Residence structure and related method

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 under U.S.C. §119(e) to co-pending U.S. Provisional Application No. 62 / 010,992, filed June 11, 2014, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] Government Support Statement This invention was made with Government support under Grant No. 5T32HL007604-28 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0003] FIELD OF THE DISCLOSURE The embodiments described herein relate generally 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, with adherence to oral treatments for chronic asymptomatic conditions 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 where treatment does not provide immediately evident benefit. Many factors contribute to low adherence, including treatment cost, access, side effects, and inconvenience of the dosing regimen.

[0005] Current state-of-the-art approaches to improve adherence include educational interventions, telephone counseling, health information technology solutions, interactive pharmacy tools, and changes in payment models such as post-myocardial infarction copayment-free plans. All of these approaches achieve only modest improvements. Meanwhile, pharmacological solutions to the adherence problem typically require invasive delivery structures and a subset of pharmacological agents formulated for sustained release. Recent advances in sustained release pharmacological systems have been limited primarily to subcutaneous, transdermal, intravaginal, and surgical implants. Traditional solutions include invasive methods such as surgical implants (including, for example, wireless programmable structures available from MicroCHIPS, Inc. (Lexington, MA)) or specialized methods such as birth control (including, for example, NuvaRing® and Implanon® (both available from Merck & Co., Inc. (Whitehouse Station, NJ)). Constructs such as those available from MicoCHIPS are also limited to the delivery of highly potent therapeutics because they can only be administered in microgram or submicrogram amounts.

[0006] Although oral administration has the potential for widest range of patient acceptance, oral delivery systems have not been shown to allow sustained release via the oral route due to several fundamental barriers. First, the transit time of a bolus of food, 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. Thus, one strategy for long-term therapeutic delivery would be to extend the transit time of orally administered therapeutics (but not food). Gastric retention and / or delayed transit in some segments of the gastrointestinal tract, as also shown in bezoars and bariatric structures, are common. Passage may be attempted and / or tolerated. Bezoars (i.e., masses found trapped in the gastrointestinal system) may form from a variety of indigestible materials (such as food aggregates and hair) and often only become clinically evident in human adults when they reach a size of several hundred grams. Bariatric constructs such as intragastric balloons administered endoscopically can be used to fill a portion of a patient's stomach to achieve non-invasive gastric reduction for weight loss. Previous attempts at gastric retention for drug delivery include mucoadhesion, gastric distension, and floating on gastric juice. However, none of these approaches alone demonstrated gastric retention greater than 24 hours that translated to clinical use. Summary of the Invention [Means for solving the problem]

[0007] Generally, 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 that connects the fillable polymer element to a second polymer element, and a second linker that comprises or connects at least a portion of 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 structure weight, 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, 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 comprising at least a portion of the fillable polymer element and / or the second polymer element, or attached to the fillable polymer element via at least one degradable linker attached 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 degradable linker comprises an elastic polymer element, the fillable polymer element constitutes at least about 60% by weight of the total structure weight, 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 attached to the fillable polymer element, and at least one degradable linker comprising at least a portion of the fillable polymer element and / or the second polymer element or attached to the fillable polymer element and / or the second polymer element, and is configured such that the retention structure is retained at a location within the subject for at least about 24 hours.

[0011] In some embodiments, the retention structure comprises a fillable polymer element and a second polymer element attached to the fillable polymer element, and at least one degradable linker comprising at least a portion of the fillable polymer element and / or the second polymer element or attached to the fillable polymer element and / or the second polymer element, wherein the fillable polymer element comprises an active agent, and the retention structure is configured such that the active agent is released from the loadable polymer material at a particular initial average rate, measured from release over an initial 24 hour period, 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 following release in the initial 24 hours.

[0012] In another aspect, a system is provided. In some embodiments, the system includes a containment structure. the retention structure constructed and arranged to have a first configuration after release from the containing structure, the retention structure constructed and arranged to have a second configuration when contained within the containing structure, the first configuration having an uncompressed cross-sectional dimension of at least about 2 cm, the second configuration having a convex hull that is at least about 10% smaller than a convex hull of the first configuration, and / or the second configuration having a maximum cross-sectional dimension that is at least about 10% smaller than a maximum cross-sectional dimension of the first configuration, and the first portion of the device is degradable under a first set of physiological conditions, while the second portion of the device is substantially not degradable under the first set of physiological conditions.

[0013] In another aspect, a method for delivering a retention structure is provided. In some embodiments, the method includes administering to a subject a containment structure that includes a retention structure, whereby the containment structure releases the retention structure at a location within the subject, the retention structure has a second configuration within the containment structure, and acquires a first configuration such that the retention structure is retained at or near a location within the subject for at least about 24 hours after the retention structure is released from the containment structure.

[0014] In some embodiments, the method includes administering to a subject a containment structure comprising a retention structure, whereby the containment structure releases the retention structure at a location within the subject, where the retention structure has a second configuration within the containment structure, where the retention device comprises a fillable polymeric element comprising an active agent, and where the retention structure is configured such that the active agent is released from the retention structure at an initial average rate of release over a first 24 hours, and where 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 in the initial 24 hours.

[0015] In another embodiment, the containment structure is constructed and arranged to be administered to a subject, where the containment structure comprises a retention structure, whereby at a location within the subject the containment structure releases the retention structure, where the retention structure has a second configuration within the containment structure, and whereby after the retention structure is released from the containment structure, the retention structure acquires the first configuration such that the retention structure 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 arranged to be administered to a subject, the containment structure comprising a retention structure whereby the containment structure releases the retention structure at a location within the subject, the retention structure has a second configuration within the containment structure, the retention device comprises a fillable polymeric element comprising an active agent, the active agent is released from the retention structure at an initial average rate of release over a first 24 hours, and the retention structure is configured such that 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 in the first 24 hours.

[0017] In some embodiments, the system comprises at least one retention structure configured to administer at least one of a therapeutic agent, a diagnostic agent, and an enhancing agent for a residence period greater than at least 24 hours, wherein the at least one retention structure has a first shape configured to maintain an in vivo position relative to the internal opening during the residence period, and the at least one retention structure comprises at least one enteric elastomeric linker positioned such that a level of dissociation of the at least one enteric elastomeric linker terminates the residence 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 at least one of transport and maintain the at least one structure during a residence period greater than at least 24 hours, wherein the at least one retention structure has a first shape configured to maintain an in vivo position relative to the internal opening during the residence period, and wherein the at least one retention structure is configured to have a level of dissociation of the at least one enteric elastomeric linker greater than or equal to 24 hours during the residence period. and at least one enteric elastomeric linker positioned to terminate the space between the inner opening and pass the at least one retention structure through the inner opening.

[0019] In some embodiments, at least one enteric elastomeric linker is configured to at least partially dissociate during the retention time.

[0020] In some embodiments, the at least one holding structure is loaded with at least one of a therapeutic agent, a diagnostic agent, and a potentiating agent prior to administration of the at least one holding structure to a subject.

[0021] In some embodiments, after administration of the at least one retention structure to a subject, the at least one retention structure is loaded in vivo with at least one of a therapeutic agent, a diagnostic agent, and an enhancing agent.

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

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

[0024] In some embodiments, the at least one containment structure is configured for ingestion, self-administration, and / or oral administration.

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

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

[0027] In some embodiments, the retention structure is configured to assume a first shape upon release from the containment structure.

[0028] In some embodiments, prior to release from the containment structure, the retention structure is stored in the second shape in the containment structure for at least any of 72 hours, 1 week, 2 weeks, 4 weeks, 1 year, and 5 years.

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

[0030] In some embodiments, at least one enteric elastomeric linker is disposed along the longitudinal axis.

[0031] In some embodiments, the at least one retention structure further comprises at least one of a core, a plurality of radial protrusions coupled to the core, and a plurality of radial protrusions integral with the core, wherein the first shape comprises a plurality of protrusions protruding in a plurality of directions from the core, and the second shape comprises a plurality of protrusions protruding from the core in directions substantially parallel to one another.

[0032] In some embodiments, the at least one enteric elastomeric linker comprises a first enteric elastomeric linker disposed along a first radial projection in the plurality of radial projections.

[0033] In some embodiments, the at least one enteric elastomeric linker comprises a first enteric elastomeric linker connecting a first radial projection in the plurality of radial projections to the core.

[0034] In some embodiments, the core comprises at least one enteric elastomeric linker.

[0035] In some embodiments, a first radial projection in the plurality of radial projections has a length corresponding to a maximum dimension of the receiving structure.

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

[0037] In some embodiments, at least one retention structure further comprises a deformable material, the first shape comprises a polygonal outline in a first plane, the second shape comprises each side of the folded polygonal outline, and at least one enteric elastomeric linker is disposed at each vertex of the polygonal outline.

[0038] In some embodiments, a first side of the polygonal outline has a length that corresponds to the length of the receiving structure.

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

[0040] In some embodiments, at least one retention structure further comprises a deformable material, the first shape comprises a ring and the second shape comprises a ring folded into a quadrant, and at least one enteric elastomeric linker is disposed at each vertex of each arc of the quadrant.

[0041] In some embodiments, at least one retention structure further comprises a core, a plurality of small, rounded loops attached to the core, and a plurality of small, rounded loops integral with the core, wherein the small, rounded loops comprise a shape memory alloy, the core comprises at least one enteric elastomeric linker, the first shape comprises a plurality of small, rounded loops extending from the core, and the second shape comprises a plurality of small, rounded loops folded against 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 by at least the retention time.

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

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

[0045] In some embodiments, at least one retention structure comprises a therapeutic agent formulated for release. It is loaded with a mass of at least one of a drug, a diagnostic agent, and an enhancing agent.

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

[0047] In some embodiments, exposure of the at least one enteric elastomeric linker to at least one alkaline solution accelerates dissociation of the at least one enteric elastomeric linker to a level of dissociation that terminates the retention time and passes the at least one retention structure through the internal opening.

[0048] In some embodiments, at least one retention structure is solvent filled. The composition further comprises at least one material configured to be loaded with drug by at least one of the following methods: loading, melt loading, physical blending, supercritical carbon dioxide, and conjugation reactions.

[0049] In some embodiments, the at least one material configured to be loaded with a drug is further configured to administer the at least one loaded drug by at least one of diffusion and slow matrix degradation, dissolution, degradation, swelling, diffusion of the at least one loaded drug, ion gradients, hydrolysis, and cleavage of conjugated bonds.

[0050] In some embodiments, at least one enteric elastomeric linker is distinct from the delivery material and is configured to at least partially withstand drug loading.

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

[0052] In some embodiments, the acryloyl amino alkylene acid monomer is acryloyl-5-aminopentanoic acid, acryloyl-6-aminocaproic acid, acryloyl-7-aminoheptanoic acid, acryloyl-8-aminooctanoic acid, acryloyl-9-aminonoanoic 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, 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, meth ... acid), 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 elastomeric linker comprises an enteric polymer blend of at least two enteric polymers, the blend comprising a first enteric polymer of claim 37 and a second enteric polymer comprising poly(methacrylic acid-co-alkyl acrylate), or a salt thereof.

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

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

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

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

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

[0059] In some embodiments, at least one enteric elastomeric linker comprises an enteric polymer composition comprising a first enteric polymer of claim 37, or a salt thereof, and optionally a second enteric poly(methacrylic acid-co-ethyl acrylate), or a salt thereof, wherein the weight ratio of the first enteric polymer to the second enteric polymer ranges from about 1:0 to about 1:3.

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

[0061] In some embodiments, the enteric 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 polymer blend exhibits reversible elongation when stretched 50% to 1500% from its initial length.

[0065] In some embodiments, the blend is soluble in an aqueous solution at a pH greater than about 6.0 and insoluble when immersed in an aqueous solution at a pH less than about 3.0, measured at room temperature over a period of 4 to 40 days.

[0066] In some embodiments, the enteric polymer blend has a Young's modulus between 0.1 MPa and 100 MPa.

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

[0068] One aspect of the invention contemplates a gastric retention device comprising a central elastic polymer element attached to three to eight fillable polymer elements, each of which projects radially from the central elastic polymer element to form a star-shaped cross-sectional shape, each of which is attached to the central elastic polymer element. A first degradable linker is present in each of the fillable polymer elements near or at the interface with the elastic polymer elements. In certain embodiments, the loadable 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 loadable polymer element comprises polycaprolactone, polylactic acid, polylactic co-glycolic acid, and / or mixtures thereof, and may further comprise an excipient, and the degradable linker is water soluble. The polymers may be hydrophilic and / or degradable polymers and blends thereof, including, but not limited to, polyvinylpyrrolidone, polyvinyl alcohol, Kollidon VA 64, polyorthoesters, polyhydroxybutyrate, Eudragit, and mixtures thereof. The device may further comprise at least one of a therapeutic agent, a diagnostic agent, and a enhancing agent, where the therapeutic agent is selected from a hydrophilic drug, a hydrophobic drug, artemectin, ivermectin, risperidone, doxycycline, an antimalarial, an antiparasitic, an antipsychotic, and an antibiotic.

[0069] The devices of these embodiments may be housed within a soluble container, such as one constructed from gelatin and optionally including excipients. In certain embodiments, the devices have a minimum uncompressed cross-sectional dimension of about 3 to 5.5 cm, about 3 cm, about 4 cm, about 5 cm, or about 5.5 cm. Intermediate minimum uncompressed cross-sectional dimensions are also contemplated. In certain embodiments, the fillable polymeric element has a length approximately equal to the length of the soluble container, such that the unencapsulated form has a diameter approximately equal to twice the length of the soluble container. In certain embodiments, the fillable polymeric element has a length of about 1.3 to about 2.7 cm. It is contemplated that the gastric retention device of the above embodiments may be retained in the gastric cavity for 24 hours to about 1 month, or for about 24 hours to 10 days.

[0070] Another aspect of the invention is a gastric retention device comprising a central elastic polymer element comprising polyurethane, the elastic polymer element being attached to six loadable polymer elements, each of which projects radially from the central elastic polymer element to form a star-shaped cross-sectional shape, each of which is attached to the central elastic polymer element by a time-dependent degradable linker, the loadable polymer elements further comprising an embedded linker comprising an enteric polymer. In certain embodiments, the loadable polymer element comprises polycaprolactone and may optionally comprise an excipient, the degradable linker being a water-soluble and / or degradable polymer and blends thereof, including, but not limited to, polyvinylpyrrolidone, polyvinyl alcohol, Kollidon VA 64, polyorthoesters, polyhydroxybutyrate, Eudragit, and mixtures thereof. In certain embodiments, the device is housed in a soluble container that may optionally comprise an excipient. The device may further comprise at least one of a therapeutic agent, a diagnostic agent, and a enhancing agent, where the therapeutic agent is selected from a hydrophilic drug, a hydrophobic drug, artemectin, ivermectin, risperidone, doxycycline, an antimalarial drug, an antiparasitic drug, an antipsychotic drug, and an antibiotic.

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

[0072] It is contemplated that the gastric retention devices of these above embodiments may be retained in the gastric cavity for between 24 hours and about 1 month, or between about 24 hours and 10 days. In certain embodiments, the linker comprising the enteric polymer degrades in response to a pH greater than about 5, thereby causing the fillable polymer element to break apart.

[0073] In some embodiments, the method includes administering to a subject at least one retention structure configured to administer at least one of a therapeutic agent, a diagnostic agent, and an enhancing agent for a residence period greater than at least 24 hours, wherein the at least one retention structure has a first shape configured to maintain an in vivo position relative to an internal opening during the residence period, and wherein the at least one retention structure is configured to inhibit dissociation of at least one enteric elastomeric linker. The level includes at least one enteric elastomeric linker positioned to terminate the residence period and pass the at least one residence structure through the internal opening.

[0074] In some embodiments, the method includes administering to a subject at least one retention structure configured to at least transport and / or maintain the at least one structure for a retention period greater than at least 24 hours, wherein the at least one retention structure has a first shape configured to maintain an in vivo position relative to the internal opening during the retention period, and the at least one retention structure comprises at least one enteric elastomeric linker arranged such that a level of dissociation of the at least one enteric elastomeric linker terminates 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 from the following detailed description of various non-limiting embodiments of the invention, taken in conjunction with the accompanying drawings. In cases where the specification and any document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control.

