Tissue anchoring articles

Related Applications This application is filed on May 17, 2017, entitled "SELF-RIGHTING ARTICLES", US Provisional Application No. 62 / 507,647, and filed on May 17, 2017, "SELF-ACTUATING ARTICLES". US Patent Law Article 119 to US Provisional Application No. 62 / 507,653 entitled US Provisional Application No. 62 / 507,665 and US Provisional Application No. 62 / 507,665 entitled "COMPONENTS WITH HIGH API LOADING" filed May 17, 2017 ( e) Claiming priority under paragraph, each of these applications is incorporated herein by reference in its entirety.

The present invention relates to self-restoring systems and related components such as self-restoring articles, self-acting articles (including, for example, self-actuating needles and / or self-acting biopsy punches), and relatively high pharmaceutical active ingredients (APIs). ) Concerning components with load.

Background GI tubes provide an incredible opportunity to diagnose and treat patients. The development of smart dosing systems and articles to make this possible has made significant progress over the last decade. One of the most important challenges in maximizing delivery and mucosal interaction is ensuring the juxtaposition of the article and / or administration system with the GI mucosa. Previous attempts to do this included the introduction of mucosal adhesives, as well as the texture of one side of the two-sided system. Orally ingested drugs generally diffuse through the GI duct tissue wall into the bloodstream. Typical ingested pills or articles randomly release their cargo into the GI tube, moving the cargo to the tissue wall by convection and diffusion. However, many biopharmaceuticals, such as insulin, can move through the liquid in the GI tube, for example, because they will be degraded by enzymes, even if they are contained in solid-state formulations. Can not.

In addition, many pharmaceutical formulations on the market, including a large number of vaccines, RNAs and peptides, require administration by injection. Injections traditionally involve the use of liquid formulations that pass through a hollow needle and enter a vein or muscle in the body. However, these liquid formulations destabilize the active ingredient of the drug (API) and may therefore require freezing and / or may significantly increase dose bulk due to the need for dilution. be.

Therefore, improved systems, articles and methods are needed.

<p>Abstract The present invention generally relates to self-restoring articles such as self-restoring capsules.</p><p>In one aspect, a self-restoring article is provided. In some embodiments, the self-restoring article comprises a first portion, a second portion adjacent to the first portion, and a hollow portion having a different average density than the first portion, and self-restoring. Articles are configured or arranged to be encapsulated in 000 capsules or smaller.</p><p>In some embodiments, the self-restoring article is configured for potential encapsulation in 000 capsules or smaller, but the self-restoring article does not necessarily have to be encapsulated in such capsules. In embodiments where the self-restoring article will be administered, eg, by ingesting the self-restoring article, the self-restoring article may be administered as such without being encapsulated. be.</p><p>In some embodiments, the self-restoring article is associated with a first part; a second part adjacent to the first part, which has a different average density than the first part; and a self-restoring article. Organization<u style="Single">connection</u>It comprises components; the ratio of the average density of the first material to the average density of the second material is greater than or equal to 2.5: 1. In some embodiments, the ratio of the average density of the second material to the average density of the first material is greater than or equal to 2.5: 1.</p><p>In some embodiments, the self-restoring article is configured to be moored to a location within the subject's body, 1 g / cm.³At least the first portion with a higher average density, the longitudinal axis perpendicular to the tissue engaging surface of the article is 0.09 × 10.^-4The first part, which is configured to maintain an orientation of 20 degrees or less from the vertical when an externally applied torque of Nm or less is applied, and at least one mooring mechanism attached to the self-restoring article. Equipped with.</p><p>In some embodiments, the self-restoring article is configured to be administered to a location within the subject's body; 1 g / cm.³At least one first part with a higher average density, where the self-healing article has a self-healing time from 90 degrees in water, less than or equal to 0.05 seconds; tissue. It comprises a tissue contact portion configured to be in contact with, and each tissue contact portion is configured to electrically communicate with the tissue, and the conductive portion is configured to not electrically communicate with the tissue. At least two tissues with an insulating part that is constructed<u style="Single">connection</u>Components; as well as at least two organizations<u style="Single">connection</u>It comprises a power source that communicates electrically with the components.</p><p>In another aspect, a self-acting article is provided. In some embodiments, the article is an outer shell, a spring that is at least partially encapsulated within the outer shell, a support attached to the spring, with at least a portion of the spring under ambient conditions, at least 5. Support material for maintaining under compressive strain of%, and the structure attached to the spring<u style="Single">connection</u>It has components.</p><p>In some embodiments, the article is configured to be moored to a location within the subject's body; an external shell; a spring that is at least partially enclosed in an external shell and at least 5 by a support. It comprises a spring that remains at least partially compressed under% compressive strain; and at least one mooring mechanism that is operably coupled to the spring.</p><p>In some embodiments, the article is configured to be administered to a location within the subject's body; an external shell; a spring that is at least partially encapsulated within the external shell and at least 5 by a support. A spring that remains at least partially compressed under% compressive strain; at least two tissues with a tissue contact portion that is configured to contact the tissue.<u style="Single">connection</u>A component, each tissue contact portion comprising a conductive portion configured to electrically communicate with the tissue and an insulating portion configured to not electrically communicate with the tissue. Organization<u style="Single">connection</u>Components; and at least two organizations<u style="Single">connection</u>It is equipped with a power supply that communicates electrically with the components.</p><p>In another aspect, the tissue<u style="Single">connection</u>Components are provided. In some embodiments, the component comprises a solid therapeutic agent and a support, and the solid therapeutic agent is a tissue.<u style="Single">connection</u>Tissue in an amount greater than or equal to 10% by weight based on the total weight of the components<u style="Single">connection</u>Present in the components, the solid therapeutic agent and support material are substantially evenly distributed and tissue.<u style="Single">connection</u>The components are configured to penetrate the organization.</p><p>In some embodiments, the component has a tip and comprises a solid therapeutic agent and a support with which the solid therapeutic agent is attached, at least a portion of the solid therapeutic agent being tissue.<u style="Single">connection</u>Attached to one or more tips of the component, solid therapeutic agents are tissue<u style="Single">connection</u>Tissue in an amount greater than or equal to 10% by weight based on the total weight of the components<u style="Single">connection</u>Present in the components.</p><p>In another aspect, the method is provided. In some embodiments, the method is a capsule comprising an external shell and a self-restoring article, wherein the self-restoring article is adjacent to a first portion, and a first portion, with the first portion. Includes administration of capsules to a subject, comprising a second portion having a different average density.</p><p>In some embodiments, the method is a capsule comprising an external shell and a self-restoring article, wherein the self-restoring article is adjacent to a first portion, a first portion, comprising a first material. It is equipped with a second part containing a second material different from the first material, and a needle with a pharmaceutically active agent, and the ratio of the average density of the first material to the average density of the second material is A step of administering a capsule to a subject, greater than or equal to 2.5: 1, aligning the self-restoring article at a location within the subject so that the needle punctures tissue close to the location within the subject. Includes a step and a step of releasing at least a portion of the pharmaceutically active agent into the tissue.</p><p>In some embodiments, the method is an external shell, and a spring that is at least partially encapsulated in the external shell, a support attached to the spring, with at least a portion of the spring under ambient conditions, at least 5. Support material to maintain under compressive strain of%, and the structure attached to the spring<u style="Single">connection</u>It involves administering to a subject an article comprising a component.</p><p>In some embodiments, the method is an external shell, a spring that is at least partially encapsulated in the external shell, a support material attached to the spring, with at least a portion of the spring under ambient conditions, at least 5%. Support material for maintaining under compressive strain, and the structure attached to the spring<u style="Single">connection</u>The step of administering to the subject the article comprising the component, as well as disassembling at least a portion of the support, resulting in spring elongation and / or tissue.<u style="Single">connection</u>It involves the steps of a component penetrating a tissue located within the subject's body.</p><p>In some embodiments, the method is 1 g / cm.³Articles with at least the first portion and at least one mooring mechanism with a greater average density under force greater than or equal to 0.6N and / or changes in orientation greater than or equal to 30 degrees or equal. Includes administering to a subject an article configured to be held in that position in.</p><p>In some embodiments, the method is at least one tissue placed internally.<u style="Single">connection</u>Each organization has components<u style="Single">connection</u>A step of administering an article to a subject, the component comprising a conductive material, a step of releasing at least one matching component from the article, a step of inserting at least one matching component within a tissue at a location within the subject. , And organization<u style="Single">connection</u>Two or more currents generated by a power source that communicates electrically with a component<u style="Single">connection</u>Including steps applied between the components, the article comprises a spring that is maintained at least partially compressed by a support under at least 5% compressive strain, each structure.<u style="Single">connection</u>The components are operably connected to the spring.</p><p>In another aspect, the tissue<u style="Single">connection</u>A method of forming components is provided. In some embodiments, the method provides a solid therapeutic agent and support; as well as the solid therapeutic agent and support together, compressed and / or heated using a pressure of at least 1 MPa. , Organization<u style="Single">connection</u>Includes steps to form components; organization<u style="Single">connection</u>The components are configured to penetrate the organization.</p><p>Other advantages and novel features of the invention will become apparent when considered with the accompanying drawings from the following detailed description of various non-limiting embodiments of the invention. If the specification and the literature incorporated by reference contain conflicting and / or contradictory disclosures, this specification shall prevail.</p><p>Non-limiting embodiments of the invention will be described as examples in connection with the accompanying drawings, but these drawings are schematic and are not intended to be drawn at an accurate scale. .. Each of the same or nearly identical components exemplified in these figures is usually represented by a single number. Not all components in all figures are labeled for clarity, and each embodiment of the invention needs to be illustrated to allow one of ordinary skill in the art to understand the invention. If not, not all components are shown. In these figures,</p>

<figref num="1">FIG. 1 is a schematic diagram of a self-restoring system according to one set of embodiments.</figref><figref num="2">FIG. 2 is a schematic cross-sectional view of an exemplary self-restoring system according to a set of embodiments.</figref><figref num="3">FIG. 3 is a schematic representation of the administration of a self-restoring system according to one set of embodiments.</figref><figref num="4">FIG. 4 is a schematic diagram of an exemplary self-restoring article according to one set of embodiments.</figref><figref num="5">FIG. 5 is a schematic cross-sectional view of an exemplary self-restoring system according to a set of embodiments.</figref><figref num="6">FIG. 6 is a schematic cross-sectional view of an exemplary self-acting component according to a set of embodiments.</figref><figref num="7">FIG. 7 is a plot of an exemplary self-restoring shape graph with one set of embodiments.</figref><figref num="8">FIG. 8 is a photograph of an exemplary self-restoring article in 000 capsules with one set of embodiments.</figref><figref num="9">FIG. 9 is a plot of the (predicted) self-restoring article recovery rate tested by a computer model with one set of embodiments.</figref><figref num="10">FIG. 10 is a plot of the (poly) self-restoring article recovery rate by high-speed camera analysis with one set of embodiments.</figref><figref num="11">FIG. 11 is a plot of (poly) self-restoring article recovery rates by high-speed camera analysis with one set of embodiments.</figref><figref num="12">FIG. 12 is a photograph of an exemplary self-restoring article according to a set of embodiments.</figref><figref num="13">FIG. 13 is a series of X-ray images of an exemplary self-restoring article in 0, 45 and 90 degree orientations compared to a control (washer) according to one set of embodiments.</figref><figref num="14">FIG. 14 is a radiograph of an exemplary series of self-restoring articles in pig GI, according to a set of embodiments.</figref><figref num="15">FIG. 15 is an endoscopic observation of an exemplary self-restoring article in pig GI with one set of embodiments.</figref><figref num="16">FIG. 16 is a plot of the restored article fractions according to one set of embodiments.</figref><figref num="17">FIG. 17 is a plot for the shape of the maximum tilt according to one set of embodiments.</figref><figref num="18">FIG. 18 is a photograph of a maximum tilt test apparatus according to one set of embodiments.</figref><figref num="19">FIG. 19 is a photograph of an exemplary self-restoring article with an air / water outlet according to one set of embodiments.</figref><figref num="20">FIG. 20 is a photograph of an exemplary self-restoring article with a magnetic moiety attached to a magnetic object, according to one set of embodiments.</figref><figref num="21">FIG. 21 is a schematic diagram of a self-operated article according to one set of embodiments.</figref><figref num="22">FIG. 22 is a schematic diagram of an exemplary self-acting article according to one set of embodiments, a photograph of the article in vivo, and a photograph of the article compared to an uncompressed spring according to one set of embodiments. ..</figref><figref num="23">FIG. 23 is a plot of force displacement for various spring constants with one set of embodiments.</figref><figref num="24">FIG. 24 is a plot of diameter time for sugar lysis according to one set of embodiments.</figref><figref num="25">FIG. 25 is a plot of the diameter of the spring actuation time according to one set of embodiments.</figref><figref num="26">FIG. 26 shows an exemplary structure associated with a spring according to a set of embodiments.<u style="Single">connection</u>It is a photograph and a figure of a component (eg, a biopsy punch).</figref><figref num="27">FIG. 27 is a histological image of a needle inserted into a tissue in vitro from a spring-attached article and reaching the muscle layer of the gastric tissue, according to one set of embodiments.</figref><figref num="28">FIG. 28 shows the organization according to one set of embodiments.<u style="Single">connection</u>It is a schematic diagram of a component.</figref><figref num="29">FIG. 29 is a photograph of an in-plane needle manufactured at 80% BSA and 20% PEG 200 kw / w exposed to a pressure of 3 metric tons at 100 ° C for 2 minutes according to one set of embodiments. ..</figref><figref num="30">FIG. 30 is a photograph of an in-plane needle manufactured with 80% human insulin and 20% PEG 200 kw / w exposed to a pressure of 3 metric tons at 100 ° C for 2 minutes according to one set of embodiments. be.</figref><figref num="31">Figure 31 shows an in-plane needle made of 80% human insulin and 20% PEG 200 kw / w exposed to a pressure of 2 metric tons, with a maltose tip, according to one set of embodiments. It is a photograph of a needle created by the dipping coat of.</figref><figref num="32">FIG. 32 is a plot of insulin release times for components with relatively high API loading according to one set of embodiments.</figref><figref num="33">FIG. 33 is a plot for load (lateral load) elongation for various components with relatively high API loads according to one set of embodiments.</figref><figref num="34">FIG. 34 is a plot for load (axial load) elongation for various components with relatively high API loads according to one set of embodiments.</figref><figref num="35">FIG. 35 is a plot of the penetration depth for an exemplary component with a relatively high load API load compared to a 32-gauge stainless needle according to one set of embodiments.</figref><figref num="36">Figure 36 shows one set of embodiments exposed at 100 ° C for 2 minutes at a pressure of 3 metric tons with 83% human insulin, 5% HPMC, 2% magnesium stearate and 10% PEG 35 k w / w. It is a photograph of a manufactured component with a relatively high API load (eg, a needle-like protrusion on a base plate).</figref><figref num="37">Figure 37 shows a relatively set of embodiments, manufactured at 85% human insulin, 5% HPMC and 10% PEG 35 kw / w, exposed to a pressure of 3 metric tons at 100 ° C for 2 minutes. It is a schematic diagram of a method of making a component (eg, a needle) with a high API load and a non-API base plate, i.e., a needle-like projection on the base plate.</figref><figref num="38">FIG. 38 is a schematic diagram of how to make components with relatively high API loads (eg, needle tips) as well as non-API base plates and needle bases. Needle-like projections on a base plate manufactured at 85% human insulin, 5% HPMC and 10% PEG 35 kw / w, exposed to a pressure of 3 metric tons at 100 ° C for 2 minutes, according to one set of embodiments.</figref><figref num="39">FIG. 39 is a plot of the axial load of a component (eg, a microneedle) with a relatively high API load according to one set of embodiments.</figref><figref num="40-1">Figure 40A shows an exemplary organization containing 95% by weight APIs from a set of embodiments.<u style="Single">connection</u>It is a photograph of the component. Figures 40B to 40C show the organizational alignment component organization in Figure 11A.<u style="Single">connection</u>It is a compression test of components.</figref><figref num="40-2">Figures 40B to 40C show the organizational alignment component organization in Figure 11A.<u style="Single">connection</u>It is a compression test of components.</figref><figref num="40-3">FIG. 40D shows the organization according to one set of embodiments.<u style="Single">connection</u>It is a plot against the temperature of the percentage of insulin recovery for the component. FIG. 40E is a plot for the temperature of percent insulin dimer formation according to one set of embodiments.</figref><figref num="41">FIG. 41 is a schematic diagram of an exemplary method of making a component with a plurality of microneedles and a relatively high API load according to one set of embodiments.</figref><figref num="42">42A-42B are confocal microscopic images of exemplary components carrying FITC-dextran according to one set of embodiments.</figref><figref num="43">FIG. 43 shows tissues with multiple microneedles and relatively high API loading after administration to various tissues according to one set of embodiments.<u style="Single">connection</u>Shows the dissolution of components.</figref><figref num="44">FIG. 44 shows tissue with multiple microneedles and relatively high API loading after administration to human buccal tissue ex vivo, according to one set of embodiments.<u style="Single">connection</u>Shows the dissolution of components.</figref><figref num="45">FIG. 45 shows a tissue with multiple microneedles and a relatively high insulin load according to one set of embodiments.<u style="Single">connection</u>It is a plot against the time of blood concentration of insulin after application to the small intestine of the pig for the component.</figref><figref num="46">FIG. 46 shows a tissue with multiple microneedles and a relatively high insulin load according to one set of embodiments.<u style="Single">connection</u>It is a plot for the time of blood concentration of insulin after application to the palatal tissue of pigs for the components.</figref><figref num="47">FIG. 47 shows a tissue with multiple microneedles and relatively high human growth hormone loading according to one set of embodiments.<u style="Single">connection</u>It is a plot against time of blood concentration of human growth hormone after application to pig lips for components.</figref><figref num="48">FIG. 48 shows a tissue with multiple microneedles and relatively high human growth hormone loading according to one set of embodiments.<u style="Single">connection</u>It is a plot for the time of blood concentration of human growth hormone after application to the palatal tissue of pigs for the components.</figref><figref num="49">FIG. 49 shows a tissue with multiple microneedles and relatively high human growth hormone loading according to one set of embodiments.<u style="Single">connection</u>It is a plot against time of blood concentration of human growth hormone after application to pig lips for components.</figref><figref num="50">FIG. 50 is a plot of adalimumab activity before and after exposure to relatively high pressure and relatively high temperatures with one set of embodiments.</figref><figref num="51">FIG. 51 is a schematic diagram of a self-restoring system used for tissue localization and ejection of hooked microposts (ie, hooks). An example of a 32-gauge stainless steel needle with a hook according to one set of embodiments is shown on the left.</figref><figref num="52">FIG. 52 is a plot of penetration into porcine gastric tissue using hooked microposts with one set of embodiments.</figref><figref num="53">FIG. 53 is a plot of hooking force based on penetration into pig gastric tissue using hooked microposts with one set of embodiments.</figref><figref num="54">FIG. 54 is a photograph of a micropost with a hook attached to the muscle fibers of the porcine gastric tissue.</figref><figref num="55">FIG. 55 is a plot of hooking force based on penetration into human gastric tissue using hooked microposts with one set of embodiments.</figref><figref num="56">FIG. 56 is a plot of hooking force based on penetration into porcine small intestinal tissue using hooked microposts according to one set of embodiments.</figref><figref num="57">FIG. 57 is a plot of pull-up height based on penetration into porcine small intestinal tissue using hooked microposts with one set of embodiments.</figref><figref num="58">FIG. 58 is a photograph of a hooked micropost attached to the porcine small intestinal tissue itself, according to one set of embodiments.</figref><figref num="59">FIG. 59 is a schematic diagram of a horizontal tissue retention test model. According to one set of embodiments, the probe pushes down on the device moored to the tissue through the needle and records the force required to detach the device.</figref><figref num="60">FIG. 60 is a plot of the force required to disengage the self-restoring system according to one set of embodiments, which increases linearly with the number of needles inserted into the porcine gastric tissue.</figref><figref num="61">FIG. 61 is a plot of the needle distance of the force required to disengage the self-restoring system from the pig stomach tissue according to one set of embodiments.</figref><figref num="62">FIG. 62 is a schematic diagram demonstrating a plan for an in-vitro experiment in which a self-aligning device is tethered to pig stomach tissue while undergoing pulsatile flow, according to one set of embodiments.</figref><figref num="63">FIG. 63 demonstrates that, according to one set of embodiments, three devices with hooked microposts held their position for an entire week, as opposed to a comparison system that was detached in less than two days. It is a plot to do.</figref><figref num="64">FIG. 64 is a plot of mooring force for in-vivo and ex-vivo pig stomachs. Ex-vivo measurements represent studies using three separate tissue samples from different stomachs, according to one set of embodiments.</figref><figref num="65-1">FIG. 65A shows, using a pig model according to one set of embodiments, when the tethered self-aligning device encounters a force parallel to the gastric tissue, rotated less than 30 degrees and 0.5N to 0.75. It is a plot demonstrating in-vivo that it can hold its position while receiving a force between N (peaks and valleys correspond to animal respiration).</figref><figref num="65-2">FIG. 65B is a plot showing the relationship between the number of assists attached to the self-restoring device and the drag torque applied to the system by gastric acid according to one set of embodiments.</figref><figref num="65-3">FIG. 65C is a plot comparing the size of the food mass colliding with the self-restoring device with the torque applied to the self-restoring device according to one set of embodiments.</figref><figref num="66">FIG. 66 shows, according to one set of embodiments, a method by which a parylene-coated electric probe can bypass mucus and conduct electricity through tissue (eg, without coating, electricity flows through mucus with lower resistance). , Will not irritate the tissue).</figref><figref num="67">FIG. 67 demonstrates an electrical stimulation pill with two probes and a self-aligning device containing a power source and a programmable microcontroller enclosed in an isolated shell (eg, PDMS), according to one set of embodiments. It is a schematic diagram.</figref><figref num="68">FIG. 68 shows that, when powered by two silver oxide batteries (1.55V, 6.8mm coin battery) according to one set of embodiments, the current does not change significantly as the radius of the tissue stimulating electrical probe increases. It is a plot demonstrating.</figref><figref num="69">FIG. 69 shows that, according to one set of embodiments, when powered by two silver oxide batteries (1.55V, 6.8mm coin battery), the current decreases as the distance between the tissue stimulating electrical probes increases. It is a plot to demonstrate.</figref><figref num="70">In FIGS. 70A-70B, according to one set of embodiments, an electrical probe powered by a voltage source measures with an oscilloscope and gives a pulse stimulus through the tissue (FIG. 70A), which is measured within the tissue. It is a plot showing that it can be compared with the background voltage (Fig. 70B).</figref><figref num="71-1">Figures 71A-71D show mechanical API localization and infusion for oral gastric delivery. (Fig. 71A) The exemplary system localizes to the endometrium of the stomach and utilizes its unique shape to rapidly orient its infusion mechanism to the tissue wall. Within 1 minute the device is activated to inject the drug payload into the mucosa and submucosa. The drug-loaded micropost then slowly dissolves and the rest of the device is expelled from the body.</figref><figref num="71-2">Figures 71A-71D show mechanical API localization and infusion for oral gastric delivery. (Fig. 71B) Illustrated device manufactured. (Fig. 71C) Comparison of leopard tortoise (Stigmochelys pardalis) with calculated optimized shape for self-orientation and stability in the stomach. The optimized shape has a more elongated body shape to allow faster orientation times while still maintaining the desired stability for the gastric environment. (Fig. 71D) An exemplary device, according to one set of embodiments, utilizes a compression spring immobilized within caramelized sucrose to provide force for micropost insertion.</figref><figref num="72-1">Figures 72A-72E show the optimization of an exemplary system and self-orientation in vivo. (Fig. 72A) High-speed imaging at 1000 FPS demonstrates that SOMA devices made from a mixture of PCL and stainless steel self-orient from 90 ° in 64 ms. (Fig. 72B) Theoretical orientation time of ellipsoids, spheres and exemplary system shapes from a given initial angle. All are manufactured from the same mass of PCL and stainless steel.</figref><figref num="72-2">Figures 72A-72E show the optimization of an exemplary system and self-orientation in vivo. (Figure 72C) Experimental measurements of relative restoration time from a 90 ° starting angle of weighted shapes in different fluids when normalized to restoration time in water (n = 6 error bars = SEM) ). (Fig. 72D) Experimental determination of the maximum tilt angle of a weighted 3D shape when exposed to a 15 ° rocking motion at 0.25 rad / s (n = 3 error bars = SEM).</figref><figref num="72-3">Figures 72A-72E show the optimization of an exemplary system and self-orientation in vivo. (E) According to one set of embodiments, two exemplary systems made from PCL and stainless steel are oriented in vivo after being dropped from a height of 5 cm in the pig stomach, but only with PCL. The three exemplary devices manufactured in Japan could not be properly oriented.</figref><figref num="73-1">Figures 73A-73I show micropost fabrication and insertion force characteristic analysis of an exemplary system. (Fig. 73A) (i) Micropost 5-part stainless steel mold. (ii) The API mixture is screen printed on the tip compartment. (iii) The vibration ensures that the powder is filled in the cavity. (iv) The top compartment is filled with biodegradable polymer. (v) The material is compressed at 550 MPa.</figref><figref num="73-2">Figures 73A-73I show micropost fabrication and insertion force characteristic analysis of an exemplary system. (Fig. 73B) Insulin micropost. (Fig. 73C) MicroCT imaging is an exemplary system for (i) barium sulfate micropost delivery, and (ii) a system for delivery to porcine gastric tissue. The bottom is larger to ensure micropost stability during imaging.</figref><figref num="73-3">Figures 73A-73I show micropost fabrication and insertion force characteristic analysis of an exemplary system. (Fig. 73D) In vivo insertion force profile measured in the stomach of pigs using insulin microposts propelled at 0.2 mm / s (n = 2 stomach, n = 8 insertion, error bar = SEM) ..</figref><figref num="73-4">Figures 73A-73I show micropost fabrication and insertion force characteristic analysis of an exemplary system. (Fig. 73E) In vivo H &amp; E stained histology results from Carr-Locke needle insertion into porcine gastric tissue. H &amp; E and insulin-stained histology (FIG. 73F) and smooth muscle-stained histology (FIG. 73H) from insulin microposts injected into pigs in vivo by a 5N spring in an exemplary system. (Fig. 73G) H &amp; E stained histology and (Fig. 73I) smooth muscle stained histology of steel microposts inserted ex vivo into the stomach of a pig with a 9N spring according to one set of embodiments.</figref><figref num="73-5">Figures 73A-73I show micropost fabrication and insertion force characteristic analysis of an exemplary system. (Fig. 73E) In vivo H &amp; E stained histology results from Carr-Locke needle insertion into porcine gastric tissue. H &amp; E and insulin-stained histology (FIG. 73F) and smooth muscle-stained histology (FIG. 73H) from insulin microposts injected into pigs in vivo by a 5N spring in an exemplary system. (Fig. 73G) H &amp; E stained histology and (Fig. 73I) smooth muscle stained histology of steel microposts inserted ex vivo into the stomach of a pig with a 9N spring according to one set of embodiments.</figref><figref num="74-1">Figures 74A-74D show API micropost delivery and device evaluation in vivo for an exemplary system. In pigs, after manual subcutaneous (SC) or intragastric (IG) infusion with an exemplary system of microposts containing human insulin (FIGS. 74A and 74B) plasma human insulin levels and (FIGS. 74C and 74D). Plasma blood glucose (BG) was recorded (n = 5, error bar = SEM). These pigs have been compared to pigs treated with an exemplary system designed to localize microposts to the tissue wall but not inject (IG-free Inj). 280 ± 15 μg of human insulin was implanted under the tissue for each infusion test. Manually placed microposts contain 20% PEO 200k in addition to human insulin. The decrease in BG was measured in comparison with the time point of 15 minutes. This is because the BG level fluctuated dramatically due to anesthesia during this time. A decrease in BG was seen during both treatments. The IG dataset contains only pigs that have been successfully fasted and have no residual food or significant gastric fluid, according to one set of embodiments.</figref><figref num="74-2">Same as above.</figref><figref num="74-3">Same as above.</figref><figref num="74-4">Same as above.</figref><figref num="75">FIG. 75 shows a stainless steel toxicity test for an exemplary system. The histology from the gastrointestinal tract of one of the six rats given a single dose of 2000 mg / kg 316 stainless steel particles suspended in 1 mL canola oil by 15 G gavage was a set. According to embodiments, there are no abnormalities compared to rats receiving 1 mL of canola oil alone.</figref><figref num="76">FIG. 76 shows in vivo SOMA-shaped X-rays for an exemplary system. Six SOMA devices were fed to pigs with one control device of the same SOMA shape but uniform density. Due to the circular metal bottom of SOMA, the device appeared on X-rays as a perfect circle if it was perfectly oriented and as a chipped circle if it was unaligned. The control device was also marked with a thin metal washer. The pig was then rotated less than 180 ° axially and tilted less than 30 ° in the other direction to simulate gait and extensive motor stress. The pigs were then examined by x-ray. This process was repeated 10 times to obtain 100% corrected orientation for SOMA devices and 50% orientation for control devices according to one set of embodiments.</figref><figref num="77">FIG. 77 shows the gastric retention characteristics of an exemplary system. Six SOMA devices have been shown to pass through the pig's GI tube in 8 days. The SOMA device spent days 1-7 in the stomach. X-rays on day 1 show one SOMA device being delivered through the esophagus and five soma devices in the stomach. On the second day, all of the SOMA devices are in the stomach and they stay there until the seventh day. On day 8, four SOMA devices were shown to have entered the intestine. Until the 9th day, there are no SOMA devices present on X-rays. This indicates that SOMA was discharged from the pig. Pigs showed no signs of obstruction throughout the experiment, according to one set of embodiments.</figref><figref num="78">FIG. 78 shows Raman spectroscopic analysis of compressed insulin for an exemplary system. Several microposts were made with insulin and PEO compressed at various pressures. Raman spectroscopy was used to analyze these API mixtures to determine if any protein folding changes would occur during exposure to high pressure. (A) Human insulin and PEO 200k standard material. Black circles represent peaks present in insulin readings that are not present in PEO readings. These peaks are analyzed in Figure (C ~ E). (B) The difference between the two components allowed the generation of visualization of the mixture using built-in pretreatment and chemometrics with imaging software. The blue area in this photo contains a larger amount of PEO. All but the 5 bands of the insulin Raman band overlapped with the PEO band. (C) Amide I band appearing at 1660 cm-1, Tyr peak appearing at 1613 cm-1, (D) Phenylalanine (Phe) peak appearing at 1003 cm-1, (E) Appearing at 622.5 cm-1 There is a Phe peak, and a Tyr peak appearing at 644.3 cm-1. No increase in band shift or bandwidth was observed. This demonstrates that there was no protein folding change according to one set of embodiments.</figref><figref num="79">FIG. 79 shows a compressed insulin needle crushing test for an exemplary system. A rectangular parallelepiped pellet with dimensions of 3.3 x 0.55 x 0.55 mm3 was made from the insulin / PEO 200k mixture described. These pellets demonstrated a Young's modulus of 730 ± 30 MPa while undergoing a crushing test. This is similar to PEO's Young's modulus. The ultimate strength of the pellet is 36 ± 2N according to one set of embodiments.</figref><figref num="80">FIG. 80 shows a micropost dissolution profile for an exemplary system. Microposts containing 80 wt% human insulin and 20 wt% PEO 200k were lysed at 37 ° C in a Falcon tube containing 2 mL PBS while shaking at 50 rpm in a laboratory shaker. Every 3 minutes for the first 15 minutes, then every 5 minutes, 200 μL of sample was taken and the removed liquid was replaced with fresh PBS. According to one set of embodiments, complete dissolution occurred within 1 hour.</figref><figref num="81">Figures 81A-81B show micropost API stability studies for exemplary systems. (A) Insulin purity and (B) High molecular weight protein (HMWP) concentration (n = 3, error bars = SEM) during a 16-week stability test with one set of embodiments.</figref><figref num="82">FIG. 82 shows a schematic and photograph of the needle insertion mechanism for an exemplary system. Video-requiring in vivo and ex vivo insertion data were acquired using a tracking device consisting of a linear glide, a stepping motor, a 0.5N or 10N load cell, and a video camera. The lower right photo shows a 10N load cell attached to the device. According to one set of embodiments, all of the devices were controlled by a custom LabView device.</figref><figref num="83">Figures 83A-83E show a characteristic analysis of the sucrose drive mechanism for an exemplary system. For sucrose, modeled in COMSOL Multiphysics, as the sucrose column dissolves in (A) a huge water mass flowing at a rate of 0.02 m / s and (B) a huge water mass without convection. Convection gradient. Black circles indicate the contraction boundaries of the sugar cylinder, and the concentration is shown in units of mol / m3. (C) Dissolution rate of sucrose cylinders in 4 experiments; slope indicates mass transfer coefficient between water and sucrose. (D) The time from when the sucrose-coated spring is immersed in DI water to the time when the spring operates. The bars represent the experimental uptime (n = 3, error bars = standard deviation) and the lines represent the time indicated by COMSOL. (E) High-speed image of a spring popping out of a sucrose coating when DI water is dropped onto the sucrose coating from above, according to one set of embodiments.</figref><figref num="84">Figures 84A-84D show the zero-order kinetic release of implantable insulin microposts for an exemplary system. (A) The micropost shaft inserted into the subcutaneous (SC) cavity delivers insulin over 30 hours (n = 6, error bar = SEM). (B) Persistent BG decline is seen over the first 15 hours. Pigs ate at 22 hours, resulting in BG spikes. These implants did not have a pointed tip and instead had a rod-shaped portion with a diameter of 1.2 mm, which was 1 mm high. (C) Micropost shafts inserted into the intragastric (IG) cavity by laparotomy and gastric incision surgery deliver insulin over a 2-hour sampling (n = 5, error bar = SEM). (D) A dramatic decrease in BG was observed, which, according to one set of embodiments, may be in part due to surgery.</figref><figref num="85">Figures 85A-85D show the enzyme activity assay of the fabrication micropost for an exemplary system. (A) Micropost tips made with 80% lysosyme and 20% PEO 200k, and (B) Micropost tips made with 40% glucose-6-phosphate dehydrogenase and 60% PEO 200k. It was lysed and an (C ~ D) enzyme activity assay was performed to ensure that the protein remained active after the manufacturing process. The control represents an uncompressed powder. According to one set of embodiments, the scale bar is 1 mm (error bar = SEM).</figref><figref num="86">FIG. 86 shows a sugar-coated spring fabrication workflow for an exemplary system. The sugar coated spring was manufactured in a short 4-step process. (I) A compression spring was placed in the silicone mold, and (II) caramelized sucrose heated to 210 ° C for 15 minutes in a furnace was injected into the mold. Isomalt was also used. The spring was compressed in caramelized sucrose with a custom plunger and the mold was allowed to cool for a few minutes. (III) The plunger was then removed and (IV) the sucrose-filled spring was pulled out of the mold. According to one set of embodiments, the size of the mold holes determined the width of the sugar-filled spring.</figref><figref num="87">FIG. 87 shows an insulin quantitative assay for an exemplary system. The ELISA and AlphaLisa experiments utilize a homogenous bead assay that utilizes two monoclonal antibodies to human insulin. This assay is more specific to human insulin than porcine insulin, according to one set of embodiments.</figref><figref num="88">FIG. 88 shows the calculation results from self-oriented shape optimization for an exemplary system with one set of embodiments.</figref>

Detailed Description Overview Self-restoring articles, such as self-restoring capsules for administration to a subject, are generally provided. In some embodiments, the self-restoring article may be configured such that the article can be oriented with respect to a surface (eg, the surface of the tissue of interest). The self-restoring articles described herein are configured to engage with a surface (eg, the surface of the tissue of interest) (eg, align with the surface, inject into the surface, or moor to the surface) 1 It may have one or more tissue engaging surfaces. For example, the self-restoring article may be placed in any orientation in close proximity to the surface, and the self-restoring article is (re) oriented so that the tissue engaging surface is in contact (eg, direct contact) with the surface. It will be. In some embodiments, the self-restoring article can have a particular shape and / or density (or mass) distribution that allows, for example, the self-restoring behavior of the article. In some such embodiments, capsules containing the self-restoring article can be administered to the subject (eg, for delivery of the self-restoring article to a location within the subject's body, such as the gastrointestinal tract). In some embodiments, self-restoration is tissue<u style="Single">connection</u>It may contain components and / or pharmaceutical agents (eg, to deliver the pharmaceutically active agent to a location within the subject's body). In some cases, the self-restoring article is one or more tissues when the tissue comes into contact with the tissue engaging surface of the article.<u style="Single">connection</u>It may be configured to emit components. In some cases, the organization<u style="Single">connection</u>The components are attached to the self-acting components. For example, self-restoring articles tissue from self-restoring articles when exposed to fluids.<u style="Single">connection</u>It can comprise a self-acting component that is configured to emit the component. In some cases, the organization<u style="Single">connection</u>The component comprises the pharmaceutical agent (eg, for delivery to a location within the subject's body) and / or may be accompanied by the pharmaceutical agent.

The self-restoring articles described herein are, for example, as a general platform for the delivery of a wide variety of pharmaceutical agents that would otherwise be commonly delivered by direct tissue injection for degradation in a GI tube. , Can be useful. In some cases, the self-restoring article may be configured to deliver the pharmaceutical agent to the subject at the desired location and / or at the desired time and / or over the desired time period. In some embodiments, the self-restoring articles described herein can be used to deliver the sensor and / or collect a biopsy sample, eg, without the need for endoscopic observation. In certain embodiments, using the self-restoring articles described herein, one or more articles may be tethered to the surface of the tissue, eg, in a GI tube. In some cases, the self-restoring articles described herein can be used to directly apply electrical stimulation to tissue.

Advantageously, in some embodiments, the self-restoring articles and / or self-acting components described herein are a wide variety, usually delivered by injection directly into the tissue for degradation in the GI tube. It can be useful as a general platform for the delivery of various pharmaceutical agents (eg APIs). For example, a self-restoring article can be localized in a designated direction on the tissue wall (so that, for example, a loaded drug avoids prolonged passage of GI tubule fluid before diffusion into the bloodstream. can do). This article can, in some cases, serve as a platform for the higher bioavailability of drugs that are now enzymatically degraded in GI tubes. In addition, the article can allow mechanical and electrical mechanisms, such as needles, plungers, anchors, sensors, etc., to operate directly at and / or into the tissue wall. Thus, in certain embodiments, the article can serve as a vehicle for delivering an electronic device or other article to the GI tube.

In some embodiments, the organization<u style="Single">connection</u>Organizations associated with components (eg, self-acting components)<u style="Single">connection</u>A component) can comprise a relatively high loading of a pharmaceutical active ingredient (eg, a drug). For example, in certain embodiments, the organization<u style="Single">connection</u>The components include solid therapeutic agents (eg, solid API), and if necessary, solid therapeutic agents are tissued.<u style="Single">connection</u>It comprises a support material (eg, a binder such as a polymer) to be present in the component in a relatively large amount (eg, greater than or equal to 80% by weight) relative to the total weight of the component. Such an organization<u style="Single">connection</u>The components may be useful for delivery of API doses (eg, to a subject). Advantageously, in some embodiments, the volume required to deliver the required API dose is reduced compared to a liquid formulation, thereby allowing different locations / tissues of a wide variety of drugs (eg, tongue). , GI mucosal tissue, skin) allows the creation of a solid needle delivery system, and / or reduces and / or eliminates the application of external force to inject the drug solution through the small opening of the needle. In some cases, a single tissue with a physiologically appropriate dose<u style="Single">connection</u>Can be present in the components (eg, a single organization)<u style="Single">connection</u>The component has a relatively high API load).

