Metal core for gastric residence system

Abstract

A metal core for a gastric residence system and a gastric residence system including a metal core are provided. A metal core according to some embodiments includes a plurality of arm mounts, each arm mount configured to receive an elongated arm of a gastric residence system, where the core is configured to be bendable into a compacted form such that each arm mount of the plurality of arm mounts is in proximity to each other, the plurality of elongated arms are arranged in a non-compacted form, and the distal ends of the plurality of elongated arms are in proximity to each other when the plurality of elongated arms are attached to the metal core, and wherein the metal of the metal core provides elasticity and shape memory to enable the metal core to deploy into a non-compacted form, and allow retention of the gastric residence system when the plurality of elongated arms are attached to the metal core.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 370,366, filed on August 3, 2022. The entire contents of that patent application are hereby incorporated by reference herein. Technical Field

[0003] The present disclosure relates to gastric retention systems and in particular to gastric retention systems including a metal core. Background Art

[0004] Gastric resident system is the delivery system of preparation, it can be resident in the stomach for several days to several weeks, or even longer, during which time, medicine or other preparation can be eluted from the system, so as to be absorbed in the gastrointestinal tract. Gastric resident system is designed to be administered to the stomach of the patient, typically in a capsule, which is introduced into the stomach by swallowing or by alternative administration methods (e.g., feeding tube or stomach tube). When the capsule dissolves in the stomach, the system expands or expands to a certain size, which is maintained in the stomach and prevented from passing through the pyloric sphincter during the desired residence time (such as three days, seven days, two weeks, etc.). This requires mechanical stability during the desired residence time. During the residence period, the system releases one or more preparations / reagents / active agents / medicaments such as one or more drugs, preferably with minimal burst release / explosion release, which requires careful selection of the carrier material of the preparation, to provide a desired release profile. When resident in the stomach, the system should not interfere with the normal passage of food or other gastric contents. The system should be discharged from the stomach at the end of the desired residence time, and is easily eliminated from the patient's body. If the system passes prematurely from the stomach into the small intestine, it should not cause intestinal obstruction and should be easily expelled from the patient. These characteristics require careful selection of the materials that make up the system, as well as the size and arrangement of the system. Summary of the invention

[0005] Provided herein is a gastric retention system having a core comprising metal. The gastric retention system described herein is designed to be administered to a patient in a compacted form / compacted form / compacted configuration. The compacted form can be achieved by bringing together the distal ends of the multiple arms of the star-shaped gastric retention form so that the gastric retention system is bent at the core (from which the multiple arms extend). When in the patient's body (e.g., in the patient's stomach), the gastric retention system is configured to open from its compacted form to an open configuration or a non-compacted form. However, when the gastric retention system is stored in its compacted form, due to material creep, its ability to return to its non-compacted form / non-compacted form / non-compacted configuration decreases over time, particularly in the case of a gastric retention system comprising an elastomeric core. This creep minimizes the shelf life of the gastric retention system.

[0006] Accordingly, the present disclosure provides a gastric retention system having a metal-containing core. As described above, the star-shaped gastric retention system bends at the core to obtain a compacted form. Using metal in the core can extend the shelf life of the gastric retention system because metal does not creep like other materials used in the core of gastric retention systems, such as polymers.

[0007] The metal used in the core of the gastric retention system described herein can be in any of a variety of configurations and / or shapes. For example, in some embodiments, the metal component of the core can be formed using metal wire and bent to form a star shape. The metal wire can include a number of "arms" or arm mounts corresponding to the number of arms of the gastric retention system. (In other words, each arm of the gastric retention system can be attached to an "arm" of the star-shaped metal wire.) Such a metal core can be formed using laser cutting or stamping (e.g., in a flat metal core configuration) or using a jig (e.g., in a continuous wire core configuration). In some embodiments, overmolding can be used to attach the arms of the gastric retention system to the metal core. Overmolding can also be used to attach a polymer to the metal core to, for example, control the hardness of the core and / or coat the metal core to prevent direct contact of the core metal with the patient's body.

[0008] In some embodiments, there is provided a gastric retention system comprising: a metal core and a plurality of elongated arms, each of the plurality of elongated arms including a distal end and a proximal end connected to the metal core, wherein the gastric retention system is configured to fold into a compacted form by bending the metal core such that each of the plurality of arm mounts is close to each other and the distal ends of the plurality of elongated arms are close to each other, wherein the metal of the metal core provides elasticity and shape memory such that the gastric retention system can be deployed into a non-compacted form and allowed to retain.

[0009] In some embodiments, there is provided a gastric retention system comprising: a metal core having a plurality of arm mounts; and a plurality of elongated arms, each of the plurality of elongated arms including a distal end and a proximal end connected to an arm mount of the metal core, wherein the gastric retention system is configured to fold into a compacted form by bending the metal core such that each of the plurality of arm mounts is close to each other and the distal ends of the plurality of elongated arms are close to each other, and wherein the metal of the metal core provides elasticity and shape memory such that the gastric retention system can be deployed into a non-compacted form and allowed to retain. The number of elongated arms is equal to the number of arm mounts such that each elongated arm is attached to a corresponding arm mount.

[0010] In some embodiments of the gastric retention system, the gastric retention system is configured to be stored in a compacted form for 30 days and then administered to a patient.

[0011] In some embodiments of the gastric retention system, the gastric retention system is configured to maintain the compacted form for 30 days and to return to the non-compacted form such that the creep angle after 30 days in the gastric retention form is within 3% of the creep angle in the gastric retention form prior to 30 days.

[0012] In some embodiments of the gastric retention system, the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

[0013] In some embodiments of the gastric retention system, the height of the metal core is the same as the width of the metal core.

[0014] In some embodiments of the gastric retention system, the metal core includes a plurality of arm mounts, wherein each elongate arm of the gastric retention system is configured to be attached to the metal core at one of the plurality of arm mounts.

[0015] In some embodiments of the gastric retention system, the metal core comprises nitinol. The nitinol may include ultra-low inclusion nitinol. The nitinol may include extra-pure nitinol. The nitinol may include ultra-low inclusion, extra-pure nitinol.

[0016] In some embodiments of the gastric retention system, each of the plurality of elongate arms is overmolded on the metal core.

[0017] In some embodiments of the gastric retention system, the gastric retention system includes a degradable connector attached to the arm mount of the metal core and an elongate arm attached to the degradable connector.

[0018] In some embodiments of the gastric retention system, the metal core is made using a metal wire.

[0019] In some embodiments of the gastric retention system, the metal core is made by stamping a metal sheet.

[0020] In some embodiments of the gastric retention system, the metal wire has a cross-section with a diameter of from 0.01 inches to 0.02 inches (0.254 mm to 0.508 mm).

[0021] In some embodiments of the gastric retention system, the metal core is formed using a flat metal sheet.

[0022] In some embodiments of the gastric retention system, at least one of the plurality of elongate arms contains a therapeutic agent.

[0023] In some embodiments, a core for a gastric retention system is provided, the core comprising: a metallic core having a plurality of arm mounts, each arm mount configured to receive an elongate arm of the gastric retention system, wherein the core is configured to be bendable into a compacted form such that each of the plurality of arm mounts are close to each other, and in the case where a plurality of elongate arms are attached to the metallic core, distal ends of the plurality of elongate arms are close to each other, wherein the metal of the metallic core provides elasticity and shape memory to enable the metallic core to expand into an uncompacted form and, in the case where a plurality of elongate arms are attached to the metallic core, permit retention of the gastric retention system.

[0024] In some embodiments of the core, the metallic core is configured to maintain the compacted form for 30 days and be able to return to the uncompacted form such that the creep angle after 30 days of the gastric retention form is within 3% of the creep angle of the gastric retention form before 30 days.

[0025] In some embodiments of the core, the metallic core has a flat shape such that the height and width of the metallic core are at least 10 times the thickness of the metallic core.

[0026] In some embodiments of the core, the height of the metallic core is the same as the width of the metallic core.

[0027] In some embodiments of the core, the metallic core is configured to maintain the compacted form for 30 days and be able to return to the uncompacted form such that the creep angle of the metallic core after 30 days is within 3% of the creep angle of the metallic core before 30 days.

[0028] In some embodiments of the core, the metallic core comprises nitinol. The nitinol may include extra-low inclusion nitinol. The nitinol may include extra-pure nitinol. The nitinol may include extra-low inclusion, extra-pure nitinol.

[0029] In some embodiments of the core, each arm mount is configured to receive an elongate arm overmolded on the arm mount.

[0030] In some embodiments of the core, each arm mount is configured to receive a degradable connector, and the elongate arm is attached to the degradable connector.

[0031] In some embodiments of the core, the metallic core is formed using a metal wire.

[0032] In some embodiments of the core, the metal wire has a cross-section with a diameter of 0.01 inches to 0.02 inches (0.254 mm to 0.508 mm).

[0033] In some embodiments of the core, the metal core is formed using a stamped metal sheet.

[0034] In some embodiments of the core, at least one of the plurality of elongated arms contains a therapeutic agent.

