Retention structure and related methods

Abstract

To provide a residence structure and a related method.SOLUTION: A residence structure, a system and a related method are provided. In a specific embodiment, a residence structure is administered (for example, oral administration) to a subject (for example, a patient) so as to hold the residence structure for a specific period (for example, almost 24 hours or longer) at an internal position of the subject before discharge of the residence structure. In some embodiment, the residence structure may be an intragastric residence structure. In some embodiments, the structure and the system herein comprise one kind or more kinds of materials which are formed for filling of high level active material (for example a remedy), stability of high active material and / or structure in an acidic environment, mechanical flexibility and intensity in an internal opening (for example, a gastric cavity), easy passage in a gastrointestinal tract to delivery to a desired internal opening (for example, a gastric cavity), and quick solution / decomposition in response to a physiological environment (for example, an intestine environment) and / or chemical stimulant (for example, taking a solution which induces quick solution / decomposition).SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] Related applications This application claims priority to concurrently pending U.S. Provisional Application No. 62 / 010,992, filed on 11 June 2014 under § 119(e) of the U.S. Patent Act (the contents of which are incorporated herein by reference in their entirety for all purposes).

[0002] Statement on government support This invention was made with government support under grant number 5T32HL007604-28 granted by the National Institutes of Health. The government has certain rights to this invention.

[0003] The embodiments described herein generally relate to retention structures, systems, and related methods. [Background technology]

[0004] Patient adherence to self-administration protocols for therapeutic and diagnostic agents over long or indefinite periods is often poor, and adherence to oral treatment for chronic asymptomatic conditions is estimated to be less than 50%. The problem of low adherence is greatest in primary and secondary prevention applications, where the disease being prevented or treated is often asymptomatic and the treatment does not provide an immediate, obvious benefit. Many factors contribute to low adherence, including the cost of administration, access, side effects, and inconveniences of the administration regimen.

[0005] Current and advanced approaches to improving compliance rates include educational interventions, telephone counseling, health information technology solutions, interactive pharmacy tools, and changes to healthcare payment models such as copayment-free plans after myocardial infarction. However, any of these approaches achieve only slight improvements. Meanwhile, pharmacological solutions to compliance problems typically require invasive delivery structures and subsets of pharmacological agents formulated for sustained release. Recent advances in sustained-release pharmacology systems are primarily limited to subcutaneous, percutaneous, intravaginal, and surgical implants. Conventional solutions include invasive methods such as surgical implants (e.g., including wirelessly programmable structures available from MicroCHIPS, Inc. (Lexington, MA)) or methods limited to specific applications such as birth control (e.g., including NuvaRing® and Implanon® (both available from Merck & Co., Inc. (Whitehouse Station, NJ))). Structures like those available from MicoCHIPS are also limited to the delivery of highly potent therapeutics because these therapeutics can only be administered in micrograms or less.

[0006] While oral administration has the potential to be accepted by the widest range of patients, oral delivery systems have not been shown to enable sustained release via the oral route due to several fundamental barriers. Firstly, the transit time of a food bolus, for example, through the human gastrointestinal tract is rapid, typically lasting only about 24–48 hours, including about 1–2 hours in the stomach, about 3 hours in the small intestine, and about 6–12 hours in the large intestine. Therefore, one strategy for long-term therapeutic drug delivery would be to extend the transit time of orally administered therapeutic drugs (excluding food). This would involve gastric retention and / or delayed passage in several segments of the gastrointestinal tract, as demonstrated in bezoar and bariatric structures. Can be attempted and / or tolerated. Bezoars (i.e., masses trapped and found in the gastrointestinal system) may form from a variety of indigestible substances such as food aggregates and hair, and often only become clinically apparent in adult humans when they reach a size of several hundred grams. Bariatric structures such as endoscopically administered intragastric balloons can be used to fill a portion of a patient's stomach and achieve non-invasive gastric reduction for weight loss. Previous attempts at gastric retention for drug delivery have included mucoadhesion, gastric swelling, and flotation on gastric fluid. However, none of these approaches alone have demonstrated gastric retention exceeding 24 hours that leads to clinical use. Summary of the Invention Means for Solving the Problems

[0007] In general, retention structures, systems, and related methods are provided.

[0008] In one aspect, a retention structure is provided. In some embodiments, the retention structure comprises a fillable polymer element, a first linker coupling the fillable polymer element to a second polymer element, and a second linker comprising at least a portion of the fillable polymer element and / or the elastic polymer element or coupled to the fillable polymer element and / or the elastic polymer element, wherein at least one of the fillable polymer element, the second polymer element, the first linker, and the second linker comprises an elastic polymer element, the fillable polymer element constitutes at least about 60% by weight of the total weight of the structure, the retention structure is characterized by a folding force of at least about 0.2 N, the first linker is degradable under a first set of physiological conditions, and the second linker is degradable under a second set of conditions different from the first set of physiological conditions and is not substantially degradable under the first set of conditions.

[0009] In some embodiments, the retention structure comprises a fillable polymer element and a second polymer element bound to the fillable polymer element via at least one degradable linker that comprises at least a portion of the fillable polymer element and / or the second polymer element, or is bound to the fillable polymer element and / or the second polymer element, wherein at least one of the fillable polymer element, the second polymer element, and the degradable linker comprises an elastic polymer element, the fillable polymer element constitutes at least about 60% by weight of the total weight of the structure, the retention structure has a folding force of at least about 0.2 N, and the retention structure has an uncompressed cross-sectional dimension of at least about 2 cm.

[0010] In some embodiments, the retention structure comprises a fillable polymer element and a second polymer element bound to the fillable polymer element, and at least one degradable linker that comprises at least a portion of the fillable polymer element and / or the second polymer element, or is bound to the fillable polymer element and / or the second polymer element, wherein the retention structure is configured to be retained at a position inside a subject for at least about 24 hours.

[0011] In some embodiments, the retention structure comprises a fillable polymer element and a second polymer element bound to the fillable polymer element, and at least one degradable linker that comprises at least a portion of the fillable polymer element and / or the second polymer element, or is bound to the fillable polymer element and / or the second polymer element, wherein the fillable polymer element comprises an active agent, the retention structure is configured such that the active agent is released from the fillable polymer material at a specific initial average rate as measured from release over the first 24 hours, and the active agent is released at an average rate of at least about 1% of the initial average rate over a 24-hour period after release during the first 24 hours.

[0012] In another aspect, a system is provided. In some embodiments, the system comprises a containment structure The device comprises a containing structure and a retaining structure contained within a containing structure, wherein the retaining structure is constructed and positioned such that it has a first configuration after being released from the containing structure, and the retaining structure is constructed and positioned such that it has a second configuration when contained within the containing structure, the first configuration having an incompressible cross-sectional dimension of at least about 2 cm, the second configuration having a convex hull at least about 10% smaller than the convex hull of the first configuration, and / or the second configuration having a maximum cross-sectional dimension at least about 10% smaller than the maximum cross-sectional dimension of the first configuration, the first part of the device being disassemblable under the physiological conditions of the first set, but the second part of the device being substantially not disassemblable under the physiological conditions of the first set.

[0013] In another embodiment, a method for delivering a retention structure is provided. In some embodiments, the method comprises administering a containment structure containing a retention structure to a subject, thereby the containment structure releasing the retention structure at a location within the subject, the retention structure having a second configuration within the containment structure, and acquiring a first configuration such that the retention structure is retained at or near the location within the subject for at least about 24 hours after the retention structure has been released from the containment structure.

[0014] In some embodiments, the method comprises administering a containment structure containing a retention structure to a subject, thereby releasing the retention structure at a location within the subject, wherein the retention structure has a second configuration within the containment structure, the retention device comprising a fillable polymer element containing an active substance, the retention structure being configured such that the active substance is released from the retention structure at an initial average rate of release over the first 24 hours, and the active substance is released at an average rate of at least about 1% of the initial average rate over a 24-hour period following the release in the first 24 hours.

[0015] In another embodiment, the containment structure is constructed and positioned to be administered to a subject, and the containment structure includes a retention structure, thereby the containment structure releasing the retention structure at a location within the subject, the retention structure having a second configuration within the containment structure, and after the retention structure is released from the containment structure, the retention structure acquires a first configuration so that it is retained at or near the location within the subject for at least about 24 hours.

[0016] In some embodiments, the containment structure is constructed and positioned to be administered to a subject, and the containment structure includes a retention structure, thereby causing the containment structure to release the retention structure at a location within the subject, the retention structure having a second configuration within the containment structure, the retention device including a fillable polymer element containing an active substance, and the retention structure is configured such that the active substance is released from the retention structure at an initial average rate of release over the first 24 hours, and the active substance is released at an average rate of at least about 1% of the initial average rate over a 24-hour period following the release in the first 24 hours.

[0017] In some embodiments, the system includes at least one retention structure configured to administer at least one of therapeutic agents, diagnostic agents, and enhancers during a retention period longer than at least 24 hours, having a first shape configured to maintain an in vivo position relative to an internal opening during the retention period, wherein the at least one retention structure includes at least one enteric elastomer linker positioned such that the level of dissociation of at least one enteric elastomer linker ends the retention period and allows the at least one retention structure to pass through the internal opening.

[0018] In some embodiments, the system includes at least one retention structure configured to transport and / or maintain at least one structure for a residence period of at least 24 hours, having a first shape configured to maintain the in vivo position of at least one retention structure relative to an internal opening during the residence period, and the level of dissociation of at least one enteric elastomer linker of the at least one retention structure during the residence period It includes at least one enteric-coated elastomer linker positioned to end the gap and allow at least one retention structure to pass through an internal opening.

[0019] In some embodiments, at least one enteric-coated elastomer linker is configured to dissociate at least partially during the retention period.

[0020] In some embodiments, at least one retention structure is filled with at least one of the therapeutic agents, diagnostic agents, and enhancers before administering the retention structure to a subject.

[0021] In some embodiments, after administering at least one retention structure to a subject, at least one retention structure is filled in vivo with at least one of the following: a therapeutic agent, a diagnostic agent, and an enhancer.

[0022] In some embodiments, the retention time is longer than at least one of 24 hours, 1 week, 2 weeks, 4 weeks, and 1 year.

[0023] In some embodiments, the system further includes at least one containment structure, each containment structure configured to maintain a second shape of retaining structure configured for packing into the containment structure.

[0024] In some embodiments, at least one containment structure is configured to allow at least one of ingestion, self-administration, and oral administration.

[0025] In some embodiments, at least one containment structure includes at least one of the following capsules: 000 capsule, 00 capsule, 0 capsule, 1 capsule, 2 capsule, 3 capsule, 4 capsule, and 5 capsule.

[0026] In some embodiments, the second shape is configured such that the retaining structure occupies a volume greater than 60% of the cavity defined by the housing structure.

[0027] In some embodiments, the retaining structure is configured to take on a first shape when released from the containment structure.

[0028] In some embodiments, prior to release from the containment structure, the retaining structure is stored in the containment structure in a second form for a period longer than 72 hours, 1 week, 2 weeks, 4 weeks, 1 year, and 5 years.

[0029] In some embodiments, at least one retaining structure further comprises a deformable material, wherein a first shape comprises an elliptical contour in a first plane comprising a major axis and a minor axis, and a second shape comprises a helix such that the axis of the helix is ​​along the minor axis, and at least one enteric elastomer linker is positioned along the minor axis.

[0030] In some embodiments, at least one enteric-coated elastomer linker is arranged along the long axis.

[0031] In some embodiments, at least one retaining structure further includes at least one of a core, a plurality of radial projections bonded to the core, and a plurality of radial projections integrated with the core, wherein a first shape includes a plurality of projections protruding from the core in a plurality of directions, and a second shape includes a plurality of projections protruding from the core in directions substantially parallel to each other.

[0032] In some embodiments, at least one enteric elastomer linker includes a first enteric elastomer linker positioned along a first radial projection among a plurality of radial projections.

[0033] In some embodiments, at least one enteric elastomer linker includes a first enteric elastomer linker that connects a first radial projection among a plurality of radial projections to a core.

[0034] In some embodiments, the core includes at least one enteric-coated elastomer linker.

[0035] In some embodiments, the first radial projection among the multiple radial projections has a length corresponding to the maximum dimension of the housing structure.

[0036] In some embodiments, the multiple radial projections are arranged such that they define N internal sector angles of approximately 360° / N, where N is the total number of radial projections.

[0037] In some embodiments, at least one retaining structure further comprises a deformable material, wherein a first shape includes a polygonal contour in a first plane, a second shape includes each side of the folded polygonal contour, and at least one enteric elastomer linker is positioned at each vertex of the polygonal contour.

[0038] In some embodiments, the first side of the polygonal contour has a length corresponding to the length of the housing structure.

[0039] In some embodiments, each side defines an inner sector angle of approximately 360° / N, where N is the total number of sides.

[0040] In some embodiments, at least one retaining structure further comprises a deformable material, the first shape comprising a ring, and the second shape comprising a ring folded into a quadrant, with at least one enteric elastomer linker positioned at each vertex of each arc of the quadrant.

[0041] In some embodiments, at least one retaining structure further comprises a core, a plurality of small rounded loops bonded to the core, and a plurality of small rounded loops integrated with the core, wherein the small rounded loops comprise a shape memory alloy, and the core comprises at least one enteric elastomer linker, the first shape comprising a plurality of small rounded loops extending from the core, and the second shape comprising a plurality of small rounded loops folded relative to the core.

[0042] In some embodiments, the first shape is configured to extend the transit time through at least a portion of the gastrointestinal tract of the subject to at least a retention time.

[0043] In some embodiments, the first shape is configured to maintain at least one retaining structure in the gastric cavity of the subject for at least a retention time.

[0044] In some embodiments, the internal opening is the pyloric sphincter.

[0045] In some embodiments, at least one retaining structure is formulated for release, therapeutic It is filled with a mass of at least one of the following: drugs, diagnostic agents, and enhancers.

[0046] In some embodiments, exposure of at least one enteric-coated elastomer linker to at least one alkaline solution accelerates the dissociation of at least one enteric-coated elastomer linker.

[0047] In some embodiments, exposure of at least one enteric-coated elastomer linker to at least one alkaline solution accelerates the dissociation of at least one enteric-coated elastomer linker to a level of dissociation that ends the retention time and allows at least one retaining structure to pass through the internal opening.

[0048] In some embodiments, at least one retaining structure is solvent-filled. The invention further comprises at least one material configured to fill a drug by at least one of the following: loading, melting and filling, physical blending, supercritical carbon dioxide, and conjugation reaction.

[0049] In some embodiments, at least one material configured to fill a drug is further configured to administer at least one filler drug by diffusion and slow matrix decomposition, dissolution, decomposition, swelling, diffusion of at least one filler drug, ionic gradient, hydrolysis, and cleavage of conjugate bonds.

[0050] In some embodiments, at least one enteric-coated elastomer linker is configured to withstand drug filling, at least partially, unlike the delivery material.

[0051] In some embodiments, at least one enteric-coated elastomer linker comprises an enteric polymer containing a polymer of acryloylaminoalkylene acid monomer or a salt thereof.

[0052] In some embodiments, the acryloyl-aminoalkylene acid monomer is acryloyl-5-aminopentanoic acid, acryloyl-6-aminocaproic acid, acryloyl-7-aminoheptanoic acid, acryloyl-8-aminooctanoic acid, acryloyl-9-aminononanoic acid, acryloyl-10-aminodecanoic acid, acryloyl-11-aminoundecanoic acid, acryloyl-12-aminododecanoic acid, methacryloyl-5-aminopentanoic acid, methacryloyl-6-aminocaproic acid, methacryloyl-7-aminoheptanoic acid, methacryloyl-8-aminooctanoic acid, methacryloyl-9-aminononanoic acid Selected from the group consisting of methacryloyl-10-aminodecanoic acid, methacryloyl-11-aminoundecanoic acid, methacryloyl-12-aminododecanoic acid, salts thereof, and combinations thereof.

[0053] In some embodiments, at least one enteric elastomer linker comprises an enteric polymer blend of at least two enteric polymers, the blend comprising a first enteric polymer as described in claim 37 and a second enteric polymer comprising poly(methacrylate-co-alkyl acrylate) or a salt thereof.

[0054] In some embodiments, the first enteric-coated polymer is a homopolymer of acryloyl-6-aminocaproic acid or a salt thereof.

[0055] In some embodiments, the first enteric-coated polymer is a copolymer of acryloyl-6-aminocaproic acid or a salt thereof.

[0056] In some embodiments, the second enteric polymer is poly(ethyl methacrylate-co-acrylate) or a salt thereof.

[0057] In some embodiments, poly(methacrylate-co-ethyl acrylate) has a molar ratio of methacrylate monomer units to ethyl acrylate monomer units of about 1:1.

[0058] In some embodiments, the first enteric-coated polymer is a homopolymer of acryloyl-6-aminocaproic acid.

[0059] In some embodiments, at least one enteric-coated elastomer linker comprises an enteric polymer composition comprising the first enteric polymer described in claim 37, or a salt thereof, and optionally a second enteric-coated poly(ethyl methacrylate-co-acrylate), or a salt thereof, wherein the weight ratio of the first enteric polymer to the second enteric polymer is in the range of about 1:0 to about 1:3.

[0060] In some embodiments, the weight ratio of the first enteric polymer to the second enteric polymer is in the range of 1:0 to about 1:2.

[0061] In some embodiments, the enteric-coated polymer blend is in the form of a polymer gel.

[0062] In some embodiments, the polymer gel has a water content of less than about 50% by weight.

[0063] In some embodiments, the polymer gel has a water content of less than about 40% by weight.

[0064] In some embodiments, the enteric-coated polymer blend exhibits reversible elongation when stretched from its initial length by 50% to 1500%.

[0065] In some embodiments, measurements taken at room temperature over a period of 4 to 40 days showed that the blend was soluble in aqueous solution at a pH above approximately 6.0 and insoluble when immersed in aqueous solution at a pH below approximately 3.0.

[0066] In some embodiments, the enteric-coated polymer blend has a Young's modulus of 0.1 MPa to 100 MPa.

[0067] In some embodiments, the enteric-coated polymer blend exhibits reversible elongation when stretched from its initial length by 50% to 1500%.

[0068] One aspect of the present invention is intended to provide a gastric retention device comprising a central elastic polymer element bonded to three to eight fillable polymer elements, each fillable polymer element projecting radially from the central elastic polymer element to form a star-shaped cross-section, and each fillable polymer element is bonded to the central elastic polymer element. A first degradable linker is present in each fillable polymer element near or at the interface with the elastic polymer element. (linker). In certain embodiments, the fillable polymer element further comprises a second degradable linker which may be the same as or different from the first degradable linker. In certain embodiments, the fillable polymer element comprises polycaprolactone, polylactic acid, polylactic co-glycolic acid and / or mixtures thereof, and may further comprise excipients, and the degradable linker is water-soluble These are hydrophilic and / or biodegradable polymers and blends thereof, which include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol, Kollidon VA 64, polyoltoesters, polyhydroxybutyrates, eudragit, and mixtures thereof. The device may further include at least one of the following: therapeutic agents, diagnostic agents, and enhancers, the therapeutic agents being selected from hydrophilic agents, hydrophobic agents, artemotherapeutic agents, ivermectin, risperidone, doxycycline, antimalarial agents, anthelmintic agents, antipsychotic agents, and antibiotics.

[0069] The devices of these embodiments can be housed in a soluble container, such as one composed of gelatin and optionally containing excipients. In certain embodiments, the device has a minimum incompressible cross-sectional dimension of about 3–5.5 cm, about 3 cm, about 4 cm, about 5 cm, or about 5.5 cm. Intermediate minimum incompressible cross-sectional dimensions are also intended. In certain embodiments, the fillable polymer element has a length approximately equal to the length of the soluble container, such that the unencapsulated form has a diameter equal to about twice the length of the soluble container. In certain embodiments, the fillable polymer element has a length of about 1.3–2.7 cm. The gastric retention devices of the above embodiments are intended to be retained in the gastric cavity for 24 hours to about 1 month, or about 24 hours to 10 days.

[0070] Another aspect of the present invention is a gastric retention device comprising a central elastic polymer element containing polyurethane, the elastic polymer element being bonded to six fillable polymer elements, each fillable polymer element projecting radially from the central elastic polymer element to form a star-shaped cross-section, each fillable polymer element being bonded to the central elastic polymer element by a time-dependent degradable linker, and the fillable polymer element further comprising an embedded linker containing an enteric-coated polymer. In certain embodiments, the fillable polymer element contains polycaprolactone and may optionally contain excipients, and the degradable linker is a water-soluble and / or degradable polymer and blends thereof, which include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol, Kollidon VA 64, polyorthoester, polyhydroxybutyrate, eudragit and mixtures thereof. In certain embodiments, the device is housed in a soluble vessel which may optionally contain excipients. The device may further include at least one of a therapeutic agent, a diagnostic agent, and an enhancer, the therapeutic agent being selected from hydrophilic drugs, hydrophobic drugs, artemulators, ivermectin, risperidone, doxycycline, antimalarial agents, anthelmintics, antipsychotics, and antibiotics.

[0071] In certain embodiments, the device has a minimum incompressible cross-sectional dimension of about 3–5.5 cm, about 3 cm, about 4 cm, about 5 cm, or about 5.5 cm. Intermediate minimum incompressible cross-sectional dimensions are also intended. In certain embodiments, the fillable polymer element has a length approximately equal to the length of the soluble container, such that the unencapsulated form has a diameter equal to approximately twice the length of the soluble container. In certain embodiments, the fillable polymer element has a length of about 1.3 to about 2.7 cm.

[0072] These gastric retention devices of the above embodiments are intended to be retained in the gastric lumen for 24 hours to about 1 month, or about 24 hours to 10 days. In certain embodiments, the linker containing the enteric-coated polymer decomposes in response to a pH greater than about 5, thereby breaking down the fillable polymer elements.

[0073] In some embodiments, the method involves administering to a subject at least one retention structure configured to administer at least one of a therapeutic agent, a diagnostic agent, and an enhancer during a retention period of at least 24 hours, wherein the retention structure has a first shape configured to maintain its in vivo position relative to an internal opening during the retention period, and the at least one retention structure is configured to dissociate at least one enteric-coated elastomer linker It includes at least one enteric-coated elastomer linker positioned such that the level ends the residence period and allows at least one residence structure to pass through an internal opening.

[0074] In some embodiments, the method involves administering to a subject a retention structure configured to transport and maintain at least one structure for a retention period longer than at least 24 hours, the retention structure having a first shape configured to maintain an in vivo position relative to an internal opening during the retention period, and comprising at least one enteric elastomer linker positioned such that the level of dissociation of at least one enteric elastomer linker ends the retention period and allows the at least one retention structure to pass through the internal opening.

[0075] Other advantages and novel features of the present invention will become apparent by considering the following detailed description of various non-limiting embodiments of the invention in conjunction with the accompanying drawings. In the event that this specification and the references incorporated herein contain conflicting and / or contradictory disclosures, this specification shall prevail.