In an exemplary embodiment, the self-restoring article is tissue<u style="Single">connection</u>Components and organization<u style="Single">connection</u>It can be equipped with a self-acting component that accompanies the component (eg, a self-acting component with a spring and / or support).

As illustrated in FIG. 1, in some embodiments, the system 100 (eg, a self-restoring article) comprises a tissue engaging surface 150. The embodiments described herein refer to a single tissue alignment surface, but in some embodiments there may be two or more tissue alignment planes. In certain embodiments, the self-restoring article is designed and configured so that the tissue engaging surface is in contact with a surface (eg, the surface of tissue at a location within the subject's body, such as the surface of the subject's stomach). You may. In some embodiments, the system 100 will be self-restoring so that the tissue engaging surface 150 is in contact with the surface (eg, it may also be used to require an external force applied to the self-restoring article. Will be oriented soon). In certain embodiments, the self-restoring article is configured such that an axis essentially perpendicular to the tissue engaging surface is preferentially aligned parallel to the direction of gravity. As described in more detail herein, the self-restoring article maintains an orientation of the axis essentially perpendicular to the tissue engaging surface at 20 degrees or less from the vertical under externally applied torque. It may be configured to be able to. In some embodiments, the self-restoring article is tissue<u style="Single">connection</u>The components are configured to have the longest longitudinal axis oriented within 15 degrees of vertical when self-restored.

Although not desired to be constrained by theory, self-restoring articles may be designed to self-restoring as a result of density (and / or mass) distribution within the self-restoring article. For example, in some embodiments, the system 100 (eg, a self-restoring article) comprises a first portion 110 and a second portion 115, the first portion and the second portion having different densities and / Or have different masses. The different densities / masses of self-restoring articles are described in more detail herein. In certain embodiments, the self-restoring article can have a particular shape that allows for self-restoring behavior. For example, as illustrated in FIG. 1, the system 100 has a monostatic shape (eg, mono = monostatic shape, rubber box shape) indicated by the outer surface 170 of the system 100. The term "monostatic", as used herein, is given its usual meaning in the art and refers to a three-dimensional shape with a single stable resting position (eg, equilibrium point). Generally refers. The term "mono-monostatic", as used herein, is given its usual meaning in the art, with a single stable resting position and a single unstable resting position. Generally refers to a three-dimensional shape having. As an example, we do not want to be bound by theory, but a sphere with a center of mass deviated from the center of geometry is generally considered to be a mono-monostatic shape. The term "rubber box", as used herein, is given its usual meaning in the art, with a single stable equilibrium point (or orientation) and a single instability when placed on a flat surface. Generally refers to a convex three-dimensional shape with an equilibrium point (or orientation). For example, although we do not want to be constrained by theory, a rubber box shape reorients to that single stable orientation when placed on the surface in any orientation other than the single stable orientation of this shape. There will be a tendency. Such shapes are described in more detail below.

FIG. 2 shows a cross-sectional explanatory view of the exemplary system 102. In some embodiments, the system 102 comprises a self-acting component 120. The self-acting component 120 is, for example, the tissue associated with the self-acting component 120 when exposed to a particular fluid.<u style="Single">connection</u>The component 130 may be configured to be ejected from the system 102. For example, in some cases, the self-actuating component 120 comprises a spring 125, so that when the self-actuating component is activated, the spring 125 unfolds and accompanies the system 102 (attached to the tissue engagement surface 150). Tissue through hole 140<u style="Single">connection</u>Extrude component 130. In some cases, the spring 125 comprises a support 160 that keeps the spring 125 under compression (eg, under compression strain of at least 5%). In some cases, the spring will have at least 10 percent of the spring's stored compressive energy (eg, at least 20 percent, at least 30 percent, at least 40 percent) when the support 160 and / or spring 125 is exposed to fluid. To release at least 50%, at least 60%, at least 70%, at least 80%, at least 90% (including any percentage of these) (eg, as a result, tissue<u style="Single">connection</u>It may be configured (so that component 130 is released). In some embodiments, the spring is attached to the support (eg, at least partially enclosed in direct contact with the support by the support) .

In certain embodiments, the organization<u style="Single">connection</u>Component 130 comprises a pharmaceutical activator. In some embodiments, the pharmaceutically active agent is tissue<u style="Single">connection</u>It can be present in relatively large amounts in the components (eg, tissue)<u style="Single">connection</u>More than or equal to 10% by weight, greater than or equal to 80% by weight, or greater than or equal to 90% by weight, based on the total weight of the components). The self-restoring articles described herein can be administered to a subject in some cases, eg, to deliver a pharmaceutical agent to the subject. For example, in some cases, the article can be administered to the subject and the pharmaceutical agent is released from the article at a location within the subject's body. Administration of the article and release of the pharmaceutical agent are described in more detail herein.

In some embodiments, the system is administered to the subject (eg, orally). In certain embodiments, the system may be administered orally, rectally, intravaginally, nasally or urethally. In certain embodiments, upon reaching a location within the subject's body (eg, the gastrointestinal tract), at least a portion of the support is disassembled, resulting in spring elongation and / or tissue.<u style="Single">connection</u>The components are aligned with the tissue located within the subject's body (eg, in contact with, penetrate into the tissue). In some embodiments, the location within the subject is the colon, duodenum, ileum, jejunum, stomach, or esophagus. As described above and herein, in some embodiments, the active ingredient of a pharmaceutical product may be released during and / or after intrusion into a tissue located in the body of the subject. good.

As an example, although not desired to be limited by such an exemplary set of embodiments, the system may be administered orally to the subject and, in some cases, the system may proceed to the subject's stomach and the subject. It sinks to the bottom of the stomach, and the system self-restores, so that the tissue engaging surface of the system comes into contact with the gastric tissue (eg, the system is at least partially supported by the gastric tissue). For example, as schematically illustrated in FIG. 3, the exemplary system 100 is administered (eg, orally) to the subject, so that the system 100 invades the subject's digestive system 198. System 100 proceeds through digestive system 198 until it reaches the subject's stomach 199 (System 100a). In some embodiments, the system 100 sinks to the bottom of the stomach 199 (system 100b), resulting in contact with the surface of the stomach 199. In certain embodiments, the system 100 self-restores (system 100c) so that the tissue engaging surface 150 of the system 100 contacts the surface of the stomach 199 and the system 100 self-operates, resulting in tissue.<u style="Single">connection</u>The component 130 is aligned with the tissue at the location within the subject (eg, the surface of the stomach 199). Figure 3 shows the organization<u style="Single">connection</u>Illustrating the alignment of the components with the surface of the stomach 199, those skilled in the art will appreciate the tissue based on this teaching.<u style="Single">connection</u>It is understood that the components may come into contact with one or more layers (or other locations within the subject's body) beneath the surface of the stomach, including, for example, the mucosal layer, submucosal layer and / or muscular tissue layer. Will be done.

In some cases, as described herein, the self-restoration of the system 100 can be driven by gravity (eg, gravity acting on the center of mass of the system 100). After the desired period, in some embodiments, the system 100 is degraded (eg, tissue).<u style="Single">connection</u>Component 130 dissolves and / or is released) and exits stomach 199 (system 100d). It will be appreciated by those skilled in the art that the above description is not intended to be limiting and that other interactions between the system described herein and the digestive system of interest may occur. In some embodiments, the system 100 is a monostatic body, as described in more detail below.

The following description provides various embodiments for self-restoring, self-operating, and API-loaded components of the systems described herein.

Self-restoration

As mentioned above, in some embodiments, the self-restoring article comprises two or more portions with different average densities, so that, for example, the self-restoring article is substantially on the surface (eg, gravity). It can be oriented substantially perpendicular to a surface that is orthogonal to each other, a surface of tissue, such as the wall of the gastrointestinal tract. In some cases, the self-restoring article can have a particular shape that allows, for example, the self-restoring behavior of the article. In some embodiments, the self-restoring article can be placed (eg, encapsulated) in a capsule. In certain embodiments, the self-restoring article is not provided within the capsule. In some embodiments, capsules containing the self-restoring article can be administered to the subject (eg, to deliver the self-restoring article to a location within the subject's body, such as the gastrointestinal tract). In some embodiments, the self-restoring article and / or capsule may comprise a pharmaceutical agent (eg, to deliver the pharmaceutically active agent to a location within the subject's body).

The self-restoring articles described herein are, for example, as a general platform for the delivery of a wide variety of pharmaceutical ingredients that would otherwise be commonly delivered by direct tissue injection for degradation in a GI tube. , Can be useful. In some embodiments, the self-restoring articles described herein can be used to deliver the sensor and / or collect a biopsy sample, eg, without the need for endoscopic observation.

Advantageously, the self-restoring article can be localized to the tissue wall in a specified direction (so that, for example, the loaded drug has a long time of GI tube fluid before diffusion into the bloodstream. You can avoid passing through). As described herein, this article can, in some cases, serve as a platform for the higher bioavailability of drugs that are now enzymatically degraded in GI tubes. In addition, the article can allow mechanical and electrical mechanisms, such as needles, plungers, anchors, sensors, etc., to operate directly at and / or into the tissue wall. Thus, in certain embodiments, the article can serve as a vehicle for delivering an electronic device or other article to the GI tube.

In some embodiments, the self-restoring article can have a particular cross-sectional shape. In certain embodiments, the shape may be any suitable cross-sectional shape, including circular, oval, triangular, irregular, trapezoidal, square or rectangular, or the like. In certain embodiments, the self-restoring article is non-spherical. In some embodiments, the self-restoring article may be a monostatic body and / or has only one stability point (eg, a self-restoring article is specified with only one given orientation). Orientation can be maintained stably). In an exemplary embodiment, the self-restoring article has a rubber box shape and / or comprises a component of the rubber box shape. A self-restoring article with a rubber box shape can self-restore to a particular orientation when displaced from its orientation without additional force. In some cases, the self-restoring article can be self-restoring in a fluid (eg, a liquid with a relatively low viscosity, a liquid with a relatively high viscosity). Advantageously, it is described that the self-restoring article orients the self-restoring article as expected and quickly, and also minimizes the movement due to the internal force of the GI tube. The shape. In some cases, at least the surface of the self-restoring article includes a flat surface. For example, as illustrated in FIGS. 1 and 2, in some embodiments, the tissue engagement surface 150 can be flat.

With reference to FIG. 1 again, in some embodiments, the self-restoring article has a different average density and / or a different mass than the first part, with the first part 110; It comprises a second portion 115 adjacent to the first portion 110. For example, in some embodiments, the self-restoring article comprises a first portion; and a second portion adjacent to the first portion, having a different average density than the first portion. For example, the first portion can have a first average density and the second portion can have a second average density different from the first average density. In some embodiments, the ratio of the average density of the first part to the average density of the second part is greater than 1: 1, greater than 2: 1 or equal, greater than 2.5: 1 or it. Equal, greater than 3: 1 or equal, greater than 3.5: 1 or equal, greater than 4: 1 or equal, greater than 4.5: 1 or equal, greater than 5: 1 or equal Equal, greater than 5.5: 1 or equal, greater than 5.5: 1 or equal, greater than 6: 1 or equal, greater than 6.5: 1 or equal, greater than 7: 1 or equal Equal, greater than 8: 1 or equal, greater than 9: 1 or equal, or greater than 10: 1 or equal. In certain embodiments, the ratio of the average density of the first part to the average density of the second part is less than or equal to 15: 1, less than 10: 1 or equal, 9 :. Less than 1 or equal, less than 8: 1 or equal, less than 7: 1 or equal, less than 6.5: 1 or equal, less than 6: 1 or Equal to it, less than 5.5: 1 or equal to it, less than 5: 1 or equal to it, less than 4.5: 1 or equal to it, 4: Less than 1 or equal, less than 3.5: 1 or equal, less than 3: 1 or equal, less than 2.5: 1 or equal, less than 2: 1 or It may be equal to, less than 1.5: 1 or equal to it. The combinations of ranges mentioned above are possible (eg, greater than or equal to 1: 1 and less than or equal to 15: 1). Other ranges are possible. Although not desired to be constrained by theory, self-restoring articles with first and second parts with different average densities result in a surface (eg, the wall of the gastrointestinal track). It can be a self-restoring article that substantially maintains a particular orientation.

In some embodiments, the ratio of the average density of the second part to the average density of the first part is greater than 1: 1, greater than 2: 1 or equal to it, greater than 2.5: 1 or it. Equal, greater than 3: 1 or equal, greater than 3.5: 1 or equal, greater than 4: 1 or equal, greater than 4.5: 1 or equal, greater than 5: 1 or equal Equal, greater than 5.5: 1 or equal, greater than 5.5: 1 or equal, greater than 6: 1 or equal, greater than 6.5: 1 or equal, greater than 7: 1 or equal Equal, greater than 8: 1 or equal, greater than 9: 1 or equal, or greater than 10: 1 or equal. In certain embodiments, the ratio of the average density of the second part to the average density of the first part is less than or equal to 15: 1, less than 10: 1 or equal, 9 :. Less than 1 or equal, less than 8: 1 or equal, less than 7: 1 or equal, less than 6.5: 1 or equal, less than 6: 1 or Equal, less than 5.5: 1 or equal, less than 5: 1 or equal, less than 4.5: 1 or equal, less than 4: 1 or equal, 3.5: 1 Less than or equal to or equal to, less than 3: 1 or equal to, less than 2.5: 1 or equal to, less than 2: 1 or equal to, or less than 1.5: 1 or It may be equal to that. The combinations of ranges mentioned above are possible (eg, greater than or equal to 1: 1 and less than or equal to 15: 1). Other ranges are possible.

In some embodiments, the self-restoring article comprises a first portion; and a second portion adjacent to the first portion, having a different mass than the first portion. For example, the first part can have a first mass and the second part can have a second mass different from the first mass. In some embodiments, the ratio of the mass of the first part to the mass of the second part is greater than 1: 1, greater than 2: 1 or equal, greater than 2.5: 1 or equal, Greater than 3: 1 or equal, greater than 3.5: 1 or equal, greater than 4: 1 or equal, greater than 4.5: 1 or equal, greater than 5: 1 or equal, Greater than 5.5: 1 or equal, greater than 5.5: 1 or equal, greater than 6: 1 or equal, greater than 6.5: 1 or equal, greater than 7: 1 or equal, It may be greater than or equal to 8: 1 or equal to it, greater than or equal to 9: 1 or equal to it, or greater than or equal to 10: 1 or equal to it. In certain embodiments, the ratio of the mass of the first part to the mass of the second part is less than or equal to 15: 1, less than 10: 1 or equal, less than 9: 1. Or equal to it, less than 8: 1 or equal to it, less than 7: 1 or equal to it, less than 6.5: 1 or equal to it, less than 6: 1 or equal to it , Less than 5.5: 1 or equal, less than 5: 1 or equal, less than 4.5: 1 or equal, less than 4: 1 or equal, less than 3.5: 1 Is or equal to, less than 3: 1 or equal to, less than 2.5: 1 or equal to, less than 2: 1 or equal to, or 1.5: May be less than or equal to 1. The combinations of ranges mentioned above are possible (eg, greater than or equal to 1: 1 and less than or equal to 15: 1). Other ranges are possible. Although not desired to be constrained by theory, self-restoring articles with different masses of the first and second parts result in a particular orientation with respect to the surface (eg, the wall of the gastrointestinal tract). It can be a self-restoring article that is substantially maintained.

In some embodiments, the ratio of the mass of the second part to the mass of the first part is greater than 1: 1, greater than 2: 1 or equal, greater than 2.5: 1 or equal, Greater than 3: 1 or equal, greater than 3.5: 1 or equal, greater than 4: 1 or equal, greater than 4.5: 1 or equal, greater than 5: 1 or equal, Greater than 5.5: 1 or equal, greater than 5.5: 1 or equal, greater than 6: 1 or equal, greater than 6.5: 1 or equal, greater than 7: 1 or equal, It may be greater than or equal to 8: 1 or equal to it, greater than or equal to 9: 1 or equal to it, or greater than or equal to 10: 1 or equal to it. In certain embodiments, the ratio of the mass of the second part to the mass of the first part is less than or equal to 15: 1, less than 10: 1 or equal, less than 9: 1. Or equal to it, less than 8: 1 or equal to it, less than 7: 1 or equal to it, less than 6.5: 1 or equal to it, less than 6: 1 or equal to it , Less than 5.5: 1 or equal, less than 5: 1 or equal, less than 4.5: 1 or equal, less than 4: 1 or equal, less than 3.5: 1 Is or equal to, less than 3: 1 or equal to, less than 2.5: 1 or equal to, less than 2: 1 or equal to, or less than 1.5: 1 or equal to Sometimes. The combinations of ranges mentioned above are possible (eg, greater than or equal to 1: 1 and less than or equal to 15: 1). Other ranges are possible.

As illustrated in FIG. 4, the system 100 may include a first portion 110 and a second portion 120 adjacent to the first portion 110. As used herein, when a part is said to be "adjacent" to another part, it may be directly adjacent to that part (eg, in contact with that part). Alternatively, one or more intervening components (eg, liquid, hollow portion) may be present. A part that is "directly adjacent" to another part means that there are no intervening components.

For example, with reference to FIG. 1 again, the first part 110 can occupy the first volume of the self-restoring article having the first average density and / or mass, and the second part 115 is the first. Can occupy the remaining volume of a self-restoring article with an average density and / or mass of 2. In certain embodiments, back to FIG. 4, the first part 110 can occupy the first volume of the self-restoring article and the second part 115 is the second of the self-restoring article. The third part 130 can be hollow and / or can contain one or more (additional) components.

In some embodiments, the first portion is greater than or equal to 1% by volume, greater than or equal to, greater than or equal to 5% by volume, greater than or equal to 10% by volume, or greater than or equal to the total volume of the self-restoring article. Equal, greater than or equal to 20% by volume, greater than or equal to 25% by volume, greater than or equal to, greater than or equal to 30% by volume, greater than or equal to, greater than or equal to 40% by volume, greater than or equal to, greater than or equal to 45% by volume, or Equal, greater than or equal to 50% by volume, greater than or equal to 55% by volume, greater than or equal to, greater than or equal to 60% by volume, greater than or equal to, greater than or equal to 65% by volume, greater than or equal to 70% by volume, or Equal to it, greater than or equal to 75% by volume, greater than or equal to 80% by volume, greater than or equal to 90% by volume, greater than or equal to 90% by volume, or greater than or equal to 95% by volume or occupying%. In certain embodiments, the first portion is less than or equal to 99% by volume, less than 95% by volume or equal to, less than 90% by volume, based on the total volume of the self-restoring article. Is or equal to, less than 80% by volume or equal to, less than or equal to 75% by volume, less than or equal to, less than or equal to 70% by volume, less than or equal to 60% by volume, Less than or equal to 55% by volume, less than or equal to 50% by volume, less than or equal to, less than or equal to 45% by volume, less than or equal to, less than or equal to 40% by volume, less than 30% by volume. Or equal to, less than 25% by volume or equal to, less than 20% by volume or equal to, less than 10% by volume or equal to, or less than 5% by volume or equal to. Occupy. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 1% by volume and less than 99% by volume). Or equal to, greater than or equal to 40% by volume, and less than or equal to 60% by volume). Other ranges are possible.

In certain embodiments, the second portion is greater than or equal to 1% by volume, greater than or equal to, greater than or equal to 5% by volume, greater than or equal to, greater than 10% by volume, or greater than the total volume of the self-restoring article. Equal, greater than or equal to 20% by volume, greater than or equal to 25% by volume, greater than or equal to, greater than or equal to 30% by volume, greater than or equal to, greater than or equal to 40% by volume, greater than or equal to, greater than or equal to 45% by volume, or Equal, greater than or equal to 50% by volume, greater than or equal to 55% by volume, greater than or equal to, greater than or equal to 60% by volume, greater than or equal to, greater than or equal to 65% by volume, greater than or equal to 70% by volume, or Equal to it, greater than or equal to 75% by volume, greater than or equal to 80% by volume, greater than or equal to 90% by volume, greater than or equal to 90% by volume, or greater than or equal to 95% by volume or occupying%. In some embodiments, the second portion is less than or equal to 99% by volume, less than 95% by volume or equal to, less than 90% by volume, based on the total volume of the self-restoring article. Is or equal to, less than 80% by volume or equal to, less than or equal to 75% by volume, less than or equal to, less than or equal to 70% by volume, less than or equal to 60% by volume, Less than or equal to 55% by volume, less than or equal to 50% by volume, less than or equal to, less than or equal to 45% by volume, less than or equal to, less than or equal to 40% by volume, less than 30% by volume. Or equal to, less than 25% by volume or equal to, less than 20% by volume or equal to, less than 10% by volume or equal to, or less than 5% by volume or equal to. Occupy. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 1% by volume and less than 99% by volume). Or equal to, greater than or equal to 40% by volume, and less than or equal to 60% by volume). Other ranges are possible.

In some embodiments, the third portion (eg, the hollow portion) is greater than or equal to 1% by volume, greater than or equal to 5% by volume, or equal to, 10 by volume, with respect to the total volume of the self-restoring article. Greater than or equal to% by volume, greater than or equal to 20% by volume, greater than or equal to 20% by volume, greater than or equal to 25% by volume, greater than or equal to 30% by volume, greater than or equal to 30% by volume, greater than or equal to 40% by volume, 45 Greater than or equal to% by volume, greater than or equal to 50% by volume, greater than or equal to 50% by volume, greater than or equal to 55% by volume, greater than or equal to 60% by volume, greater than or equal to 60% by volume, greater than or equal to 65% by volume, or equal to 70 Greater than or equal to% by volume, greater than or equal to 75% by volume, greater than or equal to, greater than or equal to 80% by volume, greater than or equal to 90% by volume, greater than or equal to, or greater than or equal to 95% by volume. Occupy. In certain embodiments, the third portion is less than or equal to 99% by volume, less than 95% by volume or equal to, less than 90% by volume, based on the total volume of the self-restoring article. Is or equal to, less than 80% by volume or equal to, less than or equal to 75% by volume, less than or equal to, less than or equal to 70% by volume, less than or equal to 60% by volume, Less than or equal to 55% by volume, less than or equal to 50% by volume, less than or equal to, less than or equal to 45% by volume, less than or equal to, less than or equal to 40% by volume, less than 30% by volume. Or equal to, less than 25% by volume or equal to, less than 20% by volume or equal to, less than 10% by volume or equal to, or less than 5% by volume or equal to. Occupy. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 1% by volume, and Less than or equal to 99% by volume, greater than or equal to 40% by volume, and less than or equal to 60% by volume). Other ranges are possible.

In some embodiments, the self-restoring article can include any suitable ratio of the first volume occupied by the first part to the second volume occupied by the second part. In certain embodiments, the ratio of the first volume to the second volume is greater than or equal to 1: 100, greater than or equal to 1:50, greater than or equal to 1:25, or equal to, Greater than 1:10 or equal to it, greater than 1: 8 or equal to it, greater than 1: 6 or equal to it, greater than 1: 4 or equal to it, greater than 1: 3 or equal to it, Greater than 1: 2 or equal, greater than 1: 1.5 or equal, greater than 1: 1.1 or equal, greater than 1: 1 or equal, greater than 1.1: 1 or equal, Greater than 1.5: 1 or equal to it, greater than 2: 1 or equal to it, greater than 3: 1 or equal to it, greater than 4: 1 or equal to it, greater than 6: 1 or equal to it, Greater than 8: 1 or equal to it, greater than 10: 1 or equal to it, greater than 25: 1 or equal to it, or greater than 50: 1 or equal to it. In certain embodiments, the ratio of the first volume to the second volume is less than or equal to 100: 1, less than 50: 1 or equal, less than 25: 1 or Equal, less than 10: 1 or equal, less than 8: 1 or equal, less than 6: 1 or equal, less than 4: 1 or equal, 2: 1 Less than or equal to, less than 1.5: 1 or equal, less than 1.1: 1 or equal, less than 1: 1 or equal, less than 1: 1.1 or it Equal, 1: 1. Less than 5 or equal, less than 1: 2 or equal, less than 1: 4 or equal, less than 1: 6 or equal, less than 1: 8 or Equal, less than 1:10 or equal, less than 1:25 or equal, or less than 1:50 or equal. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 1: 100 and less than or equal to 100: 1, greater than or equal to 1:10, and less than 10: 1). Is or is equal to, greater than or equal to 1: 2, and less than or equal to 2: 1). Other ranges are possible. Other volume ratios are also possible. Although not desired to be constrained by theory, in some embodiments the ratio of the first volume occupied by the first part to the second volume occupied by the second part is that of the self-restoring article. The center of mass can be selected to have one local minimum. Less than or equal to 1). Other ranges are possible. Other volume ratios are also possible. Although not desired to be constrained by theory, in some embodiments the ratio of the first volume occupied by the first part to the second volume occupied by the second part is that of the self-restoring article. The center of mass can be selected to have one local minimum. Less than or equal to 1). Other ranges are possible. Other volume ratios are also possible. Although not desired to be constrained by theory, in some embodiments the ratio of the first volume occupied by the first part to the second volume occupied by the second part is that of the self-restoring article. The center of mass can be selected to have one local minimum.

In some embodiments, the self-restoring article is configured to be administered directly to the subject (eg, without encapsulation). In certain embodiments, the self-restoring article is configured or placed to be encapsulated in a capsule having a shell (eg, the outer surface 170 of FIG. 4 constitutes the shell). In some such embodiments, with reference to FIG. 4, the self-restoring article may comprise a third portion 130 (eg, a hollow portion). In certain embodiments, the organization<u style="Single">connection</u>The components and / or the active ingredient of the drug can be placed in the hollow portion.

In some embodiments, the capsule is 000 capsules or less (eg, capsules are 000 capsules, 00 capsules, 0 capsules, 1 capsule, 2 capsules, 3 capsules, 4 capsules, or 5 capsules. Have shapes or sizes as described in the USP, including but not limited to these). In certain embodiments, the capsule encapsulates the first and second parts of the self-restoring article at least partially. In some embodiments, multiple devices can be placed within the capsule.

In some embodiments, the self-restoring article may be configured for potential encapsulation in 000 capsules or smaller, but the self-restoring article does not necessarily have to be encapsulated in such capsules. do not have. In embodiments where the self-restoring article will be administered, eg, by ingesting the self-restoring article, the self-restoring article may therefore be administered unencapsulated. ..

In certain embodiments, the self-restoring article may comprise a coating on at least a portion of the outer surface of the self-restoring article. In certain embodiments, the system (eg, a system containing a self-restoring article) comprises a coating (eg, a film placed at least on the surface of the system). In some embodiments, the coating can be coated as an aqueous or organic solvent based polymer based, fat and / or wax. In certain embodiments, the coating comprises one or more of polymers, plasticizers, colorants, solvents, fats, and waxes. Non-limiting examples of suitable fats and / or waxes include beeswax, carnauba wax, cetyl alcohol, and cetostearyl alcohol.

Non-limiting examples of polymers suitable for coating are cellulosic (eg, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl phthalate, ethyl cellulose, cellulose acetate, trimellitic acetate cellulose), vinyl (eg, cellulose acetate). For example, poly (vinylpyrrolidone), poly (vinyl alcohol), poly (vinylpyrrolidone) -poly (vinyl acetate) copolymer, poly (vinyl alcohol) -poly (ethylene glycol) copolymer, poly (vinyl acetate phthalate), glycol ( For example, poly (ethylene glycol)), acrylic resins (eg, aminoalkylmethacrylate polymers), other carbohydrates (eg, maltodextrin, polydextrose), and combinations thereof.

Non-limiting examples of suitable colorants include natural pigments (eg riboflavin, beta-carotene, carmine lake), inorganic pigments (eg titanium dioxide, iron oxide), water soluble dyes (FD &amp; C Yellow # 5, FD &amp; C Blue). # 2), FD &amp; C rake (FD &amp; C yellow # 5 rake, FD &amp; C blue # 2 rake), and D &amp; C rake (D &amp; C yellow # 10 rake, D &amp; C red # 30 rake).

Non-limiting examples of suitable plasticizers include polyhydric alcohols (eg, propylene glycol, glycerol, polyethylene glycol), acetates (eg, triacetin, triethyl citrate, acetyltriethyl citrate), phthalates (eg, phthalates). Diethyl phthalates), glycerides (eg, acylated monoglycerides), and oils (eg, castor oil, mineral oil).

Polymers, plasticizers, colorants, solvents, fats and / or waxes can be combined in any suitable amount to form a coating. The coating can be coated by any suitable method, including, for example, dip coating and / or spray atomization. Other methods of depositing the coating are also possible.

In some embodiments, the organization<u style="Single">connection</u>Components are attached to the self-restoring article. Organization<u style="Single">connection</u>Non-limiting examples of components include needles (eg, stainless steel needles, needles containing APIs), biopsy punches, microneedles (eg, microneedles containing APIs), protrusions, or the like. Can be mentioned.

In certain embodiments, the organization<u style="Single">connection</u>Components include jet injection components (eg, for liquid jet injection into tissues within a subject using high speed flow). In an exemplary embodiment, the jet injection component comprises a chamber comprising a polymer moiety. In certain embodiments, the polymer moiety may contain an acid (eg, a weak acid) and / or a base. In some cases, the fluid (eg, gastric fluid) enters the chamber and, as a result, reacts with acids and / or bases to form a gas. In some cases, the chamber may also include a coating (eg, to prevent the fluid from contacting the polymer moiety under the coating dissolve). In another exemplary embodiment, the jet injection component comprises a plunger / piston (eg, activated by a spring attached to the plunger / piston) for rapid ejection of material from the system.

In some embodiments, the organization<u style="Single">connection</u>The component comprises a spring actuating component. Such an organization<u style="Single">connection</u>The components are generally described in co-owned U.S. Patent Application No. 62 / 507,653 filed May 17, 2017, whose invention is named "SELF-ACTUATING ARTICLES", which is in its entirety. Is incorporated herein by reference. For example, an organization<u style="Single">connection</u>A self-restoring article with a component (eg, a needle) can be administered to the subject so that the self-righting article is tissue at a location within the subject's body.<u style="Single">connection</u>An opponent is oriented to puncture tissue close to a location in the subject's body. And, in some such modified embodiments, the active pharmaceutical ingredient associated with the self-restoring article can be released into and / or in close proximity to the tissue. In some embodiments, the organization<u style="Single">connection</u>The components can penetrate the organization. In some embodiments, the tissue is greater than or equal to 1 mN and less than or equal to 20,000 mN (eg, greater than or equal to 10 mN and less than or equal to 20 mN, 10 mN). Greater than or equal to and less than 100 mN or equal, greater than or equal to 100 mN and less than or equal to 20,000 mN or less than 20,000 mN, greater than or equal to 5,000 mN and less than 20,000 mN Penetrate with force (with or equal to).

In certain embodiments, the organization<u style="Single">connection</u>Tissue when the component is administered to a subject within a self-restoring article<u style="Single">connection</u>The components can be oriented so that they are aligned substantially orthogonally (eg, within 15 ° from a right angle) to the tissue in the subject's body (eg, GI mucosal tissue). In some embodiments, the organization<u style="Single">connection</u>The components are tissue inside the hollow portion of the self-healing device.<u style="Single">connection</u>The components may be arranged to be ejected from the self-restoring device along the longitudinal axis of the hollow portion. For example, with reference to FIG. 2 again, the self-restoring article may have a longest longitudinal axis 180 aligned within 15 degrees from a right angle to the tissue engaging surface 150. In certain embodiments, the longest longitudinal axis 180 is tissue.<u style="Single">connection</u>It is parallel to the main axis of the component 130. In some embodiments, the organization<u style="Single">connection</u>The component 130 is released (eg, when the self-actuating component 120 and / or the spring 125 is activated) so that the spring 125 unfolds along the longitudinal axis 180 and / or the tissue.<u style="Single">connection</u>The components travel parallel to the direction of longitudinal axis 180. In some such embodiments, the organization<u style="Single">connection</u>The component can exit the hole 140 and enter the tissue of interest in a direction substantially parallel to the longitudinal axis 180. However, in other embodiments, the organization<u style="Single">connection</u>The components are not aligned substantially orthogonal to the tissue in the subject's body.

In some embodiments, the self-restoring article is less than or equal to 15 degrees from the vertical, less than or equal to 10 degrees, less than 5 degrees or equal to, less than 2 degrees or equal to self-restored. , Or has the longest longitudinal axis oriented within a range less than or equal to 1 degree. In certain embodiments, the self-restoring article is greater than or equal to 0.1 degrees, greater than or equal to 1 degree, greater than or equal to 2 degrees, greater than or equal to, greater than or equal to 5 degrees, or 10 degrees. It has the longest longitudinal axis oriented in a range greater than or equal to degrees. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.1 degrees and less than or equal to 15 degrees). Other ranges are possible.

In certain embodiments, the organization<u style="Single">connection</u>When self-restored, the components are less than or equal to 15 degrees from the vertical, less than or equal to 10 degrees, less than or equal to 5 degrees or less than 5 degrees, less than or equal to 2 degrees or less than 1 degree, or less than 1 degree or more. It has the longest longitudinal axis oriented within the same range. In some embodiments, the organization<u style="Single">connection</u>Components are in the range greater than or equal to 0.1 degrees, greater than or equal to 1 degree, greater than or equal to 2 degrees, greater than or equal to 2 degrees, greater than or equal to 5 degrees, or greater than or equal to 10 degrees. It has the longest longitudinal axis oriented inward. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.1 degrees and less than or equal to 15 degrees). Other ranges are possible.

In some embodiments, the hollow portion may have a cylindrical shape. Other shapes are possible.

In an exemplary embodiment, the organization<u style="Single">connection</u>The component comprises a plurality of microneedles. In another exemplary embodiment, the organization<u style="Single">connection</u>The component comprises a single needle. In yet another exemplary embodiment, the organization<u style="Single">connection</u>The component comprises a biopsy component (eg, a biopsy jaw). In some cases, the organization<u style="Single">connection</u>The component may include a mooring mechanism (eg, hook, mucosal adhering material). Organization<u style="Single">connection</u>The components are described in more detail below.

As mentioned above, in some embodiments, the first portion comprises a first material having a first average density. In some embodiments, the first and / or second material can be selected to impart a particular mass and / or density to the first and / or second portion.

In some embodiments, the average density of the first portion is less than or equal to 2 g / mL, less than or equal to 1.8 g / mL, less than or equal to 1.6 g / mL, or equal. Less than or equal to 1.4 g / mL, less than or equal to 1.2 g / mL, less than or equal to 1 g / mL, less than or equal to 0.8 g / mL, or equal to 0.6 g Less than / mL or equal, less than 0.4 g / mL or equal, less than 0.2 g / mL or equal, less than 0.1 g / mL or equal, 0.05 g / mL Less than or equal to, or less than or equal to 0.02 g / mL. In certain embodiments, the first portion is greater than or equal to 0.01 g / mL, greater than or equal to 0.02 g / mL, greater than or equal to 0.05 g / mL, or equal to 0.1 g / mL. Greater than or equal to, greater than or equal to 0.2 g / mL, greater than or equal to 0.4 g / mL, greater than or equal to 0.6 g / mL, greater than or equal to, greater than or equal to 0.8 g / mL , Greater than or equal to 1 g / mL, greater than or equal to 1.2 g / mL, greater than or equal to 1.4 g / mL, greater than or equal to 1.6 g / mL or equal to, or greater than 1.8 g / mL It has a large or equal average density. Combinations in the ranges mentioned above are also possible (eg, greater than or equal to 0.01 g / mL and less than or equal to 2 g / mL, greater than or equal to 0.6 g / mL and 2 g / mL. Less than or equal to mL). Other ranges are possible.

In certain embodiments, the second portion comprises a second material having a second average density (eg, different from the first average density). In some embodiments, the average density of the second portion (eg, and / or the second material) is less than or equal to 20 g / mL, less than or equal to 18 g / mL, or equal to 16 g. Less than / mL or equal, less than 14 g / mL or equal, less than 12 g / mL or equal, less than 10 g / mL or equal, less than 8 g / mL Or equally, less than or equal to 6 g / mL, less than or equal to 4 g / mL, less than or equal to, or less than or equal to 3 g / L. In certain embodiments, the average density of the second portion is greater than or equal to 2 g / mL, greater than or equal to 3 g / mL, greater than or equal to 4 g / mL, or greater than 6 g / mL. Greater or equal, greater than or equal to 8 g / mL, greater than or equal to 10 g / mL, greater than or equal to 12 g / mL, greater than or equal to 14 g / mL or greater than or equal to, greater than 16 g / mL Larger or equal, or greater than or equal to 18 g / mL. Combinations in the ranges mentioned above are also possible (eg, greater than or equal to 2 g / mL and less than or equal to 20 g / mL). Other ranges are possible. In some embodiments, the second portion is the average density in one or more ranges described above in relation to the first portion (eg, greater than or equal to 0.6 g / mL, and 2 g / It may have less than or equal to mL) and may have an average density different from the average density of the first part.

The first and second parts can be selected to have any suitable mass. In some embodiments, the first portion comprises any mass between 20 mg and 15 g, greater than or equal to 20 mg, greater than or equal to 50 mg, greater than or equal to 50 mg, greater than or equal to 75 mg, 100 mg. Greater than or equal to, greater than or equal to 200 mg, greater than or equal to 300 mg, greater than or equal to 400 mg, greater than or equal to 400 mg, greater than or equal to 500 mg, greater than or equal to 750 mg, greater than 1 g Or equal to it, greater than or equal to 1.5g, greater than or equal to 2g, greater than or equal to 2g, greater than or equal to 3g, greater than or equal to 4g, greater than or equal to, greater than or equal to 5g, greater than or equal to 7g Or it may have a total mass equal to or greater than 10 g or equal to it, greater than 15 g or equal to it (eg, including all components in the first part). In certain embodiments, the first portion comprises any mass between 15 g and 20 mg, less than or equal to 15 g, less than or equal to 10 g, less than or equal to, less than 7 g or equivalent, less than 5 g or Equal to it, less than 4g or equal to it, less than 3g or equal to it, less than 2g or equal to it, 1. Less than 5g or equal, less than 1g or equal, less than 750mg or equal, less than 500mg or equal, less than 400mg or equal, less than 300mg or equal, less than 200mg or equal, 100mg It can have a total mass of less than or equal to, less than 75 mg or equal to it, less than 50 mg or equal to it, or less than 20 mg or equal to it. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 50 mg and less than or equal to 4 g, greater than or equal to 50 mg and less than or equal to 15 g). In some embodiments, the first or second portion has a mass greater than or equal to 20 mg and a mass in the range of less than or equal to 15 g. In some embodiments, the first or second portion has a mass greater than or equal to 20 mg and less than or equal to 1 g. In some embodiments, the first or second portion has a mass greater than or equal to 300 mg and less than or equal to 12 g. In some embodiments, the first or second portion has a mass greater than or equal to 100 mg and less than or equal to 250 mg. In some embodiments, the first or second portion has a mass greater than or equal to 20 mg and a mass in the range of less than or equal to 15 g. In some embodiments, the first or second portion has a mass greater than or equal to 1.5 and a mass in the range of less than or equal to 6.5 g. Other ranges are possible. Has a mass in the range of less than or equal to 5 g. Other ranges are possible. Has a mass in the range of less than or equal to 5 g. Other ranges are possible. Has a mass in the range of less than or equal to 5 g. Other ranges are possible. Has a mass in the range of less than or equal to 5 g. Other ranges are possible.