[0035] In some embodiments, a method of manufacturing a metal core for a gastric retention system is provided, including: using a fixture to wind a metal wire to form a metal core including a plurality of arm mounts.

[0036] In some embodiments of the method, winding the metal wire includes winding the metal wire around a plurality of pins of the fixture to form a circular metal form / circular metal structure.

[0037] In some embodiments of the method, the method includes advancing a plurality of inserts into the circular metal form to form a star-shaped metal form / star-shaped metal structure.

[0038] In some embodiments of the method, the method includes heating the star-shaped metal form to produce a star-shaped metal core for a gastric retention system.

[0039] In some embodiments of the method, heating the star-shaped metal form includes heating the star-shaped metal form to 500 °C or higher.

[0040] In some embodiments of the method, the metal wire contains nitinol. The nitinol may include ultra-low inclusion nitinol. The nitinol may include ultra-pure nitinol. The nitinol may include ultra-low inclusion and ultra-pure nitinol.

[0041] In some embodiments of the method, the metal wire has a cross-section with a diameter of 0.01 inches to 0.02 inches (0.254 mm to 0.508 mm in diameter).

[0042] In some embodiments of the method, the two ends of the metal wire are joined together.

[0043] In some embodiments of the method, the two ends of the metal wire are not joined together.

[0044] In some embodiments of the method, the star-shaped metal form is quenched after heating.

[0045] In some embodiments of the method, the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

[0046] In some embodiments of the method, the height of the metal core is the same as the width of the metal core.

[0047] In some embodiments of the method, the metal core is configured to be bendable into a compacted form and maintain the compacted form for 30 days and be returnable to an uncompacted form such that the creep angle of the metal core after 30 days is within 3% of the creep angle of the metal core before 30 days.

[0048] In some embodiments, a method of manufacturing a metal core for a gastric retention system is provided, the method comprising: stamping a metal sheet to form a metal core including a plurality of arm mounts.

[0049] In some embodiments of the method, the metal sheet comprises nitinol. The nitinol may comprise ultra-low inclusion nitinol. The nitinol may comprise ultra-pure nitinol. The nitinol may comprise ultra-low inclusion, ultra-pure nitinol.

[0050] In some embodiments of the method, the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

[0051] In some embodiments of the method, the height of the metal core is the same as the width of the metal core.

[0052] In some embodiments of the method, the metal core is configured to be bendable into a compacted form and maintain the compacted form for 30 days and be returnable to an uncompacted form such that the creep angle of the metal core after 30 days is within 3% of the creep angle of the metal core before 30 days.

[0053] In certain embodiments, any one or more of the features, characteristics, or elements discussed above for any embodiment may be incorporated into any other embodiment mentioned above or described elsewhere herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1A and 1B show various gastric retention system configurations according to some embodiments;

[0055] Figure 2 show a gastric retention system in a folded or compacted configuration according to some embodiments;

[0056] Figures 3A - 3D show various different configurations of a metal-containing core for a gastric retention system according to some embodiments;

[0057] Figure 4 show a wire-type core according to some embodiments;

[0058] Figure 5 show a detailed view of a wire-type core according to some embodiments;

[0059] Figures 6A - 6C Shows various different views of an example of a continuous metal wire core according to some embodiments;

[0060] Figures 7A - 7D Shows various different configurations of a flat metal core according to some embodiments;

[0061] Figures 8A - 8B Shows the core of a traditional gastric retention system and the core of a gastric retention system with a metal core according to some embodiments, respectively;

[0062] Figures 9A - 9B Shows a faulty metal core according to some embodiments;

[0063] Figures 10A - 10B Shows a top view and a bottom view of a gastric retention system including a metal core according to some embodiments, respectively;

[0064] Figures 11A - 11C Shows a wire core formed using a jig according to some embodiments;

[0065] Figures 12A - 12C Shows the process of forming a wire core using a jig according to some embodiments;

[0066] Figures 13A - 13C Shows various different configurations for fixing the arm of a gastric retention system to a metal core according to some embodiments;

[0067] Figure 14 Shows a comparison of the creep angle of a Nitinol core and the creep angle of a polymer core (i.e., a liquid silicone rubber core) according to some embodiments;

[0068] Figure 15 Shows the cyclic incubation non-planar compression test force of a Nitinol core in 2500 cycles compared to a polymer core (i.e., a liquid silicone rubber core) according to some embodiments;

[0069] Figure 16 Shows the non-planar compression test force of various different Nitinol core designs according to some embodiments; and

[0070] Figures 17A - 17E Shows Figure 18 various different geometries of the Nitinol core tested in Figure 17A and Figure 17B shows the geometries tested for Sheet #1 and Sheet #2. Figure 17E Shows the wire shapes used for the results of Wire #1 and Wire #2.

[0071] Figure 18 Fatigue testing of several different types of Nitinol cores is shown.

[0072] Figure 19A A nitinol wire core is shown with attached polymer connectors having an outer diameter of 12 mm (where the outer diameter is measured from the edge of one outermost connector to the outermost edge of the opposing connector assembly). Figure 19B A nitinol wire core having polymer connectors attached thereto having an outer diameter of 15 mm (where the outer diameter is measured from the edge of one outermost connector to the outermost edge of the opposing connector assembly) is shown.

[0073] Figure 20 Shows Figure 19A and Figure 19B Fatigue test of the core shown.

[0074] Figure 21 Shown is a view of a Nitinol wire core with a polymer connector attached.

[0075] Figure 22 Shows Figure 21 A cross-sectional view of the nitinol wire core is shown.

[0076] Figure 23 Shows Figure 21 Another cross-sectional view of the Nitinol wire core is shown.

[0077] Figure 24 Shows Figure 21 Another view of the nitinol wire core, where the parts covered by the polymer connector (i.e., hidden parts) are shown with dotted lines. DETAILED DESCRIPTION

[0078] Provided herein is a gastric retention system having a core comprising metal. The gastric retention system described herein includes a core from which a plurality of arms extend. The arms include a proximal end connected to the core and a distal end opposite the proximal end and extending away from the core. In order to administer medication to a patient, the gastric retention system must be in a compacted form. To this end, the distal ends of the gastric retention system are brought together, forcing the core to bend where the proximal ends of the arms are connected thereto. When the gastric retention system remains in its compacted form for a long time, the material of the core may creep, or undergo permanent deformation. This permanent deformation prevents the gastric retention system from assuming its open, non-compacted form after being administered to a patient.

[0079] Accordingly, the gastric retention system provided herein includes a core having metal. The metal of the gastric retention system core allows the gastric retention system to have a longer shelf life (i.e., when in a compacted form) and still be able to return to its non-compacted form after administration to a patient. The metal does not undergo creep or permanent deformation as quickly as many polymeric materials, and thus allows the gastric retention system to be stored stably in its compacted form for a longer period of time relative to a gastric retention system having only a polymeric core.

[0080] The general principles of the gastric retention system are discussed below, followed by a detailed discussion of the metal core, particularly the nitinol core, methods of manufacturing the metal core, and examples.

[0081] General Principles of Gastric Retention Systems

[0082] The gastric retention system and how it operates to deliver a therapeutic agent to a patient are described below. In particular, the discussion includes how to design the gastric retention system to deliver a therapeutic agent to a patient over an extended period of time, how to configure the gastric retention system for drug administration, how to configure the gastric retention system to deploy to deliver the therapeutic agent to the patient's stomach, how the therapeutic agent of the gastric retention system elutes from the device to deliver the therapeutic agent to the patient, how the gastric retention system traverses the stomach, and how the gastric retention system is designed to account for certain safety measures.

[0083] The gastric retention dosage form can be designed to administer to the patient's stomach by swallowing, feeding tube, gastric tube, etc. Once the gastric retention dosage form is in place in the stomach, it can remain in the stomach for a desired residence time (e.g., three days, seven days, two weeks, etc.). The gastric retention dosage form properly positioned in the stomach will block the pyloric valve that separates the stomach from the small intestine. The gastric retention dosage form can release the therapeutic agent (i.e., API or drug) in a controlled release manner during the residence period. When residing in the stomach, the dosage form does not interfere with the normal passage of food or other gastric contents. Once the desired residence time has expired, the dosage form is expelled from the stomach (i.e., via the pyloric valve) and is easily eliminated from the patient's body.

[0084] To administer the gastric retention system to a patient, the gastric retention system can be folded into a form small enough to be swallowed or otherwise administered. In some embodiments, the folded gastric retention system is held in a capsule or other container that can be swallowed by the patient. In some cases, the gastric retention system can be delivered to the patient via a gastrostomy tube, feeding tube, gastric tube, or other gastric administration route. Examples of folding and encapsulating the gastric retention system will be provided in more detail below.

[0085] Figure 1A and 1B Embodiments of a collapsible or compactable gastric retention system are provided. In particular, Figure 1A and 1B the collapsible or compactable gastric retention system shown is provided in an expanded configuration (or non-compacted configuration).