[0076] Non-limiting embodiments of the present invention are described by way of example with reference to the accompanying drawings, which are schematic and are not intended to be drawn to scale. In the drawings, each identical or nearly identical element is typically represented by a common numeral. For clarity, not every element is labeled in every figure, and not every element of each embodiment of the present invention is shown unless necessary to enable a person skilled in the art to understand the invention. [Brief description of the drawings]

[0077] [Figure 1A] FIG. 1A is a schematic diagram of a retention structure, according to one set of embodiments. [Figure 1B] FIG. 1B is a schematic diagram of a retention structure, according to one set of embodiments. [Figure 1C] FIG. 1C is a schematic diagram of a retention structure, according to one set of embodiments. [Figure 1D] FIG. 1D is a schematic diagram illustrating the convex hull volume of a structure according to one set of embodiments. [Figure 1E] FIG. 1E is a schematic diagram of an exemplary configuration of a retention structure, according to one set of embodiments. [Figure 1F] FIG. 1F is a schematic diagram of an exemplary configuration of a retention structure, according to one set of embodiments. [Figure 1G] FIG. 1G is a schematic diagram of another exemplary configuration of a retention structure, according to one set of embodiments. [Figure 1H] FIG. 1H is a schematic diagram of another exemplary configuration of a retention structure, according to one set of embodiments. [Diagram 2] FIG. 2 is a photocopy of an exemplary retention structure and a method of folding the structure, according to one set of embodiments. [Figure 3A] FIG. 3A is a copy of a photograph of an exemplary retention system and structure showing the exemplary structure and encapsulation structure according to one set of embodiments. [Figure 3B] FIG. 3B is a copy of a photograph of an exemplary retention system and structure showing the exemplary structure folded within an encapsulation structure, according to one set of embodiments. [Figure 3C] FIG. 3C is a copy of a photograph of an exemplary retention system and structure showing another view of the exemplary structure, according to one set of embodiments. [Figure 3D] FIG. 3D is a copy of a photograph of an exemplary retention system and structure showing an exemplary twisted structure according to one set of embodiments. [Figure 3E] FIG. 3E is a copy of a photograph of an exemplary retention system and structure showing the exemplary structure of (D) screwed into an encapsulation structure according to one set of embodiments. [Figure 4A] FIG. 4A is a diagram of an exemplary retention structure including protrusions and a containing capsule, according to one set of embodiments. [Figure 4B] FIG. 4B is a diagram of various representative retention structures including protrusions. [Figure 4C] FIG. 4C is a copy of a photograph of a representative retention structure. [Figure 5A] FIG. 5A is a diagram and photograph of an exemplary polygonal retention structure, according to one set of embodiments. [Figure 5B] FIG. 5B is a diagram and photograph of an exemplary polygonal retention structure, according to one set of embodiments. [Figure 6] FIG. 6 is a series of x-ray images obtained in a large animal model using a retention structure according to one set of embodiments. [Figure 7] FIG. 7 is a series of x-ray images obtained in a large animal model using a retention structure according to one set of embodiments. [Figure 8A] FIG. 8A is a diagram of an enteric elastomer for use in a retention structure, according to one set of embodiments. [Figure 8B] FIG. 8B is a diagram of an enteric elastomer preparation for use in a retention structure, according to one set of embodiments. [Figure 8C] FIG. 8C is a series of copies of photographs taken during mechanical testing of enteric elastomers according to one set of embodiments. [Figure 9A]FIG. 9A shows the materials tested and the results obtained for the mechanical characterization of several representative enteric elastomers according to one set of embodiments. [Figure 9B] FIG. 9B is a plot showing the dissolution characterization of an enteric elastomer according to one set of embodiments. [Figure 9C] FIG. 9C is a plot of cell viability (ie, cytotoxicity) of enteric elastomers according to one set of embodiments. [Figure 10] FIG. 10 illustrates the construction and in vivo evaluation of ring-shaped retention structures according to one set of embodiments. [Figure 11A] FIG. 11A is a plot of stress (MPa) versus strain (mm / mm) for various elastic polymer elements of a representative structure according to one set of embodiments. [Figure 11B] FIG. 11B is a plot of pressure (MPa) versus strain (mm / mm) for an elastic polymer element of a representative structure, according to one set of embodiments. [Figure 11C] FIG. 11C is a plot of creep strain (mm / mm) versus time (sec) for an elastic polymer element of a representative structure according to one set of embodiments. [Figure 12] FIG. 12 shows isometric, top, bottom, and side views of a finite element modeling simulation of a retention structure undergoing deformation, according to one set of embodiments. [Figure 13A] FIG. 13A is a schematic diagram of a retention structure testing apparatus, according to one set of embodiments. [Figure 13B] FIG. 13B is a plot of force versus displacement for a retention structure using the test apparatus of FIG. 13A, according to one set of embodiments. [Figure 14] FIG. 14 is a plot of the stability of doxycycline in SGF (pH=1, 37° C.) over a two-week period as analyzed by high performance liquid chromatography (HPLC) according to one set of embodiments. [Figure 15]FIG. 15 is a plot of the stability of Artemether in 70% isopropanol, 20% acetonitrile, 10% water (IAW) (pH=1, 37° C.) over a two week period analyzed by HPLC according to one set of embodiments. [Figure 16A] FIG. 16A is a plot showing the stability of ivermectin in solution under acidic conditions (pH=1, 37° C.), according to one set of embodiments. [Figure 16B] FIG. 16B is a plot showing the stability of ivermectin in polycaprolactone (PCL) structures under acidic conditions (pH=1, 37° C.), according to one set of embodiments. [Figure 17A] FIG. 17A is a plot showing the in vitro release of doxycycline-loaded PCL stars in simulated gastric fluid (SGF) (pH=1, 37° C.) according to one set of embodiments. [Figure 17B] FIG. 17B is a plot showing the in vitro release of ivermectin (IVM)-loaded star structures with different formulations in SGF and Kolliphor® RH40, a non-ionic oil-in-water solubilizer (RH40) (pH=1, 37° C.) according to one set of embodiments. [Figure 17C] FIG. 17C is a plot showing the in vitro release of IVM loaded star structures with different formulations in SGF+RH40 (pH=1, 37° C.) according to one set of embodiments. [Figure 18] FIG. 18 is a plot showing mechanical characterization according to ASTM standard D790 of various PCL-based materials, according to one set of embodiments. [Figure 19] FIG. 19 is a plot showing the probability of gastric retention at specified times for configurations of gastric retention structures, according to one set of embodiments. [Figure 20] FIG. 20 is a plot showing the probability of gastric retention at specified times for configurations of gastric retention structures, according to one set of embodiments. [Figure 21] FIG. 21 is a plot showing the probability of gastric retention at specified times for configurations of gastric retention structures, according to one set of embodiments. [Figure 22]FIG. 22 is a copy of a photograph showing endoscopic evaluation of retention of a star-shaped delivery system at 35 days according to one set of embodiments. [Diagram 23] FIG. 23 is a plot showing the cumulative release of risperidone over time for a representative retention structure according to one set of embodiments. [Figure 24] FIG. 24 is a plot showing release of doxycycline over a period of time for a representative retention structure versus a doxycycline pill, according to one set of embodiments. [Figure 25A] FIG. 25A is a plot showing the release of ivermectin over a period of time for an ivermectin pill according to one set of embodiments. [Figure 25B] FIG. 25B is a plot showing the release of ivermectin over time for lower dose formulations according to one set of embodiments. [Figure 25C] FIG. 25C is a plot showing the release of ivermectin over time for higher dose formulations according to one set of embodiments. [Figure 26] FIG. 26 is a plot showing the release of doxycycline over a period of time for a representative retention structure, according to one set of embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0078] Generally, retention structures, systems, and related methods are disclosed. Certain embodiments include administering (e.g., orally) a retention structure to a subject (e.g., a patient) such that the retention structure is retained at an internal location of the subject for a certain 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) of active agent (e.g., therapeutic agent) loading (in some cases at relatively high levels), active agent and / or structure stability in an acidic environment, mechanical flexibility and strength when contained in an internal cavity (e.g., gastric cavity), easy passage through the gastrointestinal tract to delivery to a desired internal cavity (e.g., gastric cavity), and / or rapid dissolution / degradation in a physiological environment (e.g., intestinal environment) and / or in response to a chemical irritant (e.g., ingestion of a solution that induces accelerated dissolution / degradation). In certain embodiments, the structures have a modular design that combines materials configured for controlled release of therapeutic, diagnostic and / or enhancing agents with structural materials that facilitate gastric retention, and for controlled and / or tunable degradation / dissolution to control the time at which the integrity of the retention shape is lost, allowing the structure to be emptied from the gastric cavity. For example, in certain embodiments, the retention structure includes a first elastic element, a second polymeric element configured to release an active agent (e.g., a therapeutic agent), and optionally at least one linker. In some such embodiments, the linker degrades to allow the retention structure to evolve after a predetermined time and / or upon exposure to a selected set of conditions. 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 particular configuration, including a particular size and / or shape (e.g., a multi-armed star) in a relaxed state. In certain embodiments, the retention structure may be folded from the relaxed state to 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. The capsule or other containment structure may be configured in some cases to dissolve and release the retention structure at a particular location inside the subject (e.g., in the stomach), thereby allowing the retention structure to reversibly return (e.g., by bouncing back) to the first configuration upon release. In some embodiments, the structure is configured to assume an in vivo shape and / or size that retards or prevents further passage (e.g., passage from the stomach body to the pylorus) in the cavity of the body (e.g., the stomach). In some embodiments, the structure assumes a shape and / or size configured for retention (e.g., gastric retention) upon release from the soluble capsule / container and / or soluble retention structure / element. In some embodiments, the structure is configured to assume a shape and / or size configured for gastric retention after being stored in its encapsulated shape and / or size for a period of more than 24 hours, e.g., up to about one year. In some embodiments, the mechanical properties of the structure are optimized for safe temporary retention of all or a portion of the structure in an internal cavity, such as the gastric cavity, for a period of more than 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 transit via oral administration for extended in vivo retention and administration of therapeutic, diagnostic, and / or enhancing agents. Certain embodiments of the structures and systems described herein may offer certain advantages over conventional compositions and structures and systems configured for internal retention and / or drug release, e.g., in terms of their ability to assume a shape and / or size small enough to be ingested by a subject; in terms of their ability to assume an internal shape and / or size that slows or prevents passage further in a body cavity (e.g., gastric cavity) (e.g., from the stomach body to the pylorus); in terms of their ability to load therapeutic, diagnostic, and / or enhancing agents at high levels (e.g., high mass fractions); in terms of their ability to facilitate controlled release of such therapeutic, diagnostic, and / or enhancing agents with low to no likelihood of burst release; in terms of their ability to maintain activity / stability of such therapeutic, diagnostic, and / or enhancing agents over extended periods of time in adverse environments, such as the gastric environment; in terms of their ability to maintain safety with low to no likelihood of gastric or ileus and / or perforation; and / or in terms of their ability to degrade / dissolve / dissociate into one or more forms configured to pass through the gastrointestinal tract. In certain embodiments, the structures and systems described herein can be configured to have a sustained residence period lasting at least greater than 24 hours, up to a year or more. In some embodiments, the systems, structures, and methods described herein are compatible with subjects, including, but not limited to, humans and non-human animals. In further embodiments, the systems and structures can be configured to deliver a wide variety of therapeutic, diagnostic, and / or enhancing agents, thereby allowing for increased and even maximized patient compliance with treatment therapy.

[0081] The structures and systems described herein may be modular / multiple elements (i.e., formed from multiple interconnected subcomponents). In some embodiments, the structures are configured to contain and / or release a therapeutic agent, and / or the element(s) are configured to undergo mechanical deformation without permanent deformation and / or without breaking, and / or to rebound after a certain period of time, allowing the structure to be selectively maintained in position within a subject. In some embodiments, the structure includes one or more polymer elements configured to be supported by the first polymer element. 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 is different from and in direct contact with the first polymer element. As shown in FIG. 1A, in some embodiments, the structure 100 includes a first polymer element 110 coupled to a second polymer element 120. In some such embodiments, the first polymer element may be coupled to the second polymer element via an adhesive, by chemical interactions (e.g., chemical bonds), and / or by interpenetrating and / or entangled polymer chains, and / or 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 more detail below.

[0082] In general, embodiments of the present invention may be implemented using any combination of first, second, third, etc. polymer elements, but for clarity and brevity, much of the following description is in the context of selected embodiments that include elastic polymer elements and fillable polymer elements.

[0083] In some embodiments, one or more linkers are attached to one or more polymer elements. For example, in some embodiments, the linker may be embedded within an elastic polymer element, separating or connecting two or more portions of the elastic polymer element. In certain embodiments, the linker may be embedded within a fillable polymer element, separating or connecting two or more portions of the fillable polymer element. In some cases, the linker is disposed between two or more different polymer elements (e.g., to connect two or more different polymer elements). For example, in some embodiments, two elastic polymer elements are attached by a linker. In certain embodiments, two fillable polymer elements are attached by a linker. In some cases, the elastic polymer element is attached to the fillable polymer element by a linker. In some embodiments, the structure may include a combination of polymer element and linker arrangements.

[0084] In certain embodiments, the first polymer element and the second polymer element are linked by a linker. For example, as shown in FIG. 1B, a 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 more detail below.

[0085] In some embodiments, the linker may be embedded within a first polymeric element or a second polymeric element and separate two or more portions of those elements or connect two or more portions of those elements. For example, in certain embodiments, the linker does not connect the first polymeric element and the second polymeric element, but is embedded within the first polymeric element or the second polymeric element and separates or connects two or more portions of such elements, such that when the linker degrades, the elements fall apart (e.g., the structure or part of the structure is detached).

[0086] In some embodiments, the structure is designed such that the mechanism of delivery is different from the mechanism of degradation. For example, a linker (e.g., an enteric linker, described below) may be attached, fused, bonded, embedded, or otherwise connected to the fillable material (e.g., a fillable polymeric element) that constitutes the bulk of the structure. When the fillable material / linker composite is exposed to a therapeutic, diagnostic, and / or enhancing agent for loading, loading may be selective within the fillable material, and release of the therapeutic, diagnostic, and / or enhancing agent from the fillable material may occur by diffusion or Materials may be selected such that this occurs via slow matrix degradation. In some embodiments, the fillable material has certain mechanical properties such that the fillable material resists brittle fracture, but is sufficiently rigid to facilitate the ability of the material 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, loading of such therapeutic, diagnostic and / or enhancing agents may be minimized within a separate linker material, and the separate linker material may be configured to control / tune the degradation / dissolution of the retention / delivery structure and / or the particular fillable material portion of the retention / delivery structure. Advantageously, by separating the mechanism of delivery (e.g., slow release from a relatively stable fillable material portion) from the mechanism of controllable degradation (e.g., more rapid degradation of the linker(s)), the retention / delivery structure may be configured to prevent burst release of therapeutic, diagnostic and / or enhancing agents upon degradation / dissolution.

[0087] In some embodiments, the structure comprises multiple polymer elements and / or multiple linkers. In certain embodiments, the structure comprises 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 comprises 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 comprises one or more, two or more, three or more, four or more, or five or more, etc. linkers. In an exemplary embodiment, as shown in FIG. 1C, the structure 100 comprises a first type of polymer element 110 connected via two linkers 130 to two polymer elements 120 of a second type. A person skilled in the art would be able to select additional various arrangements of polymer elements and linkers based on the teachings of the specification. Further representative arrangements are described in more detail below.

[0088] In some embodiments, the retention structure includes an elastic polymer element. In certain embodiments, the use of an elastic polymer element may impart favorable mechanical properties to the structure. For example, in some cases, the structure may be configured to undergo a relatively large compressive force (e.g., a compressive force present in the stomach and / or intestine of a subject) such that the structure does not break and / or is retained in a position within the subject (e.g., at or above an opening such as the pylorus). In certain embodiments, the structure may be configured to fold (e.g., without breaking). For example, the elastic polymer element may be configured to undergo a relatively high level of bending stress without breaking and / or without significant permanent deformation. In some embodiments, the elastic polymer element and / or the structure including the same may be configured to be substantially resilient. That is, after mechanically deforming the elastic polymer element and / or the structure including the elastic polymer element, the structure may substantially return to its original configuration prior to the application of the mechanical deformation (e.g., the elastic polymer element may be characterized by substantially minimal creep deformation).

[0089] Suitable materials for use as elastic polymer elements may be determined using appropriate screening tests. For example, elastic polymer elements may be tested for their ability to undergo 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 undergo 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 referenced ranges are also possible (e.g., from about 45 degrees to about 180 degrees, from about 60 degrees to about 180 degrees, from about 60 degrees to about 120 degrees, from 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 (e.g., at least about 45 degrees of mechanical bending deformation) for a relatively long period of time - for example, in some embodiments, the elastic polymer element may be configured to have a shelf life in such a deformed configuration 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 still substantially return (i.e., bounce back) to its pre-deformed configuration. In certain embodiments, the elastic polymer element is configured to have a shelf life in the deformed configuration of up to about 3 years or less, up to about 2 years or less, up to about 1 year or less, up to about 1 month or less, or up to about 1 week or less, and still substantially return (i.e., bounce back) to its pre-deformed configuration. Any and all closed sections having endpoints within any of the above referenced ranges are also possible (e.g., from about 24 hours to about 3 years, from about 1 week to 1 year, from 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 be configured to undergo large angular deformations for relatively long periods of time without undergoing significant inelastic deformation. In some such embodiments, the elastic polymer element may have sufficient rebound strength to cause the elastic polymer element to substantially return to its pre-deformed shape within less than about 30 minutes, within less than about 10 minutes, within less than about 5 minutes, or within less than about 1 minute after release of mechanical deformation. Those skilled in the art will appreciate that the return to its pre-deformed shape should be understood not to necessarily conform to the shape of the mathematical definition absolutely, but rather to indicate conformance to the shape of the mathematical definition to the extent possible for subject matter characterized as understood by those skilled in the art to be most closely related to such subject matter.

[0092] In some embodiments, the elastic polymer element has a particular modulus of elasticity. In some embodiments, the modulus of elasticity of the elastic polymer element ranges from 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 endpoints within any of the above referenced ranges are also possible (e.g., from about 0.1 MPa to about 30 MPa, from about 0.3 MPa to about 10 MPa). Other ranges are also possible. One of ordinary skill in the art will be able to select an appropriate method for determining the elastic modulus of a polymeric element including, for example, tensile mechanical characterization according to ASTM D638 and / or compressive mechanical characterization according to ASTM D575.

[0093] In some embodiments, the elastic polymer element undergoes a relatively small amount 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 endpoints within any of the above referenced ranges are also possible. (e.g., from about 0.01 mm / mm / hr to about 0.3 mm / mm / hr, from about 0.02 mm / mm / hr to about 0.1 mm / mm / hr, from about 0.02 mm / mm / hr to about 0.05 mm / mm / hr, from about 0.05 mm / mm / hr to about 0.3 mm / mm / hr). Other ranges are possible. In some embodiments, the minimum creep rate can be measured according to ASTM D-638. Briefly, a sheet of elastic polymeric material is prepared as described below and cut with a standard dumbbell die. The test specimen can be mounted in the grips 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 can be applied to the test specimen for 60 minutes at a constant temperature (e.g., room temperature), and the creep (mm / mm) versus time (hours) can be plotted. The minimum creep rate is the slope of the creep versus time curve before the secondary creep.