In certain embodiments, the second portion is greater than or equal to 50 mg or equal to, greater than or equal to 75 mg, greater than or equal to 100 mg, greater than or equal to 100 mg, greater than or equal to 200 mg, greater than or equal to 400 mg, or Equal, greater than or equal to 500 mg, greater than or equal to 750 mg, greater than or equal to 1 g, greater than or equal to 1.5 g, greater than or equal to 1.5 g, greater than or equal to 2 g or equal to, greater than or equal to 3 g or more Equal, greater than or equal to 4g, greater than or equal to 5g, greater than or equal to 7g, greater than or equal to, or greater than or equal to 10g or equal to the total mass (eg, all components in the second part) Including). In certain embodiments, the second portion is less than 15 g or equal, less than 10 g or equal, less than 7 g or equal, less than 5 g or equal, less than 4 g or equal, less than 3 g. Or equal, less than 2g or equal, less than 1.5g or equal, less than 1g or equal, less than 750mg or equal, less than 500mg or equal, less than 400mg or equal, less than 200mg Or equal to, less than 100 mg or equal to, or less than 75 mg or equal to total mass. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 50 mg and less than or equal to 4 g, greater than or equal to 50 mg and less than or equal to 15 g). Other ranges are possible.

In some embodiments, the first and / or second material is selected from the group consisting of polymers, ceramics, metals and combinations thereof (eg, metal-filled polymers). In some cases, the first and / or second material may be biocompatible. In some cases, the metal can be selected from the group consisting of stainless steel, iron-carbon alloys, field metal, tungsten, molybdenum, gold, zinc, iron and titanium.

In some embodiments, the ceramic can be selected from the group consisting of hydroxyapatite, aluminum oxide, calcium oxide, tricalcium phosphate, silicates, silicon dioxide, and zirconium oxide.

In certain embodiments, the polymer can be selected from the group consisting of polycaprolactone, polylactic acid, polyethylene glycol, polypropylene, polyethylene, polycarbonate, polystyrene, and polyetheretherketone, and polyvinyl alcohol.

In an exemplary embodiment, the first material comprises a metal and the second material comprises a polymer.

Self-restoring articles generally have a geometric center (eg, a geometric volume center). In certain embodiments, the density, mass and / or volume of the first and / or second portion can be selected so that the self-restoring article exhibits self-restoring behavior. For example, in some embodiments, the center of mass of the self-restoring article may deviate from the center of gravity so that an article suspended across an axis passing through the center of gravity has the center of mass lateral to the center of gravity. 0.09 × 10 because it is shifted to the direction^-4It is configured to maintain an orientation of 20 degrees or less from the vertical when an externally applied torque of Nm or less is applied.

In some embodiments, the self-restoring article is 0.09 × 10^-4When an externally applied torque of Nm or less is applied, the orientation is maintained at 20 ° or less from the vertical. In certain embodiments, the self-restoring article is 0.09 × 10^-4When externally applied torque of Nm or less is applied, 15 ° or less, 12 ° or less, 10 ° or less, 8 ° or less, 6 ° or less, 4 ° or less, from the vertical. Or maintain an orientation of 2 ° or less. In some embodiments, the self-restoring article is 0.09 × 10^-4When an externally applied torque of Nm or less is applied, it is greater than or equal to 1 ° from the vertical, greater than or equal to 2 °, greater than or equal to 4 ° or equal to it, greater than or equal to 6 °, or equal to it. Maintain orientation greater than or equal to 8 °, greater than or equal to 10 °, greater than or equal to 12 °, greater than or equal to 15 °, or equal. Combinations of the ranges mentioned above are also possible (eg, 20 ° or less, and greater than or equal to 1 °). Other ranges are possible.

In some embodiments, the self-restoring article may be characterized by having a particular self-restoring time from 90 ° in a particular fluid. The self-restoring time is the placement of the self-restoring article in a particular fluid at 90 °, and the particular orientation maintained differently by the self-restoring article in the absence of that fluid (eg, stable equilibrium of the article). It can be determined by leaving the auto-restored object back to (or the orientation corresponding to the orientation) point.

In certain embodiments, the fluid is oil. In some such embodiments, the self-restoring article is from 90 ° in oil, less than or equal to 0.15 seconds, less than or equal to 0.1 seconds, less than or equal to 0.05 seconds, or 0.02 seconds. Has less than or equal to self-restoration time. In certain embodiments, the self-restoring article is from 90 ° in oil, longer than or equal to 0.01 seconds, longer or equal to 0.02 seconds, longer or equal to 0.05 seconds, greater than 0.1 seconds. It has a self-restoring time that is long or equal, or longer than or equal to 0.12 seconds. Combinations of the ranges mentioned above are also possible (eg, less than 0.15 seconds or equivalent, and longer than or equal to 0.01 seconds). Other ranges are possible. Self-restoration time in oil is determined by completely immersing the system / article.

In some embodiments, the fluid is gastric fluid. In some such embodiments, the self-restoring article is from 90 ° in gastric fluid, less than or equal to 0.06 seconds, less than 0.05 seconds or equal, less than 0.04 seconds or equal, less than 0.03 seconds. Has a self-restoring time of less than or equal to, or less than or equal to 0.02 seconds. In certain embodiments, the self-restoring article is from 90 ° in gastric fluid, longer or equal to 0.005 seconds, longer or equal to 0.01 seconds, longer or equal to 0.02 seconds, greater than 0.03 seconds. It has a self-restoring time that is long or equal, longer than 0.04 seconds or equal to it, or longer than 0.05 seconds or equal. Combinations of the ranges mentioned above are also possible (eg, less than 0.06 seconds or equal, and longer than or equal to 0.005 seconds). Other ranges are possible. Self-restoration time in gastric juice is determined by complete immersion of the system / article.

In certain embodiments, the fluid is mucus. In some such embodiments, the self-restoring article is from 90 ° in mucus, less than 0.05 seconds or equal, less than 0.04 seconds or equal, less than 0.03 seconds or equal, or less than 0.02 seconds. Has a self-restoring time of or equal to. In certain embodiments, the self-restoring article is from 90 ° in mucus, greater than or equal to 0.005 seconds, greater than or equal to 0.01 seconds, greater than or equal to 0.02 seconds, greater than 0.03 seconds. It has a self-restoring time that is long or equal, longer than 0.04 seconds or equal to it, or longer than 0.045 seconds or equal. Combinations of the ranges mentioned above are also possible (eg, less than 0.05 seconds or equal to it, and longer than or equal to 0.005 seconds). Other ranges are possible. Self-restoration time in mucus is determined by complete immersion of the system / article.

In some embodiments, the fluid is water. In some such embodiments, the self-restoring article is from 90 ° in water, less than or equal to 0.05 seconds, less than or equal to 0.04 seconds, less than or equal to, less than 0.03 seconds or less than equal to, or less than 0.02 seconds. Or have a self-restoring time equal to that. In certain embodiments, the self-restoring article is from 90 ° in water, longer or equal to 0.005 seconds, longer or equal to 0.01 seconds, longer or equal to 0.02 seconds, longer than 0.03 seconds. It has a self-restoring time equal to or equal to, longer than 0.04 seconds or equal to it, or longer than or equal to 0.045 seconds. Combinations of the ranges mentioned above are also possible (eg, less than 0.05 seconds or equal to it, and longer than or equal to 0.005 seconds). Other ranges are possible. The self-restoration time in water is determined by completely immersing the system / article.

In some embodiments, the self-restoring article comprises one or more outlets (eg, to allow flow of air and / or fluid through the self-restoring article). In some embodiments, the self-restoring article is one or more (eg, two or more) associated with at least a portion (eg, first part, second part) of the self-restoring article. Equipped with 3 or more, 4 or more) outlets. In some such embodiments, the outlet can allow the fluid (eg, gastric fluid) to enter at least a portion of the self-restoring article, resulting in, for example, a self-acting component and / or. The spring is exposed to the fluid (eg, as a result, the self-actuating component and / or the spring is actuated). For example, with reference to FIG. 2 again, the system 102 comprises an outlet 190 attached to at least a portion of the self-restoring article (eg, first portion 110). In some cases, the outlet 190 may also have fluid communication with the self-acting component 120, the support 160 and / or the spring 125. The outlet is depicted herein as accompanying a first portion of a self-restoring article in some embodiments, but one or more outlets are a second portion of the self-restoring article. It will be appreciated by those skilled in the art on the basis of the teachings herein that it may be incidental to.

In certain embodiments, the self-restoring article does not include an outlet.

In some embodiments, the self-restoring article may have a particular size of cross-sectional dimensions. In some embodiments, the maximum cross-sectional dimension of the self-restoring article is less than or equal to 2.0 cm, less than or equal to 1.8 cm, less than or equal to, less than or equal to 1.6 cm, or less than 1.4 cm. Is or equal, less than 1.2 cm or equal, less than 1.1 cm or equal, less than 1 cm or equal, less than 0.8 cm or equal, less than 0.6 cm Or equal to it, less than 0.4 cm or equal to it, or less than 0.2 cm or equal to it, this is any dimension less than 2.0 cm (eg 0.1 cm, 0.3 cm, 0.5 cm ... 1.7 cm etc.) is included. In certain embodiments, the maximum cross-sectional dimensions of the self-restoring article are greater than or equal to 0.1 cm, greater than or equal to 0.2 cm, greater than or equal to 0.4 cm, greater than or equal to, greater than or equal to 0.6 cm, or equal to it. Equal, greater than 0.8 cm or equal, greater than 1 cm or equal, greater than 1.2 cm or equal, greater than 1.4 cm or equal, greater than 1.6 cm or equal, greater than 1.8 cm Or equal to, this includes any dimensions greater than 0.1 cm and less than 2.0 cm or equivalent (eg 0.3 cm, 0.5 cm ... 1.7 cm, 1.9 cm, etc.). Combinations of the ranges mentioned above are also possible (eg, less than 2 cm or equal to it and greater than or equal to 0.1 cm, less than 1.1 cm or equal to it, and greater than 0.1 cm). Or equal to it). Other ranges are possible.

In some embodiments, self-restoring articles can be administered to the subject (eg, orally). In some such embodiments, the self-restoring article may contain one or more pharmaceutical active ingredients. In certain embodiments, the active pharmaceutical ingredient is released at a location within the subject's body (eg, in a GI tube).

In certain embodiments, one or more sensors may be associated with the self-restoring article. For example, in some cases, one or more sensors may be used to determine the location of the self-restoring article (eg, the position within the subject's body) and / or one associated with the self-restoring article. Or multiple organizations<u style="Single">connection</u>It can induce the action of components. Non-limiting examples of suitable sensors include pH, gas, light, GPS, Bluetooth®, orientation, proximity, thermal, fluid and others.

In some cases, one or more of the first and / or second parts may be magnetic.

In an exemplary embodiment, the self-restoring article is ingestible. According to certain embodiments, the ingestible self-restoring article ingests a first portion having an average density; a second portion having an average density different from the average density of the first portion; and an article. It comprises a payload portion carrying a drug for release into the body of the subject. In certain embodiments, the self-restoring article is 1 g / cm.³It comprises at least a first portion having a higher average density. According to certain embodiments, the ratio of the average density of the first part to the average density of the second part is greater than or equal to 2.5: 1. In certain exemplary embodiments, the self-restoring article has a first portion containing a first material having a first average density; and a second having a second average density different from the first average density. It comprises a second part containing the material of. In certain embodiments, the self-restoring article comprises a first material, a second material different from the first material, and a pharmaceutically active agent associated with the self-restoring article. According to some embodiments, the ratio of the average density of the first material to the average density of the second material is greater than or equal to 2.5: 1. In some embodiments, the self-restoring article has a maximum cross-sectional dimension of less than 2 cm or equal (eg, less than or equal to 1.1 cm).

In one particular embodiment, the article is 0.09 × around the axis due to gravity because the article suspended across an axis passing through the center of geometry is laterally offset from the center of gravity by the center of mass. Ten^-4It has a geometric center and a center of mass deviated from the geometric center such that it receives an externally applied torque of Nm or less. According to some embodiments, the self-restoring article is configured to be encapsulated in 000 or smaller capsules. In other embodiments, the self-restoring article is not encapsulated. In certain embodiments, the self-restoring article is the tissue associated with the self-restoring article.<u style="Single">connection</u>It has components. Some exemplary embodiments are 0.09 × 10^-4With respect to an axis essentially perpendicular to the tissue engaging surface of the self-restoring article, which is configured to maintain an orientation of 20 degrees or less from the vertical when an externally applied torque of Nm or less is applied. According to some embodiments, the self-restoring article has the most stable, lowest potential energy physical composition and 0.05 seconds from an orientation 90 degrees out of any direction from the most stable composition in water. It has a self-restoring time less than or equal to it. According to certain embodiments, the self-restoring article has a blockage rate of less than 1% or equal (eg, less than 0.5% or equal, less than 0.1% or equal).

Certain exemplary embodiments relate to methods of delivering a pharmaceutical agent to a location within a subject's body. According to some embodiments, the method is to administer a capsule containing an external shell and self-restoring article to the subject, and at a location within the subject's body, the tissue.<u style="Single">connection</u>Includes the step of orienting the self-restoring article so that the component punctures tissue close to a location within the subject's body.

Organizational mooring

In some embodiments, the article (eg, self-restoring article) may be configured to be tethered to a location within the subject (eg, tissue at a location within the subject). As mentioned above, in some embodiments, the self-restoring article is one or more tissues comprising one or more mooring mechanisms (eg, hooks, mucosal depositors).<u style="Single">connection</u>It can be equipped with components. Hooks are described in more detail below. Mucosal deposits are described in more detail below. In some embodiments, the self-restoring article is 0.09 × 10^-4With a longitudinal axis perpendicular to the tissue engaging surface of the article, which is configured to maintain an orientation of 20 degrees or less from the vertical when an externally applied torque of Nm or less is applied; attached to the self-restoring article. In some cases, it may have at least one mooring mechanism. In another exemplary embodiment, the article is attached to the support (eg, at least partially encapsulated in the support) (eg, as a result, the spring is at least 5% compressive strain due to the support). It may be equipped with a spring (which is kept at least partially compressed underneath); and at least one mooring mechanism operably coupled to the spring. Springes and supports are described in more detail below. Other embodiments are also possible that include at least one mooring mechanism associated with a self-restoring article and / or a self-acting component.

In some embodiments, the mooring mechanism comprises a hook (eg, a hooked needle). For example, as illustrated in FIG. 5, the system 104 comprises a first portion 110 and a second portion 115. In certain embodiments, the tissue engaging surface 150 is attached to a second portion 115. In some cases, the system 104 is an organization comprising a mooring mechanism 135.<u style="Single">connection</u>It may include a component 130. In some embodiments, the mooring mechanism 135 can be a hook. In certain embodiments, the mooring mechanism 135 is placed within the system 104 and released under the desired set of conditions (eg, via hole 140) (eg, at a particular location within the subject's body). Can be done. In certain embodiments not illustrated in FIG. 5, the hook 135 may be located on the outer surface of the system 104.

Then, with reference to FIG. 6, in certain embodiments, the system 106 comprises a tethering mechanism 135 attached to a self-acting component 120 (eg, comprising a spring 125 and / or a support 160). In certain embodiments, the self-acting component is exposed to a fluid (eg, gastric juice) and / or under a particular set of conditions (eg, gastrointestinal physiologic conditions such as those in the stomach). , Acts to insert a mooring mechanism into the tissue located inside the subject's body.

In some embodiments, the mooring mechanism (and / or the article comprising the mooring mechanism) is configured to reside in a position within the subject's body. For example, in some embodiments, the mooring mechanism engages with a surface at a location within the body of the subject (eg, the surface of a tissue) and, as a result, resides at that location.

Advantageously, systems comprising one or more mooring mechanisms described herein may be inserted into the surface of tissue at a location within the body of the subject, and these systems may have a relatively large applied force. And / or can maintain contact with the tissue under relatively large orientation changes (eg, by the gastrointestinal tract and / or at high flow rates in the gastrointestinal tract, due to the compressive force applied). In some embodiments, the system described herein allows for longer contact times, eg, limiting flow, without substantially blocking the opening in the gastrointestinal tract (eg, in the pylorus). To. In certain embodiments, the natural replacement of the wall of the gastrointestinal tract allows for the desired detachment and / or drainage of the system described herein without the need for surgical and / or endoscopic recovery. sell.

For example, in some embodiments, the tethering mechanism may be inserted into the surface of the tissue at a location within the body of the subject, and the tethering mechanism may be greater than or equal to 1 degree, greater than or equal to 2 degrees, or equivalent. , Greater than 5 degrees or equal, greater than 10 degrees or equal, greater than 15 degrees or equal, greater than 20 degrees or equal, greater than 25 degrees or equal, greater than 30 degrees Or equal to, greater than or equal to 45 degrees, greater than or equal to 60 degrees, greater than or equal to 60 degrees, greater than or equal to 75 degrees or equal to, or greater than or equal to 85 degrees or equal to, under changes in system orientation. , Maintain contact with tissue (eg, keep the system moored). In certain embodiments, the system is less than 90 degrees or equal, less than 85 degrees or equal, less than 75 degrees or equal, less than 60 degrees or equal, less than 45 degrees or equal, Less than 30 degrees or equal, less than 25 degrees or equal, less than 20 degrees or equal, less than 15 degrees or equal, less than 10 degrees or equal, less than 5 degrees or equal, or 2 degrees It can remain moored under changes in system orientation that are less than or equal to the degree. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 1 degree and less than or equal to 90 degrees, greater than or equal to 1 degree and less than 45 degrees, or Equal, greater than or equal to 2 degrees, and less than or equal to 30 degrees). Other ranges are possible.

In certain embodiments, the system (eg, comprising a mooring mechanism) is greater than or equal to 0.002N per mooring mechanism, greater than or equal to 0.004N, greater than or equal to 0.004N, greater than or equal to 0.006N, or equivalent. , Greater than or equal to 0.008N, greater than or equal to 0.01N, greater than or equal to 0.012N, greater than or equal to 0.012N, greater than or equal to 0.014N, greater than or equal to 0.016N, greater than 0.018N Or equal to, greater than or equal to 0.02N, greater than or equal to 0.025N, greater than or equal to 0.03N, greater than or equal to 0.04N, greater than or equal to 0.04N, greater than or equal to 0.05N, or equal to, Greater than or equal to 0.1N, greater than or equal to 0.15N, greater than or equal to 0.15N, greater than or equal to 0.2N, greater than or equal to 0.25N, greater than or equal to 0.25N, greater than or equal to 0.3N, greater than or equal to 0.35N Or equal to it, greater than or equal to 0.4N, greater than or equal to 0.5N, greater than or equal to 0.6N, greater than or equal to 0.7N, greater than or equal to 0.7N, greater than or equal to 0.8N, or equal to or equal to it. It is configured to stay at a position within the subject's body under a vertical holding force for a vertical application force greater than or equal to 0.9N. In some embodiments, the system is less than or equal to 1N per mooring mechanism, less than or equal to 0.9N, less than or equal to 0.8N, less than or equal to 0.7N, less than 0.6N. Or equal to it, less than 0.5N or equal to it, less than 0.4N or equal to it, less than 0.35N or equal to it, less than 0.3N or equal to it, 0. Less than 25N or equal, less than 0.2N or equal, less than 0.15N or equal, less than 0.1N or equal, less than 0.05N or equal, less than 0.04N or equal, less than 0.03N Or equal to, less than 0.025N or equal, less than 0.02N or equal, less than 0.018N or equal, less than 0.016N or equal, less than 0.014N or equal, less than 0.012N or It has a vertical holding force for a vertical application force equal to, less than 0.01N or equal to it, less than 0.008N or equal to it, less than 0.006 or equal to it, or less than 0.004N or equal to it. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.002N, less than or equal to 1N, greater than or equal to 0.02N and less than or equal to 0.08N, or it. Equal, greater than or equal to 0.1N, and less than or equal to 1N). Other ranges are possible. The vertical holding force described herein inserts the mooring mechanism of the system into the surface of the tissue (eg, ex vivo pig stomach) to a penetration depth of at least 0.9 mm and then in a direction orthogonal to the surface of the tissue. Can be determined by pulling the system until it leaves the tissue. The maximum force before the system leaves is the vertical holding force. Less than 014N or equal, less than 0.012N or equal, less than 0.01N or equal, less than 0.008N or equal, less than 0.006 or equal, or less than 0.004N or equal to vertical applied force Has vertical holding power. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.002N, less than or equal to 1N, greater than or equal to 0.02N and less than or equal to 0.08N, or it. Equal, greater than or equal to 0.1N, and less than or equal to 1N). Other ranges are possible. The vertical holding force described herein inserts the mooring mechanism of the system into the surface of the tissue (eg, ex vivo pig stomach) to a penetration depth of at least 0.9 mm and then in a direction orthogonal to the surface of the tissue. Can be determined by pulling the system until it leaves the tissue. The maximum force before the system leaves is the vertical holding force. Less than 014N or equal, less than 0.012N or equal, less than 0.01N or equal, less than 0.008N or equal, less than 0.006 or equal, or less than 0.004N or equal to vertical applied force Has vertical holding power. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.002N, less than or equal to 1N, greater than or equal to 0.02N and less than or equal to 0.08N, or it. Equal, greater than or equal to 0.1N, and less than or equal to 1N). Other ranges are possible. The vertical holding force described herein inserts the mooring mechanism of the system into the surface of the tissue (eg, ex vivo pig stomach) to a penetration depth of at least 0.9 mm and then in a direction orthogonal to the surface of the tissue. Can be determined by pulling the system until it leaves the tissue. The maximum force before the system leaves is the vertical holding force. It can be determined by inserting to a penetration depth of 9 mm and then pulling the system in a direction orthogonal to the surface of the tissue until the system leaves the tissue. The maximum force before the system leaves is the vertical holding force. It can be determined by inserting to a penetration depth of 9 mm and then pulling the system in a direction orthogonal to the surface of the tissue until the system leaves the tissue. The maximum force before the system leaves is the vertical holding force.

In some embodiments, the system (eg, comprising a mooring mechanism) is greater than or equal to 0.002N per mooring mechanism, greater than or equal to 0.004N, greater than or equal to 0.004N, greater than or equal to 0.006N, or equivalent. , Greater than or equal to 0.008N, greater than or equal to 0.01N, greater than or equal to 0.012N, greater than or equal to 0.012N, greater than or equal to 0.014N, greater than or equal to 0.016N, greater than 0.018N Or equal to, greater than or equal to 0.02N, greater than or equal to 0.025N, greater than or equal to 0.03N, greater than or equal to 0.04N, greater than or equal to 0.04N, greater than or equal to 0.05N, or equal to, Greater than or equal to 0.1N, greater than or equal to 0.15N, greater than or equal to 0.15N, greater than or equal to 0.2N, greater than or equal to 0.25N, greater than or equal to 0.25N, greater than or equal to 0.3N, greater than or equal to 0.35N Or equal to it, greater than or equal to 0.4N, greater than or equal to 0.5N, greater than or equal to 0.6N, greater than or equal to 0.7N, greater than or equal to 0.7N, greater than or equal to 0.8N, or equal to or equal to it. It is configured to stay at a position in the subject's body under orthogonal holding force for a vertical application force greater than or equal to 0.9N. In some embodiments, the system is less than or equal to 1N per mooring mechanism, less than or equal to 0.9N, less than or equal to 0.8N, less than or equal to 0.7N, less than 0.6N. Or equal to it, less than 0.5N or equal to it, less than 0.4N or equal to it, less than 0.35N or equal to it, less than 0.3N or equal to it, 0. Less than 25N or equal, less than 0.2N or equal, less than 0.15N or equal, less than 0.1N or equal, less than 0.05N or equal, less than 0.04N or equal, less than 0.03N Or equal to, less than 0.025N or equal, less than 0.02N or equal, less than 0.018N or equal, less than 0.016N or equal, less than 0.014N or equal, less than 0.012N or It has an orthogonal holding force for a vertical application force equal to, less than 0.01N or equal to it, less than 0.008N or equal to it, less than 0.006 or equal to it, or less than 0.004N or equal to it. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.002N, less than or equal to 1N, greater than or equal to 0.02N and less than or equal to 0.08N, or it. Equal, greater than or equal to 0.1N, and less than or equal to 1N). Other ranges are possible. The orthogonal holding force described herein inserts the mooring mechanism of the system into the surface of the tissue (eg, ex vivo pig stomach) to a penetration depth of at least 0.9 mm and then in a direction parallel to the surface of the tissue. Can be determined by applying force to the system (see, eg, FIG. 59) until it leaves the tissue. The maximum force before the system leaves is the orthogonal holding force. Less than 016N or equal, less than 0.014N or equal, less than 0.012N or equal, less than 0.01N or equal, less than 0.008N or equal, less than 0.006 or equal, or less than 0.004N It has an orthogonal holding force for a vertical application force equal to or equal to that of. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.002N, less than or equal to 1N, greater than or equal to 0.02N and less than or equal to 0.08N, or it. Equal, greater than or equal to 0.1N, and less than or equal to 1N). Other ranges are possible. The orthogonal holding force described herein inserts the mooring mechanism of the system into the surface of the tissue (eg, ex vivo pig stomach) to a penetration depth of at least 0.9 mm and then in a direction parallel to the surface of the tissue. Can be determined by applying force to the system (see, eg, FIG. 59) until it leaves the tissue. The maximum force before the system leaves is the orthogonal holding force. Less than 016N or equal, less than 0.014N or equal, less than 0.012N or equal, less than 0.01N or equal, less than 0.008N or equal, less than 0.006 or equal, or less than 0.004N It has an orthogonal holding force for a vertical application force equal to or equal to that of. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.002N, less than or equal to 1N, greater than or equal to 0.02N and less than or equal to 0.08N, or it. Equal, greater than or equal to 0.1N, and less than or equal to 1N). Other ranges are possible. The orthogonal holding force described herein inserts the mooring mechanism of the system into the surface of the tissue (eg, ex vivo pig stomach) to a penetration depth of at least 0.9 mm and then in a direction parallel to the surface of the tissue. Can be determined by applying force to the system (see, eg, FIG. 59) until it leaves the tissue. The maximum force before the system leaves is the orthogonal holding force. Judgment can be made by inserting to a penetration depth of 9 mm and then applying force to the system in a direction parallel to the surface of the tissue until the system disengages from the tissue (see, eg, Figure 59). can. The maximum force before the system leaves is the orthogonal holding force. Judgment can be made by inserting to a penetration depth of 9 mm and then applying force to the system in a direction parallel to the surface of the tissue until the system disengages from the tissue (see, eg, Figure 59). can. The maximum force before the system leaves is the orthogonal holding force.

In some embodiments, the system is located within the subject's body under an orientation change of less than 30 degrees or equal to it, and an applied (eg, vertical, orthogonal) force of less than 1N or equal to it. It is configured to remain moored to the surface of the tissue.

In some embodiments, the system comprises two or more mooring mechanisms. In some cases, the system may comprise a single self-restoring article with two or more mooring mechanisms. In certain embodiments, the system comprises two or more self-restoring articles, each comprising one or more mooring mechanisms. In certain embodiments, the force required to disengage the mooring mechanism (eg, vertical holding force, orthogonal holding force) can be increased by increasing the number of mooring mechanisms associated with the system. can. Although not desired to be constrained by theory, the spacing between mooring mechanisms can be related to the system's holding power (eg, vertical holding power, orthogonal holding power).

In some embodiments, the system is greater than or equal to 0.1 mm, greater than or equal to 0.2 mm, greater than or equal to 0.2 mm, greater than or equal to 0.3 mm or equal to, greater than or equal to 0.4 mm or equal to, greater than 0.5 mm. Or equal to, 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 0.8 mm, greater than or equal to 0.9 mm, greater than or equal to, greater than or equal to 1 mm, 1.2 Greater than or equal to mm, greater than or equal to 1.4 mm, greater than or equal to 1.4 mm, greater than or equal to 1.5 mm, greater than or equal to 1.6 mm, greater than or equal to 1.6 mm, greater than or equal to 1.8 mm or equal to, or greater than 2 mm It can have an equal average spacing between mooring mechanisms. In certain embodiments, the system is less than or equal to 2.5 mm, less than or equal to 2 mm, less than or equal to 1.8 mm, less than or equal to 1.8 mm, less than or equal to 1.6 mm, less than or equal to 1.4 mm, 1.2. Less than or equal to mm, less than 1 mm or equal, less than 0.9 mm or equal, less than 0.8 mm or equal, less than 0.7 mm or equal, less than 0.6 mm or equal, less than 0.5 mm Or it may have an average spacing between mooring mechanisms equal to or less than 0.4 mm or equal to it, less than 0.3 mm or equal to it, or less than 0.2 mm or equal to it. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.1 mm and less than or equal to 2.5 mm, greater than or equal to 1 mm and less than or equal to 1.5 mm, or it. equal). Other ranges are possible.

The mooring mechanism can have any suitable size and / or shape. For example, in some embodiments, an organization comprising a mooring mechanism.<u style="Single">connection</u>The maximum dimensions (eg, length) of the component are less than or equal to 1 cm, less than or equal to 0.8 cm, less than or equal to 0.6 cm, less than or equal to, less than or equal to 0.5 cm, 0.4 cm. It may be less than or equal to, less than 0.3 cm or equal to it, less than or equal to 0.25 cm, less than 0.23 cm or equal to it, or less than or equal to 0.2 cm. In certain embodiments, an organization comprising a mooring mechanism.<u style="Single">connection</u>The maximum dimensions (eg, length) of a component are greater than or equal to 0.15 cm, greater than or equal to 0.2 cm, greater than or equal to 0.23 cm, greater than or equal to 0.23 cm, greater than or equal to 0.25 cm, greater than or equal to 0.3 cm, or It may be equal, greater than 0.4 cm or equal, greater than 0.5 cm or equal, greater than 0.6 cm or equal to it, or greater than or equal to 0.8 cm or equal. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.2 cm and less than or equal to 1 cm, greater than or equal to 0.15 cm and less than or equal to 1 cm, or equal). ). Other ranges are possible.

In some embodiments, the mooring mechanism has a particular anchor length. As an example, the anchor length for a mooring mechanism with a hook corresponds to the maximum cross-sectional diameter of the bent length of the hook (eg, the diameter of the hook without any unbent portions). In certain embodiments, the anchor length is greater than or equal to 10 micrometers, greater than or equal to 20 micrometers, greater than or equal to 23 micrometers, greater than or equal to 25 micrometers, or equal to. , Longer or equal to 30 micrometers, longer or equal to 34 micrometers, longer or equal to 35 micrometers, longer or equal to 40 micrometers, longer or equal to 50 micrometers , Longer or equal to 60 micrometers, longer or equal to 70 micrometers, longer or equal to 80 micrometers, longer or equal to 90 micrometers, longer or equal to 100 micrometers , Longer or equal to 120 micrometers, longer or equal to 140 micrometers, longer or equal to 160 micrometers, longer or equal to 180 micrometers, longer or equal to 200 micrometers , Or greater than or equal to 225 micrometers. In certain embodiments, the anchor length is less than or equal to 250 micrometers, less than or equal to 225 micrometers, less than or equal to 200 micrometers, or less than 180 micrometers. Or equal to it, less than 160 micrometers or equal to it, less than 140 micrometers or equal to it, not 120 micrometers Full or equal, less than 100 micrometers or equal, less than 90 micrometers or equal, less than 80 micrometers or equal, less than 70 micrometers or it Equal, less than 60 micrometers or equal, less than 50 micrometers or equal, less than 40 micrometers or equal, less than 30 micrometers or equal to, or 20 micrometers Less than or equal to. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 10 micrometers and less than or equal to 250 micrometers). Other ranges are possible.

In some cases, the mooring mechanism may be configured to have an optimal penetration depth (eg, the depth at which the mooring mechanism is located just below the surface of the tissue located in the body of the subject). In some embodiments, the mooring mechanism is 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 0.7 mm, greater than or equal to 0.8 mm, greater than or equal to 0.9 mm. Greater or equal, greater than or equal to 1 mm, greater than or equal to 1.2 mm, greater than or equal to 1.4 mm, greater than or equal to 1.4 mm, greater than or equal to 1.5 mm or equal to, greater than or equal to 1.7 mm or equal, Greater than or equal to 1.9 mm, greater than or equal to 2 mm, greater than or equal to 2 mm, greater than or equal to 2.2 mm or equal to, greater than or equal to 2.4 mm or equal to, greater than or equal to 2.5 mm or equal to, greater than or equal to 3 mm or more Equal, greater than or equal to 3.5 mm, greater than or equal to 4 mm, greater than or equal to 4.5 mm, greater than or equal to, or greater than or equal to 5 mm or equal, having a penetration depth. In certain embodiments, the mooring mechanism is less than or equal to 6 mm, less than or equal to 5 mm, less than or equal to 4.5 mm, less than or equal to 4.5 mm, less than or equal to 4 mm, less than or equal to 3.5 mm, less than 3 mm. Or equal, less than 2.5 mm or equal, less than 2.4 mm or equal, less than 2.2 mm or equal, less than 2 mm or equal, less than 1.9 mm or equal, less than 1.7 mm or it Equal, less than 1.5 mm or equal, less than 1.4 mm or equal, less than 1.2 mm or equal, less than 1 mm or equal, 0. It has a penetration depth of less than 9 mm or equal to it, less than 0.8 mm or equal to it, less than 0.7 mm or equal to it, or less than 0.6 mm or equal to it. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.5 mm and less than or equal to 6 mm, greater than or equal to 0.9 mm and less than or equal to 2.5 mm, or it. equal). Other ranges are possible. Although not desired to be constrained by theory, the displacement of the tissue may be greater than or equal to the penetration depth of the mooring mechanism. As a mere example, and in certain embodiments, the mooring mechanism can displace the tissue up to 14 mm to achieve a penetration depth of, for example, up to 4 mm.

It may stay for a relatively long period of time (exposed to fluid flowing at 1 m / s). For example, in some embodiments, a system with a mooring mechanism is on the surface of tissue located in the body of the subject, longer than or equal to 1 hour, longer than or equal to 2 hours, longer than 4 hours. Or equal to, 8 hours or more or equal, 12 hours or more or equal, 24 hours or more or equal, 2 days or more or equal, 3 days or more or equal, Resident for a period of 5 days or more, 7 days or more, or 10 days or more. In certain embodiments, the system is less than 14 days or equal, less than 10 days or equal, less than 7 days or equal, less than 5 days or equal, less than 3 days or equal, Less than 2 days or equal, less than 24 hours or equal, less than 12 hours or equal, less than 8 hours or equal, less than 4 hours or equal, or less than 2 hours or equivalent, Stay. Combinations of the ranges mentioned above are also possible (eg, longer than or equal to 1 hour and less than or equal to 14 days). Other ranges are possible. In some cases, the mooring mechanism may be configured to stay for a relatively very long period of time under physiological conditions and fluid flow. For example, in certain embodiments, the tethering mechanism is located at the tissue surface location within the subject's body at or equal to, longer than or equal to, longer than or equal to 2 months, longer than or equal to 3 months, 6 It may stay for a period longer than a month or equal to it, or longer than a year or equal to it. In some embodiments, the tethering mechanism is at tissue surface location within the subject's body for less than 2 years or equal, less than 1 year or equivalent, 6 months. It may stay for less than or equal to, less than 3 months or less, or less than 2 months or equal. Combinations of the ranges mentioned above are also possible (eg, longer than 1 hour or equal to it and less than 2 years or equal, longer than 1 month or equal to it and less than 2 years or it). equal). Other ranges are possible.

The mooring mechanism described herein can include any suitable material. In some embodiments, the tethering mechanism material is relatively non-degradable. In certain embodiments, the mooring mechanism may be configured to decompose within a particular time period. In some embodiments, the mooring mechanism is configured to decompose within one or more of the times described above in a stagnant situation. For example, in some embodiments, the mooring mechanism is longer than or equal to 1 hour, longer or equal to 2 hours, longer or equal to 4 hours, longer or equal to 8 hours, 12 Longer or equal to hours, longer or equal to 24 hours, longer or equal to 2 days, longer or equal to 3 days, longer or equal to 5 days, longer than 7 days or It is configured to decompose for a period equal to, or longer than or equal to 10 days (eg, therefore, the system no longer resides in a position within the subject's body). In certain embodiments, the mooring mechanism is less than 14 days or equal, less than 10 days or equal, less than 7 days or equal, less than 5 days or equal, less than 3 days or equal. Less than 2 days or equal, less than 24 hours or equal, less than 12 hours or equal, less than 8 hours or equal, less than 4 hours or equal, or less than 2 hours or equivalent It is configured to be disassembled into. Combinations of the ranges mentioned above are also possible (eg, longer than or equal to 1 hour and less than or equal to 14 days). Other ranges are possible. In some cases, the mooring mechanism is longer or equal to 1 month, longer or equal to 2 months, longer or equal to 3 months, longer or equal to 6 months, or longer than 1 year. Long or equal period It may be configured to disintegrate in between (eg, therefore the system no longer resides in a position within the subject's body). In some embodiments, the mooring mechanism is less than 2 years or equal, less than 1 year or equal, less than 6 months or equal, less than 3 months or equal, or less than 2 months or it. Can be decomposed in equal time periods. Combinations of the ranges mentioned above are also possible (eg, longer than 1 hour or equal to it and less than 2 years or equal, longer than 1 month or equal to it and less than 2 years or it). equal). Other ranges are possible.

In some cases, the tethering mechanism may also include a conductive material, as described below.

Electrical stimulation

In some embodiments, the systems, articles and methods described herein may be useful for providing electrical stimulation to a location within a subject's body. Advantageously, the system described herein is compared to traditional methods such as endoscopic placement and / or attachment of electrical devices to provide temporary electrical stimulation to the gastrointestinal tract. , Can be administered orally (eg, in capsules). In some embodiments, the system comprises one or more mooring mechanisms, wherein at least one mooring mechanism comprises a conductive portion (eg, for electrical communication with a tissue at a location within the body of the subject). Equipped. Such a system may be useful, for example, for iontophoresis (eg, the introduction of an API into a tissue in the subject's body during local current application). In certain embodiments where the system described herein is configured for iontophoresis, the system comprises a conductive tip (eg, contained within a first self-restoring article). First organization<u style="Single">connection</u>With components; a second tissue that is configured to contact but not penetrate the tissue (eg, contained within the second self-restoring article).<u style="Single">connection</u>It may include a component (eg, a blunt cylinder). In some embodiments, one or more electrodes have a first and / or second tissue.<u style="Single">connection</u>It may also communicate electrically with the components.

In some embodiments, the system (eg, a self-restoring system) is two or more tissues.<u style="Single">connection</u>It has components. In certain embodiments, the organization<u style="Single">connection</u>Each of the components comprises a tissue contact portion that is configured to be in contact with the tissue. In some cases, the tissue contact area may be conductive. In certain embodiments, the tissue contact area can be electrically insulating.

In some embodiments, the tissue contact portion comprises a first conductive portion and a second insulating portion. In some such embodiments, the conductive portion may be configured to communicate electrically with the tissue, and the insulating portion may be configured to not communicate electrically with the tissue. good.