[0086] As Figure 1A shown, according to some embodiments, the gastric retention system 100 may be star-shaped (stellate / radially shaped). In some embodiments, the star-shaped gastric retention system 100 is constructed around a core 106. The core 106 may include one or more elongated members 108 or "arms" that project radially. The arms may be formed by carrier polymer-formulation components 102 and 103 and a connection region 104 that includes a linking polymer. The core 106 enables the gastric retention system 100 to be folded for encapsulation in a capsule. Once the capsule dissolves in the stomach, the gastric retention system 100 unfolds to its open configuration or a circular shape in the deployed configuration, thereby preventing passage through the pyloric valve.

[0087] Although the connection region 104 is shown as having a diameter slightly larger than Figure 1A section 102 in, they may have the same diameter as the section, so that the entire arm 102-104-103 has a smooth outer surface.

[0088] In some embodiments, the stellate system may have an arm consisting of only one section, which is attached to the central elastomer through a connection region. This corresponds to removing section 103 from Figure 1A . Then, the single-section arm including section 102 is directly attached to the central elastomer 106 via a connector 104. The connector may include a coupling polymer / linking polymer or a disintegrating matrix.

[0089] Figure 1B A gastric retention system 100 including three "arms" is shown according to some embodiments. This structure may also include a core 106, from which three "arms" extend radially. Each of the three arms includes polymer-formulation components 102 and 103 and a connection region 104.

[0090] The star-shaped system can be described as a gastric retention system for delivering a drug to a patient's stomach, which includes a core and at least one carrier polymer-formulation component attached to the core. The carrier polymer-formulation component contains a carrier polymer and a formulation or a salt thereof. Each of the plurality of carrier polymer-formulation components is an arm, which includes a proximal end, a distal end, and an outer surface between the proximal end and the distal end. The proximal end of each arm is attached to the core and radially projects from the core, and the distal end of each arm is not attached to the core and is located at a radial distance farther from the core than the proximal end. Each arm independently includes one or more segments, and each segment includes a proximal end, a distal end, and an outer surface between the proximal end and the distal end. In some embodiments, when there are two or more segments in an arm, each segment is attached to an adjacent segment via a connecting region. In some embodiments, when there are two or more segments in an arm, one segment is directly attached to another segment without using a connecting region. The connecting region can be a linking polymer or a disintegrating matrix. The arm can be attached to the core via a linking polymer or a disintegrating matrix and can have an intermediate portion composed of an interfacial polymer. For a plurality of at least three arms, or for a plurality of arms, the preferred number of arms is six, but three, four, five, seven, eight, nine, or ten arms can be used. The arms should be equally spaced around a central elastomer; if there are N arms, there will be an angle of approximately 360 / N degrees between adjacent arms.

[0091] The linking polymer used as the connecting region of the gastric retention system is designed to gradually decompose in a controlled manner during the residence of the system in the stomach. In some embodiments, the connecting region can completely dissolve, such that the components connected by the connecting region are completely separated. In some embodiments, the connecting region may not completely dissolve but decompose, such that the components connected to the connecting region remain attached. However, in this case, the connecting region can decompose sufficiently to compromise the structural integrity of the gastric retention system, such that the gastric retention system can pass through the pyloric valve and through the intestine. If the gastric retention system enters the small intestine prematurely in its intact form, the system is designed to decompose faster to avoid intestinal obstruction. This can be easily achieved by using an enteric polymer as the linking polymer. Enteric polymers are relatively resistant to the acidic pH levels encountered in the stomach but dissolve at the higher pH levels found in the duodenum. Using an enteric linking polymer as a safety element can prevent the intact gastric retention system from undesirably entering the small intestine. In Figure 1A the system shown, at least the linking polymer for the connector 104 is made of such an enteric polymer.

[0092] In additional embodiments, a time-dependent linking polymer or connector can be used. This time-dependent linking polymer or connector degrades in a predictable time-dependent manner. In some embodiments, the degradation of the time-dependent linking polymer or connector can be unaffected by changes in the pH of the gastrointestinal system.

[0093] In multiple other embodiments, different types of connectors may be used for the gastric retention system. That is, both enteric connectors (or enteric linking polymers) and time-dependent connectors (or time-dependent linking polymers) may be used. In some embodiments, a single multi-segmented arm of a star-shaped system may use enteric connectors in some connection regions between segments and time-dependent connectors in other connection regions between segments.

[0094] Figure 2 A collapsible gastric retention system 200 is shown in accordance with some embodiments. As shown, the device may be folded at the core 206, bringing the ends of each "arm" together. The figure also shows how the carrier polymer-formulation components 102 and connectors 104 of each arm may be oriented in the folded configuration.

[0095] The folded configuration of the gastric retention system 200 may be bundled (i.e., held in the folded configuration) with a sleeve or strip. In some embodiments, the folded gastric retention system (with or without a sleeve or strip) may be encapsulated in a capsule to form a gastric retention dosage form. In some embodiments, the gastric retention dosage form may be coated with a reverse enteric coating to ensure deployment of the gastric retention system in the patient's stomach.

[0096] Once the gastric retention dosage form reaches the patient's stomach, the capsule and / or capsule coating of the gastric retention dosage form may dissolve / open and release the folded gastric retention system. Upon release, the gastric retention system unfolds to assume an open configuration, such as the ring or star provided in Figure 1A and 1B . The size of the open gastric retention system is adapted to prevent the device from passing through the pyloric valve during the period of time the device is to remain in the stomach. In some embodiments, the folded gastric retention system may also be secured by a dissolvable retaining strip or sleeve that may prevent premature unfolding of the gastric retention system in the event of capsule failure.

[0097] When in the stomach, the gastric retention system is compatible with digestion and other normal functions of the stomach or gastrointestinal tract. The gastric retention system does not interfere with chyme (partially digested food) or other gastric contents or impede the passage of chyme or other gastric contents through the pyloric valve and out of the stomach into the duodenum.

[0098] Once released from the capsule into the stomach, the therapeutic agent of the gastric retention system begins to exert its effect. In some embodiments, the gastric retention system comprises a plurality of carrier polymer - formulation components. The carrier polymer - formulation components may comprise a carrier polymer, a dispersant, and a therapeutic agent (or a salt thereof). The plurality of carrier polymer - formulation components are connected together by one or more linking polymer components. The therapeutic agent can be eluted from the carrier polymer - formulation components into the patient's gastric juice over the desired residence time of the system. The release of the therapeutic agent is controlled by the proper formulation of the carrier polymer - formulation components, including by using a dispersant in the formulation of the carrier polymer - formulation components and by grinding the therapeutic agent into particles of a desired particle size before blending the formulation with the carrier polymer and the dispersant.

[0099] In some embodiments, the gastric retention system may include filaments (or "meshes") between the arms of the gastric retention system. The gastric retention system with filaments can help improve the gastric retention of the gastric retention system. Specifically, the filaments can help provide a more consistent gastric residence time and / or a longer gastric residence time. Thus, the gastric retention system including filaments can provide a more predictable and / or controllable gastric residence time. A gastric retention system with a predictable and / or controllable gastric residence time can minimize the possibility that the gastric retention system passes through the stomach and subsequently unfolds in the gastrointestinal tract (i.e., the intestine), or passes through the gastrointestinal tract without unfolding at all. In each of these possible scenarios, the therapeutic agent of the gastric retention dosage form is not delivered to the patient as expected.

[0100] In some embodiments, for example, filaments that wrap around and connect the arms of the gastric retention system can help prevent premature passage through the pylorus of the patient's stomach.

[0101] In addition, a coating / encapsulation can be applied to the outer surface of the gastric retention system. The coating / encapsulation can include additional therapeutic agents or formulations that can affect the release of the therapeutic agent or the residence time of the gastric retention system.

[0102] Once the desired residence time has expired, the gastric retention system is expelled from the stomach. To this end, various components of the gastric delivery system are designed to weaken and degrade. The specific size of the system is also considered. In its fully open configuration, the gastric retention system is designed to prevent passage through the pyloric valve. However, the linking polymer components of the gastric retention system are selected such that they gradually degrade within a specific residence time in the stomach. When the linking polymer components are sufficiently weakened due to degradation, the gastric retention system loses its critical elasticity for compaction or size reduction and may split into smaller pieces. The size - reduced dosage form and any smaller pieces are designed to be able to pass through the pyloric valve. Then, the system passes through the intestine and is excreted from the patient's body. In some embodiments, the gastric retention system can be made of a soft material such that once the residence time has expired, the gastric retention system can pass through the pyloric valve intact, without degrading into many smaller pieces.

[0103] During the design and administration of a gastric retention system and a gastric retention dosage form, several safety factors need to be considered. In particular, it is important that the gastric retention system maintains its folded configuration until it reaches the stomach. If the gastric retention system opens or unfolds before reaching the patient's stomach, the patient is at risk of esophageal obstruction. Similarly, if a complete gastric retention dosage form passes through the pyloric valve without opening and the gastric retention system does not expand to its open configuration, there is a risk that it may open and expand to its open configuration in the patient's intestine, resulting in intestinal obstruction. Accordingly, the capsules and capsule coatings according to the embodiments described herein have been designed to control the deployment of the gastric retention system to enhance patient safety.