[0076] Non-limiting embodiments of the present invention are described by reference to the accompanying drawings, which are schematic and not intended to be drawn to scale. In the drawings, identical or nearly identical elements are usually represented by common numbers. For clarity, not all elements are labeled in all drawings, and not all elements of each embodiment of the present invention are shown where it is not necessary for those skilled in the art to understand the invention. [Brief explanation of the drawing]

[0077] [Figure 1A] Figure 1A is a schematic diagram of a retention structure according to one embodiment. [Figure 1B] Figure 1B is a schematic diagram of a retention structure according to one embodiment. [Figure 1C] Figure 1C is a schematic diagram of a retention structure according to one embodiment. [Figure 1D] Figure 1D is a schematic diagram showing the convex hull volume of a structure according to a set of embodiments. [Figure 1E] Figure 1E is a schematic diagram of a typical configuration of a retention structure according to one embodiment. [Figure 1F] Figure 1F is a schematic diagram of a typical configuration of a retention structure according to one embodiment. [Figure 1G] Figure 1G is a schematic diagram of another representative configuration of the retention structure according to one embodiment. [Figure 1H] Figure 1H is a schematic diagram of another representative configuration of the retention structure according to one embodiment. [Figure 2] Figure 2 is a photographic copy of a representative retention structure and a method for folding that structure, according to a set of embodiments. [Figure 3A] Figure 3A is a copy of a photograph of a representative retention system and structure, showing a representative structure and encapsulation structure according to a set of embodiments. [Figure 3B] Figure 3B is a copy of a photograph of a representative retention system and structure showing a typical structure folded within an encapsulation structure according to one embodiment. [Figure 3C] Figure 3C is a copy of a photograph of a representative retention system and structure showing another diagram of a representative structure according to a set of embodiments. [Figure 3D] Figure 3D is a photographic copy of a representative retention system and structure showing a typical twisted structure according to a set of embodiments. [Figure 3E] Figure 3E is a photographic copy of a representative retention system and structure showing a typical structure of (D) twisted into an encapsulation structure according to a set of embodiments. [Figure 4A] Figure 4A shows a typical retention structure including protrusions and a containment capsule according to one embodiment. [Figure 4B] Figure 4B shows various representative retention structures that include protrusions. [Figure 4C] Figure 4C is a photographic copy of a typical stagnant structure. [Figure 5A] Figure 5A shows a diagram and photograph of a typical polygonal retention structure according to one embodiment. [Figure 5B] Figure 5B shows a diagram and photograph of a typical polygonal retention structure according to one embodiment. [Figure 6] Figure 6 shows a series of X-ray images obtained using a retention structure on a large animal model according to one embodiment. [Figure 7] Figure 7 shows a series of X-ray images obtained using a retention structure on a large animal model according to one embodiment. [Figure 8A] Figure 8A shows an enteric elastomer for use in a retention structure according to a set of embodiments. [Figure 8B] Figure 8B shows the preparation of an enteric elastomer for use in a retention structure according to one embodiment. [Figure 8C] Figure 8C is a series of photographic copies obtained during mechanical testing of an enteric-coated elastomer according to a set of embodiments. [Figure 9A]Figure 9A shows the materials tested and the results obtained for the mechanical characterization of several representative enteric elastomers according to a set of embodiments. [Figure 9B] Figure 9B is a plot showing the solubility characteristics of enteric-coated elastomers according to one embodiment. [Figure 9C] Figure 9C is a plot of cell viability (i.e., cytotoxicity) of enteric-coated elastomers according to one embodiment. [Figure 10] Figure 10 shows the construction and in vivo evaluation of a ring-shaped retention structure according to a set of embodiments. [Figure 11A] Figure 11A shows a plot of stress (MPa) versus strain (mm / mm) for various elastic polymer elements of a representative structure according to a set of embodiments. [Figure 11B] Figure 11B shows a plot of pressure (MPa) versus strain (mm / mm) for the elastic polymer elements of a representative structure according to a set of embodiments. [Figure 11C] Figure 11C shows a plot of creep strain (mm / mm) versus time (seconds) for the elastic polymer elements of a representative structure according to a set of embodiments. [Figure 12] Figure 12 shows isometric, plan, bottom, and side views of a finite element modeling simulation of a deformed stagnant structure according to a set of embodiments. [Figure 13A] Figure 13A is a schematic diagram of a retention structure testing apparatus according to one embodiment. [Figure 13B] Figure 13B shows a force-to-displacement plot of a stagnant structure using the test apparatus shown in Figure 13A, according to one embodiment. [Figure 14] Figure 14 is a plot of the stability of doxycycline in SGF (pH=1, 37°C) over two weeks, analyzed by high-performance liquid chromatography (HPLC) according to one embodiment. [Figure 15]Figure 15 is a plot of the stability of artemeters in 70% isopropanol, 20% acetonitrile, and 10% water (IAW) (pH=1, 37°C) over two weeks, as analyzed by HPLC according to one embodiment. [Figure 16A] Figure 16A is a plot showing the stability of ivermectin in solution under acidic conditions (pH=1, 37°C) according to one embodiment. [Figure 16B] Figure 16B is a plot showing the stability of ivermectin in a polycaprolactone (PCL) structure under acidic conditions (pH=1, 37°C) according to one embodiment. [Figure 17A] Figure 17A is a plot showing the in vitro release of doxycycline-filled PCL star structures in simulated gastric juice (SGF) (pH=1, 37°C) according to a set of embodiments. [Figure 17B] Figure 17B is a plot showing the in vitro release of ivermectin (IVM)-filled star structures containing different formulations of SGF and Kolliphor® RH40, a nonionic oil-in-water solubilizer (RH40) (pH=1, 37°C), according to a set of embodiments. [Figure 17C] Figure 17C is a plot showing the in vitro release of IVM-filled star-shaped structures containing different formulations in SGF+RH40 (pH=1, 37°C) according to a set of embodiments. [Figure 18] Figure 18 is a plot showing the mechanical characterization of various PCL-based materials according to ASTM standard D790, according to a set of embodiments. [Figure 19] Figure 19 is a plot showing the probability of gastric retention of a gastric retention structure at a specified time point, according to a set of embodiments. [Figure 20] Figure 20 is a plot showing the probability of gastric retention of a gastric retention structure at a specified time point, according to one embodiment. [Figure 21] Figure 21 is a plot showing the probability of gastric retention of a gastric retention structure at a specified time point, according to one embodiment. [Figure 22]Figure 22 is a photographic copy showing the endoscopic evaluation of the retention of a star-shaped delivery system on day 35 according to one embodiment. [Figure 23] Figure 23 is a plot showing the cumulative release of risperidone over a certain period of time for a representative retention structure according to a set of embodiments. [Figure 24] Figure 24 is a plot showing the release of doxycycline over a period of time for a representative retention structure versus doxycycline pills in a set of embodiments. [Figure 25A] Figure 25A is a plot showing the release of ivermectin over a period of time from an ivermectin pill according to one embodiment. [Figure 25B] Figure 25B is a plot showing the release of ivermectin over a period of time for lower-dose formulations in one embodiment. [Figure 25C] Figure 25C is a plot showing the release of ivermectin over a period of time for a higher-dose formulation in one embodiment. [Figure 26] Figure 26 is a plot showing the release of doxycycline over a period of time from a representative retention structure in a set of embodiments. [Modes for carrying out the invention]

[0078] Generally, retention structures, systems, and associated methods are disclosed. Certain embodiments involve administering a retention structure to a subject (e.g., a patient) (e.g., orally) such that the retention structure is retained in an internal location within the subject for a specific period of time (e.g., at least about 24 hours) before being released or partially released. The retention structure may, in some cases, be a gastric retention structure. In some embodiments, the structures and systems described herein include one or more materials configured for one or more (and any combination) of the following: filling with an active substance (e.g., a therapeutic agent) (in some cases, at relatively high levels); stability of the active substance and / or structure in an acidic environment; mechanical flexibility and strength when housed in an internal cavity (e.g., the gastric cavity); easy passage through the gastrointestinal tract until delivery to a desired internal cavity (e.g., the gastric cavity); and / or rapid dissolution / degradation in a physiological environment (e.g., the intestinal environment) and / or in response to a chemical stimulant (e.g., ingestion of a solution that induces accelerated dissolution / degradation). In certain embodiments, the structure has a modular design combining materials configured for controlled release of therapeutic, diagnostic, and / or reinforcing agents, using structural materials that facilitate gastric retention, and for controlled and / or adjustable decomposition / dissolution to control the time it takes for the integrity of the retaining shape to be lost and for the structure to be expelled from the gastric lumen. For example, in certain embodiments, the retention structure includes a first elastic element, a second polymer element configured to release an active substance (e.g., a therapeutic agent), and optionally at least one linker. In some such embodiments, the linker decomposes after a predetermined time and / or upon exposure to a selected set of conditions, causing the retention structure to disintegrate. It may be configured to break apart and be released from a location within the subject.

[0079] In some embodiments, the retention structure has a specific configuration including a particular size and / or shape (e.g., multi-armed star) in a relaxed state. In certain embodiments, the retention structure may fold from a relaxed state into a second compressed configuration. For example, in some cases, the folded / compressed retention structure may be inserted into a capsule or other containment structure in the second configuration so that the retention structure can be delivered orally. In some cases, the capsule or other containment structure may be configured so that the retention structure dissolves and is released at a specific location inside the subject (e.g., in the stomach), thereby allowing it to reversibly return to the first configuration upon release (e.g., by bouncing). In some embodiments, the structure is configured to take an in vivo shape and / or size that delays or prevents further passage through the cavity of the body (e.g., the stomach) (e.g., from the stomach body to the pylorus). In some embodiments, the structure takes on a shape and / or size configured for retention (e.g., gastric retention) upon release from a soluble capsule / container and / or soluble retaining structure / element. In some embodiments, the structure is configured to take on a shape and / or size configured for gastric retention after being stored in its encapsulated shape and / or size for a period exceeding 24 hours, e.g., up to about one year. In some embodiments, the mechanical properties of the structure are optimized for the safe temporary retention of all or part of the structure in an internal cavity, such as the gastric cavity, for a period exceeding 24 hours, e.g., up to about one year.

[0080] Certain structures, systems, and methods described herein may be useful, for example, for achieving gastric retention and / or slow passage via oral administration for prolonged in vivo retention and administration of therapeutic agents, diagnostic agents, and / or enhancers. Certain embodiments of the structures and systems described herein may offer specific advantages over conventional compositions and structures and systems configured for internal retention and / or drug release, for example, in terms of their ability to take on a shape and / or size small enough to be ingested by a subject; in terms of their ability to take on an internal shape and / or size that delays or prevents them from passing further into a body cavity (e.g., the gastric cavity) (e.g., from the stomach body to the pylorus); in terms of their ability to fill therapeutic agents, diagnostic agents, and / or enhancers at high levels (e.g., high mass fraction); in terms of their ability to facilitate controlled release of such therapeutic agents, diagnostic agents, and / or enhancers with a low or no possibility of burst release; in terms of their ability to maintain the activity / stability of such therapeutic agents, diagnostic agents, and / or enhancers over extended periods in hazardous environments such as the gastric environment; in terms of their ability to maintain safety without a low or no possibility of gastric or intestinal obstruction and / or perforation; and / or their ability to decompose / dissolve / dissociate into one or more forms configured to pass through the gastrointestinal tract. In certain embodiments, the structures and systems described herein may be configured to have a persistent residence period lasting at least 24 hours, up to one year or more. In some embodiments, the systems, structures, and methods described herein are compatible with subjects, including, but not limited to, human and non-human animals. In further embodiments, the systems and structures may be configured to deliver a wide variety of therapeutic agents, diagnostic agents, and / or enhancers, thereby enabling an increase, or even maximization, of patient adherence to treatment.

[0081] The structures and systems described herein may be modular / multiple elements (i.e., formed from multiple interconnected subcomponents). In some embodiments, the structure is configured to contain and / or release a therapeutic agent, and / or to have elements (one or more) undergo mechanical deformation without permanent deformation and / or breakage, and / or to bounce back after a certain period of time, so that the structure is selectively retained in a position inside the subject. The structure includes one or more polymer elements configured to be held. In certain embodiments, the structure includes two or more polymer elements. For example, in some cases, the structure includes a first polymer element and a second polymer element that, unlike the first polymer element, is in direct contact with it. As shown in Figure 1A, in some embodiments, the structure 100 includes a first polymer element 110 linked to a second polymer element 120. In some such embodiments, the first polymer element may be bonded to the second polymer element via an adhesive, by chemical interactions (e.g., chemical bonding), and / or by interpenetrating and / or entangled polymer chains, and / or by other physical, chemical, and / or bonding interactions. In some embodiments, the first polymer element is an elastic polymer element and the second polymer element is a fillable polymer element. Elastic polymer elements and fillable polymer elements are described in further detail below.

[0082] Generally, embodiments of the present invention may be carried out using any combination of the first, second, third, and other polymer elements, but for clarity and brevity, much of the following description is in the context of selected embodiments including elastic polymer elements and fillable polymer elements.

[0083] In some embodiments, one or more linkers are bonded to one or more polymer elements. For example, in some embodiments, linkers may be embedded within elastic polymer elements to separate or connect two or more portions of the elastic polymer element. In certain embodiments, linkers may be embedded within fillable polymer elements to separate or connect two or more portions of the fillable polymer element. In some cases, linkers are positioned between two or more different polymer elements (for example, to bond two or more different polymer elements). For example, in some embodiments, two elastic polymer elements are bonded by linkers. In certain embodiments, two fillable polymer elements are bonded by linkers. In some cases, elastic polymer elements are bonded to fillable polymer elements by linkers. In some embodiments, the structure may include combinations of arrangements of polymer elements and linkers.

[0084] In certain embodiments, a first polymer element and a second polymer element are linked by a linker. For example, as shown in Figure 1B, the structure 100 includes a first polymer element 110 linked to a second polymer element 120 via a linker 130. Linkers and suitable linker materials are described in further detail below.

[0085] In some embodiments, the linker may be embedded within a first or second polymer element, separating or linking two or more portions of those elements. For example, in certain embodiments, the linker does not link the first and second polymer elements together, but is embedded within the first or second polymer element, separating or linking two or more portions of such elements, so that when the linker decomposes, the elements fall apart (e.g., a structure or part of a structure is removed).

[0086] In some embodiments, the structure is designed such that the mechanism of delivery differs from the mechanism of degradation. For example, a linker (e.g., an enteric-coated linker as described below) may be attached, fused, bonded, embedded, or otherwise connected to the fillable material (e.g., fillable polymer elements) that constitutes the majority of the structure. When the fillable material / linker composite is exposed to therapeutic agents, diagnostic agents, and / or reinforcing agents for filling, the filling may be selective within the fillable material, and the release of therapeutic agents, diagnostic agents, and / or reinforcing agents from the fillable material may be by diffusion or Materials may be selected so that decomposition occurs via slow matrix degradation. In some embodiments, the fillable material is capable of withstanding brittle fracture but is sufficiently rigid and possesses certain mechanical properties that can facilitate the material's ability to withstand internal physiological, mechanical, chemical, and / or biological challenges to maintain the retention of the structure or at least the filler material elements of the structure for a desired period of time. In some embodiments, the filling of such therapeutic, diagnostic, and / or reinforcing agents may be minimized within individual linker materials, and individual linker materials may be configured to control / regulate the decomposition / dissolution of the retaining / delivery structure and / or specific fillable material portions of the retaining / delivery structure. By separating the delivery mechanism (e.g., slow release from relatively stable fillable material portions) from a controllable decomposition mechanism (e.g., faster decomposition of linker(s)), the retaining / delivery structure may be configured to prevent burst release of therapeutic, diagnostic, and / or reinforcing agents during decomposition / dissolution.

[0087] In some embodiments, the structure includes multiple polymer elements and / or multiple linkers. In certain embodiments, the structure includes one or more, two or more, three or more, four or more, or five or more polymer elements of a first material. In some embodiments, the structure includes one or more, two or more, three or more, four or more, or five or more polymer elements of a second material. More complex structures and more types of polymer materials are possible. In certain embodiments, the structure includes one or more, two or more, three or more, four or more, or five or more linkers, etc. In an exemplary embodiment, as shown in Figure 1C, the structure 100 includes a first-type polymer element 110 bonded to two second-type polymer elements 120 via two linkers 130. Those skilled in the art will be able to select various additional arrangements of polymer elements and linkers based on the teachings of the specification. Further representative arrangements will be described in more detail hereafter.

[0088] In some embodiments, the retaining structure includes elastic polymer elements. In certain embodiments, the use of elastic polymer elements can impart desirable mechanical properties to the structure. For example, in some cases, the structure may be configured to withstand relatively large compressive forces (e.g., compressive forces present in the stomach and / or intestines of the subject) so that the structure does not break and / or is held in an internal location within the subject (e.g., an opening such as the pylorus or above it). In certain embodiments, the structure may be configured to fold (e.g., without breaking). For example, the elastic polymer elements may be configured to withstand relatively high levels of bending stress without breaking and / or undergoing significant permanent deformation. In some embodiments, the elastic polymer elements and / or structures containing them may be configured to bounce substantially. That is, after mechanically deforming the elastic polymer elements and / or structures containing elastic polymer elements, the structure can substantially return to its original configuration before the mechanical deformation was applied (e.g., the elastic polymer elements may be characterized by substantially minimal creep deformation).

[0089] Appropriate selection tests may be used to determine materials suitable for use as elastic polymer elements. For example, elastic polymer elements may be tested for their ability to withstand mechanical bending deformations of at least about 45 degrees, at least about 60 degrees, at least about 90 degrees, at least about 120 degrees, at least about 150 degrees, or about 180 degrees without breaking. In certain embodiments, elastic polymer elements may be configured to withstand mechanical bending deformations of up to about 180 degrees, up to about 150 degrees, up to about 120 degrees, up to about 90 degrees, or up to about 60 degrees without breaking. Any and all closed intervals having endpoints within any of the above reference ranges are also possible (e.g., about 45 degrees to about 180 degrees, about 60 degrees to about 180 degrees, about 60 degrees to about 120 degrees, about 90 degrees to about 180 degrees). Other ranges are also possible.

[0090] In some cases, the elastic polymer element may be configured to remain in a deformed configuration for a relatively long period of time (e.g., mechanical bending deformation of at least about 45 degrees)—for example, in some embodiments, the elastic polymer element may be configured to have a shelf life of at least about 24 hours, at least about 1 week, at least about 1 month, at least about 1 year, or at least about 2 years in such a deformed configuration, and still substantially return to its pre-deformed configuration (i.e., bounce back). In certain embodiments, the elastic polymer element is configured to have a shelf life of up to about 3 years, up to about 2 years, up to about 1 year, up to about 1 month, or up to about 1 week in a deformed configuration, and still substantially return to its pre-deformed configuration (i.e., bounce back). Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 24 hours to about 3 years, about 1 week to 1 year, about 1 year to 3 years). Other ranges are also possible.

[0091] In some embodiments, the elastic polymer element is relatively flexible. In certain embodiments, the elastic polymer element may be selected to undergo large angular deformations over relatively long periods without significant inelastic deformation. In some such embodiments, the elastic polymer element may have sufficient rebound strength to substantially return to its pre-deformation shape within about 30 minutes, about 10 minutes, about 5 minutes, or about 1 minute after the release of mechanical deformation. Those skilled in the art will understand that returning to its pre-deformation shape does not need to be an absolute agreement with the mathematically defined shape, but rather should be understood as being as close as possible to the mathematically defined shape with respect to the subject matter characterized as being most closely related to such subject matter.

[0092] In some embodiments, the elastic polymer element has a specific modulus of elasticity. In some embodiments, the modulus of elasticity of the elastic polymer element is in the range of about 0.1 MPa to about 30 MPa. In some embodiments, the modulus of elasticity of the elastic polymer element is at least about 0.1 MPa, at least about 0.2 MPa, at least about 0.3 MPa, at least about 0.5 MPa, at least about 1 MPa, at least about 2 MPa, at least about 5 MPa, at least about 10 MPa, at least about 20 MPa, or at least about 25 MPa. In certain embodiments, the modulus of elasticity of the elastic polymer element is up to about 30 MPa or less, up to about 25 MPa or less, up to about 20 MPa or less, up to about 10 MPa or less, up to about 5 MPa or less, up to about 2 MPa or less, up to about 1 MPa or less, up to about 0.5 MPa or less, up to about 0.3 MPa or less, or up to about 0.2 MPa or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 0.1 MPa to about 30 MPa, about 0.3 MPa to about 10 MPa). Other ranges are also possible. Those skilled in the art will be able to select a suitable method for determining the elastic modulus of a polymer element, for example, including tensile mechanical characterization based on ASTM D638 and / or compressive mechanical characterization based on ASTM D575.

[0093] In some embodiments, the elastic polymer element undergoes relatively small amounts of creep during mechanical deformation. For example, in certain embodiments, the elastic polymer element has a minimum creep rate of about 0.3 mm / mm / hr or less, about 0.2 mm / mm / hr or less, about 0.1 mm / mm / hr or less, about 0.08 mm / mm / hr or less, about 0.05 mm / mm / hr or less, about 0.03 mm / mm / hr or less, or about 0.02 mm / mm / hr or less. In certain embodiments, the elastic polymer element has a minimum creep rate of at least about 0.01 mm / mm / hr, at least about 0.02 mm / mm / hr, at least about 0.03 mm / mm / hr, at least about 0.05 mm / mm / hr, at least about 0.08 mm / mm / hr, at least about 0.1 mm / mm / hr, or at least about 0.2 mm / mm / hr. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible. (For example, approximately 0.01 mm / mm / hr to approximately 0.3 mm / mm / hr, approximately 0.02 mm / mm / hr to approximately 0.1 mm / mm / hr, approximately 0.02 mm / mm / hr to approximately 0.05 mm / mm / hr, approximately 0.05 mm / mm / hr to approximately 0.3 mm / mm / hr). Other ranges are also possible. In some embodiments, the minimum creep rate can be measured in accordance with ASTM D-638. Briefly, a sheet of elastic polymer material is prepared as described below and cut out with a standard dumbbell die. The test specimen is mounted on the grip of an Instron material testing machine, and the gauge length can be measured with a digital micrometer. A substantially constant stress equivalent to 30% of the ultimate tensile strength of each material may be applied to the test specimen at a constant temperature (e.g., room temperature) for 60 minutes, and creep (mm / mm) versus time (hours) can be plotted. The minimum creep rate is the slope of the creep-versus-time curve before secondary creep.

[0094] A person skilled in the art, having been given guidance and the teachings herein, will be able to determine appropriate methods for tuning the mechanical properties (e.g., elastic modulus, creep behavior) of an elastic polymer element, for example, by changing the molar ratio of monomers and / or polymer units (e.g., by increasing the amount of high molecular weight polycaprolactone or other polymer used in the elastic polymer element), by changing the crosslinking density of the polymer, by changing the concentration of the crosslinking agent used to form the polymer, by changing the crystallinity of the polymer (e.g., by changing the ratio of crystalline to amorphous regions of the polymer), and / or by using additional or alternative materials (e.g., by incorporating materials such as bis(isocyanatomethyl)cyclohexane).

[0095] In some embodiments, the elastic polymer element does not substantially swell in the presence of biological fluids such as blood, water, bile, gastric juice, or combinations thereof. In some embodiments, the elastic polymer element swells in biological fluids by about 0.01% to about 10% by volume compared to the volume of the elastic polymer element in a dry state (e.g., under atmospheric conditions and at room temperature). For example, in certain embodiments, the elastic polymer element swells by less than about 10% by volume, less than about 5% by volume, less than about 2% by volume, or less than about 1% by volume compared to the volume of the elastic polymer element in a dry state (e.g., under atmospheric conditions and at room temperature) in unagitated gastric juice or simulated gastric juice at physiological temperature.

[0096] In some cases, the retained structure swells by less than about 10% by volume, less than about 5% by volume, less than about 2% by volume, or less than about 1% by volume compared to the volume of the retained structure in a dry state (e.g., under atmospheric conditions and at room temperature) in unagitated gastric juice or simulated gastric juice at physiological temperature. Those skilled in the art will be able to select a suitable method for determining the amount of swelling of the elastic polymer element or structure based on the teachings herein, for example, by measuring the volume of the elastic polymer element or structure in a dry state under atmospheric conditions and at room temperature, immersing the elastic polymer element or structure in unagitated gastric juice or simulated gastric juice at physiological temperature, and measuring the percentage change in the volume of the element after about 60 minutes. The volume of the structure may be determined, for example, by liquid displacement methods known in the art and / or by 3D scanning techniques.

[0097] The elastic polymer elements are preferably biocompatible. In the context of polymer elements, "biocompatible" means a polymer that does not induce substantial adverse reactions (e.g., adverse immune responses) from living organisms (e.g., mammals), tissue cultures, or cell collections, or induces only reactions that do not exceed acceptable levels. In some embodiments, the elastic polymer elements include combinations of polymers, polymer networks, and / or multiblocks of polymer segments, which include, but are not limited to, polyesters such as polycaprolactone, poly(propylene fumarate), poly(glycerol sebacate), poly(lactide), poly(glycolic acid), poly(lactic acid-glycolic acid), polybutyrate, and polyhydroxyalkanoates; but are not limited to polyethers such as poly(ethylene oxide) and poly(propylene oxide); but are not limited to poly The polymers or polymer segments may include polysiloxanes such as (dimethylsiloxane); polyamides such as poly(caprolactam), but not limited to polyolefins such as polyethylene, but not limited to polycarbonates such as poly(propylene oxide), polyketals; polyvinyl alcohols; polyoxetanes; polyacrylates / methacrylates such as poly(methyl methacrylate) and poly(ethyl vinyl acetate), but not limited to polyanhydrides; and polyurethanes. In some embodiments, the polymers are crosslinked. In some embodiments, the elastic polymer elements include polymer composite materials comprising two or more chemically similar polymers or two or more chemically different polymers. In a typical embodiment, the elastic polymer elements include isocyanate-crosslinked polyurethanes produced from low molecular weight monomers such as polycaprolactone. In some such embodiments, the low molecular weight monomers comprise one or more hydroxyl functional groups (e.g., diols, triols).

[0098] In certain embodiments, the elastic polymer element includes an enteric polymer, such as an enteric elastomer. Enteric polymers and enteric elastomers are described in further detail below.