Although not desired to be constrained by theory, in some embodiments the length of the insulating portion may be configured to prevent electrical communication with a particular layer of tissue (eg, for example. The length for gastric muscle stimulation may correspond to the lateral muscle layer (eg, 2-4 mm) and the length for SI mucosa may be, for example, 0.1-1 mm). In some cases, the insulating portion may be configured to prevent the tissue gastrointestinal tract fluid and / or mucus coating from contacting the conductive portion (eg, although not constrained by theory, digestion). Tube fluid and mucous coatings are generally conductive and, in some cases, may prevent electrical stimulation from reaching the underlying tissue).

The tissue contact portion can have any suitable ratio of the conductive portion to the insulating portion. For example, in some embodiments, the conductive portion is a tissue.<u style="Single">connection</u>More than 0.1% or more than 0.1% of the total surface area of the tissue contact area of the component, more than 0.5% or equal to it, more than 1% or equal to it, more than 2% or equal to it, more than 5% or equal to it, More than 10% or equal, more than 20% or equal, more than 30% or equal, more than 40% or equal, more than 50% or equal, more than 60% or equal, 70% More or equal, more than 80% or equal to, or more than 90% or equal to it, present in the tissue contact area. In certain embodiments, the conductive portion is a tissue.<u style="Single">connection</u>Less than 100% or equal to, less than 90% or equal to, less than 80% or equal to, less than 70% or equal to, less than 60% or equal to the total surface area of the tissue contact area of the component. Less than 50% or equal, less than 40% or equal, less than 30% or equal, less than 20% or equal, less than 10% or equal, less than 5% or equal, 2% Less than or equal to, less than 1% or equal to, or less than 0.5% or equal to it, present in the tissue contact area. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.1%, less than or equal to 100%, greater than or equal to 10% and less than 100%, or Equal, more than 30% or equal to it, and less than 90% or equal to it). Other ranges are possible. In some embodiments, the tip of the tissue contact is conductive and the rest of the tissue contact is insulating.

In certain embodiments, the insulating portion is a tissue.<u style="Single">connection</u>More than 10% or more than 10% of the total surface area of the tissue contact area of the component, more than 20% or equal to it, more than 30% or equal to it, more than 40% or more than it, more than 50% or equal to it, It is present in the tissue contact area in an amount greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, or greater than or equal to 90%. In certain embodiments, the insulating portion is a tissue.<u style="Single">connection</u>Less than 100% or equal to, less than 90% or equal to, less than 80% or equal to, less than 70% or equal to, less than 60% or equal to the total surface area of the tissue contact area of the component. Less than 50% or equal to it, less than 40% or equal to it, less than 30% or equal to it, or less than 20% or equal to it, present in the tissue contact area. Combinations of the ranges mentioned above are also possible (eg, more than 10% or equal to it, less than 100% or equal to it, more than 30% or equal to it, and less than 90% or equal to it). .. Other ranges are possible.

In some embodiments, the system is the self-restoring article described herein and at least one tissue.<u style="Single">connection</u>Equipped with components and organization<u style="Single">connection</u>Each component is each organization<u style="Single">connection</u>It comprises a tissue contact portion that is attached to the component and is configured to be in contact with the tissue. In certain embodiments, the system comprises two or more self-restoring articles described herein, each self-restoring article having at least one tissue.<u style="Single">connection</u>Each organization has components<u style="Single">connection</u>The component comprises a tissue contact portion that is configured to be in contact with the tissue. For example, in an exemplary set of embodiments, two or more tissues<u style="Single">connection</u>A single self-restoring article with components can be administered to the subject, and the self-restoring article has two or more tissues.<u style="Single">connection</u>A power source that communicates electrically with the components can be installed and therefore the organization<u style="Single">connection</u>An electric current can be applied to the tissue in direct contact with the tissue contact portion of the component. In another exemplary embodiment set, at least one tissue<u style="Single">connection</u>Two (or more) self-restoring articles, each equipped with a component, can be administered to the subject, and the self-restoring article is provided with a power source that electrically communicates with the self-restoring article. Such a means of saving can be, each organization from each self-restoring article.<u style="Single">connection</u>It will be applied to tissues that are in direct contact with the tissue contact parts of the components. Other combinations are possible. Those skilled in the art will appreciate self-restoring articles, organizations based on the teachings of this specification.<u style="Single">connection</u>You will see how to combine the components and the tissue contact area.

As described herein, in some embodiments, a system comprising a self-restoring article and / or a self-acting article can be administered, the system being an article (eg, a self-describing article and). / Or at least one tissue placed within a self-actuated article)<u style="Single">connection</u>It has components. The system can be administered, so that at least one matching component is released from the article and / or inserted into the tissue at a location within the subject's body. In certain embodiments, tissues with two or more currents<u style="Single">connection</u>Apply current to flow between the components (eg, tissue by power supply)<u style="Single">connection</u>(Produces knowledgeable communication with components). In some such embodiments, the organization<u style="Single">connection</u>The components do not communicate electrically with the tissue.

The conductive moiety may include any suitable conductive material. Non-limiting examples of suitable conductive materials include conductive polymers, silver, copper, gold, stainless steel, platinum, zinc and steel. Other conductive materials are also possible.

The insulating portion may include any suitable electrically insulating material. Non-limiting examples of suitable insulating materials include polymers such as parylene, polycaprolactone and polyethylene. Other insulating materials are also possible.

Conductive and / or insulating materials, in some cases tissue<u style="Single">connection</u>It can be provided as a coating on the component. In certain embodiments, the tissue contact moiety may include bulk material, including conductive and / or insulating material.

In some embodiments, the applied current (eg, applied between tissue contact portions to electrically stimulate the tissue) is greater than or equal to 0.001mA, greater than or equal to 0.01mA, 0.1. Greater than or equal to milliamps, greater than or equal to 0.5 milliamps, greater than or equal to 1 milliamps, greater than or equal to 5 milliamps, greater than or equal to 5 milliamps, greater than or equal to 10 milliamps, greater than or equal to 50 milliamps, greater than or equal to 100 milliamps It may be greater than or equal to it, or greater than or equal to 250mA. In certain embodiments, the applied current is less than or equal to 500mA, less than or equal to 250mA, less than or equal to 100mA, less than or equal to 50mA, 10mA. Less than or equal to milliamps, less than or equal to 5 milliamps, less than or equal to 1 milliamps, less than or equal to, less than or equal to 0.5 milliamps, less than or equal to 0.1 milliamps, or less than 0.01 milliamps. Or it may be equal to it. Combinations in the ranges mentioned above are also possible (eg, greater than or equal to 0.001mA and less than or equal to 500mA, greater than or equal to 0.1mA, and less than or equal to 10mA). .. Other ranges are possible. The current can be applied using any suitable means, including, for example, an external power source (eg, a battery).

In certain embodiments, the system is under a force greater than or equal to 0.1N (eg, greater than or equal to 0.6N) and / or a change in orientation greater than or equal to 30 degrees, as described above. , Is configured to stay in a position within the subject's body.

Self-actuated

For example, self-acting tissue<u style="Single">connection</u>Self-acting articles are generally provided, including components such as self-acting needles, self-acting mooring mechanisms and / or self-acting biopsy punches. Advantageously, in some embodiments, the self-acting articles described herein are for degradation in a GI tube, for delivery of a wide variety of medicinal products normally delivered by direct tissue injection. Can be useful as a general platform for. The self-acting articles described herein can also be used to deliver the sensors, electrical stimuli, anchor systems described herein to tissues and / or biopsy samples without the need for endoscopic observation. It can also be collected. In some embodiments, the article comprises a spring (eg, a coil spring, a corrugated spring, a Belleville washer, a beam, a membrane, a material having certain mechanical recovery properties). The term spring is not intended to be limited to coil springs, but when the compressive force applied to the material / component is released, the material / component becomes the material / composition under ambient conditions. Substantially to the uncompressed length of the element (eg, within 40%, within 50%, within 60%, within 70%, within 80%, within 90%, 95% of the length of the material / component before compression. It will be appreciated by those skilled in the art to generally include any reversible compression material and / or component that returns to within% or any percentage between them.

In certain embodiments, the term self-actuated article spring may be provided as an inflatable component or may further comprise an inflatable component. The term extension component includes reversible and irreversible compression materials, and when the expansion component is stimulated and / or the inhibition is released, the expansion component is in at least one direction (eg, to its length). It will be appreciated by those skilled in the art that it is a component that extends (along). In some embodiments, the expansion component comprises a gas composition (eg, a mixture of baking soda and vinegar) that expands the gas volume expansion component.

In some embodiments, the spring and / or expansion component is a thermal expansion, swelling (eg, due to fluid absorption), gas driven process, pneumatic process, hydraulic process, electric motor, magnetic mechanism, twisting. It can be extended in at least one direction by a spring mechanism, a chemical gas generator and / or a self-catalyzed reaction. In an exemplary set of embodiments, the spring and / or expansion component can extend in at least one direction when the spring and / or expansion component is exposed to a fluid (eg, gastrointestinal fluid).

In some cases, the spring and / or expansion component can be activated by any suitable activation mechanism (eg, can be extended in at least one direction, which reverts to the uncompressed length of that component. ). Non-limiting examples of suitable activation mechanisms include pressure differential release, electric timers, optical sensors, color sensors, enzymatic sensors, capacitances, magnetism, activation by applied stress (eg, shape memory material), external activation (eg, shape memory material). , Applied magnetic field, applied light, reaction with gastrointestinal fluid such as gastric acid), and combinations thereof. In an exemplary set of embodiments, the spring and / or expansion component is triggered by an interaction (eg, reaction) with gastrointestinal fluid.

In some cases, the activation mechanism is tissue<u style="Single">connection</u>Components can be placed at specific distances (eg, less than or equal to 10 mm, less than or equal to 8 mm, less than or equal to 6 mm, less than or equal to 4 mm, less than or equal to, less than or equal to 2 mm), and / or. Displace with a specific force (eg, greater than or equal to 0.1N, greater than or equal to 0.3N, greater than or equal to 0.5N, greater than or equal to 1N, greater than or equal to 1.5N). ..

As illustrated in FIG. 21, in some embodiments, article 100 comprises a spring 110 and a support 120 attached to (eg, operably connected) to the spring 110. The support 120, in certain embodiments, maintains the spring under a first set of conditions (eg, ambient conditions (eg, room temperature, atmospheric pressure and relative humidity)) and under compressive strain. In some embodiments, the support material at least partially releases the spring from compressive strain under a second condition set that is different from the first condition set (eg, at least a portion of the support material decomposes). For example, in some embodiments, the second set of conditions comprises physiological conditions (eg, at 37 ° C or about 37 ° C, in a physiological fluid such as gastric fluid).

In some cases, the spring 110 can be an adjacent (eg, directly adjacent) support 120. As used herein, when a component is said to be "adjacent" to another component, it is directly adjacent to that component (eg, in contact with that component). ), Or there may be one or more intervening components. A component that is "directly adjacent" to another component means that there are no intervening components. In some cases, the spring may be at least partially embedded in the support. In certain embodiments, the spring is coated with a support material.

In certain embodiments, with reference to FIG. 21 again, article 100 comprises an external shell 170 (eg, such that the spring 110 is at least partially encapsulated within the external shell 170). In some cases, the support can be a coating. In some embodiments, the support is a biodegradable coating. In certain embodiments, the coating can have any suitable thickness. For example, the thickness of the coating may be thicker or equal to 3 mm, thicker or equal to 4 mm, or thicker or equal to 5 mm. In certain embodiments, the coating thickness may be less than or equal to, less than 5 mm or equal to, or less than or equal to 4 mm. Combinations of the ranges mentioned above are also possible (eg, thicker than or equal to 3 mm and less than or equal to 6 m). In certain embodiments, the biodegradable coating decomposes at least partially under physiological conditions. In some cases, the support may be a brittle material. Non-limiting examples of suitable supports include sugars and / or polymers (eg, polyethylene glycol, polyvinylpyrrolidinone, polyvinyl alcohol).

The support may have any suitable cross-sectional dimensions. In some embodiments, the average cross-sectional dimension of the support is greater than or equal to 0.1 mm, greater than or equal to 0.5 mm, greater than or equal to 1 mm, greater than or equal to 1 mm, greater than or equal to 2 mm, or equal to 3 mm. Greater than or equal to, greater than or equal to 4 mm or equal to, or greater than or equal to 5 mm or equal. In certain embodiments, the average cross-sectional dimension of the support is less than 10 mm or equal, less than 6 mm or equal, less than 5 mm or equal, less than 4 mm or equal. , Less than 3 mm or equal, less than 2 mm or equal, less than 1 mm or equal, or less than 0.5 mm or equal. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.1 mm and less than or equal to 10 mm). Other ranges are possible.

In some embodiments, the support, springs, and / or expansion components are physiologically soluble (eg, in an acidic environment, in a pH-neutral environment, in water, in a basic environment). Thermal expansion and / or shape to change rigidity (eg, in response to changes in temperature, in response to fluid absorption) to melt at temperature (eg, 37 ° C). Includes one or more materials that are configured to vary (eg, by degassing, by leakage, in response to fluid absorption).

Advantageously, the composition and / or material used for the support may allow the dissolution of the support to be adjusted. In some cases, the organization<u style="Single">connection</u>The dissolution of the support can be adjusted so that the components are released from the article at the desired location and / or at the desired time.

The support material may include any suitable material. Non-limiting examples of suitable materials include sugars and their derivatives (eg sugar alcohols such as isomalt, sugar mixtures such as toffees), starch, calcium carbonate, zinc, sodium chloride, and / or polymers (eg polyethylene). Glycol, polyvinylpyrrolidinone, polyvinyl alcohol, polyethylene oxide, diethyl carbonate, hydrogel). Other materials are also possible. Although not desired to be constrained by theory, the support can be selected to be relatively brittle (eg, the spring is released when the support melts).

In certain embodiments, the support may be configured to have a particular structure that provides the desired dissolution profile. For example, in some embodiments, the support has a defect control mode (eg, decomposition into small pieces at relatively predictable positions) to improve the dissolution profile and / or the support. May be configured to provide structural integrity of.

In some embodiments, the support has desirable mechanical properties (eg, for the spring to recover at least a portion of its uncompressed length relatively quickly). For example, in certain embodiments, the support is greater than or equal to 0.01N, greater than or equal to 0.1N, greater than or equal to 0.5N, greater than or equal to 0.5N, greater than or equal to 1N, greater than or equal to 2N. Greater than or equal to, greater than or equal to 3N, greater than or equal to 5N, greater than or equal to 7N, greater than or equal to 7N, greater than or equal to 10N, greater than or equal to 15N, greater than or equal to 15N, greater than 20N Or equal to it, greater than or equal to 25N, greater than or equal to 30N, greater than or equal to 35N, greater than or equal to 40N, greater than or equal to 40N, greater than or equal to 45N or equal to, greater than or equal to 50N or it It can have critical stresses equal to, greater than 60N, or equal to it, including any critical stress values between them. In certain embodiments, the support is less than 70N or equal, less than 60N or equal, less than 50N or equal, less than 45N or equal, less than 40N or equal, less than 35N or Equal to it, less than 30N or equal to it, less than 25N or equal to it, less than 20N or equal to it, less than 15N or equal to it, less than 10N or equal to it, less than 7N or equal to it, less than 5N or it Equal, less than 3N or equal, less than 2N or equal, less than 1N or equal, less than 0.5N or equal, or 0. It can have critical stresses less than or equal to 1N (including any critical stress values between them). Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 10N and less than or equal to 70N, greater than or equal to 30N and less than or equal to 45N). Other ranges are possible. The critical stress is generally the maximum force that the support can hold before it cracks (eg, as applied by an adjacent spring), and the critical stress:<math num="1"><img file="JP7045397B2_D0001.tif" /></math>(In the formula, σ_cIs the critical stress applied by the spring, γ is the surface energy of the material, E is the Young's modulus of the material, and a is the surface area perpendicular to the applied stress). can do. In some embodiments, the support may have a characteristic dissolution time. In certain embodiments, the characteristic dissolution time of the support is less than 10 minutes or equal, less than 9 minutes or equal, less than 8 minutes or equal, less than 7 minutes. Is or equal, less than 6 minutes or equal, less than 5 minutes or equal, less than 4 minutes or equal, less than 3 minutes or equal, or less than 2 minutes Or equal to it. In some embodiments, the characteristic dissolution time of the support is greater than or equal to 1 minute, greater than or equal to 2 minutes, greater than or equal to 3 minutes or equal, and greater than or equal to 4 minutes or it. Equal, longer or equal to 5 minutes, longer or equal to 6 minutes, longer or equal to 7 minutes, longer or equal to 8 minutes, or longer or equal to 9 minutes. Combinations of the ranges mentioned above are also possible (eg, longer than or equal to 1 minute and less than or equal to 10 minutes). Other ranges are possible. The characteristic dissolution time is determined as the time at which the support material begins to propagate cracks after exposure to gastrointestinal fluid.

Spring

In some embodiments, the support material is at least a portion of the spring, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, under the first condition set. Maintain at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% under compressive strain. In certain embodiments, the support material has at least a portion of the spring under the first condition set, less than 90% or equal to it, less than 80% or equal to it, less than 70% or equal to it. Less than 60% or equal, less than 50% or equal, less than 40% or equal, less than 30% or equal, less than 25% or equal, less than 20% or equal, 15% Maintain under compressive strain less than or equal to, or less than 10% or equal.

In certain embodiments, the spring is between 10% and 99% of the length of the spring (eg, uncompressed spring length) before and / or in the absence of compressive strain (eg, due to the support). Including any percentage of, greater than or equal to 10%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60% More than or equal to, more than 70% or equal, more than 80% or equal, more than 85% or equal, more than 90% or equal, more than 95% or equal, more than 98% or Equal to, or greater than 99% or equal to or equal to it (eg, less than 10 minutes, less than 5 minutes, less than 1 minute, less than 30 seconds, less than 10 seconds, less than 5 seconds, less than 1 second, less than 0.1 seconds, 0.01 Recover (within less than a second). In some embodiments, the spring is less than or equal to 100%, including any percentage between 20% and 100% of the length of the spring before and / or in the absence of compressive strain. Less than 99% or equal, less than 98% or equal, less than 95% or equal, less than 90% or equal, less than 85% or equal, less than 80% or equal, 75% Less than or equal to, less than 70% or equal to, less than 60% or equal to, less than 50% or equal to, less than 40% or equal to, less than 30% or equal to, or less than 20% Or recover to the same length. Advantageously, the use of springs and supports described herein is, for example, the structure associated with the spring (eg, operably linked).<u style="Single">connection</u>It can allow the release of components (eg, needles), resulting in tissue<u style="Single">connection</u>The component contacts and / or penetrates the tissue in close proximity to the article. In a helpful example, in some embodiments, the needle attached to the spring is administered to the subject so that the spring recovers when the support is disassembled and the needle is tissue close to the article. Is pushed so that the needle penetrates the tissue (eg, the GI mucosal layer). In some such embodiments, the active ingredient of the drug is organized.<u style="Single">connection</u>It can be delivered to the tissue by the component. For example, in some embodiments, the article comprises the active ingredient of a drug, and thus, when the spring is released at a position in the subject's body, the active ingredient of the drug (eg, in tissue close to the location in the body of the subject). To be released. In other embodiments, when the spring is released by the support (eg, tissue such as a biopsy device).<u style="Single">connection</u>A component) can perform a biopsy. With reference to FIG. 21 again, in some embodiments, the article 100 has a tissue attached to the spring 110.<u style="Single">connection</u>It comprises a component 115. Organization<u style="Single">connection</u>Components (eg, needles, hooks, API-heavy components) are described in more detail herein.

In certain embodiments, the organization<u style="Single">connection</u>Components include needles, needle patches or arrays (eg, microneedles), biopsy components, hooks, mucosal adhesive patches, or combinations thereof.

In some embodiments, the spring comprises an elastic material. In certain embodiments, the spring comprises a material selected from the group consisting of nitinol, metals, polymers, and combinations thereof.

In certain embodiments, the spring may have a particular spring constant. For example, in some embodiments, the spring constant of the spring is greater than or equal to 100 N / m, greater than or equal to 150 N / m, greater than or equal to 200 N / m, greater than or equal to 250 N / m, or equal to or equal to 250 N / m. , Greater than or equal to 300N / m, greater than or equal to 350N / m, greater than or equal to 400N / m, greater than or equal to 450N / m, greater than or equal to 500N / m, greater than or equal to 600N / m Greater than or equal to, greater than or equal to 700N / m, greater than or equal to 800N / m, greater than or equal to 900N / m, greater than or equal to 1000N / m, greater than or equal to 1100N / m, Greater than or equal to 1200N / m, greater than or equal to 1300N / m, or greater than or equal to 1400N / m, less than or equal to 1500N / m, less than or equal to 1800N / m, or 2000N It can be greater than or equal to / m and contains any spring constant between these values. In certain embodiments, the spring constant of the spring is less than or equal to 2200 N / m, less than or equal to 2000 N / m, less than or equal to 1800 N / m, less than 1500 N / m or Equal, less than or equal to 1400N / m, less than or equal to 1300N / m, less than or equal to 1200N / m, less than or equal to 1100N / m, less than 1000N / m or Equal, less than 900N / m or equal, less than 800N / m or equal, less than 700N / m or equal, less than 600N / m Or equal to it, less than or equal to 500N / m, less than or equal to 450N / m, less than or equal to 400N / m, less than or equal to 350N / m, less than 300N / m Any spring constant between these values, which may be or equal to, less than or equal to 250 N / m, less than or equal to 200 N / m, or less than or equal to 150 N / m. include. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 100 N / m and less than or equal to 500 N / m, greater than or equal to 100 N / m and less than 1500 N / m). Or equal to it). Other ranges are possible.

In some embodiments, the spring is longer than or equal to 1 mm, longer or equal to 2 mm, longer or equal to 3 mm along the longitudinal axis of the spring compared to the uncompressed length of the spring. , Longer or equal to 4mm, longer or equal to 5mm, longer or equal to 6mm, longer or equal to 7mm, longer or equal to 8mm, longer or equal to 9mm, 10mm Compressed longer or equal to it, longer than 12 mm or equal to it, or longer than 15 mm or equal to it (eg, by a support). In certain embodiments, the spring is less than 20 mm or equal to, less than 15 mm or equal to, less than 12 mm or equal to, less than 10 mm along the longitudinal axis of the spring compared to the uncompressed length of the spring. Or equal, less than 9 mm or equal, less than 8 mm or equal, less than 7 mm or equal, less than 6 mm or equal, less than 5 mm or equal, less than 4 mm or equal, less than 3 mm Or it is compressed to a length equal to or less than 2 mm or equal to it. Combinations of the ranges mentioned above are also possible (eg, longer than or equal to 1 mm and less than or equal to 5 mm, longer or equal to 5 mm and less than or equal to 10 mm). Other ranges are possible.

In certain embodiments, the spring is configured to release the desired amount of compressed energy stored in the spring (eg, when the support is exposed to a fluid such as gastrointestinal fluid). For example, the spring and / or the support can be exposed to a fluid, and when the support is at least partially melted, the spring can at least partially release the stored compression energy and act on the spring, for example. Organizations linked to<u style="Single">connection</u>Displace the component (eg, to release it into the tissue located within the subject's body). For example, in some embodiments, the spring is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least of the compressed energy stored in the spring. It is configured to emit 80% (including any percentage between these values). In certain embodiments, the spring has at least 90% of the stored compression energy of the spring, at least 92% of the stored compression energy of the spring, at least 94% of the stored compression energy of the spring, and the stored spring. Supports at least 96% of the compressed energy, at least 98% of the stored compression energy of the spring, or at least 99% of the stored compression energy of the spring (including any percentage between these values). It is configured to release (when the material is exposed to a fluid such as gastrointestinal fluid). In certain embodiments, the spring is less than 100% of the stored compression energy of the spring or equal, less than 99% of the stored compression energy of the spring, less than 98% of the stored compression energy of the spring, the spring. Emit less than 96% of the stored compression energy of the spring, less than 94% of the stored compression energy of the spring, less than 92% of the stored compression energy of the spring, or less than 91% of the stored compression energy of the spring. It is configured as follows. In some embodiments, the spring is less than 90% or equal to, less than 80% or equal to, less than 70% or equal to, less than 60% or equal to, less than 50% or equal to the stored compression energy of the spring. Equal, less than 40% or equal to it, less than 30% or equal to it, or less than 20% or equal to it (including any percentage between these values) (eg, support material is gastrointestinal fluid, etc.) It is configured to release (when exposed to fluid). Mentioned above A range of combinations is also possible (eg, at least 92% and less than 98% of the stored compression energy of the spring, at least 94% and less than 96% of the stored compression energy of the spring, at least 10% and less than 99%. Or equal to it). Other ranges are possible.

In some embodiments, the spring releases the stored compressive energy of the spring within any suitable time of exposure of the support to fluid and / or mechanical defects (eg, cracking, breakage) of the support. It is configured to do. For example, in some embodiments, the spring transfers the stored compressive energy of the spring (at least 10% of the stored compressive energy) to less than 5 ms, less than 4 ms, less than 3 ms, less than 2 ms of mechanical defects in the support. , Less than 1ms, less than 0.5ms, or less than 0.2ms. In certain embodiments, the spring applies the stored compressive energy of the spring to more than 0.1 ms, more than 0.2 ms, more than 0.5 ms, more than 1 ms, more than 2 ms, 3 ms of mechanical defects in the support. It is configured to release within an hour / hour that exceeds or exceeds 4 ms. Combinations of the ranges mentioned above are also possible (eg, less than 5 ms and less than 1 ms, less than 2 ms and more than 0.1 ms). Other ranges are possible.

In certain embodiments, the spring brings the stored compressive energy of the spring described herein (eg, at least 10% of the stored compressive energy) to less than 10 minutes from exposure of the support to the fluid. It is configured to release within an hour, including any time between these values, less than 9 minutes, less than 7 minutes, less than 5 minutes, less than 3 minutes, or less than 1 minute. In some embodiments, the spring applies the stored compressive energy of the spring to more than 30 seconds, more than 1 minute, more than 3 minutes, more than 5 minutes, more than 7 minutes, or more than 9 minutes. It is configured to release within an hour, including any time between these values. Combinations of ranges mentioned above (eg, less than 10 minutes and less than 30 seconds, less than 7 minutes and less than 5 minutes). Other ranges are possible.

Any combination of the ranges mentioned above is also possible. For example, in certain embodiments, the spring is configured to release at least 10% (eg, at least 90%) of the compressed energy stored in the spring within 10 minutes of exposure of the support to the fluid. ing. In certain embodiments, the spring is configured to release at least 10% (eg, at least 90%) of the stored compressive energy of the spring within 30 seconds of exposure of the support to the fluid. .. In some embodiments, the spring is configured to release less than 100% or an equivalent percentage of the stored compressive energy of the spring within 10 minutes of exposure of the support to the fluid. In certain embodiments, the spring is configured to release less than 100% or an equivalent percentage of the stored compressive energy of the spring within 30 seconds of exposure of the support to the fluid.

In certain embodiments, the spring is configured to release at least 10% (eg, at least 90%) of the compressed energy stored in the spring within 5 ms of a mechanical defect in the support. In certain embodiments, the spring is configured to release at least 10% (eg, at least 90%) of the stored compressive energy of the spring within 0.1 ms from a mechanical defect in the support. In some embodiments, the spring is configured to release less than 100% or an equivalent percentage of the stored compressive energy of the spring within 5 ms of a mechanical defect in the support. In certain embodiments, the spring is configured to release less than 100% or an equivalent percentage of the stored compressive energy of the spring within 0.1 ms from a mechanical defect in the support.

The spring can have any suitable cross-sectional dimension. In some embodiments, the maximum cross-sectional dimension of the (uncompressed) spring is greater than or equal to 1 mm, greater than or equal to 2 mm, greater than or equal to 3 mm or equal to, greater than or equal to 4 mm, or equivalent. Or greater than or equal to 5 mm. In certain embodiments, the maximum cross-sectional dimension of the (uncompressed) spring is less than 10 mm or equal, less than 6 mm or equal, less than 5 mm or equal, less than 4 mm. Or equal to it, less than 3 mm or equal to it, or less than 2 mm or equal to it. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 1 mm and less than or equal to 10 mm). Other ranges are possible.

In some embodiments, the article is administered to the subject (eg, orally). In certain embodiments, the article can be administered orally, rectally, intravaginally, nasally or urethrally. In certain embodiments, when at least a portion of the support material reaches a location within the subject's body (eg, the gastrointestinal tract), it decomposes, resulting in spring elongation and / or tissue.<u style="Single">connection</u>The components are aligned with the tissue located within the subject's body (eg, in contact with, penetrate into the tissue). In some embodiments, the location within the subject is the colon, duodenum, ileum, jejunum, stomach, or esophagus. In certain embodiments, the location within the subject's body is within the buccal space, within the venous system (eg, arteries), within the respiratory system (eg, lungs), within the renal system, within the urinary system, or within the digestive system. Is. As described above and herein, in some embodiments, the active pharmaceutical ingredient is released during and / or after penetration into a tissue located within the body of the subject.

In some embodiments, the organization<u style="Single">connection</u>The component comprises a needle and the tissue is penetrated with a force greater than or equal to 1 mN and less than or equal to 100 mN (eg, greater than or equal to 10 mN and less than or equal to 20 mN). In certain embodiments, the organization<u style="Single">connection</u>The component comprises multiple microneedles and the tissue is greater than or equal to 100 mN and less than or equal to 10N (eg, greater than or equal to 1N and less than or equal to 2N, greater than 100mN). Or equal to it, and penetrated with a force less than or equal to 6N).

In some cases, and as described herein, the organization<u style="Single">connection</u>The longitudinal axis of the component should be orthogonal to the tissue located in close proximity to the article (eg, less than 10% or equal to 90 °, less than 5% or equal to it, or less than 1% or equal to it). The article can be oriented so that it becomes). In some embodiments, as described herein (eg, tissue).<u style="Single">connection</u>A self-acting article (with components) may be attached to one or more self-restoring articles. A non-limiting example of a suitable self-restoring article is commonly found in Co-owned U.S. Patent Application No. 62 / 507,647 filed May 17, 2017, whose invention is named "SELF-RIGHTING ARTICLES". , This provisional application is incorporated herein by reference in its entirety.

In an exemplary embodiment, the article is an outer shell; a spring that is at least partially encapsulated within the outer shell; a support attached to the spring, with at least a portion of the spring under ambient conditions, at least 5%. Support material for maintenance under compressive strain; and structure operably connected to springs<u style="Single">connection</u>It has components. In certain embodiments, the article is organized.<u style="Single">connection</u>Components and organizations<u style="Single">connection</u>It comprises a spring attached to the component, which is maintained partially compressed by a support under at least 5% compressive strain. According to one particular embodiment, the spring is configured to release at least 10% (eg, at least 90%) of the compressed energy stored in the spring within 0.1 ms from a mechanical defect in the support. There is. According to one particular embodiment, the article is tissue<u style="Single">connection</u>Compress the pharmaceutical agent that accompanies the component. In some embodiments, the article is tissue<u style="Single">connection</u>Includes self-restoring articles with accompanying components.

High API

In some embodiments, as described above and herein, the system is for a solid therapeutic agent (eg, a solid API) and a second material (eg, a binder and / or a polymer, for a solid API). Support material) and solid therapeutic agent tissue<u style="Single">connection</u>A component (eg, an organization) that contains more than or equal to 10% by weight of the total weight of the component so that it is present in the component.<u style="Single">connection</u>It has a component). Such an organization<u style="Single">connection</u>The components may be useful for delivery of API doses (eg, to a subject). Advantageously, in some embodiments, the volume required to deliver the required API dose is reduced compared to a liquid formulation, thereby allowing different locations / tissues of a wide variety of drugs (eg, tongue). , GI mucosal tissue, skin) allows the creation of a solid needle delivery system, and / or reduces and / or eliminates the application of external force to inject the drug solution through the small opening of the needle. In some cases, a single tissue with a physiologically appropriate dose<u style="Single">connection</u>Can be present in the components (eg, a single organization)<u style="Single">connection</u>The component has a relatively high API load).

In certain embodiments, the API is a substantially solid (eg, powder, compressed powder, crystalline solid, amorphous solid), ie, a solid therapeutic agent. In some embodiments, the API can be in liquid form. In certain embodiments, the API can be.

In some embodiments, the organization<u style="Single">connection</u>Components include needles, biopsy components, protrusions, multiple microneedles, hooks, mucosal adhesive patches, or combinations thereof. In certain embodiments, the organization is described herein and as described above.<u style="Single">connection</u>The components are configured to penetrate tissue (eg, skin, tongue, tissue of GI ducts, eg GI mucosal tissue). In some embodiments, the tissue is greater than or equal to 1 mN and less than or equal to 20N (eg, greater than or equal to 10mN and less than or equal to 20mN, greater than or equal to 1mN, and equal). Less than 100mN or equal, greater than or equal to 20mN and less than or equal to 1N, greater than or equal to 1N and less than or equal to 20N, greater than or equal to 10N and less than or equal to 20N (Equal) is penetrated with force.

Advantageously, tissues with needles and / or multiple microneedles with a relatively high API load (eg, greater than or equal to 10% by weight of the total weight of the component).<u style="Single">connection</u>The component includes the number of needles required to deliver a particular API dose and / or the overall size of the microneedle array, including traditional microneedles (eg, generally less than 10% by weight). And / or requires multiple microneedles, roughly thousands to tens of thousands of microneedles, to deliver similar doses), which can be significantly reduced.

In some embodiments, the organization<u style="Single">connection</u>The component has a specific maximum dimension (eg, length). In certain embodiments, the organization<u style="Single">connection</u>The maximum dimensions of the components are 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 5 mm, greater than or equal to 7 mm, greater than 10 mm. Or equal, greater than 12 mm or equal, greater than 15 mm or equal, greater than 20 mm or equal, greater than 25 mm or equal, greater than 30 mm or equal, or greater than 50 mm Or equal to it. In some embodiments, the organization<u style="Single">connection</u>The maximum dimensions of the component are less than 100 mm or equal, less than 50 mm or equal, less than 30 mm or equal, less than 25 mm or equal, less than 20 mm or it. Equal, less than 15 mm or equal, less than 12 mm or equal, less than 10 mm or equal, less than 7 mm or equal, less than 5 mm or equal, less than 3 mm Is or is equal to, or is less than 2 mm or is equal to it. Combinations of the ranges mentioned above are also possible.

In certain embodiments, the organization<u style="Single">connection</u>Components are greater than or equal to 0.25 mm, greater than or equal to 0.5 mm, greater than or equal to 0.6 mm, greater than or equal to 0.6 mm, greater than or equal to 0.7 mm or equal to, greater than or equal to 0.8 mm or equal, 0.9 Greater than or equal to mm, greater than or equal to 1 mm, greater than or equal to 1 mm, greater than or equal to 1.1 mm or equal to, greater than or equal to 1.2 mm or equal to, greater than or equal to 1.3 mm or equal to, greater than or equal to 1.4 mm or equal to Equal, greater than or equal to 1.5 mm, greater than or equal to 1.7 mm, greater than or equal to 1.9 mm, greater than or equal to 1.9 mm, greater than or equal to 2.5 mm or equal to, greater than or equal to 3.0 mm or equal to, greater than 4.0 mm It has an average cross-sectional dimension (eg, diameter) that is greater than or equal to it, or greater than or equal to 5.0 mm. In some embodiments, the organization<u style="Single">connection</u>The components are less than 6.0 mm or equal, less than 5.0 mm or equal, less than 4.0 mm or equal, less than 3.0 mm or equal, less than 2.5 mm or equal, less than 1.9 mm or it. Equal, less than 1.7 mm or equal, less than 1.5 mm or equal, less than 1.4 mm or equal, less than 1.3 mm or equal, less than 1.2 mm or equal, less than 1.1 mm or equal, Average cross-sectional dimensions less than 1 mm or equal to it, less than 0.9 mm or equal to it, less than 0.8 mm or equal to it, less than 0.7 mm or equal to it, less than 0.6 or equal to it, or less than 0.5 mm or equal to it Have. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.5 mm and less than or equal to 2.0 mm). Other ranges are possible.

In some embodiments, the organization<u style="Single">connection</u>The component may include multiple microneedles. In some such embodiments, the plurality of microneedles may have a particular base maximum cross-sectional dimension (eg, base diameter), a particular height, and / or a particular spacing.

In some embodiments, the average diameter of the bases of the plurality of microns is greater than or equal to 100 micrometers, greater than or equal to 150 micrometers, greater than or equal to 200 micrometers, or equal to 250 micrometers. Greater than or equal to meters, greater than or equal to 300 micrometers, greater than or equal to, greater than or equal to 350 micrometers, greater than or equal to 400 micrometers, or greater than or equal to 450 micrometers, or equal to. In certain embodiments, the average diameter of the bases of a plurality of microneedles is less than or equal to 500 micrometers, less than 450 micrometers or equal to it, and less than or equal to 400 micrometers. Less than or equal to 350 micrometers, less than or equal to 300 micrometers, less than or equal to 250 micrometers, less than or equal to, less than 200 micrometers, or less than 150 micrometers Or equal to it. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 100 micrometers and less than or equal to 500 micrometers). Other ranges are possible.

In certain embodiments, the average height of the plurality of microneedles is greater than or equal to 0.1 mm, greater than or equal to 0.2 mm, greater than or equal to 0.5 mm, greater than or equal to 0.7 mm, 1 mm. Higher or equal, higher or equal to 1.2 mm, higher or equal to 1.5 mm, or higher or equal to 2 mm. In some embodiments, the average height of the plurality of microneedles is less than or equal to 2.5 mm, less than 2 mm or equal, less than 1.5 mm or equal, less than 1.2 mm. Is or equal, less than 1 mm or equal, less than 0.7 mm or equal, less than 0.5 mm or equal, or less than 0.2 mm or equal. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.1 mm and less than or equal to 2.5 mm). Other ranges are possible.

In some cases, the average spacing of multiple microneedle (eg, spacing between adjacent microneedle in multiple microneedle) is greater than or equal to 100 micrometers, greater than or equal to 200 micrometers, or equal to 300. Greater than or equal to micrometer, greater than or equal to 400 micrometer, greater than or equal to 500 micrometer, greater than or equal to 600 micrometer, greater than or equal to 700 micrometer, greater than or equal to 800 micrometer Equivalent, greater than or equal to 900 micrometers, greater than or equal to 1000 micrometers, greater than or equal to 1100 micrometers, greater than or equal to 1200 micrometers, greater than or equal to 1300 micrometers, or 1400 It may be greater than or equal to the micrometer. In certain embodiments, the average spacing of multiple microneedle is less than or equal to 1500 micrometers, less than or equal to 1400 micrometers, less than or equal to 1300 micrometers, or equal to 1200. Less than or equal to, less than 1100, less than or equal to, less than 1000, less than or equal to, less than 900, less than or equal to, less than 800, 800. Or equivalent, less than 700 micrometers or equal, less than 600 micrometers or equal, less than 500 micrometers or equal, less than 400 micrometers or equal, 300 micrometers Less than or equal to or equal to, or 2 Less than or equal to 00 micrometers. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 100 micrometers and less than or equal to 1500 micrometers). Other ranges are possible.

Advantageously, in some embodiments, the organization<u style="Single">connection</u>Components (eg, needles) dissolve relatively quickly, thus reducing and / or eliminating the risk of secondary intrusion by components in undesired locations. In some embodiments, the maximum cross-sectional dimension (eg, length) of the component prevents pain and / or unwanted perforation of the GI tube in any organ that the component will target. Designed to be delivered.

