tissue interface component into tissue, such as mucosal tissue or other suitable tissue. Thus, in some embodiments, the tissue interface component may be described herein as a needle or similar elongated structure that may be injected into tissue, and after injection, the needle may at least partially dissolve and release one or more APIs and / or other therapeutic agents into the tissue.

[0010] According to some aspects, a method for manufacturing a tissue interface component may include compressing a particulate material within a mold. For example, a particulate therapeutic agent and / or other particulate material (e.g., a powdered API or drug or other suitable powdered or particulate 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. Accordingly, the mold cavity may be referred to herein as a blind hole or blind cavity. After loading the particulate therapeutic agent, the particulate therapeutic agent may be compressed within the mold cavity along a direction oriented substantially along the longitudinal axis toward the distal tip to form a tissue interface component. A solid or substantially solid tissue interface component may be formed within the mold cavity, at least in part, by compression of the particulate therapeutic agent. In some embodiments, such compression of the particulate therapeutic agent may be achieved using a die 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 compressively mold the particulate therapeutic agent within the die cavity to form a solid tissue interface component. In this manner, the compressive force applied by the die punch to form the tissue interface component from the particulate therapeutic agent can be directed substantially along the longitudinal axis of the tissue interface component. For example, as noted above, in some embodiments, the tissue interface component can be formed as a needle, and therefore the compressive force applied by the die punch can be applied along the longitudinal axis of the needle toward the needle tip.

[0011] In some cases, after compressing the therapeutic agent in the mold, thereby forming the tissue interface component, the tissue interface component may be removed from the mold. In some embodiments, the mold may be constructed and arranged to facilitate such removal of the tissue interface component. For example, in some embodiments, the mold may be formed from corresponding first and second mold sections that may be coupled to each other to form a mold cavity. For example, each mold section may include a wall section that defines the mold cavity when the mold sections are coupled. In some embodiments, the mold sections may be separable along a plane that is substantially parallel to the longitudinal axis of the tissue interface component. For example, the wall section of each mold section may be configured to define approximately one half of the tissue interface component when the mold sections are coupled to each other at a parting line that is appropriately aligned with the geometry of the resulting formed tissue interface component, allowing the mold sections to be separated and allowing removal of the tissue interface component.

[0012] As used herein, a granular material generally refers to a material, such as a powder material, that includes a plurality of discrete solid granules or particles that can be compressed and compacted to form a substantially solid mass. For example, a granular therapeutic agent may include a powdered drug or other powdered API that can be compacted in a mold to form a solid drug-containing component.

[0013] As noted above, in some embodiments, the tissue interface component may be formed as a needle or other elongated structure having a pointed distal tip. In some embodiments, the mold cavity may be configured to form such a feature when the particulate therapeutic agent is compressed within the mold cavity. For example, the distal end of the mold cavity opposite the opening of the mold cavity may have a shape corresponding to a desired geometry. When the particulate therapeutic agent is compressed by the mold punch, the particulate therapeutic agent may conform to the geometry of the mold cavity to form a solid tissue interface component having a desired distal tip geometry (e.g., a pointed tip or other suitable geometry) configured to facilitate insertion into tissue.

[0014] In some embodiments, multiple granular materials may be deposited into a mold cavity to form the tissue interface component. For example, a first granular material (e.g., a granular therapeutic agent) may be first deposited into the mold cavity to form the distal portion of the tissue interface component, and a second granular material (e.g., a second granular therapeutic agent or other granular material) may subsequently be deposited into the mold to form the proximal portion of the tissue interface component. The first and second granular materials may be compressed with a mold punch to compact and solidify the first and second granular materials, thereby forming the tissue interface component. However, the disclosure is not so limited, and embodiments in which the first and second granular materials are compressed in separate compression steps are also contemplated. In some embodiments, such an arrangement may allow a desired therapeutic agent to be localized in the distal portion of the tissue interface component for dissolution after injection or other insertion into tissue, and the second granular material may provide structural support to the tissue interface component to facilitate insertion into tissue.

[0015] In some embodiments, the tissue interface component can contain a relatively high loading of an active pharmaceutical ingredient (e.g., a drug or other therapeutic agent). In certain embodiments, the tissue interface component can be formed entirely of a therapeutic agent (e.g., an API), such that the therapeutic agent comprises approximately 100% of the tissue interface component's weight. In other embodiments, the particulate therapeutic agent from which the tissue interface component is formed includes a solid therapeutic agent (e.g., a solid API) and, optionally, a support material (e.g., a binder such as a polymer) such that the solid therapeutic agent is present in the component in a relatively high amount (e.g., 80% by weight or more) relative to the total weight of the tissue interface component. Such tissue interface components with a high therapeutic agent loading can be useful for delivering API doses (e.g., to a subject). Advantageously, in some embodiments, the reduced volume required to deliver a desired API dose compared to liquid formulations can allow for the creation of solid needle delivery systems for a wide variety of drugs in a variety of locations / tissues (e.g., tongue, digestive mucosal tissue, skin). The disclosed structures can also reduce and / or eliminate the application of external force to inject a drug solution through a small needle opening. In some cases, a physiologically relevant dose may be present in a single tissue interface component (eg, having a relatively high API loading).