[0099] In some embodiments, the retaining structure is configured to be filled with one or more active substances, such as therapeutic agents, diagnostic agents, and / or enhancers, in relatively high levels (e.g., by mass). In some embodiments, the structure is formed from one or more of various materials, but not limited to polycaprolactone (PCL), poly(ethylene-co-vinyl acetate), and polyethylene glycol (PEG), which have desirable properties for controlling the filling and release of the active substance. For example, in some embodiments, the fillable polymer element is a polymer element configured to be filled with relatively high levels of active substance and configured to have desirable properties for controlling the filling and release of the active substance. In some embodiments, the fillable polymer element comprises a drug-fillable polymer matrix. In a typical embodiment, the fillable polymer element comprises polycaprolactone. Polycaprolactone is a degradable polyester with a relatively low melting point of about 60°C (degradable by hydrolysis of ester bonds under physiological conditions). In some embodiments, the fillable polymer element is selectively degradable under a specific set of conditions (e.g., a specific pH and / or temperature range). In certain embodiments, the fillable polymer element is biodegradable (e.g., in vivo degradable).

[0100] In some embodiments, the fillable polymer elements are configured to be filled with relatively high levels of active substances and / or include a drug-fillable polymer matrix. For example, in certain embodiments, the structure includes fillable polymer elements in amounts of at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, or at least about 93% by weight of the total structure weight. In some embodiments, the structure includes fillable polymer elements in amounts of up to about 95% by weight, up to about 93% by weight, up to about 90% by weight, up to about 80% by weight, or up to about 70% by weight of the total structure weight. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 60% by weight to about 95% by weight). For example, in some embodiments, a structure of about 60% by weight to about 95% by weight includes polymer elements configured to be filled with relatively high levels of active substances and / or therapeutic agents. The presence of fillable polymer elements capable of filling relatively high levels of active material in amounts exceeding approximately 60% by weight of the entire structure (e.g., exceeding approximately 80% by weight, exceeding approximately 90% by weight) provides several advantages (including the structure), such as the ability to release active material (e.g., therapeutic agents) from the structure over relatively long periods (e.g., at least approximately 24 hours, at least approximately 48 hours, at least approximately 7 days, at least approximately 1 month), and / or the ability to regulate the release rate and / or duration of release of the active material.

[0101] Several selection tests may be used to select materials suitable for use as fillable polymer elements. For example, fillable polymer elements may be selected to have a flexural modulus greater than about 100 MPa, greater than about 120 MPa, greater than about 150 MPa, or greater than about 200 MPa. In some embodiments, fillable polymer elements have a flexural modulus of about 250 MPa or less, about 200 MPa or less, about 150 MPa or less, or about 120 MPa or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 100 MPa to about 250 MPa). Other ranges are also possible. Those skilled in the art will be able to select a suitable method for determining the flexural modulus of a polymer element, for example, including plotting flexural stress versus strain and obtaining the slope of the linear portion of the curve. The flexural modulus of a fillable polymer element may be selected to impart desired characteristics to the structure, including, for example, the ability to fold and / or bend so that the structure can be encapsulated without breaking and / or the ability to withstand compressive forces such as in a gastric cavity.

[0102] In certain embodiments, the fillable polymer element may be selected to have a flexural strength of at least about 10 MPa. For example, in some embodiments, the fillable polymer element has a flexural strength of at least about 10 MPa, at least about 15 MPa, at least about 20 MPa, at least about 30 MPa, or at least about 40 MPa. In certain embodiments, the fillable polymer element has a flexural strength of about 50 MPa or less, about 40 MPa or less, about 30 MPa or less, about 20 MPa or less, or about 15 MPa or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 10 MPa to about 50 MPa). Other ranges are also possible. Those skilled in the art will be able to select a suitable method for determining the flexural strength of the fillable polymer element, for example, by determining the flexural stress at failure of the polymer material. The flexural strength of the fillable polymer element may be selected to impart desired features to the structure, including, for example, the ability to fold and / or bend so that the structure can be encapsulated without breaking and / or the ability to withstand compressive forces such as in a gastric cavity.

[0103] The fillable polymer element material may be selected to maintain its mechanical properties during the residence period (e.g., during the release of the active substance and / or during residence in a body cavity). Residence periods are described in more detail below. In some embodiments, the fillable polymer element material is selected so that the structure can be retained in a cavity located inside the subject (e.g., the gastric cavity) for at least 24 hours, at least 48 hours, at least 1 week, at least 1 month, or at least 1 year. In certain embodiments, the fillable polymer element material is selected so that the structure can be retained in a cavity located inside the subject for a maximum of about 2 years, a maximum of about 1 year, a maximum of about 1 month, a maximum of about 1 week, or a maximum of about 48 hours. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 24 hours to about 2 years, about 48 hours to about 2 years, and about 1 week to about 1 year). Other ranges are also possible.

[0104] In certain embodiments, the fillable polymer element is selected such that the material fills the element with an active substance (e.g., a therapeutic agent) for a desired retention period in a physiological environment such as the acidic environment of the stomach.

[0105] In some embodiments, one or more polymer elements and / or one or more linkers may comprise a food-grade crosslinked (FGC) polymer. For example, in certain embodiments, the fillable polymer elements comprise a polymer catalyzed with a food-grade catalyst. The use of food-grade crosslinked polymers offers several advantages over non-food-grade polymers, including easier FDA approval, lower cytotoxicity, and / or reduced (or virtually no) need to remove post-polymerization toxic catalysts. In some embodiments, food-grade crosslinked polymers comprise food-grade components crosslinked and / or polymerized using a food-grade catalyst. Food-grade crosslinked polymers can typically possess a combination of advantageous properties such as mechanical strength, biocompatibility, and / or moldability. In some cases, FGC polymers can conveniently enable controlled release of therapeutic agents while containing little to no potentially harmful auxiliary materials (e.g., solvents, catalysts, excipients) that may, in some cases, be toxic. In some embodiments, FGC polymers are formed by the reaction of one or more monomers in the presence of a food-grade catalyst. The use of a food-grade catalyst to form FGC polymers can yield several advantages, such as the formation of elements primarily (or solely) containing FDA-approved components, and biocompatibility. In certain embodiments, the FGC polymer comprises, for example, ester bonds so that the FGC polymer is biodegradable under physiological conditions. It is advantageous that the FGC polymer may include polymer materials (e.g., thermosetting polymer materials) that have the strength and integrity of epoxy resins, the biomedical applicability of hydrogels, and / or the moldability of vitrimers.

[0106] In some embodiments, the FGC polymer is crosslinked. In certain embodiments, the FGC polymer is substantially amorphous. In one embodiment, the FGC polymer is useful as a fillable polymer element of a retaining structure and is derived from crosslinked oligomers or polymer strands or chains via a reaction that does not hinder the incorporation of susceptible therapeutic agents (e.g., active substances may be directly filled into and released within the FGC polymer). The FGC polymer may be softer than conventional cured resins and may be characterized by a lower Young's modulus and crosslink density than conventional cured resins. In certain embodiments, in contrast to shape memory polymers, which typically return to their original shape after being stretched or otherwise stressed, the FGC may remain fixed in its new shape after being molded into a new position.

[0107] In some embodiments, the FGC polymer is formed by the reaction of two or more polyfunctional monomers (e.g., a first polyfunctional monomer and a second polyfunctional monomer). In certain embodiments, the FGC polymer is formed by the reaction of two or more, three or more, four or more, or five or more polyfunctional monomers. In some embodiments, each polyfunctional monomer contains a reactive functional group. In certain embodiments, two or more reactive functional groups may form a covalent bond with each other. For example, in some cases, the reaction of a first reactive functional group with a second reactive functional group forms a covalent bond between the first and second reactive functional groups. In other embodiments, the reaction between two or more reactive functional groups is a Michael addition. In other embodiments, the reaction between two or more reactive functional groups is a cycloaddition reaction, particularly a Diels-Alder reaction.

[0108] In some embodiments, one or more polyfunctional monomers are difunctional. In certain embodiments, one or more polyfunctional monomers are trifunctional. In some cases, one or more polyfunctional monomers may be tetrafunctional, pentafunctional, hexafunctional, or have higher-order functionalities. In certain embodiments, the FGC polymer is formed by the reaction of one or more difunctional monomers with one or more trifunctional monomers.

[0109] In one embodiment, the FGC polymer is of formula (I): [ka] The compound of formula (I) may be expressed as follows, where A is derived from at least one polyfunctional monomer containing at least two reactive functional groups, and B is derived from at least one polyfunctional monomer containing at least two reactive functional groups, and the compound of formula (I) contains a crosslinking bond. For example, in certain embodiments, an FGC polymer having a structure like that in formula (I) is formed by the reaction of a first polyfunctional monomer containing two reactive functional groups with a second polyfunctional monomer containing three reactive functional groups. In other embodiments, an FGC polymer having a structure like that in formula (I) is formed by the reaction of a first polyfunctional monomer containing two reactive functional groups with a second polyfunctional monomer different from the first polyfunctional monomer containing two reactive functional groups with a third polyfunctional monomer containing three reactive functional groups. In some such embodiments, the reactive functional groups of the first polyfunctional monomer may be the same as or different from the reactive functional groups of the second polyfunctional monomer and / or the third polyfunctional monomer. For example, the reactive group of the first polyfunctional monomer may react with (and form a covalent bond with) the reactive group of the second polyfunctional monomer and / or the third polyfunctional monomer.

[0110] In some embodiments, one or more polyfunctional monomers comprise an oligomer moiety. In certain embodiments, the FGC polymer of formula (I) is further characterized by the presence of at least two reactive groups capable of forming crosslinks.

[0111] In certain embodiments, the compound of formula (I) is prepared by combining two or more polyfunctional monomers, then incubating the mixture at a temperature sufficient to initiate polymerization and reach the gel point. In some embodiments, two or more polyfunctional monomers are combined in the presence of a catalyst. In certain embodiments, two or more polyfunctional monomers are combined in the presence of a subunit compound, in the presence of an active agent, or in the presence of both.

[0112] In some embodiments, the polyfunctional monomer has the structure of formula (II): Q 1 -L-Q 2 (II) wherein Q 1 and Q 2 are the same or different reactive functional groups, and L has the structure of formula (III):

化

化

[0113] In some embodiments, the polyfunctional monomer has the structure of:

化

[0114] In some embodiments, X 1 , X 2 , and X 3 They are the same or different, do not exist or (CR 1 R 2 ) m The group is selected from the group consisting of heteroatoms, alkenyls, alkynyls, cycloalkyls, aryls, heterocyclic groups, heteroaryl groups, and oligomeric groups. In certain embodiments, X 1 , X 2 , and / or X 3 It does not exist.

[0115] In certain embodiments, m is zero or any integer. For example, in some embodiments, m is 0. In certain embodiments, m is 1-3, 2-4, 3-6, 4-8, 5-10, 8-16, 12-24, 20-30, 25-50, 40-60, 50-100, 75-150, 125-200, 150-300, 250-500, 400-600, 500-800, or 750-1500. In some cases, m is 1-3. In certain embodiments, m is 2-4. In some cases, m is 4-8. In some embodiments, m is 8-16. The value of m may be selected to impart specific properties (e.g., crosslink density, Young's modulus) to the FGC polymer.

[0116] In some embodiments, y is zero or any integer. For example, in some embodiments, y is 0. In certain embodiments, y is 1-3, 2-4, 3-6, 4-8, 5-10, 8-16, 12-24, 20-30, 25-50, 40-60, 50-100, 75-150, 125-200, 150-300, 250-500, 400-600, 500-800, or 750-1500. In some cases, y is 1-3. In certain embodiments, y is 2-4. In some cases, y is 4-8. In some embodiments, y is 8-16. The value of y may be selected to impart specific properties (e.g., crosslink density, Young's modulus) to the FGC polymer.

[0117] In certain embodiments, z is zero or any integer. For example, in some embodiments, z is 0. In certain embodiments, z is 1-3, 2-4, 3-6, 4-8, 5-10, 8-16, 12-24, 20-30, 25-50, 40-60, 50-100, 75-150, 125-200, 150-300, 250-500, 400-600, 500-800, or 750-1500. In some cases, z is 1-3. In certain embodiments, z is 2-4. In some cases, z is 4-8. In some embodiments, z is 8-16. The value of z may be selected to impart specific properties (e.g., crosslink density, Young's modulus) to the FGC polymer.

[0118] In certain embodiments, m+y+z is zero. In certain embodiments, m+y+z is 1. In some cases, m+y+z is an integer, 2 or greater.

[0119] Several embodiments, each R 1 and R 2R is selected from the group consisting of hydrogen, aliphatic groups, halogens, hydroxyl, carbonyl, thiocarbonyl, oxo, alkoxy, epoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, thiol, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, cycloalkyl, heterocyclyl, aralkyl, and aromatic or heteroaromatic or Michael acceptors, and R 1 and R 2 Any two or more of the groups may be bonded to each other to form a ring system. In a particular embodiment, each R 1 and / or R 2 Q 3 (That is, it may be a reactive functional group.)

[0120] In a typical embodiment, the polyfunctional monomer is of formula (IV): [ka] It has a structure as shown in, and L is as described above. In another representative embodiment, the polyfunctional monomer is: [ka] It has a structure as shown in the formula, where L is as described above. In yet another representative embodiment, the polyfunctional monomer is of formula (V) or formula (VI): [ka] It has a structure as shown in the formula, where L is as described above. In some embodiments, the FGC polymer is formed by the reaction of a first polyfunctional monomer having a structure as shown in formula (IV) with a second polyfunctional monomer having a structure as shown in formula (V) or formula (VI).

[0121] The polyfunctional monomers described herein may contain at least two, at least three, at least four, or at least five reactive functional groups. For example, in some embodiments, Q 1 Q 2 , and Q 3 These may be the same or different electrophilic or nucleophilic functional groups.

[0122] In some embodiments, one or more reactive groups (e.g., Q 1 Q 2 , and / or Q 3 ) are electrophilic functional groups. For example, a monomer may contain at least two, at least three, at least four, or at least five electrophilic functional groups. Non-limiting examples of suitable electrophilic functional groups include alkenes, alkynes, esters (e.g., N-hydroxysuccinimide esters), acrylates, methacrylates, acyl halides, acylnitriles, alkyl halides, aldehydes, ketones, alkyl sulfonates, anhydrides, epoxides, haloacetamides, aziridines, and diazoalkanes.

[0123] In certain embodiments, one or more reactive functional groups (e.g., Q 1 Q 2 , and / or Q 3 ) is a nucleophilic functional group. For example, a monomer contains at least two, at least three, at least four, or at least five nucleophilic functional groups. That is fine. Non-limiting examples of suitable nucleophilic functional groups include alcohols, amines, aniline, phenols, hydrazines, hydroxylamines, carboxylic acids, alkoxides, alkenes, thiols, and glycols.

[0124] The polyfunctional monomers described herein may include at least one electrophilic functional group and at least one nucleophilic functional group. For example, in a typical embodiment, the first polyfunctional monomer includes both an electrophilic functional group and a nucleophilic functional group. In a specific embodiment, the first polyfunctional monomer includes two or more electrophilic functional groups, and the second polyfunctional monomer includes two or more nucleophilic functional groups.

[0125] In some cases, the reaction between electrophilic and nucleophilic functional groups forms bioresponsive bonds such as ester bonds, ether bonds, amide bonds, amine bonds, or thioether bonds. For example, in certain embodiments, the FGC polymer contains ester bonds formed by the reaction between electrophilic and nucleophilic functional groups. In some embodiments, the FGC polymer contains ether bonds formed by the reaction between electrophilic and nucleophilic functional groups. Other bonds are also possible.

[0126] In some embodiments, the FGC polymer is formed by the reaction of two or more polyfunctional monomers with additional monomer units. In some embodiments, the additional monomer units include compounds comprising one or more carboxylic acid derivatives. In some embodiments, the additional monomer units are a single compound comprising at least one ester, amide, or thioester group, or a mixture of compounds comprising at least one ester, amide, or thioester group. In certain embodiments, the additional monomer units are compounds comprising a lactone, lactam, or thiolactone group. In certain embodiments, the additional monomer units are naturally occurring lactones or lactams. In other embodiments, the lactone-containing or lactam-containing compounds of the additional monomer units are selected from those listed in the FDA's "Generally Recognized as Safe" substances database and / or 21 CFR 182. In certain embodiments, the additional monomer units are selected γ-decalactones, δ-decalactones, ω-pentadecalactones, caprolactams, and mixtures thereof.

[0127] In certain embodiments of the present invention, the additional monomer units do not contain primary or secondary amine moieties.

[0128] In some embodiments, the molar ratio of the first polyfunctional monomer (e.g., containing an electrophilic reactive group) to the mixture of additional polyfunctional monomers (e.g., containing a nucleophilic reactive group) and / or additional monomer units is in the range of about 10:1 to about 1:10. In a typical embodiment, the molar ratio of the first polyfunctional monomer to the mixture of additional polyfunctional monomers and / or monomer units is about 1:1. In certain embodiments, the molar ratio of the first polyfunctional monomer to the mixture of additional polyfunctional monomers and / or monomer units is less than about 10:1, less than about 8:1, less than about 6:1, less than about 4:1, less than about 2:1, less than about 1.5:1, less than about 1:1, less than about 1.5:1, less than about 1:2, less than about 1:4, less than about 1:6, or less than about 1:8. In some embodiments, the molar ratio of the first polyfunctional monomer to the mixture of additional polyfunctional monomers and / or monomer units is about 1:10 or greater, about 1:8 or greater, about 1:6 or greater, about 1:4 or greater, about 1:2 or greater, about 1:1.5 or greater, about 1:1 or greater, about 1:1.5 or greater, about 2:1 or greater, about 4:1 or greater, about 6:1 or greater, or about 8:1 or greater. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 10:1 to about 1:10, about 1:4 to about 4:1, about 1:2 to about 2:1).

[0129] In some such embodiments, the second polyfunctional monomer is present in the mixture of additional polyfunctional monomers and / or monomer units in amounts of at least about 10 mol%, at least about 20 mol%, at least about 25 mol%, at least about 50 mol%, at least about 75 mol%, at least about 90 mol%, or at least about 99 mol%. In certain embodiments, the second polyfunctional monomer is present in the mixture of additional polyfunctional monomers and / or monomer units in amounts of about 99.9 mol% or less, about 99 mol% or less, about 90 mol% or less, about 75 mol% or less, about 50 mol% or less, about 25 mol% or less, or about 20 mol% or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 25 mol% to about 99.9 mol%). Other ranges are also possible.

[0130] As described above, in some embodiments, two or more polyfunctional monomers are combined (i.e., reacted) in the presence of a catalyst.

[0131] In some embodiments, the catalyst is a nucleophile. In certain embodiments, the catalyst is a base (e.g., a moderate base, a weak base). In certain embodiments, the catalyst is a metal salt. In some embodiments, the catalyst is a zinc sulfate, e.g., ZnSO4 and its hydrate.

[0132] In some embodiments, the catalyst is selected from the FDA's "Generally Recognized as Safe" substances database and / or catalysts listed in 21 CFR 182. In certain embodiments, the catalyst is food-grade and / or food-derived catalyst.

[0133] In certain embodiments, the catalyst is an organic amine. In some embodiments, the catalyst is a tertiary amine. In some cases, the tertiary amine catalyst does not contain any amino NH or NH2 functional groups at all.

[0134] In some embodiments, the catalyst is an alkaloid compound. In certain embodiments, the catalyst is a purine base. Non-limiting examples of purine bases include purines, adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, and isoguanine. In typical embodiments, the catalyst is caffeine.

[0135] The use of food-grade catalysts such as caffeine may offer certain advantages over conventional catalysts, including easier FDA approval, lower cytotoxicity, and / or reduced (or virtually eliminated) the need to remove the catalyst after polymerization.

[0136] In some embodiments, the catalyst (e.g., a food-grade catalyst) is present in the FGC polymer after its formation in an amount ranging from 0.01 mol% to about 25 mol%. In some embodiments, the FGC polymer is substantially catalyst-free after its formation. In certain embodiments, the catalyst is present in the FGC polymer after its formation in an amount of at least about 0.01 mol%, at least about 0.05 mol%, at least about 0.1 mol%, at least about 0.5 mol%, at least about 1 mol%, at least about 2 mol%, at least about 5 mol%, at least about 10 mol%, or at least about 20 mol%. In certain embodiments, the catalyst is present in the FGC polymer after its formation in an amount of about 25 mol% or less, about 20 mol% or less, about 10 mol% or less, about 5 mol% or less, about 2 mol% or less, about 1 mol% or less, about 0.5 mol% or less, about 0.1 mol% or less, or about 0.05 mol% or less. Any and all closed intervals ending within any of the above reference ranges are also possible (e.g., approximately 1 mol% to 25 mol%, approximately 0.01 mol% to 5 mol%). Other ranges are also possible.

[0137] As described above, in some embodiments, FGC polymers can be formed using three or more polyfunctional monomers. In a typical reaction, polypropylene oxide is reacted with citric acid, mercaptosuccinic acid, and PPO-dimethacrylate by Michael addition in the presence of caffeine to form a branched FGC polymer.

[0138] In some embodiments, the structure (e.g., a fillable polymer element) is pre-filled with active substances such as therapeutic agents, diagnostic agents, and / or enhancers. In other embodiments, the structure (e.g., a fillable polymer element) is filled with therapeutic agents, diagnostic agents, and / or enhancers after it has already been retained in a location within the subject, such as the gastric cavity. In some embodiments, the structure is configured to maintain the stability of therapeutic agents, diagnostic agents, and / or enhancers in unsuitable physiological environments over extended periods (e.g., the gastric environment). In further embodiments, the structure is configured to control the release of therapeutic agents, diagnostic agents, and / or enhancers with a low to no possibility of burst release. In some embodiments, the structure (e.g., a fillable polymer element) is pre-filled and / or filled with a combination of active substances. For example, in certain embodiments, the structure contains one or more, two or more, three or more, or four or more active substances.

[0139] Therapeutic agents, diagnostic agents, and / or enhancers can be filled into polymer materials and other drug delivery materials by standard methods such as powder mixing, direct addition, solvent filling, melt filling, physical blending, supercritical carbon dioxide assistance, and conjugation reactions such as ester and amide bonding, but are not limited. The release of the therapeutic agents, diagnostic agents, and / or enhancers can then be carried out by methods such as dissolution of the fillable polymer elements containing the polymer matrix material, decomposition of the matrix material, swelling of the matrix material, diffusion of the drug, hydrolysis, and chemical or enzymatic cleavage of conjugation bonds, but are not limited. In some embodiments, the active substance is covalently bonded to the polymer matrix of the polymer elements (e.g., and released as polymer matrix degradation products).

[0140] In certain embodiments, the structure is constructed and positioned to release an active substance from one or more fillable polymer elements. In certain embodiments, the active substance is designed to be released from the fillable polymer elements. Such embodiments would be useful in the context of drug delivery. In other embodiments, the active substance is permanently immobilized on the fillable polymer elements. Such embodiments would be useful in the context of molecular recognition and purification. In certain embodiments, the active substance is embedded within the fillable polymer elements. In some embodiments, the active substance is bonded to the fillable polymer elements by the formation of bonds such as ionic bonds, covalent bonds, hydrogen bonds, and van der Waals interactions. Covalent bonds may be, for example, carbon-carbon, carbon-oxygen, oxygen-silicon, sulfur-sulfur, phosphorus-nitrogen, carbon-nitrogen, metal-oxygen, or other covalent bonds. Hydrogen bonds may be, for example, between hydroxyl, amine, carboxyl, thiol, and / or similar functional groups.

[0141] In some embodiments, the systems, structures, and methods described herein are compatible with one or more therapeutic agents, diagnostic agents, and / or enhancers, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the active substance is a therapeutic agent, a nutraceutical, a prophylactic agent, or a diagnostic agent. The active substance may be encapsulated within a polymer matrix or directly chemically bonded to one or more atoms in the polymer matrix. In certain embodiments, the active substance is covalently bonded to the polymer matrix. In some embodiments, the active substance is bonded to the polymer matrix via a carboxylic acid derivative. In some cases, the carboxylic acid derivative may form an ester bond with the active substance.

[0142] Drugs include, but are not limited to, any synthetic or naturally occurring biologically active compounds or compositions of substances that, upon administration to a subject (e.g., human or non-human animal), induce desired pharmacological, immunogenic, and / or physiological effects through local and / or systemic actions. For example, compounds or chemical substances that are conventionally considered drugs, vaccines, and biopharmaceuticals are useful, or potentially useful, in the context of a particular embodiment, and certain such drugs include, but are not limited to, proteins, peptides, hormones, nucleic acids, gene constructs, etc., for use in the fields of treatment, diagnosis, and / or enhancement, including the medical or veterinary treatment, prevention, diagnosis, and / or mitigation of diseases or illnesses (e.g., HMG co-A reductase inhibitors (statins) such as rosuvastatin, nonsteroidal anti-inflammatory drugs such as meloxicam, selective serotonin reuptake inhibitors such as escitalopram, anticoagulants such as clopidogrel (blood thinning agents). (agents), steroids such as prednisone, antipsychotics such as aripiprazole and risperidone, analgesics such as buprenorphine, antagonists such as naloxone, montelukast, and memantine, cardiac glycosides such as digoxin, alpha-blockers such as tamsulosin, cholesterol absorption inhibitors such as ezetimibe, metabolites such as colchicine, antihistamines such as loratadine and cetirizine, opioids such as loperamide, proton pump inhibitors such as omeprazole, antivirals such as entecavir, antibiotics such as doxycycline, ciprofloxacin, and azithromycin, antimalarial agents, and synthroid / levothyroxine); substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal sterilization); performance enhancement This may include molecules such as enhancements (e.g., stimulants such as caffeine), as well as nutrients and supplements (e.g., proteins, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, and other vitamin or mineral supplements).