[0094] One of ordinary skill in the art given the guidance and teachings herein will be able to determine a suitable method of adjusting the mechanical properties (e.g., elastic modulus, creep behavior) of the elastic polymer elements, for example, by varying 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 elements), by changing the crosslink density of the polymer, by changing the concentration of the crosslinker 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 swell substantially in the presence of a biological fluid, such as blood, water, bile, gastric fluid, or a combination thereof. In some embodiments, the elastic polymer element swells in a biological fluid by about 0.01% to about 10% by volume relative to the volume of the elastic polymer element in a dry state (e.g., at atmospheric conditions and room temperature). For example, in certain embodiments, the elastic polymer element swells by less than about 10%, less than about 5%, less than about 2%, or less than about 1% by volume in unstirred gastric fluid or simulated gastric fluid at physiological temperature relative to the volume of the elastic polymer element in a dry state (e.g., at atmospheric conditions and room temperature).

[0096] In some cases, the retention structure swells in unstirred gastric fluid or simulated gastric fluid at physiological temperature 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 retention structure in a dry state (e.g., under atmospheric conditions and at room temperature). Based on the teachings herein, a person 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, including, for example, 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 at physiological temperature in unstirred gastric fluid or simulated gastric fluid, and measuring the percent 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 element is preferably biocompatible. The term "biocompatible" as used in connection with the polymer element refers to a polymer that does not induce a substantial adverse reaction (e.g., an adverse immune response) from an organism (e.g., a mammal), tissue culture, or cell collection, or that only induces a reaction that does not exceed an acceptable level. In some embodiments, the elastic polymer element comprises a polymer, a network of polymers, and / or a multiblock combination of polymer segments, including, for example, polyesters such as, but not limited to, polycaprolactone, poly(propylene fumarate), poly(glycerol sebacate), poly(lactide), poly(glycolic acid), poly(lactic-glycolic acid), polybutyrate, and polyhydroxyalkanoates; polyethers such as, but not limited to, poly(ethylene oxide) and poly(propylene oxide); poly(ethylene oxide) and poly(propylene ... The polymer or polymer segment may include a polysiloxane such as (dimethylsiloxane); a polyamide such as, but not limited to, poly(caprolactam); a polyolefin such as, but not limited to, polyethylene; a polycarbonate such as, but not limited to, poly(propylene oxide); a polyketal; a polyvinyl alcohol; a polyoxetane; a polyacrylate / methacrylate such as, but not limited to, poly(methyl methacrylate) and poly(ethyl vinyl acetate); a polyanhydride; and a polyurethane. In some embodiments, the polymer is crosslinked. In some embodiments, the elastic polymer element comprises a polymer composite comprising two or more chemically similar polymers or two or more chemically different polymers. In an exemplary embodiment, the elastic polymer element comprises an isocyanate crosslinked polyurethane produced from a low molecular weight monomer such as polycaprolactone. In some such embodiments, the low molecular weight monomer comprises one or more hydroxyl functional groups (e.g., diols, triols).

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

[0099] In some embodiments, the retention structure is configured to be loaded with a relatively high level (e.g., by mass) of one or more active agents, such as therapeutic agents, diagnostic agents, and / or enhancing agents. In some embodiments, the structure is formed from one or more of a variety of materials, such as, but not limited to, polycaprolactone (PCL), poly(ethylene-co-vinyl acetate) and polyethylene glycol (PEG), that have desirable properties for controlling the loading and release of the active agent. For example, in some embodiments, the loadable polymer element is a polymer element that is configured to be loaded with a relatively high level of the active agent and that has desirable properties for controlling the loading and release of the active agent. In some embodiments, the loadable polymer element comprises a drug-loadable polymer matrix. In an exemplary embodiment, the loadable polymer element comprises polycaprolactone. Polycaprolactone is a degradable polyester (degradable by hydrolysis of ester bonds under physiological conditions) that has a relatively low melting point of about 60° C. In some embodiments, the loadable polymer element is selectively degradable under a particular set of conditions (e.g., a particular pH and / or temperature range). In certain embodiments, the fillable polymeric element is biodegradable (eg, in vivo degradable).

[0100] In some embodiments, the loadable polymeric elements are configured to be loaded with a relatively high level of an active agent and / or comprise a drug-loadable polymeric matrix. For example, in certain embodiments, the structure comprises the loadable polymeric elements in an amount of at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 93% by weight of the total structure weight. In some embodiments, the structure comprises the loadable polymeric elements in an amount of up to about 95% by weight or less, up to about 93% by weight or less, up to about 90% by weight or less, up to about 80% by weight or less, or up to about 70% by weight or less of the total structure weight. Any and all closed intervals having endpoints within any of the above referenced ranges are also possible (e.g., from about 60% to about 95% by weight). For example, in some embodiments, from about 60% to about 95% by weight of the structure comprises polymeric elements capable of being loaded with a relatively high level of an active agent and / or therapeutic agent and configured to be so loaded. The presence of a fillable polymeric element capable of loading relatively high levels of active agent in amounts greater than about 60% by weight (e.g., greater than about 80% by weight, greater than about 90% by weight) of the total structure provides several advantages including, for example, the ability to release the active agent (e.g., therapeutic agent) from the structure over a relatively extended period of time (e.g., at least about 24 hours, at least about 48 hours, at least about 7 days, at least about 1 month) and / or the ability to tailor the release rate and / or duration of the active agent.

[0101] A number of screening tests may be used to select suitable materials for use as the fillable polymeric element. For example, the fillable polymeric element may be selected to have a flexural modulus of greater than about 100 MPa, greater than about 120 MPa, greater than about 150 MPa, or greater than about 200 MPa. In some embodiments, the fillable polymeric element has 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 endpoints within any of the above referenced ranges are also possible (e.g., from about 100 MPa to about 250 MPa). Other ranges are also possible. Those skilled in the art will be able to select an appropriate method for determining the flexural modulus of the polymeric element, including, for example, plotting bending stress versus strain and taking the slope of the linear portion of the curve. The flexural modulus of the fillable polymeric 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 may be encapsulated without breaking and / or the ability to withstand compressive forces, such as in the 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 endpoints within any of the above referenced ranges are also possible (e.g., about 10 MPa to about 50 MPa). Other ranges are also possible. One of ordinary skill in the art will be able to select an appropriate method for determining the flexural strength of the fillable polymer element, including, for example, determining the flexural stress at failure of the polymer material. The flexural strength of the 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 may be encapsulated without breaking and / or the ability to withstand compressive forces, such as in the gastric cavity.

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

[0104] In certain embodiments, the loadable polymer element is selected such that its material stabilizes an active agent (e.g., a therapeutic agent) loaded into the element for a desired retention duration 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 cross-linked (FGC) polymer. For example, in certain embodiments, the fillable polymer elements comprise a polymer catalyzed by a food grade catalyst. The use of food grade cross-linked polymers offers several advantages over non-food grade polymers, such as easier FDA approval, less cytotoxicity, and / or reduced (or substantially eliminated) need to remove toxic catalysts after polymerization. Some In embodiments, the food grade crosslinked polymer comprises food grade components crosslinked and / or polymerized using a food grade catalyst. Food grade crosslinked polymers can typically have a combination of advantageous properties, such as mechanical strength, biocompatibility, and / or moldability. In some cases, the FGC polymer can advantageously allow for controlled release of therapeutic agents while at the same time containing little or no potentially harmful auxiliary materials (e.g., solvents, catalysts, excipients) that may be toxic agents in some cases. In some embodiments, the FGC polymer is 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 the FGC polymer can provide several advantages, such as, for example, the formation of an element that contains primarily (or only) FDA approved components, and biocompatibility. In certain embodiments, the FGC polymer comprises ester bonds, such that the FGC polymer is degradable under physiological conditions. Advantageously, the FGC polymer may comprise a polymeric material (eg, a thermosetting polymeric material) having the strength and integrity of an epoxy resin, the biomedical application of a hydrogel, and / or the moldability of a vitrimer.

[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 loadable polymeric element of the retention structure and is derived from oligomer or polymer strands or chains that have undergone crosslinking via a reaction that does not prevent the inclusion of a sensitive therapeutic agent (e.g., the active agent can be loaded and released directly into 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, the FGC may remain fixed in its new shape after being molded to a new location, in contrast to shape memory polymers that typically generally return to their original shape after being stretched or otherwise stressed.

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

[0108] In some embodiments, one or more multifunctional monomers are difunctional. In certain embodiments, one or more multifunctional monomers are trifunctional. In some cases, one or more multifunctional monomers may be tetrafunctional, pentafunctional, hexafunctional, or have higher functionality. 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 has formula (I): [ka] where A is derived from at least one multifunctional monomer containing at least two reactive functional groups, and B is derived from at least one multifunctional monomer containing at least two reactive functional groups, and the compound of formula (I) contains crosslinks. For example, in certain embodiments, the FGC polymer containing the structure as in formula (I) is formed by reacting a first multifunctional monomer containing two reactive functional groups with a second multifunctional monomer containing three reactive functional groups. In another embodiment, the FGC polymer containing the structure as in formula (I) is formed by reacting a first multifunctional monomer containing two reactive functional groups with a second multifunctional monomer different from the first multifunctional monomer containing two reactive functional groups with a third multifunctional monomer containing three reactive functional groups. In some such embodiments, the reactive functional group of the first multifunctional monomer may be the same as or different from the reactive functional group of the second multifunctional monomer and / or the third multifunctional monomer. For example, the reactive group of a first multifunctional monomer may react (and form a covalent bond) with the reactive group of a second multifunctional monomer and / or a third multifunctional monomer.

[0110] In some embodiments, one or more multifunctional monomers comprise oligomeric moieties. 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 multifunctional monomers and then incubating the mixture at a temperature sufficient to initiate polymerization and reach a gel point. In some embodiments, two or more multifunctional monomers are combined in the presence of a catalyst. In certain embodiments, two or more multifunctional 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 multifunctional monomer has formula (II): Q 1 -LQ 2 (II) wherein Q 1 and Q 2 are the same or different reactive functional groups, and L is a group of formula (III): [ka] wherein: [ka] Q 1 and Q 2 Indicates the connection point to.

[0113] In some embodiments, the multifunctional monomer is: [ka] wherein Q 1 , Q 2 and Q 3are the same or different reactive functional groups, and L has a structure as in formula (III).

[0114] In some embodiments, X 1 , X 2 , and X 3 is the same or different, does not exist or (CR 1 R 2 ) m , a heteroatom, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heterocyclic group, a heteroaryl group, and an oligomeric group. 1 , X 2 , and / or X 3 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 certain 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 certain 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 certain 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 and is 2 or greater.

[0119] In some embodiments, each R 1 and R 2are the same or different and are selected from the group consisting of hydrogen, an aliphatic group, halogen, hydroxyl, carbonyl, thiocarbonyl, oxo, alkoxy, epoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aralkyl, and aromatic or heteroaromatic or Michael acceptor; R 1 and R 2 Any two or more of the groups may be linked together to form a ring system. In certain embodiments, each R 1 and / or R 2 Q 3 (i.e., a reactive functional group).

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

[0121] The multifunctional 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 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 ) is an electrophilic functional group. For example, a monomer may include 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, acyl nitriles, 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, the monomer may include at least two, at least three, at least four, or at least five nucleophilically reactive functional groups. Non-limiting examples of suitable nucleophilic functional groups include alcohols, amines, anilines, phenols, hydrazines, hydroxylamines, carboxylic acids, alkoxide salts, alkenes, thiols, and glycols.

[0124] The multifunctional monomers described herein may contain at least one electrophilic functional group and at least one nucleophilic functional group. For example, in a representative embodiment, the first multifunctional monomer contains both an electrophilic functional group and a nucleophilic functional group. In a particular embodiment, the first multifunctional monomer contains two or more electrophilic functional groups and the second multifunctional monomer contains two or more nucleophilic functional groups.

[0125] In some cases, the reaction of an electrophilic functional group with a nucleophilic functional group forms a bioresponsive bond, such as an ester bond, an ether bond, an amide bond, an amine bond, or a thioether bond. For example, in certain embodiments, the FGC polymer comprises an ester bond formed by the reaction of an electrophilic functional group with a nucleophilic functional group. In some embodiments, the FGC polymer comprises an ether bond formed by the reaction of an electrophilic functional group with a nucleophilic functional group. Other bonds are possible.

[0126] In some embodiments, the FGC polymer is formed by the reaction of two or more multifunctional monomers with an additional monomer unit. In some embodiments, the additional monomer unit comprises a compound comprising one or more carboxylic acid derivatives. In some embodiments, the additional monomer unit is 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. In certain embodiments, the additional monomer unit is a compound comprising a lactone, lactam or thiolactone group. In certain embodiments, the additional monomer unit is a naturally occurring lactone or lactam. In another embodiment, the lactone- or lactam-containing compound of the additional monomer unit is selected from those listed in the FDA's "Generally Recognized as Safe" substance database and / or 21 CFR 182. In certain embodiments, the additional monomer unit is selected γ-decalactone, δ-decalactone, ω-pentadecalactone, caprolactam, and mixtures thereof.

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

[0128] In some embodiments, the molar ratio of the first multifunctional monomer (e.g., comprising an electrophilic reactive group) to the mixture of additional multifunctional monomers (e.g., comprising a nucleophilic reactive group) and / or additional monomer units ranges from about 10:1 to about 1:10. In an exemplary embodiment, the molar ratio of the first multifunctional monomer to the mixture of additional multifunctional monomers and / or monomer units is about 1:1. In certain embodiments, the molar ratio of the first multifunctional monomer to the mixture of additional multifunctional 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 multifunctional monomer to the mixture of additional multifunctional monomers and / or monomer units is about 1:10 or more, about 1:8 or more, about 1:6 or more, about 1:4 or more, about 1:2 or more, about 1:1.5 or more, about 1:1 or more, about 1:1.5 or more, about 2:1 or more, about 4:1 or more, about 6:1 or more, or about 8:1 or more. Any and all closed intervals having endpoints within any of the above referenced ranges are also possible (e.g., from about 10:1 to about 1:10, from about 1:4 to about 4:1, from about 1:2 to about 2:1).

[0129] In some such embodiments, the second multifunctional monomer is present in the mixture of additional multifunctional monomers and / or monomer units in an amount 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 multifunctional monomer is present in the mixture of additional multifunctional monomers and / or monomer units in an amount 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 endpoints within any of the above referenced ranges are also possible (e.g., from about 25 mol% to about 99.9 mol%). Other ranges are also possible.

[0130] As noted above, in some embodiments, two or more multifunctional monomers are combined (ie, 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 hydrates.

[0132] In some embodiments, the catalyst is selected from catalysts listed in the FDA's "Generally Recognized as Safe" substances database and / or 21 CFR 182. In certain embodiments, the catalyst is a 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 purine, adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, and isoguanine. In an exemplary embodiment, the catalyst is caffeine.

[0135] The use of a food grade catalyst such as caffeine may offer certain advantages over conventional catalysts, such as easier FDA approval, less cytotoxicity, and / or reduced (or substantially eliminated) need for post-polymerization catalyst removal.

[0136] In some embodiments, the catalyst (e.g., a food grade catalyst) is present in the FGC polymer after formation in an amount ranging from 0.01 mol% to about 25 mol%. In some embodiments, the FGC polymer is substantially free of catalyst after formation of the FGC polymer. In certain embodiments, the catalyst is present in the FGC polymer after 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 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 having endpoints within any of the above referenced ranges are also possible (eg, about 1 mol % to 25 mol %, about 0.01 mol % to 5 mol %). Other ranges are also possible.

[0137] As mentioned above, in some embodiments, the FGC polymer may be formed using three or more multifunctional monomers. In an exemplary reaction, polypropylene oxide is reacted with citric acid, mercaptosuccinic acid, and PPO-dimethacrylate in the presence of caffeine via Michael addition to form a branched FGC polymer.

[0138] In some embodiments, the structure (e.g., the fillable polymer element) is preloaded with an active agent, such as a therapeutic agent, a diagnostic agent, and / or an enhancing agent. In other embodiments, the structure (e.g., the fillable polymer element) is loaded with a therapeutic agent, a diagnostic agent, and / or an enhancing agent after the structure has already been retained in a location within the subject, such as the gastric cavity. In some embodiments, the structure is configured to maintain stability of the therapeutic agent, the diagnostic agent, and / or an enhancing agent in a hostile physiological environment (e.g., the gastric environment) for an extended period of time. In further embodiments, the structure is configured to control the release of the therapeutic agent, the diagnostic agent, and / or an enhancing agent with low to no possibility of burst release. In some embodiments, the structure (e.g., the fillable polymer element) is preloaded and / or loaded with a combination of active agents. For example, in certain embodiments, the structure includes one or more, two or more, three or more, or four or more active agents.

[0139] The therapeutic, diagnostic, and / or enhancing agents can be loaded into polymeric materials and other drug delivery materials by standard methods, including, but not limited to, powder mixing, direct addition, solvent loading, melt loading, physical blending, supercritical carbon dioxide assistance, and conjugation reactions such as ester and amide bonds. Release of the therapeutic, diagnostic, and / or enhancing agents can then occur by methods, including, but not limited to, dissolution of the loadable polymeric elements, including the polymeric matrix material, degradation of the matrix material, swelling of the matrix material, diffusion of the agent, hydrolysis, chemical or enzymatic cleavage of the conjugated bonds, and the like. In some embodiments, the active agent is covalently bound to the polymeric matrix of the polymeric elements (e.g., and released as the polymeric matrix degrades).