[0016] 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 interface component. For example, in some embodiments, the tissue interface component is formed using a pressure of at least 1 MPa, at least 2 MPa, at least 3 MPa, at least 5 MPa, at least 7 MPa, at least 10 MPa, at least 12 MPa, at least 15 MPa, at least 20 MPa, at least 25 MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 75 MPa, at least 150 MPa, at least 300 MPa, at least 600 MPa, at least 900 MPa, at least 1 GPa, or at least 1.2 GPa. In some embodiments, the tissue interface component is formed using a pressure of 1.4 GPa or less, 1.2 GPa or less, 1 GPa or less, 900 MPa or less, 600 MPa or less, 300 MPa or less, 150 MPa or less, 100 MPa or less, 75 MPa or less, 50 MPa or less, 40 MPa or less, 30 MPa or less, 25 MPa or less, 20 MPa or less, 15 MPa or less, 12 MPa or less, 10 MPa or less, 7 MPa or less, 5 MPa or less, 3 MPa or less, or 2 MPa or less. Combinations of the above-mentioned ranges are also possible (e.g., a pressure of at least 1 MPa and at most 100 MPa, a pressure of at least 20 MPa and at most 100 MPa, and a pressure of at least 100 MPa and at most 1.4 GPa). In some embodiments, the applied pressure can be from about 25 MPa to about 1000 MPa. Other ranges are also possible.

[0017] In some embodiments, the tissue interface component has a particular maximum dimension (e.g., length). In certain embodiments, the length of the tissue interface component can be from about 1 mm to about 10 mm (e.g., from about 1.5 mm to about 8 mm). In some embodiments, the length is 1 mm or more, 2 mm or more, 3 mm or more, 5 mm or more, 7 mm or more, or 10 mm or more. In some embodiments, the maximum dimension of the tissue interface component is 10 mm or less, 7 mm or less, 5 mm or less, 3 mm or less, 2 mm or less, or 1.5 mm or less. Combinations of the above-mentioned ranges are also possible, although both dimensions larger and smaller than those stated above are also contemplated.

[0018] In certain embodiments, the tissue interface component has an average cross-sectional dimension perpendicular to the largest dimension (e.g., diameter) of the component of about 0.5 mm to about 2 mm (e.g., about 0.8 mm to 1.6 mm). In some embodiments, the diameter can be 0.5 mm or more, 0.6 mm or more, 0.7 mm or more, 0.8 mm or more, 0.9 mm or more, 1 mm or more, 1.1 mm or more, 1.2 mm or more, 1.3 mm or more, 1.4 mm or more, 1.6 mm or more, or 1.8 mm or more. In some embodiments, the tissue interface component has an average cross-sectional dimension of 2.0 mm or less, 1.9 mm or less, 1.7 mm or less, 1.5 mm or less, 1.4 mm or less, 1.3 mm or less, 1.2 mm or less, 1.1 mm or less, 1 mm or less, 0.9 mm or less, 0.8 mm or less, 0.7 mm or less, 0.6 mm or less, or 0.5 mm or less. Combinations of the above-mentioned ranges are also possible (e.g., 0.5 mm or more and 2.0 mm or less). Other ranges are also possible.

[0019] 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-healing article, which can be configured to orient itself relative to a surface (e.g., the surface of a target tissue). The self-healing articles described herein can include one or more tissue-engaging surfaces configured to engage with (e.g., interface with, inject into, or retain) a surface (e.g., the surface of a target tissue). For example, the self-healing article can be placed in any orientation proximate to a surface, and the self-healing article will (re)orient itself so that the tissue-engaging surface contacts (e.g., directly contacts) the surface. In some embodiments, the self-healing article can have, for example, a particular shape and / or density (or mass) distribution that enables the self-healing behavior of the article. In some such embodiments, a capsule containing the self-healing article can be administered to a subject (e.g., for delivery of the self-healing article to a location within the subject's body, such as the digestive tract). In some embodiments, the self-healing article may include a tissue-interface component and / or a pharmaceutical agent (e.g., for delivery of an active pharmaceutical agent to a location within the body of a subject). In some cases, the self-healing article may be configured to release one or more tissue-interface components when tissue contacts a tissue-engaging surface of the article. In some cases, the tissue-interface component is associated with a self-actuating component. For example, the self-healing article may include a self-actuating component configured to release the tissue-interface component from the self-healing article upon exposure to a fluid. In some cases, the tissue-interface component may include a pharmaceutical agent and / or be associated with a pharmaceutical agent (e.g., for delivery to a location within the body of a subject).

[0020] In some cases, the tissue interface component may be configured to penetrate a particular depth into human gastrointestinal mucosal tissue with a particular force. For example, the tissue interface component may be configured to penetrate 1 mm or more (e.g., 2 mm or more, 3 mm or more, 4 mm or more, or 5 mm or more) with a force of 30 N or less (e.g., 30 N or less, 20 N or less, 10 N or less, or 5 N or less). In certain embodiments, the penetration force may be between about 6 N and about 30 N. Of course, the present disclosure is not so limited, and both penetration depths and forces greater and less than those stated above are also contemplated.