[0143] In some embodiments, the active substance is a radiopaque material such as tungsten carbide or barium sulfate.

[0144] In certain embodiments, the active substance is one or more specific therapeutic agents. As used herein, the terms “therapeutic agent” or “drug” mean a substance that is administered to a subject to treat or prevent a disease, disorder or other clinically recognized condition, and that has a clinically meaningful effect on the subject’s body to treat and / or prevent the disease, disorder or condition. A list of known therapeutic drug examples can be found, for example, in the United States Pharmacopeia (USP), Goodman and Gilman's *The Pharmacological Basis of Therapeutics*, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) *Basic and Clinical Pharmacology*, McGraw-Hill / Appleton & Lange; 8th edition (September 21, 2000); Physician's Desk Reference (Thomson Publishing), and / or *The Merck Manual of Diagnosis and Therapy*, 17th ed. (1999) or its subsequent 18th ed. (2006), Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, *The Merck Veterinary Manual*, 9th ed., Kahn, CA (ed.), Merck Publishing Group, 2005; and the U.S. Food and Drug Administration (FDA) publication *Approved Drug Products with Therapeutics*. Equivalence and Evaluations, ("Orange Book") Examples of drugs approved for human use are listed by the FDA in 21 CFR 330.5, 331–361, and 440–460 (incorporated herein by reference); drugs for veterinary use are listed by the FDA in 21 CFR 500–589 (incorporated herein by reference). In certain embodiments, the therapeutic agent is a small molecule. Representative types of therapeutic drugs include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptic drugs, antipsychotics, neuroprotective drugs, antiproliferative agents such as anticancer drugs, antihistamines, antimigraine drugs, hormones, prostaglandins, antibacterial agents (e.g., antibiotics, antifungals, antivirals, antiparasitic drugs), antimuscarinic drugs, anxiolytics, bacteriostatic agents, immunosuppressants, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatics, cardiovascular drugs, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroids or nonsteroidal anti-inflammatory drugs, corticosteroids, dopamine agonists, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional supplements, vitamins, parasympathomimetic drugs, stimulants, appetite suppressants, and anti-narcoleptic drugs. Nutritional supplements can also be incorporated into drug delivery devices. These may be vitamins, calcium or biotin, or natural ingredients such as plant extracts or plant hormones.

[0145] In some embodiments, the therapeutic agent is one or more antimalarial drugs. Representative antimalarial drugs include quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfonamides such as sulfadoxine and sulfamethoxypyridazine, mefloquine, atobakon, primaquine, halofantrine, doxycycline, clindamycin, artemisinin, and artemisinin derivatives. In some embodiments, the antimalarial drug is artemisinin or a derivative thereof. Representative artemisinin derivatives include artemetha, dihydroartemisinin, artetel, and artesunate. In certain embodiments, the artemisinin derivative is artesunate.

[0146] Active substances containing carboxylic acid groups can be directly incorporated into polymer matrices containing ester and hydroxyl groups without requiring further modification. Active substances containing alcohols can be incorporated into polymer matrices after being first derivatized as succinic acid or fumarate monoesters. Active substances containing thiols can be incorporated into olefin or acetylene-containing matrices via sulfur-ene reactions. In other embodiments, one or more agents are bonded to the polymer matrix non-covalently (e.g., dispersed or encapsulated in the matrix).

[0147] In other embodiments, the active substance is a protein or other biomolecule. Such a substance may be covalently bonded to the polymer matrix by ester bonds using available carboxylate-containing amino acids, or incorporated into a polymer material containing an olefin or acetylene moiety using a thiol-ene type reaction. In some cases, the active substance includes an amine functional group capable of reacting with an epoxide functional group to form an amide or ester bond. In other embodiments, the active substance is bonded to the polymer matrix non-covalently. In some such embodiments, the active substance may be dispersed or encapsulated internally by hydrophilic force and / or hydrophobic force.

[0148] In some cases, the partition coefficient of the active substance in the fillable polymer element material can be adjusted. For example, if the active substance is hydrophobic, in some cases a hydrophobic polymer backbone may slow its release into the aqueous solution, while a hydrophilic polymer backbone should accelerate its release. Furthermore, in some cases, a hydrophilic polymer backbone increases the rate of water absorption into the material, causing the polymer material to expand (e.g., swell), thereby accelerating the release rate. In some embodiments, the expansion and dissolution of the material will increase under conditions that include an ionizable moiety in which the free reactive group becomes charged in the presence of an aqueous medium. In some such embodiments, as the material disintegrates due to ionic repulsion, the rate of release of contents via diffusion will increase and / or better access to cleavable bonds will be given. Those skilled in the art will be able to select a suitable method for determining the partition coefficient of the active substance, such as high-performance liquid chromatography (HPLC).

[0149] The active substance may be present in any suitable amount bound to the polymer matrix and / or in the fillable polymer elements. In some embodiments, the active substance is present in the fillable polymer elements in an amount ranging from about 0.01% to about 50% by weight relative to the total weight of the fillable polymer elements. In some embodiments, the active substance is present in the fillable polymer elements in an amount of at least about 0.01% by weight, at least about 0.05% by weight, at least about 0.1% by weight, at least about 0.5% by weight, at least about 1% by weight, at least about 2% by weight, at least about 3% by weight, at least about 5% by weight, at least about 10% by weight, at least about 20% by weight, at least about 30% by weight, and at least about 40% by weight relative to the total weight of the fillable polymer elements. In certain embodiments, the active substance is present in the fillable polymer element in amounts of about 50% by weight or less, about 40% by weight or less, about 30% by weight or less, about 20% by weight or less, about 10% by weight or less, about 5% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.5% by weight or less, about 0.1% by weight or less, or about 0.05% by weight or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 0.01% by weight to about 50% by weight). Other ranges are also possible.

[0150] Conveniently, certain embodiments of the fillable polymer elements described herein may allow for the incorporation of active substances, such as therapeutic agents, at higher concentrations (weight percent) than other polymers, such as certain conventional hydrogels. In some embodiments, the active substance (e.g., active agent) may be released from the fillable polymer element. In certain embodiments, the active substance is released from the fillable polymer element by diffusion. In some embodiments, the active substance is released by the decomposition of the fillable polymer element (e.g., biodegradation, enzymatic degradation, hydrolysis). In some embodiments, the active substance is released from the fillable polymer element at a specific rate. Those skilled in the art will understand that, in some embodiments, the release rate may depend on the solubility of the active substance in the physiological fluid to which the fillable polymer element is exposed, such as gastric juice. The scope and description relating to the release and / or release rate of the active substance typically varies depending on the hydrophilic, hydrophobic, and / or lipophilic active substances in simulated gastric juice (e.g., as defined in the United States Pharmacopeia (USP)). Simulated gastric juice is known in the art, and those skilled in the art will be able to select an appropriate simulated gastric juice based on the teachings herein.

[0151] In some embodiments, 0.05% to 99% by weight of the active substance initially contained in the fillable polymer element is released over a period of 24 hours to 1 year (e.g., in vivo). In some embodiments, about 0.05% to about 99.0% by weight of the active substance is released from the fillable polymer element after a certain period of time (e.g., in vivo). In some embodiments, at least about 0.05% by weight, at least about 0.1% by weight, at least about 0.5% by weight, at least about 1% by weight, at least about 5% by weight, at least about 10% by weight, at least about 20% by weight, at least about 50% by weight, at least about 75% by weight, at least about 90% by weight, at least about 95% by weight, or at least about 98% by weight of the active substance bound to the fillable polymer element is released from that element within about 24 hours, 36 hours, 72 hours, 96 hours, or 192 hours (e.g., in vivo). In a particular embodiment, at least about 0.05% by weight, at least about 0.1% by weight, at least about 0.5% by weight, at least about 1% by weight, at least about 5% by weight, at least about 10% by weight, at least about 20% by weight, at least about 50% by weight, at least An active substance bound to polymer elements in an amount of approximately 75% by weight, at least approximately 90% by weight, at least approximately 95% by weight, or at least approximately 98% by weight is released from those elements within 1 day, 5 days, 30 days, 60 days, 120 days, or 365 days (e.g., in vivo). For example, in some cases, an active substance bound to polymer elements in an amount of at least approximately 90% by weight is released from those elements within 120 days (e.g., in vivo).

[0152] In some embodiments, the active substance is released from the fillable polymer material at a specific initial mean rate ("initial velocity") determined by the initial 24-hour release (e.g., release of the active substance at a desired location inside the test material, such as an internal cavity). In certain embodiments, the active substance is released over a 24-hour period following the initial 24-hour release at an average rate of at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, or at least about 98% of the initial mean rate. In some embodiments, the active substance is released at an average rate of about 99% or less, about 98% or less, about 95% or less, about 90% or less, about 80% or less, about 75% or less, about 50% or less, about % or less, about 30% or less, about 20% or less, about 10% or less, about 5% or less, or about 2% or less of the initial average rate over a 24-hour period following the initial 24-hour release. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 1% to about 99%, about 1% to about 98%, about 2% to about 95%, about 10% to about 30%, about 20% to about 50%, about 30% to about 80%, about 50% to about 99%). Other ranges are also possible.

[0153] The active substance may be released at an average velocity of approximately 1% to approximately 99% of the initial velocity over at least one selected consecutive 24-hour period from 48 hours to approximately 1 year (e.g., 48 hours to 1 week, 3 days to 1 month, 1 week to 1 month, 1 month to 6 months, 3 months to 1 year, 6 months to 2 years) after the initial release.

[0154] For example, in some cases, the active substance may be released on the second day, third day, fourth day, fifth day, sixth day, and / or seventh day of release at a rate of approximately 1% to approximately 99% of the initial velocity.

[0155] In certain embodiments, burst release of active material from the fillable polymer element is typically avoided. In exemplary embodiments, at least about 0.05 wt% of the active material is released from the fillable polymer element within 24 hours, about 0.05 wt% to about 99 wt% is released during day 1 of release (e.g., at internal locations within the test), and a further about 0.05 wt% to about 99 wt% is released during day 2 of release. Those skilled in the art will understand that, depending on the properties of the fillable polymer element and / or the active material, similar amounts of the active material may be further released on day 3, day 4, day 5, etc.

[0156] In certain embodiments, the active substance may be released in a pulsed release profile. For example, in some embodiments, the active substance is released on the first day after administration and during another 24-hour period, such as starting on the third, fourth, or fifth day, but substantially not on other days. Those skilled in the art will understand that other days and / or combinations of pulsed and continuous release are also possible.

[0157] The active substance is released at a relatively constant average rate (e.g., substantially zero-order mean release rate) for at least about 24 hours. In certain embodiments, the active substance is released at a primary release rate (e.g., the release rate of the active substance is usually proportional to the concentration of the active substance) for at least about 24 hours.

[0158] In some embodiments, at least a portion of the active material packed into the structure is released continuously (e.g., at varying rates) over the residence period of the structure. The residence period is described in more detail below.

[0159] As described above, in some embodiments, one or more polymer elements are bonded together via one or more linkers. Those skilled in the art will understand that the term, bond, usually means a physical bond (e.g., one that can be made by physical and / or chemical bonding forces) linking two or more elements. In some embodiments, a first (elastic) polymer element may be bonded to a second (fillable) polymer element via an adhesive, by chemical interactions, and / or by interpenetrating (e.g., entangled) polymer chains. For example, in some embodiments, the polymer backbone of the first polymer element and the polymer backbone of the second polymer element are bonded via bonds such as ionic bonds, covalent bonds, hydrogen bonds, and van der Waals interactions. Covalent bonds may be, for example, carbon-carbon, carbon-oxygen, oxygen-silicon, sulfur-sulfur, phosphorus-nitrogen, carbon-nitrogen, metal-oxygen, or other covalent bonds. Hydrogen bonds may be, for example, between hydroxyl, amine, carboxyl, thiol, and / or similar functional groups.

[0160] In certain embodiments, the elastic polymer elements and the fillable polymer elements are bonded together via an adhesive (e.g., a biocompatible adhesive). Non-limiting examples of suitable adhesives include biocompatible polyurethanes, cyanoacrylates, and the like.

[0161] In some embodiments, the polymer material of the elastic polymer element and the polymer material of the fillable polymer element may be interpenetrated and / or entangled so that the elastic polymer element and the fillable polymer element are bonded together.

[0162] In some embodiments, elastic polymer elements and fillable polymer elements are linked via linkers. In some embodiments, the structure is configured to decompose, dissolve, and / or dissociate into one or more forms configured to pass through the gastrointestinal tract. In some embodiments, the structure includes one or more linkers designed to control and / or regulate decomposition. In some embodiments, one or more linkers are linked to and / or incorporated into the structure, modularly separating the function of delivering therapeutic agents, diagnostic agents, and / or enhancers from the control (e.g., induction) and / or regulation of decomposition. Referring again to Figures 1B-1C, the first polymer element 110 and the second polymer element 120 are linked via linker 130. In certain embodiments, two or more elastic polymer elements are linked together via linkers. In some embodiments, two or more fillable polymer elements are linked together via linkers. In some embodiments, the linkers are embedded within the polymer elements. For example, in certain embodiments, the linkers are embedded within the elastic polymer elements. In some cases, the linker may be embedded within the fillable polymer element. In some such embodiments, the linker may decompose over a desired period of time and / or under desired conditions, causing the elastic polymer element or fillable polymer element to break apart.

[0163] The structure may include one or more, two or more, or three or more types of linkers. For example, in an exemplary embodiment, the structure includes a first linker configured to decompose at a first average decomposition rate and a second linker configured to decompose at a second average decomposition rate under the same conditions. In a particular embodiment, the decomposition of the linkers is pH-dependent. In another exemplary embodiment, the structure includes a first linker configured to decompose under a first set of physiological conditions (e.g., (1) in an acidic pH such as in the stomach, or (2) alternatively, in a relatively neutral pH such as in the intestines, etc.), and a first set The invention includes a second linker configured to decompose under a second set of physiological conditions different from the physiological conditions of the first set (e.g., (1) in a relatively neutral pH such as in the intestines, or (2) alternatively, in an acidic pH such as in the stomach). In some embodiments, the second linker is configured not to decompose substantially under the conditions of the first set, thereby enabling selective and partial decomposition of the structure under selective conditions and / or at selective locations within the subject (e.g., different locations along the gastrointestinal tract (GItrack)). For example, in some cases, the second linker is configured not to decompose substantially under the first physiological conditions (e.g., in an acidic pH such as in the stomach) but to decompose under second physiological conditions different from the physiological conditions of the first set.

[0164] The term “physiological conditions” typically refers to a set of external or internal environmental conditions present in a living organism or cell system (e.g., as opposed to laboratory conditions). For example, in some cases, physiological conditions are a temperature range of about 20°C to about 40°C (e.g., about 35°C to about 38°C) and / or atmospheric pressure of about 1 atmosphere. In certain embodiments, physiological conditions are the conditions of internal organs such as the stomach, intestines, bladder, lungs, and / or heart. After a certain residence period, the linker may be selected to dissolve, decompose, mechanically weaken, and / or mechanically separate at least one of one or more polymer elements. The term “residence period” typically means the length of time that a structure (or element of a structure) described herein is present in the internal location of a subject, measured from the time it is first present in the internal location of the subject (structurefrom) to the time that the structure (or element of a structure referred to) is no longer present in the internal location of the subject due to, for example, the breakdown, dissolution, and / or elimination of the structure or element(s) of the structure referred to from the internal location of the subject. In exemplary embodiments, the structure may be administered orally such that the structure is present in an internal location of the subject, such as the stomach above the pylorus, and is eliminated through the pylorus into the intestines (for example, after breakdown of at least a portion of the structure), in which case the residence period is measured as the length of time between when the structure is first present in the stomach and when the structure (or element of a structure referred to) is eliminated through the pylorus.

[0165] In some embodiments, the residence period of at least part of the structure is at least about 24 hours, at least about 48 hours, at least about 3 days, 7 days, at least about 1 month, at least about 6 months, or at least about 1 year. In certain embodiments, the residence period is about 2 years or less, about 1 year or less, about 6 months or less, about 1 month or less, about 7 days or less, about 3 days or less, or about 48 hours or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 24 hours to about 2 years, about 24 hours to about 1 year, about 48 hours to about 7 days, about 3 days to about 1 month, about 7 days to about 6 months, about 1 month to about 1 year). Other ranges are also possible. The linker is preferably biocompatible.

[0166] In typical embodiments, one or more linkers are selected, for example, to mediate the disintegration of the structure after delivery of the active substance over a desired residence period (e.g., within 24 hours, 48 ​​hours, 1 week, 1 month) and to facilitate safe passage through the lower intestinal tract of the subject. Discharge through an opening such as the gastric cavity may be achieved through a change in the mechanical properties of the linker (e.g., via biodegradation) such that the structure's ability to resist passage through the opening (e.g., through the pylorus) is impaired by the destruction of the structure, such as by designed linker rupture.

[0167] Suitable materials for use as linkers are determined by several selection tests, including, but not limited to, the ability to bond (e.g., bind) at least one or more of the polymer elements of a structure, possessing sufficient mechanical strength to withstand encapsulation, possessing sufficient mechanical strength to withstand compressive forces present in physiological environments such as the gastric environment, and / or selective degradation under desired time and / or conditions (e.g., pH). This may be done. In some embodiments, the linker is stable in a physiological environment such as the gastric environment for a certain period of time (e.g., residence period) of at least about 24 hours, at least about 48 hours, at least about 1 week, at least about 1 month, or at least about 1 year.

[0168] In certain embodiments, the linker comprises a material such that, under relatively neutral pH physiological conditions (e.g., conditions in the duodenum), the linker can undergo mechanical fracture (i.e., mechanical breakage) within about 48 hours or within about 24 hours under said neutral pH physiological conditions by a tensile force of about 2 N or less. In some embodiments, the mechanical breakage occurs within the linker material itself and not at the interface between the linker and one or more polymer elements.

[0169] Non-limiting examples of suitable linker materials include, but are not limited to, polyesters such as polycaprolactone, poly(propylene fumarate), poly(glycerol sebacate), poly(lactide), poly(glycolic acid), poly(lactic acid-glycolic acid), polybutyrate, and polyhydroxyalkanoates; but are not limited to, polyethers such as poly(ethylene oxide) and poly(propylene oxide); but are not limited to, polyamides such as poly(caprolactam); polyvinyl alcohol; polyoxetane; but are not limited to, polyacrylates / methacrylates such as poly(methyl methacrylate) and poly(ethylene-co-vinyl acetate); polyanhydrides; and polyurethanes.

[0170] In certain embodiments, the linker comprises ethyl acrylate, methyl methacrylate, and / or a low-content methacrylate ester having a quaternary ammonium group. In some embodiments, the linker comprises a water-soluble polymer such as vinylpyrrolidone-vinyl acetate copolymer (e.g., KOLLIDON® VA 64 (BASF) and KOLLIDON® SR), polyvinylpyrrolidone, cellulose acetate, hydroxypropyl methylcellulose, or polyvinyl alcohol.

[0171] In some embodiments, the linker comprises a polymer blend. In a typical embodiment, the linker comprises an isocyanate-crosslinked polyurethane produced from a low molecular weight polycaprolactone monomer.

[0172] In certain embodiments, the linker comprises an enteric polymer. In some embodiments, the linker comprises an enteric elastomer. Enteric polymers and enteric elastomers are described in further detail below.

[0173] In some embodiments, the linker and / or elastic polymer elements include enteric polymers. The term “enteric” is typically used to describe materials that are stable under relatively highly acidic pH conditions (e.g., pH less than about 5.5) and susceptible to dissolution under relatively alkaline pH conditions (e.g., pH about 6 to about 9). In some embodiments, enteric polymers include, but are not limited to, cellulose phthalate acetate (CAP), hypromellose (INN) hydroxypropyl methylcellulose (HPMC), and / or poly(ethyl methacrylate-co-acrylate) (e.g., Eudragit®, available from Evonik Industries AG (Essen, Germany)).

[0174] In some embodiments, the dissolution of the enteric-coated polymer can be induced, for example, by the ingestion of an alkaline solution. In some embodiments, the enteric-coated polymer has the ability to dissolve at pH 4 to 8. In some embodiments, the enteric-coated polymer is stable in the acidic gastric environment (i.e., pH 1 to pH 4), but dissolves in the more alkaline region of the gastrointestinal tract distal to the pylorus (i.e., in the pH region greater than 5.5) and functions as a linker. Selected to enable it.

[0175] For example, in certain embodiments, the enteric polymer does not substantially decompose in a pH range of about 1 to about 5. In some embodiments, the enteric polymer does not substantially decompose at pH levels of at least about 1, at least about 2, at least about 3, at least about 4, or at least about 4.5. In certain embodiments, the enteric polymer does not substantially decompose at pH levels of about 5 or less, about 4.5 or less, about 4 or less, about 3 or less, or about 2 or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 1 to about 4.5, about 1 to about 5, about 1 to about 4). Other ranges are also possible.

[0176] In certain embodiments, enteric-coated polymers substantially decompose in a pH range of about 4 to about 8. In some embodiments, enteric-coated polymers substantially decompose at pH levels of at least about 4, at least about 5, at least about 6, at least about 6.5, at least about 7, or at least about 7.5. In certain embodiments, enteric-coated polymers substantially decompose at pH levels of about 8 or less, about 7.5 or less, about 7 or less, about 6.5 or less, about 6 or less, or about 5 or less. Any and all closed intervals having endpoints within any of the above reference ranges are also possible (e.g., about 4 to about 8, about 5 to about 8, about 6.5 to about 7.5). Other ranges are also possible.

[0177] Those skilled in the art will be able to select a preferred method for determining the degradation of an enteric polymer based on the teachings herein, which includes determining the solubility of the enteric polymer in an aqueous solution having a pH of less than about 3 by measuring at body temperature (e.g., about 35°C to about 38°C) over a period of about 2 to 40 days, and / or dissolving the enteric polymer in an aqueous solution having a pH of about 6 or higher. In some embodiments, substantially non-degradable enteric polymers behave such that less than about 10%, less than about 5%, or less than 2% of the enteric polymer dissociates from the remaining enteric polymer. In certain embodiments, substantially degradable enteric polymers behave such that at least about 1%, at least about 2%, or at least about 5% of the enteric polymer dissociates from the remaining polymer composite.

[0178] In some embodiments, the structure is configured to maintain safety with a low or no possibility of intestinal obstruction and / or perforation. Controlled disintegration is important in some cases to reduce the risk of gastrointestinal obstruction. In some embodiments, the linker is designed to dissolve distal to the pylorus. In some embodiments, the linker is bound to and / or incorporated into the structure, and upon disintegration / dissolution of the linker, the structure breaks into smaller structures configured to pass through the gastrointestinal tract without obstruction (e.g., across the ileocecal valve). In exemplary embodiments, the linker is substantially undissolved and / or undisintegrated when located in the stomach of the subject (e.g., with a pH in the range of about 1 to about 5), and substantially dissolves when located in the intestines (e.g., with a pH in the range of about 6.7 to about 7.4) (e.g., after passing through the pylorus).

[0179] In some embodiments, the enteric polymer is an enteric elastomer. For example, in some embodiments, the linker includes a material selected to have both enteric and elastic properties. For example, in some embodiments, the linker includes an enteric elastomer that has an elastic modulus of about 0.1 MPa to about 100 MPa under relatively highly acidic pH conditions (e.g., pH less than about 5.5) and is susceptible to dissolution under relatively alkaline pH conditions.

[0180] In certain embodiments, at least one dimension of the enteric elastomer exhibits reversible elongation when the dimension is deformed from its initial length to less than about 50% of its initial length, and / or when the dimension is deformed from its initial length to at least about 1500% of its initial length. That is, in some embodiments, the enteric elastomer exhibits reversible elongation of about 10 The difference in average length after deformation compared to before deformation (e.g., elongation) is less than %, less than about 5%, less than about 2%, or less than about 1%. For example, in some embodiments, an enteric elastomer may exhibit reversible elongation when stretched by at least about 50%, at least about 100%, at least about 200%, at least about 400%, at least about 500%, at least about 1000%, at least about 1200%, or at least about 1400% of its initial length. In certain embodiments, an enteric elastomer may exhibit reversible elongation when stretched by about 1500% or less, about 1400% or less, about 1200% or less, about 1000% or less, about 500% or less, about 400% or less, about 200% or less, or about 100% or less of its initial length. Any and all closed intervals having their endpoints within any of the above reference ranges are also possible (e.g., approximately 50% to approximately 1500%, approximately 100% to approximately 1500%, approximately 200% to approximately 1000%, approximately 500% to approximately 1400%). Other ranges are also possible.