[0140] In certain embodiments, the structure is constructed and arranged to release the active agent from the fillable polymeric element(s). In certain embodiments, the active agent is designed to be released from the fillable polymeric element. Such embodiments may be useful in the context of drug delivery. In other embodiments, the active agent is permanently fixed to the fillable polymeric element. Such embodiments may be useful in the context of molecular recognition and purification. In certain embodiments, the active agent is embedded within the fillable polymeric element. In some embodiments, the active agent is attached to the fillable polymeric element by the formation of bonds such as ionic bonds, covalent bonds, hydrogen bonds, van der Waals interactions, etc. 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, diagnostic, and / or enhancing agents, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the active agent is a therapeutic, nutraceutical, prophylactic, or diagnostic agent. The active agent may be encapsulated within the polymer matrix or may be directly bonded to one or more atoms in the polymer matrix by chemical bonds. In certain embodiments, the active agent is covalently bonded to the polymer matrix. In some embodiments, the active agent 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 agent.

[0142] Pharmaceutical agents include, but are not limited to, any synthetic or naturally occurring biologically active compound or composition of matter that upon administration to a subject (e.g., a human or non-human animal) elicits a desired pharmacological, immunogenic, and / or physiological effect by local and / or systemic action. For example, useful or potentially useful within the context of certain embodiments are compounds or chemical entities traditionally considered to be drugs, vaccines, and biopharmaceuticals, and certain such agents include, but are not limited to, proteins, peptides, hormones, nucleic acids, genetic constructs, and the like, for use in the therapeutic, diagnostic, and / or enhancement fields, including the medical or veterinary treatment, prevention, diagnosis, and / or mitigation of disease or illness (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, blood thinning agents such as anticoagulants such as clopidogrel, and the like. 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, antimalarials, and synthroid / levothyroxine; substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal sterilization methods); performance enhancement enhancement (e.g., stimulants such as caffeine); and nutrients and supplements (e.g., protein, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, and other vitamin or mineral supplements).

[0143] In some embodiments, the active agent 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 term "therapeutic agent" or "drug" refers to an agent that is administered to a subject to treat disease, disorder, or other clinically recognized conditions or for preventive purposes, and that has a clinically meaningful effect on the subject's body to treat and / or prevent disease, disorder, or condition. Lists of known exemplary therapeutic agents can be found, for example, in the United States Pharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic and Clinical Pharmacology, McGraw-Hill / Appleton & Lange; 8th edition (September 21, 2000); Physician's Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th ed. (1999) or its subsequent 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 Therapeutic "Orange Book "). Examples of drugs approved for human use are listed by the FDA at 21 CFR 330.5, 331-361, and 440-460, incorporated herein by reference; drugs for veterinary use are listed by the FDA at 21 CFR 500-589, incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Representative classes of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory agents, antipyretics, antidepressants, antiepileptics, antipsychotics, neuroprotective agents, antiproliferative agents such as anti-cancer agents, antihistamines, antimigraine agents, hormones, prostaglandins, antimicrobial agents (e.g., antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, anxiolytics, bacteriostatics, immunosuppressants, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatics, cardiovascular medications, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroidal or non-steroidal anti-inflammatory agents, corticosteroids, dopamine agonists, electrolytes, gastrointestinal agents, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, appetite suppressants, and anti-narcoleptic agents. Nutritional supplements can also be incorporated into the drug delivery device. These can be nutritional supplements such as 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, atovaquone, primaquine, halofantrine, doxycycline, clindamycin, artemisinin, and artemisinin derivatives.In some embodiments, the antimalarial drug is artemisinin or its derivatives.Representative artemisinin derivatives include artemether, dihydroartemisinin, artether and artesunate.In certain embodiments, the artemisinin derivative is artesunate.

[0146] The active agent that comprises a carboxylic acid group can be directly incorporated into the polymer matrix that comprises ester and hydroxyl groups without the need for further modification.The active agent that comprises an alcohol can be first derivatized as succinic or fumaric monoester and then incorporated into the polymer matrix.The active agent that comprises a thiol can be incorporated into the olefin or acetylene-containing matrix via sulfur-ene reaction.In other embodiments, one or more drugs are non-covalently bound to the polymer matrix (e.g., dispersed or encapsulated in the matrix).

[0147] In other embodiments, the active agent is a protein or other biopolymer. Such agents may be covalently attached to the polymer matrix through ester bonds using available carboxylate-containing amino acids, or may be incorporated into polymeric materials containing olefinic or acetylene moieties using thiol-ene type reactions. In some cases, the active agent contains amine functional groups that can react with epoxide functional groups to form amide or ester bonds. In other embodiments, the active agent is non-covalently attached to the polymer matrix. In some such embodiments, the active agent may be dispersed or encapsulated within by hydrophilic and / or hydrophobic forces.

[0148] In some cases, the partition coefficient of the active agent in the loadable polymeric element material can be adjusted. For example, if the active agent is hydrophobic, in some cases a hydrophobic polymeric material scaffold may slow release into aqueous solution, while a hydrophilic polymeric material scaffold should accelerate release. Additionally, a hydrophilic polymeric material scaffold may in some cases increase the rate of water absorption into the material, causing the polymeric material to expand (e.g., swell), accelerating the release rate. In some embodiments, the swelling and dissolution of the material will be increased under conditions where the free reactive groups contain ionizable moieties that become charged in the presence of aqueous media. In some such embodiments, the rate of content release via diffusion will be increased and / or better access to cleavable bonds will be provided as the material collapses due to ionic repulsion. One of skill in the art will be able to select an appropriate method for determining the partition coefficient of an active agent, such as, for example, high performance liquid chromatography (HPLC).

[0149] The active substance may be bound to the polymer matrix and / or present in the fillable polymeric element in any suitable amount. In some embodiments, the active substance is present in the fillable polymeric element in an amount ranging from about 0.01% to about 50% by weight based on the weight of the total fillable polymeric element. In some embodiments, the active substance is present in the fillable polymeric element in an amount of at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40% by weight based on the weight of the total fillable polymeric element. In certain embodiments, the active agent is present in the fillable polymeric element in an amount 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 endpoints within any of the above referenced ranges are also possible (e.g., about 0.01% by weight to about 50% by weight). Other ranges are also possible.

[0150] Advantageously, certain embodiments of the fillable polymeric elements described herein may allow for the incorporation of higher concentrations (weight percent) of active agents, such as therapeutic agents, as compared to other polymers, such as certain conventional hydrogels. In some embodiments, the active agent (e.g., an active substance) may be released from the fillable polymeric element. In certain embodiments, the active agent is released from the fillable polymeric element by diffusion. In some embodiments, the active agent is released by degradation (e.g., biodegradation, enzymatic degradation, hydrolysis) of the fillable polymeric element. In some embodiments, the active agent is released from the fillable polymeric element at a particular rate. One of ordinary skill in the art will appreciate that the release rate may, in some embodiments, depend on the solubility of the active agent in the medium to which the fillable polymeric element is exposed, e.g., physiological fluids such as gastric fluid. The included ranges and statements regarding the release and / or release rate of the active agent typically vary depending on the hydrophilic, hydrophobic, and / or lipophilic nature of the active agent in simulated gastric fluid (e.g., as defined in the United States Pharmacopeia (USP)). Simulated gastric fluid is known in the art and one of ordinary skill in the art would be able to select an appropriate simulated gastric fluid based on the teachings herein.

[0151] In some embodiments, 0.05% to 99% by weight of the active agent initially contained in the fillable polymeric element is released (e.g., in vivo) over a period of 24 hours to 1 year. In some embodiments, about 0.05% to about 99.0% by weight of the active agent is released from the fillable polymeric element after a period of time (e.g., in vivo). In some embodiments, at least about 0.05%, at least about 0.1%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 98% by weight of the active agent bound to the fillable polymeric element is released from the element within about 24 hours, 36 hours, 72 hours, 96 hours, or 192 hours (e.g., in vivo). In certain embodiments, the glycerol complex may be 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 About 75%, at least about 90%, at least about 95%, or at least about 98% by weight of the active agent bound to the polymeric element is released from the element (e.g., in vivo) within 1 day, within 5 days, within 30 days, within 60 days, within 120 days, or within 365 days. For example, in some cases, at least about 90% by weight of the active agent bound to the polymeric element is released from the element (e.g., in vivo) within 120 days.

[0152] In some embodiments, the active agent is released from the fillable polymeric material at a particular initial average rate ("initial rate") determined over the first 24 hours of release (e.g., release of the active agent at a desired location within a subject, such as an internal cavity). In certain embodiments, the active agent is released over a 24 hour period following the first 24 hours of release at an average rate that is 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 average rate. In some embodiments, the active agent 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 %, 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 after the first 24 hour release. Any and all closed intervals having endpoints within any of the above referenced 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 agent may be released at an average rate of about 1% to about 99% of the initial rate over at least one selected consecutive 24 hour period from 48 hours to about 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).

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

[0155] In certain embodiments, burst release of the active agent from the fillable polymeric element is generally avoided. In exemplary embodiments, at least about 0.05% by weight of the active agent is released from the fillable polymeric element within 24 hours, with about 0.05% to about 99% by weight being released during the first day of release (e.g., at an internal location in the subject), and about 0.05% to about 99% by weight being released during the second day of release. Those skilled in the art will appreciate that similar amounts of the active agent may be released on the third, fourth, fifth, etc. days, depending on the properties of the fillable polymeric element and / or the active agent.

[0156] In certain embodiments, active agent may be released in a pulsed release profile.For example, in some embodiments, active agent is released during another 24 hours, such as starting on the first day after administration and on the third, fourth or fifth day, but is not substantially released 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 agent is released at a relatively constant average rate (e.g., a substantially zero order average release rate) over at least about 24 hours. In certain embodiments, the active agent is released at a first order release rate (e.g., the release rate of the active agent is generally proportional to the concentration of the active agent) over at least about 24 hours.

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

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

[0160] In certain embodiments, the elastic polymer element and the fillable polymer element are bonded 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 polymeric material of the elastic polymer element and the polymeric material of the fillable polymer element may interpenetrate and / or intertwine such that the elastic polymer element and the fillable polymer element are bonded.

[0162] In some embodiments, the elastic polymer element and the fillable polymer element are linked via a linker. In some embodiments, the structure is configured to degrade, 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 allow for controlled and / or tunable degradation. In some embodiments, one or more linkers are attached and / or incorporated into the structure to modularly separate the function of delivering therapeutic, diagnostic, and / or enhancing agents from controlling (e.g., triggering) and / or tunable degradation. Referring again to Figures 1B-1C, the first polymer element 110 and the second polymer element 120 are linked via a linker 130. In certain embodiments, two or more elastic polymer elements are linked together via a linker. In some embodiments, two or more fillable polymer elements are linked together via a linker. In some embodiments, the linker is embedded within the polymer element. For example, in certain embodiments, the linker is embedded within the elastic polymer element. In some cases, the linker may be embedded within the fillable polymer element. In some such embodiments, the linker may be degraded at a desired time and / or under desired conditions, causing the elastic or fillable polymer element to break apart.

[0163] The structure may include one or more, two or more, three or more types of linkers. For example, in an exemplary embodiment, the structure includes a first linker configured to degrade at a first average degradation rate and a second linker configured to degrade at a second average degradation rate under the same conditions. In certain embodiments, the degradation of the linker is pH dependent. In another exemplary embodiment, the structure includes a first linker configured to degrade 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 intestine, etc.), and a first linker configured to degrade 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 intestine, etc.). The second linker is configured to degrade under a second set of physiological conditions that are different from the physiological conditions of the subject (e.g., (1) at a relatively neutral pH, such as in the intestine, or (2) alternatively, at an acidic pH, such as in the stomach). In some embodiments, the second linker is configured not to substantially degrade under the first set of conditions, thereby allowing for selectable and partial degradation of the construct under selected conditions and / or at selected locations within the subject (e.g., at different locations along the gastrointestinal tract (GI track). For example, in some cases, the second linker is configured not to substantially degrade under the first physiological conditions (e.g., at an acidic pH, such as in the stomach), but to degrade under a second physiological condition that is different from the first set of physiological conditions.

[0164] The term "physiological conditions" generally refers to a set of external or internal environmental conditions (e.g., as opposed to laboratory conditions) present in an organism or cell system. For example, in some cases, physiological conditions range from a temperature of about 20°C to about 40°C (e.g., about 35°C to about 38°C) and / or an 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. The linker may be selected such that after a certain residence period, the linker dissolves, degrades, mechanically weakens, and / or mechanically separates from at least one of the one or more polymeric components. The term "residence period" generally refers to the length of time that a structure (or an element of a structure) described herein resides in an internal location of a subject, as measured from the time the structure is first present in the internal location of the subject to the time that the structure (or the element of the structure referred to) is no longer present in the internal location of the subject, e.g., due to degradation, dissolution, and / or expulsion of the structure or the element(s) of the structure referred to from the internal location of the subject. In an exemplary embodiment, the structure may be orally administered such that the structure resides in an internal location of the subject, such as the stomach above the pylorus, and is expelled through the pylorus into the intestine (e.g., after at least partial degradation 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 the element of the structure referred to) is expelled through the pylorus.

[0165] In some embodiments, the residence time of at least a portion of the construct 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 time 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 endpoints within any of the above referenced ranges are also possible (e.g., from about 24 hours to about 2 years, from about 24 hours to about 1 year, from about 48 hours to about 7 days, from about 3 days to about 1 month, from about 7 days to about 6 months, from about 1 month to about 1 year). Other ranges are also possible. The linker is preferably biocompatible.

[0166] In representative embodiments, one or more linkers are selected to mediate disassembly of the structure and facilitate safe passage through the lower intestinal tract of the subject, for example, after delivery of the active agent for a desired residence period (e.g., within 24 hours, within 48 hours, within one week, within one month). Evacuation from 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 disruption of the structure, such as by engineered linker rupture, impairs its ability to resist passage through the opening (e.g., through the pylorus).

[0167] Materials suitable for use as linkers are determined using several screening tests, including, but not limited to, the ability to link (e.g., bond) at least the surface of one or more of the polymeric elements of the structure, possessing sufficient mechanical strength to withstand encapsulation, possessing sufficient mechanical strength to withstand compressive forces present in a physiological environment, such as the gastric environment, and / or selectively degrading under a desired time and / or conditions (e.g., pH). In some embodiments, the linker is stable in a physiological environment, such as the gastric environment, for a period of time (e.g., a residence period) of at least about 24 hours, at least about 48 hours, at least about one week, at least about one month, or at least about one year.

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

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

[0170] In certain embodiments, the linker comprises a low content of methacrylic acid esters with ethyl acrylate, methyl methacrylate and / or quaternary ammonium groups. 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 an exemplary embodiment, the linker comprises an isocyanate crosslinked polyurethane made from low molecular weight polycaprolactone monomers.

[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 more detail below.

[0173] In some embodiments, the linker and / or elastic polymer element comprises an enteric polymer. The term "enteric" is generally used to describe a material that is stable at relatively highly acidic pH conditions (e.g., a pH less than about 5.5) and susceptible to dissolution at relatively alkaline pH conditions (e.g., a pH of about 6 to about 9). In some embodiments, enteric polymers include, but are not limited to, cellulose acetate phthalate (CAP), hypromellose (INN) hydroxypropyl methylcellulose (HPMC), and / or poly(methacrylic acid-co-ethyl acrylate) (e.g., Eudragit® available from Evonik Industries AG, Essen, Germany).

[0174] In some embodiments, dissolution of the enteric polymer can be induced, for example, by ingestion of an alkaline solution. In some embodiments, the enteric polymer has a capacity for dissolution at pH 4-8. In some embodiments, the enteric polymer is capable of dissolving at pH 4-8, such that the enteric polymer is stable in the acidic gastric environment (i.e., pH 1-4) but dissolves in more alkaline regions of the gastrointestinal tract distal to the pylorus (i.e., regions with a pH greater than 5.5) and functions as a linker. The method is selected so that the

[0175] For example, in certain embodiments, the enteric polymer does not substantially degrade in a pH range of about 1 to about 5. In some embodiments, the enteric polymer does not substantially degrade at a pH 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 degrade at a pH 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 endpoints within any of the above referenced 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, the enteric polymer substantially degrades at a pH range of about 4 to about 8. In some embodiments, the enteric polymer substantially degrades at a pH 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, the enteric polymer substantially degrades at a pH 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 referenced 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] Based on the teachings herein, one of skill in the art will be able to select a suitable method for determining the degradation of an enteric polymer, including determining the solubility of the enteric polymer in an aqueous solution having a pH of less than about 3 and / or dissolving the enteric polymer in an aqueous solution having a pH of about 6 or greater, measured at body temperature (e.g., about 35°C to about 38°C) over a period of about 2 to 40 days. In some embodiments, an enteric polymer that does not substantially degrade behaves such that less than about 10%, less than about 5%, or less than about 2% of the enteric polymer dissociates from the remaining enteric polymer. In certain embodiments, an enteric polymer that substantially degrades behaves 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 without the likelihood of intestinal obstruction and / or perforation. Controlled degradation 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 attached to and / or incorporated into the structure, and upon degradation / 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 does not substantially dissolve and / or degrade when located in the subject's stomach (e.g., having a pH in the range of about 1 to about 5) and substantially dissolves when located in the intestine (e.g., having 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 comprises a material selected to have both enteric and elastic properties. For example, in some embodiments, the linker comprises an enteric elastomer that has an elastic modulus of about 0.1 MPa to about 100 MPa at relatively highly acidic pH conditions (e.g., a pH of less than about 5.5) and is susceptible to dissolution at relatively alkaline pH conditions.