[0021] In some cases, the tissue interface component can be configured to deliver a specific amount of active pharmaceutical agent per square centimeter of the subject's tissue. For example, in some embodiments, the tissue interface component is configured to deliver 0.01 μg or more, 0.05 μg or more, 0.1 μg or more, 0.2 μg or more, 0.5 μg or more, 0.7 μg or more, 1 μg or more, 2 μg or more, 5 μg or more, or 10 μg or more of pharmaceutical agent per square centimeter of the subject's tissue proximate the location of penetration of the tissue interface component. In certain embodiments, the tissue interface component is configured to deliver 20 μg or less, 5 μg or less, 2 μg or less, 1 μg or less, 0.7 μg or less, 0.5 μg or less, 0.2 μg or less, 0.1 μg or less, or 0.05 μg or less of pharmaceutical agent per square centimeter of tissue. Combinations of the above-mentioned ranges are also possible (e.g., 1 μg or more and 20 μg or less). In some embodiments, the tissue interface component is configured to deliver 1 μg or more of agent per square centimeter of tissue of the target over any suitable period of time (e.g., 0.1 seconds or more, 0.5 seconds or more, 1 second or more, 5 seconds or more, 30 seconds or more, 1 minute or more, 5 minutes or more, 10 minutes or more, 30 minutes or more, 1 hour or more, 4 hours or more, 24 hours or more, 48 hours or more, 72 hours or more, 96 hours or more, 120 hours or more, 144 hours or more, 168 hours or more). Of course, the present disclosure is not limited to any particular dose and / or period of time, and delivery of both higher and lower doses than those recited above for periods of time other than those recited above are also contemplated.

[0022] In some embodiments, the tissue interface component comprises a binder. Non-limiting examples of suitable binders include sugars such as sorbitol and sucrose, gelatin, polymers such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), polycaprolactone (PCL), and polyvinylpyrrolidone (PVP), and polymers containing ethanol or other Class 3 organic solvents (e.g., acetic acid, heptane, acetone, formic acid, isobutyl acetate, etc.).

[0023] In exemplary embodiments, the tissue interface component comprises 80% or more by weight of a solid active pharmaceutical agent based on the total weight of the article. In certain embodiments, the tissue interface component comprises 1 mg or more of the active pharmaceutical agent. According to some embodiments, the pharmaceutical 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 pharmaceutical agent is cast into a mold to form the tissue interface component. In some embodiments, the mold is centrifuged. According to certain embodiments, the tissue interface component further comprises a binder. In certain embodiments, the binder comprises a sugar, such as sorbitol or sucrose, gelatin, a polymer, such as PVA, PEG, PCL, PVA, or PVP, and / or ethanol. According to certain embodiments, the tissue interface component has a Young's modulus of elasticity of 100 MPa or greater. In some embodiments, the tissue interface component is configured to penetrate at least 1 mm into human gastrointestinal mucosal tissue with a force of 20 mN or less. According to certain embodiments, the tissue interface component is configured to deliver at least 1 mg of pharmaceutical agent per square centimeter of the subject's tissue and / or the tissue interface component comprises 1 mg or more of active pharmaceutical agent per square centimeter.

[0024] In one specific, non-limiting embodiment, a method of forming a tissue interface component includes introducing into a mold a composition comprising greater than 80% by weight of a solid pharmaceutical agent based on the total weight of the composition; applying a pressure of 1 MPa or more to the composition; and heating the composition to a temperature of at least 70°C for at least 1 minute.

[0025] 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 a drug, biological agent, nutraceutical agent, prophylactic agent, diagnostic agent, contrast agent (i.e., for imaging), or any other suitable agent that can be injected into a subject's body. While much of the specification describes the use of active pharmaceutical ingredients, it should be understood that the disclosure is not so limited and that any desired therapeutic agent for any suitable application can be used.

[0026] Therapeutic agents can 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 physiological effect by local and / or systemic action. For example, useful or potentially useful within the context of certain embodiments are compounds or chemicals traditionally considered drugs, vaccines, and biopharmaceuticals; certain such agents are used for the medical or veterinary treatment, prevention, diagnosis, and / or mitigation of disease or illness (e.g., HMG-1 receptor agonists such as rosuvastatin). Co-A reductase inhibitors (statins), nonsteroidal anti-inflammatory drugs such as meloxicam, selective serotonin reuptake inhibitors such as escitalopram, 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 corticosteroids, antihistamines such as loratadine and cetirizine, opioids such as loperamide, proton pump inhibitors such as omeprazole, entecavir, dolutegravir, rilpivirine and cabotegravir; antibiotics such as doxycycline, ciprofloxacin, azithromycin, antimalarials, and synthroid / levothyroxine); substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal contraceptives); performance enhancement (e.g., stimulants like 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).