[0181] In certain embodiments, the enteric-coated elastomer has an elastic modulus in the range of about 0.1 MPa to about 100 MPa. In some embodiments, the elastic modulus of the enteric-coated elastomer is at least about 0.1 MPa, at least about 0.2 MPa, at least about 0.3 MPa, at least about 0.5 MPa, at least about 1 MPa, at least about 2 MPa, at least about 5 MPa, at least about 10 MPa, at least about 25 MPa, or at least about 50 MPa. In certain embodiments, the elastic modulus of the enteric-coated elastomer is about 100 MPa or less, about 50 MPa or less, about 25 MPa or less, about 10 MPa or less, about 5 MPa or less, about 2 MPa or less, about 1 MPa or less, about 0.5 MPa or less, about 0.3 MPa or less, or about 0.2 MPa or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 0.1 MPa to about 100 MPa, about 0.3 MPa to about 10 MPa). Other ranges are also possible. Those skilled in the art will be able to select a suitable method for determining the elastic modulus of an enteric elastomer, for example, including tensile mechanical characterization according to ASTM D638 and / or compression mechanical characterization according to ASTM D575.

[0182] In certain embodiments, the enteric elastomer comprises a polymer mixture of poly(acryloyl-6-aminocaproic acid) and poly(methacrylate-co-ethyl acrylate) in various ratios.

[0183] In some embodiments, the enteric elastomer comprises a polymer of acryloylaminoalkylene acid monomer or a salt thereof. In some embodiments, the enteric elastomer comprises acryloylaminoalkylene acid monomer, a polymer of (meth)acryloylaminoalkylene acid monomer, or a salt thereof. In certain embodiments, the acryloylaminoalkylene acid monomer is selected from the group consisting of acryloyl-5-aminopentanoic acid, acryloyl-6-aminocaproic acid, acryloyl-7-aminoheptanoic acid, acryloyl-8-aminooctanoic acid, acryloyl-9-aminononanoic acid, acryloyl-10-aminodecanoic acid, acryloyl-11-aminoundecanoic acid, acryloyl-12-aminododecanoic acid, methacryloyl-5-aminopentanoic acid, methacryloyl-6-aminocaproic acid, methacryloyl-7-aminoheptanoic acid, methacryloyl-8-aminooctanoic acid, methacryloyl-9-aminononanoic acid, methacryloyl-10-aminodecanoic acid, methacryloyl-11-aminoundecanoic acid, methacryloyl-12-aminododecanoic acid, salts thereof, and combinations thereof.

[0184] In certain embodiments, the enteric elastomer comprises a homopolymer of acryloyl-6-aminocaproic acid or a salt thereof. In some embodiments, the enteric elastomer comprises a copolymer of acryloyl-6-aminocaproic acid or a salt thereof. In certain embodiments, the enteric elastomer comprises poly(methacrylate-co-ethyl acrylate) or a salt thereof. In some cases, poly(methacrylate-co-ethyl acrylate) has a molar ratio of approximately 1:1 methacrylate monomer units to ethyl acrylate monomer units. To possess.

[0185] In some embodiments, the enteric elastomer is a blend. For example, in certain embodiments, the enteric elastomer comprises a first enteric polymer (e.g., poly(acryloyl-6-aminocaproic acid)) and a second enteric polymer (e.g., poly(methacrylate-co-ethyl acrylate)). In some such embodiments, the weight ratio of the first polymer to the second polymer is in the range of about 1:6 to about 6:1. In certain embodiments, the weight ratio of the first polymer to the second polymer is at least about 1:6, at least about 1:5, at least about 1:4, at least about 1:3, at least about 1:2, at least about 1:1, at least about 2:1, at least about 3:1, at least about 4:1, or at least about 5:1. In some embodiments, the weight ratio of the first polymer to the second polymer is approximately 6:1 or less, approximately 5:1 or less, approximately 4:1 or less, 3:1, approximately 2:1 or less, approximately 1:1 or less, approximately 1:2 or less, approximately 1:3 or less, approximately 1:4 or less, or approximately 1:5 or less. Combinations of the above reference ranges are also possible (e.g., approximately 1:6 to approximately 6:1, approximately 1:4 to approximately 4:1, approximately 1:3 to approximately 3:1, approximately 1:2 to approximately 2:1, approximately 1:3 to approximately 1:1, approximately 1:1 to approximately 3:1). Other ranges are also possible.

[0186] In some embodiments, the enteric elastomer is a polymer gel with a water content of 40% or less. For example, in some embodiments, the enteric elastomer has a water content of about 40% by weight or less, about 30% by weight or less, about 20% by weight or less, or about 10% by weight or less. In some embodiments, the enteric elastomer has a water content of more than about 5% by weight, more than about 10% by weight, more than about 20% by weight, or more than about 30% by weight. Combinations of the above reference ranges are also possible (e.g., about 5% by weight to about 40% by weight).

[0187] Enteric-coated elastomers can be used as material platforms. In some embodiments, these material platforms feature tunable elastomer properties, are stable in acidic environments, and / or soluble in more alkaline environments. Thus, enteric-coated elastomer material platforms are suitable for the acidic gastric environment and have the ability for targeted dissolution in the small intestine / colon environment. In some embodiments, but not limited to, enteric-coated elastomer material platforms are useful for many applications, such as the fabrication of gastrointestinal tract structures and gastrointestinal tract-specific drug delivery by targeted release across the pylorus.

[0188] For example, one or more enteric-coated elastomer linkers bound to and / or incorporated into structures in the gastric lumen can mitigate the risks arising from the accidental passage of macrostructures that could induce obstruction and / or perforation, as the rapid dissolution of one or more linkers during passage through the pylorus causes the macrostructures to shrink to smaller, pre-connected portions.

[0189] Structures bound to enteric-coated elastomers can be subjected to dissolution in the presence of an alkaline environment. Therefore, in some embodiments, in the case of gastric structures present in vivo and containing enteric-coated elastomers, passage of the structure can be induced when the subject ingests an alkaline solution (e.g., sodium bicarbonate) to cause dissolution of the enteric-coated elastomer, thereby enabling the breakdown of the structure.

[0190] In some embodiments, the enteric-coated elastomer linker is substantially flexible. This flexibility allows the structure to be packed and / or folded to fit into sealed / predefined containers, such as capsules for oral administration or catheters for endoscopic placement, as described herein. In some embodiments, the enteric-coated elastomer has flexibility up to 180 degrees and is dense and / or maximum Allows for packing and / or folding (for example, for use as the elastic polymer element described above).

[0191] In some embodiments, a structure (e.g., including one or more polymer elements) includes one or more configurations. For example, in certain embodiments, a structure has certain configurations such as defined shape, size, orientation, and / or volume. A structure may include any preferred configuration. In some embodiments, a structure has a certain shape defined by the cross-sectional area of ​​the structure. Non-limiting examples of preferred cross-sectional shapes include square, circular, elliptical, polygonal (e.g., pentagon, hexagon, heptagon, octagon, nonagon, dodecagon, etc.), tube, ring, star or star-shaped (e.g., 3-armed star, 4-armed star, 5-armed star, 6-armed star, 7-armed star, 8-armed star), and so on. Those skilled in the art will be able to select a preferred shape depending on the application (e.g., star shape for gastric retention structures) and based on the teachings herein.

[0192] In some cases, the structure has an initial configuration, which may be modified (e.g., deformed) to obtain a new configuration different from the initial configuration. For example, in some embodiments, the structure has a first configuration and a second configuration that differs from the first configuration when compressed, for example.

[0193] In certain embodiments, the configuration of the structure may be characterized by its maximum cross-sectional dimension. In some embodiments, the maximum cross-sectional dimension of the first configuration may be at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% smaller than the maximum cross-sectional dimension of the second configuration. In certain embodiments, the maximum cross-sectional dimension of the second configuration may be at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% smaller than the maximum cross-sectional dimension of the first configuration. Any and all closed intervals having their endpoints within any of the above reference ranges are also possible (e.g., about 10% to about 80%, about 10% to about 40%, about 20% to about 60%, about 40% to about 80%). Other ranges are also possible.

[0194] In some embodiments, the structure configuration may be characterized by the convex hull volume of the structure. The term “convex hull volume” is known in the art and usually refers to a set of surfaces defined by the periphery of a 3-D object, which define a particular volume. For example, as shown in Figure 1D, a 3D star-shaped object 150 has a convex hull volume defined by a convex hull 160. In some embodiments, the convex hull volume of a first configuration may be at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% smaller than the convex hull volume of a second configuration. In particular embodiments, the convex hull volume of a second configuration may be at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% smaller than the convex hull volume of the first configuration. Any and all closed intervals having their endpoints within any of the above reference ranges are also possible (e.g., approximately 10% to approximately 80%, approximately 10% to approximately 40%, approximately 20% to approximately 60%, approximately 40% to approximately 80%). Other ranges are also possible.

[0195] Those skilled in the art will understand that the difference between the first and second configurations does not refer to swelling or shrinking of the structure (in the presence of a solvent), but rather to a change in the shape and / or orientation of at least some part of the structure (in the presence of stimuli such as heat and / or mechanical pressure / compression), although some swelling or shrinking will occur between the two configurations.

[0196] In some embodiments, a first configuration is constructed and positioned so that the structure is held in place within the subject, and a second configuration is constructed and positioned so that the structure can be encapsulated (for example, for oral delivery of the structure in a capsule). In some cases, the first configuration is large enough so that the structure is held in place within the subject, and the second configuration is small enough so that the structure fits within a capsule of a particular size suitable for oral delivery to the subject.

[0197] In certain embodiments, the structure may be polymerized and / or cast into a first configuration, mechanically deformed to become a second configuration, and placed within a capsule or constrained by several other containment structures. The structure may be mechanically deformed using any preferred method, such as bending, twisting, folding, molding (e.g., compressing material into a mold of a new shape), expanding (e.g., applying tensile force to material), compression, and / or wrinkling. The structure may maintain the second configuration for any preferred period prior to stimulation / release. Conveniently, certain embodiments of the structure described herein may be relatively stable in the first and / or second configurations so that the structure can be stored for extended periods without significant degradation of the mechanical properties of one or more elements and / or one or more linkers. In some embodiments, the structure may be stable under ambient conditions (e.g., room temperature, atmospheric pressure, and relative humidity) and / or physiological conditions (e.g., in a physiological fluid at 37°C or about 37°C) for at least about 1 day, at least about 3 days, at least about 7 days, at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 6 months, at least about 1 year, or at least about 2 years. In certain embodiments, the structure may have a shelf life of about 3 years or less, about 2 years or less, about 1 year or less, about 1 month or less, about 1 week or less, or about 3 days or less. Any and all closed intervals having an endpoint within any of the above reference ranges are also possible (e.g., about 24 hours to about 3 years, about 1 week to 1 year, about 1 year to 3 years). Other ranges are also possible.

[0198] In some embodiments, the structure of the second configuration may bounce back to the first configuration. For example, in some embodiments, the structure of the second configuration is contained in a capsule and delivered orally to a subject. In some such embodiments, the structure travels to the stomach, and the capsule is capable of releasing the structure from the capsule, in which case the structure obtains the first configuration (e.g., bounces back to the first configuration).

[0199] As described herein, in some embodiments, the structure may include one or more linkers and / or one or more elements (e.g., elastic polymer elements) having certain mechanical properties so that the structure substantially springs back after being mechanically deformed. In some cases, the structure may be characterized by a folding force. The term “folding force” usually refers to the force required to compress the structure into a cavity (e.g., a pylorus) having a cross-sectional area of ​​less than about 2 cm. In some embodiments, the folding force of the structure is at least about 0.2 N, at least about 0.5 N, at least about 0.7 N, at least about 1 N, at least about 1.5 N, at least about 2 N, at least about 2.5 N, or at least about 3 N. In certain embodiments, the folding force of the structure is about 5 N or less, about 3 N or less, about 2.5 N or less, about 2 N or less, about 1.5 N or less, about 1 N or less, about 0.7 N or less, or about 0.5 N or less. Any and all closed intervals having their endpoints within any of the above reference ranges are also possible (e.g., approximately 0.2N to approximately 3N, approximately 0.2N to approximately 2.5N, approximately 0.5N to approximately 1.5N, approximately 1N to approximately 3N). Other ranges are also possible. The folding force may be determined, for example, by placing the structure in a funnel (shown in Figure 13A) having an upper diameter of 20 cm and a lower diameter of 2 cm (e.g., to simulate the pyloric sphincter) and measuring the force required to move the structure through the 2 cm lower diameter. The plunger is attached to the tensile crosshead of a tensile load testing machine, and the funnel is attached to a clamp, and the structure is moved through the funnel. For example, the force and displacement are measured by pushing at a speed of 10 mm / min. The folding force is usually determined by measuring the force required for the structure to fold and enter a tube with a lower diameter of 2 cm.

[0200] In certain embodiments, the structure in the first configuration has incompressible cross-sectional dimensions. Incompressible cross-sectional dimensions are typically selected so that the structure remains in a position inside the subject for a relatively long period (e.g., at least about 24 hours) even under physiological compressive forces (e.g., compressive forces in the digestive tract).

[0201] In some embodiments, the incompressible cross-sectional dimensions of the first configuration are at least about 2 cm, at least about 4 cm, at least about 5 cm, or at least about 10 cm. In certain embodiments, the incompressible cross-sectional dimensions of the first configuration are about 15 cm or less, about 10 cm or less, about 5 cm or less, or about 4 cm or less. Any and all closed sections having an endpoint within any of the above reference ranges are also possible (e.g., about 2 cm to about 15 cm). Those skilled in the art will be able to select a suitable incompressible cross-sectional dimension of the structure such that the structure is held, based on the teachings herein for a particular opening in the subject.

[0202] As described herein, in some embodiments, one or more polymer elements of a structure may be cast, molded, and / or cut to have a particular shape, size, and / or volume. For example, in a typical embodiment, one or more elastic polymer elements, one or more fillable polymer elements, and / or one or more linkers are independently polymerized into a sheet and cut into the desired shape and / or size. The cut elements and linkers may then be assembled (e.g., in a mold) and processed so that one or more elements and linkers are bonded together. In certain embodiments, one or more elastic polymer elements, one or more fillable polymer elements, and / or one or more linkers are independently polymerized in a mold of the desired shape. In some embodiments, one or more elements and / or linkers are bonded together with an adhesive. In certain embodiments, one or more elements and / or linkers are heated so that one or more elements and / or linkers are bonded together (e.g., via bonding and / or entanglement) as described herein.

[0203] In typical embodiments, the shape configured for retention, such as gastric retention, includes a three-dimensional elliptic ring structure (i.e., an elliptical contour when projected onto a plane). In some embodiments, the elliptic ring structure has a minor axis diameter comparable to the major axis of the capsule. In some embodiments, the elliptic ring structure includes a fillable polymer element, as well as one or more linkers configured to be bonded to and / or incorporated into the elliptic ring structure and to decompose in a controlled manner. In some embodiments, one or more linkers are incorporated into the elliptic ring structure at one or more points along the minor axis. In further embodiments, one or more controlled decomposition linkers are incorporated into the elliptic ring structure at one or more points along the major axis. In some embodiments, the elliptic ring structure may be twisted into a shape similar to a double helix for packing into a soluble container and / or for bonding with a retaining element. In some embodiments, the elliptic ring structure is twisted such that the axis of the helix is ​​aligned with the minor axis of the elliptic ring structure to avoid bending the helix for packing into the soluble container.

[0204] In some embodiments, shapes configured for retention such as gastric retention (e.g., held in an opening at a specific internal location of the subject) include a three-dimensional structure having multiple projections (i.e., arms). In some embodiments, the structure having projections includes a flexible material configured for elastic (non-plastic) deformation. The projections themselves may be flexible, or The structure may be rigid, having flexible links to the core. In some embodiments, one or more controlled decomposition linkers (e.g., enteric elastomers) are bonded to and / or incorporated into the structure, for example, along one or more protrusions near the core or links to the core. In some embodiments, each protrusion is slightly shorter than the length of the soluble container, such that the final unencapsulated form has a diameter equal to approximately twice the length of the soluble container. In some embodiments, each protrusion may have a length of about 0.5 cm to about 2.5 cm (e.g., such that the structure has an incompressible cross-sectional dimension of at least about 2 cm).

[0205] In certain embodiments, the projections are arranged based on a bio-inspired flower bud design in which (N) radial spokes or petals protrude from a central connecting core. In some embodiments, each of these radial projections has an inner sector angle of approximately 360° / N, where N is the total number of radial projections. In some cases, this increases the packing volume of the encapsulated structure and therefore enhances the drug delivery capacity. In some embodiments, as described herein, the projections are formed from a material having a relatively high modulus of elasticity to increase resistance to compression and gastric retention time.

[0206] In some embodiments, one or more linkers are joined to and / or incorporated into the structure. For example, as shown in Figure 1E, structure 102 includes a first configuration comprising a six-arm star shape. Although a six-arm star shape is shown here, those skilled in the art will understand that Figure 1E is not limiting, and that structures may have three, four, five, six, seven, eight, nine, ten, or more arms, each of which may vary in length and number of elements and / or linkers, as described herein.

[0207] The structure 102 includes elastic polymer elements 110 bonded to fillable polymer elements 120. For example, the fillable polymer elements 120 may be bonded to the elastic polymer elements 110 via an optional first linker 130. In certain embodiments, the elastic polymer elements 110 include an enteric elastomer. Additional fillable polymer elements 120 may be bonded together via an optional second linker 135, distinct from the optional linker 130. The number and / or positions of the linkers may be selected as part of a specific design parameter (e.g., so that the structure has a specific decomposition property and / or configuration). The positions of the linkers may also vary. For example, linkers may be embedded within one or more fillable polymer elements 120, as shown by an optional linker 134 (dotted line).

[0208] Structure 102 may be folded into a second configuration, as shown in Figure 1F, thereby encapsulating the structure. Those skilled in the art will understand that Figure 1F is not limiting, and that the structure shown in Figure 1E may be folded into a different configuration.

[0209] In some embodiments, the shape configured for retention, such as gastric retention (e.g., held in an opening at a specific internal location of the subject), includes a three-dimensional structure that, when projected onto a plane, forms a polygonal contour having, for example, 3, 4, 6, 8, 10, 12, 14, 16, 18, or 20 sides. In some embodiments, each side has a length slightly shorter than the length of the soluble container. In some embodiments, the structure includes a flexible material configured for elastic (non-plastic) deformation, and the structure is configured to bend at its vertices and pack into the soluble container. A material configured for large elastic deformation with a low modulus of elasticity, low creep deformation, and / or good rebound may be used at the vertices to facilitate stable packing. In some embodiments, each individual side has an inner sector angle of about 360° / N, where N is the total number of sides to obtain maximum packing.

[0210] In some embodiments, one or more linkers are bonded to and / or incorporated into the structure. In certain embodiments, flexible linkers configured for high elastic deformation and controlled decomposition (e.g., including enteric elastomers) are positioned at each vertex between the sides of the polygon.

[0211] For example, as shown in Figure 1G, the structure 104 includes a first configuration that includes a hexagon. Here, a hexagonal shape is shown, but those skilled in the art will understand that Figure 1G is not limiting, and that the structure may have 4, 6, 8, 10, 12, or more sides, as described herein, each of which may vary in length and number of elements and / or linkers.

[0212] The structure 104 includes an elastic polymer element 110 bonded to a fillable polymer element 120. For example, the elastic polymer element 110 and the fillable polymer element 120 may be bonded to the elastic polymer element 110 via any linker 130 or any linker 135 different from any linker 130. In some embodiments, the elastic polymer element 110 includes an enteric elastomer. The number and / or position of the linkers may be selected as part of a specific design parameter (e.g., so that the structure has a specific degradation property and / or configuration). The position of the linkers may also vary. For example, the linkers may be embedded within one or more fillable polymer elements 120, as shown by an arbitrary linker 134 (dotted line).

[0213] Structure 104 may be folded into a second configuration for encapsulation, as shown in Figure 1H. Those skilled in the art will understand that Figure 1H is not limiting, and that the structure shown in Figure 1G may also be folded into a different configuration.

[0214] In a typical embodiment, the linkers (optional linker 130) bonded to the elastic polymer element and the fillable polymer element may be time-dependently degradable linkers (e.g., such that arms of the structure detach after a certain period of time). In a particular embodiment, the linkers (optional linkers 135 and 134) bonded to and / or embedded together with the fillable polymer element may contain an enteric polymer so that the fillable polymer element is cleaved when exposed to a pH greater than about 5. For example, the structure shown in Figures 1E-1H may be delivered to a subject (e.g., orally) via a capsule (containing the structure of the second configuration), released (to obtain the first configuration), and retained in an internal location in the subject, such as the stomach anterior to the pylorus. After a certain period of time (e.g., a residence period such as at least about 24 hours), the time-dependently degradable linkers may degrade, and the structure may separate into several units, which may pass through the pylorus. Upon entering the intestines (for example, with a pH greater than approximately 5), the linker containing the enteric-coated polymer breaks down, and the arms further separate into smaller, more easily removable units.

[0215] In some cases, the active substance may be filled into beads and / or particles containing a fillable polymer material embedded in an elastic polymer, such as an elastically biodegradable linker (e.g., including an enteric elastomer). In some embodiments, the fillable polymer element includes beads and / or particles dispersed / embedded within one or more elastic polymer elements and / or one or more linkers. For example, in certain embodiments, the fillable polymer element beads / particles may be bound to the elastic polymer elements and / or additional fillable polymer element beads / particles via a linker (e.g., the linker is physically bound to the fillable polymer element or at least partially encapsulates the fillable polymer element).

[0216] In some embodiments, various packing / folding strategies are used for encapsulation. The size of the structure can be minimized and / or maximized for gastric retention. In some embodiments, a polygonal structure with a triangular cross-section forms a triangle when projected onto a plane, as shown in Figure 2. In this embodiment, each of the three sides of the triangle is configured to fold in half at a hinge, resulting in a high packing density with a total of six sides folded at once.

[0217] Typical retention structures known in the art, such as intragastric balloons, usually cause at least partial obstruction of the gastric outlet in the subject. Conveniently, in some embodiments, the structure includes a shape having sufficient gaps (or fenestrations) to allow food containing indigestible material to pass through when placed in or at an opening inside the subject, thereby avoiding partial or complete obstruction of the gastric outlet.

[0218] In some embodiments, the structure has an opening. In a typical embodiment, referring again to Figure 1G, the structure has a polygonal cross-sectional region defined by the outer surface of the structure. In some such embodiments, a structure containing one or more polymer elements and linkers has an internal cross-sectional region containing one or more cavities (i.e., not containing one or more polymer elements and linkers), thereby allowing food and other substances to pass through the structure.

[0219] In another representative embodiment, referring again to Figure 1E, the structure has a star-shaped configuration, and food and other substances can pass between the arms of the structure (for example, to remain in the internal location of the subject).

[0220] As mentioned above, in some embodiments, the initial (undeformed) configuration of the structure may be characterized by convex hull volume. In some embodiments, the structure comprising one or more polymer elements and linkers (i.e., the solid elements of the structure relative to the voids) accounts for from about 10% by volume to about 90% by volume of the total convex hull volume of the initial configuration. For example, in certain embodiments, the structure accounts for no more than about 90% by volume, no more than about 80% by volume, no more than about 70% by volume, no more than about 60% by volume, no more than about 50% by volume, no more than about 40% by volume, no more than about 30% by volume, or no more than about 20% by volume of the convex hull volume of the initial configuration. In some embodiments, the structure accounts for at least about 10% by volume, at least about 20% by volume, at least about 30% by volume, at least about 40% by volume, at least about 50% by volume, at least about 60% by volume, at least about 70% by volume, or at least about 80% by volume of the convex hull volume of the initial configuration. Any and all closed intervals having endpoints within any of the above reference ranges are also possible (e.g., from about 10% by volume to about 90% by volume, from about 30% by volume to about 90% by volume, from about 20% by volume to about 50% by volume, from about 40% by volume to about 60% by volume, from about 40% by volume to about 90% by volume). Other ranges are also possible.

[0221] As described herein, in some embodiments, the structure is configured to have a shape and / or size suitable for oral administration to a subject and / or ingestion by a subject. In some embodiments, the structure has a shape with the ability to be folded and / or packed into a stable encapsulated form. For example, in some embodiments, the structure is designed to maximally pack and fill a capsule or other soluble container (e.g., a containing structure). In some embodiments, the structure has a shape that maximally fills and / or packs a capsule or other soluble container.

[0222] In some embodiments, the system comprises a structure and a containment structure. In some embodiments, the structure constitutes more than 60 volume% of the containment structure. Pursuant to the present application, capsules may be manufactured to specific specifications, or to standard sizes including, but not limited to, 000, 00, 0, 1, 2, 3, 4, and 5, as well as larger veterinary capsules Su07, 7, 10, 12el, 11, 12, 13, 110ml, 90ml, and 36ml. In some embodiments, the structure may be provided as coated or uncoated capsules. Capsule materials may be hard or soft, and as would be understood by a person skilled in the art, generally include tasteless, easy-to-administer, water-soluble compounds such as gelatin, starch or cellulosic materials.