[0180] In certain embodiments, at least one dimension of the enteric elastomer exhibits reversible elongation when the dimension is distorted from its initial length to a length that is less than about 50% of its initial length and / or when the dimension is distorted from its initial length to a length that is at least about 1500% of its initial length. %, less than about 5%, less than about 2%, or less than about 1% difference in average length after deformation versus before deformation (e.g., elongation). For example, in some embodiments, the enteric elastomer can exhibit reversible elongation when elongated 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, the enteric elastomer can exhibit reversible elongation when elongated 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 endpoints within any of the above referenced ranges are also possible (e.g., about 50% to about 1500%, about 100% to about 1500%, about 200% to about 1000%, about 500% to about 1400%). Other ranges are also possible.

[0181] In certain embodiments, the enteric 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 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 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 endpoints within any of the above referenced 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. One of ordinary skill in the art would be able to select a suitable method for determining the elastic modulus of the enteric elastomer including, for example, 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 various ratios of poly(acryloyl-6-aminocaproic acid) and poly(methacrylic acid-co-ethyl acrylate).

[0183] In some embodiments, the enteric elastomer comprises a polymer of an acryloylaminoalkylene acid monomer or a salt thereof. In some embodiments, the enteric elastomer comprises a polymer of an acryloylaminoalkylene acid monomer, a (meth)acryloylaminoalkylene acid monomer, or a salt thereof. In certain embodiments, the acryloyl amino alkylene 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(methacrylic acid-co-ethyl acrylate) or a salt thereof. In some cases, the poly(methacrylic acid-co-ethyl acrylate) has a molar ratio of methacrylic acid monomer units to ethyl acrylate monomer units of about 1:1. Yes.

[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(methacrylic acid-co-ethyl acrylate)). In some such embodiments, the weight ratio of the first polymer to the second polymer ranges from 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 about 6:1 or less, about 5:1 or less, about 4:1 or less, 3:1, about 2:1 or less, about 1:1 or less, about 1:2 or less, about 1:3 or less, about 1:4 or less, or about 1:5 or less. Combinations of the above reference ranges are also possible (e.g., about 1:6 to about 6:1, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, about 1:3 to about 1:1, about 1:1 to about 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% or less by weight, about 30% or less by weight, about 20% or less by weight, or about 10% or less by weight. 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% to about 40% by weight).

[0187] Enteric elastomers can be used as material platforms. In some embodiments, the material platforms feature tunable elastomeric properties, are stable in acidic environments, and / or are soluble in more alkaline environments. Thus, the enteric elastomer material platform is compatible with the acidic stomach environment and has the capacity for targeted dissolution in the small intestine / colon environment. In some embodiments, the enteric elastomer material platform is useful for many applications, including, but not limited to, gastrointestinal structure fabrication and gastrointestinal specific drug delivery with targeted release beyond the pylorus.

[0188] For example, one or more enteric elastomeric linkers attached to and / or incorporated into the structure in the gastric cavity can mitigate the risk of accidental passage of the macrostructure that may induce obstruction and / or perforation due to the rapid dissolution of the one or more linkers upon passage through the pylorus, causing the macrostructure to shrink to smaller, pre-linked portions.

[0189] The structures associated with the enteric elastomer may be subject to dissolution in the presence of an alkaline environment. Thus, in some embodiments, in the case of a stomach structure present in vivo and comprising an enteric elastomer, passage of the structure can be induced when a subject ingests an alkaline solution (e.g., sodium bicarbonate) to cause dissolution of the enteric elastomer to allow degradation of the structure.

[0190] In some embodiments, the enteric elastomer linker is substantially flexible. Flexibility can allow the construct to be packed and / or folded to fit into a closed / predefined container, such as, for example, a capsule for oral administration or a catheter for endoscopic placement, as described herein. In some embodiments, the enteric elastomer has flexibility up to 180 degrees and can be compact and / or maximally flexible. (eg, for use as an elastic polymer element as described above).

[0191] In some embodiments, a structure (e.g., comprising one or more polymeric elements) comprises one or more configurations. For example, in certain embodiments, a structure has a particular configuration, such as a defined shape, size, orientation, and / or volume. A structure may comprise any suitable configuration. In some embodiments, a structure has a particular shape defined by the cross-sectional area of ​​the structure. Non-limiting examples of suitable cross-sectional shapes include squares, circles, ellipses, polygons (e.g., pentagons, hexagons, heptagons, octagons, nonagons, dodecagons, etc.), tubes, rings, stars or star-like / star-shaped (e.g., 3-arm star, 4-arm star, 5-arm star, 6-arm star, 7-arm star, 8-arm star), and the like. Those skilled in the art will be able to select a suitable shape depending on the application (e.g., star shape for gastric-retentive structures) and based on the teachings herein.

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

[0193] In certain embodiments, the configuration of the structure may be characterized by a maximum cross-sectional dimension. In some embodiments, the maximum cross-sectional dimension of the first configuration may be at least about 10% smaller, at least about 20% smaller, at least about 40% smaller, at least about 60% smaller, 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% smaller, at least about 20% smaller, at least about 40% smaller, at least about 60% smaller, or at least about 80% smaller than the maximum cross-sectional dimension of the first configuration. Any and all closed intervals having endpoints within any of the above referenced 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 configuration of the structure may be characterized by the convex hull volume of the structure. The term "convex hull volume" is known in the art and generally refers to a set of surfaces defined by the perimeter of a 3-D object, which defines a particular volume. For example, as shown in FIG. 1D, a 3D star-like object 150 has a convex hull volume defined by a convex hull 160. In some embodiments, the convex hull volume of the first configuration may be at least about 10% smaller, at least about 20% smaller, at least about 40% smaller, at least about 60% smaller, or at least about 80% smaller in volume than the convex hull volume of the second configuration. In certain embodiments, the convex hull volume of the second configuration may be at least about 10% smaller, at least about 20% smaller, at least about 40% smaller, at least about 60% smaller, or at least about 80% smaller in volume than the convex hull volume of the first configuration. Any and all closed intervals having endpoints within any of the above referenced 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.

[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 instead to a change in shape and / or orientation of at least a portion of the structure (e.g., in the presence of a stimulus such as heat and / or mechanical pressure / compression), although some swelling or shrinkage will occur between the two configurations.

[0196] In some embodiments, the first configuration is constructed and arranged such that the structure is retained at a location inside a subject, and the second configuration is constructed and arranged such that the structure may be encapsulated (e.g., for oral delivery of the structure in a capsule). In some cases, the first configuration is large enough to retain the structure at a location inside a subject, and the second configuration is small enough such that the structure fits within a capsule of a particular size suitable for oral delivery to a subject.

[0197] In certain embodiments, the structure may be polymerized and / or cast in a first configuration, mechanically deformed so that the structure is in a second configuration, and placed in a capsule or constrained by some other containment structure. The structure may be mechanically deformed using any suitable method, such as, for example, bending, twisting, folding, molding (e.g., compressing the material into a mold of a new shape), expanding (e.g., applying a tensile force to the material), compressing, and / or wrinkling the structure. The structure may maintain the second configuration for any suitable period of time before stimulation / release. Advantageously, certain embodiments of the structures described herein may be relatively stable in the first and / or second configurations such that the structure may be stored for long periods of time without significant degradation of the mechanical properties of one or more elements and / or one or more linkers. In some embodiments, the constructs may be stable under ambient conditions (e.g., room temperature, atmospheric pressure and relative humidity) and / or physiological conditions (e.g., at or about 37° C. in a physiological fluid) 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 constructs 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 endpoints within any of the above referenced 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 in the second configuration may rebound such that the structure returns to the first configuration. For example, in some embodiments, the structure in the second configuration is contained in a capsule and orally delivered to a subject. In some such embodiments, the structure travels to the stomach and the capsule is allowed to release the structure from the capsule, whereupon the structure acquires the first configuration (e.g., rebounds 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) with specific mechanical properties so that the structure will substantially bounce back after being mechanically deformed. In some cases, the structure may be characterized by a folding force. The term "folding force" generally refers to the force required to compress the structure into a cavity (e.g., the 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 sections having endpoints within any of the above referenced ranges are possible (e.g., about 0.2 N to about 3 N, about 0.2 N to about 2.5 N, about 0.5 N to about 1.5 N, about 1 N to about 3 N). Other ranges are possible. The collapse force may be determined, for example, by placing the construct in a funnel (as shown in FIG. 13A) having an upper diameter of 20 cm and a lower diameter of 2 cm (e.g., simulating the pyloric sphincter) and measuring the force required to move the construct through the lower diameter of 2 cm. The plunger is attached to the tensile crosshead of a tensile load tester, and the funnel is attached to a clamp, and the construct is forced through the funnel. The folding force is typically determined by measuring the force with which the structure folds and enters a tube with a lower diameter of 2 cm.

[0200] In certain embodiments, the structure in the first configuration has an uncompressed cross-sectional dimension that is typically selected such that the structure is retained in position within the subject for a relatively extended period of time (e.g., at least about 24 hours) even under physiological compressive forces (e.g., compressive forces in the digestive tract, etc.).

[0201] In some embodiments, the uncompressed cross-sectional dimension of the first configuration is 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 uncompressed cross-sectional dimension of the first configuration is 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 endpoints within any of the above referenced ranges are possible (e.g., about 2 cm to about 15 cm). One of skill in the art will be able to select the appropriate uncompressed cross-sectional dimension of the structure such that the structure is retained based on the teachings herein for the particular orifice of the subject.

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

[0203] In representative embodiments, the shape configured for retention, such as gastric retention, comprises a three-dimensional elliptical ring structure (i.e., an elliptical outline when projected onto a plane). In some embodiments, the elliptical ring structure has a minor axis diameter comparable to the major axis of the capsule. In some embodiments, the elliptical ring structure comprises a fillable polymer element and one or more linkers attached to and / or incorporated into the elliptical ring structure and configured to degrade in a controlled manner. In some embodiments, one or more linkers are incorporated into the elliptical ring structure at one or more points along the minor axis. In further embodiments, one or more controlled degradation linkers are incorporated into the elliptical ring structure at one or more points along the major axis. In some embodiments, the elliptical ring structure may be twisted into a shape similar to a double helix for packing into a soluble container and / or for binding with a retention element. In some embodiments, the elliptical ring structure is twisted such that the axis of the helix is ​​along the minor axis of the elliptical ring structure to avoid bending the helix to pack into the soluble container.

[0204] In some embodiments, the shape configured for retention, such as gastric retention (e.g., to be held in an opening at a particular internal location of a subject), comprises a three-dimensional structure having multiple projections (i.e., arms). In some embodiments, the projection-bearing structure comprises a flexible material configured for elastic (non-plastic) deformation. The projections themselves may be flexible or It may be rigid with a flexible connection to the core. In some embodiments, one or more controlled degradation linkers (e.g., enteric elastomers) are attached to and / or incorporated into the structure, for example, near the core or along one or more protrusions, such as at the connection to the core. In some embodiments, each protrusion has a length slightly less than the length of the soluble reservoir, such that the final unencapsulated form has a diameter approximately equal to twice the length of the soluble reservoir. 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 uncompressed cross-sectional dimension of at least about 2 cm).

[0205] In certain embodiments, the projections are arranged according to a bio-inspired flower bud design with (N) number of radial spokes or petals protruding from a central connected core. In some embodiments, each of these radial projections has an inner sector angle of about 360° / N, where N is the total number of radial projections. In some cases, this increases the packing volume of the encapsulation structure and therefore increases the drug carrying capacity. In some embodiments, as described herein, the projections are formed from a material with a relatively high elastic modulus to increase resistance to compression and gastric retention time.

[0206] In some embodiments, one or more linkers are attached to and / or incorporated into the structure. For example, as shown in FIG. 1E, structure 102 includes a first configuration that includes a six-arm star shape. Although a six-arm star shape is shown here, one of skill in the art will understand that FIG. 1E is intended to be non-limiting and that, as described herein, the structure can have 3, 4, 5, 6, 7, 8, 9, 10, or more arms, each of which may vary in length, number of elements and / or linkers.

[0207] The structure 102 includes elastic polymer elements 110 attached to fillable polymer elements 120. For example, the fillable polymer elements 120 may be attached to the elastic polymer elements 110 via an optional first linker 130. In certain embodiments, the elastic polymer elements 110 include an enteric elastomer. The additional fillable polymer elements 120 may be attached together via an optional second linker 135 that is different from the optional linker 130. The number and / or location of the linkers may be selected as part of the particular design parameters (e.g., so that the structure has particular degradation characteristics and / or configuration). The location of the linkers may also vary. For example, as shown by optional linker 134 (dotted line), a linker may be embedded within one or more of the fillable polymer elements 120.

[0208] The structure 102 may be folded into a second configuration, thereby encapsulating the structure, as shown in Figure IF. One of ordinary skill in the art will appreciate that Figure IF is intended to be non-limiting and that the structure shown in Figure IE may be folded into other configurations.

[0209] In some embodiments, the shape configured for retention, such as gastric retention (e.g., retained in an opening at a particular internal location of a subject), comprises a three-dimensional structure that, when projected onto a plane, forms the outline of a polygon having, for example, 3, 4, 6, 8, 10, 12, 14, 16, 18, or 20 sides. In some embodiments, each side has a length slightly less than the length of the soluble container. In some embodiments, the structure comprises a flexible material configured for elastic (non-plastic) deformation, and is configured such that the structure bends at its apex and packs into the soluble container. Materials configured for large elastic deformation with low elastic modulus, low creep deformation, and / or good recoil may be used at the apex 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 attached to and / or incorporated into the structure. In certain embodiments, flexible linkers configured for high elastic deformation and controlled degradation (e.g., including enteric elastomers) are positioned at each vertex between the sides of the polygon.

[0211] For example, as shown in Figure 1G, structure 104 includes a first configuration that includes a hexagon. Here, a hexagonal shape is shown, but one of skill in the art will understand that Figure 1G is intended to be non-limiting and that structures can have 4, 6, 8, 10, 12, or more sides, each of which may vary in length, number of elements and / or linkers, as described herein.

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

[0213] The structure 104 may be folded into a second configuration for encapsulation, as shown in Figure 1H. Those skilled in the art will appreciate that Figure 1H is intended to be non-limiting, and that the structure shown in Figure 1G may be folded into other configurations.

[0214] In an exemplary embodiment, the linker (optional linker 130) attached to the elastic polymer element and the fillable polymer element may be a time-dependent degradable linker (e.g., such that the arms of the structure peel off after a certain time). In a specific embodiment, the linker (optional linkers 135 and 134) attached to and / or embedded with the fillable polymer element may include an enteric polymer, which causes the fillable polymer element to detach when exposed to a pH greater than about 5. For example, the structure shown in Figures 1E-1H may be delivered (e.g., orally administered) to a subject via a capsule (containing the structure in the second configuration), released (gaining the first configuration), and retained in an internal location of the subject, such as the stomach in front of the pylorus. After a certain time (e.g., a residence period such as at least about 24 hours), the time-dependent degradable linker degrades and the structure separates into several units, which may pass through the pylorus. Upon entering the intestine (eg, at a pH greater than about 5), the linker comprising the enteric polymer degrades and the arms further separate into smaller, more easily removed units.

[0215] In some cases, the active agent may be loaded into beads and / or particles that include a loadable polymeric material embedded in an elastic polymer, such as an elastic degradable linker (e.g., including an enteric elastomer). In some embodiments, the loadable polymeric element comprises beads and / or particles dispersed / embedded within one or more elastic polymeric elements and / or one or more linkers. For example, in certain embodiments, the loadable polymeric element beads / particles may be linked to the elastic polymeric element and / or additional loadable polymeric element beads / particles via a linker (e.g., where the linker is physically attached to the loadable polymeric element or where the linker at least partially encapsulates the loadable polymeric element).

[0216] In some embodiments, various packing / folding strategies are used to provide a method for encapsulation. This can minimize the size of the structure for gastric retention and / or maximize the size of the structure for gastric retention. In some embodiments, a polygonal structure having 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 six total sides folded once.

[0217] Typical retention structures known in the art, such as intragastric balloons, usually result in at least partial gastric outlet obstruction in a subject. Advantageously, in some embodiments, the structure includes a shape with sufficient openings (or fenestrations) to allow foodstuffs, including indigestible material, to pass when placed in or at an internal opening of a subject, thereby avoiding partial or complete gastric outlet obstruction.

[0218] In some embodiments, the structure has fenestrations. In an exemplary embodiment, referring again to FIG. 1G, the structure has a polygonal cross-sectional area defined by the outer surface of the structure. In some such embodiments, the structure comprising one or more polymeric elements and linkers has an interior cross-sectional area that comprises one or more cavities (i.e., does not comprise one or more polymeric elements and linkers), thereby allowing food and other substances to pass through the structure.

[0219] In another exemplary embodiment, referring again to FIG. 1E, the structure has a star-like configuration, such that food and other substances can pass between the arms of the structure (e.g., if lodged at an internal location in the subject).

[0220] As discussed above, in some embodiments, the initial (undeformed) configuration of the structure may be characterized by a convex hull volume. In some embodiments, the structure including one or more polymer elements and linkers (i.e., the solid elements of the structure, as opposed to interstices) occupies about 10% to about 90% by volume of the total convex hull volume of the initial configuration. For example, in certain embodiments, the structure occupies about 90% or less, about 80% or less, about 70% or less, about 60% or less, about 50% or less, about 40% or less, about 30% or less, or about 20% or less by volume of the convex hull volume of the initial configuration. In some embodiments, the structure occupies at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, 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 referenced ranges are also possible (e.g., about 10% to about 90% by volume, about 30% to about 90% by volume, about 20% to about 50% by volume, about 40% to about 60% by volume, about 40% to about 90% by volume). Other ranges are also possible.