[0027] 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 abnormality, or for prophylactic purposes, and that has a clinically significant effect on the subject's body to treat and / or prevent the disease, disorder, or abnormality. 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 edition (September 21, 2000), Physician's Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th ed. (1999) or its subsequent publication, the 18th ed. (2006), Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, The Merck Veterinary Manual, 9th ed., Kahn, CA (ed.), Merck Publishing Group, 2005, and in "Approved Drug Products with Therapeutic Equivalence" (Approved Drug Products with Therapeutic Equivalence). and Evaluations,” published by the United States Food and Drug Administration (FDA) (the “Orange Book”).Examples of pharmaceuticals approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference, and drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500-589, which are incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Exemplary classes of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory agents, antipyretics, antidepressants, antiepileptics, antipsychotics, neuroprotective agents, anti-cancer agents, antihistamines, anti-proliferative agents such as antimigraine agents, hormones, prostaglandins, antimicrobial agents (including antibiotics, antifungals, antivirals, and antiparasitics), antimuscarinics, anti-inflammatory agents, bacteriostatic agents, immunosuppressants, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatics, cardiovascular agents, anesthetic enzymes, anticoagulants, enzyme inhibitors, steroids, steroidal or nonsteroidal anti-inflammatory agents, corticosteroids, dopaminergic agents, electrolytes, gastrointestinal agents, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, appetite suppressants, and antihypnotics. Nutritional supplements can also be incorporated into the drug delivery device. These can be supplements such as vitamins, calcium or biotin, or natural ingredients such as plant extracts or plant hormones.

[0028] In some embodiments, the therapeutic agent is one or more antimalarials.Exemplary antimalarials include quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfonamides such as sulfadoxine and sulfamethoxypyridazine, mefloquine, atovaquone, primaquine, halofenthrine, doxycycline, clindamycin, artemisinin, and artemisinin derivatives.In some embodiments, the antimalarial agent is artemisinin or an artemisinin derivative.Exemplary artemisinin derivatives include artemether, dihydroartemisinin, arteether, and artesunate.In certain embodiments, the artemisinin derivative is artesunate.

[0029] In another embodiment, the therapeutic agent is an immunosuppressant. Exemplary immunosuppressants include glucocorticoids, cytostatic agents (such as alkylating agents, metabolites, and cytotoxic antibodies), antibodies (such as those directed against T cell receptors or 11-2 receptors), drugs acting on immunophilins (such as cyclosporine, tacrolimus, and sirolimus), and other drugs (such as interferons, opioids, TNF-binding proteins, mycophenolic acid, and other small molecules such as fingolimod).

[0030] In certain embodiments, the therapeutic agent is a hormone or a hormone derivative, 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, progestin, testosterone, estradiol, cortisol, adrenaline, and other steroids.

[0031] 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 of 200 to 400 daltons, 400 to 1000 daltons, or 500 to 2500 daltons.

[0032] In some embodiments, the therapeutic agent is insulin, a nucleic acid, a peptide, a bacteriophage, DNA, mRNA, human growth hormone, a monoclonal antibody, adalimumab, epinephrine, a GLP-1 receptor agonist, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, a small molecule drug, proglucin, a vaccine, a subunit vaccine, a recombinant vaccine, a polysaccharide vaccine, and a conjugate vaccine, a toxoid vaccine, an influenza vaccine, a single vaccine, a pre-pneumonia vaccine, an mmr vaccine, a tetanus vaccine, a hepatitis vaccine, an HIV vaccine. and an active pharmaceutical agent such as Ad4-env Clade C, HIV vaccine Ad4-mGag, DNA vaccine, RNA vaccine, etanercept, infliximab, filgastrim, glatiramer acetate, rituximab, bevacizumab, any molecule encapsulated in a nanoparticle, epinephrine, lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, certolizumab pegol, ustekinumab, ikekizumab, golimumab, brodalumab, gucelu, ab, cesikinumab, omalizumab, TNF-alpha inhibitors, interleukin inhibitors, vedolizumab, octreotide, teriperatide, crispr cas9, insulin glargine, insulin detemir, insulin lispro, insulin aspart, human insulin, antisense oligonucleotides, and ondansetron.

[0033] In an exemplary embodiment, the therapeutic agent is insulin.

[0034] In certain embodiments, the therapeutic agent is present in the tissue interface component at a concentration such that, upon release from the tissue interface component, the therapeutic agent elicits a therapeutic response.

[0035] In some cases, the therapeutic agent may be present at a concentration lower than the minimum concentration typically associated with an active therapeutic agent (e.g., in a microdose concentration). For example, in some embodiments, the tissue interface 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(s) at a location within the subject's body (e.g., a response to contact by the tissue interface component). In some embodiments, the concentration of the therapeutic agent is a microdose of 100 μg and / or 30 nMol or less. 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.

[0036] In some embodiments, the tissue interface component is administered to a subject (e.g., orally). In certain embodiments, the article may be administered orally, rectally, vaginally, nasally, or urethrally. In certain embodiments, the tissue interface component (e.g., and / or an API contained therein) is administered by contacting the subject's skin with the component. In an exemplary embodiment, the tissue interface component (e.g., and / or an API contained therein) is administered by contacting the subject's buccal tissue (e.g., lips, palate region, cheek, sublingual, tongue) with the component. In yet another exemplary embodiment, the tissue interface component is administered orally, and upon reaching a location within the subject's body (e.g., the digestive tract, such as the colon, duodenum, ileum, jejunum, stomach, buccal cavity, esophagus, etc.), the tissue interface component interfaces with (e.g., contacts) and at least partially penetrates the subject's tissue at the location within the subject's body. In certain embodiments, at least a portion of the tissue interface component penetrates the subject's tissue, and at least a portion of the support material and / or active pharmaceutical agent dissolves in the subject's tissue.