[0223] In other embodiments, the structure is held in a compressed shape by a soluble retaining element such as a band or surgical thread. In some embodiments, the structure comprises an optimal combination of materials with high and low modulus of elasticity, which imparts the structure with the ability to change shape and / or size when the soluble container and / or soluble retaining element is removed.

[0224] For example, consider a human hypothyroid patient prescribed levothyroxine at a dosage level that remains constant at 125 µg per day for six months (e.g., between thyrotropin testing intervals). During this six-month period, the patient has 168 separate drug administration events, each involving a 125 µg administered dose. In some embodiments, a structure configured for controllable gastric retention is filled with more than 21 mg of levothyroxine (i.e., 125 µg per day for 168 days) and configured to release approximately 125 µg per day. Accordingly, the patient receives a single drug administration that provides comparable efficacy over the same period as 168 separate administration events.

[0225] Similarly, consider a human patient infected with hepatitis B and treated with a daily dose of entecavir. In some embodiments, a structure configured for controllable gastric retention is filled with approximately 84 mg of entecavir (i.e., 0.5 mg per day for 168 days), and the patient receives a single drug dose for 168 drug administration events over the same period, yielding the same results. In another example, consider a human patient suffering from at least one of Barrett's esophagus, gastric ulcer, and gastroesophageal reflux disease and treated with omeprazole. In some embodiments, a structure configured for controllable gastric retention is filled with approximately 3,360 mg of omeprazole (i.e., 20 mg per day for 168 days), and the patient receives a single drug dose for 168 drug administration events over the same period, yielding comparable efficacy.

[0226] In another example, consider a human patient whose condition has worsened or relapsed in any one of the following: chronic obstructive pulmonary disease, ulcerative colitis, asthma, and gout. The patient is prescribed prednisone at an initial daily dose level maintained constant for two weeks, followed by progressively decreasing doses over additional days, e.g., 23 or more total days of prednisone treatment. During treatment, the patient receives 23 drug administration events, each event involving at least one of two predetermined doses. In some embodiments, a structure configured for controllable gastric retention is filled with approximately 770 mg of prednisone and is configured to release a first predetermined dose daily for two weeks, followed by a smaller predetermined dose on subsequent days. Thus, the patient receives a single drug administration for 23 or more drug administration events over the same period, yielding the same results. Furthermore, the patient would not need to be careful with respect to dose changes (single or multiple) because the structure is pre-configured to automatically tape the dose.

[0227] In another example, consider a human patient with coronary artery disease receiving dual antiplatelet therapy. The patient is prescribed either clopidogrel or prasugrel at a daily dose level that is maintained at a constant level for at least three months. During the treatment, the patient should receive approximately 90 drug administration events. In some embodiments, a structure configured for controllable gastric retention is filled with approximately 6,750 mg of clopidogrel (i.e., 75 mg per day for 90 days) or 900 mg of prasugrel (i.e., 10 mg per day for 90 days). The patient receives a single drug dose that provides comparable efficacy over the same period for 90 drug administration events. In another example, consider a human patient with hyperlipidemia and at least one of coronary artery disease who is being treated with rosuvastatin. In some embodiments, a structure configured for controllable gastric retention is filled with approximately 1,800 mg of rosuvastatin (i.e., 10 mg per day for 180 days), and the patient receives a single drug dose that provides comparable efficacy over the same period for 180 drug administration events.

[0228] Where used herein, any term relating to, for example, the shape, orientation, alignment, and / or geometric relationship of one or more articles, compositions, structures, materials and / or their sub-elements and / or combinations thereof, and / or any other tangible or intangible elements not listed above that conform to the characterization by such terms should be understood not to necessarily conform to the mathematical definition of such terms unless otherwise defined or indicated, but rather to conform to the mathematical definition of such terms to the extent possible with respect to a subject that is characterized as being most closely related to such subject matter, as understood by those skilled in the art. Examples of such terms relating to shape, orientation, and / or geometric relationships include terms describing shape—e.g., round, square, circular, rectangular, triangular, cylindrical, elliptical, n-gon, etc.; terms describing angular direction—e.g., perpendicular, orthogonal, parallel, vertical, horizontal, collinear, etc.; and terms describing contours and / or trajectories—e.g., plane, coplanar, hemispherical, semi-hemispherical, straight, hyperbolic, radiating Terms describing surface and / or bulk material properties and / or spatial / temporal resolution and / or distribution—e.g., smooth, reflective, transmissive, transparent, opaque, rigid, impermeable, uniform, inert, non-wetting, insoluble, steady, invariant, constant, uniform, etc.—as well as many other terms describing those that would be obvious to those skilled in the art.As an example, a manufactured article that would be described herein as a “square” does not need to be perfectly flat or linear and have faces or edges that intersect at exactly 90-degree angles (in fact, such an article can exist only as a mathematical abstraction), but rather the shape of such an article should be interpreted to approximate a mathematically defined “square” to the extent that it is typically achievable and achievable with respect to the manufacturing techniques mentioned, which are understood or specifically described by those skilled in the art.

[0229] As used herein, the term “subject” means an individual living organism, such as a human or an animal. In some embodiments, the subject is a mammal (e.g., human, non-human primate, or non-human mammal), a vertebrate, a laboratory animal, livestock, farm animal, or companion animal. In some embodiments, the subject is a human. In some embodiments, the subject is a rodent, mouse, rat, hamster, rabbit, dog, cat, cattle, goat, sheep, or pig.

[0230] As used herein, the term “electrophile” means a functionality that is attracted to electrons and participates in a chemical reaction by accepting an electron pair to bond with a nucleophile.

[0231] As used herein, the term “nucleophile” means a functionality that donates an electron pair to an electrophile in order to bind to it.

[0232] As used herein, the terms “to react” or “to react” are used in two ways. This means forming bonds between species or more elements to produce a stable, isolateable compound. For example, a first element and a second element may be reacted to form a reaction product containing the first and second elements linked by a covalent bond. The term “reacting” may also include the use of a solvent, catalyst, base, ligand, or other material that may play a role in facilitating the occurrence of a reaction between elements (one or more). “Stable, isolateable compound” means an isolated reaction product and not an unstable intermediate or transition state.

[0233] The term "alkyl" refers to radicals of saturated aliphatic groups, including linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. Alkyl groups may be optionally substituted, as will be described more fully later. In one embodiment, the alkyl group is a C1-C8 alkyl group. Examples of alkyl groups, but not limited to, include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 2-ethylhexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A "heteroalkyl" group is an alkyl group in which at least one atom is a heteroatom (e.g., oxygen, sulfur, nitrogen, phosphorus, etc.) and the remaining atoms are carbon atoms. Examples of heteroalkyl groups, but not limited to, include alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, and morpholinyl.

[0234] The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groups similar to the alkyl groups described above, but each containing at least one double or triple bond. In one embodiment, the alkenyl group is a C2-C8 alkenyl group, and in one embodiment, the alkynyl group is a C2-C8 alkynyl group. “Heteroalkenyl” and “heteroalkynyl” refer to the alkenyl and alkynyl groups described herein in which one or more atoms are heteroatoms (e.g., oxygen, nitrogen, sulfur, etc.).

[0235] The term "aryl" refers to an aromatic carbocyclic group having a monocyclic ring (e.g., phenyl), a multicyclic ring (e.g., biphenyl), or a multi-condensed ring (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl) in which at least one is aromatic, all of which may be optionally substituted. In one embodiment, the aryl group is C6~C 10 These are aryl groups. A "heteroaryl" group is an aryl group in which at least one ring atom in the aromatic ring is a heteroatom and the remaining ring atoms are carbon atoms. Examples of heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N lower alkylpyrrolyl, pyridyl N oxide, pyrimidyl, pyrazinyl, imidazolyl, and indolyl, all of which may be optionally substituted.

[0236] The terms "amine" and "amino" refer to both unsubstituted and substituted amines, for example, the portion that can be represented by the general formula: N(R')(R”)(R'”), where R', R'', and R''' each independently represent a group permitted by the valence rules.

[0237] The terms “acyl,” “carboxyl group,” or “carbonyl group” are understood in the art and have the general formula: [ka] The formula may include a part that can be represented by (wherein W is H, OH, O-alkyl, O-alkenyl, or a salt thereof). If W is O-alkyl, the formula is This represents an "ester." When W is OH, the formula represents a "carboxylic acid." Generally, when the oxygen atom in the above formula is substituted with sulfur, the formula represents a "thiol carbonyl" group. When W is S-alkyl, the formula represents a "thiol ester." When W is SH, the formula represents a "thiol carboxylic acid." On the other hand, when W is alkyl, the above formula represents a "ketone" group. When W is hydrogen, the above formula represents an "aldehyde" group.

[0238] As used herein, the terms “heteroaromatic” or “heteroaryl” mean a monocyclic or polycyclic aromatic heterocycle (or its radical) comprising a carbon atom ring member and one or more heteroatom ring members (e.g., oxygen, sulfur, or nitrogen). Typically, an aromatic heterocycle has 5 to about 14 ring members, of which at least one ring member is a heteroatom selected from oxygen, sulfur, and nitrogen. In another embodiment, the aromatic heterocycle may be a 5 or 6-membered ring and contain 1 to about 4 heteroatoms. In yet another embodiment, the aromatic heterocycle system may have 7 to 14 ring members and contain 1 to about 7 heteroatoms. Representative heteroaryl compounds include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolidinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolidinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, carbazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl (qunizaolinyl), prinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl, and benzo(b)thienyl. These heteroaryl groups may be optionally substituted with one or more substituents.

[0239] The term "substituted" includes all permissible substituents of organic compounds, and "permissible" is intended to be within the context of chemical rules of valence known to those skilled in the art. In some cases, "substituted" generally means replacement of a hydrogen with a substituent described herein. However, as used herein, "substituted" does not encompass substitution and / or modification of the key functional group by which a molecule is identified (e.g., where substitution causes the "substituted" functional group to become a different functional group). For example, "substituted phenyl" must still contain a phenyl moiety, and under this definition, substitution cannot result in a change to, for example, a heteroaryl group such as pyridine. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. Permissible substituents can be one or more, and may be the same or different, for a suitable organic compound. For the purposes of the present invention, a heteroatom such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. The present invention is not intended to be limited in any way by the permissible substituents of organic compounds.

[0240] Examples of substituents include alkyl, aryl, aralkyl, cyclic alkyl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, halogen, alkylthio, oxo, acyl, acylalkyl, carboxy ester, carboxyl, carboxamide, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, carboxamidoalkylaryl, carboxamidoaryl, hydroxyalkyl, haloalkyl, alkyl Examples include, but are not limited to, aminoalkylcarboxy, aminocarboxamidealkyl, alkoxyalkyl, perhaloalkyl, and arylalkyloxyalkyl.

[0241] As used herein, the term "network" means a three-dimensional material having oligomer or polymer chains that are interconnected by crosslinking.

[0242] As used herein, the term "chain" means an oligomer or polymer chain of one monomer unit, or an oligomer or polymer chain of two or more different monomer units.

[0243] As used herein, the term “backbone” means the atoms and bonds to which monomer units are bonded together. As used herein, the term “prepolymer” means an oligomer or polymer chain that is not crosslinked for network formation.

[0244] As used herein, the term “crosslinking” means a link between two chains. Crosslinking may be a chemical bond, a single atom, or multiple atoms. Crosslinking may be formed by the reaction of a pendant group of one chain with the backbone of another chain, or by the reaction of one pendant group with another. Crosslinking may exist between molecules of different chains, or between different points on the same chain.

[0245] As used herein, the term “active substance” means a compound or mixture of compounds that causes an alteration of a biological substrate. Typical types of active substances in the fields of medicine and biology include therapeutic agents, prophylactic agents, and diagnostic agents. Active substances may be small molecule drugs, vitamins, nutrients, biological drugs, vaccines, proteins, antibodies, or other biomacromolecules. Active substances may be mixtures of any of the types of compounds listed above.

[0246] "Immunosuppressants" refer to drugs that inhibit or prevent the immune response to foreign substances in a subject. Immunosuppressants typically work by inhibiting T cell activation, interrupting proliferation, or suppressing inflammation.

[0247] As used herein, the terms “oligomer” and “polymer” refer to compounds consisting of repeating monomer subunits, respectively. Generally speaking, an “oligomer” contains fewer monomer units than a “polymer.” Those skilled in the art will understand that whether a particular compound is designated as an oligomer or a polymer depends on the compound’s nature and the context in which it is used.

[0248] Those skilled in the art will understand that many oligomer and polymer compounds consist of multiple compounds containing different numbers of monomers. Such mixtures are often designated by the average molecular weight of the oligomer or polymer compounds in the mixture. As used herein, the use of the singular "compound" in relation to oligomer or polymer compounds includes such mixtures.

[0249] As used herein, any reference to any oligomer or polymer material without further modifiers includes such oligomer or polymer material having any average molecular weight. For example, the terms “polyethylene glycol” and “polypropylene glycol” include polyethylene glycol and polypropylene glycol of any average molecular weight when used without further modifiers.

[0250] As used herein, the term “Michael acceptor” means a functional group having a carbon-carbon double or triple bond, where at least one of the carbon atoms is further bonded to a carbonyl group or a carbonyl analog such as an imine, oxime, or thiocarbonyl. The reaction between a Michael acceptor and a nucleophile forms a covalent bond between the nucleophile and a carbon atom that is not directly bonded to a carbonyl group or carbonyl analog. The reaction between a Michael acceptor and a nucleophile is sometimes called a “Michael addition.”

[0251] The term "aliphatic group" refers to a linear, branched, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl groups, alkenyl groups, and alkynyl groups. In one embodiment, the alkyl group is a C1-C8 alkyl group. In one embodiment, the alkenyl group is a C2-C8 alkenyl group. In one embodiment, the alkynyl group is a C2-C8 alkynyl group.

[0252] The term "alkoxy" refers to an alkyl group as defined above, which has a bonded oxygen atom. In one embodiment, the alkoxy group is an -OC1 to C8 alkyl group. Representative alkoxy groups include methoxy, ethoxy, propyloxy, and tert-butoxy. "Ether" is two hydrocarbons covalently bonded by oxygen.

[0253] The term "alkylthio" refers to the alkyl group defined above, which has a bonded sulfur atom. In some embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, and -S-alkynyl. In some embodiments, the "alkylthio" moiety is represented by one of -S-C1~C8 alkyl, -S-C2~C8 alkenyl, and -S-C2~C8 alkynyl. Representative alkylthio groups include methylthio and ethylthio.

[0254] The term "amide" is recognized in this field as an amino acid substituted with a carbonyl group.

[0255] As used herein, the term "aralkyl" means an alkyl group substituted with an aryl group. As used herein, the term "heteroaralkyl" means an alkyl group substituted with a heteroaryl group.

[0256] As used herein, the term “heteroatom” means an atom of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, and sulfur.

[0257] As used herein, the term "thiol" means -SH, the term "hydroxyl" means -OH, and the term "sulfonyl" means -SO2-.

[0258] As used herein, the term "oxo" means a carbonyl oxygen atom.

[0259] As used herein, the term “alkaloid” means a naturally occurring organic compound containing at least one non-peptide nitrogen atom. [Examples]

[0260] The following examples are intended to illustrate specific embodiments of the present invention, but not to illustrate the entire scope of the invention.

[0261] Example 1 - Elliptical Ring Design Unless otherwise specified, polycaprolactone (PCL) was selected as the fillable polymer element of the structure for reasons of its mechanical and physicochemical properties. PCL is a biodegradable polyester with a low melting point of approximately 60°C, enabling multiple processing techniques. Under physiological conditions, PCL degrades slowly by hydrolysis of its ester bonds, making it a suitable material for the preparation of specific embodiments of long-term in vivo retention structures. PCL has been used for controlled release and targeted delivery of various drugs.

[0262] Various flexible materials were tested for use as flexible linkers. Properties evaluated included the ability to withstand 180-degree deformation without breaking, the ability to remain deformed for extended periods, such as in storage pills, and the ability to bounce back to their original shape with nearly 100% accuracy. To maximize mechanical properties while maintaining biocompatibility, isocyanate-crosslinked polyurethanes derived from low molecular weight polycaprolactone monomers were used.

[0263] One such implementation consisted of the addition of hexamethylene diisocyanate to polycaprolactone diol (MW 530 g / mol): polycaprolactone triol (MW 900 g / mol): linear high molecular weight polycaprolactone (MW 45,000 g / mol) in a molar ratio of 6:1.3:0.027:9.5. The first three components were initially mixed at 70°C until well combined. The mixture was sonicated to remove trapped air bubbles. The isocyanate was added and mixed for approximately 30 minutes, while simultaneously maintaining the temperature at 70-75°C. While maintaining the temperature, the prepolymer solution was gently pipetted into a PDMS mold of the desired shape. The thermosetting resin was cured at 70-75°C for 48 hours, at which point the shape was hardened and minimal residual free isocyanate was present.

[0264] Figure 3 shows an elliptic ring structure configured for gastric retention. The elliptic ring structure includes a packable polymer element and one or more linkers incorporated into the elliptic ring structure and configured for controlled disintegration. Figure 3A shows the elliptic ring structure next to a 000-size capsule. The elliptic ring structure has a major axis diameter greater than approximately 40 mm and a minor axis diameter (i.e., approximately 26 mm) comparable to the major axis of the 000-size capsule. In Figure 3B, the elliptic ring structure is packed into (and folded within) the 000-size capsule. In Figures 3C-3D, the controlled disintegration linkers incorporated into the elliptic ring structure along the minor axis can be observed. In Figure 3D, the elliptic ring structure is twisted so that the axis of the helix aligns with the minor axis of the elliptic ring structure. The increase in packing efficiency can be observed by comparing Figure 3E with Figure 3B.

[0265] Example 2 - Multi-armed star design Design constraints were addressed by using a combination of relatively rigid elements (fillable polymer elements) and flexible, rebounding elements (elastic polymer elements) as a drug matrix to provide mechanical stability. As shown in Figures 4A-5B, two geometric families of rigid and flexible elements were further investigated: a "polygonal" family of alternating rigid and flexible elements that fold over themselves, and a "star" family in which rigid elements protrude from a central flexible element. Designs that could be efficiently encapsulated in standard-size 000 gelatin capsules were generated using Inventor CAD software and a 3D printer, and these were used as positive molds to produce PDMS-negative molds. Optimized versions for other capsule sizes, such as larger veterinary capsules and smaller capsules including 00-EL and 0-EL for easier human consumption, were also developed.

[0266] In Figure 4A, the structure includes a central core and six radial protrusions, as shown next to a 000-size capsule. The central core contains elastic polymer elements including elastic PCL, and the protrusions contain rigid fillable polymer elements. Each protrusion has a length slightly shorter than the capsule length, so that the final unencapsulated form has a circumscribed diameter equal to approximately twice the capsule length. In Figure 4B, various structures with radial protrusions having a sector shape with an inner sector angle equal to approximately 360° / N are shown. Each structure has protrusions 20 mm long within a circumscribed diameter of approximately 44 mm. In the structure with three radial protrusions, the design surface is 915 mm². 2 The design volume is 438 mm³. 3 In a structure with four radial protrusions, the design surface was 1047 mm². 2 The design volume is 723 mm³. 3 In a structure with six radial protrusions, the design surface was 1410 mm². 2 The design volume is 954 mm³. 3In a structure with eight radial protrusions, the design surface was 1658 mm². 2 The design volume is 1015 mm³. 3 In Figure 4C, three structures having 4, 6, and 8 radial projections are shown, respectively, in encapsulated and unencapsulated forms. The projections are formed from at least one material having a high modulus of elasticity to increase resistance to compression and extend the gastric retention period.

[0267] Table 1 summarizes structures of various sizes. [Table 1]

[0268] Example 3 - Polygon Design In Figure 5A, an embodiment having a hexagonal structure is shown next to a 000-size capsule. The vertices of the hexagon contain elastic polymer elements, and the sides of the hexagon contain rigidly fillable polymer elements. Each side is slightly shorter than the length of the capsule so that the final unencapsulated form has a circumscribed diameter equal to approximately twice the length of the capsule. In Figure 5B, various structures with radial projections having a sector shape with an inner sector angle equal to approximately 360° / N are shown. Four embodiments of square, hexagonal, octahedral, and dodecahedral structures are each shown in their unencapsulated forms. The shapes are formed from at least one material having a high modulus of elasticity to increase resistance to compression and extend gastric retention time.

[0269] Each side of the polygon is approximately 22 mm long, and each folded polygonal structure has a width of approximately 8.5 mm. For a structure with four sides, the circumscribed diameter is approximately 15.6 mm, and the design surface area is approximately 964 mm². 2 The design volume is approximately 640 mm³. 3 For a structure with six sides, the circumscribed diameter was approximately 22.0 mm, and the design surface area was approximately 1451 mm². 2 The design volume is approximately 998 mm³. 3For a structure with eight sides, the circumscribed diameter was approximately 28.8 mm, and the design surface area was approximately 1806 mm². 2 The design volume is approximately 1125 mm³. 3 For a structure with 10 sides, the circumscribed diameter was approximately 35.6 mm, and the design surface area was approximately 2052 mm². 2 The design volume is approximately 1148 mm³. 3 For a structure with 12 sides, the circumscribed diameter was approximately 42.5 mm, and the design surface area was approximately 2389 mm². 2 The design volume is approximately 1208 mm³. 3 The sizes are summarized in Table 2. [Table 2]

[0270] Example 4 - Ingestion of the structure Figure 6 shows a series of chest / abdominal X-ray images obtained at 3, 5, and 12 minutes after ingestion in a large animal model, illustrating the deployment of the multi-armed structure from the capsule and in vivo adoption by the structure in its original conformation over approximately 12 minutes.

[0271] Similarly, Figure 7 includes a series of chest / abdominal X-ray images obtained in large animal models after ingestion of hexagonal retaining / delivery structures (with sides formed of polycaprolactone and vertices containing enteric-coated elastomer linkers) according to several embodiments. Each retaining / delivery structure was densely packed in a 000 capsule and expanded to its original shape after reaching the gastric cavity. Figure 7A is an image taken after ingestion when the subjects were fasting, and Figure 7B is an image taken 5 days after ingestion when the subjects were consuming a normal diet. Table 3 shows the results of eight tests using the hexagonal retaining / delivery structures in six different pigs according to several embodiments. As shown in the table in Figure 7, the structures were successfully retained in the gastric cavity on days 0 and 2 in all cases, and on day 5 in three cases. In the five other cases, on day 5, the enteric-coated elastomer linkers degraded, and the structures safely passed through the gastrointestinal tract. [Table 3]

[0272] Example 5 - Enteric-coated elastomer Figure 8 is a schematic diagram of enteric-coated elastomers and methods for preparing enteric-coated elastomers according to several embodiments. In Figure 8A, a polymer gel network is illustrated, where the first set of lines represents synthesized poly(acryloyl-6-aminocaproic acid), the second set of lines represents linear poly(methacrylate-co-acrylate) (e.g., Eudragit® L100-55, available from Evonik Industries AG (Essen, Germany)), the multiple boxes represent hydrogen bonds between polymer chains, and the spots represent water molecules. Figure 8B shows the manufacturing process flow. From left to right in Figure 8B, aqueous solutions of poly(acryloyl-6-aminocaproic acid) sodium salt and aqueous solutions of poly(methacrylate-co-acrylate) sodium salt are used in various ratios ( The two polymers were mixed in a ratio (not limited to 1:0, 1:1, and 1:2, etc.) to form a homogeneous polymer sodium salt aqueous solution. The two polymers were then coprecipitated by adding an HCl solution. The polymer composite precipitate was converted into an enteric, elastic polymer gel and collected at the bottom of a centrifuge tube. The formed enteric elastomer can be cut and / or pressure-molded into various shapes for structural construction, mechanical characterization, etc.

[0273] Figure 8C shows three optical images of an elongation test of an enteric-coated elastomer. The enteric-coated elastomer contained poly(acryloyl-6-aminocaproic acid):poly(methacylic acid-co-ethyl acrylate) in a 1:2 ratio. The top image shows the enteric-coated elastomer before elongation, at a length of 1.5 cm. The middle image shows the enteric-coated elastomer after being elongated to three times its initial length. The bottom image shows the enteric-coated elastomer 5 minutes after the removal of the external force, indicating that the enteric-coated elastomer has returned to its initial length.