[0221] As described herein, in some embodiments, the structures are configured to assume a shape and / or size compatible with oral administration to and / or ingestion by a subject. In some embodiments, the structures have a shape that provides them with the ability to fold and / or pack into a stable encapsulated form. For example, in some embodiments, the structures are designed to maximally pack and fill a capsule or other soluble container (e.g., a containment structure). In some embodiments, the structures have a shape that maximally fills and / or packs a capsule or other soluble container.

[0222] In some embodiments, the system includes a structure and a containment structure. In some embodiments, the structure constitutes more than 60% by volume of the containment structure. Based on this application, capsules may be manufactured to specific specifications or standard sizes such as, but not limited to, 000, 00, 0, 1, 2, 3, 4, and 5, and larger veterinary capsules Su07, 7, 10, 12el, 11, 12, 13, 110ml, 90ml, and 36ml. In some embodiments, the structures may be provided in a capsule, coated or uncoated. The capsule material may be hard or soft and will typically comprise a tasteless, easily administered, water-soluble compound, such as gelatin, starch, or a cellulosic material, as will be appreciated by those skilled in the art.

[0223] In other embodiments, the construct is held in the packed shape by a soluble retaining element such as a strap or surgical thread. In some embodiments, the construct comprises an optimized combination of high and low modulus materials, giving the construct the ability to change shape and / or size once the soluble container and / or soluble retaining element are removed.

[0224] For example, consider a hypothyroid human patient prescribed a dosage level of levothyroxine that remains constant at 125 μg per day for six months (e.g., between thyroid stimulating hormone testing). During the six months, the patient undergoes 168 drug administration events, each event with an administered dose of 125 μg. In some embodiments, a structure configured for controllable gastric retention is loaded with more than 21 mg of levothyroxine (i.e., 125 μg per day for 168 days) and configured to release about 125 μg per day. Thus, the patient receives one drug administration for 168 drug administration events, with comparable efficacy over the same period of time.

[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 loaded with about 84 mg of Entecavir (i.e., 0.5 mg per day for 168 days), and the patient receives a single dose of the drug for 168 drug administration events, with the same outcome over the same period. 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 loaded with about 3,360 mg of Omeprazole (i.e., 20 mg per day for 168 days), and the patient receives a single dose of the drug for 168 drug administration events, with the same outcome over the same period.

[0226] In another example, consider a human patient with an exacerbation or flare-up of any one of chronic obstructive pulmonary disease, ulcerative colitis, asthma, and gout. The patient is prescribed an initial daily dosage level that is held constant for two weeks, followed by tapering off prednisone over additional days, e.g., 23 or more total days of prednisone treatment. During treatment, the patient undergoes 23 drug administration events, each event involving one of at least two predetermined dosage doses. In some embodiments, the structure configured for controllable gastric retention is loaded with about 770 mg of prednisone and configured to release a first predetermined dosage dose daily for two weeks, followed by a smaller predetermined dosage dose on subsequent days. Thus, the patient receives one drug administration for the same period of time and with the same results for 23 or more drug administration events. Furthermore, the patient would not need to be vigilant regarding the dosage change (single or multiple) because the structure is preconfigured to automatically tapering the dosage.

[0227] In another example, consider a human patient with coronary artery disease undergoing dual antiplatelet therapy. The patient is prescribed either clopidogrel or prasugrel at daily dosage levels that remain constant for at least three months. During treatment, the patient should undergo approximately 90 drug administration events. In some embodiments, a structure configured for controllable gastric retention is loaded 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). and the patient receives a single drug administration over the same time period for 90 drug administration events, with comparable efficacy. In another example, consider a human patient suffering from at least one of hyperlipidemia and coronary artery disease and being treated with rosuvastatin. In some embodiments, the structure configured for controllable gastric retention is loaded with about 1,800 mg of rosuvastatin (i.e., 10 mg per day for 180 days), and the patient receives a single drug administration over the same time period for 180 drug administration events, with comparable efficacy.

[0228] As used herein, any term relating, for example, to the shape, orientation, alignment, and / or geometric relationships of or between one or more articles, compositions, structures, materials, and / or subelements and / or combinations thereof, and / or any other tangible or intangible elements not listed above that conform to characterization by such terms, unless otherwise defined or indicated, should be understood not to necessarily conform absolutely to the mathematical definition of such terms, but rather to indicate conformance to the degree possible with the mathematical definition of such terms for the subject matter characterized as understood by one of ordinary skill in the art to be most closely related to such subject matter. Examples of such terms relating to shape, orientation, and / or geometric relationships include terms describing shape - e.g., round, square, circular / circular, rectangular / rectangular, triangular / triangle, cylindrical / cylinder, elliptical / elliptical, (n)gonal / (n)gonal, etc; terms describing angular orientation - e.g., perpendicular, orthogonal, parallel, perpendicular, horizontal, collinear, etc; terms describing contours and / or trajectories - e.g., planar / planar, coplanar, hemispherical, quasi-hemispherical, rectilinear / rectilinear, hyperbolic, radial, etc. These include, but are not limited to, terms describing boulard, flat, curved, straight, arcuate, sinusoidal, tangential, etc.; terms describing surface and / or bulk material properties and / or spatial / temporal resolution and / or distribution, such as smooth, reflective, transmissive, transparent, opaque, rigid, impermeable, uniform (uniformly), inert, non-wettable, insoluble, steady, unchanging, constant, uniform, etc.; as well as many others that will be apparent to one of ordinary skill in the art.As an example, an article of manufacture that would be described herein as a "square" does not require that such product be perfectly flat or straight and have faces or sides that intersect at exactly 90 degree angles (indeed, such an article may exist only as a mathematical abstraction); rather, the shape of such product should be interpreted to approximate a mathematically defined "square" to the extent that is typically achievable and accomplished for the referenced manufacturing techniques as understood or specifically described by one of ordinary skill in the art.

[0229] As used herein, the term "subject" refers to an individual organism, such as a human or an animal. In some embodiments, the subject is a mammal (e.g., a human, a non-human primate, or a non-human mammal), a vertebrate, a laboratory animal, a livestock animal, an agricultural animal, or a companion animal. In some embodiments, the subject is a human. In some embodiments, the subject is a rodent, a mouse, a rat, a hamster, a rabbit, a dog, a cat, a cow, a goat, a sheep, or a 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 to a nucleophile.

[0231] As used herein, the term "nucleophile" means a functionality that donates an electron pair to an electrophile for bonding to the electrophile.

[0232] As used herein, the term "react" or "reacting" refers to a "Reacting" refers to forming a bond between a species or more elements to produce a stable, isolatable compound. For example, a first element and a second element may be reacted to form a reaction product that includes the first element and the second element linked by a covalent bond. The term "reacting" may also include the use of a solvent, catalyst, base, ligand, or other material that may serve to facilitate the occurrence of a reaction between the element(s). "Stable isolatable compound" refers to an isolated reaction product, and not an unstable intermediate or transition state.

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

[0234] The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous to the alkyl groups described above, but which contain at least one double or triple bond, respectively. In one embodiment, an alkenyl group is a C2-C8 alkenyl group, and in one embodiment, an alkynyl group is a C2-C8 alkynyl group. "Heteroalkenyl" and "heteroalkynyl" refer to alkenyl and alkynyl groups, as 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 single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings, at least one of which is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), all of which may be optionally substituted. In one embodiment, an aryl group is a C6-C 10 It is an aryl group. "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 alkyl pyrrolyl, pyridyl N-oxide, pyrimidyl, pyrazinyl, imidazolyl, indolyl, etc., all of which may be optionally substituted.

[0236] The terms "amine" and "amino" refer to both unsubstituted and substituted amines, e.g., moieties that can be represented by the general formula: N(R')(R")(R'"), where R', R", and R'" each independently represent groups allowed by the valence rules.

[0237] The terms "acyl," "carboxyl," or "carbonyl" are art recognized and refer to a group having the general formula: [ka] where W is H, OH, O-alkyl, O-alkenyl, or a salt thereof. When W is O-alkyl, the formula is represents an "ester". When W is OH, the formula represents a "carboxylic acid". In general, when the oxygen atom of the above formula is replaced by 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 formula represents a "ketone" group. When W is hydrogen, the formula represents an "aldehyde" group.

[0238] As used herein, the term "heteroaromatic" or "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle (or radical thereof) containing carbon atom ring members and one or more heteroatom ring members (e.g., oxygen, sulfur, or nitrogen). Typically, aromatic heterocycles have 5 to about 14 ring members, at least one of which 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 another embodiment, the aromatic heterocyclic ring system may be 7 to 14 ring members and contain 1 to about 7 heteroatoms. Representative heteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, carbazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl, benzo(b)thienyl, and the like. These heteroaryl groups may be optionally substituted with one or more substituents.

[0239] The term "substituted" includes all permissible substituents of organic compounds, with "permissible" intended to be in the context of chemical rules of valency known to those skilled in the art. In some instances, "substituted" generally refers to the replacement of hydrogen with a substituent as described herein. However, as used herein, "substituted" does not encompass the replacement and / or modification of the critical functional group by which the molecule is specified (e.g., the functional group "substituted" is substituted with a different functional group). For example, "substituted phenyl" must still contain a phenyl moiety, and this definition cannot be modified by substitution to become, 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. Exemplary substituents include, for example, those described herein. Permissible substituents can be one or more and the same or different substituents for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner 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, carboxyester, carboxyl, carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, carboxamidoalkylaryl, carboxamidoaryl, hydroxyalkyl, haloalkyl, alkyl. These include, but are not limited to, aminoalkylcarboxy, aminocarboxamidoalkyl, alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like.

[0241] As used herein, the term "network" refers to a three-dimensional material having oligomeric or polymeric chains interconnected by cross-links.

[0242] As used herein, the term "chain" means an oligomeric or polymeric chain of one monomeric unit or an oligomeric or polymeric chain of two or more different monomeric units.

[0243] As used herein, the term "backbone" refers to the atoms and bonds by which monomer units are linked together. As used herein, the term "prepolymer" refers to oligomer or polymer chains that have not been crosslinked to form a network.

[0244] As used herein, the term "bridge" refers to a connection between two chains. A bridge may be a chemical bond, a single atom, or multiple atoms. A bridge may be formed by reaction of a pendant group of one chain with the backbone of a different chain, or by reaction of one pendant group with another pendant group. A bridge may exist between different chain molecules, or between different points on the same chain.

[0245] As used herein, the term "active agent" refers to a compound or mixture of compounds that causes a change in a biological substrate. Representative types of active agents in the medical and biological fields include therapeutic agents, prophylactic agents, and diagnostic agents. An active agent may be a small molecule drug, a vitamin, a nutrient, a biological drug, a vaccine, a protein, an antibody, or other biopolymer. An active agent may be a mixture of any of the above listed types of compounds.

[0246] "Immunosuppressant" means an agent that inhibits or prevents an immune response to a foreign substance in a subject. Immunosuppressants typically act by inhibiting T cell activation, halting proliferation, or suppressing inflammation.

[0247] As used herein, the terms "oligomer" and "polymer" each refer to a compound of repeating monomeric subunits. Generally speaking, an "oligomer" contains fewer monomeric units than a "polymer." One of ordinary skill in the art will understand that whether a particular compound is designated as an oligomer or a polymer will depend on the identity of the compound and the context in which it is used.

[0248] Those skilled in the art will appreciate that many oligomeric and polymeric compounds are composed of multiple compounds containing different numbers of monomers. Such mixtures are often designated by the average molecular weight of the oligomeric or polymeric compounds in the mixture. As used herein, the use of the singular form "compound" in reference to an oligomeric or polymeric compound includes such mixtures.

[0249] As used herein, a reference to any oligomeric or polymeric material without additional modifiers includes said oligomeric or polymeric material having any average molecular weight. For example, the terms "polyethylene glycol" and "polypropylene glycol", when used without additional modifiers, include polyethylene glycol and polypropylene glycol of any average molecular weight.

[0250] As used herein, the term "Michael acceptor" refers to 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, and 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 connected to a carbonyl group or a carbonyl analog. The reaction between a Michael acceptor and a nucleophile is sometimes referred to as a "Michael addition."

[0251] The term "aliphatic group" means a straight-chain, branched-chain, or cyclic aliphatic hydrocarbon group, including saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, and alkynyl groups. In one embodiment, an alkyl group is a C1-C8 alkyl group. In one embodiment, an alkenyl group is a C2-C8 alkenyl group. In one embodiment, an alkynyl group is a C2-C8 alkynyl group.

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

[0253] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur atom attached thereto. 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 art recognized as an amino substituted with a carbonyl group.

[0255] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group. As used herein, the term "heteroaralkyl" refers to 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. Exemplary 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] The term "oxo" as used herein means a carbonyl oxygen atom.

[0259] As used herein, the term "alkaloid" means a naturally occurring organic compound that contains at least one nonpeptidic nitrogen atom. EXAMPLES

[0260] The following examples are intended to illustrate certain embodiments of the present invention, but do not exemplify the full scope of the invention.

[0261] Example 1 - Elliptical Ring Design Except where otherwise specified, polycaprolactone (PCL) was selected as the fillable polymeric element of the constructs due to its mechanical and physicochemical properties. PCL is a degradable polyester with a low melting point of about 60° C., allowing for multiple processing techniques. PCL degrades slowly under physiological conditions by hydrolysis of its ester bonds, making it a suitable material for the preparation of certain embodiments of long-term in vivo retention constructs. PCL has been used for the controlled release and targeted delivery of various drugs.

[0262] A variety of flexible materials were tested for use as flexible linkers. Properties evaluated included the ability to undergo a 180 degree deformation without breaking, the ability to remain deformed for extended periods of time such as occurs in a storage pill, and the ability to bounce back to the original shape nearly 100%. To maximize mechanical properties while maintaining biocompatibility, an isocyanate crosslinked polyurethane made from low molecular weight polycaprolactone monomers was used.

[0263] One such run consisted of the addition of a 6:1.3:0.027:9.5 molar ratio of polycaprolactone diol (MW 530 g / mol): polycaprolactone triol (MW 900 g / mol): linear high molecular weight polycaprolactone (MW 45,000 g / mol): hexamethylene diisocyanate. The first three components were first mixed at 70°C until well mixed. The mixture was sonicated to remove any trapped air bubbles. The isocyanate was added and mixed for approximately 30 minutes while 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 thermoset was allowed to cure at 70-75°C for 48 hours, at which point the shape was rigidly cured and minimal residual free isocyanate was present.

[0264] FIG. 3 shows an elliptical ring structure configured for gastric retention. The elliptical ring structure includes a loadable polymer element and one or more linkers incorporated into the elliptical ring structure and configured for controlled degradation. FIG. 3A shows the elliptical ring structure next to a 000 size capsule. The elliptical ring structure has a major axis diameter greater than about 40 mm and a minor axis diameter comparable to the major axis of the 000 size capsule (i.e., about 26 mm). In FIG. 3B, the elliptical ring structure is loaded into (and folded within) the 000 size capsule. In FIGS. 3C-3D, the controlled degradation linkers incorporated into the elliptical ring structure at points along the minor axis can be seen. In FIG. 3D, the elliptical ring structure is twisted such that the axis of the helix is ​​along the minor axis of the elliptical ring structure. The increased loading efficiency can be seen by comparing FIG. 3E with FIG. 3B.

[0265] Example 2 - Multi-arm star design The design constraints were addressed by using a combination of relatively rigid elements (fillable polymer elements) as a drug matrix that provides mechanical stability, and flexible resilient elements (elastic polymer elements). Two geometric families of rigid and flexible elements were investigated in more detail: a "polygon" family of alternating rigid and flexible elements that fold on themselves, and a "star" family in which rigid elements protrude from a central flexible element, as shown in Figures 4A-5B. A design that could be efficiently encapsulated in a standard size 000 gelatin capsule was generated in Inventor CAD software, 3D printer, and used as a positive to create a PDMS negative mold. Optimized versions for other capsule sizes, such as larger veterinary capsules, as well as smaller capsules including 00-EL, 0-EL for easier human consumption, were developed as well.

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

[0267] Table 1 summarizes the various sized structures. [Table 1]

[0268] Example 3 - Polygonal Design In FIG. 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 rigid fillable polymer elements. Each side has a length slightly less than the length of the capsule, such that the final unencapsulated form has a circumscribed diameter approximately equal to twice the capsule length. In FIG. 5B, various structures are shown with radial projections having a sector shape with an internal sector angle equal to about 360° / N. Four embodiments of square, hexagonal, octahedral, and dodecahedral structures are each shown in the unencapsulated form. The shapes are formed from at least one material with a high elastic modulus to increase resistance to compression and extend gastric residence time.

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

[0270] Example 4 - Ingestion of Structure FIG. 6 is a series of chest / abdominal x-ray images obtained in a large animal model at 3, 5, and 12 minutes, respectively, after ingestion, showing the deployment of the multi-arm structure from the capsule and in vivo adoption by the structure in its original conformation over a period of approximately 12 minutes.