[0037] Advantageously, administration of a tissue interface component with a relatively high loading of API to the gastrointestinal tract may allow for more effective delivery of the API compared to traditional methods. For example, without wishing to be bound by theory, delivering drugs to the gastrointestinal tract via injection has been shown to have higher bioavailability compared to other methods.

[0038] 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, cows, horses, pigs, sheep, goats, dogs, cats, or rodents, such as mice, rats, hamsters, birds, fish, or guinea pigs. Generally, the present invention is intended for use in humans. In some embodiments, the subject may demonstrate a health benefit, for example, upon administration of the self-healing article.

[0039] Turning now to the figures, certain non-limiting embodiments will be described in further detail. It should be understood that the present disclosure is not limited to only the specific embodiments described herein, and that the various systems, components, features, and methods described in connection with these embodiments can be used individually and / or in any desired combination.

[0040] FIG. 1 is a schematic side view of a mold 10 that can be used to form a tissue interface component, according to some embodiments. The mold includes a first mold portion 12 and a second mold portion 14, which are matable to one another to define a mold cavity 16 disposed between the two mold portions. The mold cavity extends along a longitudinal axis 22 from a mold cavity opening 18 to a mold cavity distal end 20. The mold cavity distal end can have a distal tip geometry configured to shape the distal tip of a resulting tissue interface component shaped and sized to facilitate insertion into tissue. For example, as illustrated in the figure, the mold cavity distal end 20 can be disposed within the mold 10, and the distal end can define the mold cavity distal tip, which can be configured as a pointed tip or other suitable geometry described herein.

[0041] 1-4, as illustrated in FIG. 2, a granular material 30 (e.g., a granular therapeutic agent) may be deposited into the mold cavity 16. For example, the longitudinal axis 22 may be aligned with the vertical direction, and the granular material 30 may be deposited into the mold along this direction (e.g., via gravity feed or by otherwise pouring or dispensing the granular material along the vertical direction into the mold cavity 16). Once positioned within the cavity, the granular material may then be compressed within the mold cavity, such as with a mold punch 40, as illustrated in FIG. 4. For example, the mold punch 40 may have a portion configured to be received in the opening 18 of the mold cavity 16, and the mold punch may be moved along a direction 42, which may correspond to movement of the mold punch 40 along the longitudinal axis 22 toward the distal end 20 of the mold cavity 16. In this manner, the die punch can apply a compressive force to the granular material 30 to compress and compressively mold the granular material, thereby forming a solid tissue interface component 50 having a shape corresponding to the distal portion of the die cavity 16.

[0042] Subsequently, the tissue interface component 50 may be removed from the mold cavity 16. For example, as illustrated in FIG. 4 , in some embodiments, the first and second mold sections 12 and 14 may be separable and may be moved away from one another along directions 44 and 46, respectively, to facilitate removal of the tissue interface component. In some such embodiments, the first and second mold sections 12 and 14 may each include wall sections 24 and 26 configured to form the mold cavity 16 when the mold sections are coupled together. As illustrated, the wall sections 24 and 26 may extend from the opening 18 of the mold cavity 16 to the distal end 20 of the mold cavity. Furthermore, in some embodiments, the mold sections may be separated manually and / or the mold sections may be separated automatically during the molding process using an automatic mold opening mechanism, such as an open and return pin, a hydraulic, pneumatic, and / or electric actuator, and / or any other suitable mold opening mechanism. The mold may also, in some cases, include an ejector pin to assist in removal of the molded tissue interface component.

[0043] Although a mold including two mold sections is depicted in Figures 1-4, it should be understood that other arrangements may be suitable, such as a mold formed from three or more mold sections that can be mated together to form a mold cavity. Accordingly, it should be understood that the present disclosure is not limited to molds including any particular number of mold sections.

[0044] As discussed above, in some embodiments, the tissue interface component may be formed from a single particulate material (e.g., a particulate therapeutic agent) or multiple particulate materials. For example, FIG. 5 depicts an embodiment of a mold 10 in which two different particulate materials are deposited into the mold cavity 16. In particular, a first particulate material 32 (e.g., a first particulate therapeutic agent) may be deposited into the mold cavity first to form a distal portion of the tissue interface component, and a second particulate material 34 (e.g., a second particulate therapeutic agent or other suitable particulate material) may be subsequently deposited into the mold to form a proximal portion of the tissue interface component. While two particulate materials are depicted in FIG. 5, it should be understood that any suitable number of particulate materials may be deposited in any suitable ratio to form a tissue interface component having a corresponding number of multiple, sequentially arranged portions having different compositions.

[0045] 6A-6B, another embodiment of a mold 500 for forming a tissue interface component will be described in more detail. Similar to the previously described embodiment, the mold 500 includes first and second mold sections 502 and 504 that are matable with each other to define a mold cavity 508, and a mold punch 506 is insertable into the mold cavity to compress a particulate therapeutic agent and form a tissue interface component 520. In this embodiment, each of the mold sections includes alignment features to assist in aligning the mold sections. In particular, each mold section includes a protrusion 510 and a recess 512. When the mold sections are mated together, the protrusion 510 on one mold section is received in the corresponding recess 512 on the other mold section. While 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 geometric shape or arrangement of alignment features.