In some embodiments, the organization<u style="Single">connection</u>The component comprises a foundation portion and a tip portion. For example, as illustrated in Figure 28, the tissue<u style="Single">connection</u>The component 100 comprises a foundation portion 110 and a tip portion 115. In some embodiments, the basal and / or tip portion comprises a mucosal adhesive material. Non-limiting examples of suitable mucosal adhesive materials include polymers such as poly (vinyl alcohol), hydroxylated methacrylate, and poly (methacrylic acid), polyacrylates (eg, polyacrylic acid, thiolated poly (acrylic acid). ), Carbopol®), Cyanoacrylate, Sodium Carboxymethyl Cellulose, Hyaluronic Acid, Hydroxypropyl Cellulose, Polycarbofil, Chitosan, Mutin, Arginate, Xanthan Gum, Gellan, Poroxermer, Acetphthalate Cellulose, Methyl Cellulose, Hydroxyethyl Cellulose, Poly Examples include (amidoamine) dendrimers, poly (dimethylsiloxane), poly (vinylpyrrolidone), polycarbofyl, combinations thereof, and copolymers thereof.

In some embodiments, the basal and / or tip is tissueed with a solid therapeutic agent (eg, API) and a second material (if any).<u style="Single">connection</u>Tissue in an amount greater than or equal to 10% by weight based on the total weight of the components<u style="Single">connection</u>Include to be present in the components. In certain embodiments, the solid therapeutic agent is a tissue.<u style="Single">connection</u>More than 10% by weight or equal to, more than 20% by weight or equal to, more than 30% by weight or equal to, more than 40% by weight or equal to, more than 50% by weight or equal to the total weight of the components Equal to it, more than 60% by weight or equal to it, more than 70% by weight or equal to it, more than 80% by weight or equal to it, more than 90% by weight or equal to it, more than 95% by weight or equal to it, 98% by weight In an amount greater than or equal to%, or greater than or equal to 99.1% by weight, tissue<u style="Single">connection</u>Present in the components. In some embodiments, the solid therapeutic agent is tissue<u style="Single">connection</u>Less than or equal to 100% by weight, less than or equal to 99% by weight, less than or equal to 98% by weight, less than or equal to, less than or equal to 95% by weight, less than or equal to 90% by weight, or less than 100% by weight of the total weight of the components. Equal to it, less than 80% by weight or equal to it, less than 70% by weight or equal to it, less than 60% by weight or equal to it, less than 50% by weight or equal to it, less than 40% by weight or equal to it, 30 weight Tissue in less than or equal to, or less than or equal to 20% by weight.<u style="Single">connection</u>Present in the components. Combinations in the range mentioned above are also possible (eg, greater than or equal to 10% by weight and less than or equal to 100% by weight, greater than or equal to 80% by weight and less than 100% by weight. Or equivalent). Other ranges are possible. In an exemplary set of embodiments, the solid therapeutic agent is tissue<u style="Single">connection</u>Tissue in an amount greater than or equal to 80% by weight and less than or equal to 100% by weight based on the total weight of the components.<u style="Single">connection</u>Present in the components.

In certain embodiments, the solid therapeutic agent is greater than or equal to 0% by weight, greater than or equal to 5% by weight, greater than or equal to 10% by weight, or 20% by weight, based on the total weight of the underlying moiety. More or equal, 30% or more or equal, 40% or more or equal, 50% or more or equal, 60% or more or equal, 70% or more or equal , More than 80% by weight or equal to it, more than 90% by weight or equal to it, more than 95% by weight or equal to it, more than 98% by weight or equal to it, or more than 99% by weight or equal to it, the basis It exists in the part. In some embodiments, the solid therapeutic agent is less than or equal to 100% by weight, less than or equal to 99% by weight, less than or equal to 98% by weight, 95% by weight, based on the total weight of the underlying moiety. Less than or equal to, less than 90% by weight or equal to, less than or equal to 80% by weight, less than or equal to 70% by weight, less than or equal to 70% by weight, less than or equal to 60% by weight, less than or equal to 50% by weight , Less than 40% by weight or equal to it, less than 30% by weight or equal to it, less than 20% by weight or equal to it, less than 10% by weight or equal to it, or less than 5% by weight or equal to it. It exists in the part. Combinations in the range mentioned above are also possible (eg, greater than or equal to 10% by weight and less than or equal to 100% by weight, greater than or equal to 80% by weight and less than 100% by weight. Or equivalent). Other ranges are possible. In an exemplary embodiment, the basal portion comprises substantially only a solid therapeutic agent.

In certain embodiments, the solid therapeutic agent is greater than or equal to 0% by weight, greater than or equal to 5% by weight, greater than or equal to 10% by weight, or 20% by weight, based on the total weight of the tip. More or equal, 30% or more or equal, 40% or more or equal, 50% or more or equal, 60% or more or equal, 70% or more or equal , More than 80% by weight or equal to it, more than 90% by weight or equal to it, more than 95% by weight or equal to it, more than 98% by weight or equal to it, or more than 99% by weight or equal to it, at the tip It exists in the department. In some embodiments, the solid therapeutic agent is less than or equal to 100% by weight, less than or equal to 99% by weight, less than or equal to 98% by weight, 95% by weight, based on the total weight of the tip. Less than or equal to, less than 90% by weight or equal to, less than or equal to 80% by weight, less than or equal to 70% by weight, less than or equal to 70% by weight, less than or equal to 60% by weight, less than or equal to 50% by weight , Less than 40% by weight or equal to it, less than 30% by weight or equal to it, less than 20% by weight or equal to it, less than 10% by weight or equal to it, or less than 5% by weight or equal to it, at the tip It exists in the department. Combinations in the range mentioned above are also possible (eg, greater than or equal to 10% by weight and less than or equal to 100% by weight, greater than or equal to 80% by weight and less than 100% by weight. Or equivalent). Other ranges are possible. In an exemplary embodiment, the tip comprises substantially only a solid therapeutic agent. In another exemplary embodiment, the tip is substantially free of solid therapeutic agents.

In certain embodiments, the organization<u style="Single">connection</u>The components are organized regardless of the composition of the foundation and / or the tip.<u style="Single">connection</u>Includes solid therapeutic agents greater than or equal to 10% by weight (eg, greater than or equal to 80% by weight) relative to the total weight of the components.

In certain embodiments, the organization<u style="Single">connection</u>Components are greater than or equal to 0.1 mg, greater than or equal to 0.5 mg, greater than or equal to 0.8 mg, greater than or equal to 1 mg, greater than or equal to 1.5 mg, greater than or equal to 2 mg, greater than or equal to 2 mg, More than 2.5 mg or more, more than 3 mg or more, more than 4 mg or more, more than 5 mg or more, more than 7 mg or more, more than 9 mg or more (eg, solid therapeutic agents) )including. In certain embodiments, the organization<u style="Single">connection</u>The components are less than 10 mg or equal, less than 9 mg or equal, less than 7 mg or equal, less than 5 mg or equivalent, less than 4 mg or equivalent, less than 3 mg or equal, less than 2.5 mg. Or equal, less than 2 mg or equal, less than 1.5 mg or equal, less than 1 mg or equal, less than 0.8 mg or equal, less than 0.5 mg or equal, or less than 0.2 mg or equal Contains therapeutic agents. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 0.1 mg and less than or equal to 10 mg). Other ranges are possible.

In certain embodiments, at least a portion of the solid therapeutic agent (eg, API) is tissue.<u style="Single">connection</u>Attached to the base and / or one or more tips of the component. For example, in some embodiments, the solid therapeutic agent and the second material (if any) are tissue.<u style="Single">connection</u>It is distributed substantially uniformly in the components (eg, in the foundation and / or in the tip). In some cases, solid remedies are tissue<u style="Single">connection</u>The component is an organization<u style="Single">connection</u>It can be a coating (eg, placed on a portion of the tip) that contains a solid therapeutic agent greater than or equal to 10% by weight based on the total weight of the components.

In some embodiments, the organization<u style="Single">connection</u>The components may include additional coatings. In some embodiments, the additional coating is, for example, a tissue without the additional coating.<u style="Single">connection</u>It may include materials that are configured to slow down the dissolution time compared to the dissolution of the components. Non-limiting examples of suitable additional coating materials, including Zn, Al, Mg, polymers (eg, enteric polymers, polycaprolactone, parylene, hypromellose, polyethylene glycol), and combinations thereof. Other additional coating materials are also possible. In some embodiments, the additional coating may be configured such that the solid therapeutic agent is released over a specific period of time. For example, in some embodiments, the additional coating is less than 6 months or equal to, less than 3 months or equivalent to the solid therapeutic agent (eg, when the additional coating is exposed to a fluid such as gastric juice), 1 Less than a month or equal, less than 2 weeks or equal, less than 1 week or equal, less than 4 days or equal, less than 2 days or equal, less than 1 day or equal, less than 12 hours or equal, 6 hours Less than or equal to, less than 3 hours or equal, less than 1 hour or equal, less than 30 minutes or equal, less than 15 minutes or equal, less than 10 minutes or equal, less than 5 minutes or equal, or 2 minutes It is configured to be released for less than or equal to. In certain embodiments, the additional coating is such that the solid therapeutic agent is longer or equal to 1 minute, longer or equal to 2 minutes, longer or equal to 5 minutes, longer than 10 minutes or it. Equal, longer or equal to 15 minutes, longer or equal to 30 minutes, longer or equal to 1 hour, longer or equal to 3 hours, longer or equal to 6 hours, more than 12 hours Longer or equal, longer or equal to 1 day, longer or equal to 2 days, longer or equal to 4 days, longer or equal to 1 week, longer than 2 weeks It is configured to be released for a period of squid or equivalent, longer than 1 month or equal to it, or longer than 3 months or equal. Combinations of the ranges mentioned above are also possible (eg, longer than 1 minute or equal to it and less than 1 day or equal, longer or equal to 1 day and less than 2 weeks or Equal, longer than a week or equal to it, and less than 6 months or equal). Other ranges are possible.

In certain embodiments, the organization<u style="Single">connection</u>The component comprises a plurality of microneedles containing a solid therapeutic agent and a second material (if any).

In some embodiments, at least a portion of the solid therapeutic agent is present at least on the surface of the tip. In certain embodiments, at least a portion of the second material is present at least on the surface of the tip.

Organizations described herein<u style="Single">connection</u>The components can be formed using any suitable method. In some embodiments, the organization<u style="Single">connection</u>The components are the steps to provide the solid therapeutic agent and the second material (if any), and the solid therapeutic agent and the second material are centrifuged together and / or compressed using a pressure of at least 1 MPa. And organization<u style="Single">connection</u>It is formed by the steps that form the components. In some embodiments, the second material (if present) and the solid therapeutic agent are tissue.<u style="Single">connection</u>It is heated to form the components.

In some embodiments, the organization<u style="Single">connection</u>The components are at least 1MPa pressure, at least 2MPa pressure, at least 3MPa pressure, at least 5MPa pressure, at least 7MPa pressure, at least 10MPa pressure, at least 12MPa pressure, at least 15MPa pressure, at least 20MPa pressure, at least 25MPa pressure, at least 30MPa pressure, at least 40MPa pressure, at least 50MPa pressure, at least 75MPa pressure, at least 150MPa pressure, at least 300MPa pressure, at least 600MPa pressure, at least 900MPa pressure, at least 1GPa pressure, or Formed using a pressure of at least 1.2 GPa. In some embodiments, the organization<u style="Single">connection</u>The components are pressure less than or equal to 1.4 GPa, pressure less than or equal to 1.2 GPa, pressure less than or equal to 1 GPa, pressure less than or equal to 900 MPa, pressure less than or equal to 600 MPa, pressure less than 300 MPa or Equal pressure, pressure less than 150MPa or equal, pressure less than 100MPa or equal, pressure less than 75MPa or equal, pressure less than 50MPa or equal, pressure less than 40MPa or equal, pressure less than 30MPa or equal Pressure, pressure less than or equal to 25MPa, pressure less than or equal to 20MPa, pressure less than or equal to 15MPa, pressure less than or equal to 12MPa, pressure less than or equal to 10MPa, pressure less than or equal to 7MPa, It is formed using a pressure less than or equal to 5 MPa, a pressure less than or equal to 3 MPa, or a pressure less than or equal to 2 MPa. Combinations in the ranges mentioned above are also possible (eg, at least 1 MPa pressure and less than 100 MPa or equal pressure, at least 20 MPa pressure and less than 100 MPa or equal pressure, at least 100 MPa and less than 1.4 GPa or it. Equal pressure). Other ranges are possible.

In certain embodiments, the organization<u style="Single">connection</u>The components can be formed at a particular temperature. For example, an organization<u style="Single">connection</u>In some embodiments, the components are above or equal to 50 ° C, above or equal to 60 ° C, above or equal to 70 ° C, above or equal to 80 ° C, 90 ° C. It is formed at a temperature higher or equal to it, higher than 100 ° C or equal to it, or higher than 120 ° C or equal to it. In some embodiments, the organization<u style="Single">connection</u>Components are less than or equal to 150 ° C, less than or equal to 130 ° C, less than or equal to 120 ° C, less than or equal to 110 ° C, less than or equal to 100 ° C, 90 It is formed at temperatures below or equal to ° C, below or equal to 80 ° C, below or equal to 70 ° C, or below 60 ° C or equal. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 50 ° and less than or equal to 130 ° C). Other temperatures and ranges are possible.

To the advantage, the organization<u style="Single">connection</u>The components are, for example, an organization.<u style="Single">connection</u>It may have desirable mechanical properties (eg, Young modulus) so that the components can properly puncture the tissue of the gastrointestinal tract. In some embodiments, the organization<u style="Single">connection</u>The Young modulus of the component is greater than or equal to 100 MPa (eg, greater than or equal to 125 MPa, greater than or equal to 150 MPa, greater than or equal to 175 MPa, greater than or equal to, greater than or equal to 200 MPa, or equal to, Greater than or equal to 250MPa, greater than or equal to 300MPa, or greater than or equal to 350MPa). In certain embodiments, the organization<u style="Single">connection</u>The components are less than 400MPa or equal, less than 350MPa or equal, less than 300MPa or equal, less than 250MPa or equal, less than 200MPa or equal, less than 175MPa or equal, less than 150MPa or It has a Young modulus equal to or less than or equal to 125 MPa. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 100 MPa and less than or equal to 250 MPa, greater than or equal to 100 MPa and less than or equal to 400 MPa). Other ranges are possible.

In some cases, the organization<u style="Single">connection</u>The components may be configured to penetrate the human gastrointestinal mucosal tissue to a specific depth with a specific force. For example, an organization<u style="Single">connection</u>Components are less than or equal to 20N (eg, less than or equal to 10N, less than or equal to 5N, less than or equal to 1N, less than or equal to 1N, less than or equal to 500mN, less than or equal to 100mN, less than 50mN. Or equal to, less than 20 mN or equal to, less than 15 mN or equal to, less than 10 mN or equal to, less than 5 mN or equal to) force greater than or equal to 1 mm (eg, greater than 2 mm or equal) It may be configured to penetrate to a depth equal to, greater than or equal to 3 mm, or greater than or equal to 4 mm).

In some embodiments, the second material comprises a polymerizable monomer and / or a polymer. In certain embodiments, the second material is biodegradable. Non-limiting examples of materials suitable for the second material are polyethylene glycol, polyvinylpyrrolidone, polylactic acid, polysaccharides (eg, maltose, lactose, starch, cellulose), gum arabic, methylcellulose, gelatin, tragacant, clay, HPMC. , Stearic acid, sodium stearate, magnesium stearate, talc, polyethylene glycol, mineral oil, preservatives (eg phenol, paraben, cetrimid), antioxidants (eg gallic acid, tocopherol), derivatives of these, and theirs. Combinations can be mentioned.

In some embodiments, the organization<u style="Single">connection</u>The component comprises a coating having a yield strength greater than or equal to 50 MPa (eg, greater than or equal to 60 MPa, greater than or equal to 70 MPa, or greater than or equal to 80 MPa).

In some embodiments, the coating may consist of a thin film metal, ceramic, or diamond-like coating (DLC). In some embodiments, the organization<u style="Single">connection</u>The components do not include a coating.

In some embodiments, the coating may be composed of a corrosive material (eg, iron, zinc, aluminum or alloy) to disintegrate when the coating comes into contact with the physiological environment to provide a therapeutic agent. .. In certain embodiments, the coating may comprise a polymer described herein, eg, parylene.

In some cases, the organization<u style="Single">connection</u>The components may be configured to deliver a particular amount of pharmaceutically active agent per square centimeter of tissue of interest. For example, in some embodiments, the organization<u style="Single">connection</u>The component is the organization<u style="Single">connection</u>More than or equal to 0.01 μg or more, more than or equal to 0.05 μg, more than or equal to 0.1 μg, more than or equal to 0.2 μg, per square centimeter of tissue of interest in close proximity to the component penetration location. More than or equal to 0.5 μg, more than or equal to 0.7 μg, more than or equal to 1 μg, more than or equal to 2 μg, more or less than 2 μg, more than or equal to 5 μg, or more than or equal to 10 μg It is configured to deliver pharmaceutical agents. In certain embodiments, the organization<u style="Single">connection</u>The components are less than 20 μg or equal, less than 5 μg or equal, less than 2 μg or equal, less than 1 μg or equal, less than 0.7 μg or equal, less than 0.5 μg or less per square centimeter of tissue. Equal, less than 0.2 μg or equal to, less than 0.1 μg or equal to, or less than 0.05 μg or equivalent is configured to deliver pharmaceutical agents. Combinations of the ranges mentioned above are also possible (eg, greater than or equal to 1 μg and less than or equal to 20 μg). In some embodiments, the organization<u style="Single">connection</u>The component is a pharmaceutical agent that is greater than or equal to 1 μg per square centimeter of subject tissue over any suitable period of time (eg, greater than or equal to 0.1 seconds, greater than or equal to 0.5 seconds, greater than 1 second). Longer or equal, longer or equal to 5 seconds, longer or equal to 30 seconds, longer or equal to 1 minute, longer or equal to 5 minutes, longer than 10 minutes, longer than 30 minutes Or equal to it, longer or equal to 1 hour, longer or equal to 4 hours, longer or equal to 24 hours, longer or equal to 48 hours, longer or equal to 72 hours, 96 It is configured to deliver longer than or equal to, 120 hours or more, equal to, longer than or equal to 144 hours, longer than or equal to 168 hours).

In certain embodiments, the organization<u style="Single">connection</u>The component comprises a binder (eg, in some cases, the second material is the binder). Non-limiting examples of suitable binders include sugars such as sorbitol and sucrose; polymers such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), polycaprolactone (PCL) and polyvinylpyrrolidone (PVP); Polymers containing ethanol or other Class 3 organic solvents such as acetic acid, heptane, acetone, formic acid, isobutyl acetate, etc. can be mentioned.

In an exemplary embodiment, the article comprises a solid pharmaceutically active agent that is greater than or equal to 80% by weight based on the total weight of the article. In certain embodiments, the article comprises a pharmaceutically active agent greater than or equal to 1 mg. 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 pharmaceutically active agent is poured into a mold for forming an article. In some embodiments, the mold is centrifuged. According to certain embodiments, the article further comprises a binder. In certain embodiments, the binder comprises sugars such as sorbitol or sucrose, gelatin, polymers such as PVA, PEG, PCL, PVA or PVP, and / or ethanol. According to certain embodiments, the article has a Young modulus greater than or equal to 100 MPa. In some embodiments, the article is configured to penetrate at least 1 mm into human gastrointestinal mucosal tissue with a force of less than 20 mN or equivalent. According to certain embodiments, the article is configured to deliver at least 1 mg of pharmaceutical agent per square centimeter of tissue of interest, and / or the article is a pharmaceutically active agent greater than or equal to 1 mg per square centimeter. including.

One particular exemplary embodiment is a method of forming an article, the step of introducing into a mold a composition containing more than 80% by weight of a solid pharmaceutical agent based on the total weight of the composition, greater than 1 MPa. It relates to a method comprising applying a pressure equal to or equal to that to the composition and heating the composition to a temperature of at least 70 ° C. for at least 1 minute. As used herein, the term "pharmaceutical active ingredient" (also referred to as "drug" or "therapeutic agent") is used to treat or prevent a disease, disorder or other clinically recognized condition. A drug administered to a subject in the subject with a clinically significant effect on the subject's body for treating and / or preventing a disease, disorder or condition.

Drug

According to some embodiments, the compositions and methods described herein are compatible with one or more therapeutic, diagnostic and / or enhancers such as drugs, nutrients, microorganisms, in vivo sensors and tracers. do. In some embodiments, the active substance is a therapeutic, nutritional supplement, prophylactic or diagnostic agent. Most of this specification describes the use of therapeutic agents, but other agents listed herein may also be.

The agent, when administered to a subject (eg, human or non-human animal), induces any desired pharmacological, immunological and / or physiological effect by local and / or systemic action, any synthetic or Naturally occurring bioactive compounds or compositions may include, but are not limited to, these. For example, useful or potentially useful in the context of certain embodiments are compounds or chemicals traditionally considered to be drugs, vaccines and biologics, such as diseases or Medical or veterinary treatment, prevention, diagnosis and / or alleviation of the disease (eg, HMG, such as losbustatin) co-A reductase inhibitor (statin); non-steroidal anti-inflammatory agents such as meroxycam; selective serotonin reuptake inhibitors such as escitaloplum; antithrombotic agents such as clopidogrel; steroids such as prednison Antipsychotics such as alipiprazole and risperidone; Painkillers such as buprenorfin; Antagonists such as naroxone, montelcast and memantin; Anxious sugars such as digoxin; Alpha blockers such as tamthrosin; Cholesterol absorption inhibitors; metabolites such as corhitin; antihistamines such as loratazine and cetilidine; opioids such as loperamide; proton pump inhibitors such as omeprazole; Anti- (retro) virus agents; antibiotics such as doxicycline, cyprofloxacin and azithromycin; anti-malaria agents; and synthoids / levothyrosins); substance abuse treatments (eg, mesadon and valeniclin); family planning ( For example, hormone contraceptives); capacity building (eg, stimulants such as caffeine); as well as nutritional and nutritional supplements (eg, protein, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D). And other vitamin or mineral supplements), but not limited to, molecules used in therapeutic, diagnostic and / or improving fields, such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.

In certain embodiments, the active substance is one or more specific therapeutic agents. As used herein, also referred to as "drug", the term "therapeutic agent" is an agent administered to a subject to treat a disease, disorder or other clinically recognized condition or for prophylactic purposes. A drug that has a clinically significant effect on a subject's body to treat and / or prevent a disease, disorder or condition. A list of examples of known therapeutic agents is, for example, United States Pharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, McGraw Hill, 2001; Katzung, B. (Edit) Basic and Clinical Pharmacology, McGraw-Hill / Appleton &amp; Lange; 8th Edition (September 21, 2000); Physician's Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th Edition (1999) or 18th edition (2006) following its publication, Mark H. Beers and Robert Berkow (edit), Merck Publishing Group, or For Animals, The Merck Veterinary Manual, 9th Edition, Kahn, "Approved Drug Products with Therapeutic Equivalence and Evaluations" ("Orange") published by CA (editor), Merck Publishing Group, 2005; and the US Food and Drug Administration (FDA). You can find it in Book "). Examples of drugs approved for human use are listed by the FDA in Code of Federal Regulations Vol. 21, 330.5, 331-361, and 440-460, incorporated herein by reference, for veterinary use. The drug is listed by the FDA in Code of Federal Regulations Vol. 21, Chapters 500-589, which is incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Exemplary classes of therapeutic agents include analgesics, anti-painants, anti-inflammatory agents, antipyretic agents, antidepressants, antiepileptic agents, antipsychotics, neuroprotective agents, antiproliferative agents such as anticancer agents, antihistamines. Drugs, anti-mitiginal pain drugs, hormones, prostaglandins, anti-microbial drugs (including antibiotics, anti-fungal drugs, anti-viral drugs, anti-parasitic drugs), anti-muscarin drugs, anti-anxiety drugs, bacteriostatic drugs, immunosuppressants , Suppressants, hypnotics, antipsychiatric drugs, bronchial dilators, anti-asthma drugs, cardiovascular drugs, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroidal or non-steroidal anti-inflammatory agents, cortis Examples include, but are not limited to, costeroids, dopamine agonists, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional supplements, vitamins, parasympathomimetics, stimulants, appetite-reducing agents and narcolepsy therapeutic agents. Dietary supplements can also be incorporated into drug delivery devices. These can be vitamins, nutritional supplements such as calcium or biotin, or natural ingredients such as plant extracts or plant hormones.

In some embodiments, the therapeutic agent is one or more antimalarial agents. Exemplary antimalarial agents include quinine, lumefantrine, chloroquine, amodiaquine, pyrimetamine, proguanyl, chloroproguanyl-dapson, sulfonamides such as sulfadoxin and sulfamethoxypyridazine, meflokin, atovaquone, primaquine, halophane. Included are trin, doxicycline, clindamycin, artemisinin and artemisinin derivatives. In some embodiments, the antimalarial drug is artemisinin or a derivative thereof. Exemplary artemisinin derivatives include artemether, dihydroartemisinin, artemether and artesunate. In certain embodiments, artemisinin is an artesunate.

In another embodiment, the therapeutic agent is an immunosuppressive agent. Exemplary immunosuppressants include glucocorticoids, cell growth inhibitors (eg, alkylating agents, anti-metabolizing agents, and cytotoxic antibodies), antibodies (eg, antibodies to T cell receptors or Il-2 receptors). , Drugs that act on immunophyllin (eg, cyclosporine, tacrolimus, and silolimus) and other drugs (eg, interferon, opioid, TNF-binding protein, mycophenolate, and other small molecules, such as fingolimod). Be done.

In certain embodiments, the therapeutic agent is a hormone or a derivative thereof. Non-limiting examples of hormones include insulin, growth hormone (eg, human growth hormone), vasopressin, melatonin, tyrosin, thyroid stimulating hormone releasing hormone, glycoprotein hormone (eg, luteinizing hormone, follicular stimulating hormone, thyroid stimulation). Hormones), eicosanoids, estrogen, progestin, testosterone, estradiol, cortisol, adrenaline, and other steroids.

In some embodiments, the therapeutic agent has 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, less than about 400 daltons. It is a small molecule drug. In some cases, the therapeutic agent is a small molecule drug having a molecular weight between 200 Dalton and 400 Dalton, 400 Dalton and 1000 Dalton, or 500 Dalton and 2500 Dalton.

In some embodiments, the therapeutic agent is a pharmaceutically active agent such as an insulin, nucleic acid, peptide, bacteriophage, DNA, mRNA, human growth hormone, monoclonal antibody, adalimmab, epinephrine, GLP-1 receptor agonist, semaglutide, etc. Rilaglutide, dulaglitide, exenatide, factor VIII, small molecule drug, progrstin, vaccine, subunit vaccine, recombinant vaccine, polysaccharide vaccine, and conjugate vaccine, toxoid vaccine, influenza vaccine, herpes zoster vaccine, Prebner pneumonia vaccine, mmr vaccine, tetanus vaccine, hepatitis vaccine, HIV vaccine Ad4-env Clade C, HIV vaccine Ad4-mGag, dna vaccine, rna vaccine, etanelcept, infliximab, filgastrim, glatiramer acetate, rituximab, bebasizumab , Any molecule encapsulated in nanoparticles, epinephrine, lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, sertrizumab pegol, ustequinumab, ixekizumab, golimumab, bladrumab, gusell, ab (gusellu, ab), Sekkinumab (secikinumab), omalizumab, tnf alpha inhibitor, interleukin inhibitor, vedrizumab, octreotide, teriperatide, crispr cas9, insulin glargine, insulin detemil, insulin lispro, insulin aspart, human insulin, antisense oligonucleotide, Also selected from the group consisting of Ondancetron.

In an exemplary embodiment, the therapeutic agent is insulin.

In some embodiments, the organization described herein.<u style="Single">connection</u>The components include two or more types of therapeutic agents.

In certain embodiments, the therapeutic agent is tissue.<u style="Single">connection</u>Tissue at a concentration at which the therapeutic agent elicits a therapeutic response when released from the components<u style="Single">connection</u>Present in the components.

In some cases, the therapeutic agent may be present at concentrations below the minimum concentration generally associated with the active therapeutic agent (eg, at microdose concentrations). For example, in some embodiments, the organization<u style="Single">connection</u>The component comprises a first therapeutic agent (eg, a steroid) at a relatively low dose (eg, although it is not desired to be constrained by theory, a low dose therapeutic agent, eg, a steroid, is located in the subject's body. (For example, organization<u style="Single">connection</u>(In response to contact by the component) can mediate the foreign body response of interest). In some embodiments, the concentration of therapeutic agent is microdose &lt;100 μg and / or less than or equal to 30 nMol. However, in other embodiments, the therapeutic agent is not provided with microdose and is present in one or more amounts listed above.

In some embodiments, the organization<u style="Single">connection</u>The component comprises a self-acting component. Such self-acting tissue<u style="Single">connection</u>The components are generally described in co-owned U.S. Patent Application No. 62 / 507,653 filed May 17, 2017, whose invention is named "SELF-ACTUATING ARTICLES", which is in its entirety. Is incorporated herein by reference.

In some embodiments, the organization<u style="Single">connection</u>The component is administered to the subject (eg, orally). In certain embodiments, the article can be administered orally, rectally, intravaginally, nasally or urethrally. In certain embodiments, the organization<u style="Single">connection</u>A component (eg, and / or the API contained therein) is administered by contacting the skin of the subject with this component. In an exemplary embodiment, the organization<u style="Single">connection</u>A component (eg, and / or the API contained therein) is administered by contacting the buccal tissue of subject (eg, lip, palatal area, cheek, sublingual, tongue) with this component. .. In yet another exemplary embodiment, the organization<u style="Single">connection</u>When the component is orally administered and reaches a location within the subject's body (eg, colon, duodenum, ileum, jejunum, stomach, buccal space, esophagus, etc.), the tissue<u style="Single">connection</u>The component aligns (eg, contacts) with the subject's tissue at a location within the subject's body and penetrates the tissue at least partially. In certain embodiments, the organization<u style="Single">connection</u>At least a portion of the components penetrates the tissue of interest and at least a portion of the support and / or pharmaceutically active agent dissolves in the tissue of interest.

Advantageously, organizations with relatively high API loads<u style="Single">connection</u>Administration of the component to the GI tube may enable effective API delivery compared to traditional methods. For example, although not bound by theory, delivery of a drug by infusion into a GI tube has been shown to have higher bioavailability compared to other methods.

In some embodiments, the system is composed of a self-restoring article (eg, configured to be localized in a particular orientation within a subject's body) and a self-acting component (eg, a particular set of conditions). Underneath (configured to activate when exposed to fluids such as gastrointestinal fluid) and tissues associated with self-acting components<u style="Single">connection</u>Equipped with components and organization<u style="Single">connection</u>Includes APIs that accompany components. In certain embodiments, the system comprises a self-restoring article, a self-acting component, and the tissue associated with the self-acting component.<u style="Single">connection</u>It includes components. In some embodiments, the system is a self-acting component and the organization associated with the self-acting component.<u style="Single">connection</u>It includes components. In certain embodiments, the system comprises a self-restoring article and includes an API associated with the self-restoring article. In some embodiments, the system is an organization<u style="Single">connection</u>Equipped with components and organization<u style="Single">connection</u>Includes APIs that accompany components. In some embodiments, the system is a self-acting component and the organization associated with the self-acting component.<u style="Single">connection</u>Equipped with components and organization<u style="Single">connection</u>Includes APIs that accompany components. Self-restoring articles, self-acting components, tissues<u style="Single">connection</u>The components and APIs and related configurations are described above and are described herein.

"Subject" refers to any animal, such as a mammal (eg, a human). Non-limiting examples of subjects include humans, non-human primates, dairy cows, horses, pigs, sheep, goats, dogs, cats, or rodents such as mice, rats, hamsters, birds, fish, or guinea pigs. Can be mentioned. In general, the invention relates to human use. In some embodiments, the subject may manifest a health benefit, eg, when a self-restoring article is administered.

As used herein, "fluid" is given its usual meaning, i.e., a liquid or gas. The fluid will not be able to maintain its defined shape for an observable period and will flow to fill the container in which the fluid will be placed. Therefore, the fluid can have any suitable viscosity that allows flow. If two or more fluids are present, one of ordinary skill in the art can independently select each fluid from essentially any fluid (liquid, gas and the like).