[0274] Figure 9 shows the morphological, mechanical, soluble, and cytotoxic characterization of three enteric elastomer formulations according to several embodiments. Figure 9A shows the morphology of a dried enteric elastomer with three different ratios (1:0, 1:1, and 1:2, respectively) of poly(acryloyl-6-aminocaproic acid) (PA6ACA):Eudragit® L100-55 (L100-55) by a series of scanning electron microscope (SEM) images. The scale bar in the image is equal to 50 μm. All three enteric elastomer formulations had a porous structure, but higher concentrations of Eudragit® L100-55 correlated with a decrease in pore size. The formulations were freeze-dried for 48 hours and their water content was measured. The water content decreased from 31.6% by weight for pure poly(acryloyl-6-aminocaproic acid) to 27.7% by weight for the 1:1 ratio enteric elastomer and 26.4% by weight for the 1:2 ratio enteric elastomer, which was consistent with SEM observations.

[0275] Tensile stress tests were performed to test the elastic properties of the enteric-coated elastomer. Figure 9A shows a corresponding series of true stress-true strain plots for the enteric-coated elastomer. Young's modulus and tensile strength increase with increasing amount of Eudragitt® L100-55, while strain decreases from 857% for poly(acryloyl-6-aminocaproic acid) itself to 341% for the enteric-coated elastomer in a 1:2 ratio.

[0276] After demonstrating the elastic properties of the enteric-coated elastomers, their enteric coating ability was evaluated by dissolution tests in simulated gastric juice and simulated intestinal fluid. In Figure 9B, the plots compare the results of the corresponding dissolution tests of the enteric-coated elastomers in simulated gastric juice and simulated intestinal fluid. Poly(acryloyl-6-aminocaproic acid) showed long-term stability over 4 days in simulated gastric juice with no discernible mass loss. In contrast, within the same period, poly(acryloyl-6-aminocaproic acid) dissolved in simulated intestinal fluid at pH 6.8.

[0277] To demonstrate the biocompatibility and safety of poly(acryloyl-6-aminocaproic acid) after lysis, poly(acryloyl-6-aminocaproic acid) sodium salt was tested for cytotoxicity in HeLa cells at a range of concentrations. In Figure 9C, the plots compare the results of the corresponding cytotoxicity studies of enteric-coated elastomer formulations in HeLa cells. After 24 hours of incubation, no significant cytotoxicity was observed with respect to poly(acryloyl-6-aminocaproic acid) across the concentration range of 0.0001 mg / mL to 5 mg / mL. The cytotoxicity observed at high concentrations (above 5 mg / mL) is thought to be due to the pH change of the cell culture medium after lysis of the polymer sodium salt. Therefore, poly(acryloyl-6-aminocaproic acid) may be biocompatible.

[0278] To evaluate the in vivo stability of enteric-coated elastomers, according to several embodiments: This section describes the construction and in vivo evaluation of a structure from a polycaprolactone (PCL) arc interposed with an enteric-coated elastomer linker. In Figure 10A, six enteric-coated elastomers are fitted into a ring-shaped polydimethylsiloxane (PDMS) mold with an outer diameter of 3.0 cm, an inner diameter of 2.8 cm, and a depth of 0.2 cm. After drying the elastic enteric-coated polymer gel under vacuum, Figure 10B shows the arrangement of polycaprolactone (PCL) beads between the six enteric-coated elastomers. After melting and solidifying the PCL, Figure 10C shows the ring-shaped structure removed from the mold and also shows the method of folding the structure to achieve the result shown in Figure 10D. In Figure 10E, the folded structure is packed into a gelatin capsule with a length of 2.6 cm and a diameter of 0.9 cm. Figures 10F–G are lateral and anterior-posterior X-ray images, respectively, of pigs after administration of gelatin capsules containing ring-shaped structures (for image processing, radiopaque metal balls were embedded in the PCL segment). After the ring-shaped structures within the capsule were delivered to the pigs via the esophagus, the capsule dissolved in the stomach, releasing the ring-shaped structures and restoring their shape.

[0279] Example 6 - Linker Formation Enteric-coated linker elements were formed by compression molding. In one embodiment, Eudragit L100-55 (Evonik), an enteric-coated material known in the art to have a pH-dependent solubility profile, was blended with a plasticizer (triacetin) in a ratio between 60:40 and 80:20. 3 g of the resulting mixture was placed between two 6x6 inch Teflon® sheets and compressed on a hot press at 110-120°C at 5000 psi for 20 minutes. The Teflon® sheets were removed from the press, briefly quenched in tap water at room temperature for 10 seconds, and then the Eudragit film was removed.

[0280] Linkers with other dissolution profiles were produced in a similar manner. Eudragit RS PO (Evonik), a water-soluble polymer with a time-dependent dissolution profile, was blended with a plasticizer (triacetin) in a ratio of 70:30 to 85:15 and similarly compressed on a hot press at 100 to 110°C and 3000 psi for 10 to 20 minutes.

[0281] In some cases, other water-soluble polymers, such as vinylpyrrolidone-vinyl acetate copolymers (e.g., KOLLIDON® VA 64 (BASF) and KOLLIDON® SR), polyvinylpyrrolidone, cellulose acetate, hydroxypropyl methylcellulose, or polyvinyl alcohol, were compressed or cast into films by evaporation of a solvent (e.g., water) to produce sheets of material for use as linkers.

[0282] Time- or pH-dependent linkers can be linked to drug-filled polycaprolactone matrices. Several strategies have been attempted to achieve this. In one example, a film of elastic PCL prepolymer solution was coated onto both sides of a soluble film and cured. In the case of Eudragit L100-55, this yields covalent crosslinking of the elastic PCL to the soluble linker via urethane bonding with available reactive groups. The multilayer film produced by this method has an outer interface of elastic PCL and can be linked to linear PCL via final application of heat over a period of time in a constraining mold.

[0283] In another example, a biocompatible adhesive was used to link the soluble linker with polycaprolactone. In one example, a sheet of polycaprolactone film was produced to facilitate linking. By using a plasticizer (Pluronic P407) with polycaprolactone at a ratio of 10 w / w%, the flexibility and brittleness of the polycaprolactone film were generally improved. Urethane (e.g., Loctite® M-11FL® Hyso A polycaprolactone film was bonded to both sides of a pre-formed dissolved film using a biomedical adhesive such as (i) Medical Structure Urethane Adhesive or cyanoacrylate (e.g., Loctite (registered trademark) 3981 Hysol (registered trademark) Epoxy Structural Adhesive).

[0284] Next, linkers with appropriate geometry were cut from a multilayer film in which the exposed outer layer was polycaprolactone. These linkers could be easily bonded to a drug-filled polycaprolactone matrix by applying heat to the interface.

[0285] Example 7 - Mechanical Characterization of Elastic Polymers PCL elastomers were mechanically characterized using tensile, compressive, and creep loads. Mechanical characterization was performed according to ASTM standards D638 (tensile), D575 (compressive), and D2990 (creep).

[0286] Tension PCL elastomer was cured into a 2 mm thick polymer sheet. The sheet was cooled, and specimens were cut from the sheet using a standard dumbbell die (ASTM D-638). The specimens were mounted on the grip of an Instron material testing machine, and the gauge length was measured using a digital micrometer. Displacement was applied to the specimen at a rate of 10 mm / min until the sample fractured. The force was converted to normal stress (F / A), and the displacement was converted to strain (ΔL / L), and plotted in Figure 11A.

[0287] compression PCL elastomer was cured into a 13 mm thick slab. The slab was cooled, and a 28 mm diameter specimen was cut from the slab using a rotary hollow drill bit. The specimen was placed in a constrained load compression jig and subjected to displacement at 12 mm / min. The specimen was tested until it reached a 30% compressive strain. The force was converted to pressure (F / A) and the displacement to volume ratio (ΔV / V), and plotted in Figure 11B.

[0288] Creep PCL elastomer, polydimethylsiloxane (silicone), and polyethylene vinyl acetate (PEVA) were cured into 2 mm thick polymer sheets. The sheets were cooled, and test specimens were cut from the sheets using a standard dumbbell die (ASTM D-638). The test specimens were mounted on the grip of an Instron material testing machine, and the gauge length was measured using a digital micrometer. A constant stress equivalent to 30% of the ultimate tensile strength of each material was applied to the test specimens for 60 minutes. Forces and displacements were calculated throughout the test and converted to normal stress (F / A) and strain (ΔL / L), which are plotted in Figure 11C.

[0289] Example 8 - Finite element analysis of a retaining structure The stress and strain profiles of the structure were analyzed using the finite element method in SIMULIA Abaqus FEA software. The geometry of the structure was imported from Autodesk Inventor into Abaqus. The material properties of the PCL elastomer were defined using the Mooney-Rivlin hyperelastic model derived from the aforementioned tensile and compression tests. The linear PCL arms were assumed to be linearly elastic, and the modulus of elasticity was derived from the bending tests described above. The model was meshed using C3D4 elements, and the PCL elastomer and linear PCL were joined at the interface. A 1 mm diameter plate was introduced at the bottom of the PCL elastomer to hold the structure in place throughout the deformation. Forces were applied perpendicularly to the tops of each arm to simulate the folding of the structure into a capsule. After calculation, von Mises stress, maximum principal stress, longitudinal stress, and lateral stress were calculated. a) Stress was analyzed. The results of the finite element modeling are shown in Figure 12.

[0290] Example 9 - Simulated pyloric discharge of a retaining structure To better understand the passage of the retaining structure through the pylorus, a custom experimental setup was developed. A schematic of the experimental setup is shown in Figure 13A. The pyloric sphincter was simulated using a polypropylene funnel with an upper diameter of 20 cm and a lower diameter of 2 cm. The aforementioned star-shaped structure was placed inside the funnel, and the structure was pushed through the 2 cm spout using a custom-designed plunger. The plunger was attached to the tensile crosshead of the Instron material testing machine, and the funnel was attached to a clamp. The structure was pushed through the funnel at a speed of 10 mm / min, and forces and displacements were obtained throughout the test, as shown in Figure 13B.

[0291] Example 10 - Evaluation of gastric retention in vivo To evaluate specific formulations developed for achieving gastric retention, the aforementioned structures (e.g., hexagonal and star-shaped) were administered to a large animal model, a 35-50 kg Yorkshire pig. This model was chosen because it is known to have a gastric anatomical structure similar to that of humans and is widely used to evaluate structures within the gastrointestinal space. The prolongation of food bolus passage in pigs is usually measured in hours, and therefore, for evaluations of retention on the order of days, this should only introduce small errors, providing a good model of gastric anatomical structure and gastric emptying.

[0292] Pigs were sedated with terazol and xylazine, or optionally ketamine, or optionally isoflurane, and an endoscopic overtube was placed in the esophagus under endoscopic visual guidance during esophageal intubation. Gelatin capsules containing the structure were administered into the esophagus and / or stomach via the overtube, and the overtube was withdrawn. Immediately thereafter, serial X-rays were acquired to record the process of disintegration from the gelatin capsule. Blood samples were taken, if necessary, by cannula insertion into the mammary vein on the ventral side of the pig, usually at time 0 (before pill administration), 5 minutes, 15 minutes, 30 minutes, 2 hours, 6 hours, and then daily for a minimum of 5 days, and then at specified times three times a week. Three times a week, chest and abdominal X-rays of at least 5 fields, including anterior-posterior, lateral and lateral positions of the chest, upper abdomen, and lower abdomen and rectum, were acquired. 3-5 × 1 mm steel references were implanted in the drug delivery PCL arm by melt casting. These could be tracked by radiography to assess the deployment and integrity of the delivery system (components), as well as their position within the gastric cavity, upper abdomen, or lower abdomen. Radiographic images were also evaluated for the presence of evidence of complications such as pneumoperitoneum or bowel obstruction. Representative radiographic images are shown in Figures 6 and 7.

[0293] Example 11 - In vitro evaluation of drug stability and release The stability of drugs in the gastric environment was evaluated using HPLC and LC-MS / MS analysis. Hydrophilic drugs were dissolved in simulated gastric juice (SGF, 0.2% (w / v) NaCl, 0.83% (v / v) HCl, pH=1) in a centrifuge tube. Hydrophobic drugs were dissolved in IAW (isopropanol 70%, acetonitrile 20%, water 10%) and the pH was adjusted to 1 using HCl. As a control, the drug was dissolved in the same solvent and the pH was adjusted to 6.0 (using 1M NaOH). After vortexing for 1 minute and sonication for 10 minutes, the tubes were placed in a shaking incubator (150 rpm, 37°C). Samples were collected at predetermined time points up to 2 weeks and the stability of the drugs was quantified by HPLC and LC-MS / MS analysis.

[0294] The stability of drugs packed in PCL-based delivery matrices was also investigated. Drug packing is described in Examples 16 and 17 below. Drug-packed structures were maintained under acidic conditions (pH=1, 37°C), and drugs were extracted from the PCL matrix at specified intervals and analyzed by HPLC and / or LC-MS / MS. To extract the drugs, the structure The samples were sonicated in SGF (a hydrophilic drug) or isopropanol (a hydrophobic drug) for 10 minutes. Immediately before analysis, a new drug was prepared as a control in SGF or isopropanol.

[0295] Stability of doxycycline (hydrophilic) in SGF (pH=1, 37℃) Figure 14 shows the stability of doxycycline in SGF (pH=1, 37°C) over two weeks, as analyzed by HPLC. An Agilent 1260 infinity model HPLC system with an autosampler and a C8 reversed-phase column (4.6 × 150 mm, id, 5 μm particle size) was used. The mobile phase was ACN / water + 0.1% formic acid, pH 3.5 (60 / 40). 20 μl of sample was injected into the column at a mobile phase flow rate of 1 mL / min, and UV absorption at 350 nm was recorded for 10 minutes.

[0296] Stability of artemeter (hydrophobic) in IAW (pH=1, 37℃) Figure 15 shows the stability of artemulators in IAW (pH=1, 37°C) over a two-week period, as analyzed by HPLC. The area under the curve (AUC) related to the drug was used to quantify the stability percentage.

[0297] Stability of ivermectin in solution or in PCL structures under acidic conditions (pH=1, 37°C) Figure 16A shows that free ivermectin is unstable under acidic conditions (IAW, pH=1, 37°C). The PCL structure protected ivermectin from acidic degradation. The ivermectin (IVM)-packed structure shown in Figure 16B was placed in SGF+RH solution (pH=1, 37°C) for 72 hours. The drug was extracted by sonication of the structure in isopropanol for 10 minutes. The HPLC chromatogram of the extracted IVM was similar to that of fresh IVM dissolved in isopropanol, indicating that the PCL structure protected IVM in an acidic environment.

[0298] Example 12 - In vitro drug release study Drug-filled oral delivery structures containing various compositions were prepared as described in Examples 16 and 17. Structures filled with hydrophilic drugs were placed in sealed cups containing 100 mL of SGF. For hydrophobic drugs, Kolliphor® RH40 (a nonionic oil-in-water solubilizer) was added to the SGF (0.25% (w / v)) to increase the solubility of the released drug. The cups were placed in a shaking incubator (150 rpm, 37°C). Samples were collected at specified time points up to two weeks and analyzed by HPLC and LC-MS / MS to quantify the amount of released drug.

[0299] In vitro release of doxycycline (hydrophilic) packed structures in SGF. Figure 17A shows the in vitro release of a doxycycline-filled PCL star-shaped structure in SGF (pH=1, 37°C): Pluronic P407 (hydrophilic surfactant) was added to the PCL matrix to facilitate drug suspension in the polymer matrix and adjust the release kinetics. The drug concentration in the release medium was measured by HPLC. The PCL:PLu:Dox ratio is expressed in weight percent in the legend of the figure.

[0300] In vitro release of ivermectin (hydrophobic) packed structures in SGF+RH40 Figure 17B shows the in vitro release of ivermectin (IVM)-filled star-shaped structures containing different formulations in SGF+RH40 (pH=1, 37°C). Different excipients, namely RH40, Pluronic P407, and Soluplus, were added to adjust the release kinetics as shown in Table 4. Drug concentrations in the release medium were measured by HPLC. [Table 4]

[0301] Figure 17C shows the in vitro release of ivermectin (IVM)-filled star-shaped structures containing different formulations in SGF+RH40 (pH=1, 37°C). All formulations contain 70% PCL, 20% IVM, and 10% excipients. Excipients include 4-arm and 8-arm branched PEG, and Pluronic P407. In the "premelt" samples, IVM and PEG8 were premelted before mixing with PCL and remelting. Drug concentrations in the release medium were measured by HPLC. Error bars represent standard deviations (SD) of three independent repeats.

[0302] Example 13 - Bending properties of drug-filled PCL segments Linear PCL in bending was mechanically characterized according to ASTM standard D790 and as shown in Figure 18. Sheets of linear PCL, excipient-containing PCL, and PCL containing excipients and drugs were cured into 2 mm thick sheets. After the sheets cooled, rectangles measuring 80 mm in length and 8 mm in width were cut from the sheets to prepare specimens. Before testing, the width and thickness of the specimens were measured using a digital micrometer. The specimens were tested using an Instron material testing machine equipped with a three-point bending fixture. The test was performed at a speed of 0.85 mm / min, and a 32 mm span was used for all specimens. The test was stopped when the specimen fractured or reached a 20% flexural stain. Force was converted to bending stress, and displacement was converted to flexural stain.

[0303] Example 14 - Gastric residence time Figures 19–21 show histograms of the probability of gastric retention of three different gastric retention systems at specified time points. The gastric retention systems were formed during the polymerization of the arms, including a 1 mm stainless steel marker placed within the polymer drug delivery "arm". The gastric retention systems were administered to Yorkshire pigs (35–50 kg) under sedation via an endoscopic overtube into the gastric cavity. Serial radiographs were acquired from multiple positions (anterior-posterior, left-lateral, and right-lateral) of the chest, abdomen, and pelvis. Radiographs were acquired up to 15 minutes post-delivery to confirm deployment from the outer capsule and / or restraint system. Radiographs were then acquired daily for the next four days, and three times weekly after the first five days. The position of the retention system in the gastric cavity was confirmed from multiple radiographic fields. (Figure 19, H1–EE1) Hexagonal retention system with elastic elements at the apex, made from polycaprolactone "arm" and enteric-coated elastomer. (Figure 20, H1-F1-F1-X1) A hexagonal retention system comprising arms made from isocyanate-crosslinked polycaprolactone and elastic elements made from isocyanate-crosslinked polycaprolactone, further comprising a soluble linker made from an Eudragit L100-55 film. (Figure 21, H1-F1-R1-X2) A hexagonal retention system comprising arms made from polycaprolactone and elastic elements made from isocyanate-crosslinked polycaprolactone, as well as a soluble linker made from a blend of 90% Eudragit L100-55 and 10% poly(acrylic acid).

[0304] Example 15 - Food passage Intragastric balloons (endoscopically deployed gastric retention systems) for the treatment of obesity have been associated with symptoms consistent with partial gastric outlet obstruction, particularly nausea in 18–90% of patients. To monitor the potential for gastric outlet obstruction by the retention structures described herein, these structures were evaluated in large animal models. In particular, structures primarily constructed from non-degradable elastic polymer elements were prepared in a star-shaped configuration to observe potential outlet obstruction. These were deployed in the stomachs of approximately 50 kg pigs and clinically monitored twice daily for evidence of gastrointestinal obstruction, including abdominal distension, vomiting, and decreased fecal production. Furthermore, serial X-rays were performed three times a week to evaluate evidence of obstruction, including gastric distension. Additionally, on day 35, prior to the endoscopic procedure, the animals were given a liquid diet for 24 hours to assess their gastric emptying capacity, and the stomach was further evaluated endoscopically. During endoscopic imaging, the structures were confirmed to overly cover the pylorus, and the gastric cavity was free of food. This supports the ability of the structure to allow food to pass through the stomach, remain in the gastric cavity, and further cover the pylorus.

[0305] Figure 22 shows the endoscopic evaluation of the star-shaped delivery system after 35 days of retention. In the image, the delivery system covers the pylorus, and the probe is within the field of view. As shown in the photograph, there appears to be no significant evidence of food retention, and in fact, there are no tangled food particles at all in the prototype.

[0306] Example 16 - In vivo long-term oral doxycycline delivery Commercially available doxycycline hyclate 100 mg tablets were purchased from Patterson Veterinary. Three pigs were each administered one tablet on day 0, and serum was collected via intravenous cannula at the time of selection. Another pig was administered a total of approximately 1000 mg of doxycycline in a six-armed star-shaped formulation, intended to provide the same dose as 100 mg twice daily for approximately 5 days. 25 w / w% doxycycline-filled 45,000 MW polycaprolactone was formulated with 4 w / w% Pluronic P407 hydrophilic excipients. The blend was melted and mixed at 75°C and poured into PDMS molds. After cooling, the central portion was removed from the star-shaped mold, and an elastic PCL prepolymer solution was poured into the central cavity and cured at approximately 75°C for 48 hours. As previously described, the resulting shapes were encapsulated and administered to Yorkshire pigs. Drug levels were quantified using LC / LC-MS, as shown in Figure 24.

[0307] Example 17 - In vivo long-term oral ivermectin delivery Ivermectin was dissolved in a 50:50 EtOH and water solution, and 0.2 mg / kg was administered orally to 40-50 kg pigs via gastric tube feeding in 10 ml of the solution. Blood samples were collected in a serum separator tube by inserting a peripheral venous cannula at specified times before and after administration, and then centrifuged. The serum was frozen in aliquots for later batch analysis. Serum levels of ivermectin were measured using a Waters LC-MS with a standard method, as shown in Figure 25A.

[0308] Ivermectin was first packed into polycaprolactone by mixing 20% ​​(w / w) of the final mass of ivermectin and 10% (w / w) of the final mass of Pluronic P407 poloxamer and melting for a short time at 75°C. Next, polycaprolactone with a molecular weight of 45,000 (Sigma-Aldrich, St. Louis, MO) (70 w / w%) was added, and the mixture was melted at 75°C for 20 minutes and mixed for 5 minutes. The molten mixture was transferred into a star-shaped mold. The mold was heated at 90°C for 2 hours and then air-cooled. The arm portions were prepared and returned to the star-shaped mold, leaving the central element as a void. The elastic PCL prepolymer solution was poured into the central elastic region and cured at 70°C for 24 hours. The star shape was removed from the mold and filled with gelatin. The ivermectin was placed in capsules. The capsules were administered into the gastric cavity of sedated Yorkshire pigs via an esophageal overtube positioned under endoscopy. Three capsules, each containing 200 mg of ivermectin embedded in the formulation, were administered to three pigs. The results are shown in Figure 25B.

[0309] Elastic elements were fabricated as described above using a mold corresponding to a specially fabricated central elastic element. As shown in Figure 25B, the ivermectin-filled elements were fabricated as previously described. The molten mixture was transferred into a star-shaped mold, and the pre-formed elastic central elements were placed in the appropriate positions. The mold was heated to 90°C for 2 hours and then air-cooled. The star shape was removed from the mold and placed in a 000 gelatin capsule. The capsule was administered into the gastric cavity of sedated Yorkshire pigs via an esophageal overtube positioned under endoscopy. Ten capsules, each containing approximately 200 mg of ivermectin embedded in the formulation, were administered to three pigs. The results are shown in Figure 25C.

[0310] While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily anticipate various other means and / or structures for performing the functions described herein and / or obtaining the results and / or one or more advantages thereof, each such variation and / or modification will be considered to fall within the scope of the present invention. More generally, those skilled in the art will readily understand that all parameters, dimensions, materials, and configurations described herein are intended to be illustrative, and that actual parameters, dimensions, materials, and / or configurations will depend on the specific application (one or more) in which the teachings of the present invention are used. Those skilled in the art will be able to recognize or confirm many equivalents to the particular embodiments of the present invention described herein simply by using standard experiments. Thus, it will be understood that the embodiments described herein are presented for illustrative purposes only, and that the present invention may be carried out in ways other than those specifically described and claimed, within the scope of the appended claims and their equivalents. The present invention relates to each of the individual features, systems, articles, materials, kits, and / or methods described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included within the scope of the present invention, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0311] As used herein and in the claims, unless otherwise explicitly indicated, the indefinite articles “a” and “an” should be understood to mean “at least one.”

[0312] When used herein and in the claims, the phrase “and / or” should be understood to mean “one or both” of the elements thus combined, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Other elements other than those specifically identified by the phrase “and / or” may be present, whether related to or unrelated to those specifically identified elements, unless otherwise explicitly indicated. Thus, as a non-restrictive example, a reference to “A and / or B” when used with an open-ended term such as “including” may mean, in one embodiment, A without B (optionally including elements other than B); in another embodiment, B without A (optionally including elements other than A); in yet another embodiment, both A and B (optionally including other elements); and so on.

[0313] As used herein and in the claims, “or” should be understood to mean the same as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” is inclusive. It should be interpreted that it includes at least one number of elements or elements of a list, but also two or more number of elements or elements of a list, and optionally, additional non-list items. Only in terms that are clearly shown to be in opposition to each other, for example, “just one” or “exactly one,” or “consisting of” when used in claims, it means including some of the elements or exactly one of the list. In general, when used herein, the term “or” shall be interpreted only to indicate an exclusive choice (i.e., “one or the other, but not both”) when preceded by an exclusive term such as “either,” “one of,” “only one,” or “exactly one.” When used in claims, “essentially” shall have its usual meaning as used in the field of patent law.