[0046] 7-9, exemplary embodiments of articles for administering a tissue-interfacing component, such as a solid needle formed from a particulate therapeutic agent, will be described in more detail. However, it should be understood that the tissue-interfacing components of the present disclosure can be deployed using any suitable deployment device and are not limited to use with only the devices disclosed in the embodiments of FIGS. 7-9. In some embodiments, such articles may include a tissue-interfacing component and a self-actuating component (e.g., including a spring and / or support material) associated with the tissue-interfacing component. As illustrated in FIG. 7, in some embodiments, system 100 (e.g., a self-healing article) includes tissue-engaging surface 150. While the embodiments described herein refer to a single tissue-interfacing surface, in some embodiments, two or more tissue-interfacing surfaces may be present. In certain embodiments, the self-healing article may be designed and configured so that the tissue-engaging surface contacts a surface (e.g., a surface of tissue at a location within the subject's body, such as the surface of the subject's stomach). In some embodiments, system 100 self-heals (e.g., orients without the need for or use of an external force applied to the self-healing article) so that tissue-engaging surface 150 contacts the surface. In certain embodiments, the self-healing article is configured such that an axis essentially perpendicular to the tissue-engaging surface is preferentially aligned parallel to the direction of gravity. The self-healing article may be configured such that the axis essentially perpendicular to the tissue-engaging surface can maintain an orientation of no more than 20 degrees from perpendicular under an externally applied torque. In some embodiments, the self-healing article is configured such that the tissue-interfacing component has its longest longitudinal axis oriented within 15 degrees from perpendicular upon self-healing.

[0047] While not wishing to be bound by theory, a self-healing article may be designed to self-heal as a result of the distribution of density (and / or mass) within the self-healing article. For example, in some embodiments, system 100 (e.g., a self-healing article) includes first portion 110 and second portion 115, where the first and second portions have different densities and / or different masses. In certain embodiments, a self-healing article may have a particular shape that enables self-healing behavior. For example, as illustrated in FIG. 7 , system 100 includes a monostatic shape (e.g., a mono-monostatic shape, a rubber-box shape) as shown by outer surface 170 of system 100. As used herein, the term “monostatic” is given its ordinary meaning in the art and generally refers to a three-dimensional shape that has a single stable rest position (e.g., an equilibrium point). As used herein, the term “mono-monostatic” is given its ordinary meaning in the art and generally refers to a three-dimensional shape that has a single stable rest position and a single unstable rest position. By way of example, and without wishing to be bound by theory, a sphere with a center of gravity shifted from the geometric center is generally considered a mono-monostatic shape. As used herein, the term "rubber bock" 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 a rubber bock-type shape is placed on a surface in any orientation other than the shape's single stable orientation, the shape will tend to reorient to the rubber bock-type shape's single stable orientation.

[0048] 8 shows a cross-sectional illustration of an exemplary system 102. In some embodiments, the system 102 includes a self-actuating component 120. The self-actuating component 120 can be configured to release the tissue-interfacing component 130 associated with the self-actuating component 120 from the system 102, for example, upon exposure to a particular fluid. For example, in some cases, the self-actuating component 120 includes a spring 125 such that, upon actuation of the self-actuating component, the spring 125 expands and pushes the tissue-interfacing component 130 out of the system 102 through the hole 140 (associated with the tissue-engaging surface 150). In some cases, the spring 125 includes a support material 160 that maintains the spring 125 under compression (e.g., under a compressive strain of at least 5%). In some cases, upon exposure of the support material 160 and / or spring 125 to fluid, the spring may 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%, including any percentage therein) of the spring's stored compression energy (e.g., such that the tissue interface component 130 is released and deployed from an opening in the system). In some embodiments, the spring is associated with the support material (e.g., in direct contact with and at least partially encapsulated by the support material).

[0049] In some embodiments, a hole (e.g., hole 140 in FIG. 8 ) can include a fluid gate (e.g., a plug, coating, membrane, or other suitable barrier). In some cases, the fluid gate can prevent fluid (e.g., fluid outside the system) from entering the system at the hole until a desired time. In certain embodiments, the fluid gate includes a barrier material. Non-limiting examples of suitable barrier materials include polycaprolactone foil, thermoplastic elastomer, cellulose, and silicone. The barrier material can include one or more hydrophobic materials. In certain embodiments, the barrier material can include one or more hydrophilic materials (e.g., sugar, PEG). Possible processing methods for these coatings include spray coating, dip coating, wrapping, deposition, or other manufacturing methods. Alternatively, the fluid gate can be a separately formed membrane or film that is assembled with other components of the system. Those skilled in the art will be able to select suitable hydrophobic and hydrophilic materials as barrier materials based on the teachings herein.

[0050] In certain embodiments, the tissue interface component 130 includes an active pharmaceutical agent. In some embodiments, the active pharmaceutical agent can be present in the tissue interface component in a relatively high amount (e.g., 10% or more, 80% or more, or 90% or more by weight of API, based on the total weight of the tissue interface component). The self-healing articles described herein can, in some cases, be administered to a subject, for example, such that a pharmaceutical agent is delivered to the subject. For example, in some cases, the article can be administered to a subject and the pharmaceutical agent is released from the article at a location within the subject's body.