<p>The following examples are intended to illustrate certain particular embodiments described herein, including certain aspects of the invention, but do not illustrate the full scope of the invention.</p><p>(Example 1) Self-restoring article</p><p>Self-restoring articles, which consist of a specific shape and / or density distribution and can be encapsulated in standard "000" capsules, "00" capsules, or potentially smaller or larger capsules, as needed. offer. For example, the density distribution and / or shape: 1. The design has only one stability point and one instability point, and therefore will always be restored to a single composition and orientation; 2. Article design. However, it has a relatively short recovery time from any possible orientation to its stable configuration; 3. The design minimizes the destabilizing effects perceived by forces in the GI duct, such as fluid flow and muscle contraction. ; And / or 4. The design is a density distribution and / or shape that allows the loading of articles of various shapes and weights into the system by means of hollow gaps created at specific locations on the article. sell.</p><p>In some cases, the article shape is drawn within the two right quadrants of the Cartesian plane and results from a smooth curve that rotates about the y-axis. The shape has some salient features. It has a flat bottom perpendicular to the y-axis that transitions to the corners with high curvature and then slowly reduces its curvature as the curve continues. The flat bottom section of the curve can help meet the third specification of the article. The bottom is flat and surrounded by steep corners, so greater force is required to push the article sideways. This is similar to how an ellipsoid, not a cube, sways when pressed.</p><p>The equation below can be used to optimize the rest of the curve to meet the first and second specifications. The restoration time of the article is calculated from the following equation of motion:<math num="2"><img file="JP7045397B2_D0002.tif" /></math>(In the equation, ω is the angular velocity, t is the time, and α is the angular acceleration). Angular acceleration is calculated from the torque generated by gravity and buoyancy acting on the article. α = τ / I (in the equation, τ is the torque and I is the moment of inertia). Torque is determined from the cross product between the force vector and the distance vector:<math num="3"><img file="JP7045397B2_D0003.tif" /></math>(In the equation, d is the distance vector from the center of mass (for gravity) or the center of volume (for buoyancy) to the end of the curve in contact with the stationary surface, and F is the force vector in the direction of the generated force. , Θ is the angle between these two vectors).</p><p>In some cases, the article can be made of two different materials, one with a high density and the other with a low density. The density ratio is defined so that the center of mass of the shape is located at the origin of the coordinate system. The lower half of the plane is made of high density material, while the upper part of the plane is made of low density material. Certain holes and improvements can be added to the original form to maintain a feasible material density from currently available materials, which will be described in the examples. These holes and improvements are also utilized to accommodate the article in the system and are therefore taken into account when determining the density of other materials.</p><p>Once the 3D shape is designed, the recovery time from a given orientation can be tested by using the above equation. The weight and volume of the article determine the force of action, the force of action determines the torque, and the weight and volume of the article is set not only by the density of the material but also by the curve produced. Distance and angle measurements used to determine torque are determined solely by the generated curves. Generate a curve by drawing a smooth curve through a series of points in radial coordinates using an angular coordinate set. The code then changes the coordinate distance of the points until the minimum set of restore times is achieved.</p><p>(Example 2)</p><p>A solid shape created by rotating a smooth curve defined by the y-axis circumference (Example: Figure 7). This shape can be defined as biocompatible polymers in all regions with positive y values (eg PCL, PLA, PEG) and biocompatible ceramics in all regions with negative y values (eg hydroxyapatite). Alternatively, it is manufactured using a metal (for example, stainless steel, field metal). The density ratio of the two materials should be between 6: 1 and 16: 1. The dots in FIG. 7 depict an object that can be fitted within a capsule (FIG. 8), such as a 000 capsule, but the article can be scaled to any length.</p><p>This shape was tested for its restoring ability against ellipsoids and spheres of the same volume and similar dimensions. Objects were tested at 1000 FPS under a high speed camera in several different liquids including water, oil and gastric juice, and on different surfaces including plastic and pig gastric tissue. The results (FIGS. 9-12) showed that the article not only had a faster recovery time at an angle close to stable orientation, but also an overall faster recovery time. This shape makes the article better than the other shapes, as the article is most likely to start near its stable orientation.</p><p>The ability of the articles to remain in the correct position by placing them on a tiltable mixer was also tested. The mixer was set to tilt 15 degrees in each direction at 50 rpm. The article never deviated from its stable orientation, but the sphere was tilted 18 degrees from its optimal orientation and the ellipsoid was tilted 31 degrees from its optimal orientation (Figs. 13-16).</p><p>The object was also placed in vitro in the stomach of a complete suspended pig, using a plastic tube as an artificial esophagus, and landed in the correct orientation compared to a sphere made entirely of PCL. Compared. Of the 60 tests performed on each of the objects performed in the water-filled stomach, the oil-filled stomach and the empty stomach, the article having the shape shown in FIG. 7 landed in the correct orientation each time, but was a sphere. Was found to have only a 25% chance of landing in the correct orientation.</p><p>In addition, similar experiments were performed in vivo. Six self-restoring articles and six articles of the same shape but not self-restoring were fed to sedated pigs by gastric tube. The pig was then shaken violently to simulate walking. After shaking the pig, it was placed under X-ray and the number of articles remaining in the correct orientation was counted. These articles were identified by placing metal pieces inside them (Fig. 14). The self-restoring article already has a hemisphere whose lower half is metal, which would appear as a complete circle if self-restored and a missing moon if not self-restored. .. Circular washers were placed within the object and they were shown as a perfect circle if self-restored or as a distorted oval if not. 65/66 self-restoration tests showed the correct orientation after shaking, but only 7/31 times the control showed the correct orientation.</p><p>(Example 3)</p><p>An object similar in shape to that described in Example 2, but with holes, outlets and slits incorporated into the article. Such holes and slits could be used to allow fluid to enter the system, or could be used to store objects within the system (Figure 19). These slits can be used to hollow out the article and keep the density ratio at a reasonable value that can be achieved using the available materials. For example, by hollowing out the top section of the article, a higher density material can be used to fill the remaining top area. Higher density materials are acceptable because the only constraints on the article are the outer shape and the center of mass. When the holes are made, the article should try to remain axisymmetric or as close to axisymmetric as possible.</p><p>Examples of these holes and slits include, but are not limited to: 1. A cylinder with a radius less than the radius of the article centered on the y-axis.</p><p>2. A conic section centered on the y-axis that can change the radius as the radius of the system changes.</p><p>3. A vertical linear cut with a given width from the top or bottom of the system.</p><p>4. Any other kind of cut into the article that maintains the overall integrity of the system.</p><p>(Example 4)</p><p>An object similar in shape to that described in Examples 2 and 3, but with a drug delivery article incorporated into the system. This article may be a solid or hollow needle loaded with a drug. This may be a hollow needle connected to a reservoir, or it may be a series of needles loaded or coated with a drug. Other drug delivery articles such as patches are also possible.</p><p>In the needle example, the needle could be housed inside or outside the system. If housed outside the system, they could be glued together or fitted into the skeleton of the article. If housed inside the system, it could also be housed in a hollow hole in the article.</p><p>Needle puncture could also be passively actuated from gravity against the article. In doing this, the weight of the article will be able to push the needle into the tissue.</p><p>(Example 5)</p><p>An object having the same shape as described in Examples 2 to 4, but with electronic components incorporated into the system.</p><p>By adding electronic components to the article in combination with anchors, the article could also be used as a gastric retention electronics mechanism. The sensor will be able to approach the tissue wall or inside the GI tube due to the directivity of the article. For example, a pH sensor attached to the bottom of an article could read the pH of the gastric wall region or gastric internal region depending on its placement on the system.</p><p>(Example 6)</p><p>An object similar in shape to that described in Examples 2-4, but capable of remotely adhering other articles to the system (Fig. 20).</p><p>By applying gravitational and / or adhesive force to the walls of the system, the patient can swallow other capsules filled with new articles or filled with drugs and agglomerate them with each other in the system. Let's go. Such forces could be generated by magnets, glue, vacuum or any number of other mechanisms.</p><p>For example, a magnet could be mounted on the wall of a system, or it could be mounted on the wall of an electronic sensor. The patient will be able to swallow the self-restoring system first and then moor it to the tissue wall as described in Example 4. The patient could then ingest another capsule containing an electronic sensor. The magnetic force generated between the two articles from the placed magnets will allow the two systems to adhere. Tethering the self-restoring system to the tissue wall allows the electronic sensor to stay in the stomach, even if it does not have any gastric retention characteristics. This system could allow all kinds of articles to become gastric retention.</p><p>(Example 7) Self-operated article</p><p>It would also be possible to activate the device actively. It could include mechanisms such as shape memory nitinol, inflatable elastomers, or compressed springs. The compressed spring could be immobilized in a solid biodegradable, biocompatible polymer or sugar (eg, sucrose, maltose). This mechanism was found to work in vivo (Fig. 22). These mechanisms could then be housed inside the cavity compartment of the article or outside the article. Methods of mooring devices to system articles include, but are not limited to, the application of magnets, tying knots, and adhesives.</p><p>Further digging into the spring example, it may be desirable for the needle to penetrate the submucosal layer of the GI tube and deliver the drug, for example, the needle should penetrate at least 1 mm into the tissue. If the needle penetrates the tissue deeper than 5 mm, the patient is at risk of perforation. For this reason, the spring can be compressed between 1-5 mm. Also, the amount of force required to penetrate the GI tissue is generally small, approximately 1-10 mN, but a force of approximately 100 mN to invade the muscular layer of the stomach between the mucosal and submucosal layers. It can be necessary. In some cases, the spring will have sufficient force when compressed, pushing the tissue with a force of 100 mN plus a factor of safety of 3 to 10 times. This means that in some cases the spring could have a spring constant of approximately 100-250 N / m (Fig. 23).</p><p>In addition, the compressed spring can be encapsulated in a material capable of retaining such forces. The material may also be brittle, for example, so that the spring can escape from the material all at once. Brittle materials, such as (crystallized) sugars, generally crack quickly and completely under a given stress. Caramelized sucrose generally crumbles under a stress of 0.1 Mpa. If the compressed spring exerts a force of 1 N on the sucrose coating the spring, the sucrose coating can be at least 3.56 mm in diameter to accommodate the spring. Any additional caramelized sucrose added to the coating could also be used as a timed mechanism for the device (eg, although not constrained by theory, the thickness of the coating is required to decompose the coating. Can be at least proportional to time).</p><p>When the spring-coated sucrose is dissolved in water by coating the spring with sucrose between 4 and 6 mm using modeling software that performs diffuse mass transfer problems with interfacial equilibrium, 1 to 4 minutes. During that time, it was determined that the operation could be delayed. This was confirmed by experiments (Figs. 24 to 25). A delay of at least 20 seconds was found to be sufficient for the operation to occur in the stomach rather than in the mouth or esophagus.</p><p>To ensure that the liquid reaches the sucrose and initiates this dissolution process, drains can be added to the top and bottom of the device to allow fluid flow. These outlets provide, for example, an escape route for air trapped inside. They may also be hydraulic to allow easy passage of water.</p><p>In some cases, the mooring device will allow the system to adhere to the tissue wall of the GI tube by physical or chemical means. Such devices could include hooked needles, mucosal adhesive patches, capture and closure mechanisms (Figure 26), vacuum suction, or any number of other mechanisms. The mooring device could also be placed at the bottom of the device to ensure that it faces the tissue wall.</p><p>If the mooring device uses a hook, such as a hooked needle, the mooring device will be able to reach the muscle layer of the tissue between the mucosal and submucosal layers. FIG. 27 shows a histological slide of a piece of gastric tissue penetrated by a device that penetrates the muscle layer of interest. This penetration was caused by the use of sugar-coated springs such as those described above, which are 6 mm compressed and have a spring constant of 210 N / m.</p><p>(Example 8) High API load</p><p>Solid soluble needles (eg, tissue) containing high concentrations of API (eg, solid therapeutic agent) and binder (eg, support)<u style="Single">connection</u>The component) was formed. This API can consist of anything from small molecules to peptide drugs and vaccines. The production of needles used one or both of heat and pressure to produce. The pressure can be applied by pill press, hydraulic press, centrifugation, or any other method for applying a large amount of force. The applied force is 100 cm²1 to 3 metric tons, but may be higher if the API is not damaged and lower if sufficient heat is applied. Heat is provided either convectively or conductively by a heat gun, furnace or similar device, up to the melting temperature of the binder used. In the example below, PEG was used due to its relatively low melting point and relatively high level of plasticity. Heat and pressure can be used sequentially or simultaneously to push a mixture of powder API and binder into the in-plane or out-of-plane mold described in the examples below.</p><p>Dissolvable tissue containing binder and solid API loaded at double-digit percentages<u style="Single">connection</u>The components will be described. This organization<u style="Single">connection</u>Components (eg, needles) can be applied to the skin, GI tubes, or any other area of the body. In some cases, the needle uses the API in powder form. These needles were created by applying pressure and / or heat to the powder mixture. This is a different method than traditional soluble needles that are withdrawn or solvent cast, but such traditional methods may be used. Such needles can be added to the actuation device to obtain sufficient force to penetrate the body.</p><p>GI tubes provide an incredible opportunity for such needle formulations. The walls of certain areas of the GI tube are generally thick and have a very large surface area, so these needles can be extended and extended to hold a much larger amount of drug compared to microneedles. You can do it. For example, a formulation using an insulin load of 80% by weight allows 1 milligram of API delivery with a needle having a diameter of less than 600 μm and a length of 3.3 mm. Such needles could be delivered to the stomach without the risk of perforation. In addition, less than 100 conical needles with a length of 1 mm and a base diameter of 450 μm could deliver the same dosage of API to the slightly thinner small intestine without the risk of perforation.</p><p>(Example 9)</p><p>Using an in-plane mold, a needle was created with a projection two-dimensional design. Needles may be less than 2 mm in diameter and may be larger, but larger needles will interfere with penetration. The needle can also be no more than a centimeter long. The needle may be a blunt needle or may have a tip angle. A laser with a small focal diameter can be used to create an in-plane mold, and the tip radius is limited only by this measurement. Proteins of higher molecular weight, or proteins that are less likely to aggregate, such as BSA, may use larger amounts of binder. However, needles with a tip radius of 40 micrometers can also be produced that use 100% insulin. The amount of binder used may, in some cases, help control the dose of API given and the integrity of the needle. No binding problems were observed when 20-30 w / w percent of the binder was added to the mixture. Needles with the following dimensions (510 μm × 510 μm × 3.3 mm) with 80% API / 20% PEG 200k formulation for both insulin and BSA (Figs. 29-30).</p><p>It is also possible to manufacture a needle with two parts, one containing the API and the other not. This allows the production of needles in which only the tip contains the drug. Previous literature has shown that when a needle penetrates, the needle creates a crater within the penetrated tissue that prevents the needle from completely penetrating. The loading of the drug on the tip helps ensure that the entire API dose is delivered. This type of needle can be created by creating a partition on the mold of the needle, loading only the binder on one side and loading the API + binder on the other side. Since both processes contain the same binder, both sides will fuse under either pressure or heat to create a single needle (Fig. 31).</p><p>High insulin loading needles were shown to dissolve rapidly in PBS at 37 ° C within 20 minutes (Fig. 32). The dissolution profile of the three needles also shows the uniformity of drug loading in each of these needles. In addition, these needles were tested for their strength using an Instron machine to perform crushing tests. The needle operated with a profile similar to ductile material. This is natural because most of the needles are made of PEG (Figs. 33-34). Finally, the penetration of these needles was tested in the human stomach. It was found that the needle penetrated completely with a force of 18 mN (Fig. 35).</p><p>(Example 10)</p><p>The out-of-plane mold can produce a needle having a three-dimensional shape. This mold was created by first making a solid female mold using a 3D printer. Such a printer can produce a tip radius of approximately 1 micrometer. This female mold is then coated with a thin 10 μm chromium layer and another 200 μm copper layer using an evaporator, using a small particle size to maintain / retain the sharpness of the tip found in the printed prototype. , Create a metal shell. Next, a few millimeters of nickel are electroplated onto the copper layer to produce a male mold. The resulting nickel mold is then separated from the female mold, flattened and smoothed to allow uniform force distribution.</p><p>Needles were created by placing the powder in a mold and compressing it in one of the following methods: 1. The powder was filled in the top of the mold and compressed, all in one formulation. Create the needle and base (Fig. 36).</p><p>2. Fill the top of the mold with powder and compress to create needles and bases, all manufactured in one formulation. The base plate is then separated, resulting in the needle remaining in the mold. The mold is then repressed using the API-free formulation. The entire pressed device is removed, leaving a needle containing the API formulation attached to the API-free base plate (Figure 37).</p><p>3. Loosely fill the holes in the mold with the API product. The API-free formulation is then placed on top of the API formulation. The entire device is pressed at once, leaving the API formulation within the needle tip, the API-free formulation on the needle base and on the base plate (Figure 38).</p><p>These needles have strong integrity, as shown by axial load testing on an Instron machine. The needle from Method 3 started with a tip radius of less than 10 μm, and after applying a force of 0.06 N to the apex, the tip had a tip radius of 34 μm (Fig. 39).</p><p>(Example 11)</p><p>This example comprises a tissue comprising 95% by weight insulin (eg, API) and 5% by weight hydroxypropylmethylcellulose (HPMC) (eg, binder material).<u style="Single">connection</u>It demonstrates the formation of components. As described herein, insulin and HPMC were pressed together using a pressure above 1 MPa. A photograph of the components is shown in Figure 40A. The components were shown to withstand forces in excess of 62.7N before cracking (Figs. 40B-40C).</p><p>Tissue containing 100% by weight insulin<u style="Single">connection</u>Components were also formed.</p><p>Using insulin as an API, extruding with PCL, another tissue<u style="Single">connection</u>Generated a component. The percentage of insulin recovered was quantified. This is shown in Figure 40D. Insulin dimer formation was also tested, demonstrating that insulin is stable down to temperatures below 120 ° C to 150 ° C (Fig. 40E).</p><p>(Example 12)</p><p>The following example is a tissue with multiple microneedles with a high API load.<u style="Single">connection</u>It demonstrates the formation of components.</p><p>Simply put, the API was poured into a mold and press-fitted into a microneedle cavity, as illustrated in FIG. The mold was then centrifuged to push the API into the tip of the microneedle cavity. In some cases, a binder was added to the mold. The mold was centrifuged again to push the binder into the microneedle cavity. The microneedles were left to dry for 1-3 days. The microneedles were removed from the mold and they were ready to use. In some cases, the microneedles contained at least 1 mg of API.</p><p>To visualize the distribution of APIs in the microscope, we have a molecular weight of 3-5 kDa (eg, similar to that of insulin) and 20-22 kDa (eg, similar to that of some human growth hormone). FITC-dextran with FITC-dextran was used instead of API in the method outlined above and then imaged using confocal microscopy. Figures 42A-42B show the distribution of FITC-dextran in microneedles. In some cases, FITC-dextran was most clearly concentrated in the top 1/3 to top 2/3 of the microneedles (eg, at the tip).</p><p>Microneedles were also made using insulin as the API as described above. All microneedle patches were imaged prior to application to the buccal space of pigs. Microneedle patches were inserted in vivo into different areas of the buccal space of the pig (under anesthesia) (tongue, sublingual, cheeks, lips and palate) for different times of 5, 15 and 30 seconds. Microneedle patches were tested as controls (denoted as controls (30s)) in Figure 43 and placed only on the surface of the tissue (eg, therefore, any possible degradation occurs within the tissue). It will be related to the moisture content of the placement surface, not the decomposition). Imagery was performed again after all microneedle patches were applied.</p><p>FIG. 43 shows the dissolution of microneedles on the tongue, sublingual, cheek, lips and palatal tissue of pigs over 30 seconds. This experiment demonstrates that in some cases the microneedles lyse and the API can be delivered to the tissue in less than 30 seconds and in some cases in less than 15 seconds or less than 5 seconds.</p><p>Microneedles were recreated using insulin as the API as described in Example 5. Here, microneedle patches were inserted into ex vivo human tissue (eg, human cheeks) for different periods of 5, 15 and 30 seconds. FIG. 44 shows the dissolution of microneedles over time.</p><p>(Example 13)</p><p>The following examples demonstrate in vivo lysis of API-loaded microneedles at a location within a subject's body.</p><p>Microneedles were made as described in Example 12 using insulin as the API. Microneedle patches were inserted in vivo into different areas of the buccal space (tongue, sublingual, cheeks, lips and palate) and small intestine (SI) of the pig (under anesthesia). Set blood sample time (0, 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 135, (150, 165, 180, 210 and 240 minutes) were collected and the insulin concentration was quantified from there. Figures 45-46 show insulin after microneedle application to the small intestine (Figure 45) and palatal tissue (Figure 46) for various API loadings (1.4 mg, 1.6 mg, 2.01 mg, 2.42 mg and 3.56 mg). The plot of the blood concentration of is shown.</p><p>Microneedles were also made as described in Example 12 using human growth hormone (hGH) as an API. Microneedle patches were inserted in vivo into different areas of the buccal space (tongue, sublingual, cheeks, lips and palate) and small intestine (SI) of the pig (under anesthesia). Set blood sample time (0, 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 135, (150, 165, 180, 210 and 240 minutes) were collected and the hGH concentration was quantified from there. Figures 47-48 plot the blood levels of hGH after microneedle application to the lips (Figure 47) and palate (Figure 48) for various API loadings (1.75 mg, 2.35 mg, 2.13 mg). show.</p><p>Microneedles were also made with hGH using sorbitol (eg, sugar) as a binder. FIG. 49 shows a plot of hGH blood levels after microneedle application to pig lips in vivo.</p><p>(Example 14)</p><p>The following examples show tissues with high monoclonal antibody loadings.<u style="Single">connection</u>It demonstrates the formation of components.</p><p>The dose of adalimumab was freeze-dried and exposed to relatively high pressure (&lt;3 mT) and / or relatively high heat (&lt;70 ° C). PEG 200K was used as a binder. An ELISA assay was performed to confirm antibody activity. FIG. 50 shows a plot of the activity of lyophilized adalimumab after exposure to high pressure and high heat.</p><p>Virtual Illustrative Embodiment</p><p>(Embodiment 1) An article having an encapsulating ability having the ability to quickly orient to the tissue wall of a GI tube.</p><p>The article, wherein the shape of the article can be represented by rotating the curve of FIG. 7 about the y-axis.</p><p>b. The article made of a biodegradable, biocompatible polymer (eg, PCL) or metal (eg, stainless steel) or a combination thereof.</p><p>c. The article having two distinct compartments of the article defined by the x-axis in FIG. 7, manufactured using materials with different densities having a density ratio of 6 to 16: 1.</p><p>(Embodiment 2) The article according to embodiment 1, which can be hollow so as to retain self-restoring ability at a hole or outlet such as a cylinder, conical section, rectangular section or other geometry.</p><p>(Embodiment 3) The article according to Embodiment 1, capable of holding a drug delivery system manufactured using a needle (hollow or solid) or patch and actuation mechanism.</p><p>The article, wherein the actuating mechanism may be shape memory nitinol.</p><p>b. The article, wherein the actuating mechanism can be a compressed spring.</p><p>c. The article whose actuating mechanism can be gravity.</p><p>d. The article in which the actuating mechanism can be an inflatable material.</p><p>e. The article, wherein the needle may be attached to the drug reservoir.</p><p>f. The article, wherein the needle may be manufactured in a pharmaceutical product.</p><p>g. The article in which the needle can contain the pharmaceutical product.</p><p>(Embodiment 4) The article according to embodiment 3b, wherein the spring has a spring constant between 100 and 250 N / m, is compressed by 1 to 5 mm, and is coated with 3.6 to 6 mm of caramelized sucrose.</p><p>(Embodiment 5) The article according to Embodiment 1, which may be connected to a mooring system to maintain gastric retention.</p><p>The article in which the mooring mechanism is a needle with a hook.</p><p>b. The article whose mooring mechanism is a bear wrap mechanism.</p><p>c. The article, wherein the mooring mechanism is a mucosal adhesive patch.</p><p>d. The article whose mooring mechanism is vacuum suction.</p><p>(Embodiment 6) The article according to Embodiment 1, which may be attached to another ingestion capsule by a magnet, a chemical adhesive, a vacuum force or another attractive force.</p><p>(Embodiment 7) The article according to the first embodiment, which may be connected to an electronic system such as a sensor.</p><p>The article in which the electronic system is housed within the article.</p><p>b. The article, wherein the electronic system is ingested in a separate capsule and then adheres to the self-restoring system.</p><p>(Embodiment 8) A device having an actuating mechanism.</p><p>The device in which the actuating mechanism can be a shape memory nitinol.</p><p>b. The device in which the actuating mechanism can be a compressed spring.</p><p>c. The device in which the actuating mechanism can be gravity.</p><p>d. The device in which the actuating mechanism can be an inflatable material.</p><p>e. The device, wherein the needle may be attached to the drug reservoir.</p><p>f. The device, wherein the needle may be manufactured with the formulation.</p><p>g. The device in which the needle can contain the pharmaceutical product.</p><p>9. The device of embodiment 8b, wherein the spring has a spring constant between 100 and 250 N / m, is compressed by 1 to 5 mm, and is coated with 3.6 to 6 mm of caramelized sucrose.</p><p>(Embodiment 10) The device of embodiment 8, which may be connected to a mooring system to maintain gastric retention.</p><p>The device in which the mooring mechanism is a hooked needle.</p><p>b. The device whose mooring mechanism is a bear wrap mechanism.</p><p>c. The device in which the mooring mechanism is a mucosal adhesive patch.</p><p>d. The device in which the mooring mechanism is vacuum suction.</p><p>(Embodiment 11) A pressed and / or heated formulation of a powder API and binder with an API load greater than 10% w / w that is molded into an intrusive object.</p><p>An intrusive object that is a microneedle with a height of 0.3-1.5 mm and a base diameter of 200 μm-700 μm.</p><p>b. An intrusive object shaped into a traditional needle with a diameter of 1.5 mm or less and a length of 10 cm or less.</p><p>c. An intrusive object shaped like a protrusion with a diameter of 2 mm or less in any direction.</p><p>(Embodiment 12) An intrusive shape in which the API and the binder are concentrated in the top part of the object, and the bottom part of the object is only the binder.</p><p>(Embodiment 13) An intrusive shape produced by pressing a powder, which has structural integrity for intrusive through the GI structure.</p><p>(Embodiment 14) An intrusive shape produced by pressing a powder, which has structural integrity for intrusive through the skin.</p><p>(Embodiment 15) An intrusive shape in which the tip is created using another brittle material such as sugar.</p><p>(Embodiment 16) An intrusive shape in which the tip is created by cutting and milling an existing tip of the shape.</p><p>(Embodiment 17) An intrusive shape created by press-fitting an API and a binder into an in-plane mold.</p><p>(Embodiment 18) An intrusive shape created by press-fitting an API and a binder into an out-of-plane mold.</p><p>(Embodiment 19) An intrusive shape created by pressing the API and binder in a pill press.</p><p>(Embodiment 20) A formulation in which the powder API and a pressed and / or heated formulation of the binder are PEGs in which the binder has a molecular weight between 50 and 1,000,000.</p><p>(21) A formulation in which the API is an insulin or another peptide, which is a pressed and / or heated formulation of the powder API and binder.</p><p>(Embodiment 22) A formulation in which the API is a nucleic acid, which is a pressed and / or heated formulation of a powder API and a binder.</p><p>(Embodiment 23) A pressed and / or heated formulation of a powder API, a binder and an anti-tickening agent, wherein the anti-tickening agent is a wax, an oil and a stearate such as magnesium stearate, sodium stearyl fumarate and the like. The formulation selected from.</p><p>(Example 15) Tethering mechanism</p><p>The following examples demonstrate the formation and use of mooring mechanisms associated with the systems described herein.</p><p>This appendix of this disclosure discusses how a device can be moored onto the tissue wall of a GI tube using a hooked needle. The needle can be propelled from the self-aligning device into the GI tube by an on-board spring mechanism (Fig. 51). There are optimal ways to place the needle so that the device can stay in the stomach with greater strength, including penetration depth (Fig. 52) and hook size (Fig. 53). For example, a 32-gauge needle requires the tissue to be displaced by at least 1.9 mm in order to actually penetrate the endometrium of the stomach. This means that the device, in some cases, ejects the needle at this distance in order to produce a hooking effect. If the device ejects the needle even more, the needle will continue to penetrate the tissue and maintain a fastener on the tissue. Hook size refers to the length of bending at the tip of the needle. The needle is usually sharpened to a good point, but this part of the needle was deliberately bent to create a hook at the end. As this hook becomes larger, the needle penetration input increases. The 30 μm hook showed a length that balances the amount of penetration and the amount of suspended tissue. As can be seen from FIG. 54, the hook grips the gastric tissue and provides vertical holding force to the device. This holding force is particularly helpful for the device to withstand peristaltic ejection. The same experiment was performed on the human stomach using a needle with a 30 μm hook, and it was revealed that the device was hooked on the tissue (Fig. 55). The human stomach requires a slightly larger insertion depth than the pig stomach. It was also found that the clogs also occur in the small intestine of pigs (Figs. 56-58).</p><p>The hook at the tip of the needle provides a way to anchor the device to the tissue and provides vertical retention, while the major force in the stomach acts perpendicular to the intima of the stomach and is provided by fluid flow. .. To test this, the system was inserted into a piece of tissue and pushed down with a constant force using a probe to determine the horizontal holding force of the device (Fig. 59). By inserting more needles into the tissue, the relative horizontal holding force increased linearly with each additional needle (Fig. 60). The farther the needles are from each other, the greater the holding force is also provided (Fig. 61). The needle tethering device was capable of withstanding forces from fluid flow as well as probes. Figures 62-63 model the fluid flow in the stomach in The mechanism of in vitro is shown. The device was attached to a piece of tissue suspended perpendicular to the ground and exposed to a 0.1 m / s pulsatile flow for 1 week. Each device had only one needle that anchored the device to the tissue. Devices with straight needles lasted a day on the tissue, while devices with hooked needles lasted a whole week on the tissue. A horizontal tissue test was also performed on a surviving pig model (Fig. 64, Fig. 65A). These experiments performed on two different animals demonstrated that the device was held in vivo and ex vivo with equal amounts of force. On average, the device had a retention for between 0.6 and 0.8 N and was rotated 30 degrees before leaving the tissue.</p><p>Since the GI tube contains a thick layer of highly conductive mucus on its structure, the needle shaft was coated with a 5 μm parylene layer for insulation. Only the base and tip of the needle were conductive, which allowed electricity to flow through the tissue rather than the mucus (Fig. 66). The entire system consists of a power supply, a self-actuated device with a needle-like probe, and a microcontroller to regulate the stimulating pulse (Fig. 67). Electrical components shall be insulated to prevent short circuits. All of these components easily fit inside the 000 capsule. Figures 68 and 69 show the effect of changing the probe size and the effect of changing the distance between the fixed power supply and the probe. The distance between the probes has a great effect on the resistance of the finished circuit and therefore, when the voltage is fixed, changes the amount of current passing through the system. Surprisingly, changes in probe size had little effect on current. This is likely due to the fact that the major factor in the circuit is the tissue, not the probe. FIG. 70A shows measurements of voltage from the circuit generated by the final device embedded in the tissue wall. The background noise shown in Figure 70B is negligible compared to the output produced by the circuit. An electrical pulse was programmed into the circuit using a microcontroller. This circuit was created by using paralyene coated needles, attaching them to a self-acting system connected to a constant voltage source, and inserting these probes into the tissue wall. The self-restoring / self-actuating system has a metal bottom, which is coated with parylene to insulate it. These graphs demonstrate that the device can actually deliver the programmed current to the tissue wall of the GI tube.</p><p>Hooked needles have a small number of possible safety concerns. First, they should not pierce the tissue. The stomach tissue is about 5 mm thick and the small intestine is about 1-1.5 mm thick. Both of these tissues are extensible and the needle can displace them by a distance greater than their depth before piercing them. For the small intestine, the needle can displace the tissue by 5.9 mm ± 1.1 mm with a total tissue sample size of n = 15 from 3 different pigs. The lowest recorded value was 4.5 mm. For the stomach, it is difficult to displace the tissue by an entire centimeter, but if the displacement is slow, the displacement will not puncture the tissue. For safety, it is ideal to keep the needle at tissue thickness, especially if the needle is to be penetrated quickly.</p><p>The needle can also be non-degradable or decompose very slowly to provide gastric retention capacity. This offers the possibility of indwelling the needle in the tissue for an extended period of time. However, the tissue in the GI tube regenerates so quickly that the needle will eventually be expelled from the tissue. As long as the needles remain attached to the device, it will also be possible to retrieve them using the recovery protocol. For example, the device could be removed by endoscopic observation, or it could be attached to another swallowed device, such as an adhesive hydrogel, using a host / guest interaction.</p><p>Finally, if the needle is separated from the device, or if the device detaches from the tissue, the device must safely pass through the GI tube. The literature states that there is no risk of perforation for sharp objects, one-dimensional objects less than 1 cm in length. In general, there is little risk of perforation if the needle is less than 1 cm long. However, safety and ideal length for perforation may, in some cases, depend on the type of tissue, the type of subject (eg, animal, human), the location of the tissue, and in some cases. Then it may be longer than 1 cm.</p><p>Predictive Examples</p><p>1. Devices that use hooks to lock to the tissue wall of the GI tube 2. The hooks used are between 10-250 μm in length, with an optimal length of approximately 30 μm.</p><p>3. Penetrate the hook into the tissue for 1-3 mm.</p><p>4. Keep the hooks at least 1.5mm apart.</p><p>5. The hook is non-decomposable.</p><p>6. Needles with hooks are less than 1 cm long.</p><p>7.1 You can use more than one hook per device.</p><p>8. The hook provides vertical holding force.</p><p>9. The inserted object provides horizontal holding force.</p><p>10. Metal needles can be used for electrical stimulation.</p><p>11. Circuits can be made from one device with two needle probes, or two devices each with one needle probe.</p><p>12. The whole device mechanism can be fitted inside 000 capsules and ingested.</p><p>13. The intima of the stomach is shed, so the device stays temporary.</p><p>In humans, and in some animals such as pigs, the stomach is at the end of the esophagus, the long fibromuscular tube that connects to the mouth where food enters the GI canal. The stomach, which is the main location of food digestion in the human body, is a significant space that provides a long residence time of 1-4 hours. To digest food, the stomach contains gastric acid, which creates a low pH environment, as well as many enzymes that break down food into amino acids, such as pepsin. Due to the movement of the muscles, the stomach exerts a translational force of approximately 0.2N on its contents, which promotes solution transfer. When fully decomposed, food travels through the pyloric sphincter to the duodenum to reach the small intestine. To protect itself from the harsh environment inside, the inner surface of the stomach has a mucous coating that is 40-450 μm thick. Below the mucosa is the muscularis mucosae, a thin layer composed of smooth muscle fibers. The muscularis mucosae separates the mucosa from the submucosa that covers the major muscle fibers of the stomach used for contraction.</p><p>The system was designed to ensure its placement in order for the needle to penetrate the endometrium of the stomach. Using Gumbock's theory, a self-restoring shape was previously designed so that the device could be flipped in stomach acid with the needle pointing down. The device itself was manufactured with two different elements. The heavier bottom element is made of stainless steel, while the top element is made of polycaprolactone (PCL). At the center of the device is a needle that attaches to a sugar-coated crimped spring. When the sugar dissolves, the spring acts as a self-injector that can eject a needle from inside the device and, as a result, be inserted into the inner layer of the muscle, as shown in FIG. To increase the retention capacity of the needle, an instron machine was used to apply a force of 1N to the needle and its tip was bent as shown in Figure 51. This hook at the end of the needle was created to help the needle lock into muscle fibers near the pyloric antrum in the distal stomach, as shown in Figure 54.</p><p>An ex-vivo model was created using porcine tissue to determine the maximum force required to detach the needle from the endometrium of the stomach. The pig's gastrointestinal tract has proven to be a good model for its human counterpart. To confirm this, a preliminary ex-vivo experiment was performed. To do so, a 10 cm x 10 cm section of tissue was cut from the stomach of a Yorkshire pig. The porcine tissue was then fixed between the two acrylic plates with the inside of the stomach facing up under a plate with a hole approximately 3 cm in diameter in the center. These plates were then placed on an instron machine consisting of a moving arm with an internal force sensor with an accuracy of up to 0.1 mN. This arm of the Instron was used to secure a needle with a stainless steel hook glued to the screw in place. To determine the force required to penetrate the tissue, the instron arm must be lowered at a constant rate of 0.1 mm / sec until it reaches a depth of 5 mm, during which the device must be applied to reach that layer. The hooking force that was there was recorded. The experiment was then repeated using tissue from the stomach of a human corpse. As shown in FIGS. 52 and 55, the human stomach showed very similar properties compared to the porcine test, producing similar results.</p><p>Similar experiments were performed to determine the ideal penetration depth for maximum retention using pig tissue, which proved to be a strong model of its human counterpart. To determine the ideal penetration depth for maximum retention, the instron arm was lowered at a constant rate of 0.1 mm / sec until it reached 1 mm, 3 mm or 5 mm penetration into the tissue. In this experiment, the instron recorded the anchoring force required to reach its intrusive layer, as shown in Figure 56.</p><p>The needle was stained with a surgical dye prior to use to verify this measurement and to determine which layer of tissue maximized the anchoring force. When the experiment was completed, the tissue was fixed to paraffin. Needle puncture sites were found by making tissue sections by making parallel lateral cuts every 10 micrometers. Once the location was identified, the site was analyzed under an inverted microscope to determine the penetration depth. The results of these histological studies also confirmed that the needle was locked to the muscle fibers in the mucosal musculae layer under the mucosa of the intima of the stomach.</p><p>Finally, a similar experiment was performed to determine the force required to disengage the needle moored to the endometrium of the stomach. A needle with a stainless steel hook glued to the screw was attached to the moving arm of the Instron. The arm was then lowered at a constant rate of 0.1 mm / sec until the needle penetrated the fixed fresh pig tissue by 2.5 mm. Once this distance was reached, the arm was raised at a constant rate of 0.1 mm / sec until the needle detached from the tissue. Throughout this experiment, Instron recorded the depth of penetration and the force applied to remove the needle from the tissue. After repeating this experiment several times, it was found that the average force required for tissue penetration and needle withdrawal averaged 3.86 mN and 10 mN, respectively.</p><p>From the determination of the force required to detach the needle moored to the intima of the stomach, as well as the confirmation that the porcine tissue exhibits similar properties to that of the human stomach, of a self-restoring device with a hooked needle, We created a computational model to determine the ability to hold that position in the human stomach. In addition, this model was used to determine if a self-restoring device with a variable number of assistors that could be designed for a variety of applications had gastric retention capacity.</p><p>According to the literature, the characteristic fluid flow rate in the stomach was found to be 2 to 3 mm / sec, but its Reynolds number was determined to be approximately 0.1 to 30. This Reynolds number indicates that the flow in the stomach is laminar and is governed by viscous force. Therefore, Stokes' law, which is derived from the Navier-Stokes equation modeled for small spheres in viscous fluids, can be used to determine the drag on the device. This equation is shown in Equation 1 (where F is drag, r is the radius of the device, v is the velocity of the liquid, μ is the dynamic viscosity of the liquid).</p><p>F = 6π × r × v × μ Equation 1</p><p>In order to use this equation, we must find the dynamic viscosity of gastric acid. According to the literature, the dynamic viscosity of gastric acid can vary widely based on the rheological properties of the gastric contents. When eating a meal of 10% glucose solution, the contents of the stomach are 10^-3It can be modeled as a Newtonian fluid with a Pa · s viscosity and a density of 1 kg / L. However, some foods have been proven to have viscosities as high as 10 Pa · s. Even the introduction of 1% of more viscous foods has been shown to increase the viscosity of gastric acid. As a result, it was difficult to establish an average dynamic viscosity. However, for this primary simulation, the digested food is based on glucose, so the dynamic viscosity is approximately 10.^-3It was assumed to be Pa · s.</p><p>Using the radius of the self-healing device attached to the 4 mm needle, the Stoke equation presented in Equation 1 can be used to determine the drag on the device. This drag is 2.26 × 10 as shown using Equation 2.^-7Established as N.</p><p>F = 6π × 0.004m × 0.003m / s × 0.001Pa . s = 2.26 × 10^-7N equation 2</p><p>As mentioned earlier, this force is significantly lower than the force required to detach the device, as determined by ex-vivo experiments using an instron, so it will be discussed in Chapter 4. It provides the ability to attach another aid to the self-restoring device using surgical non-absorbable sutures that could be used in a wide range of applications. Using Equation 1 to calculate the drag against these devices, which would likely have a maximum radius of 4.5 mm to fit comfortably into 00 capsules, the drag of each device is 2.54 × 10^-7Can be found to be N.</p><p>It is also important to consider torque when determining the conditions required to disengage the needle from the endometrium of the stomach. Using the forces found for self-restoring devices and assistive bodies, the torque is calculated using Equation 3 (where τ is the torque, r is the moment arm, and F is the force). can do.</p><p>τ = r × F Equation 3</p><p>This equation can then be used to generate a plot if the moment arm in the equation is the needle length (1.25 mm) from the tissue to the bottom of the device. As shown in Figure 65B, a graph was generated to compare the number of assists attached to the self-healing device with the torque applied by the drag (red dotted line is the system before the needle is disengaged). Indicates the maximum torque that can be applied to the device, because the needle length from the 1.25 mm tissue to the bottom of the device is used as a moment arm to disengage the needle in ex-vivo experiments on the Instron. Determined from the force required for). However, as shown in this plot, even a device with nine auxiliary bodies will receive orders of magnitude less torque than is required to disengage it.