[0104] Examples of gastric retention systems can be found in PCT / US2018 / 051816, WO 2015 / 191920, WO 2017 / 070612, WO 2017 / 100367, WO 2018 / 064630, WO 2017 / 205844, WO 2018 / 227147, and US 62 / 933,211, each of which is incorporated herein by reference.

[0105] Metal core

[0106] As described above, the gastric retention systems provided herein bend at their cores to present a folded or compacted form. When the compacted gastric retention system maintains its compacted form, to increase storage stability and reduce permanent deformation of the core over time, the gastric retention systems provided herein include a core comprising a metal. In some embodiments, the core of the gastric retention system consists only of metal. In some embodiments, the metal includes nitinol. In some embodiments, the metal includes ultra-low inclusion nitinol. In some embodiments, the metal includes extra-pure nitinol. In some embodiments, the metal includes ultra-low inclusion extra-pure nitinol. In some embodiments, the metal includes spring steel, copper, or any alloy having shape memory and / or superelasticity. In some embodiments, the core of the gastric retention system comprises a metal and a polymeric material. For example, some embodiments may include a polymeric material overmolded onto a metal component. The overmolded polymeric material may help control the hardness of the core and / or it may coat a portion of the metal component to minimize the amount of the metal component in direct contact with the patient's body.

[0107] Figures 3A - 3D A variety of different configurations of a metal-containing core for a gastric retention system are shown according to some embodiments. As shown, Figure 3AIllustrated is a wire - based core made of metal wire and formed into a star shape to correspond to the core of a star - shaped gastric retention system. The wire - based core can be manufactured by molding the metal wire into a desired shape (e.g., a star). The arms of the gastric retention system can be fixed to each "arm" of the star - shaped metal core. In some embodiments, the two ends of the metal wire can be joined to form a continuous metal wire (e.g., by crimping or welding). In some embodiments, the two ends of the metal wire can remain open. The openings can be located on the "arms" of the metal core such that when the arms of the gastric retention system are fixed to the metal core, the openings can be sealed by the arms of the gastric retention system.

[0108] Figure 3B Illustrated is a wire - based core with pointed "arms". This type of metal core can be manufactured using a segmented process that includes separately forming multiple parts of the core and joining these parts together to form the wire - based core. Each arm of the gastric retention system can be fixed to the pointed "arm" of the wire - based core.

[0109] Figure 3C Illustrated is a flat metal core according to some embodiments. The flat metal core can be manufactured using laser cutting or stamping. As Figure 3B and Figure 5 shown in A - 5D, the flat metal core can be in any of a variety of different shapes. In some embodiments, the flat metal core can be star - shaped similar to the gastric retention system. As explained with reference to Figure 3A , each arm of the gastric retention system can be fixed to the "arm" of the star - shaped flat metal core.

[0110] Figure 3D Illustrated is a wire - based core with a polymer overmold according to some embodiments. The overmolded metal core can help achieve optimal core stiffness. In some embodiments, the overmolded metal core can help minimize the amount of metal exposed to the patient's body. As shown, the polymer overmold can cover only a part of the metal core. In some embodiments, the polymer can cover the entire metal core. In some embodiments, the combination of the polymer overmold and the arms of the gastric retention system can cover the entire metal core (although neither the polymer overmold nor the arms of the gastric retention system can cover the entire metal core alone).

[0111] Figure 4 Illustrated is a wire - based core 400 according to some embodiments. As shown, the wire - based core 400 includes a notch 410 and an arm mount 412.

[0112] Figure 5Shows a detailed view of the wire core 500 according to some embodiments. As shown, the wire core 500 can be star-shaped to correspond to a star-shaped gastric retention system. Here, the star-shaped wire core includes six "arms", and each arm can receive one arm portion of the gastric retention system. In some embodiments, the arm portion of the gastric retention system can be overmolded on the distal end of the arm of the wire core. In some embodiments, the two ends of the wire used to form the wire core can be located within the overmolding area such that they are embedded within the arm portion of the gastric retention system. By covering the ends of the wire with the arm portion of the gastric retention system, the possibility of internal injury to the patient caused by the wire ends is eliminated.

[0113] Figure 5 The wire core 500 includes the following marked measurements: (A) diameter; (B) wire thickness; (C) distance between two wire sides of the arm (measured between the inner surfaces of the two wire sides of the arm); (D) area within the wire end that can be joined; (E) inner diameter; and (F) angle between two adjacent arms.

[0114] Figure 5 The wire core 500 shows six "arms" to correspond to the six arm portions of the gastric retention system, but the wire core (and the gastric retention system) can have two, three, four, five, seven, eight, nine, ten, eleven, or twelve or more arms / arm portions.

[0115] Exemplary measurements (in millimeters (mm)) are as Figure 5As shown. These measurements can be applied to a wire-type core (as shown in the figure) or a flat metal core. In some embodiments, the metal core can have a diameter of 8 - 14 mm (marked as A in the figure and measured between the outer surfaces of the opposite arms such that the diameter includes the thickness of the wire). In some embodiments, the metal core can have a diameter less than or equal to 14 mm, less than or equal to 13 mm, less than or equal to 12 mm, or less than or equal to 11 mm. In some embodiments, the metal core can have a diameter greater than or equal to 10 mm, greater than or equal to 11 mm, greater than or equal to 12 mm, or greater than or equal to 13 mm. In some embodiments, when the metal core is made of a metal wire, the metal wire can have a thickness of 0.1 - 1 mm (marked as B). In some embodiments, the thickness of the metal wire can be less than or equal to 1 mm, less than or equal to 0.8 mm, less than or equal to 0.6 mm, less than or equal to 0.4 mm, or less than or equal to 0.2 mm. In some embodiments, the thickness of the metal wire can be greater than or equal to 0.1 mm, greater than or equal to 0.2 mm, greater than or equal to 0.4 mm, greater than or equal to 0.6 mm, or greater than or equal to 0.8 mm. In some embodiments, the metal core can have an inner diameter of 0.25 - 2 mm (marked as E and measured between two opposite rounded vertices or mouths, notches). In some embodiments, the metal core can have an inner diameter less than or equal to 2 mm, less than or equal to 1.5 mm, less than or equal to 1 mm, less than or equal to 0.75 mm, or less than or equal to 0.5 mm. In some embodiments, the metal core can have an inner diameter greater than or equal to 0.25 mm, greater than or equal to 0.5 mm, greater than or equal to 0.75 mm, greater than or equal to 1 mm, or greater than or equal to 1.5 mm.

[0116] Figures 6A - 6C Shows various different views of an example of a continuous wire-type core according to some embodiments. This particular embodiment uses a spring to help the gastric retention system assume a non-compacted form. Figure 6A Shows a perspective view of the metal core with a portion of the arms of the gastric retention system overmolded on each arm of the metal core. Figure 6B Shows a top view of the metal core with a portion of the arms of the gastric retention system overmolded on each arm of the metal core. Figure 6C Shows the metal core without any arms of the gastric retention system overmolded onto it.

[0117] Figures 7A - 7D Shows various different configurations of a flat metal core (or metal "sheet" core) according to some embodiments. The simpler geometry can be easily adapted to a stamping process for high-volume manufacturing. Figure 7B Shows the design of an end effector with a "forked head" that can provide the advantage of attaching molded or overmolded materials to it. Figure 7CShows a design with a deformation different from other designs, and its performance may be more easily predictable. Finally, Figure 7D Shows a design that has a Figure 7B simpler alternative end effector design than

[0118] Figure 8A Shows the core of a conventional gastric retention system without any metal. Figure 8B Shows such a core of a gastric retention system, i.e., the core has metal to enhance and improve the performance of the gastric retention system (e.g., improve the ability of the gastric retention system to assume a non-compacted form after being held in a compacted form for a long time).

[0119] Figure 9A and 9B Shows some common obstacles / problems with the metal core. Specifically, Figure 9A Shows that the wire ends of a wire-type metal core may pop out of the arm of a fixed gastric retention system. Figure 9B Shows that the metal wire may break due to bending of the metal core. These failures may occur during encapsulation (and / or when assuming an open / non-compacted configuration from a compacted configuration), in the patient's stomach, or during handling / transportation. Therefore, the form, materials, and specific manufacturing process of the metal core and the entire gastric retention system disclosed herein are important for minimizing the likelihood of such failures.

[0120] Figure 10A Shows a top view of a gastric retention system including a metal core according to some embodiments, Figure 10B Shows a bottom view of a gastric retention system including a metal core according to some embodiments.