[0051] In some embodiments, the system is administered to a subject (e.g., orally). In certain embodiments, the system may be administered orally, rectally, vaginally, nasally, or urethrally. In certain embodiments, upon reaching a location within the subject's body (e.g., the gastrointestinal tract), the spring elongates and / or at least a portion of the support material degrades such that the tissue interface component interfaces (e.g., contacts, penetrates) with tissue located within the subject's body. In some embodiments, the location within the subject's body is the colon, duodenum, ileum, jejunum, stomach, or esophagus. In some embodiments, the active pharmaceutical ingredient may be released during and / or after penetration of tissue located within the subject's body.

[0052] By way of example, and not wishing to be limited by such an exemplary set of embodiments, the system may be orally administered to a subject, where in some cases the system travels to the subject's stomach, sinks to the lower part of the subject's stomach, and self-heals such that the tissue-engaging surface of the system contacts stomach tissue (e.g., the system is at least partially supported by stomach tissue). For example, as schematically illustrated in FIG. 9 , exemplary system 100 may be administered to a subject (e.g., orally) such that system 100 enters the subject's digestive system 198. System 100 may travel through digestive system 198 until it reaches the subject's stomach 199 (system 100a). In some embodiments, system 100 may sink to the lower part of stomach 199 (system 100b) such that system 100 contacts the surface of stomach 199. In certain embodiments, system 100 self-heals such that tissue engaging surface 150 of system 100 contacts the surface of stomach 199 (system 100c), and system 100 self-actuates such that tissue interface component 130 interfaces with tissue at a location within the subject's body (e.g., stomach surface 199). While Figure 9 illustrates the interface between the tissue interface component and the surface of stomach 199, one skilled in the art will understand, based on the teachings herein, that the tissue interface component may contact one or more layers beneath the surface of the stomach (or elsewhere within the subject's body), including, for example, the mucosal layer, the submucosal layer, and / or the muscle tissue layer(s).

[0053] In some cases, as described herein, the self-healing of system 100 may be driven by gravity (e.g., acting on the center of gravity of system 100). After a desired period of time, in some embodiments, system 100 disengages (e.g., tissue interface component 130 dissolves and / or releases) 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 digestive system are possible, as described herein. Additional varieties of self-healing articles that can be used to administer the tissue interface component 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.

[0054] While several embodiments of the present disclosure have been described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or obtaining the results, and / or one or more of the advantages described herein, and each such variation and / or modification is deemed to be within the scope of the present disclosure. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the particular 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 no more than routine experimentation, many equivalents to the specific embodiments of the present invention described herein. Accordingly, the foregoing embodiments are presented by way of example only, and it should be understood that, within the scope of the appended claims and equivalents thereto, the present disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure is directed to each individual feature, system, article, material, kit, and / or method described herein. Additionally, any combination of two or more such features, systems, articles, materials, kits, and / or methods is within the scope of the present disclosure, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0055] As used herein, and in the claims, the indefinite articles "a" and "an" should be understood to mean "at least one," unless expressly stated to the contrary.

[0056] As used herein and in the claims, the phrase "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements, whether related or unrelated to those elements specifically identified, may optionally be present, unless expressly stated to the contrary. Thus, as a non-limiting example, a reference to "A and / or B," when used in combination with open-ended language such as "comprising," can, in one embodiment, refer to A without B (optionally including elements other than B); in another embodiment, refer to B without A (optionally including elements other than A); in yet another embodiment, refer to both A and B (optionally including other elements); and so forth.

[0057] As used herein and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as being inclusive, i.e., including at least one, but also including more than one, of a number of elements or list of elements, and, optionally, additional unlisted items. Only terms expressly stated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," refer to the inclusion of exactly one element of a number of elements or list of elements. In general, the term "or" as used herein should only be interpreted to indicate exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in the claims, should have its ordinary meaning as used in the field of patent law.

[0058] As used herein and in the claims, the phrase "at least one" in connection with a list of one or more elements should be understood to mean at least one selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. 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 refer in one embodiment to at least one, optionally more than one, A (and optionally including elements other than B), with no B; in another embodiment to at least one, optionally more than one, B (and optionally including elements other than A); in yet another embodiment to at least one, optionally more than one, A, and at least one, optionally more than one, B (and optionally including other elements); etc.

[0059] In the claims, as well as in the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "including," "involving," "holding," and the like, are to be understood to be open-ended, i.e., meaning including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedure.