[0271] Similarly, FIG. 7 includes a series of chest / abdominal x-ray images obtained in a large animal model following ingestion of hexagonal retention / delivery structures, the sides of which are formed of polycaprolactone and the apexes include an enteric elastomeric linker, according to some embodiments. Each retention / delivery structure was tightly packed into a 000 capsule and expanded to its original shape after reaching the gastric cavity. FIG. 7A is an image taken after ingestion when the subject was fasting, and FIG. 7B is an image taken 5 days after ingestion, when the subject was consuming a normal diet. Table 3 shows the results of eight studies using hexagonal retention / delivery structures in six different pigs, according to some embodiments. As shown in the table in FIG. 7, in all cases the structures were successfully retained in the gastric cavity on days 0 and 2, and in three cases on day 5. In five other cases, on day 5 the enteric elastomeric linker degraded and the structures safely passed through the gastrointestinal tract. [Table 3]

[0272] Example 5 - Enteric Elastomer FIG. 8 is a schematic diagram of an enteric elastomer and a method of preparing an enteric elastomer according to some embodiments. In FIG. 8A, a polymer gel network is illustrated, with a first set of lines representing the synthesized poly(acryloyl-6-aminocaproic acid), a second set of lines representing linear poly(methacrylic acid-co-ethyl acrylate) (e.g., Eudragit® L100-55 available from Evonik Industries AG, Essen, Germany), boxes representing hydrogen bonds between polymer chains, and spots representing water molecules. In FIG. 8B, the manufacturing process flow is shown. From the left in FIG. 8B, poly(acryloyl-6-aminocaproic acid) sodium salt aqueous solution and poly(methacrylic acid-co-ethyl acrylate) sodium salt aqueous solution are dissolved in various ratios ( The two polymers were mixed in one of two ratios (including but not limited to 1:0, 1:1, and 1:2) to form a homogeneous aqueous solution of the polymer sodium salts. The two polymers were then co-precipitated by the addition of HCl solution. The polymer complex precipitate was converted to an enteric, elastic polymer gel and collected at the bottom of the centrifuge tube. The formed enteric elastomer can be cut and / or pressed into various shapes for constructing structures, mechanical characterization, etc.

[0273] In FIG. 8C, three optical images of the elongation test of the enteric elastomer are shown. The enteric elastomer had a 1:2 ratio of poly(acryloyl-6-aminocaproic acid):poly(methacylic acid-co-ethyl acrylate). The top image shows the enteric elastomer before elongation to a length of 1.5 cm. The middle image shows the enteric elastomer stretched 3 times its initial length. The bottom image is the enteric elastomer 5 minutes after the external force was removed, showing that the enteric elastomer has returned to its initial length.

[0274] Figure 9 shows the morphology, mechanical, dissolution, and cytotoxicity characterization of three enteric elastomer formulations according to some embodiments. In Figure 9A, a series of scanning electron microscope (SEM) images show the morphology of dry enteric elastomers with three different ratios of poly(acryloyl-6-aminocaproic acid) (PA6ACA):Eudragit® L100-55 (L100-55) (1:0, 1:1, and 1:2, respectively). The scale bar in the images equals 50 μm. All three enteric elastomer formulations have a porous structure, but higher concentrations of Eudragit® L100-55 correlated with a decrease in pore size. The formulations were lyophilized for 48 hours to dryness, and the moisture content was measured. The water content decreased from 31.6 wt % for pure poly(acryloyl-6-aminocaproic acid) to 27.7 wt % for the 1:1 ratio enteric elastomer and 26.4 wt % for the 1:2 ratio enteric elastomer, consistent with SEM observations.

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

[0276] After the elastic properties of the enteric elastomers were demonstrated, their enteric capabilities were evaluated by dissolution tests in simulated gastric and intestinal fluids. In FIG. 9B, a plot compares the results of corresponding dissolution tests in simulated gastric and intestinal fluids of the enteric elastomers. Poly(acryloyl-6-aminocaproic acid) showed long-term stability over 4 days without any discernible mass loss in simulated gastric fluid. In contrast, within the same period, poly(acryloyl-6-aminocaproic acid) was dissolved in simulated intestinal fluid at pH 6.8.

[0277] To demonstrate the biocompatibility and safety of poly(acryloyl-6-aminocaproic acid) after dissolution, poly(acryloyl-6-aminocaproic acid) sodium salt was tested for cytotoxicity in HeLa cells at a range of concentrations. In FIG. 9C, the plot compares the results of corresponding cytotoxicity studies of enteric elastomer formulations in HeLa cells. After 24 hours of incubation, no significant cytotoxicity was observed for poly(acryloyl-6-aminocaproic acid) over the concentration range of 0.0001 mg / mL to 5 mg / mL. The cytotoxicity observed at higher concentrations (above 5 mg / mL) is likely due to pH changes in the cell culture medium after dissolving the polymer sodium salt. Thus, poly(acryloyl-6-aminocaproic acid) may be biocompatible.

[0278] To assess the stability of enteric elastomers in vivo, several embodiments were performed. The construction and in vivo evaluation of constructs made from polycaprolactone (PCL) arcs interleaved with enteric elastomer linkers are shown in FIG. 10A. In FIG. 10A, six pieces of enteric elastomer were 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 polymer gel by vacuum, FIG. 10B shows the placement of polycaprolactone (PCL) beads between the six pieces of enteric elastomer. After melting and solidifying the PCL, FIG. 10C shows the ring-shaped construct removed from the mold and also shows how the construct was folded to achieve the results shown in FIG. 10D. In FIG. 10E, the folded construct was packed into a gelatin capsule with a length of 2.6 cm and a diameter of 0.9 cm. 10F-G are lateral and anterior-posterior x-ray images of a pig after administration of a gelatin capsule containing a ring-shaped structure (radiopaque metal balls were embedded in the PCL segments for imaging purposes). After the ring-shaped structure in the capsule was delivered to the pig through the esophagus, the capsule dissolved in the stomach, releasing the ring-shaped structure and regaining its shape.

[0279] Example 6 - Formation of the linker The enteric linker elements were formed by compression molding. In one embodiment, Eudragit L100-55 (Evonik), an enteric material known in the art to have a pH-dependent dissolution 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, placed on a hot press at 110-120°C, and compressed at 5000 psi for 20 minutes. The Teflon sheets were removed from the press and briefly quenched in room temperature tap water for 10 seconds, after which 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 ratios of 70:30 to 85:15 and similarly compression molded on a hot press at 100-110°C and 3000 psi for 10-20 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 compression molded or cast into films by evaporation of the solvent (e.g., water) to produce sheets of material for use as linkers.

[0282] The time or pH dependent linker can be coupled to the drug loaded polycaprolactone matrix. Several strategies to achieve this have been attempted. In one case, a film of an elastic PCL prepolymer solution was painted onto both sides of a molten film and cured. In the case of Eudragit L100-55, this results in covalent crosslinking of the elastic PCL to the soluble linker via urethane bond formation with available reactive groups. The multilayer film produced by this method has an outer interface of elastic PCL and can be coupled to linear PCL via the final application of heat for a period of time in a constraining mold.

[0283] In another example, a biocompatible adhesive was used to couple a soluble linker to the polycaprolactone. In one example, a sheet of polycaprolactone film was produced to facilitate coupling. The use of a plasticizer (Pluronic P407) with the polycaprolactone at a ratio of 10 w / w% generally improved the flexibility and reduced brittleness of the polycaprolactone film. Urethane (e.g., Loctite® M-11FL™ Hyso Polycaprolactone films were adhered to both sides of the preformed melt film using a biomedical adhesive such as Loctite® Medical Structural Urethane Adhesive or cyanoacrylate (e.g., Loctite® 3981 Hysol® Epoxy Structural Adhesive).

[0284] Linkers with appropriate geometry were then cut from the multilayer film, where the exposed outer layer was polycaprolactone. These linkers could be easily coupled to the drug-loaded polycaprolactone matrix by applying heat to the interface.

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

[0286] Tensile The PCL elastomer was cured into a polymer sheet 2 mm thick. The sheet was cooled and specimens were cut from the sheet using a standard dumbbell die (ASTM D-638). The specimens were mounted in the grips of an Instron materials testing machine and the gauge length was measured using a digital micrometer. The specimens were subjected to a displacement at a rate of 10 mm / min until the sample broke. 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 The 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 rotating hollow drill bit. The specimen was placed in a restrained load compression jig and subjected to a displacement at 12 mm / min. The specimen was tested until a 30% compressive strain was reached. The force was converted to pressure (F / A) and the displacement to volume ratio (ΔV / V) and are plotted in FIG. 11B.

[0288] Creep PCL elastomer, polydimethylsiloxane (silicone), and polyethylene vinyl acetate (PEVA) were cured into polymer sheets 2 mm thick. The sheets were cooled and specimens were cut from the sheets using a standard dumbbell die (ASTM D-638). The specimens were mounted in the grips of an Instron materials 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 specimens for 60 minutes. Force and displacement were calculated throughout the test and converted to normal stress (F / A) and strain (ΔL / L) and are plotted in Figure 11C.

[0289] Example 8 - Finite element analysis of the support structure Finite element method was used to analyze the stress and strain profile of the structure in SIMULIA Abaqus FEA software. The geometry of the structure was imported into Abaqus from AutoDesk Inventor. The material properties of the PCL elastomer were defined using the Mooney-Rivlin hyperelastic model derived from the tension and compression tests described above. The linear PCL arms were assumed to be linear elastic and the elastic modulus was derived from the bending tests described above. The model was meshed using C3D4 elements to bond the PCL elastomer to the linear PCL 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. A force was applied perpendicularly to the top of each arm to simulate the folding of the structure into a capsule. After the calculations, the von Mises stress, maximum principal stress, longitudinal stress and transverse stress were calculated. al) stress was analyzed. The results of the finite element modeling are shown in Figure 12.

[0290] Example 9 - Simulated pyloric emptying of retention structures To better understand the passage of the retention structure through the pylorus, a custom experimental setup was developed. A schematic of the experimental setup is shown in FIG. 13A. A polypropylene funnel with a 20 cm upper diameter and a 2 cm lower diameter was used to simulate the pyloric sphincter. A structure with the star shape described above was placed into the funnel and a custom designed plunger was used to push the structure through the 2 cm spout. The plunger was attached to the tensile crosshead of an Instron materials testing machine and the funnel was attached to a clamp. The structure was pushed through the funnel at a rate of 10 mm / min and the force and displacement were captured throughout the test and are shown in FIG. 13B.

[0291] Example 10 - Evaluation of gastric retention in vivo To evaluate the specific formulations developed for their ability to achieve gastric retention, the structures described above (e.g., hexagon and star) were administered to a large animal model, the Yorkshire pig, weighing 35-50 kg. This model was chosen because it is known to have a gastric anatomy similar to humans and is widely used to evaluate structures in the gastrointestinal space. Prolongation of food bolus transit in pigs is usually measured in hours, therefore, for evaluation of retention on the order of days, this should only result in small errors and provides a good model of gastric anatomy and gastric emptying.

[0292] Pigs were sedated with Telazol and xylazine, or optionally ketamine, or optionally isoflurane, and an endoscopic overtube was placed in the esophagus under visual guidance with an endoscope during esophageal intubation. A gelatin capsule containing the construct was administered into the esophagus and / or stomach via the overtube, and the overtube was removed. Immediately after, serial x-rays were obtained to document the course of development from the gelatin capsule. Blood samples were obtained as needed by cannulation of the mammary vein on the ventral surface of the pig, usually at time 0 (before pill administration), 5 min, 15 min, 30 min, 2 h, 6 h, and daily thereafter for a minimum of 5 days, and then at designated times three times per week. Three times per week, chest and abdominal x-rays were obtained with a minimum of 5 views, including anteroposterior, left lateral, and right lateral positions of the chest, upper abdomen, and lower abdomen and rectum. Steel fiducials of 3-5×1 mm were embedded in the drug delivery PCL arms by melt casting. These could be followed radiographically to assess the deployment and intactness of the delivery system, as well as its location in the gastric cavity or upper or lower abdomen. Radiographs were also evaluated for the presence of evidence of complications such as pneumoperitoneum or ileus. Representative radiographs are shown in Figures 6 and 7.

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

[0294] The stability of drugs loaded into PCL-based delivery matrices was also investigated. Drug loading is described in Examples 16 and 17 below. The drug-loaded structures were kept under acidic conditions (pH=1, 37° C.) and at defined intervals the drug was extracted from the PCL matrix and analyzed by HPLC and / or LC-MS / MS. To extract the drug, the structures were were sonicated for 10 min in SGF (hydrophilic drugs) or isopropanol (hydrophobic drugs). Immediately prior to analysis, fresh drugs were prepared in SGF or isopropanol as controls.

[0295] Stability of doxycycline (hydrophilic) in SGF (pH=1, 37°C) The stability of doxycycline in SGF (pH=1, 37° C.) over a period of 2 weeks as analyzed by HPLC is shown in FIG. 14. An Agilent 1260 infinity model HPLC system equipped with an autosampler and a C8 reversed-phase column (4.6×150 mm, id, 5 um 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 onto the column at a mobile phase flow rate of 1 mL / min and UV absorbance at 350 nm was recorded for 10 min.

[0296] Stability of Artemether (hydrophobic) in IAW (pH=1, 37°C) The stability of Artemether in IAW (pH=1, 37° C.) over a period of two weeks analyzed by HPLC is shown in Figure 15. The drug related area under the curve (AUC) was used to quantify the stability percentage.

[0297] Stability of ivermectin in solution or in PCL structures under acidic conditions (pH = 1, 37°C) Free ivermectin is unstable under acidic conditions (IAW, pH=1, 37°C), as shown in Figure 16A. The PCL structure protected ivermectin against acidic degradation. The ivermectin (IVM)-loaded structure shown in Figure 16B was placed in SGF+RH solution (pH=1, 37°C) for 72 hours. The drug was extracted by sonicating 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 the IVM in an acidic environment.

[0298] Example 12 - In vitro drug release study Drug-loaded oral delivery structures with various compositions were prepared as described in Examples 16 and 17. Structures loaded with hydrophilic drugs were placed in a sealed cup containing 100 mL of SGF. For hydrophobic drugs, Kolliphor® RH40 (a non-ionic oil-in-water solubilizer) was added to SGF (0.25% (w / v)) to enhance the solubility of the released drug. The cup was placed in a shaking incubator (150 rpm, 37° C.). Samples were collected at specified time points up to 2 weeks and analyzed by HPLC and LC-MS / MS to quantify the amount of drug released.

[0299] In vitro release of doxycycline (hydrophilic) loaded structures in SGF Figure 17A shows the in vitro release of doxycycline-loaded PCL star structures 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 to tune the release kinetics. Drug concentrations in the release medium were measured by HPLC. The ratios of PCL:PLu:Dox were expressed in weight % in the figure legend.

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

[0301] Figure 17C shows the in vitro release of ivermectin (IVM) loaded star structures with different formulations in SGF+RH40 (pH=1, 37°C). All formulations contain 70% PCL, 20% IVM, and 10% excipients. The 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 media were measured by HPLC. Error bars represent SD of three independent replicates.

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

[0303] Example 14 - Gastric residence time Figures 19-21 show histograms of gastric retention probability at designated time points for three differently configured gastric retention systems. Gastric retention systems were formed including stainless steel 1 mm fiducials placed in the polymeric drug delivery "arms" during polymerization of the arms. Gastric retention systems were administered to Yorkshire pigs (35-50 kg) under sedation via an endoscopic overtube into the gastric cavity. Serial x-ray images were acquired of multiple locations (anteroposterior, left lateral, right lateral) of the chest, abdomen, and pelvis. X-ray images were acquired up to 15 minutes after delivery to confirm deployment from the outer capsule and / or restraint system. X-ray images were then acquired daily for the next 4 days and three times weekly after the first 5 days. The location of the retention system in the gastric cavity was confirmed from multiple radiographic views. (Figure 19, H1-EE1) Hexagonal retention system with polycaprolactone "arms" and elastic elements at the apexes made from enteric elastomer. (FIG. 20, H1-F1-F1-X1) A hexagonal retention system with arms made from isocyanate cross-linked polycaprolactone and elastic elements made from isocyanate cross-linked polycaprolactone, further with a soluble linker made from Eudragit L100-55 film. (FIG. 21, H1-F1-R1-X2) A hexagonal retention system with arms made from polycaprolactone and elastic elements made from isocyanate cross-linked polycaprolactone, and a soluble linker made from a blend of 90% Eudragit L100-55 and 10% poly(acrylic acid).

[0304] Example 15 - Food passage Intragastric balloons for the treatment of obesity (endoscopically deployed gastric retention systems) have symptoms noted consistent with partial gastric outlet obstruction, particularly nausea in patients ranging from 18-90%. To monitor the potential for gastric outlet obstruction by the retention structures described herein, these structures were evaluated in a large animal model. In particular, structures constructed primarily from non-degradable elastic polymer elements were prepared in a star-shaped configuration and observed for potential outlet obstruction. This was deployed in the stomach of a pig weighing approximately 50 kg and clinically monitored twice daily for evidence of gastrointestinal obstruction, including abdominal distension, vomiting, and reduced fecal production. In addition, serial x-rays were performed three times weekly to evaluate for evidence of obstruction, including gastric distension. Additionally, on day 35, prior to the endoscopic procedure, the animals were fed a liquid diet for 24 hours to evaluate the animals' ability to empty their stomach contents, and the stomach was further evaluated endoscopically. Upon endoscopic imaging, the structures were confirmed to overly the pylorus, and the gastric cavity was free of food. This supports the ability of the structure to permit the passage of food from the stomach and yet remain lodged in the gastric cavity and further cover the pylorus.

[0305] Figure 22 shows an 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 in the field of view. As also shown in the photograph, there appears to be no significant evidence of food retention, and in fact there are no entangled food particles at all in the prototype.

[0306] Example 16 - In vivo long-term oral doxycycline delivery Doxycycline hyclate 100 mg commercial tablets were purchased from a veterinary source (Patterson Veterinary). Three pigs were administered one tablet each on day 0, and serum was collected by intravenous cannulation at selected time points. Another pig was administered a total of approximately 1000 mg of doxycycline six-arm star formulation intended to provide the same dose as 100 mg twice daily for approximately five days. 45,000 MW polycaprolactone loaded with 25 w / w% doxycycline was compounded with 4 w / w% Pluronic P407 hydrophilic excipient. The blend was melted and mixed at 75°C and cast into a PDMS mold. After cooling, the center section was removed from the star and an elastic PCL prepolymer solution was poured into the center cavity and cured at approximately 75°C for 48 hours. The resulting shapes were encapsulated and administered to Yorkshire pigs as previously described. LC / LC-MS was used to quantitate drug levels as shown in FIG.