[0121] As used herein, the shelf life of a gastric retention system can be defined as the length of time that the gastric retention system can be stored in a compacted form without losing the ability to assume a non-compacted form. In some embodiments, if the creep angle of the gastric retention system does not decrease by more than 0 - 10%, 0 - 5%, or 0 - 2% during encapsulation (or shelf life), then it can be said that the gastric retention system successfully assumes a non-compacted form. In some embodiments, if the creep angle of the gastric retention system does not decrease by more than or equal to 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% during encapsulation (or shelf life), then the gastric retention system successfully assumes a non-compacted form. In some embodiments, if the creep angle of the gastric retention system does not decrease by less than or equal to 0%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, or 8% during encapsulation (or shelf life), then the gastric retention system successfully assumes a non-compacted form.

[0122] In some embodiments, a gastric retention system comprising a metal core according to the embodiments described herein may have a shelf life of from 1 day to 10 years, from 1 day to 5 years, from 1 day to 1 year, 1 - 30 days, 30 - 90 days, or 90 - 180 days. In some embodiments, a gastric retention system comprising a metal core according to the embodiments described herein may have a shelf life of less than or equal to 10 years, less than or equal to 8 years, less than or equal to 5 years, less than or equal to 3 years, less than or equal to 2.5 years, less than or equal to 2 years, less than or equal to 1.5 years, less than or equal to 1 year, less than or equal to 350 days, less than or equal to 300 days, less than or equal to 270 days, less than or equal to 240 days, less than or equal to 210 days, less than or equal to 180 days, less than or equal to 150 days, less than or equal to 120 days, less than or equal to 90 days, less than or equal to 60 days, less than or equal to 30 days, less than or equal to 20 days, less than or equal to 10 days, or less than or equal to 5 days. In some embodiments, a gastric retention system comprising a metal core according to the embodiments described herein may have a shelf life of greater than or equal to 1 day, greater than or equal to 5 days, greater than or equal to 10 days, greater than or equal to 20 days, greater than or equal to 30 days, greater than or equal to 60 days, greater than or equal to 90 days, greater than or equal to 120 days, greater than or equal to 150 days, greater than or equal to 180 days, greater than or equal to 210 days, greater than or equal to 240 days, greater than or equal to 270 days, greater than or equal to 300 days, greater than or equal to 350 days, greater than or equal to 1 year, greater than or equal to 1.5 years, greater than or equal to 2 years, greater than or equal to 2.5 years, greater than or equal to 3 years, greater than or equal to 5 years, or greater than or equal to 8 years.

[0123] Nitinol core

[0124] In some embodiments, the metal core may be made of Nitinol, which is a metal alloy of nickel and titanium. Nitinol has excellent shape memory and superelasticity. The deformability of Nitinol is 10 - 30 times that of ordinary metals, yet it can still return to its original shape. Whether Nitinol has shape memory or superelasticity depends on whether the material is above its transformation temperature / above its (superelasticity) or below its (shape memory). Thus, a gastric retention system having a metal core comprising Nitinol may be able to be folded into a compact form (at the Nitinol core), and later, after remaining in the compact form for a period of time (e.g., encapsulation), the gastric retention system may be able to return to its planar non - compact form. A gastric retention system comprising a Nitinol core can return to its original non - compact form more easily and conveniently than cores of other materials, especially those comprising only polymeric materials.

[0125] The Nitinol core described herein is based on "austenitic" phase Nitinol, which has the superelasticity as described above. Shape memory properties are generally associated with "martensitic" phase Nitinol, which is very prone to permanent deformation and only returns to its original shape when heated.

[0126] In some embodiments, a metal core made of nitinol is first formed (e.g., by winding a nitinol wire around a fixture, as detailed below) and heated to 500 °C or higher. Heating and quenching the formed nitinol sets the shape of the nitinol core. Thus, when the nitinol core is bent (i.e., when the gastric retention system is folded into a compact form) and subsequently released from the bent shape (i.e., when the folded encapsulated gastric retention system is released in the human body after administration), the nitinol core can return to its originally formed shape, thereby allowing the gastric retention system to effectively deliver the therapeutic agent to the patient.

[0127] In some embodiments, the nitinol used for the metal core is ultra-low inclusion nitinol. The maximum inclusion size of ultra-low inclusion nitinol is 12.0 micrometers (μm), and the maximum inclusion area fraction is 0.5%. The nitinol sold by SAES Smart Materials, LLC, New Hartford, NY, USA complies with these specifications. This nitinol is described in the following document: Yin, Weimin et al., "The Assessment of Physical and Mechanical Property Variability in a New Generation of Low Inclusion NiTi Alloy", Extended Abstracts of SMST2022: International Conference on Shape Memory and Superelastic Technologies, May 16 - 20, 2022, Carlsbad, CA, USA, Paper No.: smst2022p0091, pp. 91 - 92; doi.org / 10.31399 / asm.cp.smst2022p0091. Ultra-low inclusion nitinol has excellent fatigue resistance and complies with the ASTM F2063 - 18 standard specification for wrought nickel-titanium shape memory alloys for medical devices and surgical implants.

[0128] In some embodiments, the nitinol used for the metal core is ultra-pure nitinol. Ultra-pure nitinol has the following approximate composition:

[0129] Element [wt.%] Ni 56.02 C 0.0258 Co 0.0001 Cu 0.0001 Cr 0.0017 H <0.0050 Fe 0.009 Nb 0.0001 N 0.0012 O 0.022 Ti (Balance)

[0130] The amounts of trace elements (C, Co, Cu, Cr, H, Fe, Nb, N and O) can vary within about ±20% of the indicated values (e.g., the Co content can be in the range of about 0.00008 weight percent to about 0.00012 weight percent), while making corresponding adjustments to the Ni and / or Ti content to account for the variation in the trace element content. The amount of Ni and / or Ti can vary by about 0.05% from the indicated amount (e.g., the Ni content can vary from about 55.99 weight percent to about 56.05 weight percent). Nitinol sold by SAES Smart Materials, LLC, New Hartford, NY, USA Nitinol meets these specifications.

[0131] In some embodiments, the nitinol for the metal core is ultra-low inclusion, ultra-pure nitinol, where the nitinol meets the standards for ultra-low inclusion nitinol and also meets the standards for ultra-pure nitinol. Nitinol sold by SAES Smart Materials, LLC, New Hartford, NY, USA Nitinol meets these specifications.

[0132] Manufacturing the metal core

[0133] Figures 11A - 11C Shows a wire-type core formed using a jig. Figure 11A Shows a perspective view of a wire wound in a star shape on a jig according to some embodiments. Figure 11B Shows a wire wound in a star shape on a jig according to some embodiments. Figure 11C Shows an image of a wire wound in a star shape on a jig according to some embodiments. The jig can help improve the consistency of the wire-type core and can help ensure that the wire-type core is symmetric.

[0134] Figures 12A - 12C Shows a method of forming a wire-type core using a jig (such as the jig Figures 11A - 11C shown). Specifically, Figure 12A Shows the steps of winding a wire around the pins of a jig to form a star-shaped wire-type core. In step 1, the user feeds a lead wire into a feed channel. In step 2, the user winds the wire around a first guide pin. The wire should remain outside the guide pin but above the inner ring of the pin. In step 3, the user can wind the wire around the inner ring of the pin. In step 4, the user winds the wire into a second feed channel such that the wire will cross itself near the top pin. The wire should remain outside the guide pin.

[0135] According to Figure 12A the steps of winding the wire, a cover is attached to the jig above the wound wire. Figure 12BShows the steps of attaching the cover. In step 1, the user can push the cover onto the locating pin while holding the wire ends. The cover should be kept as parallel as possible to the board / assembly rack. In step 2, the user can tighten the wire to ensure proper formation of the wire core. The wire is tight enough when both ends of the wire are well positioned in the feed channel and the cover is flush with the board / assembly rack.

[0136] Once the wire is tightened according to the Figure 12B steps and the cover is attached correctly, a star shape can be formed. Figure 12C Shows how to apply inserts to form a star shape of the wire core. In step 1, the user can optionally attach a clamp to fix the cover to the board / assembly rack. In step 2, the user can push the insert into the radially extending channel. In step 3, the user can insert the retaining pin while keeping the inserted insert in place. In step 4, the user can repeat steps 2 and 3 for the remaining inserts and retaining pins.

[0137] Figures 13A - 13C Shows various different configurations for fixing the arms of the gastric retention system to the metal core. Specifically, Figure 13A shows Figure 13B a side view of Figure 13B Shows a slotted arm with a pin, where the arm mount of the wire core can be hooked around the pin of the allocated arm. Figure 13C Shows a metal core with a tip.