[0060] For example, terms used herein relating to the shape, orientation, alignment, and / or geometric relationships of or between one or more articles, structures, forces, fields, flows, directions / trajectories, and / or subcomponents and / or combinations thereof, and / or other tangible or intangible elements not listed above that are suitable for characterization by such terms, unless otherwise defined or indicated, shall be understood not to require absolute adherence to the mathematical definitions of such terms, but rather to exhibit adherence to the mathematical definitions of such terms to the extent possible for the subject matter being characterized as would be understood by one of ordinary skill in the art most closely related to such subject matter. Examples of such terms relating to shape, orientation, and / or geometric relationships include shapes such as round, square, rubberbock, circular / circular, rectangular / rectangle, triangular / triangle, cylindrical / cylinder, elliptical / ellipse, (n)polygon / (n)polygon; angular orientations such as perpendicular, orthogonal, parallel, perpendicular, horizontal, collinear; plane / planar, coplanar, hemispherical, hemispherical; line / linear, hyperbolic, parabolic, flat, curved, linear, arcuate, sinusoidal, tangent. These terms include, but are not limited to, terms describing contours and / or trajectories such as square / tangent, directions such as north, south, east, west, etc., surface and / or bulk material properties and / or spatial / temporal resolution and / or distributions such as smooth, reflective, transparent, clear, opaque, rigid, impermeable, uniform (uniformly), inert, non-wettable, insoluble, steady, unchanging, constant, homogeneous, etc., as well as many others that will be apparent to one of ordinary skill in the relevant art. As an example, a fabricated article described herein as "square" need not be perfectly planar or linear and have faces or edges that intersect at exactly 90-degree angles (indeed, such an article may exist only as a mathematical abstraction), but rather the shape of such an article should be interpreted as approximating a mathematically defined "square" to the extent that it is typically achievable and achieved for the cited fabrication technique, as would be understood by one of ordinary skill in the art or as specifically described.As another example, two or more fabricated articles described herein as being "aligned" need not necessarily have perfectly aligned faces or edges (indeed, such articles may exist only as a mathematical abstraction), but the arrangement of such articles should be construed as approximating the mathematically defined "alignment" to the degree that is typically achievable and achieved for the cited fabrication technique, as would be understood by one of ordinary skill in the art or as specifically described.

Claims

1. 1. A method of forming a tissue interface component, comprising: depositing a first particulate therapeutic agent into a mold cavity of a mold, wherein 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, the distal tip being sized and shaped to facilitate insertion into tissue; compressing the first particulate therapeutic agent within the mold along a direction oriented toward the distal end; forming a tissue interface component from the first particulate therapeutic agent at least in part by compressing the first particulate therapeutic agent within the mold; and removing the tissue interface component from the mold cavity.

2. compressing the first particulate therapeutic agent; inserting a die punch into the opening of the die cavity; and moving the die punch along the longitudinal axis toward the distal end of the die cavity.

3. The method of claim 1 , wherein the mold comprises a first mold portion and a second mold portion selectively matable with one another to form the mold cavity.

4. The method of claim 1 , wherein the mold comprises at least three mold sections matable together to form the mold cavity.

5. The method of claim 3 , wherein removing the tissue interface component from the mold cavity comprises separating the first and second mold portions.

6. 6. The method of claim 5, wherein separating the first and second mold parts comprises separating the first and second mold parts along a separation plane parallel to the longitudinal axis of the mold cavity.

7. The method of claim 6 , wherein when the first and second mold parts are joined together, the distal tip of the mold cavity is positioned on the parting surface.

8. The method of claim 3 , wherein the first and second mold parts include corresponding wall portions that define the mold cavity when the first and second mold parts are joined together.

9. The method of claim 8 , wherein when the first and second mold sections are joined together, each of the wall sections extends from the opening of the mold cavity to the distal tip of the mold cavity.

10. The method of claim 8 , wherein the mold cavity is a blind cavity.

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

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

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

14. 14. The method of claim 13, wherein compressing the first granular therapeutic agent in the mold comprises compressing the first granular therapeutic agent and the second granular material together in the mold.

15. The method of claim 13 , wherein the tissue interface component includes a distal portion formed from the first particulate therapeutic agent and a proximal portion formed from the second particulate material.

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

17. 1. A method of forming a tissue interface component, comprising: depositing a first particulate therapeutic agent into a mold cavity of a mold, wherein 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, the distal tip being sized and shaped to facilitate insertion into tissue; applying a pressure of 20 MPa or greater to at least a portion of the first particulate therapeutic agent along a translated direction toward the distal end to compress the first particulate therapeutic agent and form the tissue interface component; the first particulate therapeutic agent comprises 80% or more by weight of the total weight of the tissue interface component; The method, wherein the tissue interface component is configured to penetrate human gastrointestinal mucosal tissue at least 1 mm with a force of 5 N or less.

18. applying said pressure to said first particulate therapeutic agent; inserting a die punch into an opening of a die cavity of the die; and moving the die punch along a longitudinal axis of the die cavity toward a distal end of the die cavity.

19. The method of claim 17 , wherein the tissue interface component includes a distal tip sized and shaped to facilitate insertion into tissue.

20. The method of claim 17 , wherein the tissue interface component has an average cross-sectional dimension of 0.5 mm or greater.

21. The method of claim 17 , wherein the tissue interface component is a needle.

22. 18. The method of claim 17, further comprising depositing a second particulate material into the mold after depositing the first particulate therapeutic agent into the mold.

23. 23. The method of claim 22, wherein applying the pressure to the first granular therapeutic material in the mold comprises applying the pressure to the first granular therapeutic material and the second granular material together in the mold.

24. 18. The method of claim 17, further comprising separating the first and second portions of the mold along a plane parallel to a longitudinal axis of a mold cavity of the mold.

25. 20. The method of claim 17, wherein the first particulate therapeutic agent is mixed with a binder comprising no more than 20% by weight of the total weight of the tissue interface component.

26. The method of claim 1, wherein the first particulate therapeutic agent is deposited in a mold cavity to form a distal portion of a tissue interface component.

27. The method of claim 17, wherein the first granular therapeutic agent is deposited in a mold cavity to form a distal portion of a tissue interface component.

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