</p><p>From FIG. 65B, it can be determined that the drag torque remains several orders of magnitude smaller than the torque required to detach the device from the endometrium of the stomach. However, as mentioned earlier, this dynamic viscosity does not take into account food effects, so a second model must be created. In the process of chewing, the food is ground into small spherical food masses that then travel down the esophagus to the stomach. When these food masses reach the stomach, they mix with stomach acid to form chyme. Using sieving and laser diffraction measurements, studies have demonstrated that the size can vary with these chewed individual particles, based on the texture of the ingested food. For example, raw vegetables produce food masses larger than 2 mm on average, but more than half of the nut particles are less than 1 mm in diameter.²⁶。</p><p>Due to this large variation in the size of the food mass, we have created a model to determine if the food mass can exert enough torque to disengage the device when it collides with the self-restoring device. .. This simulation was made on the assumption that no auxiliary is attached to the device, but keep in mind that the needle will need to overcome the torque from the food mass in addition to its own drag. To do that, the food density is 1000kg / m³It was hypothesized that the food mass would shrink by an average of 50% in collision with a self-restoring device while moving with gastric acid at 3 mm / s. The length of the food mass was considered to range from 0.1 mm to 100 mm to cover all possible diameters. However, as shown in Figure 65C, even if the torque exerted by the food mass may increase by an order of magnitude depending on the texture of the food mass, the torque exerted on the self-restoring device is still that. It will be much smaller than what is required to disengage the device (red dotted line indicates the maximum torque that can be applied to the system before the needle is disengaged; this value is from 1.25 mm tissue. The length of the needle to the bottom of the device was used as a moment arm and was determined from the force required to detach the needle in an ex-vivo experiment with an instron).</p><p>In addition to verifying that the device can withstand the forces present in the stomach using computer simulations, we plan experiments to test its retention capacity from preliminary measurements of the determined intrusive depth and withdrawal force. did. This chapter will discuss in-vitro and in-vivo tests that are necessary to properly simulate gastric conditions to determine if a device can withstand withdrawal.</p><p>An in-vitro experiment was planned to test the ability of the micropost to retain its position in the endometrium of the stomach despite the action of drag from gastric flow. To do that, Tygon PVC tubes were connected to each other to create a closed circuit attached to the water pump. A 10 cm x 10 cm section of tissue was cut from the stomach of a Yorkshire pig and fitted inside a tube perpendicular to the ground. Three self-restoring devices with hooked needles were then placed on top of this tissue. In addition, three self-healing devices with needles without hooks, three self-healing devices without needles, and three spherical objects of the same size as the self-healing devices were placed on the tissue as controls. .. Water was then introduced into the system, the pump was turned on and the fluid was pumped at 0.1 m / s. FIG. 57 illustrates the method by which this experiment was performed.</p><p>The system was run for a week to determine the ability of the hooked needle to withstand fluid flow compared to its counterpart. As shown in Figure 58, all controls were detached by day 2, but a self-restoring device with a hooked needle was able to hold its position throughout the week, simulated by a computer. The result of was proved.</p><p>A multi-day in-vivo study was planned for the pig model with positive results from synthetic gastric experiments that confirmed the predictions from computer simulations. Using an overtube, four self-restoring devices with hooked needles were placed in a straight line on the right side of the stomach. Another four self-restoring devices with normal needles were similarly placed on the left side of the stomach for distinction. On days # 2 and # 3, an endoscope was used to monitor whether any of the self-healing devices had moved. However, when the experiment was performed, all of the devices, with or without hooks, did not retain their position in the stomach.</p><p>There are several possible explanations for why the device was withdrawn in the pig's stomach. Further experiments must be performed in-vitro to characterize the retention capacity in order to determine if the device is not as elastic as the predicted computational model. The protocols for some of these experiments will be described in Chapter 4. However, withdrawal can also be due to differences between the human stomach and the pig model, such as motility. Unlike humans, who digest food in the stomach for 1-4 hours, pigs can take longer than 6 hours to advance their diet to the small intestine.²⁷.. In addition, based on observations, pig food masses will be much larger than their human counterparts, increasing the force exerted on the device in collisions. Finally, pigs eat large amounts several times a day to keep their stomach full, while humans exert greater relaxation of food intake restrictions.</p><p>Ex-vivo experiments on an instron machine determined the force required to penetrate the endometrium of the stomach, the depth required to ensure maximum retention, and the force required to remove the hooked needle. .. We created a few computational models and used this data to validate self-restoring devices with hooked needles that would be able to hold their position regardless of gastric condition and associated effects. To simulate drag, in-vitro experiments were performed to ensure that the self-restoring device did not disengage when exposed to fluid flow. From the positive results from this experiment, in-vivo tests were performed using the pig model, but none of the hooked needles managed to hold their position over the multi-day study.</p><p>The long-term retention of microposts in the endometrium of the stomach creates a number of uses. As mentioned earlier, this allows continuous delivery of drugs that traditionally have to be administered daily, such as insulin. It will also provide a viable oral delivery method for biologics that traditionally must be injected for enzymatic degradation in the gastric environment.</p><p>Such microposts could serve as an anchor in the stomach for other devices that were previously unable to maintain long residence times in the GI duct. These devices could be attached to the self-restoring device using non-absorbable sutures and present in the stomach as an aid. One potential use could be for Bluetooth® low energy for medical monitoring. This technology creates growth areas that have the potential to help physicians and healthcare professionals monitor the condition of their home patients. For example, a small Bluetooth® monitor capable of fitting 00 capsules could be used in combination with a long-term needle retention device to monitor various properties in the stomach such as pH or temperature changes. Finally, electrical stimulation of the stomach shows promise in addressing several clinical problems such as gastroparesis and obesity. The auxiliary attached to the self-healing device is a battery, which, if created within a multi-needle system, could create an electrical circuit with the endometrium of the stomach that could facilitate this stimulus. Let's go.</p><p>Figure 51: Schematic of a self-restoring system used for tissue localization and ejection of hooked microposts. An example of a 32-gauge stainless steel needle with a hook is shown on the left.</p><p>Figure 52: Penetration into pig gastric tissue using hooked microposts shows that maximum penetration is required at a depth of 1.9 mm for both 23 mm and 30 mm hooks.</p><p>Figure 53: Penetration into pig gastric tissue using hooked microposts requires force to disengage the self-restoring system using 1.9 mm and 2.4 mm hooks when the hook is 30 mm long. Indicates that it has been maximized.</p><p>Figure 54: Hooked micropost attached to the muscle fibers of pig gastric tissue.</p><p>Figure 55: Penetration into human gastric tissue using hooked microposts is maximized when the force required to detach the self-restoring system from the body and pyloric sinus tissue is 5 mm. Show that.</p><p>Figure 56: Penetration into porcine small intestinal tissue using hooked microposts shows that the force required to disengage the self-restoring system reached the plateau after 1.5 mm penetration.</p><p>Figure 57: Penetration into porcine small intestinal tissue using hooked microposts shows that the height at which the tissue can be raised reached a plateau after 1.5 mm intrusion.</p><p>Figure 58: Micropost with hook, attached to the porcine small intestinal tissue itself.</p><p>Figure 59: Model of horizontal tissue retention test. The probe pushes down on the device moored to the tissue by the needle and records the force required to detach the device.</p><p>Figure 60: The force required to disengage the self-restoring system has been shown to increase linearly with the number of needles inserted into the porcine gastric tissue.</p><p>Figure 61: The force required to detach the self-restoring system from the porcine gastric tissue has been shown to increase statistically significantly when the three needles are placed further apart.</p><p>Figures 63A-63B: Schematic diagram demonstrating the design of an in-vitro experiment in which a self-aligned device is tethered to porcine gastric tissue while undergoing pulsatile flow (Figure 63A). Graph demonstrating that three devices with hooked microposts held their position for an entire week, as opposed to other systems that were detached in less than two days (Figure 63B).</p><p>Figure 64: Graph demonstrating that there is no statistically significant difference between the in-vivo tethering force of the self-aligning device to the pig stomach and the ex-vivo tethering force. Ex-vivo measurements represent studies using three separate tissue samples from different stomachs.</p><p>Figure 65A: Using a pig model, when a tethered self-aligned device encounters a force parallel to the gastric tissue, it is rotated less than 30 degrees and receives a force between 0.5N and 0.75N. , A graph demonstrating in-vivo that it can hold its position. Peaks and valleys are the result of animal respiration.</p><p>Figure 66: Schematic diagram demonstrating how a parylene-coated electrical probe bypasses mucus and conducts electricity through tissue. Without the coating, electricity would flow through the mucus with lower resistance and would not irritate the tissue.</p><p>Figure 67: Demonstration of an electrical stimulation pill containing a self-aligning device containing two probes and a power supply and a programmable microcontroller enclosed in an isolated shell (eg PDMS). Connect this system in a proper electrical circuit using insulated wires. This circuit is completed through the tissue. The entire system can be packaged in 000 capsules.</p><p>Figure 68: Graph demonstrating that when powered by two silver oxide batteries (1.55V, 6.8mm coin battery), the current does not change significantly as the radius of the tissue stimulating electrical probe increases.</p><p>Figure 69: Graph demonstrating that when powered by two silver oxide batteries (1.55V, 6.8mm coin battery), the current decreases as the distance between the tissue stimulating electrical probes increases.</p><p>Figures 70A and 70B: Electrical probes powered by a voltage source are measured by an oscilloscope and pulsed through the tissue (Figure 70A). This can be compared to the background voltage measured within the tissue (Figure 70B).</p><p>(Embodiment 16) Illustrative system (SOMA)</p><p>The following examples demonstrate the fabrication and design of the exemplary self-restoring system described herein.</p><p>The self-orientation capability of the Illustrative System (SOMA) helps ensure that the device is properly placed to insert the micropost into the tissue wall, and in some embodiments only in the submucosal layer. Address safety and efficacy concerns associated with insertion by delivering the micropost with sufficient force to reach. The natural ecology of the stomach provides a wide safety margin during insertion events. It was revealed that in some cases, the micropost would use an additional 4 Newtons or greater force to penetrate through the adjacent panniculus, the muscularis extracorporeal layer. SOMA was made from materials tested for biocompatibility in both rats and pigs. Its small shape factor generally prevents obstruction in the lower GI tube. SOMA is smaller in volume than the FDA-approved daily OROS system (φ9 mm × 15 mm), a non-degradable drug delivery system with an occlusion rate of approximately 1/29 million. in When tested in vivo, SOMA showed no signs of obstruction, did not perforate tissue, and delivered a similar amount of API over 2 hours compared to subcutaneously placed microposts. The unique shape of SOMA provides an optimized mechanism for micropost delivery to the stomach.</p><p>We designed a mono-monostatic body (Figs. 71A-71D) optimized for rapid self-orientation that is capable of withstanding external forces (eg, fluid flow, peristaltic motion, motion) once the stable point is reached. For example, the upper compartment of the turtle's instep, known as the shell, has a higher curvature to help self-orientation, while the lower compartment, known as the abdominal instep, has a lower curvature to increase stability. The soft tissue of the turtle occupies the lower region of the instep, thus moving the center of mass towards the abdomen, further stabilizing the preferred orientation. Since self-aligning devices generally rely on lower mass centers compared to their volume centers, a combination of polycaprolactone (PCL) and 316L stainless steel was used to generate this density gradient. Materials of similar density, such as polypropylene and field metal features, were interchangeably used during the in vitro prototyping process. Since stainless steel is not normally used for oral devices, its oral toxicity was evaluated in rats during both acute and subchronic studies. Consistent with other studies on stainless steel in the GI cavity, including those related to orthodontics, no signs of inflammation or toxicity were observed (Fig. 75).</p><p>In polar coordinates (r, θ), which minimizes the average time required for an object to orient to the GI tube tissue wall from 36 different angles, while maximizing the torque required to tilt the device from its preferred orientation. The axisymmetric shape drawn by the plane curve C was designed using the fmincon function of MATLAB. As explained below, the theoretical orientation time was calculated using Newton's angular equation of motion. For the first guess about the shape, we used a geometric model of the turtle's instep, which combines a hyperbola to represent the shell and a low-curvature arc to represent the abdomen. Mimicking the mass distribution of the turtle, this model hollowed out the upper part of the device and used it to house the actuation mechanism and API microposts. In addition, the device was scaled down to have a relatively small volume.</p><p>The optimized shape versions produced were compared to uniform density spheres and ellipsoids. Self-orientation and destabilization tests were performed in vitro using high-speed photography to verify computer modeling (Fig. 2A, Fig. 72A). The optimal shape was the fastest oriented at 69% of all possible orientations and, on average, oriented faster than the other shapes (Fig. 72B). The device reached its preferred orientation in less than 100 ms from more than 85% of all departure angles in an ideal environment. When placed in liquids found in GI tubes, such as oil, gastric juice, mucus and water, the optimized device showed less deceleration due to the viscous effect compared to the ellipsoid (Fig. 72C). .. The device also showed strong elasticity after orientation to its preferred state compared to other shapes. This is because the tilting shaker with a range of motion of ± 15 degrees did not tilt more than 1 degree when exposed to mixing at 50 rpm (Fig. 72D).</p><p>After identifying the final shape, the shape was tested for self-orientation and mucosal engagement persistence 300 times in the ex vivo experimental setting of the pig stomach and 60 times in vivo in fasting animals. A simulated test of gait and extensive motor stress was performed in vivo with 180 degree rotation and 30 degree tilt of the animal model. In order to measure proper device orientation, pig endoscopy was performed after abdominal agitation (Fig. 72E) and radiography was performed (Fig. 76). The optimized device was 100% oriented in each test, while control devices of the same shape manufactured with PCL alone had a 50% chance of being oriented. When six SOMA prototypes were administered to pigs at one time, there was no evidence of GI obstruction or other adverse clinical effects (Figure 77). By using a device with rapid and consistent self-orientation ability in vivo, drug delivery actuation events in the direction of tissue generally occurred.</p><p>After creating the localization system, we created the compression processing API micropost. Compared to liquid or solvent cast formulations, compressed solid formulations delivered up to 100 times more API per unit volume. By compressing a mixture of 80% human insulin and 20% 200k molecular weight poly (ethylene) oxide (PEO) under a pressure of 550 MPa, 0.5 mg insulin is sharpened with measurements of 1.7 mm height and 1.2 mm diameter. It was loaded onto a conical structure and attached to a shaft made of degradable biocompatible polymers such as PEO and hydroxypropylmethylcellulose (FIGS. 73A-73B).</p><p>Mechanical and chemical property analysis studies have ensured the stability of the micropost. Raman spectroscopy of the compressed micropost revealed a uniform API distribution throughout the tip of the micropost and verified the protein structure of the API after high-pressure exposure (Fig. 78, Table 1). Compression tests measured Young's modulus of 730 ± 30 MPa, similar to that of PEO, and intrinsic strength of 20.0 ± 0.7 MPa, which ensured the integrity of the microposts in the presence of external forces (Fig. 79). .. in In vitro lysis profile demonstrated complete lysis within 60 minutes (Fig. 80). Stability studies conducted at 40 ° C showed that solid insulin and PEO microposts remained stable for 16 weeks in a dry environment, maintaining purity greater than 80% and high molecular weight protein (HMWP) formation below 5%. It was shown to do (Fig. 81). This is comparable to the stability of the liquid formulation for 4 weeks. Using the same compression concept, a micropost with both a tip and a shaft, which is entirely composed of insulin due to the absence of a binder, was made with 100% insulin. Utilized 100% insulin micropost for SOMA to increase insert payload.</p><p><tables><img file="JP7045397B2_D0004.tif" /></tables></p><p>The insertion profile of insulin microposts into porcine gastric tissue in vivo was assessed. A custom controllable stage (Fig. 82) was used to insert the tip at a rate of 0.2 mm / s, and approximately 1N of force was commonly used to displace the tissue greater than 7 mm (Fig. 73D). Using this measurement as a boundary condition, a time-delayed actuation mechanism was implemented in SOMA, which has the ability to insert drug-loaded microposts into gastric tissue without causing perforation. A spring was used as a power source, for example because of its low spatial requirements and its ability to release energy along one axis almost instantly. The SOMA is equipped with a stainless steel spring that provides a force of 1.7 to 5N (k = 0.1 to 0.5N / mm) when fully compressed. The spring accelerates the 1 mm micropost and then inserts the micropost 5 mm into the tissue. After activation, they remained inside the device. Histological examination results from the SOMA insertion event were manually inserted with a stained Carr-Locke needle in Direct comparison with that from the vivo pig stomach (Fig. 73E). Microcomputer tomography (CT) imaging confirmed that the spring can propel a barium sulphate-loaded micropost from SOMA into ex vivo pig tissue, eg, less than 2 mm (Fig. 73C). Histological images from in-vivo in-situ experiments are the same depth as the Carr-Locke needle, with insulin microposts inserted into the submucosal layer of pig gastric tissue after being ejected from a SOMA with a 5N spring (Figs. 73F and 73H). Demonstrated that it reached. Stainless steel microposts were injected into ex vivo porcine tissue using 9N steel springs (k = 1.13N / mm) to ensure a safety margin of insertion force. The stainless steel microposts did not pierce the tissue with additional force and momentum (Fig. 73G and Fig. 73I).</p><p>Crystallized sugar and sugar-like materials, such as sucrose and isomalt, have been identified as useful spring encapsulation materials in order to regulate the time so that the working event occurs in the stomach rather than in the mouth or esophagus. The fragile nature of the material allows, for example, the spring to be fully released within 1 ms after the diameter of the coating has melted to a critical size. Simulations in COMSOL and in vitro experiments demonstrated the ability to adjust and release the spring over a 4-minute period with a standard deviation of 11.4s (Figs. 83A-83E). The entire spring actuation system fits easily into the hollow portion of the SOMA, but the holes located above the spring allow gastrointestinal fluid to penetrate and reach the encapsulation material.</p><p>Insulin-loaded microposts were administered to pigs and blood glucose and blood insulin levels were measured over 2 hours. Microposts inserted into the tissue, delivered intragastrically by SOMA and subcutaneously by manual infusion, were released at near zero-order kinetic rates (Fig. 74A-74D) (n = 5). Laparotomy and gastric incision surgery were also performed and the microposts were manually placed in the stomach, and this delivery method resulted in pharmacokinetic uptake comparable to SOMA (Figs. 84A-84D). Human insulin levels in porcine plasma remained in the range of 10-70 pM throughout the sampling period. PEO Manual insertion microposts made from 200K and human insulin, as well as SOMA delivery microposts made from 100% human insulin, have an API of 280 ± 20 μg buried under the tissue, estimated from weight measurements and histological examinations. I let you. All micropost insertion methods produced a hypoglycemic effect, with microposts inserted intragastrically resulting in a more pronounced drop compared to subcutaneously administered microposts. This data was compared to studies using SOMA (n = 5) designed to localize the micropost to the stomach without inserting it into the tissue. Pigs treated with non-insertion SOMA did not experience insulin uptake or hypoglycemic effects. The near-zero kinetic release rate of the inserted microposts offered the possibility of using the microposts as an implantable drug reservoir, leaving the ability of these formulations to release the API over a long period of time (Fig. 84A). ~ 84D). Micropost continued to release API intrasubcutaneously for at least 30 hours when 1 mg or more of API (n = 6) was inserted. This could generally make it possible to reduce the frequency of administration.</p><p>Micro post</p><p>SOMA generally provides a means of oral delivery of APIs such as insulin and also indicates the possibility of being used with other APIs. Since some methods of micropost fabrication use high pressure doses, the delivered molecule must remain active under such stress. Activity assays for microposts made with lysozyme and glucose-6-phosphate dehydrogenase demonstrate that multiple APIs maintain their activity after the manufacturing process (FIGS. 85A-85D). In addition, the deliverable dose is constrained by the volume of microposts that invade the gastric mucosa. Increasing the penetration depth and width of the microposts will allow primary and secondary increases in dosing capacity, respectively, which can impair the gastric mucosal barrier and increase the risk of perforation. Sometimes. SOMA represents a platform that has the potential to deliver a wide range of biopharmacy products, including but not limited to those based on other proteins and nucleic acids. The effectiveness of drug delivery achieved using this novel technique suggests that this method could replace the traditional subcutaneous injection of insulin, further evaluation of other biopolymers. Justify.</p><p>material and method</p><p>Dulbeccoline Phosphate Buffered Saline (PBS) was purchased from Life Technologies' Gibco (Woburn, USA). Human insulin was obtained from Novo Nordisk (Maalov, Denmark). 200,000 molecular weight PEO, 45,000 molecular weight polycaprolactone (PCL), and sucrose were purchased from Sigma Aldrich (Saint Louis, USA). The 301 steel springs are custom made by Madsens Fjedrefabrik (Brondby, Denmark). The three custom made springs had the specifications shown in Table 2. The 1.7N spring was purchased from Lee Spring Company (Brooklyn, USA) and has the serial number CI008B05S316. Isomalt was purchased from CK Products (Fort Wayne, USA).</p><p><tables><img file="JP7045397B2_D0005.tif" /></tables> Device production:</p><p>The two-part male type was designed in Solidworks (Dassault Systemes, Velizy-Villacoublay, France) and printed with a Form 2 3D printer (Formlabs, Somerville, USA) for ellipsoids, spheres and SOMA tops. Each device was designed to have a weight of 0.77 g, 88% of which is made of stainless steel and the remaining weight is made of PCL. The top part of the PCL was poured into a male mold in a molten state to form the top section of the device, and the bottom part was made from 316L stainless steel using a milling machine.</p><p>A molten PCL was then used to secure the spring to the top compartment of the device, and the PCL was used again to attach the drug loading micropost to the spring. Finally, PCL was used to attach the devices to each other.</p><p>Before making the stainless steel parts, he made a prototype model from field metal purchased from Alfa Aesar (Haverville, USA). The low melting point of this metal alloy makes it easy to make devices, its 7.88 g / cm.³Density is the density of stainless steel (7.7g / cm)³) Is similar. These prototypes were used to rate devices in vitro and ex vivo. Stainless steel and PCL devices were used in all in vivo experiments and were also used in experiments to measure the orientation ability of SOMA in air and water, inside the resected stomach, and in the presence of motion.</p><p>Sugar spring encapsulation:</p><p>Sucrose was heated to 210 ° C for 15 minutes in a mold made from the SYLGARD 184 Elastomer Kit (Dow Chemical, Midland, USA) with holes of three different diameters (4 mm, 5 mm and 6 mm) (Figure 86). ). The spring was placed in a mold filled with molten sucrose and caramelized in a furnace for an additional 5 minutes. The mold was removed from the furnace, the spring was compressed into sucrose using a custom-made plunger, the sucrose spring was left to cool, and then removed from the mold. Isomalt springs were made using the same method but did not caramelize the material.</p><p>Insulin micropost production</p><p>Insulin microposts were made as described herein and in Figure 73A.</p><p>Self-orientation experiments in various fluids</p><p>Recorded at 1000 fps using a Vision Research Phantom v7.1 monochrome high-speed video camera (Vision Research, Homewood, USA) to calculate the restore speed of the device. SOMA manufactured from PCL and field metal and from PCL and 316L stainless steel, 2 x 5 x 10 cm³Opened from an angle of 90 ° while immersed in one of the following fluids in a clear plastic container: Canola oil (Crisco, Orrville, USA); taken from Yorkshire pigs and filtered using a 10 μm syringe filter. , Gastric fluid; 10 mg / mL reconstituted mucin from the stomach of pigs in 1 M NaOH (Sigma-Aldrich, St. Louis, USA); and tap water (Cambridge, USA). A line was drawn on the axis plane of the device to determine the angle within a given frame, and sequential image analysis with Image J (open source) was used to determine the orientation rate. The device was considered oriented when the drawn line was perpendicular to the bottom of the container.</p><p>Self-orientation experiment in the stomach of a moving pig</p><p>Pig tissue for ex vivo evaluation was obtained from Blood Farm Slaughterhouse (West Groton, USA). Pigs were euthanized, fresh tissue was obtained and stored on ice. Tissues were tested within 6 hours of euthanasia. To determine the efficiency of device orientation within the stomach, an intact Yorkshire pig stomach was placed suspended so that the esophageal and pyloric sphincters were elevated above the body of the stomach. A 12.7 cm long, 1.9 cm diameter Tygon tube was then inserted into the gastric esophageal sphincter and clamped to mimic the esophagus. The stomach was then filled with water and the device was passed through a tube and lowered into the stomach. The device was rated by a window cut out over the top compartment (less curvature) of the stomach to determine if the desired aspect of the device was in contact with the tissue wall. This experiment was performed using the SOMA shape manufactured only with PCL and the SOMA shape manufactured with field metal and PCL and 316L stainless steel and PCL. In addition, ellipsoidal and spherical devices were also tested.</p><p>Resistance test to external exercise</p><p>Resistance to external motion was tested in vitro by immersing the device in water in a 500 mL Erlenmeyer flask and recording using a tiltable shaker at 50 rpm with a 15 ° tilt. Image J was used to rate the film image frame by frame, and the tilt angle was calculated by determining the maximum angle between the axis plane of the device and the plane of the shaker base over a tilt period.</p><p>In vivo simulated walking test</p><p>All animal experiments were approved by and followed by the MIT Committee on Animal Care. Female Yorkshire pigs for in vivo experiments were obtained from Tufts University (Medford, USA). Two devices were fed to the pig using an overtube. One device was SOMA, while the other device had the same shape as SOMA but contained steel washers for X-ray visualization and was manufactured entirely using PCL. The pig was moved axially and laterally, making two rotations from the left side to the right side. Then the pig was put back on the table and rolled 180 degrees. Finally, X-rays were taken to visualize the orientation of the device. These x-rays were compared to in vitro x-rays in which the device was placed at a known angle. Since the pig's stomach has various curvatures, the device was considered oriented if it was within 30 degrees of the vertical plane of the X-ray (Fig. 76).</p><p>In vivo needle penetration test</p><p>A special stage was constructed to test the force insertion profile in vivo (Fig. 82). The device consisted of a linear device that moved downward to a piece of tissue at a control rate of 0.2 mm / s. The force gauge and camera were placed on the moving stage. As the needle penetrates the tissue, the force and video measurements are recorded in LabVIEW along with the video image. Yorkshire pigs were sedated as described in the "Evaluation of In vivo Insulin Delivery" method section. A laparotomy was performed to approach the gastric surface mucosa. At least 7.5 x 7.5 cm²The stomach tissue was projected to show the working area of. A custom device was then placed over the tissue and used to insert a micropost at 0.2 mm / s. Surgical measurements were affected by respiration and the displacement caused by respiration was determined to be the major cause of the extra 3 mm insertion. This was measured using a ruler and confirmed by comparing the force on the inhaling needle with the force on the exhaling needle during the entire insertion process. The force read during exhalation was found to correspond to the force perceived during inspiration 3 mm earlier. Force measurements in vivo were read by a 10N force gauge (Shimpo, Cedarhurst USA) with an accuracy of ± 0.03N and a resolution of 0.01N.</p><p>In vitro dissolution of insulin microposts</p><p>Three 50 ml falcon tubes were filled with 2 mL of PBS and incubated at 37 ± 0.1 ° C. At the beginning of the test, one insulin micropost tip was immersed in each Falcon tube. The rack containing the tubes was placed in an Innova 44 Shaker Series incubator (New Brunswick Scientific, Edison, USA) set at 37 ± 0.1 ° C and 50 rpm.</p><p>Samples were taken from the tube every 3 minutes until 15 minutes and then every 5 minutes until 60 minutes. At each of these time points, the test tube rack was removed from the incubator and 200 μL of solution was pipetted into an HPLC vial. Then, 200 μL of PBS was pipetted back into the tube at 37 ± 0.1 ° C. The test tube rack was reinserted into the incubator. Blank reference samples were also taken from vials of pure PBS incubated at 37 ± 0.1 ° C.</p><p>HPLC vials were tested on an HPLC machine (Agilent, Santa Clara, USA) and the method obtained from the article below was used with varying execution times to determine the amount of dissolved insulin at a given time point. Simply put, 7.8 x 300 mm²An insulin HMWP column (Waters Corp, Milford, USA) was used and set to room temperature. Elution used mobile phases made from 15% acetic acid (v / v), 20% acetonitrile (v / v) and 0.65 g / L L-arginine, all purchased from (Sigma-Aldrich). For 26 minutes, the flow rate was 0.5 mL / min.</p><p>Insulin stability test</p><p>The tip of the insulin micropost was placed inside a dry pill container and left in an air-conditioned room set at 40 ° C and 75% relative humidity. The tips of the microposts of the same batch were placed in an air conditioning chamber at 5 ° C and 15% relative humidity. In addition, a liquid formulation of pure insulin dissolved in PBS at a concentration of 4 mg / mL was also placed in the two temperature and humidity control chambers. Samples were left for 0, 2, 4 and 16 weeks. Upon removal, dissolution tests for microposts were performed in addition to high molecular weight protein (HMWP) analysis, activity testing, and Raman spectroscopy. Raman analysis is described later in the section entitled "Raman spectroscopy", while HMWP analysis is "in". In vitro lysis was performed using the HPLC method described in the section and activity tests were performed using the receptor binding assay. Briefly, a scintillation proximity assay (SPA) was performed with human insulin from the micropost and the binding receptor affinity was validated by competition between human insulin from the micropost and [125I] TyrA14 labeled insulin in the SPA. .. Affinities were analyzed using a 4-parameter logistic model and the results were compared to untreated human insulin.</p><p>Raman spectroscopy</p><p>A DXRxi EM-CCD Raman imaging microscope (Thermo Fisher Scientific, Waltham, USA) was used to image the insulin and PEO compressed mixture. The sample was exposed to a laser wavelength of 780 nm at an output of 24 mW and a frequency of 200 Hz. The laser beam was focused with a 20x NA0.40 objective and the scatter was collected by the same lens. Rayleigh and anti-Stokes scattering were blocked by an edge filter prior to entry into the spectroscope configured to have a grating line number of 400 lines / mm. 200 x 200 μm²Area was scanned with a scan step size of 5 μm in each dimension. 300 scans were performed on each section. To smooth the data, principal component analysis was performed to eliminate noisy spectra, and root mean square analysis was performed to further filter the data. The peak detection tool in MATLAB was used to determine the peak position and width of the desired peak. Only insulin peaks that did not overlap with the PEO peak were analyzed. The results are shown in Figure 78.</p><p>Enzyme activity assay</p><p>The tip of the micropost was made as described above, but instead of using insulin as the active ingredient, glucose-6-phosphate dehydrogenase (G6PD) expressed in lysozyme (Sigma Aldrich) from chicken eggs and E. coli. ) (Sigma Aldrich) was used as the API. To perform the activity assay on G6PD, an activity assay kit (Sigma Aldrich) was used to measure the amount of oxidized glucose-6-phosphate. Three micropost tips were made using 40% G6PD and 60% PEO 200k, all of them were dissolved together for assay, and then uncompressed to the micropost tips. Compared with. A double repeat assay was performed on the lysing solution.</p><p>To measure the activity of lysozyme, the assay provided by Sigma Aldrich, which measures the amount of lysed Micrococcus lysodeikticus cells, was used. Briefly, 200 units / mL lysozyme solution in 50 mM potassium phosphate buffer was added to 0.015% [w / v] Micrococcus lysodeikticus cell suspension in the buffer. A for 5 minutes₄₅₀Recorded a decrease in. Nine micropost tips were made from 80% lysozyme and 20% PEO 200k, and a set of three micropost tips were melted together. Triple repeat assays were performed with each lysate solution for a total of 9 tests and the results were compared to the results of the solution made with lysozyme uncompressed to the tip of the micropost.</p><p>In vivo insulin delivery evaluation</p><p>To assess the insulin micropost formulation, the API formulation was administered to a large animal model (female Yorkshire pig, 35 kg to 65 kg) by three separate methods: intragastric infusion (IG) with a SOMA device; manually. IG; and subcutaneous infusion (SC). The pig model was selected because of the human anatomical similarity of the GI tube, as well as its widespread use and device evaluation in the GI tube. No adverse effects were observed during the experiment. To deliver the SOMA device, the pigs were fed a liquid diet 24 hours prior to the procedure and the pigs were fasted overnight. Intramuscular injection of terrazole (tiletamine / zolazepam) (5 mg / kg), xylazine (2 mg / kg) and atropine (0.05 mg / kg) and, if necessary, isoflurane supplementation with a face mask (1-3% in oxygen) ) Was used to sedate the pig. An oral gastric tube or overtube was placed with gastroscopic guidance and retained in the esophagus to facilitate passage of the device. The SOMA device was placed in the stomach through an overtube. The pigs were fasted, but some pigs still had food in the stomach during SOMA delivery. Blood samples taken after operation from SOMA devices that landed on food or SOMA devices that did not inject their drug payload were discarded from the samples. Blood samples are taken by the central venous line every 10 minutes for the first 2 hours, every 30 minutes for 2-4 hours, and at designated time points including, but not limited to, 6, 12 and 24 hours. did. LifeScan Inc. Blood glucose levels in blood samples were immediately tested using the OneTouch Ultra Blood Glucose Monitor by (Milpitas, USA). Additional blood was collected in K3 tubes of ethylenediaminetetraacetic acid (Sarstedt, Numbrecht, Germany) and centrifuged at 2000 Relative Centrifugal Force for 15 minutes. The collected plasma was shipped for analysis using dry ice. Briefly, the homogenius bead assay utilized two monoclonal antibodies against human insulin, resulting in a stack of acceptor beads, insulin, and donor beads. This produced a signal proportional to the concentration of insulin. This study was specific for human insulin and did not detect other endogenous insulin (Fig. 87).</p><p>Insulin microposts were delivered subcutaneously by creating a 3 mm deep guide hole in the pig's skin using an 18G needle and inserting the micropost into the guide hole. The microposts were delivered by intragastric infusion during open surgery, approaching the gastric mucosa using a 3 cm incision and manually inserting the microposts into the gastric surface epithelium. Blood samples and sedation were performed in the same manner as described above.</p><p>The amount of insulin inserted into the tissue by the SOMA device was estimated using histological test results from in-situ in vivo experiments (Fig. 73F). Since the SOMA micropost shaft and tip were made from 100% human insulin, not all APIs were considered payloads. The micropost insertion depth was evaluated and used to calculate the volume of microposts buried in the tissue. This volume was then multiplied by the density of the microposts to estimate the amount of API delivered. The amount of human insulin delivered by manually placed microposts made from 80% human insulin and 20% PEO 200k is assumed to be 100% of the integrated API as all microposts have been inserted into the tissue. did.</p><p>In vivo retention and safety assessment</p><p>Six SOMAs with 32G stainless steel needles protruding 3 mm from the lower part of the device and permanently fixed were placed in the pig's stomach using an overtube. While these devices are still inside the stomach, they mimic the translational movements of the pig (which can be experienced while the device is inside the body, as described in the "simulated gait test" method section). (Because of) simulated. Endoscopic observations were then performed to check for any bleeding caused by the needle. After that, radiographs were taken every day to determine the residency time of the device. X-rays were taken until all devices passed. In addition, animals were clinically evaluated for normal feeding and defecation patterns during device retention.</p><p>Rat toxicity test</p><p>Acute toxicity study: 2000 mg / kg stainless steel with measurements 100-300 μm in diameter in 1 mL soybean oil (Crisco Orrville, USA) in 3 rats (Charles River Labs, Sprague Dawley body weight 400-450 g) Particles (McMaster Carr Elmhurst, USA) were administered once. These rats were compared to a control group of 3 rats receiving only 1 mL of soybean oil. After 14 days, both groups were euthanized by overdose of inhaled carbon dioxide, autopsied, heart, lung, stomach, small intestine, colon, liver, kidney, spleen, pancreas and bladder samples fixed with formarin and H &amp; E. Was stained and analyzed by a pathologist to determine if any abnormalities were found.</p><p>Subchronic study: 6 rats (Charles River Labs, Sprague Dawley, body weight 330-450 g) with 80 mg / kg stainless steel particles with measurements between 100-300 μm in diameter in 1 mL soybean oil for 4 weeks. It was administered by gavage oral administration 5 days a week. These rats were compared to a control group of 6 rats receiving only 1 mL of soybean oil at the same frequency and duration. Whole blood samples were taken on days 1, 15 and 26 and tested for traces of chromium and nickel. On day 15, urine samples were also taken to test for traces of chromium and nickel. On the 8th day, an X-ray photograph of the GI tube was taken using the Faxitron Multifocus (Faxitron, Tucson, USA) to confirm the passage of stainless steel. At the end of the 26th day study, all 12 rats were euthanized by overdose of inhaled carbon dioxide and autopsied. Samples of the heart, lungs, stomach, small intestine, colon, liver, kidneys, spleen, pancreas and bladder are fixed with formarin, stained using H &amp; E and analyzed by a pathologist to see if any abnormalities are present. Judged.</p><p>Computation optimization:</p><p>A two-dimensional curve was optimized over a 180-degree plane in quadrants I and IV, and the optimized shape was created by rotating the curve around the Y-axis. FIG. 88 illustrates the optimization curve as well as the vectors and methods described in this section. The optimization function varied the radii of 25 different points spaced at equal angles along a curve drawn in polar coordinates. When reconverting to Cartesian coordinates, the space inside the rotation curve and below the XZ plane is a high density material (7.7 g / cm).³), While the space above the XZ plane and inside the rotation curve is a low density material (1.1 g / cm).³) Was set to be included. To simulate the hollow upper section, a cylinder with a radius of 4 mm centered on the Y axis, starting in the XZ plane and ending at the curved boundary, was moved from the top of the shape. The masses of the springs and microposts were incorporated into the model. To define the scale of the shape, the center of mass was constrained to the origin and the highest possible point was constrained to the coordinates [0, 1]. The final shape was scaled to fit the size constraints. These constraints met the requirements for axisymmetric mono-monostatic shapes, so that possible solutions were not lost.</p><p>The optimization itself used Newton's equation of motion to find the self-orientation time of a given shape, t:<math num="4"><img file="JP7045397B2_D0006.tif" /></math></p><p>The angular acceleration α and the angular velocity ω in the equation are determined based on the moment of inertia I of the device and the torque τ. Gravity F acts as an external force in this model and uses gravity F to calculate the simulated torque on the lever arm d (defined as the distance between the center of mass of the device and the point of contact with the tissue wall). did.</p><p>The angular acceleration of the device in a given orientation, as defined by Equation 2, determines the orientation velocity and varies with torque and moment of inertia. The moment of inertia was calculated along with the total weight of the device by dividing the 3D space into 50 × 50 × 50 arrays of blocks of equal size, specifying the density of each block, and summing up as described in Equation 4.</p><p>The calculation of torque for the device required determination of both the direction and magnitude of the force and distance vectors according to Equation 5. The force vector was the gravity on the object, starting from the center of mass and pointing in the direction perpendicular to the contact plane. The distance vector was calculated as the distance between the center of mass and the center of rotation of the device on the contact surface. When determining the center of rotation, the region with the concave curvature does not touch the surface, so the larger curvature of the device was taken into account.</p><p>Sucrose-encapsulated dissolution modeling</p><p>The radius at which sucrose encapsulation will propagate the crack, the condition of Griffith;<math num="5"><img file="JP7045397B2_D0007.tif" /></math>(In the formula, σ_cIs the critical stress applied by the spring, γ is the surface energy of the material, E is the Young's modulus of the material, and a is the surface area perpendicular to the applied stress). .. All variables in this equation remain constant except for the surface area, so the dissolution rate defines the cracking event and the time to spring release. COMSOL models and experimental tests are based on springs that provide a force of 1N. Physical springs were created by cutting the purchased springs to the appropriate size.</p><p>COMSOL Multiphysics (Stockholm, Sweden) was used to mathematically model the dissolution of sucrose cylinders in both still water and water flowing at 0.02 m / s, similar to that of the human stomach. Fick's laws were used to estimate the rate of diffusion process at the contractile boundary between sucrose and water. 5.2 × 10^-10m²Diffusion coefficient of / s, 6720 mol / m³Equilibrium concentration of sucrose in water, and 7.8 × 10^-4The mass transfer coefficient of m / s (found in the experiment) was used as a parameter. The COMSOL model is run with starting sucrose cylinder diameters of 6 mm, 5 mm and 4 mm, and the time it takes for the cylinder to dissolve to a diameter of 1.7 mm is used to operate when the spring is present in the cylinder. I predicted the timing.</p><p>To calculate the mass transfer coefficient of sucrose in water, sucrose was caramelized at 215 ° C for 15 minutes in a PDMS mold with a hole 6 mm in diameter to create a cylindrical shape. Caramelized sucrose cylinders were placed in a 500 mL beaker of room temperature water and the diameter of sucrose was measured every minute. The dissolution rate was modeled and the slope of the linear fit was determined to be the mass transfer coefficient.</p><p>To test the dissolution of the sucrose coating on the spring, the sucrose-filled spring was placed in a 500 mL beaker of room temperature water and the timing of spring actuation for 4 mm, 5 mm and 6 mm diameter sucrose springs was tested and recorded three times each. ..</p><p>(Example 17) Coating</p><p>This example demonstrates the use of the various coatings described herein for the system.</p><p>Instron was used for various coatings (PDMS dip coating, PDMS film coating, PCL dip coating, and PCL 3 x dip coating) and compressed at 0.1 mm / s. The results are summarized in Table 4.</p><p><tables><img file="JP7045397B2_D0008.tif" /></tables></p><p>Exemplary embodiments</p><p>(Embodiment 1) An ingestible self-restoring article, a first portion having an average density; a second portion having an average density different from the average density of the first portion; and an object to ingest the article. An ingestible self-healing article that comprises a payload portion that carries a drug for release into the body; is configured to be encapsulated.</p><p>(Embodiment 2) An ingestible self-restoring article comprising a payload portion carrying a drug to be released into the body of an ingested object, which is suspended via an axis passing through a geometric center. Since the center of mass is laterally offset from the center of geometry, it is 0.09 × 10 around the axis due to gravity.^-4An ingestible self-restoring article that has a geometric center and a mass center that is offset from the geometric center, such as receiving externally applied torque of Nm or less; it is configured to be encapsulated.</p><p>(Embodiment 3) A first part having an average density of a self-restoring article; a second part having an average density different from the average density of the first part; and a tissue attached to the self-restoring article.<u style="Single">connection</u>A self-restoring article comprising components; the ratio of the average density of the first part to the average density of the second part is greater than or equal to 2.5: 1.</p><p>(Embodiment 4) The self-restoring article according to any one of the above-described embodiments, which is a rubber box type.</p><p>(Embodiment 5) 0.09 × 10^-4The self-restoring article according to any of the above embodiments, which maintains an orientation of 20 degrees or less from the vertical when an externally applied torque of Nm or less is applied.</p><p>(Embodiment 6) The self-restoring article according to any of the above embodiments, wherein the first portion has an average density of less than or equal to 2 g / mL and greater than or equal to 0.6 g / mL.</p><p>(Embodiment 7) The self-restoring article according to any of the above embodiments, wherein the second portion has an average density of less than 20 g / mL and greater than or equal to 3 g / mL.</p><p>(Embodiment 8) The self-restoring article according to any one of the above-described embodiments, wherein the first part contains the first material and the second part contains the second material.</p><p>(Embodiment 9) The self-restoring article according to any one of the above embodiments, wherein the first material and / or the second material is selected from the group consisting of polymers, ceramics and metals.</p><p>(Embodiment 10) The self-restoring article according to any one of the above-described embodiments, wherein the first material and / or the second material is biocompatible.</p><p>(Embodiment 11) The self-restoring article according to any one of the above-described embodiments, wherein the first material and / or the second material is biodegradable.