[0138] For example, Figure 6A or Figure 13C several of the cores shown in

[0139] show metal cores where the arm mounts are covered by polymer connectors and / or elongated arms, but the innermost part of the metal core is exposed. In some embodiments, the metal core can be used in a gastric retention system where the innermost part of the metal core is exposed. In some embodiments, the metal core can be coated with a thin polymer layer, particularly using a polymer that is stable and non-reactive in the gastric environment, such as polytetrafluoroethylene (PTFE). The entire metal core, including the arm mounts, can be covered by a thin polymer layer, or the part of the metal core that is not covered by the polymer connectors and / or elongated arms (the innermost part of the metal core) can be covered by a thin polymer layer. The thickness of the thin polymer layer can be from about 1 μm to about 100 μm, such as from about 1 μm to about 75 μm, from about 1 μm to about 50 μm, from about 1 μm to about 40 μm, from about 1 μm to about 30 μm, from about 1 μm to about 25 μm, from about 1 μm to about 20 μm, from about 1 μm to about 10 μm, from about 10 μm to about 20 μm, from about 10 μm to about 30 μm, or from about 20 μm to about 30 μm.In some embodiments, the metal core portion not covered by the polymeric connector and / or the elongate arm portion may be covered by a thick polymeric layer having a thickness and cross-sectional shape substantially the same as the polymeric connector on the metal core arm mount, e.g., within about 20%, about 10%, about 5%, or about 1% of the thickness of the polymeric connector on the metal core arm mount.

[0140] Figure 21 An embodiment of a wire-type core with a connector mounted on an arm mount is shown. The wire-type core 2110 has an internal connector 2104 and an external connector 2102, where "internal" refers to the component closer to the center of the core and "external" refers to the component farther from the center of the core. The external connector 2102 may optionally have a bump 2116 that can be used as a guide when other parts of the gastric retention system are connected to the connector 2102.

[0141] The internal connector 2104 can be made of a variety of different materials, such as polycarbonate or polycaprolactone. Polycarbonate (medical grade) is particularly useful due to its strength and ease of manufacture; polycarbonate made from bisphenol A is typically used. The external connector 2102 generally includes polycaprolactone, which can be laser welded or otherwise joined to the elongate arm portion of the gastric retention system or to a section that makes up the elongate arm portion. In some embodiments, the external connector may include the connector formulations disclosed in WO 2021 / 092487, the entire contents of which are incorporated herein by reference, e.g., the formulations listed in Tables 3-7 and 9-11 of WO 2021 / 092487; preferably, a connector formulation that can be injection molded is used. A blend of polycaprolactone and thermoplastic polyurethane (TPU) can be used. In some embodiments, the external connector may include the connector formulations disclosed in WO 2022 / 159529 or WO 2023 / 141524, the entire contents of both of which are incorporated herein by reference, e.g., the following connector formulations (amounts are given in approximate weight percentages and it should be understood that when ranges are provided, these amounts are chosen to total 100%):

[0142] Matrix composition Formulation 1 Formulation 2 Formulation 3 Formulation 4 PCL (viscosity midpoint 1.7 dl / g) 40-50 43-47 44.95 45 PDLG5004A 30-40 33-37 35 35 PDLG5004 10-25 15-20 18 18 PEO (100k) 0.5-5 1-3 2 2 Colorant (optional) 0.005-0.2 0.01-0.1 0.05 (e.g., E172) 0

[0143] Matrix composition Formulation 1 Formulation 2 Formulation 3 Formulation 4 PCL (viscosity midpoint 1.2 dl / g) 40-50 43-47 44.95 45 PDLG5004A 30-40 33-37 35 35 PDLG5004 10-25 15-20 18 18 PEO (100k) 0.5-5 1-3 2 2 Colorant (optional) 0.005-0.2 0.01-0.1 0.05 (e.g., E172) 0

[0144] Matrix composition Formulation 1 Formulation 2 Formulation 3 Formulation 4 PCL (viscosity midpoint 1.2 dl / g) 40-50 43-47 44.95 45 PDLG5002A 48-58 51-55 53 53 PDLG5002 0-5 0-2 0 0 PEO (100k) 0.5-5 1-3 2 2 Colorant (optional) 0.005-0.2 0.01-0.1 0.05 0

[0145] Figure 22 Figure 21 Figure 23 Figure 21 Figure 24 Figure 21 40-50 43-47 44.95 45 Figure 14 48-58 51-55 53 53 Figure 15 0-5 0-2 0 0 Figure 16 0.5-5 1-3 2 2 Figure 17A 0.005-0.2 0.01-0.1 0.05 0

[0146] Optional colorants may be iron oxides such as iron oxide E172. PCL = polycaprolactone; PDLG 5004 = GMP grade copolymer of DL-lactide and glycolide (50 / 50 molar ratio) with an inherent viscosity midpoint of 0.4 dl / g; PDLG5004A = acid-terminated GMP grade copolymer of DL-lactide and glycolide (50 / 50 molar ratio) with an inherent viscosity midpoint of 0.4 dl / g; PDLG 5002 = GMP grade copolymer of DL-lactide and glycolide (50 / 50 molar ratio) with an inherent viscosity midpoint of 0.2 dl / g; PDLG 5002A = acid-terminated GMP grade copolymer of DL-lactide and glycolide (50 / 50 molar ratio) with an inherent viscosity midpoint of 0.2 dl / g; PEO = polyethylene oxide.

[0147] Figure 17B shows a Figure 17C cross-sectional view of a wire-type core, showing the wire-type core 2210, the internal connector 2204, the external connector 2202, and the bump 2216. The feature structure 2208 is shown as a wire passing through the internal connector 2204. The feature structure 2206 is shown as a protrusion of the internal connector 2204 extending into the external connector 2202. The external connector 2202 may be overmolded onto the internal connector 2204 to enclose / seal the protrusion 2206 of the internal connector 2204. Overmolding the external connector 2202 to enclose the protrusion 2206 of the internal connector 2204 strengthens the connection between the internal connector 2204 and the external connector 2202. Additional connector assemblies are shown, e.g., the internal connector 2214 and the external connector 2212 on different arm mounts, and additional unlabeled internal and external connectors.

[0148] Figure 17D shows a Figure 17E another cross-sectional view of the wire-type core. The wire-type core 2310, the internal connector 2304, the external connector 2302, the bump 2316, the wire 2308 passing through the internal connector 2304, the protrusion 2306 of the internal connector 2304 extending into the external connector 2302, and additional connector assemblies including the internal connector 2314 and the external connector 2312 on different arm mounts and additional unlabeled internal and external connectors are shown.

[0149] Figure 18 shows a Figure 17A another view of the nitinol wire core, where the components covered by the polymer connectors (i.e., the hidden components) are shown in dashed lines.

[0150] Example

[0151] Example 1: Figure 17B Shows the creep angle difference between a nitinol metal core and a polymer (liquid silicone rubber) core (tested / experimented using the method described below). As shown, the nitinol core wire largely maintains its creep angle within 30 days, while the creep angle of the polymer core steadily decreases within 30 days.

[0152] Example 2: Figure 17E Shows the cyclic incubation non - planar compression (CINCT) force of a nitinol core and a polymer (i.e., liquid silicone rubber) core during 2500 cycles. The CINCT force of the nitinol core remains relatively stable throughout the 2500 cycles, while the CINCT force of the polymer core steadily decreases throughout the 2500 cycles.

[0153] Example 3: Figure 19A Shows the cyclic incubation non - planar compression (CINCT) force of various nitinol core designs. In particular, Figure 19B Sheet 1 is depicted in; Figure 19A Sheet 2 is depicted in; Figure 19B Sheet 3 is depicted in, Figure 20 Sheet 4 is depicted in, Figure 19A Sheet 5 is depicted in.

[0154] NCT test: This test represents the "non - planar compression test". In this test, the star - shaped body is compressed between two blocks. Two arms contact each block, while the other two arms are unconstrained. These blocks apply stress to the core, causing it to deviate from the plane of its original flat configuration. This test measures the core stiffness. In some versions of this test, compression is applied cyclically to measure the fatigue characteristics of the core (referred to as "CINCT", or "cyclic incubation non - planar compression test").

[0155] Creep angle test: In this test, the star - shaped body is fully folded and stored in a capsule. At a certain point in time, the star - shaped body is removed from the capsule and snapped back to an almost flat position. Using a special imaging mount, the angle formed by two opposite arms and the flat base is measured. This test measures the ability of the core to snap back elastically to the flat position after being stored in the capsule.

[0156] Example 4: Figure 19B Shows the performance of two nitinol core sheet designs (Sheet #1 and Sheet #2) and two nitinol core wire designs (Wire #1 and Wire #2) in the cyclic incubation non - planar compression test (CINCT). Figure 19B And Figure 19A Shows the geometries for the tests of Sheet #1 and Sheet #2, while ​Shows the wire shapes for the results of wire #1 and wire #2. In the CINCT test, the wire core was able to undergo significantly more cycles than the sheet core before fracture.

[0157] ​ and ​ Shows Nitinol wire cores of different sizes, where the connectors are mounted on the arm mounts. ​ Shows a Nitinol wire core with an outer diameter (OD) of 12 mm from the outer edge of one connector to the outer edge of the opposite connector. The wire core itself has an outer diameter of 9 mm from the outer edge of one arm mount to the outer edge of the opposite arm mount. ​ Shows a Nitinol wire core with an outer diameter (OD) of 15 mm from the outer edge of one connector to the outer edge of the opposite connector. The wire core itself has an outer diameter of 12 mm from the outer edge of one arm mount to the outer edge of the opposite arm mount. The longer arm mounts distribute the stress over a larger amount of material, thus reducing the local stress along the core.