[0307] Example 17 - In vivo long-term oral ivermectin delivery Ivermectin was dissolved in a 50:50 solution of EtOH and water and administered at 0.2 mg / kg by oral gavage in 10 ml of solution to pigs weighing 40-50 kg each. At the indicated times before and after dosing, blood samples were collected into serum separator tubes by peripheral venous cannulation and centrifuged. Serum was frozen in aliquots for later batch analysis. Serum levels of ivermectin were measured using standard methods on a Waters LC-MS as shown in Figure 25A.

[0308] Ivermectin was loaded into polycaprolactone by first mixing 20% ​​(w / w) of the final mass of ivermectin with 10% (w / w) of the final mass of Pluronic P407 poloxamer and briefly melting at 75°C. Next, 45,000 molecular weight polycaprolactone (Sigma-Aldrich, St. Louis, MO) was added (70 w / w%) and the mixture was melted at 75°C for 20 minutes and mixed for 5 minutes. The molten mixture was transferred into a star-designed mold. The mold was heated to 90°C for 2 hours and then air-cooled. The arms were prepared and placed back into the star-shaped mold, leaving the central element as a void. 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 0.1000 gelatin was added. The capsules were administered into the gastric cavity of sedated Yorkshire pigs via an esophageal overtube placed under an endoscope. 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 made as described above in a mold corresponding to the specially made central elastic element. Ivermectin-filled elements were made as previously described in FIG. 25B. The molten mixture was transferred into a star-designed mold in which the preformed elastic central element was placed in the appropriate position. The mold was heated to 90° C. for 2 hours and then air-cooled. The star shapes were removed from the mold and placed into 000 gelatin capsules. The capsules were administered into the gastric cavity of sedated Yorkshire pigs via an esophageal overtube placed under an endoscope. Ten capsules, each containing approximately 200 mg of ivermectin embedded in the formulation, were administered to three pigs each. The results are shown in FIG. 25C.

[0310] While several embodiments of the invention have been described and illustrated herein, one of ordinary skill in the art will readily envision various other means and / or structures for performing the functions and / or results and / or obtaining one or more advantages described herein, and each such variation and / or modification is deemed to be within the scope of the invention. More generally, one of ordinary skill in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application(s) for which the teachings of the invention are used. One of ordinary skill in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Thus, it will be understood that the foregoing embodiments are presented by way of example only, and that, within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described and claimed. The present invention relates to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is encompassed within the scope of the present invention, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0311] As used in this specification and the claims, unless specifically and expressly indicated to the contrary, the indefinite articles "a" and "an" should be understood to mean "at least one."

[0312] As used herein and in the claims, the phrase "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Other elements, either related or unrelated to those elements specifically identified, other than the elements specifically identified may be optionally present, unless otherwise expressly indicated to the contrary. Thus, as a non-limiting example, a reference to "A and / or B," when used with an open-ended term such as "comprising," can 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 forth.

[0313] As used in the specification and 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 construed as including at least one number or list element, but also including two or more number or list elements, and optionally additional non-list items. Only where terms are clearly indicated to the contrary, e.g., "only one" or "exactly one," or, when used in the claims, "consisting of," shall mean including exactly one of some or a list of elements. In general, as used herein, the term "or" shall only be construed as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by an exclusive term, such as "either," "one of," "only one of," or "exactly one." When used in the claims, "consisting essentially" shall have its ordinary meaning as used in the field of patent law.

[0314] As used herein and in the claims, the phrase "at least one," in connection with a list of one or more elements, should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can mean, in one embodiment, at least one, optionally, two or more, A and no B (and optionally including elements other than B); in another embodiment, at least one, optionally, two or more, B and no A (and optionally including elements other than A); in yet another embodiment, including at least one, optionally, two or more, A, and including at least one, optionally, two or more, B (and optionally including other elements); etc.

[0315] In the claims as well as in the above specification, all transitional phrases, such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," and the like, are to be understood to be open-ended, i.e., to mean including, but not limited to. As set forth in the U.S. Patent Office Manual of Patent Examining Procedures at § 2111.03, only the transitional phrases "consisting of" and "consisting essentially of" are closed or semi-closed transitional phrases, respectively. For example, the present invention provides the following: (Item 1) A retention structure, comprising: A fillable polymer element; a first linker that connects the fillable polymer element to a second polymer element; a second linker comprising at least a portion of the fillable polymer element and / or the elastic polymer element or attached to the fillable polymer element and / or the elastic polymer element; 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 comprises at least about 60% by weight of the total 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; A retention structure, wherein the second linker is degradable under a second set of physiological conditions different from the first set of conditions, and is not substantially degradable under the first set of conditions. (Item 2) 2. The retention structure of claim 1, wherein the first linker comprises an elastic polymer element. (Item 3) 2. The retention structure of claim 1, wherein the second linker comprises an elastic polymer element. (Item 4) A retention structure, comprising: A fillable polymer element; a second polymer element attached to the fillable polymer element via at least one degradable linker; wherein the degradable linker comprises at least a portion of the fillable polymer element and / or the second polymer element or is attached 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 degradable linker comprises an elastic polymer element; the fillable polymer element comprises at least about 60% by weight of the total structure weight; having a folding force of at least about 0.2 N; A retention structure having an uncompressed cross-sectional dimension of at least about 2 cm. (Item 5) A retention structure, comprising: a fillable polymer element and a second polymer element bonded to the fillable polymer element; at least one degradable linker comprising at least a portion of the fillable polymer element and / or the second polymer element or attached to the fillable polymer element and / or the second polymer element; A retention structure configured to be retained in place within a subject for at least about 24 hours. (Item 6) 6. The retention structure of item 5, wherein at least one of the fillable polymer element, the second polymer element, and the degradable linker comprises an elastic polymer element. (Item 7) A retention structure, comprising: a fillable polymer element and a second polymer element bonded to the fillable polymer element; at least one degradable linker comprising at least a portion of the fillable polymer element and / or the second polymer element or attached to the fillable polymer element and / or the second polymer element; the fillable polymeric element comprises an active agent; the retention structure is configured such that the active agent is released from the fillable polymeric material at a specified initial average rate measured from the release over an initial 24 hour period; A retention structure wherein said active agent is released at an average rate over a 24 hour period following said initial 24 hour release that is at least about 1% of said initial average rate. (Item 8) 8. The retention structure of item 7, wherein at least one of the fillable polymer element, the second polymer element, and the degradable linker comprises an elastic polymer element. (Item 9) 9. The retention structure according to any one of items 4 to 8, wherein the second polymer element comprises the elastic polymer element. (Item 10) 10. The retention structure according to any one of items 4 to 9, wherein the degradable linker comprises an elastic polymer element. (Item 11) 11. The retention structure according to any one of items 4 to 10, further comprising additional elastic polymer elements. (Item 12) 12. The retention structure according to any one of items 4 to 11, wherein the degradable linker comprises at least a portion of the fillable polymer element and / or the second polymer element or is attached to the fillable polymer element and / or the second polymer element. (Item 13) 6. The retention structure according to any one of items 1 to 5, comprising an active substance. (Item 14) 14. The retention structure of item 7 or 13, wherein the active agent is a therapeutic agent. (Item 15) 2. The retention structure of any preceding item, having a first configuration configured to maintain an in vivo position relative to the internal opening. (Item 16) 2. The retention structure of any of the preceding items, wherein the first configuration has a polygonal shape. (Item 17) 16. The retention structure according to any one of items 1 to 15, wherein the first configuration has a multi-arm star shape. (Item 18) 18. The retention structure according to item 17, having 3 to 8 arms. (Item 19) 2. The retention structure according to any of the preceding items, wherein the fillable polymer element is bonded to the second polymer element via an adhesive, by chemical bonds, and / or by interpenetrating polymer chains. (Item 20) 2. The retention structure of any of the preceding items, wherein the second polymer element is configured to undergo a 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 of any of the preceding items, wherein the second polymer element is configured to remain in the deformed configuration for a period of at least about 24 hours, at least about one week, at least about one month, at least about one year, or at least about two years, and is configured to return substantially to its pre-deformed configuration after said period. (Item 22) Item 2. The retention structure according to any of the preceding items, wherein the elastic modulus of the second polymer element is in the range of about 0.1 MPa to about 30 MPa. (Item 23) The retention structure of any of the preceding items, wherein the second polymeric element does not substantially swell in the presence of biological fluids such as blood, water, bile, gastric fluids, and the like. (Item 24) 24. The retention structure of item 23, which does not substantially swell in the presence of gastric fluid. (Item 25) The retention structure of any of the preceding items, wherein the device swells in unstirred gastric fluid or simulated gastric fluid at physiological temperature 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. (Item 26) 26. The retention structure according to item 25, wherein the biological fluid is gastric fluid. (Item 27) The retention structure of any of the preceding 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-glycolic acid), polybutyrate, and polyhydroxyalkanoates; 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) 2. The retention structure of any of the preceding 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 preceding items, wherein the fillable polymer element comprises polycaprolactone (PCL), poly(ethylene-co-vinyl acetate), and / or polyethylene glycol (PEG). (Item 30) The retention structure according to any of the preceding 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, based on the total structure weight. (Item 31) Item 15. The retention structure according to any one of items 13 or 14, wherein the active substance is present in the fillable polymer element in an amount ranging from about 0.01% by weight to about 50% by weight based on the weight of the total fillable polymer element. (Item 32) 34. The retention structure according to any one of items 4 to 33, wherein the at least one degradable linker is configured to at least partially dissociate over a retention period. (Item 33) Item 33. The retention structure according to item 32, wherein the retention period is in the range of 24 hours to 2 years. (Item 34) 34. The 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 period of time of at least about 24 hours, at least about 48 hours, at least about one week, at least about one month, or at least about one year. (Item 35) 35. The retention structure according to item 34, wherein the physiological environment is a gastric environment. (Item 36) 36. The retention structure of item 35, wherein the gastric environment comprises the gastric cavity. (Item 37) 37. The retention structure according to any one of items 4 to 36, wherein at least one degradable linker comprises an enteric polymer. (Item 38) 38. The retention structure according to item 37, wherein the enteric polymer comprises cellulose acetate phthalate, hypromellose, hydroxypropyl methylcellulose, and / or poly(methacrylic acid-co-ethyl acrylate). (Item 39) 38. The retention structure according to item 37, wherein the enteric polymer comprises poly(acryloyl-6-aminocaproic acid) and poly(methacrylic acid-co-ethyl acrylate). (Item 40) 40. The retention structure according to any one of items 37 to 39, wherein the enteric polymer is a polymer gel having a water content of 40% by volume or less. (Item 41) 41. The retention structure according to any one of items 37 to 40, wherein the enteric polymer comprises a polymer of an acryloylaminoalkylene acid monomer, or a salt thereof. (Item 42) 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) 43. The 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, said blend comprising a first enteric polymer as described in item D25 and a second enteric polymer comprising poly(methacrylic acid-co-alkyl acrylate), or a salt thereof. (Item 44) 44. The 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) 45. The retention structure according to any one of items 37 to 44, wherein the enteric polymer is configured to exhibit reversible elongation when stretched from 50% to 1500% of its initial length. (Item 46) 46. ​​The retention structure according to any one of items 37 to 45, wherein at least one linker is soluble in an aqueous solution at a pH greater than about 6.0, and is substantially insoluble in an aqueous solution at a pH less than about 3.0 for a period of 4 to 40 days, measured at room temperature. (Item 47) 47. The retention structure according to any one of items 37 to 46, wherein the enteric polymer has an elastic modulus of 0.1 MPa to 100 MPa. (Item 48) 15. The retention structure of any one of items 13 or 14, wherein the active agent comprises at least one of statins, antimalarials, hormones, levothyroxine, ivermectin, antiretrovirals, anthelmintics, antipsychotics, antidepressants, and caffeine. (Item 49) 15. The retention structure according to any one of items 13 or 14, wherein the active substance comprises at least one of protein, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, and vitamin D. (Item 50) The retention structure of any of the preceding items, wherein one or more elements and / or one or more linkers comprise a food grade cross-linked polymer. (Item 51) 16. The retention structure according to any one of items 1 to 15, wherein the structure has a shape having a fenestration. (Item 52) The structure occupies about 10% by volume to about 90% by volume of the convex hull volume of the structure. 2. The retention structure according to claim 1 . (Item 53) 1. A system for delivering a retention structure, comprising: A containment structure; a retention structure contained within the containment structure; the retention structure is constructed and arranged to have a first configuration after release from the containment structure; the retention structure is constructed and arranged to have a second configuration when contained within the containment structure; the first configuration has an uncompressed 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, wherein a first portion of a device is degradable under a first set of physiological conditions, but a second portion of said device is substantially not degradable under said first set of physiological conditions. (Item 54) 54. The system of claim 53, wherein the retention structure comprises a fillable polymer element and at least one degradable linker attached to the fillable polymer element. (Item 55) 55. The system of claim 53 or 54, wherein a second portion of the device is degradable under a second set of physiological conditions. (Item 56) 56. The system of any one of items 53 to 55, wherein at least a portion of the device is bendable and / or flexible. (Item 57) 57. The system of any one of items 53 to 56, wherein the containment structure is configured for at least one of ingestion, self-administration, and oral administration. (Item 58) 58. The system of any one of items 53 to 57, wherein the containment structure includes at least one of a 000 capsule, a 00 capsule, a 0 capsule, a 1 capsule, a 2 capsule, a 3 capsule, a 4 capsule, and a 5 capsule. (Item 59) 59. The system of 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 a cavity defined by the storage structure. (Item 60) 60. The system of any one of items 53 to 59, wherein the retention structure is configured to adopt the first configuration upon release from the containment structure. (Item 61) 61. The system of any one of items 53 to 60, wherein the retention structure comprises an elastic polymer element. (Item 62) Item 62. The system of item 61, wherein the elastic polymer element has sufficient rebound strength to cause the elastic polymer element to substantially return to its pre-deformation shape after release of mechanical deformation in less than about 30 minutes, and in less than about 10 minutes, less than about 5 minutes, or less than about 1 minute. (Item 63) 63. The system of 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 at least one of 72 hours, 1 week, 2 weeks, 4 weeks, 1 year, and 5 years. (Item 64) 64. The system of any one of items 53-63, wherein the maximum cross-sectional dimension of the first configuration is at least about 10% smaller, at least about 20% smaller, at least about 40% smaller, at least about 60% smaller, or at least about 80% smaller than the maximum cross-sectional dimension of the second configuration. (Item 65) 65. The system of any one of items 53 to 64, wherein the convex hull volume of the first configuration is at least about 10% smaller, at least about 20% smaller, at least about 40% smaller, at least about 60% smaller, or at least about 80% smaller than the convex hull volume of the second configuration. (Item 66) 1. A method for delivering a retention structure, comprising: administering to a subject a containment structure containing a retention structure, whereby the containment structure releases the retention structure at a location within the subject; the retention structure has a second configuration within the containment structure; The method, wherein after the retention structure is released from the containment structure, the retention structure acquires a first configuration such that it is retained at or near a location within the subject for at least about 24 hours. (Item 67) Item 67. The method of item 66, wherein the location within the subject is an orifice or cavity. (Item 68) 1. A method for delivering a retention structure, comprising: administering to a subject a containment structure containing a retention structure, whereby the containment structure releases the retention structure at a location within the subject; the retention structure has a second configuration within the containment structure; The retention device comprises a fillable polymeric element containing an active agent; the retention structure is configured such that the active agent is released from the retention structure at an initial average rate over an initial 24 hour period; The method, wherein said active agent is released at an average rate over a 24 hour period after said initial 24 hour release that is at least about 1% of said initial average rate. (Item 69) the retention structure includes an elastic polymer element and a fillable polymer element mechanically coupled to the elastic polymer element; the fillable polymer elements constitute at least about 60% by weight of the total structure weight; 70. The method of claim 66 or 68, wherein the retention structure has a folding force of at least about 0.2 N. (Item 70) Item 69. The method of 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 according to any one of items A-D35. (Item 72) 72. The method of any one of items 66-71, wherein the retention structure is loaded with at least one of a therapeutic agent, a diagnostic agent, and a potentiating agent prior to administering the retention structure to the subject. (Item 73) 69. The method of claim 68, wherein 0.05% to 99% by weight of the active agent is released between 24 hours and 1 year after the administering step. (Item 74) 74. The method of any one of items 66 to 73, wherein the location inside the subject is an internal cavity and the retention structure is retained within the cavity by an internal opening. (Item 75) Item 75. The method of item 74, wherein the retention structure does not substantially restrict the flow of liquid through the internal opening during the period the retention structure is retained within the cavity. (Item 76) 76. The method of claim 75, wherein the internal opening is the gastric pyloric orifice. (Item 77) 77. The method according to any one of items 66 to 76, wherein the retention structure comprises at least one degradable linker attached to the fillable polymer element. (Item 78) 78. The method of claim 77, wherein dissociation of the at least one linker terminates the residence period and allows passage through the interior opening of the residence structure. (Item 79) 79. The method of any one of items 66 to 78, wherein after the retention structure is released from the containment structure, the retention structure releases the active agent at an average rate over a continuous 24 hour period, measured at at least one time point during a period of 48 hours to about 1 year after the initial release, that is from about 1% to about 99% of the initial average release rate measured over an initial 24 hour period beginning immediately after release.

Claims

[Claim 1] The invention as depicted in the drawings.

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