</p><p>(Embodiment 12) The self-restoring article according to any one of the above-described embodiments, wherein the first material is metal, ceramic, or a combination thereof.</p><p>(Embodiment 13) The self-restoring article according to any one of the above embodiments, wherein the metal is selected from the group consisting of stainless steel, iron-carbon alloy, field metal, tungsten, molybdenum, gold, zinc, iron and titanium. ..</p><p>(Embodiment 14) The self according to any one of the above-described embodiments, wherein the ceramic is selected from the group consisting of hydroxyapatite, aluminum oxide, calcium oxide, and tricalcium phosphate, zirconium oxide, silicate, and silicon dioxide. Restored goods.</p><p>(Embodiment 15) The self-restoring article according to any one of the above-described embodiments, wherein the second material is a polymer.</p><p>(Embodiment 16) The embodiment according to any one of the above embodiments, wherein the polymer is selected from the group consisting of polycaprolactone, polylactic acid, polyethylene glycol, polypropylene, polyethylene, polycarbonate, polystyrene, and polyetheretherketone, and polyvinyl alcohol. Self-restoring goods.</p><p>(Embodiment 17) The self-restoring article according to any one of the above-described embodiments, wherein the first material is different from the second material.</p><p>(Embodiment 18) The self-restoring article according to any one of the above-described embodiments, wherein the active ingredient of a pharmaceutical product is arranged in a hollow portion.</p><p>(Embodiment 19) Self-restoration time from 90 degrees in oil less than or equal to 0.15 seconds, self-restoration time from 90 degrees in gastric juice less than or equal to 0.06 seconds, less than or equal to 0.05 seconds. The self-restoring article according to any of the above embodiments, which has a self-restoring time from 90 degrees in mucus.</p><p>20. The self-restoring article according to any of the above embodiments, which has a self-restoring time from 90 degrees in water less than or equal to 0.05 seconds.</p><p>21. The self-restoring article according to any of the above embodiments, comprising one or more outlets.</p><p>(Embodiment 22) The self-restoring article according to any of the above embodiments, having a maximum cross-sectional dimension of less than or equal to 1.1 cm.</p><p>(Embodiment 23) A capsule comprising an external shell and the self-restoring article according to any of the above embodiments.</p><p>24. The capsule according to embodiment 23, comprising a spring actuating component.</p><p>(Embodiment 25) A method of orienting a capsule in a subject, comprising administering to the subject a capsule comprising an external shell and a self-restoring article; the first portion of the self-restoring article having an average density; A second part with an average density different from the average density of the first part; and the tissue associated with the self-restoring article<u style="Single">connection</u>A method that comprises components.</p><p>26. The method of embodiment 25, wherein the self-restoring article comprises a pharmaceutically active agent.</p><p>27. The method of embodiment 26, wherein at least a portion of the pharmaceutically active agent is released to a location within the body of the subject.</p><p>28. The method of embodiment 25, comprising administering to the subject a sensor such as that associated with a self-restoring article.</p><p>(Embodiment 29) A method of delivering a pharmaceutical agent to a location within a subject, comprising administering to the subject a capsule comprising an external shell and a self-restoring article; the self-restoring article has a first average density. The first part containing the first material with; the second part containing the second material having a second average density different from the first average density; and placed in the self-restoring article, Tissues associated with pharmaceutical activators<u style="Single">connection</u>Equipped with components; the ratio of the average density of the first material to the average density of the second material is greater than or equal to 2.5: 1; the self-restoring article is tissue at a location within the subject's body.<u style="Single">connection</u>A method in which the components are oriented to puncture tissue close to a location in the body of the subject; at least a portion of the pharmaceutically active agent is released into the tissue.</p><p>(Embodiment 30) A self-restoring article comprising a first material, a second material different from the first material; and a pharmaceutically active agent associated with the self-restoring article, 0.09 × 10.^-4When an externally applied torque of Nm or less is applied, the axis essentially perpendicular to the tissue engaging surface of the self-restoring article is configured to maintain an orientation of 20 degrees or less from the vertical, first. A self-restoring article in which the ratio of the average density of the material to the average density of the second material is greater than or equal to 2.5: 1.</p><p>(Embodiment 31) 1 g / cm³A self-restoring article with at least the first portion with a higher average density, having a maximum cross-sectional dimension of less than or equal to 1.1 cm, 0.09 x 10^-4A self-restoring article in which the axis perpendicular to the tissue engaging surface of the self-restoring article is configured to maintain an orientation of 20 degrees or less from the vertical when an externally applied torque of Nm or less is applied.</p><p>(Embodiment 32) A first portion comprising a first material having a first average density; and a second portion comprising a second material having a second average density different from the first average density. A self-restoring article to be equipped with the most stable, lowest potential energy physical composition and less than 0.05 seconds or equal to an orientation 90 degrees off the most stable composition in water in any direction. A self-healing article having a self-healing time; the ratio of the average density of the first material to the average density of the second material is greater than or equal to 2.5: 1.</p><p>(Embodiment 33) 1 g / cm³A self-restoring article with at least the first portion with a higher average density, having a maximum cross-sectional dimension of less than 1.1 cm or equivalent, and self from 90 degrees in water less than or equal to 0.05 seconds. A self-restoring article with a recovery time.</p><p>(Embodiment 34) 1 g / cm³A self-restoring article with at least the first portion with a higher average density, having a self-restoring time from 90 degrees in water less than or equal to 0.05 seconds, 0.09 × 10^-4When an externally applied torque of Nm or less is applied, the longitudinal axis perpendicular to the tissue engaging surface of the self-restoring article is configured to maintain an orientation of 20 degrees or less from the vertical and / or 1 Self-restoring articles with occlusion rates less than or equal to%.</p><p>(Embodiment 34) External shell; Spring that is at least partially encapsulated within the external shell; Support material attached to the spring to maintain at least a portion of the spring under ambient conditions and at least 5% compressive strain. ; And the tissue operably connected to the spring<u style="Single">connection</u>An article comprising a component.</p><p>35. The article of any of the above embodiments, wherein the support material at least partially opens the spring under physiological conditions.</p><p>(Embodiment 36) Organization<u style="Single">connection</u>The article according to any of the above embodiments, wherein the component comprises a needle, a biopsy component, a hook, a mucosal adhesive patch, or a combination thereof.</p><p>(Embodiment 37) The article according to any one of the above embodiments, which comprises a pharmaceutically active agent.</p><p>(Embodiment 38) The article according to any of the above embodiments, wherein at least a part of the pharmaceutically active agent is released from the article when the support material is at least partially decomposed.</p><p>39. The embodiment of any of the above embodiments, wherein the support is configured to maintain the spring under compression and thus the spring is restored when the support is at least partially disassembled. Goods.</p><p>(Embodiment 40) The article according to any one of the above-described embodiments, wherein the support material contains a brittle material.</p><p>41. The article of embodiment 40, wherein the brittle material comprises a sugar and / or a polymer.</p><p>(Embodiment 42) The article according to any of the above embodiments, wherein the support is a coating having a thickness greater than or equal to 3 mm and less than or equal to 6 mm.</p><p>43. The article of any of the above embodiments, wherein the spring comprises a material selected from the group consisting of nitinol, metal and polymer.</p><p>(Embodiment 44) The article according to any of the above embodiments, wherein the spring has a spring constant greater than or equal to 100 N / m and less than or equal to 20000 N / m.</p><p>45. The article of any of the above embodiments, wherein the spring is compressed from the uncompressed length of the spring to greater than or equal to or less than 5 mm or equal to it.</p><p>(Embodiment 46) The article according to any of the above embodiments, wherein the external shell is a capsule.</p><p>(Embodiment 47) The article according to any of the above embodiments, which is attached to the self-restoring system.</p><p>(Embodiment 48) The article according to any of the above embodiments, wherein the spring has an average cross-sectional dimension greater than or equal to 1 mm and less than or equal to 10 mm.</p><p>(Embodiment 49) A method comprising administering an article to a subject, wherein the article is at least partially encapsulated in an external shell; a spring; at least a portion of the spring under ambient conditions, at least 10%. Support material attached to the spring to maintain under compressive strain; and tissue attached to the spring<u style="Single">connection</u>A method that comprises components.</p><p>(Embodiment 50) A method of puncturing a tissue located within a subject's body, comprising administering the article to the subject; an external shell; a spring in which the article is at least partially encapsulated by an external shell; a spring. Support material attached to the spring to maintain at least a portion of the spring under ambient conditions and at least 10% compressive strain; and tissue attached to the spring.<u style="Single">connection</u>It comprises components; at least a portion of the support is disassembled, resulting in spring elongation and / or tissue.<u style="Single">connection</u>A method by which a component penetrates a tissue located within a subject's body.</p><p>51. The method of embodiment 50, wherein the pharmaceutically active agent is released during and / or after intrusion into a tissue located in the body of the subject.</p><p>(Embodiment 52) Organization<u style="Single">connection</u>51. The method of embodiment 51, wherein the self-restoring article is oriented such that the longitudinal axis of the component is orthogonal to the tissue located in close proximity to the self-restoring article.</p><p>(Embodiment 53) Organization<u style="Single">connection</u>Components and organization<u style="Single">connection</u>An article comprising a spring attached to a component, wherein the spring is maintained partially compressed by a support under at least 5% compressive strain, and the spring supports the fluid. Articles that are configured to release at least 10% of the stored compressive energy of the spring within 10 minutes of exposure of the material.</p><p>(Embodiment 54) Organization<u style="Single">connection</u>25. The article of embodiment 53, comprising a pharmaceutical agent associated with a component.</p><p>(Embodiment 55) Organization<u style="Single">connection</u>The article according to embodiment 53 or 54, including a self-restoring article associated with a component.</p><p>(Embodiment 56) Tissue comprising a solid therapeutic agent and a support material<u style="Single">connection</u>The component, the solid therapeutic agent, is the tissue<u style="Single">connection</u>Tissue in an amount greater than or equal to 10% by weight based on the total weight of the components<u style="Single">connection</u>Tissue that is present in the components and has a substantially even distribution of solid therapeutic agents and supports.<u style="Single">connection</u>An organization that is a component and is configured to penetrate the organization<u style="Single">connection</u>Component.</p><p>57. The tissue according to embodiment 56, comprising a plurality of microneedles and supports comprising a solid therapeutic agent.<u style="Single">connection</u>Component.</p><p>(Embodiment 58) Organization<u style="Single">connection</u>The organization according to embodiment 56, comprising a support material attached to the component.<u style="Single">connection</u>Component.</p><p>(Embodiment 59) Tissue having a tip<u style="Single">connection</u>It comprises a solid therapeutic agent and a support material to which the solid therapeutic agent is attached, and at least a part of the solid therapeutic agent is a tissue.<u style="Single">connection</u>Attached to one or more tips of the component, the solid therapeutic agent is the tissue<u style="Single">connection</u>Tissue in an amount greater than or equal to 10% by weight based on the total weight of the components<u style="Single">connection</u>The organization that exists in the components<u style="Single">connection</u>Component.</p><p>60. The tissue according to embodiment 59, comprising a plurality of microneedles comprising a solid therapeutic agent and a support material.<u style="Single">connection</u>Component.</p><p>61. The tissue according to embodiment 59 or 60, wherein at least a portion of the solid therapeutic agent is present on at least the surface of the tip.<u style="Single">connection</u>Component.</p><p>(Embodiment 62) The tissue according to any one of embodiments 59 to 61, wherein at least a part of the tip thereof contains a solid therapeutic agent.<u style="Single">connection</u>Component.</p><p>(Embodiment 63) The tissue according to embodiment 62, wherein the tip comprises a solid therapeutic agent greater than or equal to 70% by weight based on the total weight of the tip.<u style="Single">connection</u>Component.</p><p>(Embodiment 64) The structure according to embodiment 59 or 60, wherein at least a part of the support material is present on at least the surface of the tip portion.<u style="Single">connection</u>Component.</p><p>(Embodiment 65) Organization<u style="Single">connection</u>A method of forming a component, the step of providing a solid therapeutic agent and a support, and the solid therapeutic agent and the support together, compressed and / or heated using a pressure of at least 1 MPa. , Organization<u style="Single">connection</u>Organization, including steps to form components<u style="Single">connection</u>A method in which the components are configured to penetrate the organization.</p><p>(Embodiment 66) The method of embodiment 65, wherein the step of compression comprises centrifuging the solid therapeutic agent and the support.</p><p>67. The method of embodiment 65, wherein the compressing step comprises the use of a pressure of at least 20 MPa.</p><p>(Embodiment 68) The structure according to any one of the above-described embodiments, wherein the support material is biodegradable.<u style="Single">connection</u>Component or method.</p><p>(Embodiment 69) The structure according to any one of the above-described embodiments, wherein the support material contains a polymer.<u style="Single">connection</u>Component or method.</p><p>(Embodiment 70) The structure according to embodiment 69, wherein the polymer is selected from the group consisting of polyethylene glycol and HPMC.<u style="Single">connection</u>Component or method.</p><p>(Embodiment 71) The tissue according to any one of the above-described embodiments, wherein the solid therapeutic agent is selected from the group consisting of active pharmaceutical pharmacological ingredients, insulin, nucleic acid, peptide and antibody.<u style="Single">connection</u>Component or method.</p><p>(Embodiment 72) Organization<u style="Single">connection</u>The structure according to any of the above embodiments, wherein the component comprises a coating.<u style="Single">connection</u>Component or method.</p><p>(Embodiment 73) The structure according to any of the above embodiments, wherein the coating has a yield strength greater than or equal to 50 MPa.<u style="Single">connection</u>Component or method.</p><p>(Embodiment 74) An article containing a solid pharmaceutically active agent greater than or equal to 80% by weight based on the total weight of the article, having a Young modulus greater than or equal to 100 MPa and less than or equal to 20 mN. An article that is configured to penetrate at least 1 mm into the mucosal tissue of the human gastrointestinal tract by force.</p><p>(Embodiment 75) A method of forming an article, the step of introducing a composition into a mold containing a solid pharmaceutically active agent in excess of or equal to 80% by weight based on the total weight of the composition; greater than 1 MPa. The step of applying a pressure equal to or equal to that to the composition; as well as the step of heating the composition to a temperature of at least 70 ° C for at least 1 minute; A method that is configured to penetrate 1 mm.</p><p>(Embodiment 76) An article comprising a solid pharmaceutically active agent that is greater than or equal to 80% by weight based on the total weight of the article and is configured to deliver at least 1 mg of the pharmaceutically active agent per square centimeter of tissue of interest. Articles containing and / or pharmaceutically active agents greater than or equal to 1 mg per square centimeter.</p><p>(Embodiment 77) The article or method according to any of the above embodiments, wherein the pharmaceutically active agent is poured into a mold for forming the article.</p><p>(Embodiment 78) The article or method according to any of the above embodiments, wherein the mold is centrifuged.</p><p>(Embodiment 79) The article or method according to any of the above embodiments, further comprising a binder.</p><p>80. The article or method of embodiment 79, wherein the binder comprises sugars such as sorbitol or sucrose, gelatin, polymers such as PVA, PEG, PCL, PVA or PVP, and / or ethanol.</p><p>(Embodiment 81) The article or method according to any of the above embodiments, wherein the article comprises a pharmaceutically active agent greater than or equal to 1 mg.</p><p>(Embodiment 82) The article according to any of the above embodiments, wherein the pharmaceutically active agent is selected from the group consisting of bacteriophage, DNA, insulin, human growth hormone, monoclonal antibody, adalimumab, epinephrine, and ondansetron. Or how.</p><p>(Embodiment 83) A self-restoring article configured to be moored to a position within the subject's body, 1 g / cm.³It comprises at least the first portion with a higher average density, 0.09 × 10^-4When an externally applied torque of Nm or less is applied, the longitudinal axis perpendicular to the tissue engaging surface of the article is configured to maintain an orientation of 20 degrees or less from the vertical, with at least one mooring mechanism. Ancillary, self-restoring items.</p><p>(Embodiment 84) An article configured to be tethered to a position within the subject's body, at least partially encapsulated by an external shell; a support, under at least 5% compressive strain. An article comprising a spring; and at least one mooring mechanism operably coupled to the spring, which is maintained at least partially compressed.</p><p>(Embodiment 85) A method of mooring an article at a position inside the target body, which is 1 g / cm.³Containing the administration of an article comprising at least a first moiety having a higher average density and at least one mooring mechanism to a subject, the article having a force greater than or equal to 0.6 N and / or more than 30 degrees. A method that is configured to be held in that position under large or equal orientation changes.</p><p>(Embodiment 86) The method or article according to any of the above embodiments, wherein each mooring mechanism comprises a hook.</p><p>(Embodiment 87) The article or method according to any of the above embodiments, wherein each mooring mechanism is a hooked needle.</p><p>(Embodiment 88) Described in any of the aforementioned embodiments, wherein each mooring mechanism is configured to penetrate tissue at a location within the body of the subject at a depth greater than or equal to 1 mm and less than 3 mm or equal to it. Goods or methods.</p><p>(Embodiment 89) The article or method according to any of the above embodiments, wherein the hook comprises a non-degradable material under physiological conditions.</p><p>(Embodiment 90) The article or method according to any of the above embodiments, wherein the mooring mechanism has a length greater than or equal to or equal to and less than or equal to 250 micrometers.</p><p>(Embodiment 91) The article or method according to any of the above embodiments, wherein each mooring mechanism has a locking force greater than or equal to 0.002N and less than or equal to 1N.</p><p>(Embodiment 92) The article or method according to any of the above embodiments, wherein the article is configured to be held in its position under a lateral force greater than or equal to 0.6N. ..</p><p>(Embodiment 93) The article or method according to any of the above embodiments, wherein the article is configured to be held in its position after a change in orientation greater than or equal to 30 degrees.</p><p>(Embodiment 94) The article or method according to any of the above embodiments, wherein the article comprises two or more mooring mechanisms disposed at least 1 mm apart.</p><p>(Embodiment 95) A self-restoring article configured to be administered to a location within the body of a subject, the first portion having an average density greater than at least 1 g / cm3. The first part, which has a self-restoring time from 90 degrees in water less than or equal to 0.05 seconds; each tissue contact part comprises a tissue contact part configured to be in contact with the tissue. At least two tissues comprising a conductive portion configured to electrically communicate with and an insulating portion configured to not electrically communicate with the tissue.<u style="Single">connection</u>Components; as well as at least two organizations<u style="Single">connection</u>A self-restoring article with a power source that communicates electrically with the components.</p><p>(Embodiment 96) An article configured to be administered to a subject's internal position, at least partially encapsulated by an external shell; at least under 5% compressive strain by a support. A spring that is maintained in a partially compressed state; it comprises a tissue contact portion that is configured to contact the tissue, and each tissue contact portion is configured to electrically communicate with the tissue. At least two tissues with a conductive portion that is present and an insulating portion that is configured to be electrically non-communicable with the tissue.<u style="Single">connection</u>Components; and at least two organizations<u style="Single">connection</u>An article with a power source that is in electrical communication with a component.</p><p>(Embodiment 97) A method of applying an electrical stimulus to a position in a subject's body, at least one tissue placed inside.<u style="Single">connection</u>Each organization has components<u style="Single">connection</u>The step of administering the article to the subject, the component containing the conductive material; the step of releasing at least one matching component from the article; the step of inserting at least one matching component into the tissue at a location within the subject's body; And organization<u style="Single">connection</u>Two or more currents generated by a power source that communicates electrically with a component<u style="Single">connection</u>Includes steps applied between the components; each structure comprises a spring in which the article is maintained at least partially compressed by a support under at least 5% compressive strain.<u style="Single">connection</u>A method in which the components are operably connected to a spring.</p><p>98. The method of embodiment 97, comprising the step of administering to the subject two or more articles, and the step of applying an electric current between the two articles.</p><p>(Embodiment 99) The article is configured to be held in a position within the subject's body under a force greater than or equal to 0.6 N and / or a change in orientation greater than or equal to 30 degrees. The article or method according to any of the above embodiments.</p><p>(Embodiment 100) Organization<u style="Single">connection</u>Components and organization<u style="Single">connection</u>A self-restoring article with a spring attached to the component and maintained under at least 5% compressive strain by the support, with a maximum cross-sectional dimension of less than or equal to 1.1 cm, 0.09 × Ten^-4When an externally applied torque of Nm or less is applied, the axis essentially perpendicular to the tissue engaging surface of the self-restoring article is configured to maintain an orientation of 20 degrees or less from the vertical, and / Or a self-healing article with a self-healing time from 90 degrees in water, less than or equal to 0.05 seconds.</p><p>Embodiment 101. The self-restoring article of embodiment 100, wherein the spring is configured to release at least 10% of the compressed energy stored in the spring within 10 minutes of exposure of the support to the fluid. ..</p><p>(Embodiment 102) The self-restoring article according to embodiment 100 or 101, which has a self-restoring time from 90 degrees in water, less than or equal to 0.05 seconds.</p><p>(Embodiment 103) An article for delivering a pharmaceutical agent to a subject, which is a tissue.<u style="Single">connection</u>Components; and organization<u style="Single">connection</u>It has a spring that accompanies the component and is maintained under at least 5% compressive strain by the support; structure.<u style="Single">connection</u>The component is an organization<u style="Single">connection</u>An article comprising a solid pharmaceutical agent in an amount greater than or equal to 110% by weight based on the total weight of the constituents.</p><p>(Embodiment 104) The article according to embodiment 103, wherein the spring is configured to release at least 90% of the compressed energy stored in the spring within 10 minutes of exposure of the support to the fluid.</p><p>(Embodiment 105) Organization<u style="Single">connection</u>The article according to embodiment 103 or 104, wherein the component is a needle.</p><p>(Embodiment 106) Organization<u style="Single">connection</u>The article according to any one of embodiments 103-105, wherein the component has a Young elastic modulus greater than or equal to 100 MPa.</p><p>(Embodiment 107) An article for delivering a pharmaceutical agent to a subject, which is a tissue.<u style="Single">connection</u>Components; and organization<u style="Single">connection</u>Equipped with a spring attached to the component; the needle contains an amount of solid pharmaceutical agent greater than or equal to 80% by weight based on the total weight of the needle, and the spring contains 10 minutes from exposure of the support to the fluid. Articles that are configured to release at least 10% of the stored compression energy of the spring within.</p><p>(Embodiment 108) The article of embodiment 107, wherein the spring is maintained under at least 5% compressive strain by a support.</p><p>(Embodiment 109) One or more tissues associated with a self-restoring article<u style="Single">connection</u>A self-healing article with components having a self-healing time from 90 degrees in water of less than or equal to 0.05 seconds and at least one tissue.<u style="Single">connection</u>A self-restoring article in which the components are configured to have the longest longitudinal axis oriented within 15 degrees of vertical when self-restored.</p><p>(Embodiment 110) Tissue attached to a self-restoring article<u style="Single">connection</u>A self-restoring article with components and an organization<u style="Single">connection</u>The component is an organization<u style="Single">connection</u>Contains 0.09 × 10 solid pharmaceuticals in an amount greater than or equal to 10% by weight based on the total weight of the components.^-4When an externally applied torque of Nm or less is applied, the axis essentially perpendicular to the tissue engaging surface of the self-restoring article is configured to maintain an orientation of 20 degrees or less from the vertical, self-restoring. Goods.</p><p>(Embodiment 111) A method of delivering a pharmaceutical agent to a subject, the tissue to which the pharmaceutical agent is attached.<u style="Single">connection</u>Including the step of administering to the subject an article comprising the component; and the step of releasing at least a portion of the pharmaceutical agent from the article at a position within the subject; upon reaching a position within the subject, the article is perpendicular to the subject. Has a longitudinal axis of the article, configured to be oriented at about 90 degrees; and / or 0.09 × 10^-4When an externally applied torque of Nm or less is applied, it has a longitudinal axis that maintains an orientation of 20 degrees or less from the vertical; and / or can penetrate the mucosal tissue with a certain amount of force; and / Or has a self-restoring time from 90 degrees in water, less than or equal to 0.05 seconds; and / or 1 g / cm³Has a higher average density; and / or tissue<u style="Single">connection</u>A method comprising a spring that is configured to be released immediately; and / or contains an amount of solid pharmaceutical agent greater than or equal to 10% by weight based on the total weight of the component.</p><p>(Embodiment 112) A method of collecting a sample from a subject, the step of administering to the subject an article comprising a spring, a support, and a biopsy mechanism; and collecting a sample by the biopsy mechanism at a location within the subject. Includes steps to; an axis essentially perpendicular to the tissue engagement surface of the self-restoring article is 0.09 x 10 upon reaching a position within the subject's body.^-4An externally applied torque of Nm or less is exerted to maintain an orientation of 20 degrees or less from the vertical, and the spring accumulates within 0.1 ms of mechanical failure of the support. A method that is configured to release at least 10% of the compression energy.</p><p>(Embodiment 113) Tissue in the target body fluid<u style="Single">connection</u>Exposure of components, resulting in tissue<u style="Single">connection</u>12. The method of embodiment 112, comprising the step of operating at least a portion of the components.</p><p>(Embodiment 114) comprising a spring and a support having a structure adapted to keep the spring at least partially compressed and having a structure that at least partially decomposes when exposed to a biological fluid. , Self-actuating components; and tissues associated with pharmaceutically active agents<u style="Single">connection</u>A self-restoring article comprising the components, which is configured as a monostatic body due to the center of mass of the self-restoring article and the shape of the self-restoring article.</p><p>(Embodiment 115) When the self-restoring article is at least partially supported by the tissue of interest, the tissue<u style="Single">connection</u>The self-restoring article of embodiment 114, wherein the components are oriented in a direction that allows the release of at least a portion of the pharmaceutically active agent into the tissue.</p><p>(Embodiment 116) First portion having a mass; Second portion having a mass different from the mass of the first portion; Self-acting component; A pharmaceutically active agent is attached and the self-acting component operates. Possible connected organizations<u style="Single">connection</u>A self-restoring article comprising a component; and a tissue engaging surface configured to contact the surface of the tissue in the body of the subject, due to the center of mass of the self-restoring article and the shape of the self-restoring article. Constructed as a monostatic body; when the self-restoring article is at least partially supported by the tissue of interest, the tissue<u style="Single">connection</u>A self-restoring article oriented in a direction that allows the components to release at least a portion of the pharmaceutically active agent into the tissue.</p><p>(Embodiment 117) The first portion comprises the first material, the second portion comprises the second material, and the first material and the second material are the same, according to embodiment 116. Self-restoring goods.</p><p>(Embodiment 118) The self-restoring article according to embodiment 116, wherein the first part contains the first material, the second part contains the second material, and the first material and the second material are different. ..</p><p>(Embodiment 119) A first portion comprising a first material and having a mass; a second portion comprising a second material and having a mass different from the mass of the first portion; self-acting component; pharmaceutical activity. Tissue associated with the agent and operably linked to the self-acting component<u style="Single">connection</u>A self-restoring article comprising a component; and a tissue engaging surface configured to contact the surface of the tissue located within the body of the subject, 1 g / cm.³It has a higher average density; is configured as a monostatic body due to the mass center of the self-restoring article and the shape of the self-restoring article; when the self-restoring article is at least partially supported by the tissue of interest, Organization<u style="Single">connection</u>A self-restoring article oriented in a direction that allows the components to release at least a portion of the pharmaceutically active agent into the tissue.</p><p>(Embodiment 120) Any one of embodiments 116-119, wherein the first material and / or the second material is selected from the group consisting of polymers, ceramics, metals, metal alloys, and combinations thereof. Self-restoring goods described in.</p><p>(Embodiment 121) The self-restoring article according to embodiment 120, wherein the metal is selected from the group consisting of stainless steel, iron-carbon alloys, field metal, tungsten, molybdenum, gold, zinc, iron and titanium.</p><p>(Embodiment 122) The self-restoring article according to embodiment 120, wherein the ceramic is selected from the group consisting of hydroxyapatite, aluminum oxide, calcium oxide, tricalcium phosphate, zirconium oxide, silicates, and silicon dioxide.</p><p>(Embodiment 123) The self-restoration according to embodiment 120, wherein the polymer is selected from the group consisting of polycaprolactone, polylactic acid, polyethylene glycol, polypropylene, polyethylene, polycarbonate, polystyrene, and polyetheretherketone, and polyvinyl alcohol. Goods.</p><p>(Embodiment 124) The self-restoring article according to any one of embodiments 117 to 123, wherein the first material is a metal and the second material is a polymer.</p><p>(Embodiment 125) The self-restoring article according to any one of embodiments 117 to 123, wherein the first material is a polymer and the second material is a metal.</p><p>(Embodiment 126) Self-actuating components are adapted to keep the spring and the spring at least partially compressed and at least partially decomposed in the biofluid. The self-restoring article according to any one of embodiments 117 to 125, comprising a support material.</p><p>(Embodiment 127) The self-restoring article according to embodiment 126, wherein the spring has a spring constant in the range of 100 N / m to 1500 N / m.</p><p>(Embodiment 128) Organization<u style="Single">connection</u>The self-restoring article according to any one of embodiments 115 to 127, wherein the component comprises a pharmaceutically active agent.</p><p>(Embodiment 129) The pharmaceutically active agent is a tissue.<u style="Single">connection</u>The self-restoring article of embodiment 128, which is present in the tissue interaction component in an amount greater than or equal to 80% by weight of the total weight of the component.</p><p>(Embodiment 130) The self-restoring article according to embodiment 128, wherein 100% by weight of the tissue interaction component is a pharmaceutically active agent.</p><p>(Embodiment 131) The self-restoring article according to any one of embodiments 115-130, wherein the self-acting component comprises one or more outlets configured to communicate fluid with the external environment. ..</p><p>(Embodiment 132) The self-restoring article according to any one of embodiments 115 to 131, wherein the biofluid is gastric juice.</p><p>(Embodiment 133) The self-restoring article according to any one of embodiments 115 to 132, wherein the shape is a rubber box shape.</p><p>Although some embodiments of the invention have been described and exemplified herein, those skilled in the art will perform the functions described herein and / or the results and / or one described herein. Alternatively, various other means and / or structures for obtaining multiple advantages will be readily envisioned, each of such modified and / or modified forms being within the scope of the invention. think. More generally, all parameters, dimensions, materials and configurations described herein are intended to be exemplary, as well as actual parameters, dimensions, materials and / or configurations. It will be readily appreciated by those skilled in the art that the teachings of the present invention will depend on the particular application (s) in which they are used. One of ordinary skill in the art will be aware of many equivalents of the particular embodiments of the invention described herein, or will be able to determine such equivalents using only routine experiments. .. Accordingly, the above embodiments are merely presented as examples, and the invention is specifically described and claimed within the scope of the appended claims and their equivalents. It should be understood that it can be carried out differently than described in the section. The present invention relates to each of the individual features, systems, articles, materials, kits and / or methods described herein. In addition, any combination of two or more such features, systems, articles, materials, kits and / or methods may have such features, systems, articles, materials, kits and / or methods with each other. If there is no contradiction, it is included within the scope of the present invention.</p><p>The indefinite articles "a" and "an", as used in the specification and claims of the present application, should be understood to mean "at least one" unless expressly indicated otherwise.</p><p>The phrase "and / or", as used herein and in the claims, is "either or both" of the elements so combined, i.e., if present syntactically. It should be understood that it means an element that may exist in a selective manner. In addition to the elements specifically specified by the "and / or" clause, other elements may be present as needed, whether related or unrelated to those specifically specified elements. There is also a swearing, unless there is a clear indication that it is not. Thus, as a non-limiting example, the reference to "A and / or B", when used with a non-limiting word such as "contains", is A without B in one embodiment (as needed). B without A in another embodiment (including elements other than A), and both A and B in another embodiment (other elements as needed) Includes), etc.</p><p>As used in the specification and claims of the present application, "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" shall be construed as inclusive, i.e., a number of elements or element lists and optionally additional unlisted. It shall be construed to include at least one of the items, as well as more than one. The term "only" with explicit indication that it is not, for example, "only one of" or "exactly one of", or "consisting of" as used in the claims. Means to include exactly one element in any number of elements or element lists. In general, the term "or" as used herein is an exclusivity term such as "either", "one of", "only one of" or "exactly one of". If preceded by, shall be construed exclusively as indicating an exclusive option (ie, "one or the other, not both"). "Being essentially from" shall have its usual meaning when used in the art of patent law, when used in the claims.</p><p>As used in the specification and claims of the present application with respect to a list of one or more elements, the phrase "at least one" is at least selected from any one or more of the elements in the element list. One, but not necessarily at least one of each and every element specifically listed in the element list, and at least one element that does not exclude any combination of elements in the element list. Please understand that it means. This definition is irrelevant whether elements other than the specifically specified elements are related to those specifically specified elements in the list of elements pointed to by the phrase "at least one". It is also acceptable that it may or may not exist as needed. 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". ")" In one embodiment, B does not exist (and elements other than B are included as needed), more than one is included as needed, at least one A, in another embodiment. A does not exist (and contains elements other than A as needed), contains more than one as needed, at least one B, and in yet another embodiment more than one as needed May refer to at least one A and at least one B (and other elements as needed), including, more than one, as needed, and so on.</p><p>Not only in this specification but also in the claims, "comprising", "including", "carrying", "having", "containing". , "Involving," "holding," and the like, all transitional clauses are non-limiting, i.e., meaning that they are included but not limited to them. It shall be interpreted. Only the transitional phrases "consisting of" and "consisting of essentially" shall be restrictive or semi-restrictive transitional phrases, respectively, as described in US Patent Office, US Patent Examination Handbook, 2111: 03.</p><p>For example, shape, orientation, alignment, of one or more articles, structures, forces, fields, flows, directions / trajectories, and / or their dependent components and / or combinations thereof, or between them. And / or any term as used herein with respect to geometrical relationships, and / or any other tangible or intangible element not listed above that follows the characterization by such term. Unless defined or instructed, it shall be understood that no absolute adaptation of such terms to the mathematical definition is required, but rather the subject matter is most closely related to the subject matter. It shall be understood to indicate conformance to the mathematical definition of such terms to the extent that they can be characterized as known by those skilled in the art. Examples of such terms for shape, orientation, and / or geometric relationships include, but are not limited to, the following terms that describe: Shape-eg, circle (i). , Square, rubber box, circular / circle, rectangular / rectangular, triangular / triangular, cylindrical / cylindrical, elliptical / oval, poly (n) square / poly (n) square, etc .; angular orientation -For example, vertical, orthogonal, parallel, vertical, horizontal, collinear, etc .; contour and / or orbit-for example, planar / planar, coplanar, hemispherical, hemispherical, etc. Line / linear, bi-curved, parabolic, flat, curved, linear, arched, sine-curved, tangent / tangent, etc; Direction-eg, north, south, east, west, etc .; surface And / or bulk material properties and / or spatial / temporal resolution and / or distribution-for example, smooth, reflective, permeable, transparent, opaque, rigid, impermeable, uniform (uniform). ), Inactive, non-wetting, insoluble, stationary, invariant, constant, homogeneous, etc .; And many others that are readily apparent to those skilled in the art of related technology. As an example, the artifacts that are to be described herein as "squares" require such articles to be perfectly planar or linear and have faces or sides that meet at an exact 90 degree angle. Not necessarily (in fact, such articles can only exist as a mathematical abstraction), rather the shape of such articles is as known or specifically described by those skilled in the art. The production method mentioned above should be interpreted as an approximation of a mathematically defined "square" to the extent that it is generally achievable and achievable. As another example, two or more manufactured articles that are to be described herein as "aligned" have faces or sides that are perfectly aligned. Rather, the arrangement of such articles is as known or concrete by one of ordinary skill in the art, rather than asking for it (in fact, such articles can only exist as a mathematical abstraction). It should be interpreted that the production methods mentioned in the above are generally achievable and, to the extent that they are achieved, approximate the mathematically defined "alignment".</p><p>The present invention provides, for example, the following items.</p><p>(Item 1) Organization<u style="Single">connection</u>Components and said organization<u style="Single">connection</u>A self-restoring article comprising a spring attached to the component, wherein the spring is maintained under at least 5% compressive strain by a support and has a maximum cross-sectional dimension of less than or equal to 2 cm. , 0.09 × 10^-4When an externally applied torque of Nm or less is applied, the axis essentially perpendicular to the tissue engaging surface of the self-restoring article is configured to maintain an orientation of 20 degrees or less from the vertical, self-restoring. Goods.</p><p>(Item 2) Organization<u style="Single">connection</u>Components and said organization<u style="Single">connection</u>A self-restoring article comprising a spring attached to the component, wherein the spring is maintained under at least 5% compressive strain by a support and has a maximum cross-sectional dimension of less than or equal to 2 cm. A self-healing article with a self-healing time from 90 degrees in water, less than or equal to 0.05 seconds.</p><p>(Item 3) Item 1 or 2, wherein the spring is configured to release at least 10% of the compressed energy stored in the spring within 10 minutes of exposure of the support to the fluid. Self-restoring goods.</p><p>(Item 4) The self-restoring article according to any of the above items, which has a self-restoring time from 90 degrees in water, less than or equal to 0.05 seconds.</p><p>(Item 5) An article for delivering a pharmaceutical agent to a subject, which is an organization.<u style="Single">connection</u>Components; and said organization<u style="Single">connection</u>It comprises a spring that accompanies the component and is maintained under at least 5% compressive strain by the support, said structure.<u style="Single">connection</u>The component is an organization<u style="Single">connection</u>An article comprising a solid pharmaceutical agent in an amount greater than or equal to 110% by weight based on the total weight of the constituents.</p><p>(Item 6) The article of item 5, wherein the spring is configured to release at least 90% of the compressed energy stored in the spring within 10 minutes of exposure of the support to the fluid. ..</p><p>(Item 7) The organization<u style="Single">connection</u>The article according to item 5 or 6, wherein the component is a needle.</p><p>(Item 8) The organization<u style="Single">connection</u>The article according to any of the above items, wherein the component has a Young modulus of elasticity greater than or equal to 100 MPa.</p><p>(Item 9) An article for delivering a pharmaceutical agent to a subject, which is an organization.<u style="Single">connection</u>Components; and said organization<u style="Single">connection</u>Equipped with a spring attached to the component, the needle contains a solid pharmaceutical agent in an amount greater than or equal to 80% by weight with respect to the total weight of the needle, within 10 minutes of exposure of the support to the fluid. An article, wherein the spring is configured to release at least 10% of the stored compression energy of the spring.</p><p>(Item 10) The article according to item 9, wherein the spring is maintained under at least 5% compressive strain by a support material.</p><p>(Item 11) One or more tissues associated with self-restoring articles<u style="Single">connection</u>A self-healing article with components that has a self-healing time from 90 degrees in water less than or equal to 0.05 seconds and, when self-healing, at least one tissue.<u style="Single">connection</u>A self-restoring article in which the components are configured to have the longest longitudinal axis oriented within 15 degrees of vertical.</p><p>(Item 12) Tissue attached to self-restoring goods<u style="Single">connection</u>A self-restoring article comprising the components, said tissue.<u style="Single">connection</u>The component is an organization<u style="Single">connection</u>Contains solid pharmaceuticals in an amount greater than or equal to 10% by weight based on total component weight, 0.09 x 10^-4When an externally applied torque of Nm or less is applied, the axis essentially perpendicular to the tissue engaging surface of the self-restoring article is configured to maintain an orientation of 20 degrees or less from the vertical, self-restoring. Goods.</p><p>(Item 13) A method of delivering a pharmaceutical agent to a subject, the tissue to which the pharmaceutical agent is attached.<u style="Single">connection</u>The article comprises the step of administering the article comprising the components to the subject and the step of releasing at least a portion of the pharmaceutical agent from the article at a position within the subject when the article reaches a position within the subject. Has a longitudinal axis of the article configured to be oriented at about 90 degrees with respect to the vertical; and / or 0.09 × 10^-4It has a longitudinal axis that maintains an orientation of 20 degrees or less from the vertical when an externally applied torque of Nm or less is applied; and / or mucosa with a force greater than or equal to 1 mN and less than or equal to 20,000 mN. Can penetrate tissue; and / or have self-restoration time from 90 degrees in water less than or equal to 0.05 seconds; and / or tissue<u style="Single">connection</u>A method comprising a spring comprising a solid pharmaceutical agent in an amount greater than or equal to 10% by weight based on the total weight of the component and / or being configured to be released immediately.</p><p>(Item 14) 1g / cm³13. The method of item 13, which has a higher average density.</p><p></p>