[0158] ​ Shows the results of the cyclic culture non - planar compression test (CINCT) for ​ and ​ the two cores shown. The 15 - mm outer diameter core made of 0.020 - inch (0.508 - mm) diameter wire ​ was able to withstand more compression cycles without fracture compared to the 12 - mm outer diameter core made of the same type of wire ​ and

[0159] For purposes of explanation, the foregoing description has been presented with reference to specific embodiments. However, the above - mentioned illustrative discussion is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Given the above teachings, many modifications and variations are possible. The embodiments were chosen and described in order to best explain the principles of these techniques and their practical application. Thus, other technicians in the art will be able to best utilize these techniques and various embodiments with various modifications that are suitable for the particular purposes contemplated.

[0160] Although the disclosure and embodiments have been described in full with reference to the accompanying drawings, it should be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be understood to be included within the scope of the disclosure and embodiments as defined by the claims. Finally, the entire disclosures of the patents and publications mentioned in this application are hereby incorporated by reference.

[0161] Any system, method, technique, and / or feature disclosed herein may be combined in whole or in part with any other system, method, technique, and / or feature disclosed herein.

[0162] Embodiment

[0163] Embodiment 1. A gastric retention system, comprising: a metal core; and a plurality of elongated arms, each of the plurality of elongated arms including a distal end and a proximal end connected to the metal core, wherein the gastric retention system is configured to be folded into a compact form by bending the metal core such that each of the plurality of arm mounts are close to each other and the distal ends of the plurality of elongated arms are close to each other, wherein the metal of the metal core provides elasticity and shape memory to enable the gastric retention system to be deployed into a non-compact form and allow retention.

[0164] Embodiment 2. The gastric retention system according to Embodiment 1, wherein the gastric retention system is configured to be stored in a compact form for 30 days and then administered to a patient.

[0165] Embodiment 3. The gastric retention system according to Embodiment 1 or 2, wherein the gastric retention system is configured to maintain the compact form for 30 days and be able to return to the non-compact form such that the creep angle after 30 days of the gastric retention form is within 3% of the creep angle of the gastric retention form before 30 days.

[0166] Embodiment 4. The gastric retention system according to any one of Embodiments 1-3, wherein the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

[0167] Embodiment 5. The gastric retention system according to any one of Embodiments 1-4, wherein the height of the metal core is the same as the width of the metal core.

[0168] Embodiment 6. The gastric retention system according to any one of Embodiments 1-5, wherein the metal core includes a plurality of arm mounts, wherein each elongated arm of the gastric retention system is configured to be attached to the metal core at one of the plurality of arm mounts.

[0169] Embodiment 7. The gastric retention system according to any one of Embodiments 1-6, wherein the metal core contains nitinol.

[0170] Embodiment 8. The gastric retention system according to any one of Embodiments 1-7, wherein each of the plurality of elongated arms is overmolded on the metal core.

[0171] Embodiment 9. The gastric retention system according to any one of Embodiments 1-8 includes a degradable connector attached to the arm mount of the metal core and an elongated arm attached to the degradable connector.

[0172] Embodiment 10. The gastric retention system according to any one of Embodiments 1-9, wherein the metal core is formed using metal wire.

[0173] Embodiment 11. The gastric retention system according to any one of Embodiments 1-10, wherein the metal core is formed using a stamped metal sheet.

[0174] Embodiment 12. The gastric retention system according to Embodiment 11, wherein the metal wire has a cross-section with a diameter of 0.01 inches to 0.02 inches.

[0175] Embodiment 13. The gastric retention system according to any one of Embodiments 1-10, wherein the metal core is formed using a flat metal sheet.

[0176] Embodiment 14. The gastric retention system according to any one of Embodiments 1-13, wherein at least one of the plurality of elongated arms contains a therapeutic agent.

[0177] Embodiment 15. A core for a gastric retention system, comprising: a metal core having a plurality of arm mounts, each arm mount configured to receive an elongated arm of the gastric retention system, wherein the core is configured to be bendable into a compact form such that each of the plurality of arm mounts is close to each other, and in the case where the plurality of elongated arms are attached to the metal core, the distal ends of the plurality of elongated arms are close to each other, wherein the metal of the metal core provides elasticity and shape memory to cause the metal core to unfold into a non-compact form and, in the case where the plurality of elongated arms are attached to the metal core, allow the retention of the gastric retention system.

[0178] Embodiment 16. The core for a gastric retention system according to Embodiment 15, wherein the metal core is configured to maintain the compact form for 30 days and be able to return to the non-compact form such that the creep angle after 30 days of the gastric retention form is within 3% of the creep angle of the gastric retention form before 30 days.

[0179] Embodiment 17. The core for a gastric retention system according to Embodiment 15 or 16, wherein the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

[0180] Embodiment 18. The core for a gastric retention system according to any one of Embodiments 15-17, wherein the height of the metal core is the same as the width of the metal core.

[0181] Embodiment 19. The core of the gastric retention system according to any one of Embodiments 15-18, wherein the metal core is configured to maintain the compacted form for 30 days and be able to return to the non-compacted form, such that the creep angle of the metal core after 30 days is within 3% of the creep angle of the metal core before 30 days.

[0182] Embodiment 20. The core for a gastric retention system according to any one of Embodiments 15-19, wherein the metal core comprises nitinol.

[0183] Embodiment 21. The core for a gastric retention system according to any one of Embodiments 15-20, wherein each arm mount is configured to receive an elongate arm overmolded thereon.

[0184] Embodiment 22. The core for a gastric retention system according to any one of Embodiments 15-21, wherein each arm mount is configured to receive a degradable connector, and the elongate arm is attached to the degradable connector.

[0185] Embodiment 23. The core for a gastric retention system according to any one of Embodiments 15-22, wherein the metal core is formed using metal wire.

[0186] Embodiment 24. The core for a gastric retention system according to Embodiment 21, wherein the metal wire has a cross-section with a diameter of 0.01 inches to 0.02 inches.

[0187] Embodiment 25. The core for a gastric retention system according to any one of Embodiments 15-22, wherein the metal core is formed using a stamped metal sheet.

[0188] Embodiment 26. The core for a gastric retention system according to any one of Embodiments 15-25, wherein at least one of the plurality of elongate arms comprises a therapeutic agent.

[0189] Embodiment 27. A method of manufacturing a metal core for a gastric retention system, the method comprising:

[0190] Using a fixture to wind metal wire to form a metal core including a plurality of arm mounts.

[0191] Embodiment 28. The method according to Embodiment 27, wherein winding the metal wire comprises winding the metal wire around a plurality of pins of the mounting rack to form a circular metal form / circular metal structure.

[0192] Embodiment 29. The method according to Embodiment 28, comprising advancing a plurality of inserts into the circular metal form to form a star-shaped metal form / star-shaped metal structure.

[0193] Embodiment 30. The method according to Embodiment 29, comprising heating the star-shaped metal form to produce a star-shaped metal core for the gastric retention system.

[0194] Embodiment 31. The method according to Embodiment 30, wherein heating the star-shaped metal form comprises heating the star-shaped metal form to 500 °C or higher.

[0195] Embodiment 32. The method according to any one of Embodiments 27-31, wherein the metal wire comprises nitinol.

[0196] Embodiment 33. The method according to any one of Embodiments 27-32, wherein the metal wire has a cross-section with a diameter of 0.01 inches to 0.02 inches.

[0197] Embodiment 34. The method according to any one of Embodiments 27-33, wherein the two ends of the metal wire are joined together.

[0198] Embodiment 35. The method according to any one of Embodiments 27-33, wherein the two ends of the metal wire are not joined together.

[0199] Embodiment 36. The method according to any one of Embodiments 30-34, wherein the star-shaped metal form is quenched after heating.

[0200] Embodiment 37. The method according to any one of Embodiments 27-36, wherein the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

[0201] Embodiment 38. The method according to Embodiment 37, wherein the height of the metal core is the same as the width of the metal core.

[0202] Embodiment 39. The method according to any one of Embodiments 27-38, wherein the metal core is configured to be bendable into a compact form and maintain the compact form for 30 days and be able to return to the non-compact form such that the creep angle of the metal core after 30 days is within 3% of the creep angle of the metal core before 30 days.

[0203] Embodiment 40. A method of manufacturing a metal core for a gastric retention system, comprising: stamping a metal sheet to form a metal core including a plurality of arm mounts.

[0204] Embodiment 41. The method according to Embodiment 40, wherein the metal sheet comprises nitinol.

[0205] Embodiment 42. The method according to Embodiment 40 or 41, wherein the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

[0206] Embodiment 43. The method according to Embodiment 42, wherein the height of the metal core is the same as the width of the metal core.

[0207] Embodiment 44. The method according to any one of Embodiments 40-43, wherein the metal core is configured to be bendable into a compacted form and maintain the compacted form for 30 days and be able to return to the non-compacted form such that the creep angle of the metal core after 30 days is within 3% of the creep angle of the metal core before 30 days.