[0314] As used herein and in the claims, in relation to a list of one or more elements, the phrase “at least one” should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each element specifically listed in the list of elements and all elements together, and not excluding any combination of elements in the list of elements. This definition also allows for the presence of elements other than those specifically identified in the list of elements to which the phrase “at least one” refers, whether related to or unrelated to those specifically identified elements, at the discretion of the user. Therefore, as a non-restrictive example, “at least one of A and B” (or, in the same sense, “at least one of A or B” or, in the same sense, “at least one of A and / or B”) may mean, in one embodiment, at least one optionally containing two or more A's and no B (and optionally containing elements other than B); in another embodiment, at least one optionally containing two or more B's and no A (and optionally containing elements other than A); in yet another embodiment, at least one optionally containing two or more A's and at least one optionally containing two or more B's (and optionally containing other elements); and so on.

[0315] In the claims and the above specification, all transitional clauses, such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” and “holding,” should be understood to be open-ended, meaning they include but are not limited to them. As described in U.S. Patent and Trademark Office Manual of Examination Procedure 2111.03, only the transitional clauses “consisting of” and “consisting essentially of” are considered restrictive or semi-restrictive transitional clauses, respectively. For example, the present invention provides the following items: (Item 1) A retention structure, Fillable polymer elements, A first linker that bonds the fillable polymer element to a second polymer element, A second linker bonded to the fillable polymer element and / or elastic polymer element, comprising at least a portion of the fillable polymer element and / or elastic polymer element, The fillable polymer element, the second polymer element, and the first linker, and at least one of the second linker, include an elastic polymer element. The fillable polymer elements constitute at least about 60% by weight of the total structural weight. The aforementioned retention structure is characterized by a folding force of at least about 0.2N, The first linker is decomposable under the physiological conditions of the first set, The second linker is a retained structure that is decomposable under a second set of physiological conditions different from those of the first set, and is substantially not decomposable under the conditions of the first set. (Item 2) The retention structure according to item 1, wherein the first linker includes an elastic polymer element. (Item 3) The retention structure according to item 1, wherein the second linker includes an elastic polymer element. (Item 4) A retention structure, Fillable polymer elements, It comprises a second polymer element bonded to the fillable polymer element via at least one decomposable linker, Here, the decomposable linker comprises at least a portion of the fillable polymer element and / or the second polymer element, or is bonded to the fillable polymer element and / or the second polymer element. At least one of the fillable polymer element, the second polymer element, and the decomposable linker includes an elastic polymer element. The fillable polymer elements constitute at least about 60% by weight of the total structural weight. It has a folding force of at least approximately 0.2N, A retention structure having an incompressible cross-sectional dimension of at least approximately 2 cm. (Item 5) A retention structure, A fillable polymer element and a second polymer element bonded to the fillable polymer element, A fillable polymer element and / or a portion of the second polymer element, or a fillable polymer element and / or a portion of the second polymer element, comprising at least one decomposable linker bonded to the fillable polymer element and / or the second polymer element, A retention structure configured to be held in a position inside the subject for at least approximately 24 hours. (Item 6) The retention structure according to item 5, wherein at least one of the fillable polymer element, the second polymer element, and the decomposable linker comprises an elastic polymer element. (Item 7) A retention structure, A fillable polymer element and a second polymer element bonded to the fillable polymer element, A fillable polymer element and / or a portion of the second polymer element, or a fillable polymer element and / or a portion of the second polymer element, comprising at least one decomposable linker bonded to the fillable polymer element and / or the second polymer element, The fillable polymer element contains an active substance, The retention structure is configured such that the active substance is released from the fillable polymer material at a specific initial average rate measured from the release over the first 24 hours. A retaining structure in which the active substance is released over a 24-hour period following the initial 24-hour release at an average rate of at least about 1% of the initial average rate. (Item 8) The retention structure according to item 7, wherein at least one of the fillable polymer element, the second polymer element, and the decomposable linker comprises an elastic polymer element. (Item 9) The retention structure according to any one of items 4 to 8, wherein the second polymer element includes the elastic polymer element. (Item 10) The retention structure according to any one of items 4 to 9, wherein the decomposable linker comprises an elastic polymer element. (Item 11) A retention structure according to any one of items 4 to 10, further comprising additional elastic polymer elements. (Item 12) The retention structure according to any one of items 4 to 11, wherein the decomposable linker comprises at least a portion of the fillable polymer element and / or the second polymer element, or is bonded to the fillable polymer element and / or the second polymer element. (Item 13) A retaining structure containing an active substance, as described in any one of items 1 to 5. (Item 14) The retention structure according to item 7 or 13, wherein the active substance is a therapeutic agent. (Item 15) A retention structure according to any of the above items, having a first configuration configured to maintain an in vivo position relative to an internal opening. (Item 16) A retention structure according to any of the above items, wherein the first configuration has a polygonal shape. (Item 17) The retention structure according to any one of items 1 to 15, wherein the first configuration has a multi-armed star shape. (Item 18) A retention structure as described in item 17, having 3 to 8 arms. (Item 19) A retention structure according to any of the above items, wherein the fillable polymer element is bonded to the second polymer element via an adhesive, by chemical bonding, and / or by interpenetrating polymer chains. (Item 20) The retention structure according to any of the preceding items, wherein the second polymer element is configured to withstand mechanical bending deformation of at least about 45 degrees, at least about 60 degrees, at least about 90 degrees, at least about 120 degrees, at least about 150 degrees, or at least about 180 degrees without breaking. (Item 21) The retention structure according to any of the above items, wherein the second polymer element is configured to remain in a deformed configuration for a period of time of at least about 24 hours, at least about 1 week, at least about 1 month, at least about 1 year, or at least about 2 years, and to substantially return to its pre-deformed configuration after the said period. (Item 22) The retention structure according to any of the above items, wherein the elastic modulus of the second polymer element is in the range of approximately 0.1 MPa to approximately 30 MPa. (Item 23) The retention structure according to any of the above items, wherein the second polymer element does not substantially swell in the presence of biological fluids such as blood, water, bile, or gastric juice. (Item 24) A retention structure as described in item 23, which does not substantially swell in the presence of gastric juice. (Item 25) A retention structure according to any of the above items, wherein the device swells by less than about 10% by volume, less than about 5% by volume, less than about 2% by volume, or less than about 1% by volume compared to the volume of the first polymer element in a dry state in unagitated gastric juice or simulated gastric juice at physiological temperature. (Item 26) The retention structure described in item 25, wherein the aforementioned biological fluid is gastric juice. (Item 27) A retention structure according to any of the above items, wherein at least a portion of the second polymer element comprises polyesters such as polycaprolactone, poly(propylene fumarate), poly(glycerol sebacate), poly(lactide), poly(glycolic acid), poly(lactic acid-glycolic acid), polybutyrate, and polyhydroxyalkanoate; polyethers such as poly(ethylene oxide) and poly(propylene oxide); polysiloxanes such as poly(dimethylsiloxane); polyamides such as poly(caprolactam); polyacrylates / methacrylates such as poly(methyl methacrylate) and poly(ethyl vinyl acetate); polyanhydrides; and polyurethanes. (Item 28) The retention structure according to any of the above items, wherein at least a portion of the second polymer element comprises a multiblock polymer. (Item 29) The retention structure according to any of the above items, wherein the fillable polymer element comprises polycaprolactone (PCL), poly(ethylene-co-vinyl acetate), and / or polyethylene glycol (PEG). (Item 30) A retaining structure according to any of the above items, comprising the fillable polymer element in an amount of at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, or at least about 93% by weight, relative to the total weight of the structure. (Item 31) The retention structure according to either item 13 or 14, wherein the active substance is present in the fillable polymer elements in an amount ranging from about 0.01% by weight to about 50% by weight relative to the total weight of the fillable polymer elements. (Item 32) The residence structure according to any one of items 4 to 33, wherein the at least one decomposable linker is configured to dissociate at least partially over the residence period. (Item 33) The retention structure described in item 32, wherein the aforementioned retention period is in the range of 24 hours to 2 years. (Item 34) A retention structure according to any one of items 4 to 33, wherein at least one degradable linker is stable in a physiological environment for a set period of time of at least about 24 hours, at least about 48 hours, at least about 1 week, at least about 1 month, or at least about 1 year. (Item 35) The retention structure described in item 34, wherein the physiological environment is the gastric environment. (Item 36) The retention structure described in item 35, wherein the gastric environment includes the gastric cavity. (Item 37) A retention structure according to any one of items 4 to 36, wherein at least one degradable linker comprises an enteric-coated polymer. (Item 38) The retention structure according to item 37, wherein the enteric-coated polymer comprises cellulose phthalate acetate, hypromellose, hydroxypropyl methylcellulose, and / or poly(ethyl co-acrylate methacrylate). (Item 39) The retention structure according to item 37, wherein the enteric-coated polymer comprises poly(acryloyl-6-aminocaproic acid) and poly(methacrylate-co-ethyl acrylate). (Item 40) The retention structure according to any one of items 37 to 39, wherein the enteric-coated polymer is a polymer gel with a water content of 40% by volume or less. (Item 41) The retention structure according to any one of items 37 to 40, wherein the enteric-coated polymer comprises a polymer of acryloylaminoalkylene acid monomer or a salt thereof. (Item 42) The retention structure according to item 41, wherein the acryloylaminoalkylene acid monomer is selected from the group consisting of acryloyl-5-aminopentanoic acid, acryloyl-6-aminocaproic acid, acryloyl-7-aminoheptanoic acid, acryloyl-8-aminooctanoic acid, acryloyl-9-aminononanoic acid, acryloyl-10-aminodecanoic acid, acryloyl-11-aminoundecanoic acid, acryloyl-12-aminododecanoic acid, methacryloyl-5-aminopentanoic acid, methacryloyl-6-aminocaproic acid, methacryloyl-7-aminoheptanoic acid, methacryloyl-8-aminooctanoic acid, methacryloyl-9-aminononanoic acid, methacryloyl-10-aminodecanoic acid, methacryloyl-11-aminoundecanoic acid, methacryloyl-12-aminododecanoic acid, salts thereof, and combinations thereof. (Item 43) A retention structure according to any one of items 37 to 42, wherein at least one linker comprises an enteric polymer blend of at least two enteric polymers, the blend comprising a first enteric polymer as described in item D25 and a second enteric polymer comprising poly(methacrylate-co-alkyl acrylate) or a salt thereof. (Item 44) A retention structure according to any one of items 37 to 43, wherein at least one linker has a water content of less than about 40% by weight. (Item 45) The retention structure according to any one of items 37 to 44, wherein the enteric-coated polymer is configured to exhibit reversible elongation when stretched from 50% of its initial length to 1500%. (Item 46) A retention structure according to any one of items 37 to 45, wherein at least one linker is soluble in aqueous solution at a pH greater than approximately 6.0 as measured at room temperature, and substantially insoluble in aqueous solution for a period of 4 to 40 days at a pH less than approximately 3.0. (Item 47) The retention structure according to any one of items 37 to 46, wherein the enteric-coated polymer has an elastic modulus of 0.1 MPa to 100 MPa. (Item 48) The retention structure according to any one of item 13 or 14, wherein the active substance comprises at least one of the following: statins, antimalarial agents, hormones, levothyroxine, ivermectin, antiretroviral agents, anthelmintics, antipsychotics, antidepressants, and caffeine. (Item 49) The retention structure according to any one of item 13 or 14, wherein the active substance comprises at least one of the following: protein, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, and vitamin D. (Item 50) A retention structure according to any of the preceding items, wherein one or more elements and / or one or more linkers comprise a food-grade crosslinked polymer. (Item 51) The retention structure according to any one of items 1 to 15, wherein the structure has a shape that includes an opening. (Item 52) The said structure occupies approximately 10% to approximately 90% of the volume of the convex hull of the said structure. A retention structure as described in any of the items. (Item 53) A system for delivering retained structures, Containment structure and The accommodation structure includes a dwelling structure housed within the aforementioned accommodation structure, The retention structure is constructed and arranged to have a first configuration after being released from the containment structure. The aforementioned storage structure is constructed and arranged to have a second configuration when housed within the aforementioned accommodation structure. The first configuration has an incompressible cross-sectional dimension of at least about 2 cm, The second configuration has a convex hull that is at least about 10% smaller than the convex hull of the first configuration, and / or the second configuration has a maximum cross-sectional dimension that is at least about 10% smaller than the maximum cross-sectional dimension of the first configuration. A system in which a first part of the device is disassembled under the physiological conditions of a first set, but a second part of the device is substantially not disassembled under the physiological conditions of the first set. (Item 54) The system according to item 53, wherein the retention structure comprises a fillable polymer element and at least one degradable linker bonded to the fillable polymer element. (Item 55) The system according to item 53 or 54, wherein the second part of the device is disassembled under the physiological conditions of a second set. (Item 56) The system according to any one of items 53 to 55, wherein at least a portion of the device is bendable and / or flexible. (Item 57) The system according to any one of items 53 to 56, wherein the containment structure is configured to be used for at least one of ingestion, self-administration, and oral administration. (Item 58) The system according to any one of items 53 to 57, wherein the containment structure includes at least one of 000 capsules, 00 capsules, 0 capsules, 1 capsule, 2 capsules, 3 capsules, 4 capsules, and 5 capsules. (Item 59) The system according to any one of items 53 to 58, wherein the second configuration is configured such that the retention structure occupies a volume greater than 60% of the cavity defined by the containment structure. (Item 60) The system according to any one of items 53 to 59, wherein the retention structure is configured to assume the first configuration upon discharge from the containment structure. (Item 61) The system according to any one of items 53 to 60, wherein the retention structure includes an elastic polymer element. (Item 62) The system according to item 61, wherein the elastic polymer element has sufficient rebound strength to substantially return the elastic polymer element to its pre-deformation shape in less than about 30 minutes, and in less than about 10 minutes, less than about 5 minutes, or less than about 1 minute after the release of mechanical deformation. (Item 63) The system according to any one of items 53 to 62, wherein, prior to release from the containment structure, the retention structure is stored in the containment structure in the second configuration for a period longer than at least one of 72 hours, 1 week, 2 weeks, 4 weeks, 1 year, and 5 years. (Item 64) The system according to any one of items 53 to 63, wherein the maximum cross-sectional dimension of the first configuration is at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% smaller than the maximum cross-sectional dimension of the second configuration. (Item 65) The system according to any one of items 53 to 64, wherein the volume of the convex hull of the first configuration is at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% smaller than the volume of the convex hull of the second configuration. (Item 66) A method for delivering a retained structure, A step of administering a containment structure containing a retaining structure to a subject, wherein the containment structure releases the retaining structure at a location within the subject, The aforementioned storage structure has a second configuration within the accommodation structure, A method for obtaining a first configuration such that, after the retention structure is released from the containment structure, the retention structure is retained in or near the subject for at least about 24 hours. (Item 67) The method according to item 66, wherein the location within the test body is an opening or a cavity. (Item 68) A method for delivering a retained structure, A step of administering a containment structure containing a retaining structure to a subject, wherein the containment structure releases the retaining structure at a location within the subject, The aforementioned storage structure has a second configuration within the accommodation structure, The retention device includes a fillable polymer element containing an active substance, The retention structure is configured such that the active substance is released from the retention structure at an initial average rate over the first 24 hours of release. A method wherein the active substance is released over a 24-hour period following the initial 24-hour release at an average rate of at least about 1% of the initial average rate. (Item 69) The retention structure includes an elastic polymer element and a fillable polymer element mechanically bonded to the elastic polymer element, The fillable polymer elements constitute at least about 60% by weight of the total structural weight. The method according to item 66 or 68, wherein the retaining structure has a folding force of at least about 0.2 N. (Item 70) The method according to item 66 or 68, wherein the second configuration has a convex hull that is at least about 10% smaller than the convex hull of the first configuration, and / or the second configuration has a maximum cross-sectional dimension that is at least about 10% smaller than the maximum cross-sectional dimension of the first configuration. (Item 71) The method according to any one of items 66 to 70, wherein the retention structure is the retention structure described in any one of items A to D35. (Item 72) The method according to any one of items 66 to 71, wherein the retention structure is filled with at least one of a therapeutic agent, a diagnostic agent, and an enhancer before the retention structure is administered to the subject. (Item 73) The method according to item 68, wherein 0.05% to 99% by weight of the active substance is released between 24 hours and 1 year after the administration step. (Item 74) The method according to any one of items 66 to 73, wherein the internal location of the subject is an internal cavity, and the retention structure is held within the cavity by an internal opening. (Item 75) The method according to item 74, wherein the retention structure does not substantially restrict the flow of liquid through the internal opening during the period in which the retention structure is held within the cavity. (Item 76) The method according to item 75, wherein the internal opening is the gastric pylorus. (Item 77) The method according to any one of items 66 to 76, wherein the retention structure includes at least one degradable linker bonded to the fillable polymer element. (Item 78) The method according to item 77, wherein the dissociation of at least one linker ends the residence period and allows passage through the internal opening of the residence structure. (Item 79) The method according to any one of items 66 to 78, wherein, after the retaining structure is released from the containment structure, the retaining structure releases the active substance at a continuous 24-hour average rate measured at at least one point in time between 48 hours and about 1 year after the initial release, which is about 1% to about 99% of the initial mean release rate measured over an initial 24-hour period beginning immediately after the release.

Claims

1. A method for creating a gastric retention structure containing an active substance, The steps of forming one or more arms comprising one or more polymer elements and at least one active substance; and The step of connecting one or more arms to an elastic element using at least one linker. Including; here: a) The gastric retention structure has a first configuration and a second configuration different from the first configuration and is constrained by a restraint, the gastric retention structure is configured to bounce in the second configuration so as to return to the first configuration, and the elastic element is configured such that the gastric retention structure bounces substantially after being mechanically deformed by the restraint; and / or b) The at least one linker is decomposable and configured to decompose so that, after exposure to gastric lumen conditions, the gastric retention structure breaks apart and is released from its position within the subject. method.

2. A method according to claim 1, wherein the step of forming the one or more arms includes filling the one or more polymer materials of the one or more polymer elements with the at least one active substance by direct addition, conjugation reaction, powder mixing, solvent filling, melt filling, or physical blending the one or more polymer materials with the at least one active substance.

3. A method according to claim 1 or 2, wherein the elastic element does not contain an active substance.

4. A method according to any one of claims 1 to 3, wherein the active substance is: a) Encapsulated within a polymer matrix of one or more polymer elements; or b) Chemically bonded to the polymer of one or more polymer elements, method.

5. A method according to any one of claims 1 to 4, wherein, a) The one or more polymer elements include polycaprolactone (PCL), poly(ethylene-co-vinyl acetate), and / or polyethylene glycol (PEG); and / or b) The one or more polymer elements contain an active substance in an amount of 0 to 50% by weight of the total weight of the one or more polymer elements; and / or c) The linker element comprises at least one polymer selected from the group consisting of polycaprolactone, poly(propylene fumarate), poly(glycerol sebacate), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), polybutyrate, polyhydroxyalkanoate, polyether, polyamide, polyvinyl alcohol, polyoxetane, polyacrylate, polymethacrylate, polyanhydride, polyurethane, enteric polymer, and copolymers thereof. method.

6. A method according to any one of claims 1 to 5, wherein the active substance is a) Therapeutic drugs; and / or b) Diagnostic agents; and / or c) Antiviral agents; and / or d) Antiretroviral agents; and / or e) Antipsychotic drugs; and / or f) Immunosuppressants; and / or g) Neuroprotective agents Methods that include...

7. A method according to any one of claims 1 to 6, wherein the active substance is a nonsteroidal anti-inflammatory drug, a selective serotonin reuptake inhibitor, an anticoagulant, a steroid, an antipsychotic, an antagonist, a cardiac glycoside, an alpha-blocker, a cholesterol absorption inhibitor, a metabolite, an antihistamine, an opioid, a proton pump inhibitor, an antiviral agent, an antibiotic, an antimalarial agent, a sulfonamide, a drug abuse treatment, a contraceptive, a stimulant, an analgesic, an anti-analgesic, an anti-inflammatory drug, Methods involving antipyretics, antidepressants, antiepileptics, antipsychotics, neuroprotective agents, antiproliferative agents, anticancer agents, antimigraine agents, antibacterial agents, antifungal agents, antiviral agents, antiparasitic agents, antimuscarinic agents, anxiolytics, bacteriostatic agents, immunosuppressants, sedatives, hypnotics, bronchodilators, antiasthmatics, cardiovascular drugs, anesthetics, anticoagulants, dopamine agonists, electrolytes, gastrointestinal drugs, muscle relaxants, parasympathetic agonists, appetite suppressants, antinarcolepsy drugs, proteins, peptides, hormones, nucleic acids, gene constructs, HMG co-A reductase inhibitors, minerals, prostaglandins, nutritional supplements, corticosteroids, dietary supplements, plant extracts, or plant hormones.

8. The method according to claim 7, wherein the active substance is rosuvastatin, meloxicam, escitalopram, clopidogrel, prasugrel, prednisone, aripiprazole, risperidone, buprenorphine, naloxone, montelukast, memantine, digoxin, tamsulosin, ezetimibe, colchicine, loratadine, cetirizine, loperamide, omeprazole, entecavir, doxycycline, ciprofloxacin, azithromycin, quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanyldapsone, sulfadoxine, sulfamethoxypyridazine, mefloquine, atobakon, primaquine, halophanthrine, doxycycline, clindamycin, artemisinin, artemisinin derivatives, artemetha, dihydro The method involves lutemisinin, artetel, artesunate, synthroid / levothyroxine, methadone, varenicline, caffeine, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, or vitamin D.

9. A method according to claim 7, wherein the active substance is a selective serotonin reuptake inhibitor, an antidepressant, an anxiolytic, a sedative, a hypnotic, an opioid, an anti-migraine agent, a cholesterol absorption inhibitor, a drug abuse treatment, an immunosuppressant, an HMG co-A reductase inhibitor, an anticoagulant, a cardiac glycoside, an antibiotic, a contraceptive, an analgesic, an anesthetic, a nonsteroidal anti-inflammatory drug, an antiepileptic drug, or an alpha-blocker.

10. The method according to claim 7, wherein the active substance is prednisone, risperidone, memantine, methadone, rosuvastatin, doxycycline, buprenorphine, aripiprazole, meloxicam, or azithromycin.

11. A method according to any one of claims 1 to 10, wherein at least a portion of the elastic element comprises a polyester selected from polycaprolactone, poly(propylene fumarate), poly(glycerol sebacate), poly(lactide), poly(glycolic acid), poly(lactic acid-glycolic acid), polybutyrate, and polyhydroxyalkanoate; a polyether selected from poly(ethylene oxide) and poly(propylene oxide); a polysiloxane which is poly(dimethylsiloxane); a polyamide which is poly(caprolactam); a polyacrylate which is poly(methyl methacrylate); a poly(ethyl vinyl acetate); a polyanhydride; and a polyurethane.

12. A method according to any one of claims 1 to 11, wherein, a) The one or more polymer elements constitute at least 60% by weight of the total structural weight; and / or b) The gastric retention structure has a folding force of at least 0.2 N, where the folding force is determined by measuring the force required to move the structure through the 2 cm lower diameter by placing the structure in a funnel having an upper diameter of 20 cm and a lower diameter of 2 cm, attaching a plunger to the tensile crosshead of a tensile load testing machine, attaching the funnel to a clamp, and pushing the structure through the funnel at a speed of 10 mm / min, while measuring the force and displacement, where the folding force is determined by measuring the force required to fold the structure and enter the tube of the 2 cm lower diameter; and / or c) The retention structure has an incompressible cross-sectional dimension of at least 2 cm; and / or d) The retention structure is configured to be held in a position inside the subject for at least 24 hours. method.

13. A method according to any one of claims 1 to 12, wherein the gastric retention structure is configured such that the active substance is released from the one or more polymer materials at a specific initial average rate determined over an initial 24-hour period of release; and wherein the active substance is released at an average rate of at least 1% of the initial average rate over a 24-hour period following the initial 24-hour period of release.

14. A method according to any one of claims 1 to 13, wherein the gastric retention structure is compressed by constraints including a retaining element and / or a capsule.

15. First elastic element, A second polymer element containing an active substance and configured to release the active substance, and at least one linker A method for creating a retention structure including, The method includes the step of linking the first elastic element to the second polymer element using at least one linker, Here, a) The structure has a first configuration and a second configuration different from the first configuration and is constrained by a restraint, the structure in the second configuration is configured to bounce back so that the structure returns to the first configuration, and the elastic element is configured such that the structure substantially bounces back after being mechanically deformed by the restraint; and / or b) The at least one linker is decomposable and configured to decompose so that, after exposure to gastric lumen conditions, the retained structure breaks apart and is released from its position inside the subject. method.

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