Claims

1. A gastric retention system, comprising: a metal core having a plurality of arm mounts; and a plurality of elongated arms, each of the plurality of elongated arms including a distal end and a proximal end connected to the arm mount of the metal core, wherein the gastric retention system is configured to be folded into a compact form by bending the metal core such that each of the plurality of arm mounts approaches each other and the distal ends of the plurality of elongated arms approach each other, and wherein the metal of the metal core provides elasticity and shape memory such that the gastric retention system can be deployed into a non-compact form and allowed to maintain.

2. The gastric retention system according to claim 1, wherein, the gastric retention system is configured to be stored in a compact form for 30 days and then administered to a patient.

3. The gastric retention system according to claim 1 or 2, wherein, the gastric retention system is configured to maintain the compact form for 30 days and be able to return to the non-compact form such that the creep angle after 30 days of the gastric retention form is within 3% of the creep angle of the gastric retention form before 30 days.

4. The gastric retention system according to any one of claims 1-3, wherein, the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

5. The gastric retention system according to any one of claims 1-4, wherein, the height of the metal core is the same as the width of the metal core.

6. The gastric retention system according to any one of claims 1-5, wherein, the metal core includes a plurality of arm mounts, and each elongated arm of the gastric retention system is configured to be attached to the metal core at one of the plurality of arm mounts.

7. The gastric retention system according to any one of claims 1-6, wherein, the metal core contains nitinol.

8. The gastric retention system according to claim 7, wherein, the nitinol contains ultra-low inclusion nitinol.

9. The gastric retention system according to claim 7, wherein, the nitinol contains ultra-pure nitinol.

10. The gastric retention system according to claim 7, wherein, the nitinol contains ultra-low inclusion and ultra-pure nitinol.

11. The gastric retention system according to any one of claims 1-10, wherein, each of the plurality of elongated arms is overmolded on the metal core.

12. The gastric retention system according to any one of claims 1-11, comprising a degradable connector attached to the arm mount of the metal core and an elongated arm attached to the degradable connector.

13. The gastric retention system according to any one of claims 1-10, comprising an internal connector and an external connector attached to the arm mount of the metal core, and an elongated arm attached to the external connector.

14. The gastric retention system according to claim 13, wherein, the internal connector contains polycarbonate.

15. The gastric retention system according to claim 13 or 14, wherein, the external connector contains polycaprolactone.

16. The gastric retention system according to any one of claims 13 - 15, wherein, the protrusion of the internal connector extends into the external connector.

17. The gastric retention system according to any one of claims 1 - 16, wherein, the metal core is formed using a metal wire.

18. The gastric retention system according to any one of claims 1 - 16, wherein, the metal core is formed using a stamped metal sheet.

19. The gastric retention system according to claim 18, wherein, the metal wire has a cross - section with a diameter of 0.01 inches to 0.02 inches.

20. The gastric retention system according to any one of claims 1 - 16, wherein, the metal core is formed using a flat metal sheet.

21. The gastric retention system according to any one of claims 1 - 20, wherein, at least one of the plurality of elongated arms contains a therapeutic agent.

22. A core for a gastric retention system, the core comprising: a metal core having a plurality of arm mounts, each arm mount configured to receive an elongated arm of the gastric retention system, wherein the core is configured to be bendable into a compact form such that each of the plurality of arm mounts is close to each other, and when the plurality of elongated arms are attached to the metal core, the distal ends of the plurality of elongated arms are close to each other, and wherein the metal of the metal core provides elasticity and shape memory to enable the metal core to expand into a non - compact form and, when the plurality of elongated arms are attached to the metal core, allow the retention of the gastric retention system.

23. The core for a gastric retention system according to claim 22, wherein, the metal core is configured to maintain the compact form for 30 days and return to the non - compact form such that the creep angle after 30 days of the gastric retention form is within 3% of the creep angle of the gastric retention form before 30 days.

24. The core for a gastric retention system according to claim 22 or 23, wherein, the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

25. The core for a gastric retention system according to any one of claims 22 - 24, wherein, the height of the metal core is the same as the width of the metal core.

26. The core for a gastric retention system according to any one of claims 22 - 25, wherein, the metal core is configured to maintain the compact form for 30 days and return to the non - compact form such that the creep angle of the metal core after 30 days is within 3% of the creep angle of the metal core before 30 days.

27. The core for a gastric retention system according to any one of claims 22 - 26, wherein, the metal core contains nitinol.

28. The core for a gastric retention system according to claim 27, wherein, the nitinol contains ultra - low inclusion nitinol.

29. The core for a gastric retention system according to claim 27, wherein, the nitinol contains ultra - pure nitinol.

30. The core for a gastric retention system according to claim 27, wherein, the nitinol comprises ultra-low inclusion, ultra-pure nitinol.

31. The core for a gastric retention system according to any one of claims 18 - 30, wherein, each arm mount is configured to receive an elongate arm overmolded thereon.

32. The core for a gastric retention system according to any one of claims 18 - 31, wherein, each arm mount is configured to receive a degradable connector, and the elongate arm is attached to the degradable connector.

33. The core for a gastric retention system according to any one of claims 18 - 30, wherein, each arm mount is configured to receive an internal connector and an external connector, and the elongate arm is attached to the external connector.

34. The core for a gastric retention system according to claim 33, wherein, the internal connector comprises polycarbonate.

35. The core for a gastric retention system according to claim 33 or 34, wherein, the external connector comprises polycaprolactone.

36. The core for a gastric retention system according to any one of claims 33 - 35, wherein, a protrusion of the internal connector extends into the external connector.

37. The core for a gastric retention system according to any one of claims 18 - 36, wherein, the metal core is formed using metal wire.

38. The core for a gastric retention system according to claim 37, wherein, the metal wire has a cross-section with a diameter of 0.01 inches to 0.02 inches.

39. The core for a gastric retention system according to any one of claims 18 - 36, wherein, the metal core is formed using a stamped metal sheet.

40. The core for a gastric retention system according to any one of claims 18 - 39, wherein, at least one of the plurality of elongate arms comprises a therapeutic agent.

41. A method of manufacturing a metal core for a gastric retention system, the method comprising: using an assembly jig to wind metal wire to form a metal core including a plurality of arm mounts.

42. The method according to claim 41, wherein, winding the metal wire includes winding the metal wire around a plurality of pins of the assembly jig to form a circular metal structure.

43. The method according to claim 42, comprising advancing a plurality of inserts into the circular metal form to form a star-shaped metal structure.

44. The method according to claim 43, comprising heating the star-shaped metal form to produce a star-shaped metal core for a gastric retention system.

45. The method according to claim 44, wherein, heating the star-shaped metal form includes heating the star-shaped metal form to 500 °C or higher.

46. The method according to any one of claims 41 - 45, wherein, the metal wire comprises nitinol.

47. The method according to claim 46, wherein, the nitinol comprises ultra-low inclusion nitinol.

48. The method according to claim 46, wherein, the nitinol comprises ultra-pure nitinol.

49. The method according to claim 46, wherein, the nitinol comprises ultra-low inclusion, ultra-pure nitinol.

50. The method according to any one of claims 41-49, wherein, the metal wire has a cross-section with a diameter of 0.01 inch to 0.02 inches.

51. The method according to any one of claims 41-50, wherein, the two ends of the metal wire are joined together.

52. The method according to any one of claims 41-50, wherein, the two ends of the metal wire are not joined together.

53. The method according to any one of claims 44-52, wherein, the star-shaped metal form is quenched after heating.

54. The method according to any one of claims 41-53, wherein, the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

55. The method according to claim 54, wherein, the height of the metal core is the same as the width of the metal core.

56. The method according to any one of claims 41-55, wherein, the metal core is configured to be bendable into a compacted form and maintain the compacted form for 30 days and be able to return to the non-compacted form such that the creep angle of the metal core after 30 days is within 3% of the creep angle of the metal core before 30 days.

57. A method of manufacturing a metal core for a gastric retention system, the method comprises: stamping a metal sheet to form a metal core including a plurality of arm mounts.

58. The method according to claim 57, wherein, the metal sheet comprises nitinol.

59. The method according to claim 58, wherein, the nitinol comprises ultra-low inclusion nitinol.

60. The method according to claim 58, wherein, the nitinol comprises ultra-pure nitinol.

61. The method according to claim 58, wherein, the nitinol comprises ultra-low inclusion, ultra-pure nitinol.

62. The method according to any one of claims 57-61, wherein, the metal core has a flat shape such that the height and width of the metal core are at least 10 times the thickness of the metal core.

63. The method according to claim 62, wherein, the height of the metal core is the same as the width of the metal core.

64. The method according to any one of claims 57-63, wherein, the metal core is configured to be bendable into a compacted form and maintain the compacted form for 30 days and be able to return to the non-compacted form such that the creep angle of the metal core after 30 days is within 3% of the creep angle of the metal core before 30 days.

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